Abstract 

Bacteriophages have been used as effective therapy against bacterial biofilms on devices such as catheters, in the lungs such as in cystic fibrosis, and even in infected food. Unlike antibiotics, they are bacteria-specific and produce the desired effect without systemic complications; they can develop bacterial resistance, although in ways different from antibiotics.

The present study aimed to assess the effect of bacteriophages against multidrug-resistant Pseudomonas aeruginosa in a mouse wound model. P. aeruginosa obtained from laboratory culture of burn wounds were characterized, harvested, and titrated, and biofilms were generated on sterile catheter sections (10⁵ colony forming units/mL). Subcutaneous pockets were created on the backs of 24 male albino mice. Animals were randomized into 4 groups of 6 each. After evaluating a significant phage-bacteria interaction in vitro, 2 biofilm-laden catheter sections were implanted in subcutaneous pockets in mouse groups C and D. Sterile catheter sections only were implanted in group B. Group A had only a subcutaneous pocket without any catheter section. Phage cocktail solutions (10 µL of 10⁷ phage forming units/mL) were injected daily in group D pockets only. Groups B and C received 10 µL of normal saline. After 10 days, the catheter sections were explanted from groups B, C, and D and tissue biopsy was taken from group A pockets and cultured for bacterial and phage colony counts. A significant drop in bacterial counts from 3.87 x 10⁶ to 3.52 x 10⁴ was observed in group D when compared with group C  (3.87 x 10⁶ to 3.85 x 10⁵, P<0.05)  A significant rise in the phage counts from 1 x 10⁷ to 6.81 x 10⁸ (P<0.05)  also was observed in group D when compared with the baseline counts, indicating active phage proliferation and successful bacterial kill in group D. The present laboratory study could be indicative of a new treatment approach for multidrug-resistant bacterial infections, including wound infections.

Potential Conflicts of Interest: none disclosed

Biofilm is a multicellular community composed of prokaryotic and/or eukaryotic cells embedded in a matrix composed, at least partially, of material synthesized by the sessile cells in the community.¹ It is essentially a survival strategy adopted by micro-organisms to resist environmental stress and antibiotics and disinfectants, which have been shown in vitro to be otherwise effective against the planktonic forms.^2,3 The biofilms thus formed have been shown in various in vitro, in vivo, and ex vivo studies to colonize indwelling medical devices such as catheters, intravenous cannula, stents, pacemakers, artificial heart valves, and orthopedic prosthesis.⁴ Once biofilms have formed, as shown in vitro, they are difficult to eradicate and are highly resistant to antibiotic therapy, often resulting in persistent and endemic populations.^5,6 A number of clinical studies have found such persisters are a source of subtle continuous and chronic infections within the host.⁷ Furthermore, colonization of indwelling medical devices results in deterioration, blockages, and loss of function, necessitating frequent replacement.⁷

In a cross-sectional study that involved 50 patients with chronic wounds and 16 with acute wounds recruited consecutively, James et al8 observed biofilms in 60% of the chronic wounds in comparison with 6% of acute wounds. Although the authors used light microscopy, biopsy culture, and polymerase chain reaction to detect bacterial types, they confirmed the presence of biofilms on detection of extracellular polymeric substance (EPS) and 3-dimensional confluent bacterial colonies using scanning electron microscope. Reviews of the literature8,9 have speculated biofilm bacteria are associated with chronic wound infections and difficult to eradicate or kill because these organisms are encased in EPS and are able to resist phagocytic action and impede the action of the host immune system and antimicrobials. Moreover, lipopolysaccharide molecules in the bacterial cell wall have been shown to inhibit keratinocyte migration in laboratory study.10 All of these factors may contribute to the inability of wounds with biofilms to heal.

Pseudomonas aeruginosa is known for infection in chronic wounds11 and one of the most common organisms responsible for hospital-acquired infections.12 Given the degree of morbidity infections generate, it appears prevention is a more logical option than treatment. No technique currently is known to successfully prevent or control the formation of unwanted biofilms without causing adverse side effects, although some efforts using hydrogel-coated catheter pretreated with bacteriophage bred against Staphylococcus epidermidis13 and a phage cocktail against P. aeruginosa14 have shown promise. Because these are both in vitro studies, the outcome in clinical settings is not known.

Bacteriophages are viruses that infect bacteria and may provide a natural, highly specific, nontoxic, feasible approach for controlling several micro-organisms involved in biofilm formation.15 These are better than traditional antibiotics in that they are bacteria-specific and kill selectively without generating any systemic complications to the host. This high degree of specificity along with potential for deeper penetration through water channels in biofilms makes them an attractive mode of therapy. The fact bacteriophages multiply in the presence of sensitive bacteria (active therapy) allows limited delivery and dose control and prevents recurrent application. Furthermore, unlike antibiotics dose titration is not required in the presence of comorbid conditions such as renal or hepatic compromise. However, bacteriophages have been shown in vitro16 to form bacterial resistance in ways different from that of antibiotics such as adsorption resistance, restrictions, superinfection immunity, or abortive infection. The technology for harnessing this benefit successfully has been shown in laboratory settings,17-19 although its application in clinical settings is still evolving20 but not as yet convincing. In view of concerns regarding emerging multidrug-resistant bacteria,21 finding an alternative antibacterial approach should be pursued. The present study aims to evaluate the potential for use of novel phages for P. aeruginosa to control biofilm infection in vitro and in a murine wound model.

Methods

Overview. The present study was conducted in several steps, including P. aeruginosa identification and culture; bacteriophage characterization, reharvesting, and titration; enumeration of phage morphology and host range; P. aeruginosa biofilm formation on catheter; phage-biofilm interaction in vitro and in vivo; and identification of colony forming unit (CFU) and phage forming unit (PFU) counts after phage therapy of biofilms. The study was approved by the authors’ Institute Ethics Committee and the Institute Animal Ethics Committee for research. Care of the laboratory animals was provided according to the Indian Council of Medical Research Guidelines for use of Laboratory Animals in Medical Colleges 2001.22

Pseudomonas aeruginosa identification and culture. Multidrug-resistant strains of P. aeruginosa were procured from stock culture collected from the Burn Unit of the authors’ University Hospital. One hundred (100) strains from stock were streaked on Muller Hilton agar plates (Hi media, India) and incubated overnight. Smears were prepared on a glass slide from 1 loopful of bacterial colony, Gram-stained and observed under microscope, and subjected to oxidase and catalase tests. For further experiments, the bacterial strains were grown in Luria Bertani (LB) broth at 37˚ C and harvested while in the exponential phase of the growth cycle. The harvested bacteria were washed with saline (0.85% NaCl in distilled water) and resuspended in saline to achieve 108 CFU/mL.

Phage characterization and re-harvesting and titration. Eleven (11) phages against P. aeruginosa were obtained from Bacteriophage Research Lab (BRL) of the Microbiology department of the University. The phages had been isolated from samples of various bodies of water including rivers, ponds, and sewers. The processing and reharvesting of the phages were done using the double agar overlay plaque assay technique,23 and PFU was measured. Small-scale concentration of  Banaras Hindu University (BHU) bacteriophages was performed by spreading phages on the top-agar layer containing the respective host bacterium. The  BHU bacteriophage titer was analyzed as described by Adams.24 Phages were characterized on the basis of their lytic profile, and a dendogram was obtained (see Figure 1), which depicts the level of similarity between the different phages used. When the 11 BHU phages were screened against the 40 MDR strains of P. aeruginosa, 11 strains were found to be lysed by 9 or more phage strains (see Table 1). These 11 strains then were re-subjected for testing against the  BHU phages, leading to the conclusion P. aeruginosa strain 10958 is lysed by all the BHU phages; it was selected for further experimentation.

Enumeration of phage morphology and host range. Polyethylene glycol-precipitated BHU bacteriophage particles were subjected to transmission electron microscopy for viral morphology. The host range specificity and lysis efficiency in screening tests against different P. aeruginosa strains were measured. Eleven (11) strains, which showed lysis by 9 or more phages, were rechecked by repeating the process.

P. aeruginosa biofilm formation on catheter sections.P. aeruginosa biofilms were formed on 0.5 cm, presterilized polyurethane catheter sections (6 French, single lumen) according to the method described by Cerca et al²⁵ with some alterations. Longitudinally cut open catheter sections were placed in a conical flask containing 6 mL of yeast peptone dextrose medium. A culture (10 µl) of P. aeruginosa strain 10958 with an optic density of 2.0 at 600 nm (corresponding to approximately 1.79 × 10⁸ cells/mL) was added and incubated at 37˚ C on an orbital shaker for 48 hours at a constant speed of 120 rpm with the change of medium every 12 hours. The number of cells present on these catheter sections was assessed after 48 hours of biofilm formation in order to estimate the infective dose. CFU counts varied from 2 x 10⁶ to 6 x 10⁶. Presence of P. aeruginosa biofilm was confirmed in vitro after crystal violet staining of the catheter sections and viewed under oil immersion microscopy (100x) and biochemical analysis (oxidase and catalase positive). 

Phage-bacterial interaction in vitro. Biofilm were infected with a cocktail of 11 BHU phages (100 µl each). The catheter sections with biofilm were immersed twice in phosphate buffer saline (PBS) and placed in microcentrifuge tubes with 0.5 mL of tris-magnesium sulphate-gelatin (TMG) buffer and 0.5 mL of phage cocktail solution in a concentration of 10⁷ PFU/mL. The microcentrifuge tubes were incubated at 37˚ C. Control experiments were performed at the same conditions with the catheter sections after immersion in PBS in new microcentrifuge tubes with 0.5 mL of TMG and 0.5 ml of saline.

Phage-bacterial interaction in vivo. Male albino mice (25 ± 6 g) procured from the central animal house of the authors’ Institute were acclimatized in laboratory conditions for 7 days as per Indian Council of Medical Research guidelines.²² They were housed at 25˚ C, 45%–55% relative humidity, and 10:14 hours of light-dark cycle and had free access to rat pellets and water ad libitum. The animals were anesthetized with intraperitoneal ketamine (75 mg/kg). The back was shaved and disinfected with 0.5% chlorhexidine in 70% alcohol. A 10-mm transverse skin incision was made and a subcutaneous pocket was created between the skin and panniculus. Two catheter sections (with or without biofilm) were implanted in the subcutaneous pocket (see Figure 2). The incision was closed with interrupted 3-0 nylon stitches and disinfected with 0.5% chlorhexidine in 70% alcohol. The number of catheter sections to be used was assessed from a pilot study in which increasing numbers of catheter sections were implanted in 5 mice (ie, the first mouse had 1 catheter section while the fifth mouse had 5 sections). All developed pus formation in the subcutaneous pocket, but the first mouse showed complete resolution of pus, while the fourth and fifth mice perished after 48 hours of infection. The second and third mice showed pus formation without resolution for a week. Therefore, it was decided 2 catheter sections were optimum for the experiment. 

The animals were randomly allocated into 4 groups of 6 mice each. In group A, the skin incision was followed by the creation of a subcutaneous pocket and 10 µl of sterile normal saline (NS) was injected daily into the pocket for 10 days. Group B had an incision with pocket creation in which uninfected catheter sections were placed; this group also had NS injections every day. In group C, catheter sections containing biofilm were placed in the pocket and the animals received daily NS injections. In group D, everything was similar to group C except instead of NS, 10 µl of the phage cocktail solution containing 10⁷ PFU/mL phages was injected in the subcutaneous pocket.

After 10 days, the animals were anesthetized and after local disinfection the subcutaneous pockets were explored and wounds were examined macroscopically for signs of infection. Catheter sections were removed in an aseptic technique and washed twice with PBS and analyzed for bacterial and phage colony counts.

CFU and PFU counts after phage therapy. After washing twice with PBS, the catheter sections were put in microcentrifuge tubes containing 0.5 mL of NS solution. The tubes were thoroughly mixed (vortexed 4 × 30 seconds) and serial dilutions were immediately performed in NS solution for CFU counts and in TMG buffer for PFU counts. For CFU counts, the samples were immediately plated on Mueller Hinton agar plates, and for PFU counts samples were immediately plated using the method described above for phage titration.

Data collection and statistical analysis. The data generated from phage titration, bacterial colony counts, and phage colony counts both in vitro and in vivo were retrieved by a laboratory assistant blinded to the study. The statistical program SPSS version 16.0 (SPSS Inc, Chicago, IL) was used for data entry and analysis. An independent sample t-test was used to compare categorical variables between 2 groups. Analysis of variance (ANOVA) along with post-hoc Bonferroni test was done to compare variables in more than 2 groups. A P value <0.05 was considered statistically significant.

Results

Phage-bacterial interaction in vitro.At the time of primary culture on the blood agar plate after the action of cocktail of  BHU phages, no colony appeared after 24 hours of incubation. The CFU count on catheter sections was in the range of 10⁶ CFU/mL (see Table 2). Following treatment of these catheter sections with phage solution (10⁷ PFU/mL) for 24 hours, no growth was observed after 24 hours when these sections were plated on blood agar. Similarly, no plaque was observed when these catheter sections were processed for PFU counts. 

Phage-bacterial interaction in vivo. When the mean baseline bacterial colony count was compared with that of group C (3.87 x 10⁶ versus 3.85 x 10⁵) and group D (3.87 x 10⁶ versus 3.52 x 10⁴), respectively, both were found to be significantly higher than the baseline value (P<0.001) (see Table 3). The bacterial counts also were found to be significantly higher in group C than that in group D (3.85 x 10⁵ versus 3.52 x10⁴; P<0.045), respectively. No phage was detected from any explanted catheter in group B and group C. However, in group D, phages were detected in range of 10⁷ to 10⁹, which was significantly higher than the baseline value (10⁷ versus 6.81 x 10⁸; P<0.05), indicating active multiplication of the phages in vivo (see Table 4). 

Discussion

Although planktonic forms of bacteria usually are controlled by conventional doses of antibiotics, bacteria in biofilms are notably resistant to antibiotic therapy.⁵ Several in vitro studies^16,17,19 demonstrate the successful action of bacteriophages on biofilms. A number of in vivo studies^26-28 also have shown the potential of using phages to treat infectious diseases in animals and in humans infected with antibiotic-resistant bacteria.²⁹ In the present study, P. aeruginosa biofilms were challenged with the lytic  BHU phages both in vitro and in vivo. The data presented here show the potential of  BHU phages for controlling and reducing P. aeruginosa. Similar observations of reduction in bacterial cell count (between 10³ and 10⁵) also have been reported in a number of experimental models.^4,30-33 Current findings indicate promising potential of  BHU phages as controlling agents for P. aeruginosa. 

Although the formation of biofilms on catheters immersed in the growth media are unlike conditions observed in a variety of biological environments, it is a simple, rapid, and reproducible method and makes it easy to assess the influence of different parameters required for phage therapy. However, potential concerns for the use of this therapy must be carefully considered, such as narrow host range of phages, the development of resistance of host bacteria to phages during therapy, potential of inactivation of phages by patient’s immune system, and the safety of phage application in humans.³⁴

In the present study, a significant bacterial load reduction was observed in the test group. The reduction in the control group is probably due to the intrinsic immune response activated following implantation of the infected catheter sections. Therefore, the significant reduction in the test group is likely due to a combined effect of phage and host immune system-mediated bacterial death. Catheter sections were completely sterile in 1 mouse in the test group. This may be due to a widespread phage-induced bacterial kill supplemented with strong immune response. Furthermore, it also may be argued that a weak immune response toward the phage particles allowed abundant phage proliferation and subsequent eradication of the bacteria. Interestingly, in the same mouse, no phage was detectable on the catheter sections. A possible explanation of this finding may be that because all of the bacteria on this specimen were eradicated by the phages, in the absence of a host to act upon, the phage particles became inactive and were subsequently inactivated by the host immune system. This hypothesis is supported by the observation from the in vitro aspect of the study, which also demonstrates absence of phages after complete eradication of bacteria.

Although the phage cocktail was given in the dose of 10⁷ PFU/mL daily for 10 days (passive therapy), it is interesting to note phages were found in abundance (10⁸–10⁹ PFU/mL) on the catheter sections when removed after 10 days. This indicates the phages were actively multiplying in the presence of bacteria (active therapy), which is possible only when the bacteria remain sensitive to the phages. Thus, it may be extrapolated that continuing phage therapy for a longer duration could have eradicated bacterial population on the catheter sections. However, further research is needed to confirm.

It is interesting to observe the huge difference in efficacy of phage action in the in vitro and in vivo model. A number of factors may be responsible for this discrepancy. It has been proposed the P. aeruginosa biofilm EPS may impede penetration by trapping the phage particles or may produce proteolytic enzymes that cause bacteriophage inactivation.³⁵ This may be overcome by the phage elaboration of EPS degrading depolymerase in P. aeruginosa biofilms.³¹ However, this is unlikely to be the cause in the present study because the biofilm was effectively penetrated in vitro. Alternatively, active local inflammatory response could have acted directly against the viruses by producing antibodies against the viral proteins, leading to their neutralization. Issues such as temperature and culture medium composition may be responsible for the difference between in vitro and in vivo results.³⁶  In in vitro study, Sillankorva et al¹⁸ demonstrated a temperature of 26˚ C is favorable for the best effects of phage, which is unlikely to be achieved in the animal body. Similarly, a favorable medium is also beneficial for bacterial kill,¹⁸ which is probably responsible for the better in vitro outcome. The different metabolic status of the biofilm bacteria may affect phage-induced lysis; it has been observed that Escherichia coli in exponential phases of growth are lysed faster than those in the later growth phase.³⁷ Only a marginal reduction of susceptibility of old P. aeruginosa biofilm to phage-induced killing has been observed.³² The detection of the actual factor(s) responsible for the reduced phage efficacy in vivo will help researchers and clinicians refine this natural form of therapy to a newer level in healing of wounds with biofilms.

The phage therapy may be active or passive depending on the mode of use. In active therapy, a single small dose of phages can be useful in circumstances when bacteria are multiplying fast, which leads to active multiplication of the phages as well. But when bacteria are slow multipliers, endogenous multiplication of the viral particles is inadequate for bacterial kill. In these cases, phages may be required to be given repeatedly in large doses (passive therapy). Both slow-multiplying and fast-multiplying bacteria are inhabitants of a biofilm. Accordingly, a single small dose of phages may be inadequate to completely eradicate the slow multipliers. Therefore, phage therapy used repeatedly over a prolonged period of time is likely to act against both types of bacterial population in the biofilm.

Limitations

The present study is not without limitations. The murine model does not closely mimic human wound healing, wound infection, and wound-biofilm interaction. Also, it is not known how the immune system of rodents reacts to the biofilm; these animals demonstrate strong immunogenic reaction and are mostly resistant to wound infection. Therefore, the behavior of the Pseudomonas biofilm in the presence of bacteriophages may differ in human wounds. However, in vivo models are better than in vitro models because the phage-biofilm interaction can be studied in the midst of host immune response.

In addition, the phage-bacteria interaction in the present study is limited to the effect of the phages on the bacteria only. It is not known to what extent this interaction influences the wound healing process. The passive mode of phage delivery is possible in well-controlled laboratory conditions that may not always be possible in the clinical setting. Although phage multiplication was observed after passive delivery, it is not known to what extent the response will be clinically significant.

Conclusion

In this study, P. aeruginosa organisms in the biofilm were sensitive to the respective phages in vivo and in vitro. In the presence of the biofilm, phages were capable of multiplication and bacterial kill and in combination with the host immune system were found to lead to significant reduction in bacterial population locally. The difference between in vitro and in vivo results indicates interplay of factors at the tissue level, which may slow bacterial kill. Repeated doses of phage application remain a promising technique to overcome these factors in wound biofilms. In the future, devising a technology for delivering phages to a chronic wound with biofilm would be challenging and may usher a new era of biological dressings for biofilms. 

Dr. Basu is Associate Professor of Surgery; Dr. Agarwal is a surgical resident cum research scholar; Dr. Bhartiya is Assistant Professor of Surgery; Dr. Nath is Professor of Microbiology; and Dr. Shukla is Professor of Surgery, The Departments of General Surgery and Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. Please address correspondence to: Dr. Vijay Kumar Shukla, Department of General Surgery, Institute of Medical Sci-ences, Banaras Hindu University, Varanasi 221005, India; email: vkshuklabhu@gmail.com.

Abstract

Many ostomy patients experience peristomal skin lesions. A descriptive study was conducted to assess the validity, usability, and reliability of the Peristomal Skin Lesions Assessment instrument (SACS instrument) adapted to Turkish from English. The SACS Instrument consists of 2 main assessments: lesion type (utilizing definitions and photographs) and lesion area by location around the ostomy.

  The study was performed in 2 stages: 1) the SACS language was changed and its content validity established; and 2) the instrument’s content validity and inter-observer agreement (consistency) were determined among pairs of nurses who used the tool to assess peristomal skin lesions. Patients (included if they were >18 years old and receiving treatment/observation at 1 of the 4 participating stomatherapy units) and 8 stomatherapy nurses also completed appropriate sociodemographic questionnaires. Of the 393 patients screened during the 7-month study, 100 (average age 56.74 ± 14.03 years, 55 men) participated; most (79) had a planned operation. A little more than half (59) of the patients had colorectal cancer and 28 had their stoma site marked preoperatively by a stomatherapy nurse. The most common peristomal skin lesion risk factors were having an ileostomy and unplanned surgery. The content validity index of the entire Turkish SACS instrument was 1, and the inter-observer agreement Kappa statistic was very good (K = 0.90, 95% CI 0.80- 0.99). Individual SACS item K values ranged from K = 0.84 (95% CI 0.63–1) to K = 1 (95% CI 1). Most (62.5%) nurses found the terms and pictures used in the SACS classification adequate and suitable, and 50% believed the Turkish version of the SACS instrument was a valid and suitable assessment tool for use by Turkish stomatherapy nurses. Validity and reliability studies involving larger and more diverse patient and nurse samples are warranted.

Potential Conflicts of Interest: none disclosed

A stoma (from the Greek meaning opening or mouth) is a surgical intervention that may be used to manage cancer related to the urinary system, colorectal cancers, ulcerative colitis, Crohn’s disease, diverticular diseases, imperforate anus, traumas, intestinal obstruction, familial polyposis, and congenital abnormalities.^1,2 One of the most common stoma types is the intestinal stoma.⁴ The creation of a stoma for the purpose of evacuation, a fundamental human need, may lead to physiological, social, and psychological problems for the individual. Gas and odor, fecal leakage, skin problems, fatigue, loss of appetite, indigestion, nausea, diarrhea, constipation, and pain are among the physiological problems.^3,4 According to a descriptive study by Baykara et al,² odor and fecal leakage are the most discomforting problems. In a multicenter prospective observational study by Bosio et al,⁵ surgical technique and experience, procedure type (planned or emergency), patient health problems such as obesity and diabetes, and the ability of the individual to perform self-care have been shown to have an impact on the prevalence of complications.

Stoma complications can develop instantly (ie, within 12 hours of ostomy creation) and include hemorrhage and ischemia.^1,6 Early stage complications (those that develop within 1 month of stoma surgery) include hemorrhage, ischemia, excessive output, obstruction, retraction, peristomal skin irritation, peristomal infection/abscess/fistula, acute peristomal herniation, and early postoperative intestinal perforation.⁶ Later-stage complications can occur months after the operation; these include peristomal skin problems, stenosis, retraction, hernia, prolapse, fistula, perforation, fluid/electrolyte loss, renal calculus, and gallstones.^1,7 Peristomal skin problems can occur at any stage of living with a stoma.

Stoma complication prevalence varies in the literature⁸ from 10% to 70%. In a retrospective extensive study of 20 years of ileostomy and colostomy data by Park et al,⁹ the most frequently observed early stage complication was peristomal skin irritation (12%). In a retrospective study conducted on 128 individuals regularly observed at a stomatherapy clinic, Karadağ¹⁰ found 32.8% experienced stoma complications and the most frequently encountered complication was peristomal skin irritation (17.9%).¹⁰ Akçam et al^1,11 obtained data from the records of 120 patients with a stoma; 24.1% experienced stoma complications and the most frequent complication was dermatitis (5.8%). Reasons for the discrepancies in data could be inconsistencies in the terminology, as well as the absence of a standard observation (data collection, assessment) instrument.^12,13

Even though peristomal skin complications are not life-threatening, they make the placement of the ostomy appliance difficult and may cause leakage, odor, fear of appliance nonadherence, and difficulty choosing clothing, which can lead to social isolation, anxiety, and depression.^1,3,5,14,15 Observational prospective, cross-sectional, and quantitative studies have shown peristomal skin complications and the accompanying symptoms also lengthen the course of treatment, increase of the cost of care, and cause loss of labor.^14,16,17 All of these outcomes lead to an adverse impact on activities of daily living and reduce individual quality of life. In prospective, observational, and systematic review studies, prevention of peristomal skin complications has been shown to be easier and cheaper than treatment,^12,18,19 making assessment of the peristomal area important in diagnosis and treatment decisions.^14,17,20 Using a stomal complication assessment instrument with proven validity has been shown in prospective observational and cross-sectional quantitative studies^5,16 to help establish the prevalence and incidence of peristomal complications, be a factor in the comfort and life quality of the patient, and decrease care costs and frequency of use of many products.

Ostomy Care and Ostomy Nurses in Turkey

The first stoma care unit was opened in the Turkish capital of Ankara in Gazi University Hospital in 2000; by 2013, there were 22 stoma care units with 376 certified stoma care nurses. Most of these nurses are employed in university and public hospitals and involved in ostomy and wound care. Stoma care nurses in these units provide stoma care and counseling; teach patients, their families, and health care professionals; and conduct research. The stoma care units provide service free of charge based on an appointment system.²³ If a decision has been made to create a stoma, the patient will be referred to a stoma care nurse for an appointment at the policlinic for the patient and his/her family. During the appointment, stoma care nurses provide information about the stoma and stoma care, answer questions, and mark the stoma site. After the surgery, stoma nurses visit the patient in the intensive care unit or ward, assess the stoma and peristomal area, change the pouch, and show the patient and his/her relatives how to empty the pouch. Finally, the stoma nurse provides a booklet that includes information about stoma and stoma care to the patient and his/her relatives and makes an appointment to change the pouch with the patient or his/her relative for the purpose of correcting their mistakes. These services are designed to decrease the length of hospitalization; improve quality of life by addressing physiological, psychological, and social problems; and perform scientific studies. The Turkish Wound Ostomy Incontinence Nurses Society (TWOINS) has 136 members; 111 are certified stoma care nurses.²²

Peristomal Skin Assessment Instruments

Although the literature discusses instruments utilized in the assessment of peristomal skin lesions,^18,24 these instruments have undergone only limited validity-reliability studies. Salvadalena¹⁸ conducted a meta-analysis of 21 studies assessing stomal or peristomal complications to determine their incidence. The author concluded differences in study designs, absence of standard definitions, and variation in assessment times thwarted determination of the incidence of stomal or peristomal complications.

Ostomy Skin Tool (OST). The validity and reliability of 3 instruments/scales that assess stomal and peristomal skin complications have been tested, including the OST,^14,16,24 the Ostomy Algorithm,^14,16 and the Studio Alterazioni Cutanee Stomali (SACS Instrument).^5,24 The OST is a standardized assessment tool developed by a team of 12 ostomy nurses for assessing peristomal skin. The OST consists of standardized descriptions of the abnormal peristomal skin: discoloration (D), erosion (E) and tissue overgrowth (T). Each domain facilitates assessment of the affected area (scored between 0 and 3) and the severity of the problem (scored between 0 and 2); therefore, for each domain the score is between 0 and 5, and the resultant total DET value is between 0 and 15.^24,31 Jemec et al’s¹⁴ OST validation study in Denmark and Spain among 20 ostomy nurses demonstrated a high inter-nurse assessment agreement of this scale according to Kappa analysis (K = 0.84).

Ostomy Algorithm. The Ostomy Algorithm is comprised of 11 assessments: type of ostomy, type and volume of output, stoma type, stoma profile, stoma shape, abdominal contour, level pouching surface, presence/absence of devices, presence/absence of stoma complications, SACS score, and presence/absence of peristomal skin complications. Preliminary face validity of the Ostomy Algorithm was established by 9 wound ostomy continence (WOC) nurses in the United States with extensive ostomy experience (7 WOC nursing consultants and 2 WOC nurse employees of ConvaTec [Skillman, NJ], the company that supported development of the algorithm). When used properly, it allows for the selection of a suitable pouching system, maintenance of intact peristomal skin, and effective prevention, identification, and management of commonly identified stomal and peristomal complications. The section that includes the SACS instrument allows clinicians to assess and classify peristomal skin lesions.¹⁶ 

Beitz et al¹⁶ conducted a content validation of the Ostomy Algorithm in which validity-reliability studies were performed on real patients. As part of this study, the SACS instrument’s content validity index (CVI) was determined to be 0.94. Based on the content validation assessment results (the overall content validity score was 0.95), the Ostomy Algorithm was well received by expert WOC nurses, and the number of persons willing to participate in the survey (n = 166) suggests a clear need for this instrument.¹⁶ 

SACS instrument. The SACS instrument was developed in Italy between 2003 and 2006 and a validity study was performed. The instrument consists of 3 main parts: assessment of lesion types (5 options with definitions and photographs), assessment of lesion areas (5 options using a clockwise orientation), and documentation examples. Lesion types include hyperemic (L1: peristomal redness with intact skin), erosive (L2: open lesion not extending into subcutaneous tissue; partial-thickness skin loss), ulcerative (L3: open lesion extending into subcutaneous tissue and below; full-thickness skin loss), ulcerative (L4: full-thickness skin loss with nonviable, dead tissue), and proliferative (L5: abnormal growths present; ie, hyperplasia, granulomas, neoplasms). The peristomal lesion areas are determined according to a topographic (T) location scale: TI: left upper peristomal quadrant, 12–3 o’clock; TII: left lower peristomal quadrant, 3–6 o’clock; TIII: right lower peristomal quadrant, 6–9 o’clock; TIV: right upper peristomal quadrant, 9–12 o’clock; and TV: all peristomal quadrants.

The first reliability study of the SACS instrument was performed by Bosio et al⁵ in 2007. Researchers sent 20 lesion photographs to clinicians who assessed them using the SACS instrument. Inter-observer agreement percentage according to kappa analysis was K = 0.91. A reliability study of the SACS instrument was performed through independent inter-observer agreement and also analyzed using the Kappa statistic. Inter-observer agreement percentage was determined to be very good (K = 0.90). The confidence interval (CI) of the instrument was determined to be between 0.80 and 0.99.

Validated in Italy and the United States, the SACS instrument is currently the only content-validated peristomal skin assessment and classification instrument. As previously noted, the SACS instrument was assessed as part of the Ostomy Algorithm, with a content validity index of 0.94 out of 1.0 (N = 166).^16,25

The current descriptive study was conducted for the purpose of assessing the validity, usability, and reliability of the SACS instrument adapted for Turkish patients.

Materials and Methods

Patient sample. The study involved a convenience sample of 100 patients with a peristomal skin lesion. This number was chosen in accordance with Kappa statistic and Number Cruncher Statistical System (NCSS, Kaysville, UT) statistical programs for ample sample size to power statistical analyses. Inclusion criteria stipulated participants must agree to participate in the study, be >18 years old, and receiving treatment/observation at one of the stomatherapy units at a university hospital, located in 4 different regions. The study was conducted between December 2012 and June 2013.

Nurse sample. The study involved 8 certified stoma and wound care nurses working in the stomatherapy units. To determine inter-observer agreement, 2 nurses in each unit assessed all the patients using the SACS instrument and recorded the results. Nurses provided and recorded the care of all patients with existing or newly developed peristomal skin lesions.

Ethical aspects of the study. Written consent to translate and adapt the SACS for use in Turkey was obtained from the ConvaTec (Skillman, NJ), which holds the right to commercial use of the instrument. The Clinical Research Ethics Board approved use of the data collection forms, and written permission to conduct the study was obtained from the hospitals where the study was performed. Patient participation was voluntary, and written informed consent was obtained from patients included in the study. The nurses used the forms with the patients who agreed to participate in the study.

Data collection instruments. Peristomal skin variables were collected using the SACS instrument record form, which consists of 3 columns in which nurses can mark the lesion type (L1-L5), lesion area (TI-TV), and record the obtained assessment result for each patient. Skin lesion severity is assessed on a scale from 1 to 5; for instance, L1 is used for low severity skin complications and L5-LX is used for very severe skin complications (see Figure 1).         

Demographic data were collected using a Patient Characteristics Form. The form contains 26 questions about sociodemographic characteristics, health conditions, and risk factors associated with peristomal lesions, including medical diagnosis (eg, diabetes, obesity), stoma type (eg, ileostomy, urostomy), form of feeding (eg, no oral intake, total parenteral nutrition), material allergy (eg, hydrocolloid, adhesive), presence of creases, stoma level (eg, flat), stool amount (eg, excessive), and form of stool (eg, liquid, semisolid). Treatment was determined exclusively from the information on the SACS instrument.

Participating nurses also completed the Nurse Characteristics Form, which contains 9 questions including age, time as a stoma nurse, and 2 questions regarding the prevention of peristomal skin lesions. Nurses also completed a Nurse SACS instrument evaluation form consisting of 20 questions on the practical characteristics of the instrument (including time to complete, practicality, comprehensibility, whether the instrument addresses all peristomal skin lesions and determines peristomal skin lesions correctly, and the relevance of terms and pictures used).

The data were collected using multichoice data collection paper forms during patient visits at wards or when the patients visited the stomatherapy unit and stored at these units by nurses who completed the forms.

Study process. The study was performed in 2 stages. First, the instrument was adapted from English to Turkish and its content validity established. Then, nurses used the instrument to assess peristomal skin lesions on real patients and inter-observer agreement (consistency) of the nurses’ assessment was measured.

Language adaption of the SACS instrument. Before assessing the content validity of the SACS instrument, language validity studies of the instrument were performed. For language adaptation, the SACS instrument was first translated to Turkish from English by a faculty member from the Faculty of Medicine and 2 faculty members from the Nursing Department of the Faculty of Health Sciences, all competent in English. The SACS instrument was translated back to English from Turkish by a faculty member competent in English from the Faculty of Nursing. The instrument translated to Turkish from English and retranslated back to English from Turkish was compared by the researchers and necessary corrections were performed. The revised instrument was evaluated to determine its suitability in terms of Turkish language grammar and sentence structure and finalized by a Turkish language expert.

Determining SACS instrument content validity. Content validity refers to the degree an instrument covers the content it is supposed to measure and determined using the CVI developed by Waltz and Baussel.²⁷ Items are rated 1 (irrelevant), 2 (needs to be made relevant), 3 (relevant but needs minor changes), or 4 (very relevant); space also is allocated for comments regarding each item.²⁷ This type of assessment can help ensure construct validity and ensure confidence for the users and researchers. Two judgments are necessary: the measurable extent of each item for defining the traits and the set of items that represents all aspects of the traits.²⁶

The content validity of the translated SACS instrument relied on the opinion of 7 experts: 4 faculty members from the Nursing Department, 2 stomatherapy nurses, and 1 faculty member from the Faculty of Medicine. The CVI for each item was calculated by dividing the number of experts grading the items with 3 and 4 points and the total number of experts.

Nurse implementation of the SACS instrument. In this stage of the study, 2 nurses used the SACS instrument to assess the peristomal skin lesions on a real patient and then inter-observer agreement between nurses was measured. The authors sent all data collection forms to nurses who agreed to participate in the study through post. At the same time, a written directive was sent to the nurses about how to apply the forms, collect the data, and keep the forms confidential. According to this directive, nurses completed nurse characteristics forms first and then completed patient characteristic forms and used the SACS instrument to assess patients. Nurses working in the stomatherapy units were asked to use the SACS to assess skin lesions and classify and record data independently of each other at every patient visit when they changed the ostomy bag/system, each recording data on a separate data collection form. Every patient visited at least once up to 3 times until discharged, but every patient was assessed 1 time by 2 nurses independently at the same time. At the end of the study, all nurses sent the data forms through post to the authors and the authors recorded data in statistical analysis programs databases.

After implementation of the instrument, nurses were asked to complete the Nurse SACS instrument evaluation form.

Data assessment. Nurse characteristics, patient characteristics, and nurse SACS instrument evaluation data were assessed using descriptive analyses (percentage, frequency), hypothesis tests, and consistency analyses using the SPSS 15 (IBM, New York, USA) program.

Items such as physical exam findings, radiographic interpretations, or other diagnostic tests often rely on some degree of subjective interpretation by observers. The Kappa statistic (or Kappa coefficient) is the most commonly used statistic for this purpose.²⁹ Inter-observer agreement among the nurses was assessed using the Kappa statistic. The Kappa statistic was designed to provide a numeric value for the size of the consistency between observers.³⁰ A Kappa coefficient of <0 is construed as having no agreement, 0.0–0.20 implies agreement at an insignificant level, 0.21–0.40 implies having agreement at a medium level, 0.41–0.60 implies good agreement, 0.61–0.80 implies significant agreement, and 0.80–1.00 means agreement at a nearly perfect level.³⁰ The understandability of the SACS instrument also was assessed using the CVI statistic as previously described; space also was allocated for comments regarding each item.²⁸ For the purpose of assessing usability of the SACS instrument, the Kappa statistic was applied. Inter-observer variation between 2 or more independent observers evaluating the same thing is calculated based on agreement between the observations (see Table 1 and Table 2). 

Results

Content validity. All experts scored each item 3 or 4; thus, the CVI was determined to be 1. For this study, the minimum value from the table created by Veneziano and Hooper²⁸ for content validity at a significance level of  = 0.05 was determined to be 0.99. As a result, the content validity of the Turkish SACS instrument was determined suitable for use. Once expert suggestions from their comments were incorporated, the SACS instrument was finalized. No major changes were necessary before the instrument’s content validation except minimal word changes according to expert suggestions. After these changes, the Turkish language expert assessed the instrument to ensure suitability regarding Turkish language grammar and sentence structure.

Usability of the SACS instrument. Inter-observer agreement for the entire instrument was very good (K = 0.90). The confidence interval of the instrument ranged from 0.80 (lower limit) to 0.99 (upper limit).

Patient population. During the study period, 171 (Gazi University), 108 (Çukurova University), 58 (İstanbul University), and 56 (Uludağ University) patients received care at the 4 stomatherapy units; the 100 patients with peristomal complications participating in the study comprised 25.44% of the total population. Of these patients, 33 were observed at Gazi University, 32 at Çukurova University, 24 at Istanbul University, and 11 at Uludağ University. Ostomy types included ileostomy (67), colostomy (25), and urostomy (8); coincidentally, all of the patients were using a 2-piece bag/adaptor system. More than half of the patients (52) were 40–64 years old, average age was 56.74±14.03, 55 were men, 55 had completed primary school or lower, 32 were diagnosed with rectal cancer, and 27 with colon cancer. Twenty-six (26) had a chronic disease. Six (6) had an allergy (although not to hydrocolloids), which affected the development of peristomal skin lesions. The majority of patients (96) performed normal oral feeding, and 86 had no problem performing their stoma care.

Among the 100 participating patients, 79 had planned operations, 28 had their stoma area marked preoperatively by the stomatherapy nurse, and the average period of living with a stoma was 6.49 ± 1.69 years  (range 1 day to 12 years). The majority (77) had later-developing complications. Among these complications, 34 had a stoma at the same level as their skin, 23 had an improperly shaped stoma (ie, not circular/smooth edged), 93 had soft peristomal skin, 8 had a supporting rod, 50 had a liquid stool, 15 had excessive output, 14 had mucocutaneous separation, 2 had a peristomal hernia, and 35 had a crease in the peristomal area.

The nurse participants included 8 women, 6 with Bachelor’s and 2 with graduate degrees in nursing. All were certified stomatherapy nurses and had been working in that capacity for an average of 5.5 ± 3.17 years; 62.5% said they provided care to 10 individuals with a stoma per week, and 37.5% said they provided care to more than 20 individuals. The nurses stated they had not previously used a peristomal skin lesion assessment instrument. A large majority (87.5%) had received information on basic stoma and wound care nursing with regard to the prevention/treatment of peristomal skin lesions. Despite her certification, one of the nurses stated she did not have enough knowledge on prevention/treatment of peristomal skin lesions.

Inter-observer comparisons. The inter-observer agreement for the individual lesion types in the SACS instrument was very good (see Table 1). For hyperemic lesions (L1), agreement was K = 0.89 (95% CI, 0.80–0.98); for erosive lesions (L2) K = 0.85 (95% CI, 0.75–0.95); for ulcerative lesions (L3) K = 0.84 (95% CI, 0.70–0.97); ulcerative lesions (L4) K = 0.84 (95% CI, 0.63–1); and proliferative lesions (L5) K = 1 (95% CI 1).

The inter-observer agreement percentage of the SACS instrument by lesion areas was also very good and ranged from TII K= 0.88 (95% CI 0.78–0.98) to TV K = 0.94 (95% CI  0.87–1) (see Table 2).

Nurse opinion of the SACS instrument. All nurses stated the use of instruments with validity-reliability studies performed was necessary for the assessment of peristomal skin lesions. All nurses believed validity-reliability testing is needed before an instrument is used. Half of the nurses did not agree that SACS classification addressed all lesions; 62.5% found the terms and pictures used in the SACS classification adequate and suitable and that the SACS instrument determined lesions correctly, but they did not believe nonostomy care experts/clinicians would be able to correctly assess peristomal skin lesions using the SACS instrument. Most nurses (87.5%) said the instrument was practical and facilitated the provision of care to patients with peristomal skin lesions; that same percentage did not experience difficulties using the SACS instrument and thought use of the SACS instrument is important in terms of determining and documenting skin lesions, that it would contribute to the exact measurement of the prevalence and incidence of skin lesions, and that it would provide assistance in clinical decision making. In addition, 75% of the nurses found using the SACS instrument helped them determine correct care management and reduced costs by reducing the use of excessive products.

Discussion

In the 7-month study period, 100 of 393 patients (25.4%) had peristomal skin lesions, between the rates that mentioned in the literature both in Turkey and in the world.^8-13 Among participants, 65% of the patients had an ileostomy, 72% of the stoma sites had not been marked before the operation, 49% of the patient’s had a flat or retracted stoma, 35% of the patients had a stoma in the abdominal contour, 50% of the patients had liquid stool, and 15% had an excessive output — all risk factors for peristomal skin lesions as reported in the literature.^{1,5-7,9,12,18}

The SACS instrument was developed and accepted by a consensus of health care professionals in Italy and subsequently content-validated in both Italy and the United States  (CVI of latter = 0.94^16,18). In the current study, validity, usability, and understandability were assessed for use of the SACS instrument in Turkey. Content validity was found to be 1, higher than defined minimum values (Confidence coefficient: 1-α = 1-0.05 = 0.95, although half of the nurses thought the SACS instrument did not include all possible lesions.

According to the literature,^5,14 use of an assessment instrument with proven validity will reduce costs and enable clinicians to accurately measure the prevalence and incidence of stomal and peristomal complications. In this study, 75% of participating nurses agree the use of the SACS instrument would assist them determining the correct method of care and will decrease costs by decreasing the use of excessive products. Using valid and reliable instruments will assist caregivers in identifying the skin lesion type, location, and characteristics more expediently and more accurately to help clinicians avoid providing care by trial and error.

In the planning stage of the study, no other instrument with proven validity and reliability was found in Turkey. The results of this study suggest the Turkish version of the SACS instrument is valid and suitable for the assessment of peristomal skin lesions.

Study Limitations

Only stoma nurses participated in the study; in addition, the nurses performing the peristomal skin lesion assessment both worked at the same stomatherapy unit, and although the nurses were instructed to perform the assessment independently of each other, it was not observed whether this occurred. A larger reliability study with a larger sample and additional advanced statistical methods (as well as kappa) is recommended.

Conclusion

A descriptive study conducted among 8 stomatherapy nurses assessing 100 patients in Turkey found the use of the SACS instrument for peristomal skin lesion assessment to have a CVI of 1, as well as adequate independent inter-observer agreement regarding suitability and practical use (CI 0.80–0.99). The Turkish version demonstrated validity and usability for persons speaking this language. The SACS instrument is recommended for use in clinics as a peristomal skin lesion assessment instrument. Repetition of the validity and reliability study with a larger sample group of nurses and patients and the use of the SACS instrument in studies regarding cost of care, prevalence, and incidence of peristomal complications is warranted.

Abstract 

Tension on the suture line of flap donor sites raises the risk of delayed healing and wound dehiscence. Closing a large flap donor site without a skin/flap graft is a major surgical challenge.

   Recently, the authors started using a skin-stretching wound closure system designed to harness both mechanical creep and stress-relaxation principles for the management of a variety of surgically closed wounds, including flap donor sites. The system consists of a pair of attachment plates connected by a long, flexible approximation strap that can be invasively (sutured) or noninvasively (by adhesion) secured to the skin wound edges and gradually tightened. The care and outcomes of 2 of the 41 patients whose wounds were managed with this system at the authors’ plastic/reconstructive and wound repair center during a period of 7 months are described. The first case involved a 20-year-old patient with a 16 cm x 8 cm deep inferior epigastric perforator flap to reconstruct a malignant tumor resection of the groin. The second patient required a 10 cm x 8 cm anterolateral thigh free-flap to repair a traumatic dorsal skin, soft tissue defect. Wounds were assessed and tension adjusted every 2 or 3 days. Both lesions healed by primary intention and with a good cosmetic outcome. Controlled clinical studies are needed to examine the effectiveness, efficacy, indications, complications, and cost effectiveness of this closure system.

Tissue transfer has rapidly developed over the last half century to become a mainstay of reconstructive surgery. A reevaluation and reclassification of human anatomy has occurred, searching for possible donor tissue types from a variety of anatomical areas. This knowledge has been applied to best fulfill demands of the recipient site.¹ However, to date focus on the donor site in terms of either the potential for acute complications or long-term morbidity has been limited. Flap donor sites subjected to direct suture stress are at increased risk of delayed healing and dehiscence due to tension on the closure. The highest rate of dehiscence/rupture,  as reported in a review by Mahoney,¹ is 31%. According to personal opinion based on a case report, Addison et al² noted excessive wound tension increases the risk of wound dehiscence or delayed healing, unsightly scarring, and distal deep venous thrombosis. In a 2-center, retrospective review (N = 53), Shindo et al³ reported that, for the fibula osteocutaneous flap, major wound complications developed in 12% of patients who underwent primary closure.

Prevention and management of these defects poses a challenge for the reconstructive surgeon. Traditional management of these short-term complications involves skin grafts, local flaps, tissue stretching and expansion, and closure by secondary intention.¹ However, potential risks such as necrosis of the grafted/expanded skin also may leave large defects that cannot be primarily closed.⁴ In addition, these sites often may be aesthetically inferior to tensionless primary wound closure.⁵

In 2012, Topaz et al⁵ first reported their clinical experience with their TopClosure^® 3S System (I.V.T. Medical Ltd, Israel), an innovative, simple, skin stretching and wound closure system designed to harness both mechanical creep (a phenomenon where skin will stretch and elongate with time as long as force is applied) and stress relaxation principles. This tension release system (TRS) consists of a pair of attachment plates (APs) connected by a long, flexible approximation strap (AS) that can be invasively (sutured) or noninvasively (by adhesion) secured to the wound edge skin to close the wound by gradual tightening. Topaz et al shared their experiences of using these methods of skin stretching and elongation to secure the wound edges and improve scar aesthetics: the device was applied to 21 wounds in 20 patients 6 years and older for various clinical applications, including preoperative skin lesion removal, closure of a variety of surgical wounds, following trauma, and to secure the wound closure as noted in case 2 and case 4 of their study. Slow, gradual skin stretching was applied with minimal pull on the skin. Intermittent application of tension to the skin led to an incremental skin elongation through the stress-relaxation mechanism, facilitating closure of the wound.⁵ Their single-center case series of 3 representative patients indicated an acceptable outcome and validated use of the system.⁵ 

The Department of Plastic Surgery and Burn/Wound Center, Second Affiliated Hospital, College of Medicine, Zhejiang University, is one of the major plastic/reconstructive and wound repair centers in East China, annually treating approximately 2,500 inpatients and more than 12,000 outpatients with all different kinds of wounds. The TRS was first introduced in China in this health care facility. From September 2013 to March 2014, the TRS was used to close 43 different surgical wounds and protect the sutures in 41 Chinese patients (20 women and 21 men) with good results.

Closing a large flap donor site without a skin/flap graft is among the most challenging surgical tasks. Two typical cases treated at the wound center that involved donor site healing using the TRS are presented.

Case Reports 

Case 1. Twenty-year-old Ms. Q was admitted for a 10 cm x 8 cm, partially necrotic and bleeding cutaneous tumor in her left groin (see Figure 1a). Before she came to the center, only 2 months had elapsed for her lesion to develop from a small eczema-like plaque to the present status. She had not received any previous treatment, had no other self-reported health conditions or comorbidities, and none were identified during presurgical health screening. Computer tomography (CT) scan indicated a solid, homogeneous tumor without involvement of the left femur artery, vein, or nerve (see Figure 1b). Biopsy result indicated small cell carcinoma. A multidisciplinary surgical team was assembled comprising an orthopedic oncology surgeon and a plastic and reconstructive surgeon. Before surgery, the patient’s ipsilateral and contralateral inferior epigastric arteries were located by noninvasive Doppler sensor, and a potential deep inferior epigastric perforator (DIEP) flap was designed to address the defect (see Figure 1c). Radical resection of the tumor then was completed, leaving a huge groin skin and soft tissue defect (see Figures 1d,e). A 16 cm x 8 cm contralateral DIEP flap was harvested and transferred to cover the wound (see Figures 1f–1h). The donor site margins were sutured, and 3 pair of APs were invasively placed along the suture line and interconnected by a long, flexible AS to relax the tension (see Figure 1i).

All of Ms. Q’s presurgical and postsurgical care was provided by the plastic surgeons and nurses at the center. After the operation, her gauze dressing was changed and the wound evaluated every 2 days. The suture line was disinfected with benzalkonium chloride and the sutures and adjacent skin assessed to evaluate the risk of rupture or skin trauma (ie, pressure ulcer) under the APs. The APs were carefully adjusted to gradually loosen the skin while protecting the sutures from excessive tension. At 4 weeks, Ms. Q’s wound was firmly closed and the sutures and APs were removed (see Figure 1j).

Because the pathology report indicated the lesion was a nonHodgkin’s lymphoma and positron emission tomography (PET) CT scan indicated several suspicious lymph nodes, Ms. Q was transferred to the Department of Hematology to receive chemotherapy.

Case 2. Mr. K is a 53-year-old man whose left foot and ankle were crushed in a traffic accident by the wheel of a heavy truck, causing a 10 cm x 8 cm skin and soft tissue avulsion on the ankle joint and dorsal site. Mr. K had no other self-reported health conditions or comorbidities; presurgical health screening indicated no other positive findings except for a smoking index of 600 (60 cigarettes per day times 10 years).

To cover this defect, right anterolateral thigh, free-flap transplantation was performed in the Orthopedic Wound and Fracture Department. Simultaneously, the donor site, too wide for primary closure, was covered with a split-thickness skin graft. However, both the grafted skin and the transplanted flap became necrotic, leaving a 10 cm x 16 cm defect on the right upper leg (see Figure 2a,b). The orthopedic surgeon took a cotton swab sample from the donor site defect wound for microbiological culture; the result indicated Serratia marcescens infection (sensitive to most antibiotics). Mr. K then was transferred to the wound center for treatment of both wounds by a plastic surgeon. After careful physical examination and discussion, the plastic surgeons decided to perform stress relaxation and assisted closure. This involved complete surgical debridement, followed by installation of 3 pair of APs, invasively placed along the wound axis and interconnected by a long, flexible AS (see Figure 2c). The wound was initially covered with Vaseline gauze (Jiujiang Huada Medical Dressing Co, Ltd, Gongqing City Jiangxi Province, P.R. China) (see Figure 2d). Simultaneously, for the foot and ankle wound, the necrotic grafted flap was removed, exposing thrombosis of the drainage vein (see Figure 2e). After debridement, another split-thickness skin graft was used to cover the left foot ankle wound (see Figure 2f). The plastic surgeons first changed the dressing 3 days after the surgery, using SeaSorb-Ag dressing (Coloplast Group, Humlebaek, Denmark) to cover the wound and absorb wound exudate; the dressing was changed every 2 days thereafter. During each dressing change, the wound and skin were assessed and wound measurements obtained, and the skin was gradually stretched by adjusting the AS. During this procedure, great care was taken (including daily check, adjusting AS, and placing soft gauze beneath the APs) to avoid inducing pressure ulcers beneath the APs (see Figure 2g). Nineteen (19) days after surgery, the residual wound measured 2 cm and was filled with granulation tissue that blocked the APs and skin (see Figure 2h). At a second surgery performed 19 days after the first, excess granulation tissue was resected and the wound was sutured closed (see Figure 2i). Another 2 pair of APs were placed to relax the tension (see Figure 2j). Fifteen (15) days later, both the suture and APs were removed. The muscle and fascia defect was firmly closed, leaving only several superficial skin gaps that healed with regular wound care, comprising daily dressing change, disinfection, and assessment (see Figure 2k); a skin graft was applied to the left foot ankle wound (see Figure 2l). At the 6-month follow-up, slight scarring at the donor site and foot wound was observed (see Figure 2m,n).

Discussion

Donor site wound necrosis and dehiscence are among the most common early-stage complications after flap grafting. Risk for such complications is size-dependent: a larger flap will cause larger defect, and hence produce more tension for primary closing and lead to higher risk of dehiscence/rupture,⁶ which has been observed. The result of a recent meta-analysis by Salgarello et al⁶ that included 510 patients from 6 studies showed wound dehiscence and delayed wound healing in DIEP patients occurred at a rate of 7.2% (95% confidence interval [CI] = 4.1–12.4%). The key to preventing and managing these complications is control of the tension.

The TRS herein described was designed to either noninvasively or invasively harness the viscoelastic properties of the skin using mechanical creep and stress-relaxation principles. In the cases described, the mechanical creep properties of the skin were utilized by preoperative continuous skin stretching; the method has been applied in cases of unhealed ulcers, skin tumors, scars, and birth marks — ie, lesions needing plastic removal and reconstruction. Such a system also can provide acute skin stretching by stress relaxation through intraoperative, invasive, cyclical skin elongation and for postoperative invasive or noninvasive scar tension release to secure wound closure.⁵

The 2 cases reported demonstrated the viscoelastic properties of the TRS. In the first case, continuous stress relaxation was used because of the risk of wound dehiscence in this patient. In a case report⁷ of 1 patient, skin stretching was shown to allow a gradual decrease in the tension of the wound closing over time, allowing primary closure of relatively large defects. In the second case, slow, gradual skin stretching was applied by minimal pull on the skin every 2 days post surgery. Intermittent application of tension to the skin led to an incremental skin elongation through the stress relaxation mechanism, facilitating the wound closure.⁸ The TRS enabled a selective distribution of a minimal load on the injured skin edges according to the specific clinical condition. An advantage of using a technique to facilitate primary closure is the closed wound may have a much smaller scar when compared with split-thickness skin graft⁵; hence, the result preserves the aesthetic and functional properties of the skin (eg, sweating, sensitivity) better than in grafted skin.

According to the system’s inventors (Topaz et al⁵), applying the TRS has a notable advantage: the ability to apply presurgical mechanical creep through external skin stretching (for low tension wound closure) and postoperative acute intraoperative stress relaxation (for high tension wound closure). Undermining skin edges and adjacent tissues can be avoided, maintaining adequate blood supply to the wound margins and securing the viability of the skin edges even under extreme tension. Avoidance of undermining eliminates dead space and reduces the risk of seroma and hematoma accumulation; it also removes the need for drainage and reduces the risk of infection.⁵ Skin can be further approximated following stress relaxation by advancing the AS as a bedside procedure by using mechanical creep, in some cases under local anesthesia.

In the authors’ experience, when used as a topical tension-relief platform for tension sutures, TRS alleviates the frequently observed tearing and scarring inflicted by tension sutures. Because of its simplicity, TRS can be used for a wide scope of indications in a wide range of surgical settings.⁹ The authors of the current study also appreciated the fact that the TRS design facilitated better daily assessment and adjustment compared with a planted inner balloon expander that is another option.

Limitations

The ability to draw conclusions from this and other case studies is limited. At this time, evidence about the effectiveness and efficacy of TRS is incomplete. These case study results are encouraging and similar to those reported in the literature.⁵ Multicenter, cohort studies comparing wound and patient outcomes of TRS management and other donor site management methods are needed to help clinicians make evidence-based donor site closure decisions.

Conclusion

In this case study, the TRS was successfully applied to gradually stretch skin and soft tissues involved in large defect flap donor sites and facilitate primary closure without overwhelming tension. Moreover, TRS protected the primary suture lines from tensions risk for rupture.

This is the second report worldwide and the first in China to describe the clinical application of the TRS. A large-scale, randomized, controlled study to examine the effectiveness, efficacy, indications, complications, and cost effectiveness of this closure system is warranted.

Abstract

The Braden Scale is the most widely used pressure ulcer risk assessment in the world, but the currently used 5 risk classification groups do not accurately discriminate among their risk categories. To optimize risk classification based on Braden Scale scores, a retrospective analysis of all consecutively admitted patients in an acute care facility who were at risk for pressure ulcer development was performed between January 2013 and December 2013.

Predicted pressure ulcer incidence first was calculated by logistic regression model based on original Braden score. Risk classification then was modified based on the predicted pressure ulcer incidence and compared between different risk categories in the modified (3-group) classification and the traditional (5-group) classification using chi-square test. Two thousand, six hundred, twenty-five (2,625) patients (mean age 59.8 ± 16.5, range 1 month to 98 years, 1,601 of whom were men) were included in the study; 81 patients (3.1%) developed a pressure ulcer. The predicted pressure ulcer incidence ranged from 0.1% to 49.7%. When the predicted pressure ulcer incidence was >10.0% (high risk), the corresponding Braden scores were <11; when the predicted incidence ranged from 1.0% to 10.0% (moderate risk), the corresponding Braden scores ranged from 12 to 16; and when the predicted incidence was <1.0% (mild risk), the corresponding Braden scores were >17. In the modified classification, observed pressure ulcer incidence was significantly different between each of the 3 risk categories (P<0.05). However, in the traditional classification, the observed incidence was not significantly different between the high-risk category and moderate-risk category (P>0.05) and between the mild-risk category and no-risk category (P>0.05). If future studies confirm the validity of these findings, pressure ulcer prevention protocols of care based on Braden Scale scores can be simplified.

The Braden Scale is an assessment tool for pressure ulcer risk that was developed in 1987.^1,2 A series of studies subsequently showed the Braden Scale is both reliable and valid, with correlation coefficients (ICC) of ~0.9 for reliability³ and the area under curves (AUC) for receiver operating characteristic (ROC) of 0.707 for validity.⁴ A recent systematic review5 compared the reliability and validity of the Braden Scale, the Norton Scale, and the Waterlow Scale and concluded the Braden Scale demonstrated the best reliability and validity indicators in a variety of settings and was a better predictor of pressure ulcers than nurse judgment. These findings underscore why the Braden Scale is the most widely used pressure ulcer risk assessment scale in the world.

The Braden Scale is composed of 6 subscales: sensory perception, skin moisture, activity, mobility, nutrition, and friction and shear; Braden sum scores range from 6 to 23.^1,2 The first study of the predictive validity^1,2 of the Braden Scale determined a total score of 16 resulted in the best balance between sensitivity and specificity; known as the cut-off point, this value represents the point at which pressure ulcer risk begins. Although Braden and Bergstrom6 initially proposed 3 general risk categories based on total scores (mild [15–16], moderate [12–14], and severe [<11]), the version used by Braden6 in 2002 divides pressure ulcer risk into 5 categories, with scores of 6–9 indicating very high risk, 10–12 high risk, 13–14 as moderate risk, 15–18 at risk, and 19–23 no risk.⁷

The purpose of this study was to assess the feasibility of redefining the risk classification of Braden Scale.

Methods

Patient population. A retrospective analysis was conducted between January 2013 and December 2013 among consecutive patients admitted to a 3,000-bed teaching hospital. Inclusion criteria stipulated patients be at risk for pressure ulcer on admission or when they entered the intensive care unit (ICU) and were recognized to be at risk (ie, patients with spinal cord injury, patients undergoing cardiac surgery, patients experiencing a long operation time). Patients were excluded if they were admitted with a pressure ulcer or died before a pressure ulcer developed.

The study was approved by the medical ethics committee of the authors’ hospital. Patient confidentiality was maintained.

Data collection. Data were retrospectively collected from electronic and paper medical records and recorded in an Excel  form predesigned by 2 of the authors. The form included 3 parts: 1) demographic characteristics, which included patients’ age, gender, weight, and disease; 2) Braden scores, including item scores; and 3) pressure ulcer information (pressure ulcer occurrence [yes or no], ulcer severity determined by National Pressure Ulcer Advisory Panel7 [NPUAP] classification system,7 number of the ulcers, anatomical location, and outcomes). Microsoft Office Excel was used to collect the data. All data were collected by a nurse experienced in pressure ulcer care and verified by another nurse.

Statistical analysis. Measurement data were described as mean ± standard deviation. A logistic regression model (Logit [P] =-0.425 x Braden Scale + 2.538) was used to predict pressure ulcer risk using only Braden score. Using this model, the predicted incidence was calculated. The risk classification of the Braden Scale then was modified based on the predicted incidence. The observed pressure ulcer incidence was compared between different risk categories in the modified classification and the traditional classification by chi-square test; odds ratios (OR) with 95% confidence intervals (CI) also were calculated. Statistical analyses were performed using IBM SPSS software (version 19.0, Chicago, IL).

Results

Patient characteristics. Two thousand, six hundred, twenty-five (2,625) patients (mean age 59.8 ± 16.5 years, range 1 month to 98 years; 1,601 men [~61%]) were included in the study. The patients came from 7 clinical departments: neurosurgery, ICU, orthopedics, neurology, respiratory medicine, spine surgery, and cardiothoracic surgery. Mean traditional Braden score was 15.3 ± 2.3 (range 6–22) (see Figure 1). 

Pressure ulcer incidence. Among the 2,625 patients, 81 developed a pressure ulcer for an overall incidence of 3.1% (95% CI 2.5%–3.8%). Among the 81 patients with a pressure ulcer, 23 (28.4%) developed a Stage I pressure ulcer, 47 (58.0%) developed a Stage II, and 2 developed a Stage III (2.4%); 9 (11.1%) developed more than one pressure ulcer (6 had a Stage I and a Stage II; 3 had a Stage II and Stage III). The most common locations for pressure ulcers were the sacrum, coccyx, heels, and ischial tuberosities.

Predicted pressure ulcer incidence. The logistic regression model for the Braden Scale predicting pressure ulcer incidence is listed in Table 1. According to logistic regression, the predicted pressure ulcer incidence for Braden scores 6 to 22 was 49.7%, 39.2%, 29.7%, 21.6%, 15.3%, 10.5%, 7.2%, 4.8%, 3.2%, 2.1%, 1.4%, 0.9%, 0.6%, 0.4%, 0.3%, 0.2%, and 0.1%, respectively (see Table 2). 

Modified risk classification. When the predicted pressure ulcer incidence was >10.0%, the corresponding Braden Scale scores were <11; when the predicted incidence ranged from 1.0% to 10.0%, the corresponding Braden Scale scores ranged from 12 to 16; and when the predicted incidence was <1.0%, the corresponding Braden Scale scores were >17 (see Table 2). Therefore, the authors defined Braden Scale scores ≤11 as high risk, 12–16 as moderate risk, and ≥17 as mild risk.

Comparison of different risk categories. In the modified classification, the observed pressure ulcer incidences were significantly different among the 3 risk categories (P <0.05). However, in the traditional classification, the observed incidences were not significantly different between the high-risk category and the moderate-risk category (P >0.05) and between mild-risk category and no-risk category (P >0.05) (see Table 3 and Figure 2). 

Discussion

In this study, predicted pressure ulcer incidence was used to define risk classification. Using the modified classification, the observed pressure ulcer incidence was significantly different between the 3 risk categories, suggesting the modified classification is valid and clearly distinguishes the different incidence in 3 risk levels. However, using the traditional risk classification, the observed incidence was not significantly different between the high-risk category and moderate-risk category (P >0.05) and between the mild-risk category and no-risk category (P >0.05). Based on these study results, it appears separating the high-risk category from the moderate-risk category and separating the mild-risk category from the no-risk category may be unnecessary.

Initially, Braden and Bergstrom8 proposed a 3-category scale: mild risk (15–16), moderate risk (12–14), and severe risk (< 11). Their initial categories closely match the current findings.

Cordrey9 developed pressure ulcer prevention interventions based on Braden Scale risk level. When at risk (15–18), patients should use a cushion on a chair when sitting, limit sitting time to a maximum of 2 hours if the patient is unable to reposition him/herself, use a draw sheet or mechanical lift to move patient, and limit friction and shear. When at moderate risk (13–14), patients should use positioning aids as needed, be checked frequently if incontinent, limit sitting time to 1 hour or less, and have prealbumin levels checked every 4 days. When at high risk (10–12), patients should utilize passive range of motion for all extremities. When at very high risk (5–9), patients should use a product such as  Flexicare Eclipse (Hill-Rom, Batesville, IN). However, these preventive interventions are complex and difficult to remember, and their effectiveness has not been confirmed in clinical studies. In the modified risk classification discussed herein, pressure ulcer risk is classified according to 3 levels, simplifying prevention interventions strategies (see Table 4). 

Another reason to reconsider traditional classification is scores of 19–23 were classified as no risk. However, in the current study, the actual observed pressure ulcer incidence among patients with that risk score was 1.4% (95% CI: 0.03%-7.9%) (ie, patients were still at risk). Thus, the current authors believe a score of 19–23 should not be regarded as no risk.

According to research,10-13 pressure ulcer incidence ranges from 1% to 50% and varies greatly among medical centers. In the current study, pressure ulcer incidence was 3.1%. The modified risk classification was based on the predicted pressure ulcer incidence, which may or may not be different in other medical centers.

Limitations

This was a retrospective study with the inherent limitations related to patient record accuracy and completeness. In addition, patients from only 1 medical center were included and the sample size was too small to analyze scores by ulcer stage. The results of this study should be confirmed in additional prospective multicenter studies.

Conclusion

Based on the findings, the risk classification of patients using Braden Scale scores should comprise only 3 levels: high risk, with a total score ≤11; moderate risk, with a total score of 12 to 16; and mild risk, with a total score ≥17. This 3-level risk categorization may be more convenient and feasible in clinical practice. 

References

1.         Bergstrom N, Braden BJ, Laguzza A, Holman V. The Braden Scale for Predicting Pressure Sore Risk. Nurs Res. 1987;36(4):205–210.

2.         Bergstrom N, Demuth PJ, Braden BJ. A clinical trial of the Braden Scale for Predicting Pressure Sore Risk. Nurs Clin North Am. 1987;22(2):417–428.

3.         Kottner J, Halfens R, Dassen T. An interrater reliability study of the assessment of pressure ulcer risk using the Braden scale and the classification of pressure ulcers in a home care setting. Int J Nurs Stud. 2009;46(10):1307–1312.

4.         Seongsook J, Ihnsook J, Younghee L. Validity of pressure ulcer risk assessment scales; Cubbin and Jackson, Braden, and Douglas scale. Int J Nurs Stud. 2004;41(2):199–204.

5.         Pancorbo-Hidalgo PL, Garcia-Fernandez FP, Lopez-Medina IM, Alvarez-Nieto C. Risk assessment scales for pressure ulcer prevention: a systematic review. J Adv Nurs. 2006;54(1):94–110.

6.         Ayello EA, Braden B. How and why to do pressure ulcer risk assessment. Adv Skin Wound Care. 2002;15(3):125–131.

7.         2014 Prevention and Treatment of Pressure Ulcers: Clinical Practice Guideline. Available at: www.npuap.org/wp-content/uploads/2014/08/Updated-10-16-14-Quick-Referenc.... Accessed August 11, 2015.

8.         Braden BJ, Bergstrom N. Risk assessment and risk-based programs of prevention in various settings. Ostomy Wound Manage. 1996;42(10A suppl):6S–12S.

9.         Cordrey R. Pressure Ulcer Prevention Interventions, per Braden Scale Score. Available at: http://woundostomycontinence.com/pressure.doc. Accessed August 25, 2014.

10.       Meesterberends E, Halfens RJ, Heinze C, Lohrmann C, Schols JM. Pressure ulcer incidence in Dutch and German nursing homes: design of a prospective multicenter cohort study. BMC Nurs. 2011;10:8.

11.       Jenkins ML, O’Neal E. Pressure ulcer prevalence and incidence in acute care. Adv Skin Wound Care. 2010;23(12):556–559.

12.       Manzano F, Navarro MJ, Roldán D, Moral MA, Leyva I, Guerrero C, et al. Pressure ulcer incidence and risk factors in ventilated intensive care patients. J Crit Care. 2010;25(3):469–476.

13.       Langemo D, Anderson J, Hanson D, Hunter S, Thompson P. A quick overview on measuring pressure ulcer prevalence and incidence. Adv Skin Wound Care. 2007;20(12):642–644.

Potential Conflicts of Interest: This work was supported by the Nantong Municipal Science and Technology Bureau (grant BK2013014).

Abstract

Phosphodiesterase-5 is an enzyme that inactivates cyclic guanosine monophosphate and regulates the balance of nitric oxide (NO). NO is an important molecule synthesized during wound repair.

An in vivo study was conducted to evaluate the effect of sildenafil, known to have a role in regulating the effect of NO in perfusion, on the wound healing process under ischemic conditions in rats. Reepithelialization, neovascularization, inflammatory cells, and amount and maturation of granulation tissue were scored on a scale of 0–3 (none, partial, complete but immature/thin, complete and mature, respectively). Data were analyzed using ANOVA one-way test, with statistical significance determined at P <0.05. Forty-two (42) Sprague-Dawley rats were anesthetized, wounded with H-shaped flaps, and randomized into 2 groups: 1 group received 10 mg/kg sildenafil (dissolved in 1 mL distilled water) orally via orogastric tubes and the other group received a 0.9% NaCl solution via intraperitoneal injection (0.1 mL). On days 3, 5, and 10, 7 rats from each group were sacrificed. Blinded investigators analyzed skin samples for the wound healing evaluating criteria using from hematoxylin/eosin staining under an optical microscope at 10X and 40X magnification. Histopathological analysis showed sildenafil significantly reduced reepithelialization, neovascularization, amount of granulation tissue, and number of inflammatory cells on day 3 and increased inflammatory cells on day 10 (P <0.05). Further research is needed to clarify the potential role of oral or topically applied different doses of sildenafil for ischemic wound healing as well to evaluate its safety and efficacy when administered alone or in combination with other therapies.

Wound healing is a complex reconstructive process to restore damaged tissues that involves soluble mediators, blood cells, extracellular matrix, and parenchymal cells.¹ Stadelmann et al’s² review of impediments to wound healing found insufficient perfusion may cause a wound to become chronic depending on the degree of ischemia. Recently, experimental research studies have been focused on different effects of sildenafil, a phosphodiesterase inhibitor known for its effects on erectile dysfunction, on the wound healing process.³ Phosphodiesterase-5 (PDE5) is an enzyme that has been shown in in vivo studies⁴ to inactivate cyclic guanosine monophosphate (cGMP) and regulate the balance of nitric oxide (NO).⁴ The increase of NO has a positive effect on wound healing with regard to angiogenesis, inflammation, cell proliferation, matrix deposition, and remodeling; however, high levels of NO may be responsible for the increase of apoptosis in cells due to free-radical damage and increased levels of tumor necrosis factor (TNF) in ischemic conditions.⁴

A controlled, single-blinded, in vivo study was conducted to create an ischemic wound healing animal model and explore the possible mechanism and effects of sildenafil on the wound healing process under ischemic conditions in rats.

Materials and Methods

Animals and experimental ischemic wound model. The study design was approved by the ethical comity of Istanbul University Cerrahpasa School of Medicine (IUCSM), and the study was performed in the animal research laboratory of the IUCSM.

Forty-two (42) male adult Sprague-Dawley rats (250–300 g) were used in the study. All animals were kept under standard environmental conditions. After general anesthesia with intramuscular 40–50 mg/kg ketamine hydrochloride (Ketalar, Pfizer, Turkey) and 10 mg/kg xylazine hydrochloride (Rompun, Bayer, Turkey), the surgical area was shaved and cleaned with povidone-iodine solution. The skin wounds of the rats were rendered ischemic using the method described by Quirinia et al.⁵ This model, consisting of a cranially based and a caudally based flap 2 cm wide by 4 cm long, is marked on the dorsal skin. The cutaneous blood flow in flaps initially decreases to ischemic level but subsequently gradually increases, reaching the flow of intact skin and a normally healing incisional wound. The flaps were sutured back in position with 4/0 silk sutures placed at 1-cm intervals (see Figure 1). The hypoxic and ischemic areas were located at the distal part of the superior and inferior based flaps. The animals were randomly assigned to 2 groups of 21 samples each. Group 1 received 10 mg/kg sildenafil (Viagra®, Pfizer, Istanbul, Turkey), dissolved in 1 mL distilled water, orally via an orogastric tube. Group 2 received a 0.9% NaCl solution via intraperitoneal injection (0.1 mL). All medication was administered daily at the same time. Seven rats in each group were killed by decapitation method on day 3, day 5, and day 10. The distal edges of the superior and inferior portion of the flaps were taken for histological evaluation and were fixed in 10% formalin.

Wound evaluation scale. At each time point, the distal edges of the superior and inferior portion of the flaps were harvested and their histologic features were assessed by the same blinded expert in paraffin-embedded sections using hematoxylin & eosin stains under light microscopy at a magnification of 10X–40X. The histological evaluation was made according to the wound healing evaluation scale. Reepithelialization, neovascularization, inflammatory cells, and amount and maturation of granulation tissue were scored on a scale of 0–3 (none, partial, complete but immature/thin, complete and mature) as shown in the Table 1. The scoring system was modified from the one used by Sevimli-Gür et al.⁶ 

Statistical analysis. The means of the wound healing evaluation scores were analyzed by ANOVA one-way test using the SPSS statistical software (Version 21.0, Chicago, IL, USA). Bonferroni post hoc test was performed for multiple comparisons when appropriate. Data were presented as mean ± SD. Values of P <0.05 were considered statistically significant. 

Results

Two rats from Group 1 and 1 rat from Group 2 died due to wound abscess and sepsis during the study. Reepithelialization was more accelerated in Group 2 than Group 1 on day 3 and day 10 (Group 1 day 3: 0.00 ± 0.00; day 10: 0.00 ± 0.00); Group 2 (day 3: 1.80 ± 0.37; day 10: 2.00 ± 0.89); P <0.05). The neovascularization scores of Group 2 on day 3 were higher than Group 1 (Group 1 day 3: 1.43 ± 0.53; Group 2 day 3: 2.50 ± 1.00; P <0.05). The granulation tissue amount in Group 2 on day 3 was higher than Group 1 (Group 1 day 3: 0.86 ± 0.38; Group 2 day 3: 1.75 ± 0.50; P <0.05). The inflammatory cell scores of Group 1 (1.00 ± 0.00; P <0.05) were observed to be the lowest on day 3, but these scores were increased day 5 and day 10. Group 2 had the highest inflammatory cell scores (2.40 ± 0.89; P <0.05) on day 3, but these scores decreased on day 10 (0.69 ± 1.03; P <0.05). The differences in the other wound healing scores evaluating time points between groups were not statistically significantly different (see Table 2). 

Discussion

The present in vivo study on ischemic skin wound healing in rats showed sildenafil reduced reepithelialization, neovascularization, and amount of granulation tissue and inflammatory cells on day 3; increased inflammatory cells on day 10; and reduced reepithelialization at the wound site on day 10.

An organism responds to damage to tissue integrity by reestablishing homeostasis, which includes inflammatory, proliferative, and remodeling phases.⁷ After the first insult, the inflammatory phase provides hemostasis by vasoconstriction and thrombus formation. Platelets adhere to the damaged tissue and secrete coagulation factors and growth factors that are in the platelet alpha-granules. Vasoconstriction is followed by vasodilatation, where growth factors have chemotactic effects on macrophages and neutrophils.⁸ Macrophages and neutrophils try to move bacteria and necrotic tissue away from the injury.⁹ Substances such as NO are rapidly transmitted to the tissue, directly affect vascular cells, and play an active role in inflammation and other wound healing phases.¹⁰

NO is synthesized from arginine by NO synthase (NOS). NOS has 3 genetically different isoforms: eNOS (endothelial NO synthase) is produced in small amounts and facilitates the vascular tonus; nNOS (neuronal-type NO synthase) provides synaptic signaling events and neurotransmission; and iNOS (inducible NO synthase) is produced in large amounts and plays a role in immune/inflammatory processes and cellular immune response.¹¹ In all acute events (eg, trauma, stress, acute inflammation), the secreted iNOS may provide either a protective or a harmful effect.¹² These harmful effects are caused by the antioxidative effects of NO that inactivate superoxide and produce radicals such as peroxynitrite.¹³ The harmful effects of NO, which is produced in high concentration by biological systems, are actualized by 3 mechanisms.¹⁴ In the first mechanism, NO transfers into the cells like oxygen because it has an electron that is not shared, adheres to transmission metals such as iron that exist in protein structure, and releases free iron to the environment. In the second mechanism, by oxidation NO forms N-nitroso compound and N2O3 (N-nitroso compounds [NOC] including 2 chemical classes, nitrosamines, and nitrosamides, which are formed by the reaction of amines and amides, respectively, with nitrosating agents derived from nitrite) that are harmful to DNA. Lastly, NO reacts with oxygen radicals and produces DNA, proteins, and peroxynitrite, which oxidize membrane lipids.¹⁴

Sildenafil increases the concentration of NO in the environment by inhibiting PDE5; subsequently, the NO concentration in the medium increases. Effects on wound healing in ischemic tissue may be visualized both as protective or damaging to tissue depending on the increase in NO concentration.¹⁵ The different results (improved survival of skin flaps versus decreased viability of skin flaps) in recent animal studies¹⁶ are due to the methodological differences such as route of administration (oral, topical, intraperitoneal), drug dosage (3 mg/kg to 20 mg/kg), and duration of sildenafil treatment (1–21 days). In the current study, an ischemic wound healing model with insufficient perfusion was employed to worsen the wound healing conditions; the authors aimed to observe the already known vasodilation effect of sildenafil on inflammation and proliferation phases of wound healing.

Sarıfakıoğlu et al¹⁷ pioneered a study of the efficacy of sildenafil on wound healing in rats (n = 32) with caudally based skin flaps. The authors found sildenafil administered orally for 7 days at doses of 3, 10, and 20 mg caused a dose-dependent increase in wound healing. Also, sildenafil has been used by different routes and at different doses and durations in various preclinical studies. The results of these studies support the beneficial effects of sildenafil in the early phase of wound healing in various conditions. However, studies in which medications were administered for >7 days demonstrate this beneficial effect disappears and harmful effects are encountered. Hart et al¹⁸ investigated the short-term and long-term effect of intraperitoneal sildenafil on cutaneous flap survival in rats (N = 109). They observed the group receiving sildenafil had lower necrosis and stasis of the flap on day 1 and day 3 as compared to the control group, but this beneficial effect disappeared after day 5. This beneficial effect in the first days may be due to the greater vasodilator effect of sildenafil when applied at the early stages of postoperative period. With this finding, Hart et al suggested sildenafil alone is not sufficient for long-term maintenance of flap viability.

Tsai et al19 conducted a study with sildenafil and vascular endothelium growth factor (VGEF) in rats (N = 123), but this combination therapy revealed no statistically significant benefit as compared to sildenafil alone. This failure may be attributed to the insufficient VGEF dosage. Further studies are needed to assess the most effective amount of VGEF dosage for inducing angiogenic effect. Also, slow-release VGEF formulations for successful late-stage survival may be more useful than a single-shot administration that causes a rapid and short effect; they are yet to be developed.

The presence of excessive NO caused by sildenafil in ischemic tissues may result in free oxygen radical formation and increased apoptosis. In an in vivo study involving rats, Uzun et al20 showed the amount of NO in the anastomosis region after sildenafil application was lower on day 3 in ischemic anastomosis as compared to normal anastomosis. NO level on day 7 was higher in the ischemic group. The authors suggest the effects of sildenafil on normal and ischemic anastomosis may depend on the phase of the inflammation. This scenario also may be valid for ischemic wounds. In the current study, the sildenafil group, according to the duration of medication, developed necrosis and abscess of the flap. Two rats from the group that received sildenafil for 10 days died on day 8 because of sepsis. The increase in inflammatory cells of the wound site on day 10 in the sildenafil group is believed to be due to abscess formation in the wound and sepsis. The excessive secretion of NO into the wound environment may be a significant factor in toxic shock formation and may be associated with increased TNF levels.

Limitations

This study is limited in that microcirculation and the tissue concentration of NO to support the conclusion they were impaired were not measured. In addition, different routes of drug usage were employed: the study group received sildenafil via the enteral route, and the control group received 0.9% NaCl via the intraperitoneal route. In order to generalize the current results, experimental and clinical studies are needed to define effective and safe dose, route of administration, and treatment duration with sildenafil for ischemic wound healing.

Conclusion

An in vivo study on ischemic skin wound healing in rats showed sildenafil reduces reepithelialization, neovascularization, and the amount of granulation tissue and inflammatory cells on day 3 of administration, increases inflammatory cells on day 10, and reduces reepithelialization at the wound site on day 10. Further research is needed to evaluate the safety, efficacy, and usefulness of oral or topically applied different doses of sildenafil alone or when combined with other therapies on ischemic wound healing. 

References

1.         Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–746.

2.         Stadelmann WK, Digenis AG, Tobin GR. Impediments to wound healing. Am J Surg. 1998;176(2A suppl):39S–47S.

3.         Derici H, Kamer E, Unalp HR, Diniz G, Bozdag AD, Tansug T, et al. Effect of sildenafil on wound healing: an experimental study. Langenbecks Arch Surg. 2010;395(6):713–718.

4.         Salcido RS. Viagra and wound healing: the NO connection. Adv Skin Wound Care. 2008;21(3):106–109.

5.         Quirinia A, Jensen FT, Viidik A. Ischemia in wound healing. I: design of a flap model — changes in blood flow. Scand J Plast Reconstr Surg Hand Surg. 1992;26(1):21–28.

6.         Sevimli-Gür C, Onbaşılar I, Atilla P, Genç R, Cakar N, Deliloğlu-Gürhan I, Bedir E. In vitro growth stimulatory and in vivo wound healing studies on cycloartane-type saponins of Astragalus genus. J Ethnopharmacol. 2011;134(3):844–850.

7.         Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012;49(1):35–43.

8.         Lazarus GS, Cooper DM, Knighton DR, Percoraro RE, Rodeheaver G, Robson MC. Definitions and guidelines for assessment of wounds and evaluation of healing. Wound Repair Regen. 1994;2(3):165–170.

9.         Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol. 2007;127(3):514–525.

10.       Isenberg JS, Ridnour LA, Espey MG, Wink DA, Roberts DD. Nitric oxide in wound-healing. Microsurgery. 2005;25(5):442–451.

11.       Çekmen M, Turgut M, Türköz Y, Aygün D, Gözükara E. Nitric oxide (NO) and nitric oxide synthase (NOS): physiologic and pathologic characteristics. T Klin J Pediatr. 2001;10(4):226–236.

12.       Kuyumcu A, Düzgün AP, Ozmen MM, Besler HT. The role of nitric oxide in trauma and infection. Ulus Travma Acil Cerrahi Derg. 2004;10(3):149–159.

13.       Moseley R, Stewart JE, Stephens P, Waddington RJ, Thomas DW. Extracellular matrix metabolites as potential biomarkers of disease activity in wound fluid: lessons learned from other inflammatory diseases? Br J Dermatol. 2004;150(3):401–413.

14.       Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. 1996;271(5 Pt 1):C1424–1437.

15.       Jamshidzadeh A, Azarpira N. The effects of topical sildenafil on wound healing in rat. Iranian J Pharm Sci. 2011;7(1):43–48.

16.       Farsaie S, Khalili H, Karimzadeh I, Dashti-Khavidaki S. An old drug for a new application: potential benefits of sildenafil in wound healing. J Pharm Pharm Sci. 2012;15(4):483–498.

17.       Sarifakioglu N, Gokrem S, Ates L, Akbuga UB, Aslan G. The influence of sildenafil on random skin flap survival in rats: an experimental study. Br J Plast Surg. 2004;57(8):769–772.

18.       Hart K, Baur D, Hodam J, Lesoon-Wood L, Parham M, Keith K, et al. Short- and long-term effects of sildenafil on skin flap survival in rats. Laryngoscope. 2006;116(4):522–528.

19.       Tsai JW, Ayubi FS, Hart KL, Baur DA, Parham MA, Moon JK, et al. Evaluation of the effect of sildenafil and vascular endothelium growth factor combination treatment on skin flap survival in rats. Aesthetic Plast Surg. 2008;32(4):624–631.

20.       Uzun H, Konukoglu D, Nuri MK, Ersoy EY, Ozçevik S, Yavuz N. The effects of sildenafil citrate on ischemic colonic anastomotic healing in rats: its relationship between nitric oxide and oxidative stress. World J Surg. 2008;32(9):2107–2113.

Potential Conflicts of Interest: none disclosed

Abstract

Pyoderma gangrenosum (PG) is an uncommon chronic and progressive skin disorder that can lead to severe tissue necrosis, pathergy, horrendous pain, and disfigurement if not properly and promptly diagnosed and treated. Systemic treatment traditionally consists of long-term immunosuppression. Topical care of the painful wound often represents a clinical challenge.

A 77-year-old woman with multiple comorbidities including venous insufficiency and diabetes mellitus was diagnosed through exclusion with refractory, painful PG. She was managed for 3 months by a multidisciplinary team comprised of an internist, 2 dermatologists, and a podiatric wound care specialist using immunosuppressive therapy, several local wound care modalities, and supportive bandages. During that time, severe wound pain continued unabated and the affected area changed from 3 separate wounds measuring 1.4 cm x 1.0 cm x .01 cm, 1.2 cm x 0.5 cm x 0.1 cm, and 0.6 cm x 0.5 cm x 0.1 cm to 1 wound measuring 8.0 cm x 10.3 cm x 0.1 cm. At that time, dehydrated human amnion/chorion membrane (dHACM) allograft, previously reported to facilitate healing venous leg and diabetic foot ulcers, was incorporated into the treatment plan. The patient reported wound pain decreased from 10 out of 10 to 5 out of 10 within hours following application. At the 4 day follow-up visit, she reported no pain; after 1 week, the wound decreased 6.4 cm x 9.4 cm x 0.1 cm in size and after 2 months (3 applications) the wound had reduced in area from 103 cm² to 57.96 cm² (reduced by more than half [56%]). In this patient, following the application of dHACM as an adjunct to immunosuppressive therapy, pain receded and wound healing commenced. Additional controlled studies are needed to ascertain the generalizability of this observation.

Pyoderma gangrenosum (PG) is an uncommon, inflammatory, destructive neutrophilic dermatosis.¹ PG may be greatly debilitating and extremely painful and can lead to pathergy (ie, wound enlargement secondary to insidious trauma), severe tissue necrosis, and disfigurement if not properly diagnosed and treated.² The pathophysiology of this disease is not well understood but thought to be initiated by an inflammatory immune response leading to the nonspecific finding of neutrophilic infiltration.¹ Although the etiology is idiopathic, 50% of PG cases have been associated with other systemic autoimmune diseases such as ulcerative colitis, Crohn’s disease, rheumatoid arthritis, and irritable bowel syndrome.³ 

Unfortunately, dermatopathologists have no pathognomonic markers to unequivocally diagnose this malady; therefore, it is a diagnosis of exclusion and usually based upon clinical presentation. According to a retrospective chart review,⁴ many clinicians misdiagnose PG with other conditions that overlap in symptoms, such as venous leg ulcers, arterial insufficiencies, vasculitis, and various polymicrobial infections. In a review of 86 cases,³ wound enlargement secondary to insidious trauma (pathergy) was shown to occur in approximately 25% to 50% of PG cases, leading to dramatic enlargement of wounds and often accompanied by severe pain.

PG may be chronic, lasting for months or even years. Although immunosuppression is the mainstay of treatment, literature reviews^5,6 show a variety of topical and systemic agents also are utilized in conjunction with local wound care. The hallmark of systemic treatment for PG remains corticosteroids and cyclosporine; however, several other regimens, used individually or in tandem, have been successful, including the use of various chimeric and human biologics.^5,6 Additionally, researchers⁷ hypothesize treatment with mycophenolate mofetil in conjunction with prednisolone may be highly efficacious and even synergetic in cases of PG. Negative pressure wound therapy (NPWT) has been widely used on patients with various wound types and has been shown to improve the rate of healing in lower extremity ulcerations.⁸ However, this modality has not been studied in PG; therefore, overall success rates as a treatment for PG are currently unknown. Other therapies, including low-dose tetracycline (for its anti-inflammatory effect) and diaminodiphenyl sulfone, also have been shown in retrospective studies⁷ to facilitate healing. Because PG often is associated with other underlying systemic issues, a multidisciplinary team approach that includes internists, dermatologists, and podiatric wound care specialists is often necessary in order to correctly diagnose and treat the condition.

Human amniotic membrane comprised of both amnion and chorion layers has been used for a number of clinical applications for more than a century.⁹ In scientific laboratory studies, the molecular fabric of this tissue has demonstrated many key functions: it provides a matrix for cellular migration and proliferation,¹⁰ contains proteins shown to reduce inflammation^11-13 and development of scar tissue, ^12,13 has antibacterial properties,¹³ and reduces pain at the site of the wound from baseline pain levels.¹² Therapies such as dehydrated human amnion/chorion membrane (dHACM) allografts (EpiFix®, MiMedx Group, Inc, Marietta, GA) have been shown in observational studies and randomized controlled trials to enhance healing of diabetic, venous, and other wounds compared to standard wound care with debridement, moist wound dressing, and compression.^14-16

Laboratory studies¹⁷ show matrices such as dHACM induce angiogenesis due to the presence of multiple proangiogenic factors found within the dehydrated tissue that retain their molecular composition. To help elucidate the potential angiogenic properties of dHACM allografts in vitro, Koob et al¹⁷ demonstrated dHACM grafts contain angiogenic growth factors that retain their biologic activity, promote amplification of angiogenic cues by inducing endothelial cell proliferation and migration, aid in upregulating production of endogenous angiogenic growth factors by endothelial cells, and support the formation of blood vessels in vivo. Additional laboratory studies¹⁸ suggest these scaffolds may foster cell-mediated regeneration of extracellular matrix while acting as a magnet for mesenchymal stem cells. These properties suggest dHACM allografts may be an effective treatment for conditions such as PG.

The purpose of this case study is to describe the care of a patient with painful PG whose wound was managed with dHACM as part of her treatment plan. The patient has given written informed consent for publication of the details of her case.

Case Report

Presentation and medical history. Ms. J is a 77-year-old Caucasian woman with a medical history that includes diabetes mellitus, hypertension, hyperlipidemia, macular degeneration, microalbuminuria, venous insufficiency, and obesity. Her past surgical history includes a 3-vessel coronary artery bypass graft, right hip replacement, right femur fracture with internal fixation, a remote history of sternal wound infection, and left shoulder surgery. Her current medications include losartan, insulin (Lantus^®, Sanofi-Aventis US, LLC, Bridgewater, NJ; and Novolog^®, Novo Nordisk, Plainsboro, NJ), indapamide, metformin, Plavix (Sanofi-Aventis US, LLC), and metoprolol.

Ms. J presented with a chief complaint of severely painful lesions on her right anterior shin of 4 months’ duration. During that time, Ms. J was told by her previous wound care specialist/podiatrist she had ulcers secondary to varicose veins. According to information obtained from the patient, previous treatments included local wound debridement, topical cadexamer iodine, foam dressings, and multilayer compression wraps. Ms. J stated the lesions initially started as “pimples” but within 1 week became open wounds. She said the pain was increasing and the wounds were enlarging despite treatment. Multiple biopsies had been performed several weeks before her first encounter with her wound care specialist/podiatrist who reported the results failed to reveal malignancy, vasculitis, or vasculopathy, although scattered neutrophillic infiltrates were observed throughout the specimens and special stains for bacteria and fungus proved negative. The fact that the wounds “grew larger” after the biopsies prompted Ms. J to seek a second opinion at the authors’ clinic.

Physical examination. Physical examination revealed 3 open ulcerative lesions with blisters at the posterior aspect of the right anterior shin. The wounds showed no signs of infection and did not probe to bone, but they were copiously draining.

The 3 separate small lesions had irregular violaceous borders and minor yellowish slough, with isolated patches of necrotic tissue (see Figure 1). No significant pitting edema was observed. Vascular examination revealed weakly palpable pedal pulses on the left and nonpalpable pedal pulses on the right lower extremities. Ms. J’s ankle brachial index was 1.3 bilaterally, typically observed in patients with diabetes mellitus with “pipe-stem” arteries and medial calcinosis.¹⁹ Signs of venous insufficiency, including hemosiderosis, lipodermatosclerosis, and torturous varicosities, were noted in both lower legs. Capillary refill was delayed. Homan’s sign was absent bilaterally. Neurological examination with Semmes-Weinstein monofilament revealed loss of protective sensation consistent with diabetic neuropathy. 

Wound management. The authors initially treated Ms. J’s wounds with an absorptive silver dressing prophylactically. Due to concerns regarding arterial vascular disease, compression was deferred and Ms. J was urgently referred to an interventional vascular specialist who performed a CT angiogram. The right leg arteriogram demonstrated scattered moderate to severe stenosis along the distal superficial femoral artery and upper popliteal artery, which was successfully treated with angioplasty alone. Ms. J was started on clopidogrel 75 mg daily in combination with 81 mg of aspirin daily post procedure. Although vascularity improved, attempts at multilayered compression were followed by intense pain and therefore discontinued in favor of lower-level compression with Tubigrip™ (Mölnlycke Health Care, Marietta, GA). Local wound management with a silver-impregnated foam dressing and selective debridement failed to garner improvement. In weekly follow-up visits over the next month, the wounds were increasing in size (see Figure 2). 

Over the next month, the ulcerations continued to enlarge (see Figure 3). Necrotic tissue/slough was treated with topical cadexomer iodine (Iodoflex, Smith & Nephew Inc, St. Petersburg, FL) and perilesional triamcinolone steroid ointment. The perilesional topical was subsequently changed to tacrolimus ointment (Protopic, Astellas Pharma US, Inc, Northbrook, IL). Low-dose doxycycline 20 mg was administered orally for its anti-inflammatory affect. Pentoxifylline (400 mg, 3 times daily) was prescribed for venous disease, and L-arginine (6 g daily) was dispensed as a final common pathway to nitric oxide. During this time, no aggressive debridement was performed due to concerns about potential pathergy. Ms. J reported severe, ongoing pain (10 out of 10). 

Diagnosis of PG. Although Ms. J clearly exhibited symptoms of venous insufficiency, treatments failed to improve the lesions and her wounds continued to worsen. A working diagnosis of PG with pathergy was formulated by the multidisciplinary team, which included an internist, 2 dermatologists, and a podiatric wound care specialist. The diagnosis of PG was developed 1 month after her initial presentation at the authors’ facility based on the following clinical picture:

1. The wounds did not respond to supportive bandaging, local wound care, and pentoxophylline.
2. The ulcers had elements of necrosis in the absence of ischemia.
3. The patient exhibited severe and unremitting pain in the absence of ischemia. Symptoms appeared to far exceed those accompanying venous disease.
4. The wounds exhibited pathergy, a symptom not observed in venous leg ulcers.
5. Biopsies were negative for malignancy, vasculitis, and vasculopathy. Special staining for bacterial or fungal infection was negative.
6. Behçet’s Disease (another disease that can cause pathergy) was ruled out based on lack of recurrent oral lesions and ocular abnormalities.

As previously stated, multiple punch biopsies were procured by Ms. J’s previous physician. The authors believe that due to the micro-trauma of the biopsies, pathergy occurred and the lesions continued to increase in size unabated. The diagnosis of PG was corroborated by multiple physicians on the multidisciplinary team.

Treatment of PG. Over the next 3 months, Ms. J received care for PG coordinated by her multidisciplinary team. Goals of care included wound healing, pain control (ie, using a fentanyl patch and hydrocodone for breakthrough pain), control of wound exudate and bioburden, and management of her diabetes and concomitant diseases. Ms. J was given a combination of systemic and local treatment for the lesions. When low-dose doxycycline proved ineffective, she was referred to a dermatologist who prescribed diaminodiphenyl sulfone, (25 mg twice daily) after it was determined Ms. J did not suffer from glucose-6-phosphate dehydrogenase deficiency (G-6-PD). Ms. J also was prescribed prednisolone (60 mg per day) initiated in divided doses with a plan to titrate the drug slowly as symptoms improved. Her blood sugars were monitored daily and determined to be under control by her internist. When the lesions failed to progress, Ms. J was referred to a tertiary medical center for pulse steroid therapy. To augment the steroids, she initially was treated with cyclosporine (100 mg, twice daily) but due to side effects (nausea and vomiting) was subsequently switched to 500 mg mycophenolate mofetil (Cellcept®, Genentech, San Francisco, CA) to further augment immunosuppressant therapy. However, this drug was discontinued as well due to untoward effects (abdominal pain and confusion). Topical and systemic therapies utilized during the course of treatment are listed in Table 1. 

Debridement was contraindicated at this time due to concomitant pathergy. With a goal to improve granulation tissue formation, decrease periwound edema, increase local blood flow, and stimulate wound contraction, NPWT was initiated when deemed safe from a pathergic standpoint (ie, use of chronic immunosuppression). This therapy was used for <1 month and garnered some improvement but was painful and therefore discontinued at Ms. J’s request.

After 3 months of treatment for PG, the wounds appeared to improve clinically (eg, drainage and periwound hyperemia decreased), but they had coalesced and continued to be extremely painful.

dHACM. At this time, to potentially help reduce inflammation and facilitate wound healing, the decision was made to incorporate advanced wound therapy in the form of a dHACM allograft, consisting of a bilayer matrix of amnion/chorion, into the treatment plan. Before initiation of dHACM, the wound measured 8.0 cm x 10.3 cm x 0.1 cm, with local necrosis and slough (see Figure 4). Because Ms. J had been receiving immunosuppressive medications, loose devitalized tissue was carefully debrided using an iris scissors and pick-up. The 7 cm x 7 cm allograft was carefully placed at the margins of the wound edge in order to promote epithelialization and keratinocyte migration while avoiding waste; the allograft was covered with an outer dressing consisting of foam, gauze, and Kerlix (Medtronic, Minneapolis, MN) that was changed daily. The inner nonadherent foam dressing and graft were left in place until Ms. J returned to the clinic 1 week later. 

At the follow-up visit, Ms. J stated that within hours after graft placement her pain had reduced substantially to 5 out of 10 and within a few days disappeared (0/10). Within 1 week, wound size decreased 6.4 cm x 9.4 cm x 0.1 cm (approximately 27%). Over the next 3 weeks, a total of 3 dHACM allografts were utilized (see Figure 5). Over the course of 2 months, wound size decreased (56%) from 103 cm² to 57.96 cm² with continued absence of pain (see Figure 6). 

Prognosis. The PG lesions continue to improve and although after 7 months Ms. J has not completely healed, wound size and pain severity have dramatically lessened. No adverse effects were observed related to dHACM. Ms. J currently is receiving 20 mg of prednisone daily; this will be titrated slowly over the next several months as symptoms further improve. 

Discussion

In the case discussed, PG initially presented as pustules and wounds that rapidly enlarged secondary to pathergy and evolved into painful ulcers. A patient-centered, multidisciplinary team approach was utilized to effect a positive outcome. Despite appropriate diagnosis involving rule-out of conditions with symptoms similar to PG and treatment, the condition of her wound remained largely unchanged until dHACM was applied.

dHACM and wound healing. The dHACM allograft represents 1 of many treatment options for refractory chronic wounds. Theoretically, these tissue grafts may help reduce pain, in large part, due to their anti-inflammatory properties,^11-13 although the act of covering nerve endings and vital structures also may play a role. The level of near immediate pain reduction reported by Ms. J after the dHACM was applied was remarkable and seemed to represent a turning point in her recovery. 

It is important to note molecular components contained in dHACM (cytokines, growth factors, cell signaling molecules, and defensins) are known to provide a framework for proper wound healing.^17,18 The authors believe these components may have helped facilitate healing in this case. Additionally, clinical studies²⁰ have shown the application of the amniotic membrane aids in providing a scaffold to properly regulate adequate levels of proteases within the wound environment. The mechanism behind this process can be deducted from corneal studies²⁰ that showed a reduction of metalloproteinase activity and an increase of tissue inhibitor of metalloproteinase with the application of amniotic membrane.

The use of amniotic membrane as a treatment for PG is not totally without precedent. In 1978, Gruss²¹ reported the use of natural amniotic membrane in a large case series of 120 patients with wounds of diverse origin. In 1 patient with PG completely resistant to all forms of treatment for 18 months, pain was relieved after commencing treatment with amniotic membrane and within 6 weeks the wound reduced in size by 66%. The present report, the first on the contemporary use of dHACM in PG, showed similar results. Current results also are consistent with studies of other wound types. Previous clinical studies have shown application of dHACM is an effective treatment option in patients with diabetic foot ulcers and venous leg wounds. Zelen et al¹⁵ conducted a prospective, randomized, single-center clinical trial to compare healing characteristics of diabetic foot ulcers treated with dHACM versus standard care including debridement, moist therapy, standardized use of Silvasorb gel (Medline Inc, Mundelien, IL)/Aquacel AG (deRoyal, Powel, TN) compression dressing, and offloading  (N = 25). After 4 and 6 weeks of treatment, the overall healing rates for dHACM were 77% and 92%, respectively, while the control group healing rates were 0% and 8.0% (P<0.001). Pain reduction was not a study outcome. Serena et al¹⁶ implemented an 84-patient multicenter randomized controlled clinical trial to evaluate the use of dHACM and multilayered compression therapy versus multilayered therapy alone (Coban^™2, 3M^™, St. Paul, MN) in the treatment of venous leg ulcers. In this study, 53 patients were randomized to receive the allograft and 31 were randomized into the control group. At 4 weeks, 62% in the allograft group and 32% in the control group demonstrated >40% wound closure (P = 0.005), a significant difference noted between the allograft-treated group and the control group at the 4-week surrogate endpoint. During the study period, 35 out of 44 patients (79.5%) in the dHACM group reported a reduction in pain from the randomization visit when dHACM was applied to the 4-week visit.

 The results of these clinical trials show dHACM is an effective treatment for the management of diabetic foot and venous ulcers. In this case study, 3 applications of dHACM also facilitated healing of a PG ulcer.

Although reduction of pain after treatment with amniotic membrane has been previously reported,^12,16,21 the exact mechanism of action for pain reduction is unknown. However, anecdotal reports of similar events with cadaveric allograft are available. More research is required to explain this phenomena.²²

Conclusion

PG is a difficult-to-diagnose, potentially serious malady that often is recalcitrant to recognized treatment regimens. In the case presented, utilization of dHACM allograft may have been the catalyst in fostering wound healing and mitigating pain. Because this is a report of 1 case, more research is required to determine the generalizability of this observation. 

References

1.         Ruocco E, Sangiuliano S, Gravina AG, Miranda A, Nicoletti G. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol. 2009;23(9):1008–1017.

2.         Harris AJ, Regan P, Burge S. Early diagnosis of pyoderma gangrenosum is important to prevent disfigurement. BMJ. 1998;316(7124):52–53.

3.         Bennett ML, Jackson JM, Jorizzo JL, Fleischer AB Jr, White WL, Callen JP. Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine (Baltimore) 2000;79(1):37–46.

4.         Weenig RH, Davis MD, Dahl PR, Su WP. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med. 2002;347(18):1412–1418.

5.         Brooklyn T, Dunnill G, Probert C. Diagnosis and treatment of pyoderma gangrenosum. BMJ. 2006;22;333(7560):181–184.

6.         Snyder R. Pyoderma gangrenosum: this condition is not common, but its diagnosis may be underutilized. Wound Care & Diabetes Q&A. 2002;21(6):75–78.

7.         Li J, Kelly R. Treatment of pyoderma gangrenosum with mycophenolate mofetil as a steroid-sparing agent. J Am Acad Dermatol. 2013;69(4):565–569.

8.         Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care. 2008;31(4):631–636.

9.         John T. Human amniotic membrane transplantation: past, present, and future. Ophthalmol Clin North Am. 2003;16(1):43–65.

10.       Koob TJ, Lim JJ, Zabek N, Massee M. Cytokines in single layer amnion allografts compared to multi-layered amnion/chorion allografts for wound healing. J Biomed Mater Res B Appl Biomater. 2015;103(5):1133–1140.

11.       Hao Y, Ma DH, Hwang DG, Kim WS, Zhang F. Identification of antiangiogenic and antiinflammatory proteins in human amniotic membrane. Cornea. 2000;19(3):348–352.

12.       Pigeon J. Treatment of second-degree burns with amniotic membranes Can Med Assoc J. 1960;83(16):844–845.

13.       Fetterolf D, Snyder R. Scientific and clinical support for the use of dehydrated amniotic membrane in wound management. Wounds. 2012;24(10):299–307.

14.       Zelen CM, Snyder RJ, Serena TE, Li WW.  The use of human amnion/chorion membrane in the clinical setting for lower extremity repair: a review. Clin Podiatr Med Surg. 2015;32(1):135–146.

15.       Zelen CM, Serena TE, Denoziere G, Fetterolf D. A prospective randomized comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502–507.

16.       Serena TE, Carter MJ, Le LT, Sabo MJ, DiMarco DT, Epifix VLU Study Group. A multi-center randomized controlled trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multi-layered compression therapy vs. multi-layer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen. 2014;22(6):688–693.

17.       Koob TJ, Lim JJ, Massee M, Zabek N, Rennert R, Gurtner G, Li WW. Angiogenic properties of dehydrated human amnion/chorion allografts: therapeutic potential for soft tissue repair and regeneration. Vasc Cell. 2014;6-10. Available at: http://dx.doi.org/10.1186/2045-824x-6-10. Accessed Augustb20, 2015.

18.       Shultz GS, Davidson JM, Kirsner RS, Bornstein P, Herman IM. Dynamic reciprocity in the wound microenvironment. Wound Repair Regen. 2011;19(2):134–148.

19.       Snyder RJ, Kirsner RS, Warriner RA, Lavery LA, Hanft JR, Sheehan P. Consensus recommendations on advancing the standard of care for treatment of neuropathic foot ulcers in patients with diabetes. Ostomy Wound Manage. 2010;56(4 suppl):S1–S24.

20.       Heiligenhaus A, Li HF, Yang Y, Wasmuth S, Steuhl KP, Bauer D. Transplantation of amniotic membrane in murine herpes stromal keratitis modulates matrix metalloproteinases in the cornea. Invest Ophthalmol Vis Sci. 2005;46(11):4079–4085.

21.       Gruss JS, Jirsch DW. Human amniotic membrane: a versatile wound dressing. Can Med Assoc J. 1978;118(10):1237–1246.

22.       Snyder RJ, Simonson DA. Cadaveric allograft as adjunct therapy for nonhealing ulcers. J Foot Ankle Surg. 1999;38(2):93–101.

Potential Conflicts of Interest: Dr. Snyder serves as a consultant for MiMedx Group, Inc, Marietta, GA.

Dr. Snyder is Director, Clinical Research and Fellowship Program; and Professor; and Mr. Ead is a first-year student, Barry University School of Podiatric   Medicine (SPM), Miami Shores, FL. Dr. Glick is a dermatologist, Margate, FL. Dr. Cuffy is Assistant Professor, Barry University SPM. Please address correspon-dence to: Robert J. Snyder, DPM, MSc, CWS, Director of Clinical Research and Fellowship Program, Barry University SPM, 7301 N. University Drive, Suite 305, Tamarac, FL 33321; email: drwound@aol.com.

Abstract

Patients with a stoma undergo physiological, psychological, and social adjustment to their new life situation. A descriptive, prospective study was conducted to assess adaptation among patients >18 years of age with a new temporary or permanent colostomy or ileostomy living in Turkey and receiving care at a participating stomatherapy unit.

The study took place between September 1, 2011, and September 1, 2012. During hospitalization and following discharge, patients with a stoma received training and counseling according to their individual characteristics and their physiological, psychological, and social needs. Each participant completed the 19-item  “Identification Form for Patients with a Stoma” at the beginning of the study to document sociodemographic and stoma characteristics. To assess adjustment to the stoma, The Ostomy Assessment Inventory (OAI-23) was administered 2 times — the first within 1 month and the second within 6 months after surgery or when a temporary stoma was closed (whichever came first). This instrument comprised 23 items regarding adaptation to the stoma using Likert-type response options (0–4 range). Total scores ranged from 10 to 92, with higher scores indicating better adjustment. The instruments were completed by stoma and wound care nurses during face-to-face interviews. Data were analyzed using the Kruskal-Wallis, Mann-Whitney, and Wilcoxon tests. Of the 135 participants, the majority (77, 57.0%) were male; 73 (54.1%) had a colostomy, and 106 (78.5%) had a temporary stoma. The primary reason for stoma creation was cancer (89, 65.9%). Mean total OAI-23 scores were 48.63 ± 13.75 at the first administration and 50.59 ± 13.89 for the second. In terms of sociodemographic factors, significant increases in mean scores from the first to the second survey time were noted among patients in the 50–69 age group, women, married persons, and unemployed persons (P<0.05). With regard to stoma characteristics, the OAI-23 scores of patients with planned stoma operations and persons with permanent stomas increased significantly (P<0.05) between assessments. Significant increases in OAI-23 scores also were noted among persons who did not receive information before the operation, patients whose stoma site was not marked, and patients who had experienced a complication (P<0.05). Postoperatively, it is important to consider sociodemographic and stoma characteristics as well as preoperative variables that may influence adaptation to stoma. Additional larger, multicentered studies with extended patient follow-up are warranted.

Stomas are commonly created in the treatment of diseases of the gastrointestinal and urinary systems.^1,2 Even though the creation of a stoma is considered a relatively simple surgical procedure, having an ostomy can adversely affect the lives of patients with a stoma and their relatives.

A significant majority of the 1 million new stomas created annually are due to colorectal cancer.^1-3 According to the literature,⁴ colorectal cancer is the third most common cause of death among males (10%) after lung and prostate cancer and the second among females (9.2%) after lung cancer throughout the world; the number of cases requiring the creation of a stoma exceeds tens of thousands each year. Intestinal stomas also are created to improve the patient’s condition and quality of life in the treatment of various diseases other than cancer, such as acute diverticulitis, rectal trauma, and inflammatory bowel disease.^5-7

According to descriptive studies and literature reviews,^8-10 patients with a stoma experience a range of physiological, psychological, and social difficulties and challenges during the postoperative period. Physiologically, patients with an intestinal stoma encounter changes in defecation habits, lack of defecation control, involuntary gas discharge, odor, dependence on a pouch, complications associated with the stoma and peristomal area, changes in daily living habits, and deterioration in sleeping habits or the sleeping process.

Descriptive and prospective studies and literature reviews^11-15 addressing quality of life, image, sexuality, and living with stoma in patients with a permanent or temporary ostomy have shown the change in physical appearance and problems encountered may cause patients to experience psychological problems such as anxiety, depression, loneliness, thoughts of suicide, and deterioration in body image and self-respect. According to a descriptive, prospective study by Silva et al¹⁶ among 25 patients (18 ileostomy, 7 colostomy; median of 8 weeks since surgery, range 6–16 weeks), stoma care self-efficacy, stoma acceptance, interpersonal relationships, and location of the stoma were strongly associated with adjustment. In Simmons et al’s¹ prospective study among 51 patients who had a stoma for at least 6 months, patients perceived themselves to be socially different from others and were embarrassed by their condition; they deliberately avoided and feared social relations. These studies that investigated problems of stoma patients in the postoperative period also reported patients experienced a deterioration in their relationships due to the change in their body image and the new lifestyle limitations associated with their stoma^{11,12,14,18-21}; these studies also have shown behaviors such as getting together with family and friends less frequently, quitting or changing their jobs, decreasing work hours, and limiting social activities, including traveling and entertaining, can be observed postoperatively in patients with a stoma.

In a descriptive, prospective study conducted by Mahjoubi et al²² among 155 Iranian patients with a stoma and in a qualitative study performed by Karabulut et al²³ investigating the effects of planned group interactions on social adaptation in 50 patients with stoma, it was determined that in order to cope with their problems, patients with a stoma needed to adjust physiologically, psychologically, and socially to their condition, to stoma care, and to a life with a stoma before and after surgery. A descriptive, prospective study by Karadağ et al¹⁹ evaluated the quality of life of 43 patients with a permanent colostomy, and it was determined the physiological problems experienced by patients with a stoma can be reduced substantially through appropriate care, training, and counseling provided in a hospital setting by stoma and wound care nurses. However, these studies also noted that psychological, social, and sexual problems can continue to persist in certain stoma patients. Understanding and assessing the psychosocial issues or problems ostomates face is important for the provision of appropriate interventions to decrease difficulties adjusting to the stoma.

Stoma and wound care nurses play an important role in assessing and facilitating the adjustment process of patients with a stoma.^20,23 Assessing the individual’s adaption to living with a stoma and specific factors influencing adjustment is crucial to nurses fulfilling these responsibilities comprehensively and accurately. Even though many studies on identifying problems experienced by stoma patients have been published,^{9,10,12,13,21} research into what determines a patient’s level of adjustment to the stoma and ways to enhance adjustment remain limited.^17,23,24

In Turkey, few studies have been conducted thus far assessing patients’ adjustment to their stomas. Karabulut et al’s²³ quasi-experimental investigation found 6-week, planned group interactions (ie, interactions conducted among several individuals with a stoma focusing on adjustment to and living with stoma) effectively enhanced the social adjustment of patients with a stoma.

The purpose of this descriptive, prospective study was to assess variables that may affect adaptation of patients living with a colostomy or ileostomy within the first 6 months following surgery. In this study, the participants’ sociodemographic properties and stoma-related attributes were investigated. 

Methods and Procedures

Study sample and design. The study sample included patients with a stoma that accepted an invitation to participate in the research and who were monitored in the stomatherapy units of 7 hospitals in Turkey that 1) maintained the necessary patient records and 2) employed stoma and wound care nurses. Meetings were conducted with the stomatherapy units to introduce the study, and the study procedures were reiterated at the units that agreed to participate. Inclusion criteria stipulated participants: 1) had a colostomy or ileostomy created between September 1, 2011 and September 1, 2012; 2) were at least 18 years of age; and 3) had voluntarily agreed to participate in the study. 

Study instruments.

Identification Form for Patients with a Stoma. Investigators developed a 19-item instrument based on a review of the literature.^12,16,25 The form consists of 2 main sections: 10 questions on sociodemographic characteristics of the patients (including age, gender, marital status, educational status, and level of income) and 9 questions on the individual’s stoma type, reason for stoma creation, length of time with the stoma, stoma care, and status of complication development.

Ostomy Adjustment Inventory-23 (OAI-23). This self-evaluation scale, composed of 23 items across 4 subfactors, was developed by Simmons et al²⁶ to determine levels of adaption among patients with stomas. Each item is evaluated on a Likert-type scale with a score range of 0–4, with a higher score indicating better adaptation. Total adjustment scores range from 10 to 92. Twelve (12) items on the scale (items 2, 5, 7, 8, 10, 11, 12, 13, 16, 17, 18, and 21) present respondents with negative sentences and are reverse scored (see Figure 1). In a study of the scale’s validity and reliability with 570 stoma patients, the OAI-23’s Cronbach’s  was found to be 0.93 and its test-retest correlation coefficient (r) was 0.83.²⁶

This scale was translated to Turkish by Karadag et al.²⁷ The validity and reliability of the scale were measured in a Turkish sample of stoma patients,²⁷ and the test-retest correlation coefficient (r) was 0.76.

Study procedure. All units were under the leadership of Turkish Association of Wound Ostomy Incontinence Nurses; each unit is owned by a different hospital in Turkey. The Association provided written permission to conduct the research, and patients provided verbal consent to participate. During hospitalization and following discharge, patients with a stoma were provided training and counseling according to their individual characteristics and their physiological, psychological, and social needs by stoma and wound care nurses. Each participant was evaluated once with the Identification Form for Patients with a Stoma at the beginning of the study. The OAI-23 was administered twice to assess adjustment in participants: the first time within 1 month of the stoma operation and the second time within 6 months of stoma creation or immediately before the stoma was closed in persons with a temporary stoma. Study data were collected through face-to-face interviews with patients by stoma and wound care nurses working in participating hospitals; these patients had received periodic training, care, and consultancy services from these nurses at the hospitals where they were monitored. Stoma and wound care nurses read the questions on the data collection forms; patient answers were recorded in the forms and all data forms were mailed to the principle researcher for statistical analysis.

Data analysis. The data obtained in the study were analyzed using SPSS for Windows, Version 20.0 (SPSS Inc, Chicago, IL, USA). Number and percentile calculations and Kruskal-Wallis, Mann-Whitney, and Wilcoxon tests were performed. The Kruskal-Wallis test and the Mann-Whitney U-test were used to compare the differences between the patients’ mean adjustment scores according to their sociodemographic characteristics and the characteristics of their stoma during the time of the first and second assessments. The Wilcoxon test was used to compare the differences between the patients’ mean adjustment scores according to their sociodemographic characteristics and the characteristics of their stoma at the 2 different assessment times. 

Results

One hundred, thirty-five (135) patients (mean age 51.56 ± 15.49 years, 77 [57.0%] male) agreed to participate. One hundred, six (106, 78.5%) were married, 49 (36.3%) were primary school graduates, 45 (33.3%) were secondary school graduates, 21 (15.6%) were university graduates; and 78 (57.8%) were not working. More than half (74, 54.8%) perceived they were in the middle income range,  and the majority (124, 91.9%) lived with their families (see Table 1).

Eighty-nine (89, 65.9%) had a stoma created due to cancer. The majority of stomas created were colostomies (73, 54.1%). One hundred, six patients (106, 78.5%) had a temporary stoma. Stomas were created in a planned (nonemergent) manner for 104 patients (77%), 123 (91.1%) received information from a stoma and wound care nurse or surgeon before stoma surgery, and 86 (63.7%) had their stoma site marked by a stoma and wound care nurse. A little more than half (68, 50.4%) of study participants did not care for their stoma by themselves. The majority (115, 85.2%) did not experience stomal or peristomal complications (see Table 2).

The average OAI-23 scores were 48.63 ± 13.75 for the first round and 50.59 ± 13.89 for the second assessment. Although the mean scores of patients increased, the difference in scores was not statistically significant (P >0.05) (see Table 3). 

When mean scores on the inventory were examined in relation to the participants’ sociodemographic characteristics, the average scores of patients in the 50–69 age group, women, those who were married, and those who were unemployed were found to increase significantly over time (P<0.05).

No statistically significant differences were observed in the adjustment inventory scores of the patients according to their education level, income level, and the persons they lived with (P>0.05) (see Table 4). 

The OAI-23 scores of patients with planned stoma operations increased from 48.12 ± 13.43 to 50.73 ± 13.96 and with permanent stomas from 49.10 ± 15.48 to 56.04 ± 10.54 (P<0.05). After the second OAI-23 administration, the mean scores of patients with a permanent stoma (56.04 ± 10.54) were significantly higher than those of patients with a temporary stoma (49.38 ± 14.29) (P<0.05; see Table 4). The average scores of patients who did and did not receive information before stoma surgery increased from 48.99 ± 14.09 to 50.58 ± 14.42 and from 45.30 ± 9.69 to 50.66 ± 7.95, respectively; however, only the increases among persons who did not receive information before the operation were significant. Likewise, only OAI-23 mean scores in patients whose stoma site was not marked increased significantly over time (from 47.10 ± 12.28 to 52.93 ± 16.65; P<0.05) (see Table 4).

At the first questionnaire administration, the scores of patients who experienced stomal or peristomal complications were lower than patients who had not experienced complications; however, increases in adjustment scores in the second evaluation were more pronounced for patients who had experienced a complication (P<0.05) (see Table 4).

Discussion

Mean scores of participants on the OAI-23. In this study that aimed to assess the social adjustment of 135 patients with a stoma, the mean scores for the OAI-23 and its subdimensions demonstrated only limited change over the short study period. This finding is consistent with that of several studies assessing adjustment in stoma patients. In Cheng et al’s²⁸ interventional study in which 92 colostomy patients were provided an Expert Patient Program (EPP) for 3 weeks, the mean adjustment inventory score increased from 47.59 before program participation to 53.37 after completing the program. The EPP included knowledge, stoma care self-efficacy, self-management, and psychosocial adjustment in patients who had a permanent colostomy. In a qualitative study performed in patients with stoma (N = 50) by Karabulut et al,²³ the mean OAI-23 of patients in the study group was lower before planned group interactions for 6 weeks of sessions designed to enhance the adjustment to and living with a stoma in ostomy patients (53.04) and gradually increased following group meetings (70.91); however, no significant changes were noted in the scores of persons in the control group, whose averages were 51.07 and 53.07 at first and second evaluation, respectively.

Several previous investigations have reported high adjustment scores among patients with a stoma. Simmons et al²⁶ randomly selected 570 persons with a colostomy, ileostomy, or urostomy with complete records from 3 national databases and found their mean adjustment score was 63.81. In a descriptive, experimental study by Martin,²⁹ the adjustment scores of 20 patients (12 experimental group, 8 control group) with recent stomas in the sixth and eighth postoperative weeks were 82.42 in the experimental group and 78.58 in the control group. In their review article on ostomies in cancer patients, Hurny and Holland³⁰ observed stomas led to anxiety and made it more difficult for patients to adapt to their new lives, thus extending their adjustment process and period. Adjusting to an ostomy is affective (ie, requires changes in the individual’s interest, attitude and emotions toward living with stoma); a slow, gradual progression over time is expected. Moreover, many factors influence adjustment to a stoma. Within this context, the adjustment of patients with a stoma can be expected to vary according to these different variables. 

Participants’ sociodemographic attributes.

Age. Sociodemographic variables such as age, gender, education, and occupation have been found to influence adjustment to a stoma.^12,31 The current study demonstrated the mean adjustment scores of patients 29 years old or younger decreased over time, while scores of patients in the 30–69 age group increased. In a cross-sectional study by Piwonka and Merino³¹ that studied the influence of age on social adjustment among 60 patients with a stoma, the most salient factors affecting adjustment to a stoma in patients under 62 years were the amount of time since the operation, body image, social support, and a low number of postoperative complications. The most relevant factors for patients 62 years of age and older were being able to take care of the stoma and body image. Many external factors are thought to influence adjustment in young and middle-aged patients, but as patients get older, external factors influencing adjustment have been known to decrease, with only the status of the disease and being able to assume care remaining important.²³

Gender. In this study, the adjustment scores in the first OAI-23 assessment were lower in women than men; however, in the second assessment, the men’s scores remained unchanged, while women’s gradually increased and the difference between adjustment scores was statistically significant (P = 0.002). In a descriptive study by Karadağ and Baykara³² on 126 patients with a stoma, 35.7% of women and 58.4% of men reported the stoma made them dependent or semidependent (P<0.05) on others. Thus, the findings regarding the faster rate of adjustment to the stoma in women, relative to men, were expected.

Education and income status. Although mean scores increased over time depending on patient level of education and income and living status (ie, alone or with parents), the differences were not statistically significant (P>0.05) (see Table 4). When these factors were examined in relation to patient characteristics associated with the stoma, adjustment scores did not appear to change according to stoma type, although they increased over time, if not significantly (P>0.05) (see Table 4).

Working status. In the current study, the initial OAI-23 scores of unemployed patients were significantly lower than those of employed patients. These scores increased significantly in subsequent evaluation of adjustment (P<0.05). From these results, the authors inferred unemployed patients may have a tendency to constantly focus on their ostomy and hence may require a longer period to effectively adjust to their stoma

Marital status. Current results indicated significant improvements in adjustment among married patients over time. Support from one’s partner has been identified as being a contributing factor to adjustment.²⁴ Social support provided by an individual’s family, children, or friends also had a positive influence on adjustment.³¹ In a descriptive study (N = 30), Altschuler et al³³ found performing care together with one’s partner has a positive impact on psychosocial adjustment. Having a stoma presents a social issue that influences not only patients with the stoma, but also their partners, families, and close circles. Support from a partner is highly important to an individual’s adjustment to a stoma.

Stoma-related attributes.

Preoperative preparation. The study found the initial mean adjustment scores of patients who were informed of the stoma operation and whose stoma site was marked were higher than those of patients who were not informed of the surgery and whose stoma site was not marked before surgery. Additionally, the current study reported adjustment in patients who underwent a planned operation and in persons who were not informed of the operation increased significantly with time (P<0.05). In a clinical study conducted by Person et al³⁴ on 105 patients with a stoma (60 men, 45 women), quality of life and independence increased over time among patients whose stoma site was marked and their complications decreased significantly over time. Educating patients during the preoperative and postoperative stages of life about the stoma and its care and marking the site before surgery appears to facilitate acceptance of the stoma and adjustment to the postoperative process.

In a multicenter, retrospective, descriptive study (N = 748) conducted by Baykara et al³⁵ involving individuals who underwent stoma site marking, the rates of peristomal complications were found to be significantly lower compared to individuals with no preoperative stoma site marking. The current authors believe stoma site marking will directly and indirectly increase adaptation. Thus, the low OAI-23 scores of patients whose stoma site was not marked before the operation was an expected finding.

Stoma type. The mean inventory scores of patients with a permanent stoma in the first and second evaluations were higher than those of patients with a temporary stoma (P <0.05). According to Karabulut et al,²³ patients with a permanent stoma may make an effort to adjust more quickly because they know they will be experiencing this condition for the rest of their lives, whereas patients with a temporary stoma — aware the condition is temporary and the stoma will be closed — may not feel the need to adjust as urgently. As such, decreases in the OAI-23 scores from first to second measurement were anticipated. The literature^26,31 notes characteristics of the stoma such as stoma duration, stoma type, and nature (ie, temporary or permanent) are among the variables most likely to affect adjustment. In Wade’s²⁴ study on patients with colostomies, the incidence of depression was higher in patients with a temporary stoma (13%) compared to patients with a permanent stoma (6%). The authors believe the large majority (78.5%) of individuals with a temporary stoma in the current study might have negatively affected the mean OAI-23 score.

Stomal problems. Approximately 14.8% of the stoma patients in the study experienced stomal/peristomal complications (see Table 2). The rate of stomal/peristomal complications was measured at 32.8%, 35%, 24.1%, and 48%, respectively, in a retrospective descriptive study by Karadağ³⁶ (N =128), a prospective, descriptive study by Ratliff et al³⁷ (N = 220), a retrospective, descriptive study by Akçam et al³⁸ (N = 120), and a retrospective study by Özaydın et al³⁹ (N = 96). Stoma complications have been known to vary between 10% and 70%.³ In the current short-term study, although patients who experienced stomal and peristomal complications scored comparatively low on the OAI-23 first measurement, they showed marked improvements in adjustment when assessed at a subsequent point in time (second measurement). Descriptive, prospective studies^6,40 in the literature demonstrated stomal and peristomal complications adversely impact adjustment to and living with the stoma.

Among patients experiencing stomal/peristomal complications in the current study, persons whose stoma care was performed by someone else scored the lowest on the OAI-23 initially (43.31). However, their scores increased significantly by the final assessment (55.68; P<0.05). Previous research^26,31 shows many factors (such as status of performing stoma care, body image perception, amount of social support, the period following the surgery) influence the extent to which patients are able to adapt to the stoma. In their 4-year longitudinal study of 59 stoma patients and 64 bowel-resected nonstoma patients, Bekkers et al⁴¹ observed adjustment scores and the provision of stoma care were significantly affected by the occurrence of stoma-related complications within the 4 months following the creation of the stoma. In cases where no complications were observed, adjustment to the stoma was reported to take 2 years or longer, which could be extended by complications.

As these results and the literature demonstrate, many factors potentially enhance or inhibit adjustment among patients with a stoma. Furthermore, the relationships among these various factors significantly influence adjustment to the stoma. At times, many different factors can simultaneously influence a contributing factor. Given this information, an individual’s adjustment to the stoma may be influenced by the sum of his or her experiences rather than a single determinant.

Limitations

The main limitations of the present study were its relatively small sample size and short monitoring period of adjustment (6 months) — the authors were not able to observe the long-term adjustment of patients with a stoma. Therefore, the generalizability of the results obtained may be limited.

Conclusion

The results of this study suggest patients start adjusting to living with an intestinal stoma after surgery. Many factors, such as preoperative information, the ability to perform care, and countermeasures against stomal and peristomal complications, influence adjustment.

It is also essential for training and supportive services to be individually tailored to patients according to their characteristics and physiological, psychological, and social needs. Stoma care nurses should be alert to risk factors for less-than-optimal adjustment. For example, in this study, it was determined that factors such as age, gender, marital status, working status, chemotherapy/radiotherapy applications, planned/emergent operation, being informed before the operation, stoma site marking, complications, stoma care, and temporary/permanent stoma had a statistically significant effect on the OAI-23 score. It also was determined that the educational status and income level did not have an effect on the OAI-23 score.

Multicentered studies with larger populations should be conducted. Ostomy patients should be monitored in the postoperative 6 months, 1 year, and for longer periods to assess social adjustment. n

References

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Potential Conflicts of Interest: none disclosed

Dr. A. Karadağ is Professor, School of Nursing, Koç University, İstanbul, Turkey. Dr. Karabulut is Assistant Professor, Department of Nursing, Faculty of Health Science, Nuh Naci Yazgan University, Kayseri, Turkey. Dr. Baykara is a lecturer, Department of Nursing, Faculty of Health Science, Gazi University, Ankara, Turkey. Dr. Harputlu is a lecturer, Department of Nursing, Faculty of Health Science, İzmir University of Economics,  İzmir, Turkey. Ms. Toyluk is a Stomatherapy Unit Enterostomal Therapy Nurse, Istanbul University Cerrahpasa Hospital, Istanbul, Turkey. Ms. Ulusoy is a Stomatherapy Unit Enterostomal Therapy Nurse, Uludag University Hospital, Bursa, Turkey. Ms. S. Karadağ is a Stomatherapy Unit Enterostomal Therapy Nurse, Turkey High Specialization Education and Research Hospital, Ankara, Turkey. Ms. Kahraman is a Stomatherapy Unit Enterostomal Therapy Nurse, Ege University Hospital, Izmir, Turkey. Ms. Hin is a Stomatherapy Unit Enterostomal Therapy Nurse, Gazi University Hospital, Ankara, Turkey. Ms. Altinsoy is a Stomatherapy Unit Enterostomal Therapy Nurse, Istanbul University Capa Hospital, Istanbul, Turkey. Ms. Akil is a Stomatherapy Unit Enterostomal Therapy Nurse, Çukurova University Hospital, Adana, Turkey. Dr. Leventoğlu is an Associate Professor, Gazi University Faculty of Medicine, Department of Surgery, Colorectal Cancer Surgery. Please address correspondence to: Zehra G. Baykara, RN, PhD, Gazi Universitesi Sağlık Bilimleri Fakültesi Hemşirelik Bölümü, Emniyet Mah, Muammer Yaşar Bostancı Cad, No: 16, PK: 06500 Beşevler/Ankara, Turkey; email: gocmenzehra@yahoo.com.

Abstract

Lower extremity ulcers in patients with diabetes mellitus may take a long time to heal despite the use of advanced topical therapies. A retrospective review of cases was conducted to assess the use of a dehydrated amniotic membrane allograft (DAMA) in a convenience sample of 9 wounds in 8 patients (5 men, 3 women, average age 62 years [range 31–81 years]) with diabetes mellitus and/or vascular disease.

Wound data and patient characteristics were abstracted from medical records. Descriptive statistics were used to summarize the data. In 5 of 9 wounds, DAMA was applied after a failure to demonstrate a 50% reduction in area after 4 weeks of treatment with advanced wound care, offloading, and compression as indicated. In 4 wounds, DAMA was applied 2–4 weeks after presentation because of concerns about existing patient risk factors for nonhealing. Wounds were present for an average of 11 weeks (range 1–35 weeks) before application of DAMA. Mean baseline wound area and volume were 3.11 cm² (± 3.73) and 0.55 cm³ (± 0.58), respectively. All wounds healed in an average of 5.7 (± 2.9) weeks (range: 1–9 weeks) after a mean of 2.7 applications (± 1.7) (range 1–5 applications). No adverse events occurred. These observations suggest prospective, randomized, controlled clinical studies to compare the use of DAMA to other topical treatment modalities are warranted.

Results of a meta-analysis¹ suggest diabetic foot ulcers (DFUs) are notoriously hard to heal. The prolonged healing time associated with DFUs puts patients at increased risk for morbidity, infection, hospitalization, and amputation.^2,3 Consensus recommendations³ outline standard treatment that includes management of underlying disease, wound debridement, infection control, and offloading.

Unfortunately, despite the use of recommended wound management strategies, clinical studies^1,4 have shown many DFUs are slow to heal. A meta-analysis of clinical trial data by Margolis et al¹ reported healing rates of 24.2% at 12 weeks and 30.9% at 20 weeks. Post-hoc analysis⁵ from 2 randomized controlled trials found the proportion of DFUs healed at 12 weeks was 57% and 52%, respectively. More recently, control groups using standard care collagen-alginate dressing or saline-moistened gauze as a comparison in randomized controlled clinical trials of cellular and/or tissue-based products (CTPs) for the treatment of DFUs found healing rates of 30% to 35% at 4 and 6 weeks, respectively,⁶ and 18.3% at 12 weeks.⁷

Compounding factors may allow patients to progress from neuropathy and diabetes to amputation. The importance of healing DFUs rapidly and avoiding this progression is underscored by the fact DFUs precede 85% of all nontraumatic lower extremity amputations, and 5 years post-lower-extremity amputation the mortality rate is 45%.^8,9 As shown by a cross-sectional study¹⁰ of adult patients with diabetes treated in a tertiary foot clinic who had foot ulcers within the preceding 2 years (N = 104), delayed healing also can decrease patient mobility and negatively impact quality of life.

With respect to time to healing, a retrospective analysis of data from 2 randomized controlled trials (N = 120) noted a 50% reduction in wound area at 4 weeks as a critical cut-off point for evaluating DFU treatment success. Thus, with a primary goal of rapid wound closure to reduce the risk of complications and improve outcomes, based on the healing rates previously stated and further post-hoc and economic analyses of clinical trial data, the use of advanced wound care modalities such as CTPs is recommended if wound area is not reduced by 50% after 4 weeks of standard care with moist wound healing and offloading.^3,11,12

Amniotic tissue has been used to treat a variety of wounds due to the many characteristics that make it suitable for use in tissue engineering. In vitro studies show amniotic tissue contains growth factors and biological macromolecules and possesses nonimmunogenic¹³ and anti-inflammatory¹⁴ properties. Pregnancy often is referred to as an immunological paradox based on the “immune privilege” of the placental organ due to the low risk of immune rejection.¹⁵ A review¹⁶ of the properties of amniotic membrane notes placental membrane cells do not express MHC Class II antigens, which are responsible for immunologic rejection of allografts in humans. In addition to the absence of MHC Class II molecules, recent in vitro scientific research16 suggests placental membranes secrete compounds that may actively mask the placenta and the fetus from immunological detection by the maternal cells.

AMNIOEXCEL® (registered trademark of BioD, LLC made available by Derma Sciences Inc, Princeton, NJ) is a dehydrated amniotic membrane allograft (DAMA). DAMA is derived from the innermost layer of the placental sac that surrounds the fetus in the womb. DAMA is processed by BioD, LLC via a proprietary DryFlex® technique to make it easy to handle and conform to the wound bed immediately upon application without the need of prior hydration.

In vivo and in vitro studies show DAMA supports wound healing.^17-19 Its mechanism of action is based on the ability of amniotic membrane to provide a natural matrix for cellular attachment and assist in cell migration and proliferation.¹⁶ In vitro studies^17,20,21 demonstrate reconstruction of the wound is mediated through regenerative cytokines, including epithelial growth factor, transforming growth factor-beta, fibroblast growth factor, and platelet-derived growth factors alpha and beta, which stimulate protein and collagen synthesis, collagenase activity, and chemotaxis of fibroblasts and smooth muscle cells. Because amniotic tissue contains growth factors and biological macromolecules in addition to its nonimmunogenic,¹³ anti-inflammatory,¹⁴ and antibacterial²² properties, it may play a role during the inflammatory, proliferation, and maturation phases of wound healing.²¹

The objective of this retrospective case series was to assess the clinical experience of using DAMA in a variety of wounds using a convenience sample of 9 challenging wounds in patients with comorbidities that impact healing (eg, diabetes mellitus, vascular disease) and/or have ceased to heal using other advanced wound care modalities.

Methods

Data from patients with lower extremity wounds treated between November 2013 and August 2014 at Wayne Memorial Wound Healing and Hyperbaric Center were collected retrospectively based on a convenience sample and as such followed no specific inclusion or exclusion criteria. All patients included in this series provided informed consent for the use of their information for educational and research purposes. IRB approval was obtained from the Wayne Memorial Hospital Institutional Review Board.

Standard care. The Center follows wound care guidelines/algorithms that are proprietary to Healogics Inc (Jacksonville, FL). The guidelines and algorithm are based on Sheehan et al’s²³ findings from a prospective randomized controlled trial involving patients with DFUs (N = 203). The study found wounds that failed to demonstrate a 50% wound reduction after 4 weeks of treatment are unlikely to heal. Wound care is directed by a physician and follows the basic tenets of proper chronic wound care, including nutritional support, debridement, bioburden control, and the use of dressings that support moist wound healing. Specific situations will determine if multicomponent dressings are selected for the management of bioburden, infection, or pain in addition to the use of offloading and compression therapy as appropriate. In general, treatment choices were based on the wound and patient characteristics combined with the physician’s discretion.

Wounds referred to the center are usually challenging (eg, long duration, limited response to previous treatments, and patient comorbidities such as diabetes mellitus, vascular disease, atypical dermatologic conditions); thus, first-line treatment includes advanced dressings such as silver dressings, negative pressure wound therapy (NPWT), and protease-modulating dressings. For wounds that do not demonstrate a 50% reduction after 4 weeks of treatment, the next treatment option is CTPs. 

Use of DAMA. DAMA was a newly available CTP at the Center. It was used in the first 5 patients whose wounds failed to demonstrate a 50% reduction in area after 4 weeks of treatment with advanced wound care, offloading, and other care. Following this initial experience with DAMA, it was applied 2–4 weeks after a wound presented in 4 additional patients whose risk factors (eg, the presence of comorbidities, vascular status, and overall health status) deemed quick wound closure a priority to assess where this new treatment option best fit in the treatment algorithm.

Procedure. Before DAMA application, the wound received sharp debridement to ensure it was free of necrotic tissue, detritus, and nonviable tissue and to assess for clinical signs and symptoms of infection (eg, heat, pain, redness and swelling, delayed healing, friable granulation tissue, and so on).³

DAMA is stored at room temperature and is ready to use directly out of the package. The allograft membrane was carefully removed from the sterile package and trimmed to size, if necessary, to overlap the wound margins by approximately 1 mm. Once the membrane was placed in the wound, it self-adhered. A moistened cotton swab was used to remove any air bubbles. In the case of dry wounds, extra moisture (saline) was added to the wound bed by a single dose vial using a quantity sufficient to hydrate the entire graft (after the graph was secure) to help achieve optimal moisture balance. A nonadherent dressing was placed over the membrane (eg, a silicone contact layer) followed by a secondary dressing to absorb exudate (eg, foam dressing).

DAMA was applied every 2 weeks. One week following application, the wounds were assessed for signs of infection and the secondary dressings were changed. At each dressing change, wounds were measured with a ruler (length, width, and depth), photographed, and assessed per wound appearance (eg, percent of granulation tissue, visual inspection for signs of infection mentioned previously). All treatment plans were documented in the patient’s electronic medical file. Wound management included compression or offloading as needed based on best practice and physician discretion. All patient data were entered into i-heal™ Electronic Health Records Program 2.0 (Healogics Inc, Jacksonville, FL), which calculates area and volume.

Data collection and analysis. Demographics and patient and wound characteristics, including measurements, were manually abstracted from the patients’ medical records. Wound closure was defined as a wound that was reepithelialized, did not have any wound drainage, and did not require a dressing. Using Microsoft Excel, wound area and volume changes were calculated using descriptive statistics. Percent area reduction (PAR) and volume reduction at each time point were calculated using the difference from baseline divided by baseline measurement and multiplied by 100. 

Results

Eight (8) patients (average age 62 years, range 31–81 years; 5 men; 3 women), with 9 wounds were included in the case series. The patients had a variety of comorbidities including diabetes mellitus, vascular disease, coronary artery disease, kidney disease, hypertension, and dyslipidemia. The patients’ wounds were present for an average of 11 weeks (range 1–35 weeks) before application of DAMA, and mean baseline wound area and volume were 3.11 cm2 (± 3.73) and 0.55 cm3 (± 0.58), respectively (see Table 1).

Area and volume reduction. In all cases, wounds showed marked improvement, including an increase in the appearance of red, healthy granulation tissue and a decrease in wound size within 2 weeks of the first application of DAMA. By 4 weeks (1 or 2 applications), mean wound volume decreased from 0.48 cm3 (± 0.60) to 0.14 cm3 (± 0.23), an 85.6% (± 13.72%) volume reduction. Similarly, mean wound area decreased from 3.19 cm2 (± 3.93) to 1.38 cm2 (± 2.32) in 4 weeks, a 71.0% (± 6.29%) mean PAR (see Figure 1). 

Time to wound closure. The wounds closed in an average of 5.7 (± 2.9) weeks (range: 1–9 weeks) after a mean of 2.7 applications (±1.7) (range 1–5 applications) (see Table 2). All wounds were closed within 9 weeks.

Subset analysis: pretreatment comparison. Wound measurement data were available for the weeks before DAMA application for 5 of the 9 wounds (cases 3, 4, 5, 6, and 8), allowing for comparison of the PAR achieved before and after the application of DAMA in this subset of patients. In these 5 wounds, the mean area reduced from to 5.06 cm2 (± 5.45) to 2.88 cm2 (± 3.21), representing a mean PAR of 43.1% (± 29.2) for the 6 weeks before DAMA application, compared to a mean decrease from 2.88 cm2 (± 3.21) to 0.50 cm2 (± 2.31) after initiating DAMA, representing an 82.6% (± 11.5%) PAR for the 6 weeks following DAMA application. The lack of closure before DAMA, despite the use of a variety of advanced wound care modalities including dressings, NPWT, and advanced skin and tissue substitutes, was noted. In many cases, patients had tried several advanced strategies with little or suboptimal response.

The following 2 cases are described in detail to provide representative examples of the cases included in this series.

Case Reports

Case 1 (Patient 1). In January 2014, 60-year-old Mr. B, (not his actual initial) who had a history of type 2 diabetes and end-stage renal disease, presented with infected bilateral heel wounds. They were surgically debrided and treated with local wound care and IV antibiotics. He was discharged from the hospital on February 27, 2014 with NPWT for postsurgical wound management and was to remain nonweight-bearing. On March 4, 2014, he presented to the wound care clinic for his first postsurgical assessment where 2 additional wounds similar to the original were noted. His clinicians decided this was a good opportunity to investigate how DAMA compares to standard wound care (NPWT); the first DAMA was applied to one of the wounds (left heel) 1 week later. At that time, the wound measured 3.5 cm x 4 cm x 0.1 cm and was granular and clean (see Figure 2a). Within 2 weeks, 40% PAR was noted (see Figure 2b) and the wound continued to progress to closure at 8 weeks (see Figure 2c). By contrast, the wound treated with NPWT (right heel) with similar wound protocol as previously described decreased very slowly to its smallest size of 3.0 cm x 3.8 cm x 10.1 cm 3 weeks after initiating NPWT then increased again and plateaued at a size of 4 cm x 5.3 cm x 0.2 cm at weeks 16–20, at which point NPWT was stopped due to a lack of progress. Meanwhile, as of September 2014, the wound closed using DAMA remained closed. However, this comparison should be interpreted with caution because the wound treated with NPWT was larger at 

baseline (15.9 cm2 versus 11.0 cm2).

Case 2 (Patient 3). Mr. D (not his actual initial), a 64-year-old patient with well-controlled diabetes and a history of chronic venous and arterial disease and recurrent ulcerations over the past 5 years, presented with a full-thickness venous leg ulcer on his right medial malleolus. The wound had developed 5 months prior and had been treated at another facility with topical antimicrobials and compression stockings. At presentation, the wound bed was covered with 100% slough and bioburden as determined by clinical and visual inspection and measured 3.8 cm x 1.5 cm x 0.2 cm. Following surgical debridement, the wound bed remained fibrotic, with slight periwound erythema and tenderness to palpation. Wound treatments included high-grade multilayer compression wraps and a bilayered bioengineered skin substitute, which was used 5 times over 14 weeks without a great deal of impact on wound healing. After a lack of marked progression following 2 months of advanced treatments, DAMA was applied at week 35 (see Figure 3a) and compression therapy was continued. DAMA was applied every 2 weeks with a total of 3 applications. At 4.5 weeks, marked improvement was noted with a decrease in wound size from 3.0 cm x 0.7 cm x 0.2 cm to 1.0 cm x 0.3 cm x 0.2 cm, which represented a 85.7% PAR (see Figure 3b). The wound closed after 7 weeks using DAMA (see Figure 3c). 

Discussion

In all 9 wounds, despite slowed or absent improvement with regular wound care or use of multiple advanced modalities such as NPWT and other CTPs, the application of DAMA resulted in healing. In addition to the average 71.0% PAR noted at 4 weeks, all wounds achieved closure within 9 weeks, with an average time to closure of 5.7 weeks. This is particularly important in wounds in which healing has stalled or slowed or where risk factors, such as diabetes mellitus and vascular disease, make expedient closure a priority.

Data on the use of CTPs in difficult-to-heal wounds demonstrate similar or decreased rates of healing. Notably, in a large randomized prospective trial24 of 208 patients with DFUs, 56% of wounds were healed at 12 weeks. This is similar to the rates seen in other randomized controlled trials7,22,23 of DFUs with healing rates of 30% to 56% at 12 weeks based on almost 300 wounds total. In addition, randomized controlled trials involving more than 300 patients with venous leg ulcers reported healing rates of 47% to 63% at 6 months with CTPs.25,26

Two recent case studies18,27 describing CTPs derived from placental tissue used in venous and DFUs in a total of 7 patients demonstrate a decrease in wound size following 1 to 3 applications, similar to the overall time to heal and number of applications observed in the current cases. Furthermore, a prospective, randomized, comparative parallel group study28 of a dehydrated amniotic membrane in the management of DFUs of at least 4 weeks’ duration (N = 25) found wound areas were reduced by a mean of 97.1% in the treated group (applied every 2 weeks) compared to 32% in the group receiving standard care of moist wound therapy with silver dressing (changed daily or as needed) after 4 weeks and by 98.4% versus 1.8% (ie, wounds increased in size), respectively, at 6 weeks. A retrospective analysis29 of a different dehydrated amniotic membrane in the treatment of various chronic wounds found after 12 weeks of care, 76.1% of wounds were closed (67.6% of venous leg ulcers and 85.2% of DFUs). A recent retrospective review19 of medical records compared the effectiveness of bioengineered living cellular construct and a dehydrated amniotic/chorionic membrane in 218 patients and found the bioengineered construct reduced median time to closure (13.3 weeks versus 26 weeks) and a significantly higher proportion of wounds healed at both 12 weeks (48% versus 28%) and 24 weeks (72% versus 47%) (P = 0.01), suggesting CTPs vary in their efficacy.

Lastly, the authors’ clinical experience with DAMA found it easy to use and to require minimal maintenance; wounds were checked every week. DAMA was kept in place for 2 weeks and only secondary dressings were changed more frequently as needed. No adverse events were observed. Overall, the use of DAMA provided a convenience benefit for both the Wound Care Center and the patients.

Limitations

The results in this case series cannot be extrapolated to other patient populations. Controlled clinical studies are needed to compare the effect of DAMA to other topical treatment modalities in the care of chronic wounds.

Conclusion

In these clinical cases, following the application of DAMA, all wounds proceeded to heal within 9 weeks. All wounds were considered difficult-to-heal, in part due to underlying venous and arterial disease and/or poorly controlled diabetes mellitus, and had previously failed to close following the use of multiple advanced wound care strategies. These observations suggest prospective, randomized, controlled clinical studies to compare the use of DAMA to other topical treatment modalities are warranted. 

Acknowledgments

The authors thank Derma Sciences, Inc (Princeton, NJ) for funding editorial support services.

References

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2.         Armstrong DG, Wrobel J, Robbins JM. Guest editorial: are diabetes-related wounds and amputations worse than cancer? Int Wound J. 2007;4(4):286–287.

3.         Snyder RJ, Kirsner RS, Warriner RA 3rd, Lavery LA, Hanft JR, Sheehan P. Consensus recommendations on advancing the standard of care for treating neuropathic foot ulcers in patients with diabetes. Ostomy Wound Manage. 2010;56(4 suppl):S1–S24.

4.         Warriner RA, Snyder RJ, Cardinal MH. Differentiating diabetic foot ulcers that are unlikely to heal by 12 weeks following achieving 50% percent area reduction at 4 weeks. Int Wound J. 2011;8(6):632–637.

5.         Snyder RJ, Cardinal M, Dauphinee DM, Stavosky J. A post-hoc analysis of reduction in diabetic foot ulcer size at 4 weeks as a predictor of healing by 12 weeks. Ostomy Wound Manage. 2010;56(3):44–50.

6.         Zelen CM, Gould L, Serena TE, Carter MJ, Keller J, Li WW. A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J. epub ahead of print.

7.         Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft Diabetic Foot Ulcer Study G. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701–1705.

8.         National Diabetes Data Group. Diabetes in America. Bethesda, MD: National Institutes of Health;1995.

9.         Centers for Disease Control. National Diabetes Fact Sheet. 2011. Available at: www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed March 25, 2015.

10.       Goodridge D, Trepman E, Sloan J, et al. Quality of life of adults with unhealed and healed diabetic foot ulcers. Foot Ankle Int. 2006;27(4):274–280.

11.       Eckman MH, Greenfield S, Mackey WC, et al. Foot infections in diabetic patients. Decision and cost-effectiveness analyses. JAMA. 1995;273(9):712–720.

12.       Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen. 2006;14(6):680–692.

13.       Ueta M, Kweon MN, Sano Y, et al. Immunosuppressive properties of human amniotic membrane for mixed lymphocyte reaction. Clin Exp Immunol. 2002;129(3):464–470.

14.       Hao Y, Ma DH, Hwang DG, Kim WS, Zhang F. Identification of antiangiogenic and antiinflammatory proteins in human amniotic membrane. Cornea. 2000;19(3):348–352.

15.       Moffett A, Loke YW. The immunological paradox of pregnancy: a reappraisal. Placenta. 2004;25(1):1–8.

16.       Niknejad H, Peirovi H, Jorjani M, Ahmadiani A, Ghanavi J, Seifalian AM. Properties of the amniotic membrane for potential use in tissue engineering. Eur Cell Mater. 2008;15:88-99.

17.       Fetterolf DS, Snyder RJ. Scientific and clinical support for the use of dehydrated amniotic membrane in wound management. Wounds. 2012;24(10):299–307.

18.       Sheikh ES, Sheikh ES, Fetterolf DE. Use of dehydrated human amniotic membrane allografts to promote healing in patients with refractory non healing wounds. Int Wound J. 2014;11(6):711–717.

19.       Kirsner RS, Sabolinski ML, Parsons NB, Skornicki M, Marston WA. Comparative effectiveness of a bioengineered living cellular construct vs. a dehydrated human amniotic membrane allograft for the treatment of diabetic foot ulcers in a real world setting. Wound Repair Regen. 2015;epub ahead of print.

20.       Lynch SE, Nixon JC, Colvin RB, Antoniades HN. Role of platelet-derived growth factor in wound healing: synergistic effects with other growth factors. Proc Natl Acad Sci USA. 1987;84(21):7696–7700.

21.       Schultz GS, Davidson JM, Kirsner RS, Bornstein P, Herman IM. Dynamic reciprocity in the wound microenvironment. Wound Repair Regen. 2011;19(2):134–148.

22.       Kjaergaard N, Hein M, Hyttel L, et al. Antibacterial properties of human amnion and chorion in vitro. Eur J Obstet Gynecol Reprod Biol. 2001;94(2):224–229.

23.       Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care. 2003;26(6):1879–1882.

24.       Veves A, Falanga V, Armstrong DG, Sabolinski ML, Apligraf Diabetic Foot Ulcer Study Group. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001;24(2):290–295.

25.       Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch Dermatol. 1998;134(3):293–300.

26.       Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen. 1999;7(4):201–207.

27.       Shah AP. Using amniotic membrane allografts in the treatment of neuropathic foot ulcers. J Am Podiatr Med Assoc. 2014;104(2):198–202.

28.       Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502–507

29.       Regulski M, Jacobstein DA, Petranto RD, Migliori VJ, Nair G, Pfeiffer D. A retrospective analysis of a human cellular repair matrix for the treatment of chronic wounds. Ostomy Wound Manage. 2013;59(12):38–43.

Potential Conflicts of Interest: Derma Sciences, Inc (Princeton, NJ) provided funding for editorial support services.

Dr. Lintzeris is Medical Director; Ms. Yarrow, Ms. Johnson, Ms. White, Ms. Hampton, and Mr. Strickland are wound care nurses; and Ms. Albert and Ms. Cook are hyperbaric technicians, Wayne Memorial Wound Healing and Hyperbaric Center, Goldboro, NC. Please address correspondence to: Dimitrios Lintzeris, DO, CWS, Wayne Memorial Wound Healing and Hyperbaric Center, 2700 Wayne Memorial Drive, Goldsboro, NC  27534; email: dimitrios.lintzeris@waynehealth.org.

Abstract

A variety of conditions result in lower extremity edema, such as deep vein thrombosis, cellulitis, venous stasis insufficiency, and congestive heart failure (CHF). A case study is presented to illustrate the dynamics of the lymphatic system, the pathology of CHF, the importance of obtaining a pretreatment differential diagnosis, and how to implement a safe treatment plan.

The patient was a 69-year-old overweight woman with bilateral lower extremity lymphedema of almost equal volume (~9,100 mL) of >2 months’ duration. She had 11 draining wounds and a reported history of chronic obstructive pulmonary disease (COPD) but no cardiac dysfunction. Treatment consisted of 6 sessions of manual lymph drainage (MLD), remedial exercises, and compression wrapping and weekly volumetric measurements over a period of 3 weeks. A 4-L decrease in lower extremity edema volume was noted, but fatigue and shortness of breath increased markedly. Treatment was discontinued and the patient was referred back to her physician for cardiac evaluation and treatment. The literature suggests patients, as well as health care professionals, do not always distinguish CHF symptoms from COPD. Proper assessment, monitoring, and lymphedema treatment adjustments are paramount to providing safe care for patients with signs and symptoms of COPD and suspected CHF. More research to elucidate best practice approaches in patients with lymphedema and concurrent CHF/COPD before the start of MLD treatment is warranted.

Lymphedema is an accumulation of protein-rich fluid that can be present for a number of reasons, including damage to the lymphatic network as a result of trauma, removal of lymph nodes, and genetics, as in the case of some primary lymphedema syndromes.¹ A patient with lymphedema may have swelling in the trunk, face/neck, genitals, or extremities as a result of compromised lymphatic flow pursuant to lymph node removal, trauma, or a possible genetic predisposition.

As of 2002, a literature review of more than 1,900 references to determine the incidence of both primary and secondary types of the condition in the United States Medicare age group (65+) showed lymphedema affected upwards of 6.8 million individuals.² Research, by literature review, is underway to determine the incidence in the nonMedicare-age group population, specifically persons with breast cancer, trauma, and primary lymphedema, but currently collection of these data by an online website forum² is not complete.

According to the Position Statement of the National Lymphedema Network (NLN),³ a qualified health care professional should help determine the diagnosis of lymphedema in the earliest possible stage for more effective treatment. Patients referred for lymphedema treatment can have a variety of diagnoses; therefore, it is important to obtain a thorough patient and cardiovascular/pulmonary systems history, integumentary review, musculoskeletal and neuromuscular assessment, and determination of communication capabilities and to conduct a physical therapy examination to diagnose the cause of lower extremity swelling. The physical therapist (PT) or the health care professional who is differentially diagnosing patients with lower extremity swelling needs to know the duration, distribution, and accompanying symptoms of the leg edema in order to render an effective differential diagnosis.⁴ Five diagnostic tests necessary to properly diagnose lymphedema include magnetic resonance imaging (MRI), computed tomography scan (CT), lymph vessel imaging, volumetric measurements, and assessment of changes in biomechanical or electrical properties of the fluid.

According to the NLN³ and a literature review by Young,⁵ swelling distribution (bilateral versus unilateral) is important in determining pathology, and bilateral leg edema is usually an indication of a systemic process.⁴ The PT/health care provider needs to have full knowledge of patient medication and reports of pain, trauma, and surgery to help determine the cause of edema. Any accompanying symptoms, such as dyspnea with exertion, orthopnea, and/or paroxysmal nocturnal dyspnea, most likely are indicative of congestive heart failure (CHF).⁴ Physical examination to determine the presence of heart failure such as distended neck veins, listening for ventricular gallop, and conducting echocardiography⁴ are also an important part of the evaluation process. Determining what diagnostic tests have been performed on the patient is essential. For example, the PT should obtain, if possible, previous medical records on the patient and have ongoing communication with the referring physician to order appropriate laboratory tests.

Ciocon et al⁴ conducted a review of the literature on the differential diagnosis of leg edema. Their review showed increased peripheral venous pressure is the most common cause of leg swelling. Chronic venous insufficiency (CVI) is the most common condition resulting from increased venous pressure⁴ and can result in extravasation of large molecules and red blood cells to the dermis and cause inflammation and possibly ulceration.⁶

According to Lampe’s⁷ literature review on lower extremity chronic venous disease, the pathogenesis of venous disease can have many origins, including venous failure, venous reflux, and venous hypertension. Lampe’s review⁷ also explains CVI may occur as a result of long-term vein malfunction, potentially leading to ulceration. Venous hypertension along with increased capillary hydrostatic pressure can lead to fluid leakage into the interstitial space, which essentially is one of the causes of secondary lymphedema.^1,7 According to Bolton et al’s⁸ literature review on the global efforts to address wounds and lymphedema, the estimated prevalence of chronic ulcers in patients >60 years old with venous insufficiency is 1% to 3%. Bolton et al concluded saving limbs and lives requires correct diagnosis, addressing the cause of skin breakdown early, and managing the wound well. Lampe⁷ stresses adequate edema assessment is necessary. Recent soft pitting edema may indicate trauma or early stages of venous insufficiency, and hard/indurated or brawny tissue is related to longstanding venous hypertension and venous insufficiency.

Due to the progressive nature of lymphedema, early intervention will lead to more effective treatment. According to a consensus document of the International Society of Lymphology,¹ manual lymph drainage (MLD) in combination with remedial exercises and compression, termed complete decongestive therapy, is the standard treatment approach for patients seeking lymphedema management.

MLD. MLD is a standard treatment approach to peripheral lymphedema that involves a specific type of light touch massage. This gentle, light, superficial massage technique stimulates the lymphatic system to allow proficient uptake and movement of lymphatic fluid. This therapy typically is performed by either a PT or occupational therapist who is a Certified Lymphedema Therapist (CLT).¹

CHF. According to the consensus document of the International Society of Lymphology,¹ the second most significant diagnosis that results in leg edema is CHF. Each year, 660,000 individuals are newly diagnosed with CHF.⁹ It is imperative that patients and health care providers be familiar with the signs and symptoms of CHF. The presence of CHF can dramatically change the treatment approach for the patient. For example, the health care provider will need to closely monitor the patient’s vital signs and symptoms throughout treatment sessions to make sure the heart is not being overworked. A baseline assessment of all vital signs will help determine if the patient is progressing and tolerating the treatment in a stable manor without adverse effects. A literature review by Frese et al¹⁰ discusses blood pressure (BP) guidelines for PTs; the BP measurement gives the PT information on how the patient is responding to treatment/exercise and guides exercise prescription or when to potentially stop treatment. This is critical when performing MLD therapy, because additional fluid is moved toward the heart. Being able to recognize signs and symptoms of CHF as a health care provider and as a patient is important in the diagnostic process.

Albert et al⁹ investigated patients’ perceptions of signs and symptoms of heart failure before an ambulatory visit/hospitalization. Using a convenience sample of 276 patients with systolic heart failure, researchers had participants complete a 1-page checklist of signs and symptoms. The authors found patients may not report their signs and symptoms to health care providers because they do not perceive them as indicative of a heart-related problem and may cope by ignoring or denying such symptoms. The authors also found 100% of participants in their study reported shortness of breath (SOB), while less than half (126 out of 276) reported edema/swelling.

Many patients seeking lymphedema treatment as a result of lower extremity swelling have comorbidities that may produce SOB, profound fatigue, and/or generalized weakness. In the study by Albert et al,⁹ patients documented these symptoms without realizing they are symptoms of CHF and the incidence of lower extremity edema in that patient population was 46%. This finding is relevant, considering many patients seeking lymphedema treatment may have underlying symptoms of CHF but are not aware that they actually have CHF; therefore, it is important for the health care provider to perform a complete history/screen.⁹

Theories about the origin of CHF abound. Based on their literature review of the development of dyspnea and edema symptoms, Churchouse and Thomas¹¹ theorized the development of CHF is a result of right ventricular failure occurring secondary to severe left ventricular failure. The cardiac lymphatic system also plays a role in the development of leg edema when anatomical and/or functional abnormalities of the lymphatic vasculature are present that can lead to lymph flow impairment, a known cause of edema.¹¹

Primary functions of the lymphatic system are to maintain fluid homeostasis and to provide a route for large protein molecules.¹² Cui’s¹² literature review investigated the connection between the cardiac system and the lymphatic system; evidence indicates blocking the cardiac lymph flow may contribute to several forms of cardiac injury. This review also reported lymphatic fluid drains passively into the heart, relying completely on powerful cardiac muscular contraction and relaxation. In other tissues, active lymphatic pumping has been found to be an important lymphatic fluid draining mechanism.¹²

Because these systems are intimately linked, the PT must be cautious not to overload the heart with the fluid that is being moved from the extremity to the thoracic duct when applying MLD to persons with CHF. Depending on the stage of CHF, movement of fluid toward the heart could be life-threatening. It is intuitive to stop MLD when a patient is showing classic signs of CHF, but research that states at what stage of CHF MLD is contraindicated is lacking.

To investigate the consequences of thoracic duct drainage in CHF patients, Witte et al¹³ focused on patients (N = 12) with severe CHF in whom a cannula was inserted in the thoracic duct to relieve symptoms. These researchers found initial high lymph flow pressure before cannulation and the presence of edema, indicating the flow of the unvented lymphatic system, was unable to keep pace with the rate of lymph formation. The investigators also found 4 of the 12 participants experienced significant CHF symptom relief within a few hours following insertion of the cannula into the thoracic duct. These changes included relief in dyspnea, orthopnea, and abdominal discomfort. It is important to note cannulation is a dangerous procedure that was fatal in 5 of the 12 patients. Although the study sample size was small, the morbidity rate suggests MLD must be considered a potentially dangerous treatment in patients with active acute heart failure.

An awareness of the relationship between the lymphatic system and the cardiac system will allow the PT a better understanding of the risks involved in treating patients with mild CHF symptoms, especially because patients seeking MLD may be unaware of signs and symptoms of CHF. On initial examination, a complete checklist of CHF signs and symptoms will help complete a thorough screening.

The basics of examining a patient with lymphedema and concurrent circulation and integumentary concerns are described in the Guide to Physical Therapist Practice.¹⁴ Examination of the patient, per the Guide, should include 3 main components: patient/client history, systems review, and tests and measures. The patient/client history is a systematic gathering of past and current information from the client/family regarding why this patient is seeking the services of physical therapy.¹⁴ The systems review is a brief examination of physiological status of the cardiovascular/pulmonary systems; for this patient, that involves collection of vital signs, including heart rate, respiratory rate, blood pressure, and edema assessment, as well as integumentary assessment that addresses measurement of any wounds, odor, or drainage and overall skin integrity/texture. Systems review also includes musculoskeletal and neuromuscular assessment. The final part of the systems review is assessment of the patient’s ability to communicate, his/her affect, cognition, language, and learning style. Appropriate standardized tests and measures are selected by the PT as part of the examination and may include aerobic capacity/endurance, edema/girth measurements, balance testing, and functional tasks such as the ability to transfer out of bed safely and independently.

The purpose of this case report is to illustrate the principles of care and potential complications of treating lower extremity edema in a patient with COPD/CHF.

Case Report

Patient background. Ms. K is a 69-year-old woman who was referred to a PT for the treatment of bilateral lower extremity lymphedema. She presented with weeping wounds on both distal anterior lower extremities. At the time of examination, no wound measurements or photographs were taken. The patient was married and worked full time as a Medicare insurance consultant.

History and symptom review. At the time of examination, Ms. K reported symptoms of bilateral lower extremity swelling and her wounds had been present for at least 2 months. She was asked about her cardiac history and denied any past or current significant cardiac problems, past cardiac procedures, and/or past medical history of CHF. She was observed to have mild dyspnea with exertion. When questioned about this symptom, she reported a history of emphysema and asthma that caused SOB as opposed to any past history of CHF.

Ms. K was asked about any past or present kidney problems/voiding, and she denied any issues with her urinary system. She was seen by a physician for the evaluation of her bilateral lower extremity edema and SOB and was referred to physical therapy for management of her lower extremity lymphedema. No tests were performed or ordered to screen for cardiac conditions. The lower extremity tissues felt hard and fibrotic. She was observed to be overweight for her height, but no body mass index was calculated. Her cardiac/pulmonary status at rest exhibited normal respiratory and heart rates; however, she developed SOB with minimal exertion.

Tests and measures. Tests and measurements for the patient with lymphedema include functional mobility, volumetric measurements, and other standardized testing customized to the client (eg, a specific balance test such as the Berg Balance test or a test for fall risk, such as the Timed Up and Go test¹⁴). Unfortunately, no baseline functional cardiac/endurance tests, such as the 6-minute walk test (a test developed by Enright¹⁵ commonly performed and indicated for patients with COPD, heart failure, and/or with the elderly to determine baseline cardiac functional ability and to determine exercise prescription), were performed on initial examination by the examining PT. Baseline volumetric measurements were taken every 4 cm with a tape measure using a mathematical formula to calculate total volume, a technique acceptable according to the NLN.⁴ Leg volumes were almost equal bilaterally, with the right lower extremity measuring 9,107.62 mL and the left lower extremity 9,176.64 mL. This provided the therapist with a baseline volume that was reevaluated on a weekly basis to determine the effectiveness of interventions. All weekly circumferential measurements, reported as volume, performed from the initial examination until discharge were taken by the same PT (see Table 1). 

Functional limitations included the inability to bend over due to poor mobility and obesity; her distended abdomen prevented her from physically reaching her lower legs to don/doff stockings/socks. Transfers required minimal assistance: the increased weight of the lower extremities made them difficult to lift onto the bed. Ms. K’s gait was slow, and she manifested a slight trunk lean from side-to-side due to chronic bilateral hip pain. She did not require an assistive device for safety or stability. Based on these evaluative findings, Ms. K’s problem list was prioritized: 1) lymphatic overload in bilateral lower extremities; 2) functional transfer limitations from sit to supine as a result of increased fluid/weight of her legs; 3) infection risk due to open, draining wounds; and 4) bilateral hip pain with activity rated at 8 out of 10 (visual analog scale) that interfered with her ability to function at work and at rest that at times kept her awake at night.

It was determined that addressing lymphatic overload would help resolve all other problems on the list; with decreased volume and pressure in her lower extremities, transfers would become easier, wound fluid would diminish and the wounds would heal, and she would have less pain with functional mobility.

Differential diagnosis. A differential diagnosis of venous stasis-induced lymphedema was made based on the onset of the patient’s symptoms, the location of the edema, and the fibrosis present in bilateral lower extremities.

Treatment. According to the Guide to Physical Therapist Practice,¹⁴ Ms. K could fall into in 2 practice patterns: 1) Practice pattern 6H, Impaired Circulation and Anthropometric Dimensions Associated with Lymphatic System Disorders; and 2) Practice 232 Pattern 7A, Primary Prevention/Risk Reduction for Integumentary Disorders. Based on prognosis and expected range of number of visits in the Guide, the therapist anticipated approximately 9 visits in 30 days (approximately twice a week for 4 weeks) were appropriate based on Ms. K’s mild lymphedema classification.¹⁴ The focus of intervention was to address her edema, strength, and functional limitations and to relieve pressure on the lymphatic system. Short-term and long-term goals addressed her pain, wound healing, functional limitations, ability to perform self-massage, and assistance with donning and doffing compression wraps/garments (see Table 2). 

Interventions. Before interventions, Ms. K provided consent for treatment. Interventions began with patient education, which specifically addressed what lymphedema is, what might be causing the problem in this particular case, and how the planned interventions were anticipated to help heal the wounds and improve functional mobility.

Ms. K was educated on the function and purpose of the lymphatic system and the problems that typically occur when the system is compromised. She also was informed that MLD facilitates movement of the fluid to the thoracic duct and to the heart. She also was instructed on the importance of self-monitoring her breathing and SOB using the Borg Scale of Perceived Exertion,¹⁶ a subjective measure of physical activity intensity. Based on the physical sensations experienced during exercise, the person assesses respiration, breathing, sweating, heart rate, and muscle fatigue. The scale ranges from 6 to 20 (6 being no exertion at all to a 20 being maximum exertion); the number reported from the patient correlates highly with the actual heart rate. Ms. K also was asked to monitor urinary output to make sure voiding was at or above what was typical for her; decreased urinary output (voiding less than her usual amount) would lead the therapist to suspect fluid might be moving elsewhere in the body and not being excreted through the kidneys.

Ms. K understood her treatment would consist of MLD massage and remedial exercises and that compression wraps (1-way stretch) to stimulate the lymphatic system and allow efficient fluid movement would be applied after massage was completed. The amount of pull/pressure applied with the wraps would be a graduated level of compression, with more pressure applied distally. Her spouse was given a printed handout detailing how to wrap Ms. K’s legs; in addition, the therapist provided a demonstration of the wrapping procedure. Ms. K was instructed to wear the wraps 23 out of 24 hours. She was further instructed to wash her legs in the hour off with an antibacterial soap and water and to apply lotion to the areas on her legs where she did not have weeping wounds. Instructions were given to rewrap her legs immediately if at any time the wraps became loose (due to volume reduction) or if they bunched uncomfortably and thus restricted circulation or fluid movement. Ms. K and her spouse demonstrated understanding of all instructions.

MLD was started during the first visit and instruction on basic remedial lower extremity exercises to encourage more fluid movement was provided during the second MLD session 5 days later. Following MLD massage, a light compression stockinette (10 mm Hg) was applied along with moderately dense foam around the areas with the greatest fibrosis and 3 rolls of 1-way stretch compression wraps to both lower extremities. Rolls are of various widths, with the smaller width over the foot (8 cm) and increasing width (10 cm to 12 cm) wrapping up the leg depending on the size of the extremity. No chemical applications were placed on the wounds for the treatment of the leg ulcers; however, a basic ABD pad was applied to absorb drainage and placed directly on the wound.

Outcomes. Ms. K’s fluid volume in her lower extremities was reassessed with circumferential measurements on the second visit (see Table 1). She experienced large amounts of fluid loss in her legs (Table 1), but her breathing at rest was becoming progressively more difficult. She was advised to pay close attention to any symptoms of SOB with minimal exertion because this may be a potential sign of CHF; she also was advised to monitor her urine output, although no issues were apparent at this time. At the third visit (week 2), the therapist contacted the physician office because Ms. K’s symptoms indicated potential onset of CHF. At this point, Ms. K was told that if her breathing worsened at any time of the day or night, she should remove her compression wraps; she also was advised to weigh herself daily to monitor fluid retention. An appointment with her physician was made for late in the following week.

On visit 4, <2 weeks from initiation of treatment, the patient’s SOB had worsened slightly; a Borg rate of perceived exertion was not obtained. Despite the loss of lower extremity fluid (see Table 1), Ms. K reported no significant increase in urine output or change in weight. She indicated she was scheduled for an echocardiogram at the same time as the physician recheck. 

At the fifth visit, approximately 2-and-a-half weeks from the initial examination, Ms. K continued to lose fluid volume in her legs, for a total loss of 4,104.19 mL (approximately 4L) between both lower extremities. Her wounds were closed and no longer draining, and no redness was present. She expressed satisfaction with the volume reduction in her lower extremities; however, her SOB with any functional mobility had become intolerable. Echocardiogram results were not available, but she was advised to discontinue her compression wraps. Removal of the compression wraps was projected to decrease pressure on the thoracic duct and the heart.

Her volumetric measurements at the sixth visit (third week) increased due to the discontinuation of her compression wraps at the previous visit (see week 3 increase from week 2 on Table 1).  Her wounds remained healed. At this last visit, Ms. K’s treatment options were discussed at length, with particular reference to her complicated medical condition. The therapist strongly recommended discontinuing lymphedema treatment as a means of ensuring Ms. K’s safety, and she was discharged from physical therapy due to the progressive nature and symptoms of the CHF and returned to the care of her physician. Any further MLD/compression treatment was contraindicated. She was educated with regard to this fact and was comfortable with the discharge plan.

Discussion

Reflecting on the management and outcomes of this case, therapists can appreciate the intimate connection between the cardiac and lymphatic systems and how important it is to educate patients about the signs and symptoms of CHF.

In examining the differential diagnosis of this patient, a concerning question remains regarding the patient symptoms of asthma, COPD, and the further connection this may have with her developing heart failure. The pathogenesis of COPD and CHF are similar, with overlapping signs and symptoms.^17,18 Practitioners examining and following these patients should collaborate in order to facilitate the differential diagnosis process. Inadequate assessment can lead to improper treatment if the patient has both COPD and CHF,¹⁷ which is the case with Ms. K. She and her referring physician were not able to recognize her COPD symptoms coincided with her CHF symptoms, resulting a less-than-optimal outcome for the patient.

Laboratory tests that would have been valuable for this and other patients include plasma level of natriuretic peptides (NP).¹⁸ These levels are a fast and sensitive biomarker for heart failure in patients with COPD.¹⁵ B-type natriuretic peptide (BNP) levels ranging from 100 pg/mL to 500 pg/mL in COPD patients may indicate cor pulmonale, moderate left ventricular heart failure, or both.¹⁸ The Diez et al¹⁸ literature review of these laboratory values goes into more specific detail and references several other authors confirming their findings. Diez et al¹⁸ supported the fact if the BNP level is below 100 pg/mL, it is unlikely the patient has heart failure; however, levels above 500 pg/mL are suggestive of acute heart failure in COPD patients.¹⁸ Other tests such as echocardiography, which is a reference test for detection and diagnosis of CHF, are limited in obese patients or persons with COPD because of the poor echocardiographic window and pulmonary hyperinflation. In these cases, an MRI is a better choice to evaluate the right ventricle.¹⁸ Hawkins et al’s¹⁷ literature review on the relationship between heart failure and COPD and the pitfalls of differential diagnosing suggests testing all patients suspected of having CHF and COPD should include an echocardiograph and pulmonary function test. These are tests that could be performed in the differential diagnosis process to help confirm the appropriate pathway of treatment. 

Albert et al⁹ noted patients may not report signs or symptoms to their health care providers because the provider does not ask appropriate questions or because the patient is not aware these signs/symptoms are related to impaired heart function. This may explain why Ms. K associated her symptoms of dyspnea and fatigue with a chronic lung condition rather than CHF. She was not provided a complete checklist of signs and symptoms of CHF on the initial patient/history questionnaire. The treatment approach was cautious, and she was educated about recognizing symptoms that would indicate active CHF and necessitate cessation of wrapping and self-massage. Churchouse and Thomas¹¹ mention leg massage and remedial lower extremity exercises and elevation are helpful in the management of peripheral leg edema. Future investigation of other safe options for the treatment of lower extremity edema in patients with CHF is necessary.

Additional studies address this concern. Roberts’¹⁹ outcomes study with 21 subjects of various comorbidities with both CHF and lower extremity lymphedema noted a decrease in CHF symptoms and weight loss and increased diuresis by initiating the low-sodium diet that comprises 900 mg of sodium, 70 g of protein, 20 g of fat, 3.5 g of potassium, 250 mg of magnesium, and substantial amounts of essential vitamins and minerals consumed daily. Educating patients with lymphedema on this diet combination or insisting on dietitian referral may be an essential part of their treatment plan. In addition to diet, Pierce and McLeod,²⁰ as part of their pilot prospective clinical study, incorporated plantar micro-mechanical stimulation to the calf muscle for 30–60 minutes per day for peripheral edema in 6 patients with CHF. Lean mass of the legs decreased an average of 0.5 kg with no significant changes in health after 1 month of calf muscle pump stimulation. A limitation of this study was the short duration/dosage of the muscle pump stimulation.  These early research results are encouraging because they indicate safe treatment options to reduce peripheral edema in CHF patients are being tested.

Similarly, Leduc et al²¹ investigated the hemodynamic parameters of 9 patients with heart failure who received MLD. They observed it was safe to perform MLD on patients with confirmed CHF but not in conjunction with compression wraps, garments, or pumps. The study sample size limits the ability to draw firm conclusions but does provide some evidence for a safe approach and guidance for CLTs.

The inherent limitations of case studies also apply to this case report of a patient with lymphedema and symptoms of CHF/COPD. However, the outcome observed is consistent with currently available literature and illustrates the importance of obtaining a differential diagnosis before treating patients with bilateral lymphedema.

Conclusion

The literature related to managing lymphedema in patients who also present with symptoms of heart failure suggests it is imperative to obtain a differential diagnosis before treating the lymphedema. This case study illustrates and confirms the importance of that recommendation. Further research is needed to obtain more outcomes data and define optimal interdisciplinary collaboration requirements among cardiologists, pulmonologists, and CLTs to facilitate optimal patient outcomes. 

References

1.         Consensus Document of the International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema. Lymphology. 2003;36(2):84–91. 

2.         Weiss R. The Incidence of Lymphedema. Available at: www.lymphnotes.com/article.php/id/401/ Updated 2007. Accessed February 23, 2011.

3.         NLN Medical Advisory Committee. The Diagnosis and Treatment of Lymphedema; 396 Position Statement of the National Lymphedema Network. Updated February 2011. Available at: www.lymphnet.org/resources/nln-position-paper-the-diagnosis-and-398 treatment-of-lymphedema. Accessed September 30, 2014.

4.         Cicocon JO, Fernandez BB, Cicocon DG. Leg edema: clinical clues to the differential diagnosis. Geriatrics. 1993;48(5):34–45.

5.         Young JR. The swollen leg. Clinical significance and differential diagnosis. Cardiol Clin. 1991;9(3):443–456.

6.         Simon EB. Leg edema assessment and management. Medsurg Nurs. 2014;23(1):44–53. 

7.         Lampe KE. Lower extremity chronic venous disease. Cardiopulm Phys Ther. 2004;15(1):13–22.

8.         Bolton LL, Macdonald J, Geyer MJ. Global efforts address wounds and lymphedema. Ostomy Wound Manage. 2010;56(5):6–8.

9.         Albert N, Trochelman K, Li J, Lin S. Signs and symptoms of heart failure: are you asking the right questions? Am J Crit Care. 2010;19(5):443–452.

10.       Frese E, Fick A, Sadowsky HS. Blood pressure measurement guidelines for physical therapists. Cardiopulm Phys Ther. 2011;22(2):5–12.

11.       Churchouse W, Thomas E. Dyspnoea and oedema in chronic heart failure. Pract Nurs. 2010;39(9):35–41. 

12.       Cui Y. The role of lymphatic vessels in the heart. Pathophysiology. 2010;17(4):307–314.

13.       Witte MH, Dumont AE, Clauss RH, Roder B, Levine N, Breed ES. Lymph circulation in congestive heart failure. Effect of external thoracic duct drainage. Circulation. 1969;39:723–733.

14.       American Physical Therapy Association (APTA). Guide to Physical Therapist Practice, 2nd ed. Phys Ther. 2001;81:9-744.

15.       Enright PL. The six-minute walk test. Respir Care. 2003;48(8):783–785.

16.       Center of Disease Control and Prevention. Perceived Exertion. (Borg Rating of 422 Perceived Exertion Scale). Updated. March 30, 2011. Available at: www.cdc.gov/physicalactivity/everyone/measuring/exertion.html. Accessed May 29, 2015.

17.       Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn F, McMurry JJ. Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology. Eur J Heart Fail. 2009;11(2):130–139.

18.       de Miguel Diez J, Chancafe Morgan J, Jimenez Garcia R. The association between COPD and heart failure risk: a  review. Int J Chron Obstruct Pulmon Dis. 2013;8:305–312.

19.       Roberts H. Use of a low-sodium formula as an improved Karell diet, with emphasis upon the outpatient management of heart failure and lymphedema. Am Heart J. 1963;65:32–49.

20.       Pierce C, McLeod KJ. Feasibility of treatment of lower limb edema with calf muscle pump stimulation in chronic heart failure. Eur J Cardiovasc Nur. 2009;8(5):345–348.

21.       Leduc O, Crasset V, Leleu C, et al. Impact of manual lymphatic drainage on hemodynamic parameters in patients with heart failure and lower limb edema. Lymphology. 2011;44(1):13–20. 

Potential Conflicts of Interest: none disclosed

Dr. Vaassen is Assistant Professor of Physical Therapy, Clarke University, Dubuque, IA. Please address correspondence to: Madeline M. Vaassen, PT, DPT, GCS, CLT, Physical Therapy, Clarke University, 1550 Clarke Drive, Dubuque, IA  52001; email: mimi.vaassen@clarke.edu.

Abstract

Good quality systematic reviews (SRs) summarizing best available evidence can help inform clinical decisions, improving patient and wound outcomes. Weak SRs can misinform readers, undermining care decisions and evidence-based practice.

To examine the strengths and weaknesses of SRs and meta-analyses and the role of SRs in contemporary evidence-based wound care practice, and using the search terms systematic review, meta-analysis, and evidence-based practice, the authors searched Medline and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for important terminology and recommendations to help clinicians evaluate SRs with meta-analysis. Reputable websites, recent textbooks, and synthesized available literature also were reviewed to describe and summarize SR strengths and weaknesses. After developing a checklist for critically evaluating SR objectives, inclusion/exclusion criteria, study quality, data extraction and synthesis methods, meta-analysis homogeneity, accuracy of results, interpretation, and consistency between significant findings and abstract or conclusions, the checklist was applied to topical wound care SRs identified in Cochrane and MEDLINE searches. Best available evidence included in the SRs from 169 randomized controlled trials on 11,571 patients supporting topical intervention healing effects on burns, surgical sites, and diabetic, venous, or pressure ulcers was summarized and showed SRs and clinical trials can demonstrate different outcomes because the information/data are compiled differently. The results illustrate how evidence insufficient to support firm conclusions may still meet immediate needs to guide carefully considered clinical wound and patient care decisions while encouraging better future science.

As new knowledge in health sciences (including wound care) continues to expand, the need for rigorous syntheses of the best available evidence also has increased. As the number of published studies increases, so does the ability to stay current. In the course of making sense of these multiple studies, the number of synthesized reviews also has increased. These purposely combined or synthesized studies are called systematic reviews (SRs). Sometimes SRs include an accompanying quantitative technique called meta-analysis.¹

Combining available information into an integrated result can save considerable time and provide evidence to modify clinical practice.² The publication of SRs and meta-analyses will continue to grow; however, this involves many critical caveats in performing and interpreting them. Poorly developed and written SRs and meta-analyses can yield misleading information.¹ Meta-analysis can be particularly challenged to quantify a treatment effect size across clinical trials due to the diverse clinical variables involved, such as varied wound types and clinical settings and myriad of potential patient differences across studies.³

The purpose of this scholarly review is to examine the strengths and weaknesses of SRs and meta-analyses and the role of SRs in contemporary, evidence-based wound care practice. Discussion of selected problematic issues is offered with clinical exemplars.

Epidemiology of Wound Care: the High Stakes

The economic burden of chronic wound care for the United States is sobering. Currently, more than 70 million acute surgical wounds and approximately 7 million chronic wound patients require care every year.⁴ For pressure ulcer care alone, the cost is estimated to approach $11 billion annually.⁵

The population is aging. By 2030, 19% of Americans will be >65 years old, a group that includes 9 million frail elders.⁶ Age is a risk factor for chronic wounds. Diabetes care will challenge the American health care system. Currently, 29.1 million Americans are diabetic (mostly type 2); 86 million are prediabetics. Diabetes is a risk factor for wounds and the seventh leading cause of death in the United States.⁷

Chronic wound prevalence is not just an American issue. A recent market forecast report⁸ described global predictions: chronic wounds (pressure, venous, and diabetic ulcers) are on course to increase globally from 40 million to >60 million by 2017. The need for good evidence on which to base wound care is imperative, but available high-level evidence is rare. Calls for quality conduct and reporting of randomized controlled trials (RCTs) are occurring in the wound literature.⁹

Evidence-Based Practice (EBP) and How/Why it is Used

EBP is a term describing a problem-solving approach to health care delivery that crosses all disciplines¹⁰; it involves the conscientious, explicit, and judicious use of current best evidence in making decisions about clinical patient care.¹¹ The literature supports that best evidence should be integrated with patient/family preferences and values, individual clinical expertise, and the patient’s clinical context.^10,12,13

EBP is critical to current and future clinical care, especially in light of the Affordable Care Act. According to expert researchers and clinicians,^10-12 EBP can lead to the highest quality of care and the best patient outcomes. Interventions for patients with clinical conditions have to be selected with effectiveness in mind. Scarce resources will become more so as the patient burden in the nation increases.^4,10 In addition, in contemporary care reimbursement for interventions is provided based on clinical outcomes. The legal community also is aware of recommended approaches. Clinicians will be expected to keep current with effective techniques and interventions and provide legally defensible care. Patients seek advice from many sources, too. Clinicians will be expected to explain why they do or do not select a treatment. The specialty of wound care will be heavily impacted by these factors because extensive explanations are time-consuming, and time is money in this costly arena.^10,12

The process of EBP is first enacted by obtaining the best research evidence available. In the hierarchy of EBP, where clinical evidence is ranked according to strength of freedom from biases, meta-analyses and SRs are ranked at the top of describing quantitative effectiveness.¹⁴ If feasibility, appropriateness, and meaningfulness are the goals, qualitative meta-syntheses provide the strongest evidence.¹⁵ Researchers will have synthesized numerous high-quality studies (RCTs) or clinical trial (CTs) results from the literature.¹² Then EBP researchers will approach the literature review based on the PICO or PICOT format — that is, the heart of the SR is a focused question based on a population or group of participants regarding an intervention of interest. The intervention is compared to a control or standard treatment. The outcomes of the intervention are specified. Some researchers include timing issues as well. A sample PICOT question for a SR may read: “In patients with chronic wounds (eg, diabetic foot ulcers), how does use of negative pressure wound therapy (NPWT) affect rate and quality of wound healing in the first 2 weeks of use?” Researchers then perform a systematic search of the literature using clearly specified search terms (Medical Subject Headings or MESH) in a variety of databases (eg, Medline, EMBASE, CINAHL), and RCTs and CTs that match the search processes are retrieved and reviewed.

Using a mnemonic should not infer this is a simplistic activity. The protocol process used in SRs is highly rigorous. Inclusion/exclusion criteria and terminology are thoroughly discussed and explicitly defined. The entire process must be clearly and succinctly detailed in any SR.^16,17

The EBP approach is not without critics. In a narrative review, Berguer¹⁸ argues the evidence-based medicine (EBM) approach, for example, implies only one right way. Proponents suggest EBM embodies scientific truth, and those who critique it must be opting for “non-evidential unscientific data.”¹⁸ Berguer¹⁸ cautions the need to examine how “best evidence” is selected, how pertinent best evidence recommendations are to individual patients, and how the epistemic limitations of RCTs relate to the mechanics of disease.

The Language of Research: Helpful Terminology

Research and EBP use terminology with which clinicians may not be familiar. Just as wound care providers have to learn the correct terms to document wound assessment, they will have to learn new words to comprehend SRs. Table 1 contains a list of selected commonly used terms and definitions for easy reference. 

SR. A SR is a structured comprehensive synthesis of the research literature to determine the best research evidence to address a health care question (frequently an intervention). Most often groups of researchers (at least 2) conduct the quantitative SR using meta-analysis (if appropriate).^19,20 A qualitative SR summarizes primary quantitative studies but does not combine the study results using statistical methods.²¹ This latter form should not be confused with synthesis of qualitative research studies, a process called meta-synthesis.

Also known as a research synthesis, a SR has well-defined characteristics^17,21:

•  Clearly describes objectives and focused questions
•  Specifies explicit inclusion/exclusion criteria before work begins
•  Involves an exhaustive search to identify published and unpublished relevant studies
•  Appraises the validity and quality of studies and reporting of inclusion/exclusion choices
•  Includes a data analysis of included studies
•  Presents synthesized extracted findings
•  Provides transparent explicit reporting of methodology used to conduct the review.¹⁹

To promote rigor and transparency and to reduce potential error, a protocol for the SR is developed a priori. The finished SR publication must address explicitly all the multiple steps and decisions. At least 2 reviewers conduct the data extraction.²²

Two international groups commonly conduct SRs related to health care. The Cochrane Collaboration usually involves clinical effectiveness questions utilizing CTs and RCTs.²³ Another group, Joanna Briggs Institute, is more focused on nursing issues that include a greater focus on qualitative research as well as the publication of meta-syntheses.²⁴

The plethora of SRs across health care disciplines is so substantial some researchers are doing SRs of SRs to identify trends, strengths, and gaps in areas of health care.^25,26 The literature supports that SRs have the power to change practice positively when done well. For example, most clinical practice guidelines are a combination of clinical experience, expert opinion, and research evidence. Narrative reviews²⁷ note many guidelines rely on SRs to bolster the evidence base of the guideline.

Meta-analysis. Meta-analysis refers to statistical techniques for combining results from distinct clinical studies. In a sense, a meta-analysis is conducting research on existing research. Meta-analysis is usually conducted to answer a clinical question and should employ research studies that closely match the topic of interest. Gene Glass, who coined the term, called meta-analysis the analysis of analyses.²⁸

The purpose of a meta-analysis is to gather and combine information from research studies to gain higher statistical power for some common metric (a single numerical value of overall treatment effect) across the studies.²⁹ Many wound care RCTs sample too few patients to tell if clinically important outcome differences are statistically significant. If P is the probability of incorrectly rejecting the null hypothesis (the conclusion there is no effect of the treatment tested), the recognized acceptable P value for statistical significance is P <0.05 — ie, differences this large would be found by chance alone only 5% of the time (1 time in 20 replications of the RCT). Combining small studies all measuring the same outcome in the same way adds to the statistical power: the probability the test correctly rejects the null hypothesis when it is false. This allows reviewers to report significant trends not observable in any one of the individual RCTs. An essential belief in meta-analysis is all trials measure a common treatment effect; any observed differences between the trials are due primarily to chance. For example, this common treatment effect can be estimated as a weighted average of the treatment effects in the individual trials.³⁰

Critical to meta-analysis is the inclusion of all relevant primary studies (significant/not significant, published/not published). Narrative descriptions³¹ note unpublished studies, doctoral dissertations, and, if possible, data from primary researchers should be included to enhance the quality of the meta-analysis; therefore, searching for all available studies can be quite complex.²²

Notably, investigators have to make critical choices in conducting a meta-analysis. Studies have to be selected on a set of well-defined objective criteria. Incomplete data issues have to be addressed, data have to be analyzed appropriately, and correct data entered (eg, no typographical errors). Researchers must choose to address publication bias (or not), including the impact of retracted studies.

Because of the ability of SRs and meta-analyses to support best patient management decisions (if done well) or to deleteriously erode quality care (if done poorly), standards for the conduct and reporting of SRs and meta-analyses have been published.³² This statement — Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA)^{33 —} and the Institute of Medicine³⁴ recommended standards for developing SRs provide guidance for research authors and clinician users. Synthesized meta-analyses are being conducted to allow other researchers to identify trends and weaknesses inherent in published studies when meta-analysis is the study focus.³⁵

Strengths and Weaknesses of SR and Meta-analysis

Narrative literature reviews^{3,14,32,36,37} support that the strengths of SRs and meta-analyses are substantive. Combining studies in SRs and meta-analysis increases sample size and gives more precise estimates of effect size (increasing power and precision); clinicians can evaluate a body of evidence pertinent to a clinical question in a facilitated way by encapsulating information into a single result³⁶ that includes all eligible studies related to the clearly defined topic. Statistics can be applied to assess clinical variation or heterogeneity and include Cochran’s Q Statistic or the Inconsistency Index (I²); users must understand how to interpret, but they provide help with understanding the big picture.¹⁴

When done well, SRs and meta-analysis can result in conclusions more informative than any individual trials they combine³⁰; meta-analysis should act to decrease bias because all included trials will likely not be affected equally by a source of bias. Meta-analysis can include studies (trials) that do and do not feature statistically significant results; the latter may have not been published because of a lack of statistical power or small sample size.¹³ As such, using both kinds of studies increases external validity (real world applicability).

Because meta-analysis uses objective statistical techniques, researcher bias should be much less than what would be present in a traditional narrative review.³⁸ In summary, a well-designed and well-conducted meta-analysis can provide valuable information for clinicians, researchers, and policy-makers.¹

Narrative reviews^29,30,39-43 also note SRs and meta-analysis have potential flaws or criticisms. The problematic issues raised about SRs and meta-analyses are serious given their power to positively inform or seriously degrade good clinical treatment. The reality is even good SRs with meta-analysis cannot summarize a research field. By definition, the literature suggests meta-analysis should synthesize effect sizes and not report just a summary effect. A reported summary effect that ignores heterogeneity is “missing the point of the synthesis.”³⁹

Another issue is the file drawer effect. Because unpublished studies may be missed in a meta-analysis, the use of primarily published studies may overestimate true effect size. Meta-analysis has the goal of accurately synthesizing all existing data, so experts suggest attempts to obtain unpublished trials have to be described. Otherwise, publication bias may occur.^44-46

Publication bias is defined as a bias against publishing negative findings (eg, those that do not achieve statistical significance). Several ways exist to identify publication bias in SRs. The most common approach is the funnel plot, which visually identifies possible bias. Statistical tests can be used, including Rosenthal’s Fail-Safe-N and the “trim and fill” analysis.^45,46

The “apples and oranges” problem (also called clinical heterogeneity) is another potential flaw. If dissimilar clinical trials are combined in the SR and meta-analysis, the ultimate meaning of results is potentially threatened. Clinical trials in a meta-analysis will differ somewhat in their characteristics. The challenge for researchers is to decide just how similar they need to be. Data from chronic and parasitic wounds may appear statistically homogeneous, but it may not be clinically relevant to combine such data to inform clinical decisions about one of these wound types. If chosen comparisons are not logical, the validity of the results is eroded. The literature supports that sources of heterogeneity have to be investigated and identified.⁴⁷

Quality of clinical trials used in SR with meta-analysis matters — the flaw is called garbage in-garbage out. Inclusion criteria of selection must be clear and applied fastidiously. Close attention to bias and individual study quality is paramount. One approach is to set a quality threshold (ie, explicit selection criteria established in advance that is logically and systematically applied).² A meta-analysis of poor quality studies cannot yield good results in most circumstances.⁴⁰

Another potential flaw is important studies may be left out of the SR. Good researcher judgment, transparently applied, must be used to make sure all studies meeting the inclusion criteria to address the SR objective are included and studies subjected to combined analysis are similar enough to yield interpretable results.

Potential exists for meta-analyses to disagree with large-scale randomized trials. Clinician users need to beware of discounting the results of the meta-analysis or individual clinical trials. This is not a scenario of the large clinical trial or meta-analysis being right or wrong. Upon closer review, it is likely something inherent in the 2 publications, such as patient risk factors or co-interventions, differ significantly.³⁹

Another problem or flaw with SR and meta-analysis is poorly performed work. Meta-analysis is very complex; researcher mistakes are inevitable. Reviewers and clinician users need to consider the impact of these errors on the validity of the SR and meta-analysis. Research suggests the methodological qualities of SRs vary considerably.⁴² A large potential for bias exists in the selection and interpretation of data in retrospective research. Narrative reviews note meta-analysis can be influenced by biases inherent in data-derived analyses.⁴⁰

Another problem is variation of standards of treatment over time. “Usual care” controls add 2 sources of error variability to a SR. First, the actual interventions applied in the study are omitted from the SR. Second, interventions representing or concomitant to “usual care” change over time and across settings, with no consistent meaning to readers. The influence of concomitant treatments in standard treatment protocols may influence meta-analysis interpretation.⁴⁰

SRs also can differ substantially from real world practice. For example, clinical practice guidelines are usually consistent with clinical practices in disciplines and are an advancement of best practices. SRs potentially reflect the biases and philosophies of the authors who control the choice of included studies,⁴¹ which can lead to stark differences in practical usage and clinical relevance.

Due to limited availability of relevant RCTs, the recognized gold standard for reducing bias in subject treatment assignment, researchers may resort to other experimental studies that are not RCTs. Researchers must acknowledge biases inherent in the chosen designs and make definitive recommendation about practice with great caution.²² Because publication bias occurs more frequently in small trials, meta-analyses based on only small studies cannot be trusted.³⁵

Meta-analyses on the same topic even can have discrepant results. This discrepancy is likely a multifactorial problem and can be due to differences in inclusion/exclusion criteria for study design, outcomes, populations, interventions, settings, definitions, and other factors.⁴⁸

To avoid some of these concerns, researchers conducting meta-analysis should adhere to a few basic requirements. Given the need for a conclusion about a treatment, the minimum number of studies needed is 2.³⁷ In addition, the usefulness of small meta-analyses (<200 to 300 events) to guide practice is very limited.⁴⁰ Also, because of the limitations of meta-analyses and when adequately powered RCTs exist on a topic, the meta-analysis should not be given preferential treatment.⁴⁹

In summary, with all the limitations or flaws inherent in SRs and meta-analysis noted in the literature, it is important to remember to “not forget to critique the critique.”⁵⁰

Critically Evaluating SRs

Although utilization of SR by busy clinicians seems challenging, key strategies for critical assessment, described in the literature, can help with evaluation and critique.^{13,16,22,26,32,36} The clinician needs to ask 8 yes-no questions:

1. Objective(s) of the SR: Do the included studies meet the SR objective(s)?
2. Inclusion/exclusion criteria: Do the studies in the SR match inclusion/exclusion intervention criteria?
3. Quality of studies: Is there critical appraisal of included studies for “quality indicators” such as adequate randomization, allocation concealment, dropout rates, reporting accuracy, blinding, and appropriate statistical analyses?³²
4. Data extraction/synthesis: Were data from the included studies extracted correctly and synthesized appropriately? Are inconsistencies and problems explained?
5. Homogeneity: Do the foci of interest (eg, types of wounds) pass the similarity test (comparing apples to apples)?
6. Accuracy of results: Has a clear and accurate summary of each included RCT been provided in the Results text and analyses?
7. Interpretation: Are descriptions or implications of the SR supported by the data provided? Are limitations acknowledged?
8. Consistency: Do the Abstract and Conclusions of the SR reflect the SR’s significant RCTs results appropriately?

Although this checklist does not guarantee appropriate differentiation of good quality versus erroneous SRs with meta-analyses, it does offer analytical clarity assistance to clinicians.

One of the challenges to clinician users of SRs with meta-analysis is to understand why certain statistics are reported. In addition, clinicians must be able to interpret graphical or visual displays of results. For selected statistical usage of effect size, the nature of the variable being targeted (eg, effect of a wound intervention) is the determining factor. For dichotomous (yes/no) variables (developed a disease; did not develop a disease), the literature suggests the most commonly used effect size estimate is the odds ratio (OR). Risk ratio or relative risk also can be used, but OR usually is utilized. For continuous variables (eg, decrease in wound size or pain intensity scales), the most commonly utilized presentation is the standardized mean difference (SMD) — ie, the mean difference between groups (trials) divided by the pooled standard deviation (SD) of the groups, also called a Cohen’s D statistic.¹³ Mean difference also can be used.

The visual (graphical) display of the meta-analysis is called a forest plot. A forest plot offers valuable information: the number of RCTs and subjects reporting a specific outcome favoring the subject intervention and whether each RCT result was statistically significant at P<0.05, as well as overall significance of the result and potential lack of data homogeneity. It is beyond the scope of this article to discuss interpretation, but excellent, easy-to-understand resources are available for clinicians.¹³

Although utilization of SRs and meta-analysis may seem daunting, the literature also contains articles targeting critical appraisal and clinical application. The reader is encouraged to read more about these processes. The best way to learn to appraise and apply SR with meta-analysis is to do it.^16,29,36,43

SRs and meta-analyses are valuable processes that, without additional resources, permit exploration of treatment benefits from previously completed studies. Clinicians reading their results should have a clear understanding of their strengths and weaknesses, as illustrated in the following sections of this article. Knowledge works only if used. The following provides examples of getting optimal results from SRs even when they have issues.

The Role of SRs in Informing Clinical Practice

Taking a critical thinking approach to reading relevant SRs can enhance their usefulness in improving wound care outcomes. The literature^51,52 provides guidance on using clinical expertise with a healthy dose of critical thinking gleaned from the authors’ experience as Cochrane²³ or Joanna Briggs reviewers.²⁴ Below are some ways to use the critical thinking checklist to improve benefits from a SR or meta-analysis to inform clinical practice decisions.

Look past the abstract. Ideally, best available RCT evidence supporting effects of the SR’s topic intervention on its subject outcome for each clinical indication addressed by the SR is detailed in the Results and Analysis sections. This is where clinical expertise is useful, sifting out results relevant to a challenging patient or wound. To get the most value from a SR, wound care providers need to find clinically relevant RCT content that meets the needs of current patients and wounds. Rather than accepting a SR abstract on faith, diligent wound care professionals will stay focused on finding RCTs that match their patient’s characteristics, capabilities, and wound care needs to glean relevant RCT evidence that may help improve wound and patient outcomes. If a SR abstract omits significant results from RCTs most relevant to the patient at hand, an astute decision maker will likely find them in its Results or Analyses.

Do not wait for perfection. One should not be discouraged from using evidence in a SR that concludes there is insufficient evidence to support an intervention. Many SRs teach clinicians how to aim for perfect evidence to inform clinical decisions. Patients and practitioners who cannot wait for perfect evidence can still find valuable evidence in such SRs to inform choices of care. Authors^51,52 suggest the scientific method will sort out SR flaws and improve evidence-based guidelines of care to optimize results. Today’s patient needs the best possible help now, informed with the best evidence available. One or more relevant RCTs in the Results section of a SR may better inform clinical decisions than 1,000 less-informed opinions or selected cases. Wise professionals can use the best quality of evidence found in SRs to inform clinical decisions instead of giving up on SRs that conclude evidence is insufficient to inform their decisions.

Watch for red flags. Common flaws, discrepancies, or errors such as those described can warn observant readers a SR may not be robust. Inaccurate or inconsistent elements of a SR diminish its credibility. Even if SR conclusions do not reflect its results, one still can check accuracy, then use its relevant, valid RCT results to optimize wound care outcomes for relevant patients.

Clinical Illustration: A Search with Checklist Application

Clinical objectives. The first purpose of this activity is to empower busy practitioners to critically evaluate a SR’s clinically useful information by illustrating use of the above tips and checklist. Example Cochrane SRs were reviewed to illustrate how one can critique even a meticulously conducted, high-quality SR using the checklist to discover potential flaws and to reveal practice gems to inform clinical wound management decisions. The second purpose is to provide an example of how to mine practice gems from example SR Results and Analysis sections by surveying them, in this instance, for evidence supporting topical therapy.

Search methods. To locate example SRs to review in order to accomplish these objectives, the Cochrane Library and MEDLINE reference databases were searched for the combined terms topical wound healing. First, the SR quality checklist was applied to each example SR to identify potential issues in each, summarized in Table 2.^53-75 

To accomplish the second purpose of this work, example SRs addressing common wounds including burns, surgical wounds, diabetic foot ulcers, pressure ulcers, and venous ulcers were reviewed for all significant (P<0.05) healing outcomes, including percent healed, healing time, or percent reduction from baseline wound area or dimensions. The rationale for this approach was these SRs were packed with RCTs summarizing less biased, more dependable evidence supporting topical wound care efficacy than nonrandomized clinical trials, which can only support an intervention’s safety or suggest RCTs needed to prove its efficacy. This is why RCTs are so valuable in informing professionals whether the intervention is likely to work on patients and wounds they manage. The more compelling a SR’s RCT support of efficacy and safety and the more relevant to one’s own patients and wounds, the more valuable it will be in informing clinical decisions.

Results. The Cochrane Library search returned 22 Cochrane SRs. Ten SRs with no RCTs reporting relevant wound healing outcomes were excluded. The MEDLINE search found 5 more relevant Cochrane SRs for a total of 17 qualifying Cochrane SRs ^{53,61,66,74,76-88} and 4 additional similar non-Cochrane SRs,^65,89-91 increasing the total to 21 unique, relevant SRs. The same SRs from this literature search provided examples of SR RCT healing outcomes to inform clinical decisions summarized in Figure 1. To develop Figure 1, one author (LB) tabulated in an EXCEL file all RCT results from RCTs included in the Results or Analysis sections of the included SRs. Studies were tabulated summarizing numbers of subjects and listing whether any healing difference was statistically significant (P<0.05) as reported in any included SR Results section for each major wound etiology pertinent to the literature search. The number of studies reporting statistically significant healing benefits for each intervention for each major wound etiology were counted and displayed as stacked bars with each color corresponding to one of the major wound etiologies in Figure 1. Interventions with only 1 RCT supporting the topical agent were not included in Figure 1, because 1 RCT is not generally considered the highest level of evidence.⁹² 

Table 2 describes results of applying the SR readers’ checklist to guide critical thinking focused on meeting patient and wound needs. The second column shows clinical information that is still available despite flaws.

Using the checklist to critically analyze SRs. It is important to note most information in the Cochrane SRs was carefully searched and well documented. The few checklist issues reported in Table 2 most commonly involved inappropriate inclusion or exclusion of RCTs in the SR, omission of significant results from the SR Abstract, combining unlike wounds in meta-analyses, and misinterpretation of results leading to Abstract and Authors Conclusions that contradicted evidence summarized. Checklist flaws that could change SR conclusions were rare, found in only 3 of the 18 Cochrane SRs reviewed. In general, wound care professionals and patients are well served by these thorough reviews — they are laden with pearls of evidence capable of informing clinical decisions to improve outcomes.

In addition to the critical analysis of SR checklist flaws in Table 2, a pattern of 3 retractions was observed for honey interventions that may have potential to bias related literature and prevent access to RCTs, potentially biasing future SRs. Erasing from the literature a rigorously controlled RCT on 108 subjects reporting faster healing in large, sloughy venous ulcer dressed with foam dressings impregnated with honey compared to hydrogel⁶² presents a disservice to clinicians by rendering these clinically important data unavailable to inform practice or to include in future SRs. Without a clearer description of the rationale for retraction than “due to errors in the data analysis which affect the article’s findings,” it would seem more appropriate to have published an erratum statement clarifying and correcting the data analysis error(s). This would allow the valuable clinical information gleaned from this important study to continue to inform clinical decisions.

A second retraction⁹³ relating to the pH of wounds treated with honey may help explain findings of reduced antibiotic use^56,94 or earlier reduced bacterial burden^56,94-99 in burns, infected surgical sites, or diabetic foot ulcers receiving primary dressings impregnated with honey. Eradicating this research from the literature, rather than publishing a correction of any errors discovered, disserves clinical readers and researchers and interrupts the continuum of scientific discovery.

The third retraction¹⁰⁰ was a critical comment about inappropriate negative statements in the publication of a large RCT on small venous ulcers with varying “usual care” control interventions. A co-author on this RCT accurately clarified inappropriate statements that treating venous leg ulcers with honey dressings was “unlikely to help healing” stating, “The reality is that the results were inconclusive, not negative.” The retracted statement also clarified inappropriately negative interpretations of health economic and pain outcomes in this study. This disagreement between the 2 authors was retracted from the literature with no apparent explanation and no further effort to ensure a more accurate fair, balanced summary of the study results. Absence of this perspective may cause discrepancies in SRs of the topical honey literature.^61,65

Finding evidence in SRs to inform clinical decisions. Astute clinicians will view evidence from any SR through a lens focused on patient and wound needs, applying concepts such as those listed in the SR checklist to ensure a fair, balanced appraisal of relevant evidence. To illustrate how wound care professionals can search SRs to inform clinical decisions while compensating for checklist flaws such as those described in Table 2, Figure 1 displays numbers of RCTs reporting at least 1 significant (P<0.05) effect on any measured healing parameter in response to topical interventions for each of the major wounds listed. This is not a comprehensive SR meeting stringent definitions of what constitutes a healing benefit. Unlike a Cochrane SR, no judgment is made about individual study quality. The visual display illustrates a way to summarize best available RCT evidence, defined as RCTs meeting standards adequate for inclusion in at least 1 peer-reviewed SR, reporting recognized healing parameters relevant to informing clinical decisions about the common wounds represented. For a more stringent, comprehensive meta-review of all outcomes for local and systemic wound care, readers are referred to Brölmann et al.¹⁰¹

Figure 1 summarizes best available SR evidence from 169 RCTs involving 11,571 patients, favoring each specified topical intervention when compared to a control intervention on the indicated type of wound. Of these RCTs, the 78 that reported a statistically significant (P<0.05) healing benefit are summed for all clinical wounds reviewed. To avoid counting any study more than once, each RCT was counted only for the intervention reporting at least 1 statistically superior healing difference compared to at least 1 other control topical intervention in an RCT. For example, an RCT¹⁰² on 32 patients reporting faster healing (P<0.05) of skin graft donor sites dressed with foam dressings compared to nanocrystalline silver was counted only once in the visual display as supporting healing efficacy of foam dressings. Healing metrics qualifying for inclusion in any bar of Figure 1 included statistically significant improvement in time to complete epithelialization, percentage of wounds completely healed, and percent or absolute reduction in wound area or length, width, or depth. Including all healing parameters underscored the study time frame was too short for most chronic wounds to achieve complete epithelialization. This approach does inform readers of the most possible clinically relevant healing outcome information.

The top 8 interventions with the most evidence significantly supporting any healing parameter were in order of descending numbers of RCTs with significant supportive evidence:

1. Hydrocolloid dressings: 17 RCTs reporting a healing benefit (P<0.05) among 34 favorable healing RCTs on 2,487 patients, including 8 of 21 RCTs on 1,528 individuals with a venous ulcer, 4 of 5 RCTs on 364 pressure ulcers, 2 of 5 RCTs on 240 partial-thickness burns, 2 of 2 RCTs on 140 surgical wounds, and 1 of 2 RCTs on patients with 175 mixed chronic wounds;
2. Honey: 15 RCTs reported a healing effect (P<0.05) among 20 RCTs reporting any healing benefit on a total of 2,625 subjects. This included 9 out of 10 RCTs on 1,654 persons with partial-thickness burns, 3 of 5 RCTs on 375 patients with a mixed acute or chronic wound, 1 RCT each on 40 patients with an infected Caesarian section incision, 108 individuals with a large, 50% slough-covered venous ulcer, and 40 persons with a pressure ulcer;
3. Biosynthetic dressings: 10 RCTs reported a healing benefit (P<0.05) among 13 favorable RCTs on 498 patients with partial-thickness burns;
4. Iodine complexes: 9 RCTs reported a healing benefit (P<0.05) among 14 RCTs on 788 patients. All 9 significant RCTs studied people with a venous ulcer;
5. Silver compounds: 8 RCTs reported a healing benefit (P<0.05) among 20 RCTs on 2,267 patients, mainly on burns, with 1 RCT each on individuals with a pressure ulcer, venous ulcer, or mixed chronic ulcers;
6. Hydrogels: 5 RCTs reported a healing benefit (P<0.05) among 13 favorable RCTs on 993 patients. Significant effects were mainly on partial-thickness burns, diabetic foot ulcers, or venous ulcers;
7. Foam dressings: 3 RCTs reported a healing benefit (P<0.05) among 16 favorable RCTs on 807 patients. Significant effects were reported in 1 RCT each on individuals with a diabetic foot ulcer, venous ulcer, or a surgical wound;
8. NPWT: 3 RCTs reported a healing benefit (P<0.05) among 6 favorable RCTs on 184 patients with a diabetic foot ulcer or a venous ulcer or on persons with an acute or chronic wound of any origin.

Limitations. Only healing outcomes are summarized visually in Figure 1. Future summaries may address other measured outcomes, such as patient-reported pain, incidence of infections or antibiotic use, debridement, restoration of negative wound cultures, quality of life, or economic outcomes. The visual display does not summarize comparisons within any dressing category; for example, comparing one foam dressing with another would not inform a clinical choice to use a primary foam dressing compared to some other topical intervention.

The results’ visual display illustrates how much RCT information one can glean from SRs that can help inform wound care decisions about topical agent healing RCT-level evidence. Figure 1 is not intended to fulfill the higher purpose of judging study quality or sufficiency of evidence as many SRs do. It simply summarizes the volume of evidence supporting each topical intervention by counting RCTs and patients with the indicated wounds, focusing on RCTs supporting statistically significant (P<0.05) healing differences favoring each intervention listed.

Only healing outcomes such as increased percent of patients achieving a predefined healing outcome (eg, 100% epithelialization) or reductions in wound dimensions (length, width, depth) or area or time to heal are displayed in Figure 1. The figure does not summarize other important wound-related outcomes, such as time to achieve a bacteria-free wound culture, patient-reported pain reduction, improvement in health-related quality of life, or measured debridement parameters. RCTs with >30% of intent-to-treat patients withdrawn before the healing outcome was measured were not included, because they may unfairly represent the clinical population sampled. In addition, interventions with only 1 RCT significantly supporting healing on only 1 clinical indication found in the SR search were not included in the visual display. These were: amniotic membrane, benzoate complex, benzoyl peroxide, dextranomer beads, enzymes, ethacridine lactate, film dressings, mupirocin, phenytoin, or saline gauze.

A limitation of focusing on Cochrane SRs was that examples found in this limited search did not contain all healing RCTs on all the listed indications. For example, several recognized RCTs on growth factors or on hydrocolloid dressings did not appear in the SRs returned by the search. This review did not seek to perform a comprehensive search of all healing RCTs, only to identify enough SRs to illustrate 1) how to use the SR reader’s checklist to identify possible flaws and 2) ways to look past SR flaws to wield evidence of sufficient quality to meet Cochrane inclusion standards to inform clinical practice.

Conclusion

Wound care professionals have final responsibility for their patients. SRs or the RCTs they contain such as those summarized for healing (see Figure 1) can help inform decisions about patients and wound care, but they may not preempt clinicians’ decisions. Unlike content-validated guidelines, based on evidence plus expert opinion or, in some cases independently compiled content validation,⁶⁷ SRs should not recommend a course of action. A SR is designed to tell readers if evidence is sufficient to inform clinical decisions about comparative efficacy and/or safety of an intervention on a given type of wound. Only involved wound care professionals know the patient’s wound care needs and capabilities well enough to select the right care. The responsibility for knowing and applying best available evidence to inform care decisions that can improve patient outcomes belongs solely to responsible care providers. Limited time and resources make it essential to use the best quality evidence available.

Cochrane reviewers have provided important summaries of best available evidence on wound care options. Even if the compiled evidence is insufficient to support practice decisions by Cochrane standards, it represents a good source of the best available evidence, providing helpful perspective to supplement basic wound care knowledge. Authors of each SR have saved wound care providers time and effort of compiling and analyzing the RCT evidence. Implications for practice are substantial. Even if a SR contains potential issues such as those described in Table 2, wound care professionals can look past the flaws to examine evidence compiled for relevant statistically significant outcomes that may help inform decisions to meet patients’ needs. By using best available evidence found in a SR, a person stands on the shoulders of past researchers to see a bit further, better informing clinical decisions. If a wound care professional focuses on patient and wound challenges at hand while reading the Results section of a SR, its best available evidence, even if imperfect or “insufficient”, informs clinical decisions better than opinion alone. Future research will help determine how intermediate findings become compelling standards of care. 

Acknowledgment

The authors gratefully acknowledge this work was supported by an unrestricted educational grant from Derma Sciences, Inc, Princeton, NJ. Neither author has any financial interest in Derma Sciences, Inc. Dr. Bolton consults for Derma Sciences, Inc on the development of acleristide, a topical active agent to treat diabetic foot ulcers unrelated to the topic of systematic reviews. 

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79.       Dumville JC, O’Meara S, Deshpande S, Speak K. Alginate dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2013;6:CD009110.

80.       Dumville JC, Deshpande S, O’Meara S, Speak K. Foam dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2013;6: CD009111.

81.       Dumville JC, Deshpande S, O’Meara S, Speak K. Hydrocolloid dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2013;8:D009099.

82.       Dumville JC, O’Meara S, Deshpande S, Speak K. Hydrogel dressings for healing diabetic foot ulcers. Cochrane Database Syst Rev. 2013;7: CD009101.

83.       Hoogewerf CJ, Van Baar ME, Hop MJ, Nieuwenhuis MK, Oen IM, Middelkoop E. Topical treatment for facial burns. Cochrane Database Syst Rev. 2013;1:CD008058.

84.       Martinez-Zapata MJ, Martí-Carvajal AJ, Solà I, Expósito JA, Bolíbar I, Rodríguez L, Garcia AJ. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2012;10:CD006899.

85.       O’Meara S, Martyn-St James M. Alginate dressings for venous leg ulcers. Cochrane Database Syst Rev. 2013;4:CD010182.

86.       Storm-Versloot MN, Vos CG, Ubbink DT, Vermeulen H. Topical silver for preventing wound infection. Cochrane Database Syst Rev. 2010;3:CD006478.

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94.       Kamaratos AV, Tzirogiannis KN, Iraklianou SA, Panoutsopoulos GI, Kanellos IE, Melidonis AI. Manuka honey-impregnated dressings in the treatment of neuropathic diabetic foot ulcers. Int Wound J. 2014;11(3):259–263.

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96.       Moghazy AM, Shams ME, Adly OA, Abbas AH, El-Badawy MA, Elsakka DM, et al. The clinical and cost effectiveness of bee honey dressing in the treatment of diabetic foot ulcers. Diabetes Res Clin Pract. 2010;89(3):276–281.

97.       Mphande AN, Killow C, Phalira S, Jones HW, Harrison WJ. Effects of honey and sugar dressings on wound healing. J Wound Care. 2007;16(7):317–319.

98.       Subrahmanyam M. Honey impregnated gauze versus polyurethane film (OpSite) in the treatment of burns – a prospective randomised study. Br J Plast Surg. 1993;46(4):322–323.

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100.    Molan P. Comment on Jull A, Walker N, Parag V, Molan P, Rodgers A. Honey as Adjuvant Leg Ulcer Therapy trial collaborators. Randomized clinical trial of honey-impregnated dressings for venous leg ulcers. Br J Surg. 2008;95(2):175–182. Comment in: Evidence-based Nurs. 2008;11(3):87.

101.    Brölmann FE, Ubbink DT, Vermeulen H, Evidence-based decisions for local and systemic wound care. Available at: www.bjs.co.uk. Accessed March 10, 2013.

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Potential Conflicts of Interest: This work was supported by an unrestricted educational grant from Derma Sciences, Inc (Princeton, NJ). Neither author has any financial interest in Derma Sciences, Inc. Dr. Bolton consults for Derma Sciences, Inc on the development of acleristide, a topical active agent to heal diabetic foot ulcers. 

Abstract

Offloading heel ulcers is a challenging task because strategies deemed to be most optimal from a medical perspective may be unacceptable to patients. Observed adverse dressing events and problems with offloading devices led to a pilot study and subsequent change in practice at the authors’ Foot and Leg Ulcer Clinic.

Starting in 2004, patients requiring offloading received a nonremovable padded heel dressing (PHD) that was changed twice a week by the visiting nurse. A retrospective quality improvement review was conducted to compare outcomes, nursing visits, and nursing visit costs for 40 consecutive patients with heel ulcers treated at this clinic with a nonremovable PHD (n = 20) or without a PHD (n = 20) between January 20, 2001 and December 31, 2006. Patient demographic data, relevant comorbidities, wound depth, weeks of care, adverse events, and treatment-related narrative comments were abstracted from patient records. Relevant comorbidities were similar in both groups. The PHD group was younger (average age of 74.6 [range 35–91] years) compared to PHD nonuse group (average age 79.5 [range 25–95] years; P<0.04). The PHD group required fewer total weeks of care compared to the nonuse group  (368 versus 527 weeks, respectively; P<0.001), and average duration of clinic treatment in the PHD group was 18.40 (range 5–51) weeks versus 40.54 (range 6–88) weeks in the nonuse group. The PHD group had fewer total nursing visits (736 versus 1,581, P<0.001); the average number of nursing visits for the PHD was 36.80 (range 10–102) compared to 121.61 (range 18–264) for the nonuse group. Nursing visit costs were lower for PHD users ($114,080 versus $245,055, P<0.001), and the cost-efficiency ratio was less than one third (1:3.3) of PHD nonuse for the average heel ulcer. All 20 patients in the PHD use group had wound closure compared with the PHD nonuse group, in which 13 out of 20 wounds closed, 3 amputations were performed, and 4 patients were lost to review (P<0.000). No adverse events were reported in the records of the PHD use group; the PHD nonuse group reported periwound maceration, skin stripping, pressure injury, and sensitivity. Patient and nurse feedback identified pain relief, improved mobility, easy technique, low cost, and reduced workload as benefits of PHD. The results of this quality improvement review warrant a prospective clinical study to examine the efficacy, effectiveness, and cost-effectiveness of PHD for the care of patients with heel ulcers.  

Heel ulcers are a life-altering condition associated with a substantial risk for delayed healing, infection, amputation, or death.¹ The quality-of-life impact is noteworthy; patients with diabetes who have experienced foot ulcers have a better quality of life with healed than with open ulcers and a lower quality of life if amputation was required.^2-4 Among pressure ulcers, the heel is the second most common anatomical ulcer site after the sacral area.⁵ The incidence of heel ulcers has been reported to be between 19% and 32% in patients with and without diabetes in acute and residential care facilities, respectively.¹ Improving ulcer healing, reducing amputations, and preventing ulcer reoccurrence requires knowledge of the etiology of heel ulcers and critical evaluation of efficacy of interventions.

Anatomy of the heel. Plantar soft tissue, a specialized, pressure-absorbing, closed-cell structure of fibrous septae-containing adipocytes, serves to protect the structures of the foot.⁶ Just below the dermis, this tissue is organized into microchambers; deeper in the foot, over bone or tendon, plantar soft tissue is organized into macrochambers. The plantar soft tissue covering the calcaneus is commonly known as the heel pad. The soft tissue layer covering the calcaneus, lateral foot, metatarsal heads, distal phalanges, and distal hallux is thicker than over the medial foot, proximal hallux, and proximal and intermediate phalanges (see Figure 1). When a person is standing, pressure is unevenly distributed over the plantar surface, with the highest pressure over the heel; the first, second, and third metatarsal heads; and the hallux. 

The principal arteries supplying the heel are the posterior tibial and peroneal arteries.⁷ The subdermal plexus and periosteal plexus are well vascularized, with vessels within the fibrous septae that travel between the 2 arteries. The panniculus canosus muscle, located in the subcutaneous tissue, is sensitive to damage from pressure, mechanical trauma, and shear. These forces also may injure blood vessels and other tissues of the foot. A unique feature of plantar adipose tissue is that it is not replaced after injury or loss, and maintenance of the resilient, shock-absorbing heel tissue depends on pressure absorption, adequate arterial supply, and prevention of injury.

Risk factors for heel ulcers. Reviews of the literature^1,5 list the causes of heel ulcers as callus, trauma, diabetes, foot deformities, neuropathy, peripheral arterial disease, reduced joint mobility, and limb immobility. Hsu et al⁸ studied a convenience sample of 33 volunteers with no heel problems to determine the effect of age on the mechanical properties of the heel pad. Two groups, divided by age into young (18–36 years) and elderly (62–78 years), were provided ultrasound examination of the heel pad during sequential loading and unloading using increments of 0.5 kg to a maximum of 3 kg to produce a load-displacement curve. Heel pads were found to be significantly thicker, more compressible, and less elastic in the elderly (all P<0.001). The combination of these findings, along with the increased fragmentation of elastic fibers and collagen reduction occurring with age, may help explain the reduced pressure absorbency of the heel pad and higher risk of tissue injury in older individuals. 

Multiple factors may be linked to diabetic foot ulcer development. Reiber et al⁹ used the Rothman model of causation, a blinded multidisciplinary group of foot specialists, and a modified Delphi process to identify causal pathways for 92 persons with diabetes and diabetic foot ulcers from Manchester, United Kingdom and 56 from Seattle, WA. The process identified a critical triad of neuropathy, minor foot trauma, and foot deformity in the causal pathway of 63% of patients. Edema and ischemia were present in more than one third of cases. Single causes were callus formation (30%), trauma (6%), and edema (1%).

Descriptive studies^10-12 focusing on preventing heel ulcers or characterizing patients with heel ulcers, conducted in inpatient and community settings, indicate risk assessment tools, such as the Braden Scale for Predicting Pressure Sore Risk, appear to be relatively insensitive to risks associated with heel ulcer development, at times placing patients with ulcers in the mild or not-at-risk categories.

Pressure Offloading in Heel Ulcer Management

A Cochrane review found nonremovable, pressure-relieving casts are more effective in healing foot ulcers in persons with diabetes mellitus than removable casts or dressings alone.¹³ A systematic review and meta-analysis¹⁴ of the clinical effectiveness of different offloading devices found any type of nonremovable offloading device to be more effective than removable devices in the treatment of diabetic foot ulcers, likely because patient adherence is facilitated. At this time, pressure offloading with a total contact cast (TCC) or instant total contact cast (iTCC) is considered the optimal method of pressure management in patients with foot ulcers; both options are considered equally effective.^15,16 Although TCC and iTCC are effective for offloading, these devices may be associated with clinical disadvantages, including joint stiffness, muscle atrophy, and the risk of new ulceration; elderly, frail, or immobile patients may not tolerate TCC.^17-19 An additional concern is the need to transition offloading effectively to maintenance footwear (both shoes and slippers) to prevent recurrence.¹⁷ However, in terms of heel ulcer prevention, a systematic review²⁰ of pressure redistribution strategies and heel protection devices found insufficient evidence to select any particular device over a foam pillow.

A prospective pilot study²¹ compared a “football” dressing (consisting of a topical silver primary wound dressing, cast padding, and a self-adhesive wrap) with TCC or iTCC in 15 patients with chronic neuropathic ulcers that had a mean duration of 6 weeks. All 15 patients healed in 3.80 ± 2.60 weeks (range 1–10 weeks), but pressure relief over the metatarsal heads was 30% less with the football dressing than with TCC or iTCC. The incidence of infection was similar in both groups, and no dressing-related injuries were reported. A retrospective, multicenter analysis²² of the football dressing confirmed these findings and concluded the wound outcomes, coupled with ease of application and low cost, made the football dressing a useful choice in managing foot ulcers. 

Dressing-related and offloading device-related injury. In the authors’ clinic, dressings and offloading devices have been linked with adverse events contributing to patient injury. Dressing-related injuries observed included periwound maceration, skin stripping, and pressure injury (see Figure 2). 

Offloading devices may contribute to pressure ulcer development, foot-drop, or lower limb rotation; thorough patient assessment is essential before selecting a device to reduce these risks. It is critical to consider the impact of the loss of protective sensation, peripheral arterial disease, infection, and exudate management.¹⁷ It is also important to examine patients while they are using the device and to assess comfort and any impact on their ability to reposition, stand, or walk.

Adverse events and patient intolerance may be associated with interventions such as the use of pillows to “float” the heel, heel protectors, and nonremovable or removable pressure-relief devices. Although clinical guidelines recommend the use of pillows to float the heel, it is essential to ensure adequate calf support to prevent Achilles pressure ulcers.²³ Incorrect placement or displacement because of patient movement may result in Achilles tendon pressure ulcer development, especially in the presence of peripheral arterial disease. Removable devices, such as the Aircast^® (Aircast Inc, Vista, CA) or ankle foot orthoses, have been noted in the authors’ clinic to cause pressure injury, trauma to the unaffected limb, and patient complaints of back or hip pain. Figure 3 illustrates pressure injuries associated with offloading interventions. 

Evolution of the Padded Heel Dressing

The padded heel dressing (PHD) was conceived at the Foot and Leg Ulcer Clinic in Victoria, British Columbia (BC), when one of the authors, a clinical wound specialist, wrapped a heel ulcer in a patient with advanced peripheral arterial disease with cast padding in an attempt to relieve his intractable pain. The patient experienced immediate pain relief and was able to ambulate wearing running shoes with laces adjusted for the dressing size. Previously, he had been unable to tolerate use of an Aircast because of back and hip pain experienced with the device. Protected by the PHD, the ulcer healed in 2 months.

Pressure mapping. The clinic team then performed a pressure mapping study in 5 healthy adult volunteers (2 men, 3 women) to determine if the PHD affected heel pressure. The volunteer sat on a plinth at 45˚ with the foot straight in a natural comfortable extension. A CONFORMat^® (Tekscan, Boston, MA) was placed under the heel. Measurements were performed for a bare heel as a baseline and for 1-roll and 2-roll padding with 4-inch Zimmer Orthopedic Cast Padding (Zimmer Orthopedic Surgical Products, Dover, OH) to determine appropriate dressing recommendations. Compared with the baseline pressure for a bare heel, average pressure reductions were 23% with 1 roll of padding and 39% with  2 rolls of padding (see Figure 4). This pressure-mapping result indicates the PHD may reduce heel pressure. 

Pilot project. To address existing issues with standard dressings (including adverse events), facilitate offloading for heel ulcers, and potentially provide PHD pain relief, the clinic team decided to conduct a pilot study of the PHD among primary care nurses treating patients in both community and residential care settings. The team trained the nurses on dressing application procedure (see Table 1) and evaluated outcomes after the first 10 cases. Nurses reported the PHD was easy to apply, stayed intact between twice-weekly dressing changes, improved exudate control, facilitated wound healing, resolved the problem of periwound skin stripping, required fewer dressing changes, and reduced confusion about dressing selection. With a cost of between $6 and $8 CAN, the PHD was less expensive than previously used heel dressing of various types (eg, hydrocolloid, foam, alginate) with or without a topical antimicrobial product that ranged from $12.50 to $25.00 per change except for adhesive bandages, gauze, and gauze wrap, which cost $0.50 to $5.00. Patients using the PHD could wear loose clothing and resume social activities. Ambulatory patients could use footwear modified by an occupational therapist or pedorthist to ambulate at their previous level; nonambulatory patients could reposition themselves independently; and immobile patients were easier for staff to reposition. Community and residential management reported reductions in nursing time, number of dressing changes, and dressing product inventory.

Based on the results of the community and residential pilot of the PHD, in 2004 the Foot and Leg Ulcer Clinic decided to recommend the PHD for heel ulcers, and in 2007 a quality improvement review was approved.

Quality Improvement Review

The quality improvement review analyzed data from a retrospective chart review to answer the following questions:

1. Did patient characteristics (age, peripheral arterial disease, diabetes, and neuropathy) differ between the PHD use and nonuse groups?
2. Did ulcer outcomes (closure, amputation, and lost to review), weeks of care, number of nursing visits, nursing costs, and cost-efficiency ratio (CER) differ between the PHD use and nonuse groups?
3. What were the average weeks of care, nursing costs, and CER for the PHD use and nonuse groups by depth of tissue involved (superficial skin and muscle, heel pad or tendon, and bone)?
4. What was the feedback from primary care nurses and management about adverse events, utility, cost, and satisfaction for the PHD use and nonuse groups?
5. What feedback did patients in the PHD use and nonuse groups provide about dressings and offloading devices, dressing experience, pain relief, comfort, physical activity, social interaction, and quality of life?

Methods

Standard care at the Foot and Leg Ulcer Clinic. The standard care at the clinic for lower extremity ulcers involves a comprehensive multidisciplinary admission assessment, including comorbidity assessment, lower limb vascular assessment, neuropathy screening, infection screening, ulcer assessment and wound management, pressure offloading, gait analysis, and footwear assessment. Additional investigations, treatments, and referrals are performed as required to manage identified problems.

After comprehensive assessment, investigation, and setting care priorities at the clinic, patients return with their care plans (including information about patient risks) to their primary care providers for management. Primary care providers consult with the clinic as required, and the clinic team reviews each patient monthly or more frequently, if necessary.

All primary care providers using the PHD were provided with an illustrated procedure used in the clinic (see Table 1) and access to application training. Primary care nurses continued using the PHD for 2 weeks after ulcer healing to allow the pedorthist adequate time to arrange for appropriate footwear to reduce the risk of ulcer recurrence. The only difference in wound management was the use or nonuse of the PHD for wound management and offloading the heel ulcer. 

Patient population. Patient data analyzed for the quality improvement review were collected from regional health authority records on patients with heel ulcers who had been treated at the Foot and Leg Ulcer Clinic between January 20, 2001 and December 31, 2006. Patient records were hand-searched to identify the study population, which comprised a convenience sample of 20 consecutive patients with a heel ulcer who had been treated with the PHD throughout their treatment and 20 consecutive patients with a heel ulcer who had been treated with an alternative dressing. Patients with heel ulcers that were referred for amputation after the clinic admission assessment were excluded. 

Clinic patients routinely provide consent for treatment and have consented that clinical data may be used for clinical, education, or research purposes. In addition, patients were consulted and agreed to treatment throughout their care process. As a result, the Research Ethics Committee in Victoria, British Columbia, decided ethical approval was not required for performing the PHD quality improvement review.

Data abstraction and analysis. Members of the clinic team extracted the following data from patient records: patient age; presence of peripheral arterial disease, diabetes, or neuropathy; deepest tissue involved in the heel ulcer (superficial skin and muscle, heel pad or tendon, or bone); wound outcomes (closed, amputation, or lost to review); weeks of care; number of nursing visits; and adverse events. 

Documented information about the patient’s mobility status, pain, and dressing experience was extracted for the purposes of the review. Consultation with primary care nurses and residential care management contributed feedback about their perception of the role of the dressings in patient care, social functioning, and operational considerations such as cost, inventory management, and elimination of dressing selection confusion. Feedback from patients and primary care nurses was discussed by the 2 wound specialist clinic nurses and noted, but not tabulated, in a log book to inform beneficial clinical changes (eg, the illustrated PHD application procedure) and guide development of a heel ulcer management plan.

The clinic nurses entered the data into Microsoft Excel spreadsheets. The Department of Mathematics and Statistics at the University of Victoria provided assistance in performing the statistical analysis of comparisons for the total PHD use and nonuse groups of wound outcomes (one-way ANOVA) and comorbid conditions and age (Pearson chi square). The clinical wound specialist calculated the CER, which quantifies the differences in cost between alternatives, for the PHD use group compared with the PHD nonuse group by dividing the higher by the lower cost. Patient data for average weeks of care and average nursing visit costs also were analyzed by depth of tissue involved and the CER calculated for these averages by the clinical wound specialist.

Results

Patient demographics. A significant difference (P<0.04) was found between the groups for age; the PHD nonuse group was older (average age 79.5 [range 25–95 years] versus 74.6 [range 35–91 years). No difference was found in the proportion of patients with comorbid diseases, peripheral arterial disease, diabetes, neuropathy, or ulcer depth classification (see Table 2). 

Wound outcomes. Overall wound outcomes differed significantly (P<0.000) between the groups; 20 out of 20 (100%) heel ulcers closed in the PHD use group, compared with 13 out of 20 for the PHD nonuse group. Total weeks of care was significantly shorter for the PHD use than the nonuse group (368 versus 527 weeks, respectively; P<0.001). The PHD nonuse group had 3 amputations and 4 patients lost to review; all resided in nonaffiliated care agencies where data for duration of care, number of nursing visits, and nursing visit costs were not accessible. To compensate for missing data, the averages and range data for known heel ulcer patients were used to compare duration of care, number of nursing visits, nursing visit costs, and CER. 

The number of nursing visits, a measure of the number of weeks for ulcer closure plus 2 weeks, was significantly greater in the PHD nonuse than in the use group (1,581 versus 736, respectively; P<0.001). The cost of nursing visits, based on an administrative cost for a community or clinic visit of $155 CAN, was significantly greater for the PHD nonuse (n = 13) than the PHD use (n = 20) group ($245,055 versus $114,080, respectively; P<0.001). A CER of 1:3.3 for the average heel ulcer indicates the cost of nursing visits for the PHD nonuse was more than 3 times higher than the PHD use group.

Depth of tissue involvement. To gain insight into the influence of the depth of tissue involvement on the number of nursing visits, nursing visit costs, and CER, per-patient averages were calculated for both groups for each depth of tissue involved (see Table 3). On admission, the number of heel ulcers by depth was equal for use and nonuse groups: 10 superficial, 6 heel pad and 4 bone. Data were not available for the PHD nonuse group due to amputations and lost patients, leaving 7 (out of 10) superficial, 4 (out of 6) heel pad, and 2 (out of 4) bone tissue depth ulcers. PHD group average weeks of care were 15, 12, and 39 compared to the PHD nonuse average weeks of care of 32, 37, and 83 for superficial, heel pad, and bone, respectively

The average number of nursing visits and nursing visit costs were lower in the PHD use group than in the PHD nonuse group for ulcers of all tissue depths. Average nursing costs for the PHD group included $4,588 (superficial), $4,288 (heel pad), and $12,168 (bone) compared to costs in the PHD nonuse group of $14,946 (superficial), $19,898 (heel pad), and $38,595 (bone). The CER demonstrates that compared to the PHD use group, the nursing visit costs for the PHD nonuse group were 3.3 times greater for superficial ulcers, 2.31 times greater for ulcers reaching the heel pad or tendon, and 3.17 times greater for ulcers reaching bone (see Table 3). 

Adverse events. No adverse events were reported in the PHD use group, whereas periwound maceration, skin stripping, pressure injury, inadequate exudate management, premature detachment, contact dermatitis, and pressure injury associated with an ankle foot orthosis (possibly related to improper fit or application) were reported in the PHD nonuse group.

Pain and patient experience. Patients in the PHD use group infrequently reported heel ulcer pain, resumed their previous level of physical activity, and participated in social activities. Previous dressings were associated with several patient concerns, such as inadequate exudate management, skin problems, and odor, but these concerns were not reported with the PHD. Both patients and care providers reported the PHD was less awkward, lighter, and easier to apply than heel offloading devices they had used previously.

Patients who declined or discontinued commercial heel offloading devices such as the Aircast because of price, inability to walk or imbalance, back or hip pain, and the weight of device were able to tolerate the PHD as an alternative.

Discussion

Pressure offloading is a critical factor in achieving wound closure in heel ulcers. The superior effectiveness of the TCC and the iTCC over removable devices is supported by strong evidence.^15-17,24 Although these devices are recommended as first-line offloading options, clinical experience indicates they tend to be underused in practice because they can be both expensive and difficult for patients to manage: they are heavy, restrictive, and can cause balance problems.¹⁸ These physical disadvantages can be especially important to the population with heel ulcers, often elderly, who may have limited physical capacity for standing, walking, or repositioning. In addition, TCC is usually contraindicated in the presence of infection or ischemia and there is insufficient evidence for the management of heel ulcers, because TCC may transfer significant pressure to the posterior foot.^17,18

An online survey²⁵ of Australian podiatrists investigated the offloading strategies used for patients with diabetes-related plantar neuropathic ulcers; the survey respondents considered patient adherence, adverse effects, psychosocial factors, restrictions to patients’ daily life, and wound features when selecting an offloading option. Of the 36 (out of 41, 88%) who responded to the survey, the majority of participants (30, 83%) considered nonremovable casts or walkers to be the gold standard for offloading plantar ulcers based on the evidence. However, numerous barriers, especially patient-related issues, made nonremovable casts their last choice for offloading in clinical practice after felt padding and removable casts or walkers. Participants identified numerous patient barriers to use of nonremovable devices, including lack of acceptance of or inability to tolerate a nonremovable device, poor adherence to instructions, negative impact on patient lifestyle, issues with transportation or driving, and difficulties managing the device in the patient’s home environment. Wound-related barriers identified by respondents included a reduced ability to monitor and dress the wound. In addition, study participants believed highly exudative, deep, large, or infected wounds requiring frequent monitoring or care were unsuitable for nonremovable casts. Practitioner-related barriers to the use of nonremovable devices generally included the need for adequate staff resources, primarily in terms of time, expertise, and on-call emergency availability. Armstrong et al²⁶ discussed contraindications for TCC (soft tissue infection, osteomyelitis, or peripheral arterial disease) and cautioned use for heel ulcers due to excessive pressure on the hind foot.

The results of the survey²⁵ demonstrate identifying the most appropriate offloading strategy for an individual patient can be a complex process requiring consideration of multiple variables. Furthermore, the results highlight the need for broad-based research into factors affecting the success of offloading strategies, including patient experience, quality of life, and the effectiveness of alternative offloading approaches. Generating such information could help guide selection of an offloading strategy when the TCC and iTCC are either unsuitable or not accepted by the patient.

This retrospective quality improvement review found the PHD can overcome many patient-related barriers associated with use of other nonremovable offloading devices such as the TCC and iTCC. The ability of patients to maintain their previous physical activities with the PHD helps prevent deconditioning from mobility restrictions with other devices. Furthermore, because patients can wear running shoes with the PHD, balance is not affected as it can be with more cumbersome devices. The PHD is also fast and simple for clinicians to apply, and the clinician is able to monitor wound healing because the PHD is changed twice weekly.

Limitations

The Foot and Leg Ulcer Clinic is a referral clinic that serves a specific patient population with complicated conditions. Patients may be referred to the clinic for nonresponse to therapy, debridement of necrosis, wound deterioration, amputation risk, clinical management problems, or other complications. As a result, the outcomes of this quality improvement review apply to dressing selection in this high-risk population. In addition, because a quality improvement review is a decision-making support tool, not a clinical trial, a prospective clinical trial is needed to evaluate the outcomes obtained in this review.

Conclusion 

A quality improvement review demonstrated good clinical outcomes in terms of number of ulcers healed, number of nursing visits required, and decreased costs with the PHD. Based on the positive outcomes of this retrospective review, it would be beneficial to investigate the performance of the PHD as a dressing, a nonremovable offloading device, and a preventive strategy for the management of primary and the prevention of recurrent heel ulcers. 

Acknowledgments

This quality improvement review was independent of any corporate influence. The authors thank the clinic team and patients who consented to have their pictures and experiences accessible for education and research purposes. Thank you also to Karen Li of the British Columbia Ministry of Health, who performed the statistical analysis and consulted on interpretation of the data. Editorial support was provided by Joanna Gorski of Prescriptum Health Care Communications Inc.

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10.       McElhinny ML, Hooper C. Reducing hospital-acquired heel ulcer rates in an acute care facility: an evaluation of a nurse-driven performance improvement project. J Wound Ostomy Continence Nurs. 2008;35(1):79–83.

11.       Clegg A, Kring D, Plemmons J, Richbourg L. North Carolina wound nurses examine heel pressure ulcers. J Wound Ostomy Continence Nurs. 2009;36(6):635–639.

12.       Walsh JS, Plonczynski DJ. Evaluation of a protocol for prevention of facility-acquired heel pressure ulcers. J Wound Ostomy Continence Nurs. 2007;34(2):178–183. 

13.       Lewis J, Lipp A. Pressure-relieving interventions for treating diabetic foot ulcers.  Cochrane Database Syst Rev. 2013;1:CD002302.

14.       Morona JK, Buckley ES, Jones S, Reddin EA, Merlin TL. Comparison of the clinical effectiveness of different off-loading devices for the treatment of neuropathic foot ulcers in patients with diabetes: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2013;29(3):183–193.

15.       American Diabetes Association. Consensus Development Conference on Diabetic Foot Wound Care, Boston, Massachusetts. American Diabetes Association. Diabetes Care. 1999;22(8):1350–1360.

16.       Piaggesi A, Macchiarini S, Rizzo L, et al. An off-the-shelf instant contact casting device for the management of diabetic foot ulcers: a randomized prospective trial versus traditional fiberglass cast. Diabetes Care. 2007;30(3):586–590.

17.       Snyder RJ, Lanier KK. Diabetes: Offloading Difficult Wounds. Available at http://lermagazine.com/article/diabetes-offloading-difficult-wounds. Accessed September 19, 2015.

18.       Armstrong DG, Isaac AL, Bevilacqua NJ, Wu SC. Offloading foot wounds in people with diabetes. Wounds. 2014;26(1):13–20.

19.       Mulder G, Alfiere D. The diabetic foot: considerations for pressure reduction and off-loading. Prim Inten. 2007;15(2):58–65.

20.       Junkin J, Gray M. Are pressure redistribution surfaces or heel protection devices effective for preventing heel pressure ulcers? J Wound Ostomy Continence Nurs. 2009;36(6):602–608.

21.       Rader AJ, Barry T. Football dressing for neuropathic forefoot ulcerations. Wounds. 2006;18(4):85–91.

22.       Rader AJ, Barry TP. The football: an intuitive dressing for offloading neuropathic plantar forefoot ulcerations. Int Wound J. 2008;5(1):69–73.

23.       National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance. Prevention and Treatment of Pressure Ulcers: Quick Reference Guide. Perth, Australia: Cambridge Media:;2014:26–27.

21.       Katz IA, Harlan A, Miranda-Palma B, et al. A randomized trial of two irremovable off-loading devices in the management of plantar neuropathic diabetic foot ulcers. Diabetes Care. 2005;28(3):555–559.

22.       Raspovic A, Landorf KB. A survey of offloading practices for diabetes-related plantar neuropathic foot ulcers. J Foot Ankle Res. 2014;7:35.

23.       Armstrong DG, Isaac A, Bevilacqua NJ, Wu SC. Offloading foot wounds in people with diabetes. Wounds. 2014;26;1:13–20.

Potential Conflicts of Interest: none disclosed

Ms. N. Campbell was the Clinical Specialist (Wound Care), Ms. D. Campbell was a Clinical Leader, and Ms. Turner is presently an Acting Clinical Leader at the Foot and Leg Ulcer Clinic, Vancouver Island Health Authority, Vancouver, British Columbia, Canada. Please address correspondence to: Andrea C. Turner, 5631 West Saanich Road, Victoria, BC V9E 2G1, Canada; email: aturner@shaw.ca.

Abstract

The term constipation with regard to patients with a stoma is defined as impaired bowel movements associated with increased stool consistency or long periods without bowel movements that lead to discomfort, flatulence, and abdominal pain. Information about constipation in patients with a stoma is limited. A prospective, descriptive study was conducted among patients attending ostomy and proctology outpatient clinics in Poznan, Poland between January 2011 and December 2014 to assess the role of dietary and pharmacological strategies in the management of constipation in patients with a stoma.

Patients were included if they experienced a 3-day period without bowel movements leading to abdominal discomfort and bloating. Patients who were terminally ill from neoplastic disease or could not provide informed consent for study participation were not eligible to participate. Patients underwent 3 evaluations 3 months apart: the first assessed problems with passing stool through the stoma, at which time patients were told to increase fiber and fluid intake. During the next 2 visits, patients were asked if their symptoms had improved. If dietary changes were not successful, first-line pharmacological interventions were suggested (laxatives, osmotic agents, and probiotics). If no improvement was reported during the third assessment, second line pharmacologic therapy (eg, stimulant laxatives) were prescribed. Of the 405 patients initially assessed for participation, 331 met the initial screening criteria and were scheduled for follow-up. Of those, 93 (28%) had constipation; 50 (15%) required a surgical referral for morphological stoma changes and 43 (12.9%) met the study inclusion criteria for dietary recommendations. Almost all (42) had a colostomy and most (28) had a history of stoma creation due to diverticular disease. Twenty-five (25) men and 18 women (average age 55.9 ± 9.3 years) received dietary recommendations during the first visit. Diet modifications were effective and sufficient to resolve the problem with constipation in more than half (24) of the patients. Among the remaining 19 patients, only 2 did not improve after using first-line or second-line pharmacological management strategies. One patient required emergency surgery due to complicated colonic diverticulosis (perforation). The results of this study suggest constipation among patients with a stoma can be associated with morphological stoma changes and in the absence of morphologic changes the majority of patients respond well to a change in diet. Additional studies are needed to increase understanding about the incidence and optimal management strategies of constipation in persons with a stoma.

One of the goals of modern colorectal surgery is to preserve the anal sphincters and maintain physiological colonic transit. However, in some clinical situations, creating a stoma is unavoidable, recommended, or crucial to save a patient’s life. The creation of an artificial anus may impair overall quality of life. Patients with stomas may experience certain disorders associated with colonic transit, including chronic constipation. In their technical review, Bharucha et al¹ found the overall median prevalence of constipation in the general population is 16% (range 0.7%–79%) in adults and 33.5% in adults 60 to 101 years old. Most, but not all, studies suggest the prevalence of constipation in the general population is higher in the non-Caucasian population than in the Caucasian population and also higher in women (median female-to-male ratio of 1.5:1).² A cross-sectional survey³ conducted in various settings found general health, mental health, and social functioning were impaired in patients with constipation as compared to healthy patients in the control group, particularly among hospitalized patients in comparison to patients in the community.

The term constipation is rarely used with regard to patients with a stoma. It is difficult to quantify the frequency of bowel movements in this group of patients. Constipation among patients with a created stoma is defined as impaired bowel movements associated with increased stool consistency or long periods without bowel movements that lead to discomfort, flatulence, and abdominal pain and refers almost exclusively to patients with a colostomy. Constipation rarely occurs in patients with an ileostomy due to the liquid consistency of intestinal content secreted by ileostomy. However, ileostomy patients may experience food blockage proximal to the ostomy site, which can occur because the ileal lumen is <3 cm in diameter and potential exists for further narrowing at the point where the bowel passes through the fascia/muscle layer. If a patient consumes large amounts of insoluble fiber, the undigested fiber may create an obstructing mass (bezoar). Common products that can cause obstruction include popcorn, coconut, mushrooms, black olives, stringy vegetables, unpeeled fruit, dried fruit, and meats with casings. Food blockage prevention instructions advise adding potential causative products 1 at a time in small amounts, chewing them thoroughly, and monitoring the response.⁴

Few publications address constipation in persons with a stoma. In the authors’ experience, patients with a stoma usually have an increased risk of constipation if they present with symptoms of constipation before stoma creation. In their cross-sectional cohort study, Vironen et al⁵ explored the effect of bowel and urogenital dysfunction on social functioning. Quality of life after rectal cancer surgery was not necessarily decreased as compared to the general population; Veronen et al⁵ and Rauch et al⁶ noted a permanent colostomy is not always the primary factor that disrupts a person’s quality of life.

Gallegos-Orozco et al’s⁷ review of the literature focused on the epidemiology of chronic constipation, diagnostic approaches, and nonpharmacological as well as pharmacological management of chronic constipation in a general population of elderly patients. According to the authors, certain risk factors for constipation affect the general population; these factors also may be applied to patients with a colostomy.

Previously diagnosed chronic constipation. The incidence rate of constipation is estimated to be between 2% to 28% in the general population. The most common risk factors include insufficient fiber intake and lack of physical activity. Other reasons include use of drugs that inhibit normal peristalsis, metabolic and endocrine disorders, neurological diseases, and congenital and acquired diseases causing intestinal obstruction (adhesions, obstructive benign and malignant colorectal tumors, or inflammatory bowel disease). Chronic constipation is also one of the important risk factors for diverticulosis. Complications of diverticulosis are serious and management usually includes creating a stoma (Hartmann procedure). Following the surgery, a short-term improvement in constipation is usually observed in this group of patients but usually reappears.⁸

Stoma creation in a patient diagnosed with colorectal cancer. In this group of patients, constipation is usually associated with either progression of the primary disorder (colorectal cancer) or impaired colonic patency proximally to the site of the stoma creation. It is also caused by the use of opioid analgesics that significantly decrease colonic transit.⁹ Currently, the administration of opiates in Poland is ordered by a Palliative Outpatient Care Unit; prokinetic drugs are routinely prescribed with opiates but not all patients are well informed about the need for prokinetic drug administration.⁷

Patient age. Patients 60–70 years most frequently require stomas due to the prevalence of 2 major indications for their creation: colorectal cancer and diverticulitis.¹⁰ Slow colonic transit in general and varying comorbidities such as neurological, cardiovascular, and metabolic disorders, as well as reduction of physical activity and insufficient intake of daily fluids, result in an increasing tendency for constipation.¹

Use of drugs. Elderly people usually are prescribed various medications to manage their comorbidities. Some medications may exacerbate constipation as a side effect. It is important to note opioid analgesics, antispasmodic drugs, medications containing calcium (antacids, dietary supplements), iron supplements, antiemetics, calcium channel blockers (eg, verapamil), some diuretics (furosemide), antihistamines (diphenhydramine), diastolic (anticholinergic drugs), psychotropic drugs (eg, chlorpromazine), medications used for Parkinson’s disease, tricyclic antidepressants (eg, amitriptyline), and nonsteroidal anti-inflammatory drugs (eg, ibuprofen) may influence constipation.⁷

Inappropriate diet and insufficient intake of liquids. In Proctology Outpatient Clinics, the authors observed patients who are not well-educated about stoma management try to reduce the frequency of emptying the stoma bag and formation of loose stools, thinking such actions may reduce the leak beneath the plate of the stoma. According to these mistaken beliefs, patients restrict fluid and fruit intake, achieving the desired effect for only a short period of time. However, chronic constipation may be a long-term result.⁷

Constipation in patients with a stoma also can lead to further complications. In their clinical review, Basilisco and Coletta¹¹ note the most common problems in addition to constipation are flatulence, abdominal pain, peristomal hernia, prolapse of the stoma, and diverticulosis of the spared part of the colon. Appropriate diagnostic and therapeutic management of patients with constipation and stoma presence may substantially improve quality of life.

The purpose of this study was to evaluate the effect of dietary changes and pharmacological management on constipation in patients with a stoma.

Material and Methods

Patients. A prospective, descriptive study was designed in accordance with the Helsinki declaration and the regulations of the Ethics Committee of Poznan University of Medical Sciences. Patients were recruited from 2 Ostomy and Proctology Outpatient Clinics in Poznan, Poland. Patients were eligible to participate if they believed they were constipated. Because there is a lack of established criteria for the diagnosis of constipation in patients with a stoma, for the purpose of this study the same criteria for constipation were used as for patients without a stoma — that is, constipation was considered a 3-day period without bowel movements leading to discomfort in the abdomen, bloating, and abdominal pain. Patients who met the above criteria for the diagnosis of constipation were eligible for study participation. Patients were excluded if they were terminally ill from neoplastic disease, did not provide informed consent for study participation, or exhibited limited awareness and decreased mental status (neurological disorders, alcoholism, and/or mental disorders).

Procedure. The study was conducted by surgeons working in Proctology Outpatient Clinics between January 2011 and December 2014 and involved 3 assessment visits. During the initial visit, patients were informed about the aim of the study and screened for study eligibility. The primary focus was on the episodes of constipation experienced by the patients and symptoms such as abdominal discomfort, bloating, and abdominal pain. Every patient with a stoma admitted to the Outpatient Clinic was routinely evaluated by a surgeon. Patients were advised to report to the outpatient clinic every 3 months for follow-up visits.

First visit. During this visit, the patient’s medical history (reason for stoma creation, comorbidities, family history, surgeries) and other data (age, dietary habits, addictions) were collected in individual charts. Patients were asked about their problems with passing stool through the stoma. Patients who demonstrated significant dysfunction of the stoma and reported difficulties with emptying the stoma were sent for further surgical investigation; patients requiring surgical treatment were excluded from the study. Patients diagnosed with constipation received detailed information about dietary and lifestyle modification recommendations; the first line of conservative treatment for constipation in patients with a stoma was diet modification. Based on the current guidelines of the American Society for Parenteral and Enteral Nutrition (ASPEN)¹² and the American Dietetic Association (ADA),¹³ recommended fiber intake of at least 14 g per 1,000 kcal should be consumed each day (20–35 g/day according to National Academy of Science Institute of Medicine¹⁴), and fluid intake should be approximately 3 L per day. Patients were provided verbal instructions and written information that advised them to reduce the volume of each meal and increase the total number of daily meals. Reduction of monosaccharaides also was recommended.^12-14 Patients also were informed about lifestyle modification recommendations, including daily exercise (for example, walk at least 30 minutes once a day), hydration (fluid intake), and reserving enough time for bowel movements.¹⁵

Second visit. During the next visit, the effectiveness of the dietary recommendations was evaluated. Subjective assessment of symptom improvement was ascertained with a single closed-end question requiring a Yes/No answer: Did you observe adequate relief of constipation symptoms related to abdominal pain or discomfort within the past 3 months? In the case of sufficient efficacy of the diet recommendations, the existing management was maintained. In the absence of clinical response to previous recommendations, pharmacological management was implemented and included bulk-forming laxatives (psyllium seed: 1–2 tablespoons per day), osmotic agents (lactulose: 15–45 mL per day), and probiotics (combined products containing selected strains of live micro-organisms such as Lactobacillus and Bifidobacterium, 1 capsule per day).

Third visit. Patients were asked about the effectiveness of pharmacological management. In cases of sufficient efficacy of pharmacological recommendations, the existing management was maintained. In the absence of clinical response to previous recommendations, additional prokinetics were implemented (metoclopramide or/and itopride hydrochloride: 3 tablets per day). Moreover, provision of a glycerin suppository and/or stoma irrigation was performed periodically when indicated. The study design is shown in Figure 1. 

Data collection and analyses. Information about constipation and its symptoms were collected by the patients on spreadsheets and then analyzed by a nurse during follow-up visits. The described data are presented as mean ± standard deviation (mean ± SD).

Results

From the initial pool of 405 patients from the Ostomy and Proctology Outpatient Clinics enrolled in the study, 74 patients were excluded because they did not fulfill study inclusion criteria. The remaining 331 patients with a stoma (146 women, 185 men; average age 61.3 ± 12.7 years) were included for the first visit. Of those, 273 patients (82.5%) had an end stoma and 58 (17.5%) had a loop stoma; 132 stomas (40%) were formed due to complications of diverticular disease, 114 (34%) because of rectal cancer, 35 (10.5%) due to inflammatory bowel disease, 23 (7%) because of other cancers, 14 (4.2%) were due to injuries, and 13 (3.9%) due to a rectovaginal fistula (see Table 1). 

At first follow-up visit, 93 (28%) patients with a diagnosis of constipation qualified for further investigation. Among them, constipation was associated with late stomal complications¹⁶ such as a stomal stenosis or prolapse and parastomal hernia in 50 patients (54% of patients with constipation). Late complications are defined as problems occurring after the period of physiological adjustment, which is usually 6–10 weeks. In a retrospective analysis, Park et al¹⁷ noted 93% of late complications occurred within the first 6 months. In the current group of patients, the diagnosis of stomal complication usually was determined during the first follow-up visit. In the authors’ hospital, the first routine visit after stoma creation is 4 weeks after surgery; earlier visits are scheduled when there are stoma complications. Thus, 43 patients (46% of patients with constipation) — 42 with a colostomy and 1 with an ileostomy — presenting with constipation were included into the final stage of the study and scheduled for follow-up visits 2 and 3. These included 18 women and 25 men (average age 55.9 ± 9.3 years). Of those, 28 had a stoma secondary to complications of diverticular disease, 6 had a history of rectal cancer, 2 had inflammatory bowel disease, 3 had other cancers, 3 had stoma surgery following injuries, and 1 had a rectovaginal fistula.

At the second follow-up visit, lifestyle and diet modifications were effective and sufficient to resolve the problem with constipation in more than half (24) of the patients. In 19 patients, it was necessary to introduce pharmacological management. During the third follow up visit, 17 of the 19 patients reported the pharmacological regimen was successful. In 2 patients, both lifestyle and diet modification as well as pharmacological management were ineffective. One patient required urgent surgery due to complicated colonic diverticulosis (perforation), and a right hemicolectomy with ileostomy procedure was performed. Another patient did not agree to surgery despite severe abdominal pain (see Table 1 and Table 2). 

Based on the American Gastroenterological Association technical review¹ on constipation and American Gastroenterological Association³ medical position statement on constipation, along with the authors’ experience and the results of this study, an algorithm for managing constipation in patients with a stoma was proposed (see Figure 2). It has not been tested as yet. Key points of the algorithm include: assessing the entire colon (particularly in patients with a history of cancer); considering use of a rectal dilatator (especially in case of moderate stomal stenosis); avoiding use of an excessive amount of paraffin and vegetable oil (patients often report problems with leakage beneath the stoma plate); modifying laxative dosage to avoid too strong an effect; particular care with patients with a stoma created due to Crohn’s disease; and considering MR enterography due to the high risk of changes in the ileum terminale. 

Discussion

As far as the authors are aware, this study is the first to assess the effectiveness of dietary and pharmacological management of constipation in patients with a stoma, including the effect of recommended dietary behaviors on the treatment of obstruction in patients with a stoma and patients’ subjective impression of symptom improvement over 3 months.

The problem of constipation in patients with a stoma is challenging due to the fact it is difficult to determine stool frequency and output. Approximately 28% of the patients with a stoma treated in the Ostomy and Proctology Outpatient Clinics had constipation on the first follow-up visit 4 weeks post surgery. In this group, 54% of patients experienced constipation due to problems with the stoma such as hernia, prolapse, or narrowing. Physical examination during the first follow-up visit focused on the morphological changes within the stoma and showed almost 15% of all patients with stomas presented with structural stomal disturbances. In the authors’ opinion, this is a relatively high percentage of patients who were referred for further surgery and required further analysis to eliminate the need for reoperation in the future.

In 46% of patients (13% of the entire study group), constipation was associated with impaired motility, not morphological impairment; 95% of these patients reported improvement of their constipation symptoms after implementing dietary recommendations or pharmacological treatment. It should be emphasized that patients usually do not obtain sufficient support from primary care physicians to establish a regular pattern of bowel movement. In the authors’ experience, the discomfort associated with constipation in the presence of a stoma (bloating, abdominal pain, flatulence, and the like) is frequently considered a side effect of having a stoma. In the authors’ department, a stoma nurse instructs patients how to deal with potential stoma problems (ie, care and problems with bowel movements) before hospital discharge. The authors have observed this is not standard care in most of the surgical departments in Poland (small, not clinical hospitals), which do not have stoma nurses. As such, after discharge, patients use an Outpatient Clinic such as the authors’.

Results of the current study are difficult to compare with any other studies because of limited data in the literature regarding constipation in stoma patients. Data can be compared only to research studies analyzing constipation in the general population. Current results were similar to Bharucha et al’s¹ review: constipation affected 16% (range 0.7%–79%) adults overall and 33.5% adults ages 60 to 101 years. The current study was conducted among a Caucasian population and involved more men who experienced constipation than women.

No clear guidelines exist for endoscopy surveillance after colorectal cancer in patients with a stoma; care is based on individual features of patients and may differ between surgical centers.^18-20 In this study, 50 of the 93 patients with constipation had morphological stoma changes requiring surgical follow-up.

The results of this study confirm the importance of dietary modification for constipation in patients with a stoma. Approximately 55.8% of patients with constipation and without any stomal morphological changes reported improvement or complete resolution of symptoms after implementing dietary modifications. These results suggest the problem of constipation in patients with a stoma often can be solved at the primary level of care and dietary recommendations should be the first line of treatment.²¹

Of the 19 patients who required first-line pharmacologic therapy, the vast majority (14% to 74%) improved. Flatulence associated with inappropriate diet is a common problem in patients with constipation. Probiotics and prebiotics should be considered in dietary recommendations. According to Quigley²² and Hamer et al’s²³ reviews of the literature, adequate intake of pro- and prebiotics positively influences the intestinal mucosa, resulting in normalization of intestinal transit and the proper secretion of mucus by goblet cells of the large intestine. Moreover, these products contribute to appropriate and balanced intestinal flora. Both pro- and prebiotics may be delivered in natural food sources (eg, yogurt) or dietary supplements (eg, butyric acid or combined products of probiotics).^24,25

Patients in this study who did not improve with dietary changes alone also received bulk-forming laxatives. Some clinical studies²⁶ indicate the benefit of bulk-forming laxatives (eg, psyllium, methylcellulose), softeners (eg, surfactants), and osmotic agents (eg, lactulose). However, long-term use of these laxatives may cause flatulence, diarrhea, and electrolyte disturbances. Moreover, a possibility of a drug tolerance for this group of medications is well known and their high sugar content can be problematic for some patients.²⁷ Of the 5 patients who did not report improvement after trying dietary changes and first-line pharmacologic therapy, 3 reported improvement after using stimulant laxatives. The mechanism of action of these agents includes increased electrolytes and water secretion across the intestinal mucosa and enhanced intestinal motility by stimulating intramural ganglia. Unfortunately, a multicenter, randomized controlled trial²⁸ has shown intestinal peristaltic stimulation may cause abdominal pain and flatulence. In addition, a review of diverticular disease²⁹ has shown long-term use of a stimulant laxative may ultimately lead to atony of the intestines with a characteristic endoscopic feature of “leopard skin.” At the authors’ clinic, use of stimulant laxatives is generally not recommended because they can cause abdominal pain, especially in a patient population with a history of surgery and potential adhesions.

In this study, stoma irrigation is not recommended as a measure to address constipation, in part because it is not commonly recommended in the clinics. However, results of a prospective, descriptive evaluation³⁰ showed it can be an effective way to regulate bowel movements in patients with constipation.

Diverticular disease. Constipation among ostomy patients was most commonly observed in patients with a history of stoma creation due to diverticular disease. Fifty-four (54) of the 132 patients (40.1%) with diverticular disease had constipation, constituting 58% of the entire study group. Alterations in colonic motility have been implicated in the development of diverticular disease, but it is not known whether constipation and impaired motility cause diverticulosis or are a result of changes in the large intestine wall structure.³¹

Implementation of dietary recommendations and pharmacological recommendations if needed resolved problems with constipation in almost all patients. The symptoms of only 2 patients (4.6% of patients with diagnosed constipation with exclusion of morphological stomal changes) did not improve.

Limitations

The current study has several limitations. A larger sample size would be beneficial, especially in the context of comorbidities that might influence constipation. Diagnostic criteria of constipation in patients with a stoma are based on clinical symptoms; they are subjective and reflect a physician’s individual assessment and experience and as such are difficult to standardize and compare. Although the question for subjective clinical symptom improvement seemed to be practical, it has not been validated for constipation. A larger study with multi-institutional input would be valuable. A longer observation period is necessary to assess whether the duration of the stoma  has an impact on stoma constipation.

Conclusion

The problem of constipation in patients with a stoma often is not discussed but can be an indication of morphological changes and, similar to patients without a stoma, have negative effects. In this study, almost half of all patients who presented with constipation required further evaluation to address morphological stoma changes. Constipation symptoms in the majority of patients (55%) who did not require further evaluation responded well to dietary changes. Constipation resistant to conservative (nonsurgical) interventions occurred only in 2 patients (stoma created because of complications of diverticular disease); both patients qualified for surgery (colectomy) because of colonic inertia, but they refused that method of treatment.

The creation of a stoma may not solve problems with constipation. Using approaches known to help persons without stomas, along with educating stoma nurses and patients on appropriate stoma care, may help provide relief from this problem. 

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31.       Hobson KG, Roberts PL. Etiology and pathophysiology of diverticular disease. Clin Colon Rectal Surg. 2004;17(3):147–153.

Potential Conflicts of Interest: none disclosed

Dr. Krokowicz, Dr. Bobkiewicz, and Dr. Borejsza-Wysocki are surgeons and Ms. Kuczynska is a dietitian, Department of General, Endocrinological Surgery and Gastroenterological Oncology; Dr. Lisowska is a pediatrician, Chair of Pediatrics, Department of Gastroenterology and Metabolism; Dr. Skowronska-Piekarska and Dr. Paszkowski are surgeons, Department of General, Endocrinological Surgery and Gastroenterological Oncology; Dr. Walkowiak is a pediatrician, I Chair of Pediatrics, Department of Gastroenterology and Metabolism; and Dr. Drews and Dr. Banasiewicz are surgeons; Department of General, Endocrinological Surgery and Gastroenterological Oncology, Poznan University of Medical Sciences, Poznan, Poland. Please address correspondence to: Lukasz Krokowicz, MD, Department of General, Endocrinological Surgery and Gastroenterological Oncology, Poznan University of Medical Sciences, 49, Poznan, Poland; email: lkrokowicz@gmail.com.

Abstract

Bilateral internal thoracic artery (BITA) grafting may be associated with a higher risk of postoperative deep sternal wound infection than monolateral internal thoracic artery grafting due to a limited blood supply to the thoracic chest wall. Because preliminary studies suggest negative pressure wound therapy (NPWT) may reduce the risk of infection, a retrospective chart review of 129 patients who underwent BITA between February 2003 and October 2014 was conducted.

Of those, 21 patients received NPWT for 5 days immediately following surgery and the incisions of 108 patients were covered with a conventional gauze dressing. Patient demographic and history variables as well as surgical procedure and outcome variables were abstracted. Outcome variables assessed included infection, need for transfusion, and length of hospital stay. The NPWT group was significantly younger (average age 55.9 ± 7.6 versus 60 ± 10.5 years, P = 0.049), had fewer urgent/emergent surgeries (4 [19%] versus 36 [33.3%], P = 0.247), and had significantly lower surgical risk scores (2.0 ± 2.3 versus 3.8 ± 2.8, P = 0.010). The rate of deep sternal wound infections was lower in the NPWT than in the control group, but the difference was not statistically significant (0% versus 5.6%, P = 0.336). Sternal instability was noted in 4 control patients, requiring wound re-exploration versus 0 in the NPWT group (3.7% versus 0%, P = 0.487). One (1) patient in the NPWT group had postoperative bleeding that required removal of the device. The rates of re-thoracotomy due to bleeding were 9.3% in the control compared to 4.8% in the NPWT group (P = 0.435), which translated into a greater need for blood transfusions (1.77 ± 3.4 units versus 0.3 3± 0.7 units, P = 0.056) and larger chest drainage volume (997.8 ± 710 mL versus 591.2 ± 346 mL, P = 0.012) in the control group. Hospital stay was longer in the control group, but the difference was not statistically significant (12 ± 8.8 days versus 9.4 ± 4.2 days, P = 0.184). These preliminary results are encouraging, and prospective, randomized, controlled clinical studies to compare the efficacy, effectiveness, and cost-effectiveness of NPWT to other wound management modalities following cardiac surgery are warranted.

According to an analysis of the Society of Thoracic Surgeons¹ adult cardiac surgery database, although available evidence shows bilateral internal thoracic artery (BITA) revascularization provides long-term survival benefits as compared to monolateral internal thoracic artery (ITA) plus saphenous vein bypass, many cardiac surgery centers are reluctant to make it a routine procedure. As shown in an experimental study² conducted on 50 fresh specimens of the anterior thorax wall, BITA grafting presents a higher risk for postoperative deep sternal wound infection than single ITA grafting. Sternal complications mainly develop from the distal third of the sternal region, the most ischemic area after ITA harvesting and therefore an ideal acid ambience for bacteria (predominantly Staphylococcus) to grow as demonstrated in in vitro cellular cultivation.³ The use of BITA for standard procedures of surgical revascularization should be the goal of coronary surgery¹; strategies to reduce sternal complications would enable the widespread application of BITA grafting even in high-risk patients and in the elderly.

In addition, limited blood supply to the thoracic chest wall is a known risk factor for sternal wound complications after coronary artery bypass grafting.² A recent meta-analysis with literature review⁴ showed a 2.81% incidence of sternal wound infection with use of skeletonized ITA compared to 7.15% in patients who received conventional pedicled ITA harvesting.

The Prevena^™ Incision Management System (KCI, Wiesbaden, Germany) is a negative pressure wound therapy (NPWT) product specifically designed for managing surgically closed incisions (see Figure 1a-d). The peel-and-place dressing protects the incision site from bacterial contamination. In vitro studies⁵ have demonstrated vacuum-assisted closure (VAC) therapy results in microdeformations of open wounds, promoting both cell proliferation in the wound microenvironment and angiogenesis. In addition, using laser Doppler flowmetry, results of a controlled clinical study⁶ (N = 20) showed a significant increase in peristernal perfusion with VAC therapy compared to control after ITA harvesting. A porcine sternotomy wound model⁷ showed similar results. Up to now, no data have been available on human patients undergoing sternotomy and BITA harvesting.

The aim of this retrospective study was to compare overall outcomes and the incidence of deep sternal wound infection in patients undergoing BITA grafting with or without closed incision management.

Methods

Data for 129 consecutive patients with ischemic heart disease who underwent myocardial revascularization and received BITA grafting according to the surgeon’s preference and experience (BITA or ITA plus vein grafts) at the authors’ center from February 2003 to October 2014 were retrospectively analyzed. Data abstracted included age, surgical indication (elective, urgent, emergency), Log EuroSCORE and EuroSCORE (institutional surgical risk score for mortality and morbidity, where 0–5 indicates low risk, 5–10 mean risk, 10–15 moderate risk, and >15 high risk), left ventricular ejection fraction, diabetic status, insulin therapy, chronic obstructive pulmonary disease, cortisone therapy, immunosuppressive therapy, combined procedures, number of coronary artery bypass grafts, cross-clamp time, cardiopulmonary bypass time, and procedural time. The postoperative incidence of wound infections and deep sternal wound infections, clinical and radiographic indications of sternal instability, incidence of pneumonia, bleeding events, compliance with the NPWT protocol (eg, patient reports of itching, pain, or pressure in the chest, documented in the medical record), transfusions, amount of chest drainage, and length of hospital stay were recorded for patients who did/did not use NPWT, as well as discomfort with negative pressure; data on discomfort with negative pressure were retrieved from paper records and recorded by the facility’s ward doctors. All patients were in accordance with the use of their personal data and provided signed privacy consent.

Surgical procedures. All procedures were performed through longitudinal median sternotomy by 5 experienced cardiac surgeons. Conventional medication (ie, standard care) comprised adsorbent adhesive gauze dressings (usually Cosmopor E (Paul Hartmann AG, Heidenheim, Germany), 25 cm x 10 cm , changed once daily every day for 5 postoperative days; if excessive bleeding, dirt, and wetness were evident, the dressing was changed more frequently. The wound also was disinfected with an iodine solution. This care continued for the non-NPWT patients. Beginning in August 2013, the NPWT device was used for closed incision management for 21 consecutive patients. Written consent for the use of the NPWT was obtained preoperatively from the patients.

According to standard protocol, the NPWT system is applied under sterile conditions in the operating room immediately after closure of the skin incision with absorbable 4-0 Monocryl sutures (see Figure 1a-d). Following disinfection with an iodine solution, the NPWT system was placed once the skin was dry on the skin surrounding the incision and remained in place at a continuous negative pressure of -125 mm Hg for the first 5 postoperative days, as recommended by the manufacturer (see Figure 2). 

Data analysis. Statistical analysis was performed with SPSS 17.0 statistical software (SPSS Inc, Chicago, IL). Continuous and normally distributed data were reported as mean ± standard deviation. Student’s t-test corrected for Bonferroni’s adjustment was used for paired data testing. A P value <0.05 indicated statistical significance. Outcomes data assessed on day 30 postoperatively were the postoperative incidence of wound infections, sternal instability, pneumonia, bleeding events, compliance with the NPWT protocol, transfusions, chest drainage, and length of hospital stay.

Results

The mean age for all patient participants was 60 ± 10.5 years old; 18 patients (13.9%) had diabetes (see Table 1). The NPWT and control group differed significantly in age (55.9 ± 7.6 years versus 60.8 ± 10.8 years, respectively; P = 0.049) and EuroSCORE value (2.0 ± 2.3 versus 3.8 ± 2.8, respectively; P = 0.010). Other preoperative and perioperative risk factors did not differ significantly between the 2 groups (see Table 2). 

No superficial or deep sternal wound infections occurred in the 21-patient NPWT group, but 6 of the 108 patients (5.6%) in the control group developed a deep sternal wound infection. The difference in infection rate was not statistically significant (P = 0.336). The incidence of sternal instability was 3.7% (4 of 108) in the control group and 0 (0%) in the NPWT group (P = 0.487); the 4 patients with instability were not infected, but the 6 persons with deep sternal wound infection were unstable. No suction-related complications or patient discomfort were recorded. One (1) patient in the NPWT group had postoperative bleeding that required removal of the device. In the remaining 20 patients, the device was left in place for 5 days according to standard protocol. One NPWT patient versus 10 control patients underwent re-thoracotomy due to bleeding (4.8% versus 9.3%, P = 0.435), which translated into a greater need for blood transfusions (0.33 ± 0.7 versus 1.77 ± 3.4 units, P = 0.056) and larger chest drainage volume (591.2 ± 346 mL versus 997.8 ± 710 mL P = 0.012) in the control group. Hospital stay was longer in the control group, but the difference was not statistically significant (9.4 ± 4.2 days versus 12 ± 8.8 days, P = 0.184).

The incidence of pneumonia in the NPWT and control groups (2 and 9 patients, respectively [9.5% versus 8.3%, P = 0.565]) and 30-day mortality (0 versus 3 patients [0% versus 2.8%, P = 0.584]) were similar in the 2 groups.

Discussion

NPWT may be beneficial to wound healing; it stimulates angiogenesis in the underlying tissue (as demonstrated in a porcine sternotomy wound model⁷), minimizing the risk for sternal wound ischemia due to decreased blood supply to the sternum after BITA harvesting. A recent systematic review and meta-analysis⁸ showed BITA grafting was associated with a higher incidence of sternal wound infection compared to ITA. Underscoring this research, deep sternal wound infection requiring revision surgery with staple removal occurred in 3.7% of patients in the control group, but data on superficial wound complications were not recorded in this group. The rate of deep sternal infections was low, considering conventional pedicled ITA harvesting⁴ was used. None of the patients in the NPWT group developed a deep infection or were treated for superficial sternal wound infection. None of the outcome variables evaluated were statistically significantly different. 

In a biomechanics lab study using finite element analysis, Wilkes et al⁹ showed the application of closed incision management with NPWT decreased lateral stress around the incision by 50%, contributing to normalization of tissue forces and closure. In addition, Atkins et al⁶ documented (using laser Doppler flowmetry) increased peristernal perfusion in 10 patients who received NPWT at -125 mm Hg for 4 days, compensating for the lower perfusion after ITA harvesting. In a previous retrospective review¹⁰ of 57 adult cardiac surgery patients, the same authors reported no treatments for sternal wound infections were needed.

Although the clinical benefits of closed incision management with NPWT have been reported in a prospective cohort study,¹¹ results are to be considered preliminary owing to the small sample sizes and the heterogeneity of the study populations. This limitation also applies to the current study, in part because the NPWT group was small and the control group was statistically significantly older and with higher risk for mortality. Ingargiola et al’s¹² systematic review of 10 selected studies that investigated the outcomes of 626 incisions on 610 patients who underwent not only sternotomy, but also laparotomy and leg incisions showed possible evidence of a decreased incidence of wound infection with application of incisional NPWT, suggesting the need for further research before recommending NPWT. The results from studies performed in general surgery patients with multiple comorbidities are inconsistent; no benefit from the use of the NPWT system could be demonstrated in a prospective, randomized controlled study¹³ comparing NPWT to standard dry dressings on surgical incisions.

A retrospective chart review¹⁴ was performed on 63 consecutive patients with incisions (longitudinal or transverse femoral cutdown for vascular procedures) managed with traditional gauze and 52 consecutive incisions managed with NPWT. The NPWT dressing was found to significantly reduce the incidence of groin wound infection in vascular surgery patients. In a prospective study among a high-risk group of 150 consecutive obese patients undergoing cardiac surgery via median sternotomy, Grauhan et al¹⁵ reported a significant reduction in the rate of wound infection if a negative pressure wound dressing was used. However, no patient included in their prospective study underwent BITA grafting, which makes the present study sample of particular interest. Current preliminary results demonstrating the absence of superficial or deep sternal wound infection in all patients in the NPWT group prompted the authors to plan a prospective, randomized multicenter study where the number of patients is appropriate to the number of endpoints and is aimed at confirming or refuting current data.

Limitations

The study design and sample size, especially the sample size of the intervention group, have inherent limitations. In addition, the groups differed significantly in terms of age and EuroSCORE. Patients in the control group were older and had a higher risk for mortality.

Conclusion

Results of a retrospective chart review of 129 patients undergoing BITA showed a lower rate of deep sternal wound infection in patients managed with NPWT (0%, n = 21) compared to patients whose incisions were covered with a conventional gauze medication (3.7%, n = 108). This difference was not statistically significant. Prospective, randomized, multicenter clinical studies comparing the effects of different wound treatment modalities on outcomes of adult cardiac surgery patients undergoing BITA through full sternotomy are needed. n

References

1.         ElBardissi AW, Aranki SF, Sheng S, O’Brien SM, Greenberg CC, Gammie JS. Trends in isolated coronary artery bypass grafting: an analysis of the Society of Thoracic Surgeons adult cardiac surgery database. J Thorac Cardiovasc Surg. 2012;143(2):273–281.

2.         Berdajs D, Zünd G, Turina MI, Genoni M. Blood supply of the sternum and its importance in internal thoracic artery harvesting. Ann Thorac Surg. 2006;81(6):2155–2159.

3.         Zhou ZH, Yi QF, Ling YL, Zhou JN, Liu LH, Liu XP. Mineralization and osteoblast response to bioactive glass in vitro. J Med Eng Technol. 2010;34(4):285–290.

4.         Saso S, James D, Vecht JA, Kidher E, Kokotsakis J, Malinovski V, et al. Effect of skeletonization of the internal thoracic artery for coronary revascularization on the incidence of sternal wound infection. Ann Thorac Surg. 2010;89(2):661–670.

5.         Saxena V, Hwang CW, Huang S, Eichbaum Q, Ingber D, Orgill DP. Vacuum-assisted closure: microdeformations of wounds and cell proliferation. Plast Reconstr Surg. 2004;114(5):1086–1096.

6.         Atkins BZ, Tetterton JK, Petersen RP, Hurley K, Wolfe WG. Laser Doppler flowmetry assessment of peristernal perfusion after cardiac surgery: beneficial effect of negative pressure therapy. Int Wound J. 2011;8(1):56–62.

7.         Petzina R, Gustafsson L, Mokhtari A, Ingemansson R, Malmsjö M. Effect of vacuum-assisted closure on blood flow in the peristernal thoracic wall after internal mammary artery harvesting. Eur J Cardiothorac Surg. 2006;30(1):85–89.

8.         Wu YC, Zhang JF, Ning G, Zhao Q. Bilateral versus single internal mammary artery grafting in patients with severe coronary artery disease and diabetes mellitus: a systematic review and meta-analysis. J Diabetes. 2015;Jun 29. [Epub ahead of print].

9.         Wilkes RP, Kilpad DV, Zhao Y, Kazala R, McNulty A. Closed incision management with negative pressure wound therapy (CIM): biomechanics. Surg Innov. 2012;19(1):67–75.

10.       Atkins BZ, Wooten MK, Kistler J, Hurley K, Hughes GC, Wolfe WG. Does negative pressure wound therapy have a role in preventing poststernotomy wound complications? Surg Innov. 2009;16(2):140–146.

11.       Colli A, Camara ML. First experience with a new negative pressure incision management system on surgical incisions after cardiac surgery in high risk patients. J Cardiothorac Surg. 2011;6(Dec 6):160.

12.       Ingargiola MJ, Daniali LN, Lee ES. Does the application of incisional negative pressure therapy to high-risk wounds prevent surgical site complications? A systematic review. Eplasty. 2013;13(Sep 20):e49.

13.       Masden D, Goldstein J, Endara M, Xu K, Steinberg J, Attinger C. Negative pressure wound therapy for at-risk surgical closures in patients with multiple comorbidities: a prospective randomized controlled study. Ann Surg. 2012;255(6):1043–1047.

14.       Matatov T, Reddy KN, Doucet LD, Zhao CX, Zhan WW. Experience with a new negative pressure incision management system in prevention of groin wound infection in vascular surgery patients. J Vasc Surg. 2013;57(3):791–795.

15.       Grauhan O, Navasardyan A, Hofmann M, Müller P, Stein J, Hetzer R. Prevention of poststernotomy wound infections in obese patients by negative pressure wound therapy. J Thorac Cardiovasc Surg. 2013;145(5):1387–1392.

Potential Conflicts of Interest: none disclosed

Dr. Santarpino is Assistant Professor of Cardiac Surgery; Dr. Gazdag is a medical doctor; Dr. Sirch, Dr. Vogt and Dr. Ledwon are Staff Cardiac Surgeons; Dr. Fischlein is Professor of Cardiac Surgery; and Dr. Pfeiffer is Assistant Professor of Cardiac Surgery, Department of Cardiac Surgery, Cardiovascular Center, Paracelsus Medical University, Klinikum Nürnberg. Nuremberg, Germany. Please address correspondence to: Giuseppe Santarpino, MD, Department of Cardiac Surgery, Cardiovascular Center, Paracelsus Medical University, Klinikum Nürnber, Breslauer Strasse 201 - 90471 Nuremberg, Germany; email: giuseppe.santarpino@klinikum-nuernberg.de.

Abstract

A trophic ulcer is a pressure ulcer caused by external trauma to a part of the body that is compromised due to disease, vascular insufficiency, or loss of afferent nerve fibers. Spinal dysraphism (ie, neural tube defects [NTD]) such as meningomyelocele is a risk factor for developing these ulcers in adults and pediatric patients.

Information regarding the occurrence of trophic ulcers in pediatric patients with NTD is lacking. A review of the English-language literature on skin/neuropathic ulcers in patients with NTDs, irrespective of study design, published between 1975 and 2014, was undertaken using the PubMed database. Search terms included trophic ulcer, neuropathic ulcer, NTDs, and meningomyelocele. From among the more than 200 papers related to skin care in neonates and pediatric patients, 11 addressed skin ulcers in patients of NTD — 1 in French (a review article), 1 in German (a case report), and 9 in English (7 cohort studies and 2 reviewing surgical techniques). Typically, ulcers in patients with NTD are neuropathic (ie, related to nerve pathology). The most common type is meningomyelocele. Patients with NTD present with a spectrum of functional and sensory deficits that impair mobility; other causative factors that may contribute to the occurrence of ulcers include stress to the tissue, the length of time the stress occurs, muscle spasticity, infection, moisture, and nutritional status of the patient. Awareness of ulcer risk and preventive measures, such as maintaining foot flexibility or careful handling bony prominences such as kyphosis, is important. Once an ulcer occurs, management is challenging and involves collaboration of multiple medical, surgical, nutrition, and other specialists. If an ulcer develops and NTD has not been previously treated surgically or the MRI shows evidence of retethering, surgical treatment is needed. More research is needed to help guide ulcer prevention and treatment strategies in pediatric patients with NTD.

Atrophic ulcer is defined as a pressure ulcer caused by external trauma to a part of the body that is in compromised condition because of disease, vascular insufficiency, or loss of afferent nerve fibers.¹ In the lower extremities, trophic ulcers can be caused by spinal dysraphism (also known as neural tube defects [NTDs]) such as meningomyelocele (MMC), a breach in the continuity of skin or mucous membrane, as well as by trauma and diabetes mellitus.^2-4 Although NTD incidence is declining due to better prenatal care and/or termination of pregnancy when the fetus is affected, it ranges from 0.17 to 6.39 per 1,000 live births.⁵

Because it is often assumed children usually do not develop trophic ulcers, evaluation and appropriate measures to prevent ulceration may be missing.^4,6 As such, no specific study regarding the occurrence of trophic ulcers in pediatric patients with NTD has been conducted. The purpose of this literature review is to examine the occurrence, clinical features, pathophysiology, and management of such ulcers in pediatric patients.

Methods

A search was conducted of the PubMed database of English-language literature on neuropathic ulcers due to NTDs in persons of all ages published between 1975 and 2014. Search terms included trophic ulcer, neuropathic ulcer, NTDs, and meningomyelocele. Any publication related to the subject skin ulcers in patients with NTD was included for review regardless of study type, as well as abstracts of relevant articles. Publications pertaining to pediatric skin care in illness or traumatic spinal cord injury also were considered, as were reports of skin problems due to orthopedic issues related to NTD such as club foot. All of the authors collected the papers searched via Pubmed database. The papers were analyzed for their relevance to the topic. All papers related to neuropathic ulcers due to NTD were included in the study. Full texts of the articles, if possible, were accessed to assess their relevance to the subject. Because most of the papers were cohort studies with a long follow-up period, the ages ranged from pediatric to beyond pediatric (ie, more than 18 years of age). However, because the disease is of congenital origin, none of the papers was excluded from the review.

Results

More than 200 papers related to skin care in neonates and pediatric patients were found; only 11 addressed skin ulcers in patients with NTD (see Table 1). Of the 11 papers, 1 was in French (review),⁷ 1 in German (case report),⁸ and 9 in English (7 cohort studies ^2,9-14 and 2 reviews of surgical techniques^15,16). 

Trophic ulcers in NTD. Spinal dysraphism, or NTD, is a broad term encompassing a heterogeneous group of congenital spinal anomalies that result from defective closure of the neural tube early in fetal life and anomalous development of the caudal cell mass.^17,18 Typically, ulcers in NTDs are neuropathic (ie, related to nerve pathology).⁹ Various cohort studies^10,11 have found the incidence of skin breakdown ranges from 11% to 45%; however, incidence of skin compromise in children with orthopedic abnormalities may be as high as 90%.¹² Skin breakdown is an important cause of morbidity in children with NTD and may lead to hospitalization.¹⁰

Pathophysiology. Because neural tube formation is faulty in NTDs, sensory and motor innervation to the lower limbs is erratic. The most common NTD with which people can live is MMC. Patients with NTD present with a spectrum of impairments, but the primary functional deficits are lower limb paralysis and sensory loss, bladder and bowel dysfunction, and cognitive dysfunction.¹⁹ Spinal and lower extremity deformities and joint contractures are prevalent in children with MMC (see Figure 1); foot deformities may be present in more than 90% of these patients.¹² According to a review,¹⁴ multiple causes may be involved, including intrauterine positioning, congenital malformations, muscle imbalances, progressive neurologic dysfunction, poor postural habits, and reduced or absent joint motion. 

Because of sensory and motor imbalance, movement is restricted, potentially inciting tissue ischemia leading to pressure necrosis.⁹ In addition, foot abnormalities may create pressure points, which may further lead to pressure necrosis. Cohort studies⁹ have shown older children may have higher risk of skin breakdown because of increased pressure of a larger body habitus, with asymmetric weight-bearing from acquired musculoskeletal deformities. Various factors may contribute to the occurrence of ulcers, such as stress to the tissue, the length of time the stress occurs, muscle spasticity, infection, moisture, and nutritional status of the patient.¹⁵ All of these factors may be present in patients with NTDs (see Figure 2 and Figure 3). 

Ankle-brachial index (ABI) and transcutaneous pO2 measurements (TcO2) in a standardized location in the forefoot also have been evaluated in these patients. A prospective cohort study¹³ involving patients 2 to 20 years old has shown patients with myelodysplasia have a lower ABI but similar TcO2 compared to persons without NTD. The study also showed among the patients with myelodysplasia, ABI and TcO2 do not vary according to the level of neurologic deficit or the patient’s age; however, persons who had prior surgery to correct NTD have a significantly higher ABI and TcO2 compared with those without prior surgery, suggesting patients with myelodysplasia may have decreased peripheral circulation compared with patients without myelodysplasia. In a cohort study²⁰ of patients with spinal cord injury, pressure loading revealed higher baseline skin temperature and lower sacral blood flow as compared to persons without the condition. A cohort study²¹ has shown neurogenic and endothelial activities in relation to the regulation of tissue perfusion are weakened in patients with NTD; therefore, vascular insufficiency may contribute to increased skin breakdown in such patients. 

Other factors potentially responsible for the occurrence of ulcers include casts or orthotic devices, abrasions, burns, and incontinence-related dermatitis and skin maceration from urine and stool. A cohort study¹⁰ (N = 227 pediatric patients) showed incidence of skin breakdown also is increased in patients with mental retardation, large head size, and kyphoscoliosis. Also, the authors have observed children with NTD are especially susceptible to burns because their lower extremities lack sensation and may not detect an elevated temperature.

Clinical features. Lesions over the perineum or gibbus tend to appear more frequently in the presence of paraplegia, whereas higher rates of breakdown over the lower extremities may be seen in paraparesis and patients who are insensate.¹⁰ Neuropathic foot ulceration is common in patients who have low lumbar or sacral MMC.¹²

Clinically, patients may present with a nonhealing, painless ulcer at increased pressure points such as the sacrum, buttocks, back, and feet. The appearance of ulcers includes blister formation, full-thickness skin ulceration, and persistent symptomatic callous formation.^22,23 Serosanguineous discharge may be present; the amount of the discharge may require dressing changes 3 to 4 times a day.² Patients may have paraparesis or paraplegia and may be incontinent of bladder and bowel. The authors have observed on examination all sensations such as touch and pain are either absent or diminished. Motor evaluation shows limb power is a factor of the level and extent of weakness.

Ulcers may vary in size and appearance. Depending on the patient’s circulation, the base may appear pink/red or brown/ black. The borders may be punched out, while the surrounding skin often is calloused. The ulcer may be surrounded by edema; in cases of lower limb involvement, limb edema may be present. The abnormal shape of the foot may be obvious in case of pressure ulcers at those points. In severe circumstances, osteomyelitis also may occur, potentially leading to repeated infections and, in neglected cases, ultimately bone resorption and subsequent autoamputation.^2,9

The most important distinguishing clinical finding in these patients may be found on the back, where a scar from previous surgery may be present. In the authors’ experience, patients in lower socioeconomic stratas may not have had surgery and/or exhibit skin complications. In addition, patients may have undiagnosed occult NTD and seek attention for a nonhealing ulcer over the foot — thus, the cause of the ulcer is diagnosed only when the patient’s spine is examined (eg, examining the back reveals the actual cause of the ulcers to be spina bifida occulta).

Pressure ulcers are classified into 1 of 4 stages to facilitate treatment.²² Stage I is characterized by continued erythema of skin, which cannot be blanched with a gloved finger. The skin is still intact and no ulceration is evident. Stage II involves damage to the skin via ulceration, blistering, or abrasion. Stage III lesions represent full-thickness destruction of the skin. Although the ulcer may not visibly extend into muscle, the pressure itself usually causes necrosis of the underlying muscle. Stage IV lesions include involvement of muscle, tendons, joints, nerves, and even bone. Full-thickness pressure or venous ulcers typically take longer to heal than partial-thickness ulcers of similar etiology and area.²⁴

Management. Because pediatric and adult populations differ in their anatomical and physiological parameters, such as integumentary and immunologic systems, children require care specialized to their needs.^25,26

Despite loss of sensation, even over the entire sole of the foot, there may be full weight-bearing and resultant abnormal distribution of load, which creates local areas of high pressure. These ulcers occur rapidly but are usually slow to heal. Management is challenging and involves collaboration of multiple specialties, including a pediatric neurosurgeon, orthopedic surgeon, radiologist, and nutritionist. Their liaison will improve the outcome. Because pediatric patients may not be able to communicate effectively, special care such as attention to infection, care of the feet, and weight-bearing are important considerations in managing their ailments.

Ulcer assessment. Certain examinations may help in the evaluation of the ulcer and NTD. Culturing the ulcer may be helpful to determine the presence of local infection. Total leucocyte count, differential leucocyte count, and C-reactive protein (CRP) ascertain the presence of systemic infection.⁴ Magnetic resonance imaging (MRI) of the spine informs about the spinal abnormality and tethering of the cord. Radiographs of the involved areas are used to check for osteomyelitis⁴; an abnormal radiograph, bone scan, or CRP level also may help distinguish an infected ulcer requiring long-term antibiotic therapy from a chronic ulcer that might benefit from consultation with a wound care specialist or plastic surgeon.¹⁵

Treatment. Treatment is based on the primary cause of the ulcer (ie, presence of NTD). If NTD has not been previously treated surgically or the MRI shows evidence of retethering, treatment is needed. Not addressing the primary causative pathology (ie, NTD) will prohibit the neuropathic ulcer from healing completely.

Certain mechanisms help explain healing of ulcers after release of a tethered spinal cord²:

• the release of tension on the tethered conus medullaris leads to changes in the axoplasmic flow of the affected nerves;
• the release produces a neurotrophic effect;
• tethering at the conus medullaris causes a reduction in the activity of the caudal parasympathetic nerves with a resultant overactivity of the sympathetic nervous system, and the release of tension on the conus medullaris helps restore balance. 

Other protocols of care regarding wound assessment and management do not differ in this population.²⁷ Actual treatment includes nutrition considerations,²⁸ edema management, offloading and management of gait and foot deformity, medication management (including topical treatment), surgical options, adjunctive therapies, patient education, and health care provider follow-up.²⁹

Treatment also includes nonsurgical or surgical therapy. Nonsurgical or conservative therapy is utilized in the early stage of the condition. The first step in treatment of such ulcers is offloading the pressure and immobilization. This will prevent further insult to the affected area (see Figure 4). Tissue biopsy may provide information about the putative organism, and antibiotic therapy may be initiated pending findings.

Although various dressings for wound healing are mentioned in the literature, their use in patients with ulcers due to MMC is not specifically reported. In general, hydrocolloids provide a moist environment for the wound with small-to-moderate amounts of exudate and are used in the management of shallow Stages II and Stage III pressure ulcers.³⁰ Hydrocellular foams are used for the absorption of moderate-to-heavy exudates while maintaining a moist wound environment.³¹ An absorbent primary dressing can prolong dressing wear time and reduce frequency of dressing changes when applied beneath a secondary moisture-retentive film or hydrocolloid dressing that seals in fluid to maintain a moist healing environment.³² Alginate and hydrofiber dressings are used for moderate-to-heavy draining wounds²⁷; these dressing are indicated for Stage II to Stage IV pressure ulcers and react with wound exudate to form a soft gel, creating a moist wound environment and facilitating autolytic debridement.³³ Like hydrocellular foams, alginate and hydrofiber dressings should not be used on dry wounds. If the wound is dry, hydrogels can be initiated for management of Stage II to Stage IV ulcers.³⁴ Transparent film dressings also do not absorb exudates; they help to maintain a moist wound environment and promote autolytic debridement.³⁵ In a cohort study⁴ of the neuropathic foot, it was observed that with adequate rest and protection of the limb, the average uncomplicated ulcer healed in about 6 weeks. 

New modalities. Newer modalities for ulcer treatment are available, but studies are limited to ulcers in adults with diabetes mellitus and foot ulcers.^23,36-38 Studies are needed to evaluate the efficacy, effectiveness, and cost-effectiveness of these modalities in young patients with neuropathic ulcers and MMC. Negative pressure wound therapy also has been used in adult patients with inconsistent results.^39,40

Surgical intervention. Patients who have had unsuccessful, nonoperative management or who continue to deteriorate may require surgery. In cases of excessive or severe biomechanical malalignment, recurrent ulceration, or unmanageable instability, surgery is warranted.⁵ The correction of foot deformities is imperative to prevent recurrence of ulceration and includes removal of infective foci such as sequestra and localized bony irregularities that may cause ulceration from within.⁴ Realignment of bones to produce a more functional unit also is performed. It has been suggested arthodesis operations in patients of MMC poses significant risk for skin damage and ulcer formation¹²; hence, if needed, such surgery  must be performed with caution. Alternative procedures such as osteotomy, talectomy, and soft tissue release may be helpful to maintain plantigrade foot position and maintain flexibility, thereby preventing skin compromise.¹²

Other surgical modalities may facilitate ulcer healing. Debridement of the necrotic area may be warranted for optimal ulcer healing, although a review of the literature⁴¹ reported autolytic debridement with a hydrogel is the only form of necrotic tissue debridement that increases the healing rate of neuropathic diabetic foot ulcers compared to mechanical debridement with gauze. Skin grafting is an option; however, flaps have been found in a randomized trial⁴² to be superior to the grafts.

It may be difficult to heal foot ulcers, particularly in the plantar area. The skin in this area is thicker and more rigid, which does not allow primary suturing. The bilobed flap, in which a healthy flap of healthy tissue is rotated from nonweight-bearing part of the sole to the involved site, has been described as a simple reconstructive technique.⁴³

Thus, the treatment of NTD has been shown in cohort to help heal the ulcer^3,8; removing bony irregularities that predispose to ulceration and using wedge osteotomies and arthrodeses to improve the functional shape of the affected foot may be necessary in certain patients. Various types of musculocutaneous flaps also have been shown in case reports^44-47 to be effective in promoting healing of the pressure ulcers. A sensate flap from the thigh to the buttock often can restore sensation because the lateral femoral cutaneous nerve is intact in many of these patients.¹⁵ For the same reason, tensor fascia lata flaps with itslateral femoral cutaneous nerve also have been used according to case reports.¹⁶

Ulcer prevention.

Assessment. Various scales have been devised to assess the risk of ulcer development, most notably the Braden Scale.⁴⁸ The Braden Q scale and modified Braden Q scale also have been used for pediatric cases.⁴⁹ Other scales include the Neonatal Skin Risk Assessment Scale (NSRAS) and its updated version^50,51 and the Glamorgan Scale.⁵² However, studies using these assessment scales have not been performed in the NTD population.

Diagnostic modalities such as ultrasonogrphy (USG) have been used to detect the possibility of ulcer development. USG elastography assesses the strain of the tissue and provides information about excessively deformed regions in danger of ischemia⁵³; subsequently, preventive measures can be taken. Spectroscopic assessment to detect early stage of ulcer detection also has been attempted.⁵⁴

Management of risk factors. Maintaining foot flexibility, handling bony prominences such as kyphosis or foot with care, avoiding prolonged pressure, and addressing other risk factors will help prevent skin breakdown.^12,14 Neuropathic ulcers due to NTDs may present at various pressure point according to the site of involvement. Treatment depends on the stage of the ulcer and status of the NTD treatment.

Conclusion

Pediatric patients with NTD are at risk for developing neuropathic ulcers, most commonly in the feet or sacral regions. Avoidance of prolonged pressure, care of bony prominences, and maintenance of foot flexibility are important. Once an ulcer develops, both the ulcer and the NTD require treatment. Several available diagnostic modalities may help in assessing the patient’s condition, including MRI of the spine, hematological tests, and radiograph of the involved part. Newer modalities such as USG elastography and spectroscopy are being investigated. Careful evaluation, adequate attention to medical and surgical concerns, and conservative or surgical management may be effective. Various topical dressing options are available, and surgery may be needed in recalcitrant cases. Unfortunately, few studies on the prevention and management of trophic ulcers in pediatric patients with NTD have been conducted, limiting clinicians’ ability to make evidence-based decisions. 

References

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23.       Blume P, Driver VR, Tallis AJ, Kirsner RS, Kroeker R, Payne WG, et al. Formulated collagen gel accelerates healing rate immediately after application in patients with diabetic neuropathic foot ulcers. Wound Repair Regen. 2011;19(3):302–308.

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31.       Brett DW. Impact on exudate management, maintenance of a moist wound environment, and prevention of infection. J Wound Ostomy Continence Nurs. 2006;33(6 suppl):S9–S14.

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Potential Conflicts of Interest: none disclosed

Dr. Pandey is Assistant Professor, Pediatric Surgery, King George’s Medical University, Lucknow, Uttar Pradesh, India. Dr. Gupta is Associate Professor; Dr. Singh is Professor of Surgery; Dr. Kumar is Associate Professor, Neurosurgery; and Dr. Verma is Assistant Professor of Surgery, UP Rural Institute of Medical Sciences and Research, Saifai, Etawah, Uttar Pradesh, India. Please address correspondence to: Anand Pandey, MD, MCh, Department of Pediatric Surgery, King George’s Medical University, Lucknow, 226010, Uttar Pradesh, India; email: dranand27@rediffmail.com.

Abstract

Calciphylaxis is characterized by calcification in the medium and small vessel arterioles and can be a life-threatening complication often associated with chronic kidney disease (CKD). A review of the literature was conducted to explore existing evidence about the relationship between obesity and calciphylaxis.

A total of 54 publications (published between 1962 and 2015) were identified. Most studies noted a variety of risk factors for calciphylaxis, including CKD, female gender, Caucasian race, liver disease, and lower serum albumin. Obesity was identified as a risk factor in 6 of the 8 studies reviewed. In one study, obesity was found to increase the risk of calciphylaxis 4-fold. The majority of calciphylaxis lesions in obese persons were proximal in distribution; all studies report proximal lesions are associated with a higher mortality rate than distal lesions. The mortality rate of persons with CKD and calciphylaxis is 8 times higher than that of persons with CKD without calciphylaxis. There is no definitive evidence to support the belief current epidemic rates of obesity, diabetes, (diabesity), and chronic renal disease will predispose more patients to the development of calciphylaxis. However, until more information from the calciphylaxis registries and other studies is available, clinicians should maintain a high index of suspicion when a patient presents with indurated, painful nodules or necrotic ulcers, especially if the patient also has CKD. 

Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), was first described in 1898 by Bryant and White, but the term calciphylaxis was not coined until 1961 when Hans Seyle induced a calcification process in a rodent model by introducing both a sensitizer and a challenger to create what he believed was an anaphylactic inflammation and calcification process.¹ Although it has been described in patients with normal renal function and calcium/phosphate metabolism, CUA is considered a more accurate term than calciphylaxis because this syndrome most often occurs in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism.^2-14

Calciphylaxis (CUA) is considered to be rare, occurring in approximately 1% to 5% of people on dialysis due to end-stage renal disease (ESRD).^2-19 Even though information is limited and difficult to interpret because some studies report prevalence while others report incidence, many believe the rate of CUA has been increasing each year.^2-14,19-25 Inability to determine the precise prevalence and incidence of calciphylaxis is likely due to under-recognition of early disease, misdiagnosis, and a lack of centralized data collection through registries.^2,24,26,27 Currently, 3 calciphylaxis registries in the world are studying this disorder: the University of Kansas Medical Center (KUMC) in the United States28 and 1 each in the United Kingdom²⁹ and Germany.²⁷ So far, the German registry reports (from small international surveys) an incidence range of 1:1.000 to 1:1.500 cases per year in patients who are on chronic renal replacement therapy (dialysis or renal transplant).²⁷ All US clinicians are encouraged to enter data at www2.KUMC.edu/calciphylaxisregistry regarding patients with a confirmed diagnosis of calciphylaxis.²⁸

Pathophysiology. The calcification process in the medium and small vessel arterioles leads to skin ischemia and often to ulcerations, the hallmark sign of the disease.^2,30,31 Early disease presentation of the syndrome is characterized by soft-tissue calcifications that manifest as painful nodules with a mottled or a livedo reticularis pattern (see Figure 1).^2,32,33 Not all patients who present with early disease progress to the ulcerative state. In their case series, Fine and Zacharias²⁰ recognized early presentation of calciphylaxis (indurated plaques in the legs) in 80% of a group of 36 patients. Only 20% of the 36 patients presented with late disease or ulcerations. The mortality rate in this group was 67%. Half of these patients were treated with prednisone therapy; 80% improved. Of those not treated, more than half worsened and died with ulcerations. With such dramatic results, the center began treating all patients with early disease with steroid therapy. 

In late disease or metastatic calciphylaxis, the disorder has progressed and the skin is ischemic and painful; dense nodules ultimately become necrotic and ulcerate^{2-5,7-13,14,16,17,19,24,31,34} (see Figure 2). Ninety percent (90%) of ulcerations have a sacral or distal distribution (eg, forearms, hands, fingers, genitalia, calves, feet, and toes); proximal lesions (10%) occur in areas with more adipose tissue (eg, shoulders, breasts, trunk, thighs, and buttocks) and have a poorer prognosis. ^{2,3,7,10,11,20,24,25,35} 

Calciphylaxis or CUA is generally a clinical diagnosis; however, histopathological features of intravascular calcium depositions in the media of the dermal and subcutaneous arterioles confirm the clinical appearance.^{2,5,7,8,13,24} Morbidity and mortality of CUA range from 60% to 80%; mortality is higher when open ulcers become infected, leading to sepsis and death. Survival is higher in patients with distal or sacral lesions (75.5% sacral versus 26.2% proximal). Bhambri and Del Rosso³ reviewed a retrospective study of 64 patients³¹ and a case series³⁶ of 5 patients with calciphylaxis: more than half of the patients died within 1 year of diagnosis and most did not survive longer than 1 to 6 months after developing necrotic ulcerations.^{3,7,8,9,13,14,18-20,22,24,26,31,34,37,38}

The exact pathogenesis of this disorder in humans is not completely understood; however, many researchers now believe this devastating condition to be of a multifactorial etiology.^13,22,37 The following risk factors for calciphylaxis have been identified: CKD/renal failure, dialysis, secondary hyperparathyroidism, hypercalcemia, hyperphosphatemia, an elevated calcium phosphate end product (Ca2+ x PO4 >70mg2/dL2), use of corticosteroids and/or warfarin, a hypercoagulable state, diabetes mellitus, malnutrition, low serum albumin, female gender, Caucasian race, and obesity.^{2,4,6,8,10,11,14,16,20-25,31,36}

Obesity. The World Health Organization39 (WHO) defines overweight as a body mass index (BMI) >25 kg/m2 and obesity as a BMI >30 kg/m2. According to the WHO, obesity has more than doubled since 1980. In 2013, 42 million children <5 years of age were overweight or obese. Childhood obesity is associated with future risks of obesity as people age, premature death, and disability in adulthood. In 2014, more than 600 million of the more than 1.9 billion overweight adults (>18 years) were obese. This epidemic and the related illnesses are the leading cause of 200,000 annual preventable deaths.⁴⁰ The Centers for Disease Control and Prevention⁴¹ (CDC) reports obesity has hit epidemic proportions: 35.7% of adults in the US are obese and 71.1% are either overweight or obese. These statistics regarding obesity are staggering, and most of the world’s population now lives in countries where being overweight or obese is killing more people than being underweight^39,42 (see Figure 3). 

Renal failure. Chronic renal failure, like obesity, is an escalating health problem throughout the world. From 1980 –1990 and 1996–2000, a 10-fold increase of obesity-related glomerulopathy was observed.⁴³ Long-term prognosis of the obese patient with focal segmental glomerulosclerosis is poor; almost 50% develop advanced renal failure. Predictions a decade ago estimated that end-stage kidney disease (ESKD) in the general population would double, approximately 600,000 people would be on dialysis by the year 2010, and 20 million people would have either persistent proteinuria or substantial kidney damage (hypertension and type 2 diabetes mellitus accounting for a large proportion).^44-46 Based on a report on the National Kidney and Urologic Disease Information Clearinghouse⁴⁷ website, this prediction was accurate.

Now, more than 20 million American adults have CKD and among them more than 637,000 are on some form of renal replacement therapy such as dialysis and/or renal transplant.^43,48,49 The purpose of this narrative review is to explore existing evidence about the relationship between obesity and calciphylaxis.

Methods and Procedures

An initial search of PubMed, CINAHL, MEDLINE, Nursing Reference Center, Scopus, and The Cochrane Library was performed using the terms calciphylaxis, calcific uremic arteriolopathy, dialysis, risk factor, kidney disease, and obesity. Inclusion criteria for articles to review and/or reference were based on article content containing information about etiology, diagnostics in determining calciphylaxis, and review of prior literature; articles written in English with date restrictions of 1962 – 2015 were used. Articles excluded had a primary focus of discussing treatment for calciphylaxis.

A spreadsheet was developed listing each definition of calciphylaxis, all risk factors listed, if the risk factors were studied and found to be statistically significant, prevalence/incidence, morbidity/mortality, and any explanation of obesity’s role in calciphylaxis. Once all data were reviewed, the variables collected were sorted by number of times cited.

Results

Fifty-four (54) references, published between 1962 and 2015, were identified. Of these, 42 publications were not reviewed in this study because they were either a review of calciphylaxis, obesity, or renal disease; did not provide data; or had a sample size of only 1 to 5. The remaining 12 were published primarily in peer-reviewed journals by nephrologists, followed by dermatologists. Obesity was cited in 25 out of 35 references, and it was found to be the third highest occurring risk factor behind hemodialysis and ESRD.

In a retrospective case-controlled study from December 1989 to January 2000 to determine risk factors and mortality in ESRD uremic calciphylaxis, Mazhar et al²³ compared 19 cases of calciphylaxis to 54 control cases matched to date of initiation of hemodialysis and alive at the time of diagnosis of calciphylaxis in the study group. The risk factors identified to be most associated with ESRD-related calciphylaxis were female gender (OR = 6.04, 95% CI 1.62–22.6, P = 0.007), hyperphosphatemia (OR = 1.19, 95% CI 1.00–1.40, P = 0.045), and a low serum albumin rate (OR=0.80, 95% CI 0.67–0.96, P = 0.019); BMI and diabetes mellitus were not independently predictive of calciphylaxis. Of the 19 cases of calciphylaxis, 14 had proximal distribution of CUA ulcers and 9 had both proximal and distal lesions. The majority of patients who died (11 out of 14) had proximal lesions. A diagnosis of calciphylaxis was independently associated with an 8-fold risk of death (OR = 8.58, 95% CI 3.26–22.6, P <0.001).

In a computer-based, case-controlled study of skin biopsy pathology reports between 1990 and 1996, Bleyer et al²⁵ found Caucasian race, morbid obesity, and poor nutritional status were risk factors associated with proximal calciphylaxis in ESRD patients on dialysis. Despite referrals from dialysis units with approximately 50% African-Americans, all CUA patients were Caucasian. Nine CUA patients studied were consistently obese to extremely obese (highest proportion at BMI >40 kg/m2) as compared to the 347 control patients (data extracted from 1995 cross-sectional survey of patients in a hemodialysis unit that compared age, race, duration of time in dialysis, blood pressure, CPP, and height/weight [highest proportion at BMI 20–25 kg/m2]). Although the control group had 7 obese patients with a BMI >35 kg/m2, these patients did not develop CUA. Significantly lower serum albumin levels also were found in these CUA patients at the time of diagnosis. Obese patients who did not develop calciphylaxis had higher serum albumin levels (3.9 ± 0.19 g/dL versus 2.9 ± 0.63 g/dL; P <0.01).

Naguib³⁷ reported on Bleyer’s²⁵ work that obesity was implicated as a risk factor in the development of calciphylaxis in patients with CKD. Based on Bleyer’s clinical series with markedly obese patients who had fewer calcium and phosphate metabolism imbalances, Naguib concluded obesity is a more important risk factor than calcium and phosphate imbalances in the development of calciphylaxis.

Fine and Zacharias²⁰ conducted a prospective descriptive study involving 36 consecutive patients with calciphylaxis presenting to their center in a period of 7 years. Dense, nonulcerating plaques in the calves were the most common presentation (considered to be early disease); only 20% had ulcers (considered late disease) on presentation. In their simultaneous case control study, for every patient presenting with “calciphylaxis,” 2 patients with nonulcerating plaques were studied. During the last 3 years of the 7-year period, the authors found an increased rate of calciphylaxis in dialysis patients. Based on their findings, a rate of 4.5/100 patient-years over the last 3 years of their study supported the theory calciphylaxis is no longer rare and incidence has increased. Elevations in phosphate (univariate: OR = 2.40, 95% CI 1.009–5.714, P = 0.048; multivariate: OR = 2.6, 95% CI 1.05 – 6.45, P = 0.038) and calcium-phosphate product (univariate: OR = 1.43, 95% CI 1.013–2.02, P = 0.042; multivariate: OR = 1.46, 95% CI 1.02–20.9, P = 0.038) along with 3 to 4 months of calcium salts and vitamin D therapy also increased the likelihood of disease (univariate: OR = 3.25, 95% CI 1.009 – 10.529, P = 0.048; multivariate: OR = 4.05, 95% CI 1.14 – 14.5, P = 0.03). In many instances, the condition could be improved because most cases presented with early disease and were treated with steroids. Of the 36 new cases, persons who presented with early disease (n = 27) had a mortality rate of 33%; persons who ulcerated or developed late disease had an 80% mortality rate.

Angelis et al’s² prevalence study retrospectively reviewed the charts of 242 patients with ESRD receiving hemodialysis to determine the prevalence and characteristics of patients who had calciphylaxis. The researchers found a 4.1% prevalence (10 out of 242). However, the study did not reveal if the clinical variables of height, weight, or BMI, were collected, so obesity as a risk factor could not be assessed. The demographics studied revealed dialysis patients were younger (49 versus 60 years; P = 0.01) and had been on dialysis longer (80 versus 20 months; P <0.0001). The ranges for age and months on dialysis were 27 to 66 years (median of 45.5 years) and 41 to 209 months (range 3.42 years to 17.42 years), respectively. The other significant findings were slightly elevated calcium (9.7 mg/dL versus 9.2 mg/dL; P = 0.03), serum phosphate (8.2 mg/dL versus 5.7 mg/dL; P = 0.001), and alkaline phosphatase levels (188 IU/L versus 89 IU/L; P = 0.0001) and calcium phosphate product (81.5 versus 52.9; P = 0.0004). However, the authors concluded increases in cases of calciphylaxis are likely due to the increasing number of patients undergoing long-term dialysis.

 Weenig et al’s³¹ retrospective 11-year (1992–2002) study of 64 patients showed a 4-fold increase in the likelihood of calciphylaxis among patients who were obese and at risk (univariate OR = 3.91, P = 0.001; multivariate OR = 4.77, P <0.001); for every 1-unit increase in BMI, the risk increased by 10% (OR = 1.10, P <0.001). Steroid use was 3 times more common in the dialysis group (univariate OR = 3.19, P = 0.005; multivariate OR = 2.89, P = 0.026). Another independent risk factor was liver disease, with an 8-fold risk (univariate OR = 8.0, P = 0.007; multivariate OR = 14.9 P = 0.002). Seventy-seven percent (77%) of calciphylaxis patients were on dialysis (23% were nondialysis patients with moderate to severe renal impairment). The results of this study led researchers to conclude this condition is multifactorial.

Sowers and Hayden⁸ believe the increasing incidence of calciphylaxis is likely due to increases in the prevalence of CKD and the associated epidemic of obesity.^6,20 They found an increased reporting of calciphylaxis in the literature from 2005 to 2010, noting that case reports appeared almost monthly.

Nigwekar et al¹⁴ theorized they could more accurately identify cases of CUA and determine incidence and mortality using a novel algorithm in the Partners Research Patient Data Registry (clinical data warehouse of 1.8 million patients from January 2002 to December 2011). In October 2006, calciphylaxis was added to the International Classification of Disease- 9th version50 (ICD-9) code 275,Other Disorders of Calcium Metabolism. Calciphylaxis is the only disorder in this ICD-9 code requiring a skin biopsy to confirm the diagnosis. When the ICD-9 and Current Procedure Terminology (CPT) codes were applied simultaneously to claims in the United States Renal Data System (USRDS), Nigwekar et al²⁶ found 649 cases of CUA. The original study period was from January 2002 to December 2011, but with the ICD-9 coding change in 2006, the group focused their study on the years 2007 to 2011. Incidence of CUA in the USRDS was calculated by dividing the number of new cases in a given year by the number of the total chronic hemodialysis patients for that year. The number of dialysis patients increased from 188,598 in the year 2002 to 252,569 in 2011. A steady increase in incidence from 2007 to 2011 was statistically significant (r = 0.91, P = 0.02). In 2007, the incidence per 10,000 chronic hemodialysis patients was 3.7; in 2011, the incidence was 5.7. The mortality rates ranged from 2.5 to 3 times higher for patients with CUA as compared to the average mortality rate (200 to 210 deaths per 1,000 patients)26 among chronic hemodialysis patients.

In her review, Feeser²⁴ hypothesized the increased incidence of calciphylaxis may be due to the “epidemic of obesity and metabolic syndrome resulting in an increased incidence of both type 2 diabetes mellitus and ESRD.”

In 2006, Janigan and Hirsch⁴ explored whether obesity plays a role in the pathogenesis of CUA. In a subgroup of 69 obese and overweight patients, the majority of the cases were women who had proximal calciphylaxis. Based on Janigan and Hirsch’s past observations, their unpublished case series of 9 additional patients, and 2 case-controlled studies showing obesity as a significant risk factor, they concluded excess adipose tissue exerts chronic tension on the septa and associated arterioles, thus predisposing a person to or exacerbating the risk of obese patients developing proximal calciphylaxis.

A case report from Kalajian et al²² in 2009 found the prevalence of calciphylaxis is increasing in nonuremic patients despite the lack of collective analysis of reported cases. For instance, a 58-year-old morbidly obese (defined as a BMI            >35 kg/m2) woman presenting with proximal ulcerating calciphylaxis was studied. The authors’ examination revealed active stage IIIc endometrial carcinoma treated with surgery and chemotherapy, venous thromboembolism, and a Pseudomonas aeruginosa lower urinary tract infection. Her comorbidities included morbid obesity (BMI = 53), hypertension, anemia, hypothyroidism, and lower extremity venous disease. Despite having proximal calciphylaxis (ulcerations and necrosis of thigh, hips, and pannus), which carries a greater risk of death, this patient survived. This patient was not uremic and her levels of calcium, phosphorus, parathyroid hormone, and alkaline phosphatase were normal. The authors note contradictions are present in statistically associated risk factors due to small case series and reviews.

Hayden et al²¹ reviewed the pathophysiology of vascular ossification-calcification and the effects on people with pro-atherosclerotic disease processes such as diabetes, obesity, and metabolic syndrome and found the incidence of calciphylaxis is rising. The authors hypothesized the increase is likely due to improved recognition and reporting of the syndrome by nephrologists, dialysis centers, and dermatologists. Additionally, the authors believe the rise in CKD and ESRD patients could lead to near epidemic rates of calciphylaxis given the current and continued epidemic of obesity, diabetes, and metabolic syndrome.

Obesity sets off a domino effect of morbidity- and mortality-related illnesses, but the progression of kidney disease is rarely mentioned.⁴⁴ When BMI increases, so does the risk of cardiovascular disease, diabetes (including prediabetes, insulin-resistance, and hyperinsulinemia), hypertension, musculoskeletal disorders, cancers, single nephron hyperfiltration, CKD, and ESRD.^{21,31,37,39,44,49} Obesity is an important and often preventable risk factor for all these diseases, including chronic renal failure. Ejerblad et al’s research⁴⁹ of the Swedish population and a review of the literature^44,48,49 has shown obese persons of any age are 3 to 4 times more likely to develop chronic renal failure. For women, morbid obesity is a risk factor for chronic renal failure.^38,49 Risk also increases for overweight persons (persons who did not have BMI >30 kg/m2), with risk tripling for both men and women >20 years of age with a BMI >25 kg/m2. It is estimated obesity causes 15% of chronic renal failure in men and 11% in women in Sweden. The author postulates that the percentage of men and women with CKD in the US is higher due to the greater prevalence of obesity.⁴⁹

Obesity as a risk factor for diabetes and hypertension is widely known. Diabetes and hypertension are also known risk factors for CKD.30 The development of CKD seems to be causally linked to obesity by a high prevalence of hypertension and/or type 2 diabetes.⁴⁹ Obesity also is associated with an increased risk of albuminuria and glomerulosclerosis and worsens the course of CKD regardless of the primary renal disease.^43,45,49

Discussion

The purpose of this review of the literature was to explore existing evidence about the relationship between obesity and calciphylaxis. The evidence for increasing frequency of calciphylaxis is lacking; the scarcity of comparative studies on calciphylaxis is astonishing considering how long the condition has been identified and how potentially lethal it often becomes. The literature primarily reports opinions, but occasionally incidence or prevalence rates are reported for short time frames. In a 1996 prevalence study,2 researchers found a 4.1% prevalence but failed to disclose a time period or a comparison. Another facility documented an incidence rate of 4.5/100 patient-years from 1999–2001.²⁰ Kalajian et al²² and Nigwekar et al¹⁴ both reported the prevalence of calciphylaxis is increasing in nonuremic patients despite the lack of collective analysis of reported cases. Nigwekar et al²⁶ examined incidence over a period of 11 years using pathology results to confirm a calciphylaxis diagnosis and found an incidence ranging from 3.7 to 5.7 per 10,000 chronic hemodialysis patients during 2007–2011. Without standardized reporting of both prevalence and incidence rates, it becomes difficult to determine if the incidence of calciphylaxis is changing.

Small case series and reviews^4,51 show differences in associated risk factors. Sowers and Hayden⁸ believe the incidence of calciphylaxis is increasing, likely due to increases in the prevalence of CKD. As previously noted, the associated epidemic of obesity is believed to be a significant factor in the rising numbers of people with CKD.^43-46 Angelis² found younger patients on dialysis contribute to the increasing incidence of calciphylaxis. Obesity is theorized to exert chronic tension on the septa and associated arterioles from excess adipose tissue, thus predisposing a person to, or exacerbating the risk of, developing proximal calciphylaxis.^4,52 The weight of adipose tissue is known to place pressure on vessels, thus obstructing the inflow of arterial blood to the subcutaneous adipose tissue causing ischemia and obstructing the outflow of venous blood and lymph and facilitating an increase in metabolic wastes, toxins, and localized lymphedema.^34,53,54 However, the role of obesity as a predisposing factor for tissue ischemia remains uncertain, and physical or structural disturbances within adipose tissue may contribute to a localized role in impairing tissue perfusion.^26,36,54

Although Caucasian, morbidly obese, dialysis patients were uncommon in 1990–1996, morbid obesity, Caucasian race, and lower serum albumin level are risk factors for developing calciphylaxis.²⁵ During those years, the percentage of adults who were obese was 11.6% to 15.9%, as compared to 29.4% in 2014.^39,42

Because female gender is one of the most commonly associated risk factors6 and because women have a higher proportion of adipose tissue, proximal distribution of lesions could be more likely.23 In addition, although the literature reports 90% of lesions are distal, the proximal lesions tend to be more challenging to manage and carry a higher mortality rate (80% to 89%).⁶ Reported mortality rates are 2.5 to 3 times higher for patients with CUA as compared to chronic hemodialysis patients (per the USRDS).²⁶

According to Mazhar et al,²³ a diagnosis of calciphylaxis carries an 8-fold risk of death; however, the group concluded BMI did not independently predict calciphylaxis. Without further research linking obesity, understanding the epidemiology, pathophysiology, and treatment, this challenging problem is believed to likely grow in light of the current obesity epidemic^{4,6,8,21,24,25,31,55} and diabetes rate,^6,8,21,24,55 as well as the rising number of people with CDK requiring renal replacement therapies.^2,25

If clinicians begin entering calciphylaxis patient data into a calciphylaxis registry, more comparative and retrospective studies can be done with larger sample sizes. Ultimately, as data are collected, these registries could facilitate the provision of valuable information toward the discovery of the etiology, prevalence, incidence, risk factors, and treatment of this puzzling condition.

Conclusion

With obesity linked to diabetes mellitus (a pro-atherosclerotic disease process) and CKD, increasing rates of obesity may contribute to increasing rates of calciphylaxis. Although obesity was found to be associated with calciphylaxis, a definitive correlation has yet to be established. Additional research will likely validate the current belief this devastating condition is multifactorial and continue to categorize obesity as one of many risk factors and not causation for the development of calciphylaxis.^{3,4,6,17,18,31} The literature available on calciphylaxis offers no definitive cause(s). With rising rates of obesity and obesity-related sequelae such as pre-diabetes, diabetes, insulin resistance, hyperinsulinemia, hypertension, CKD, and the potential risk factors for calciphylaxis, it is not out of the realm of belief that calciphylaxis rates are rising and that more of the affected patients will be obese. If more obese patients develop calciphylaxis, especially in proximal locations, not only will they have a high mortality rate, but they also will have increased morbidity with the sequelae.^19,25 The literature to date shows calciphylaxis is multifactorial and more research needs to be undertaken to determine the role other factors, along with obesity. Clinicians are advised to maintain a high index of suspicion when faced with indurated, painful nodules or necrotic ulcers especially in patients with CKD. Hopefully, calciphylaxis registries around the world will be able to offer more statistically significant data and unlock the mysteries of this deadly disorder.

Acknowledgment

The author thanks Susan Gallagher, PhD, RN for her invitation to provide the manuscript and her support through the writing/editing process.

References

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Ms. Davis is a Clinical Skin and Wound Care Specialist, 3M Critical and Chronic Care Solutions Division, St. Paul, MN. Please address correspondence to: Janet M. Davis, MSN, RN, GNP, CWOCN, 2631 Southwick Street, Houston, TX  77080; email: jdavis4@mmm.com.

Abstract

Sitting-acquired pressure ulcers (PUs) are a potentially life-endangering complication for wheelchair users who are obese and have diabetes mellitus. The increased body weight and diabetes-related alterations in weight-bearing tissue properties have been identified in the literature to increase the risk for PUs and deep tissue injuries (DTIs).

A computer modeling study was conducted to evaluate the biomechanical effect of an air cell-based (ACB) cushion on tissues with increased fat mass and diabetes, which causes altered stiffness properties in connective tissues with respect to healthy tissues. Specifically, 10 finite element (FE) computer simulations were developed with the strain and stress distributions and localized magnitudes considered as measures of the theoretical risk for PUs and DTIs to assess the effects of fat mass and pathological tissue properties on the effective strains and stresses in the soft tissues of buttocks during sitting on an ACB cushion. The FE modeling captured the anatomy of a seated buttocks acquired in an open magnetic resonance imaging examination of an individual with a spinal cord injury. The ACB cushion facilitated a moderate increase in muscle strains (up to 15%) and stresses (up to 30%), and likewise a moderate increase in size of the affected tissue areas with the increase in fat mass, for both diabetic and nondiabetic conditions. These simulation results suggest wheelchair users who are obese and have diabetes may benefit from using an ACB to minimize the increased mechanical strains and stresses in the weight-bearing soft tissues in the buttocks that result from these conditions. Clinical studies to increase understanding about the risk factors of both obesity and diabetes mellitus for the development of PUs and DTIs, as well as robust preclinical comparative studies, may provide much-needed evidence to help clinicians make informed PU prevention and wheelchair cushion decisions for this patient population and other wheelchair-bound individuals. 

In the medical literature and clinical guidelines,¹ pressure ulcers (PUs) are defined as localized injury to the skin and/or underlying tissues that develop as a result of excessive and sustained pressure and/or shear, usually under a weight-bearing bony prominence. After more than a decade of rigorous research work, it is now well established that severe PUs are caused primarily due to exposure to sustained large tissue deformations over critical time periods that compromise the integrity and homeostasis of cells and the viability of tissues.^1-6

PUs are categorized with respect to either their depth or the types of tissues involved. Superficial (skin) PUs are commonly associated with frictional forces, shear loads, and microclimate factors, whereas deep tissue injuries (DTIs) are caused by sustained deformations and localized forces in muscle and fat.^1,7,8 PUs are generally associated with a number of contributing or confounding factors, primarily impaired mobility and sensory capacities, as well as compromised perfusion, abnormal body mass index (BMI), and type 2 diabetes, to name a few.^9,10 Populations at general risk are the elderly and frail; patients who sustained a spinal cord injury (SCI); individuals with neurological diseases, brain trauma or stroke, and neuromuscular diseases that restrict mobility; and surgical patients.⁹ All of these individuals are more likely to spend prolonged time periods in a static position in a bed or a wheelchair.

Bariatric patients, who are less mobile as well, are known to be at risk for DTIs, particularly when undergoing a surgery that results in prolonged immobility.^11,12 According to obesity.org, obesity is highly correlated with type 2 diabetes; nearly 90% of people living with type 2 diabetes are overweight or obese. This increases the risk of neuropathy/sensory impairment; it is common to see not only bariatric tissue changes, but also diabetes-related tissue changes in these patients, a syndrome often termed diabesity. 

Sitting-acquired PUs and DTIs are a common and life-endangering complication for individuals who chronically sit or depend on a wheelchair for mobility. As described in the prospective, inception cohort study by Allman et al¹³ and the phenomenological pilot study of Hopkins et al,¹⁴ the onset of sitting-acquired DTIs can lead to septicemia, osteomyelitis, renal failure, organ system failure, and serious infection, hindering functional recovery, causing pain, and reducing the quality of life for both patients and caregivers. Reddy et al’s¹⁵ systematic review demonstrated the burden on health care systems: the management of a single full-thickness PU can cost up to $70,000, and annual PU treatment costs are estimated at $11 billion in the United States alone. Therefore, prevention should be the primary strategy for minimizing the impact of sitting-acquired DTIs.

Tremendous effort is being invested to thoroughly understand DTI etiology, with the aim of facilitating more efficient risk assessment and revision of prevention strategies targeting population-specific risk factors. In particular, the purpose is to minimize internal tissue deformations and localized forces, now recognized in the scientific literature^16-18 as well as in the current (2014) International Guidelines for Pressure Ulcer Prevention and Treatment¹ as the most important factors causing the injury.

Many studies, both clinical and computational,^16,18-21 recently have shown persons with obesity (defined by the World Health Organization²² [WHO] to be a BMI >30) and/or diabetes are at an increased risk for PUs. For individuals who are obese and especially morbidly obese according to the WHO classification (BMI >40), greater body-weight loads are transferred to the soft tissues of the buttocks through the ischial tuberosities (ITs) during sitting. Previous computer simulation studies^16,18 have shown increased body-weight loads cause increased internal tissue loads, which are quantified by means of the mechanical strains (dimensionless deformations, measured by means of magnetic resonance imaging [MRI] and/or through biomechanical modeling) and stresses (forces per unit area of tissue evaluated, again, using biomechanical modeling) in the muscle and fat tissues of the buttocks. Per the clinical study of Cox et al,²³ for example, individuals with a SCI are expected to gain 1.3–1.8 kg per week during their rehabilitation phase due to a lower level of physical activity. Additionally, as mentioned previously, obesity is commonly associated with diabetes, which increases the risk for PU development due to impaired perfusion, which can be amplified by vascular disease, ischemic heart disease, or congestive heart failure.²⁴ Moreover, diabetes inflicts abnormal biomechanical changes to tissue stiffness. As shown in both animal studies and human cadaveric measurements,^25-27 type 2 diabetes is associated with stiffening of collagen-rich connective tissues such as skin and subcutaneous fat. These changes to the biomechanical properties of tissues, where the affected tissues cannot adequately deform to dissipate body-weight loads, may add to the overall risk of injury. Furthermore, as suggested by Gefen,²⁸ in the case of type 2 diabetes, peripheral sensory neuropathy may prevent patients from detecting the onset and progression of tissue damage.

Given the knowledge that sustained excessive and localized strains and stresses in soft tissues may jeopardize cell and tissue viability, the most important principle in preventing sitting-acquired PUs and DTIs is to minimize exposure to these strains and stresses in tissues. For this purpose, clinicians are normally guided to prescribe a soft, thick cushion on the wheelchair to better redistribute the buttocks-support contact pressures as well as the internal tissue loads.¹ However, despite the known increased risk of PUs for persons with obesity and diabetes, no specific recommendations of a preferred support surface type (a cushion in particular) are available for these populations.

Finite element (FE) computational modeling is a powerful tool in PU research. It facilitates determination of internal mechanical loads (eg, deformations, strains, and stresses measured in Pascals) in tissues of weight-bearing body parts such as the heels and buttocks. Based on these data, FE modeling further facilitates isolation of the influence of specific intrinsic and extrinsic biomechanical risk factors for PUs and DTIs.^{10, 29-32} In practice, the sophisticated 3-dimensional (3D) geometry of body organs, typically acquired from medical imaging (such as MRI), is used to build an anatomically realistic reconstruction in the computer, which then is divided into numerous small elements (“finite” elements), each with a simple geometry (eg, bricks or pyramids). Then, the equations that describe the biophysical mechanical interactions between the weight-bearing tissues and the support surface are solved for each element with respect to its neighboring elements to ultimately form diagrams of the transfer of mechanical loads within the entire studied organ. This method allows researchers to artificially manipulate the anatomy and biophysical properties of the tissues (through changes in the geometrical features or mechanical properties assigned to the tissues) in order to identify the influence of different biomechanical factors (eg, muscle atrophy, presence of scars, and so on) on the resulting loads and hence their affect on PU and DTI risk.

The authors have been investigating the biomechanical efficacy of flat foam cushions, contoured foam cushions, and air cell-based (ACB) cushions for several years, using state-of-the-art, imaging-based FE modeling.^30,31,33,34 The effect of increased BMI or fat mass on internal tissue loads in the buttocks also has been studied.^16,18,33 However, work regarding these specific patient populations was limited to interactions of the seated buttocks with uniform flat or contoured foam cushions; more sophisticated cushion designs were not studied, although such data are needed to strengthen the volume of evidence in the field, particularly in light of certain findings. ACB technology was found to be superior to foams,^31,34 and ACB cushions were noted to be used extensively on bariatric wheelchairs in clinical practice.

Accordingly, a computer modeling study was conducted using ACB cushions (provided by the manufacturer, ROHO Inc, Belleville, IL) to integrate previous modeling concepts regarding the ACB technology with documented pathoanatomical and biomechanical tissue changes that result from obesity and diabetes. The purpose of this biomechanical modeling study, which had a theoretical (computer simulation) study design, was to determine the trends of changes in internal tissue loads (strains and stresses) in individuals seated on an ACB cushion if obesity and diabetes occurs and evolves to assess the efficacy of the ACB technology in protecting these individuals if these diseases are present. 

Methods

In order to examine the effects of increased fat tissue mass and the presence of diabetes on the resulting biomechanical risk for developing PUs and DTIs, a theoretical/computational study was designed. Taken together, the literature reviewed in the Introduction section of this article indicates the higher the internal tissue load in the seated buttocks, the greater the biomechanical risk for the aforementioned injuries. A set of 10 computational model variants was developed to assess the biomechanical characteristics of sitting using the ACB cushion. Each computational model variant included a geometrical description of the IT bone, the gluteus maximus skeletal muscle, the colon smooth muscle, fat tissues, skin, and an ACB cushion (see Figure 1a). A single coronal MRI slice of the left buttock of a 21-year-old man 1 year post SCI was used for segmenting the anatomical features, as described in detail in previous publications.^30,31,33,35 Briefly, the ScanIP^® module of the Simpleware^® software suite (Simpleware, Exeter, UK) was used to segment the different tissue components from the MRI slice. Then, a uniform 4-mm thickness was defined for the entire computational model.³⁶ In 8 of the model variants, 4 levels of increased fat mass were incorporated by artificially increasing the original fat volume shown in the MRI, consistent with the work of Shoham et al,³³ with either diabetic or nondiabetic tissue conditions (see Table 1: 4 fat masses times 2 tissue conditions equals 8 variants). The 2 other variants were the reference anatomy directly extracted from the MRI with nondiabetic or diabetic tissue properties (see Table 1). 

To generate the geometrical model of the ACB cushion, the tops of the pre-inflated air cells were cut. Detailed considerations regarding the geometrical and mechanical modeling of the ACB cushion are available in a previously published study.³¹ Briefly, the computer aided design (+CAD) module of the Simpleware^® software suite was used to convert a CAD slice to a voxel-based array database and then define a uniform 4-mm thickness to the ACB cushion computational model.³⁶ Next, to simulate the interaction between the buttocks anatomy and the ACB cushion, the anatomical model variants were incorporated with the ACB cushion geometric models using the Preview module of the FEBio FE simulation software package.^37,38 To achieve a thin slice model, the front and back planes of the anatomical model and the ACB cushion were fixed in the perpendicular direction to eliminate any out-of-plane motions. The bottom surface of the cushion model was fixed in all directions, and frictional sliding was defined between the outer surface of the skin and the cushion, as was done in previously published studies.^31,34 Distributed forces were applied over the inner surfaces of the air cells in order to stabilize the numerical calculations and to achieve a realistic collapse pattern of the air cells, as was done previously.³¹ 

The mechanical behaviors and properties of all tissues were adopted from the literature and were the same as in the previously published studies with regard to sitting on ACB cushions^31,34; a list of the relevant tissue types and stiffness properties is provided in Table 2. The specific considerations and description of the experimental evaluation of the material and structural behavior of the ACB cushion have been detailed previously.³¹ Diabetic skin and fat tissues were considered as being 40% stiffer than nondiabetic tissues, as noted by the measurements of Pai and Ledoux²⁵ of cadaveric plantar tissues undergoing shear loading (see Table 2). 

Vertical mechanical forces were applied on the buttocks model in the computer simulations to represent weight-bearing of the seated buttocks when immersing into the ACB cushion, as described in previous studies.^30,31,34 Assuming the increased fat mass in model variants 3 through 10 (see Table 1) directly reflects changes in body weight, the pressure inside the air cells was iteratively adjusted until the total vertical reaction force acting back from the ACB cushion was linearly proportional to the change in the fat tissue mass in each model variant. As noted in previous studies,³¹ the collapse pattern of the air cells was verified to be realistic using photographs of the deformed ACB cushion through a transparent physical phantom of the buttocks made of plastic and representing the external anatomical surfaces of the human buttocks.

The simulations were constructed using the PreView module of the FEBio FE software suite (Version 1.14), analyzed using the Pardiso linear solver of FEBio (http://mrl.sci.utah.edu/software/febio) (Version 2.0.1), and post-processed using PostView of FEBio (Ver. 1.6).³⁷ The runtime of each model variant was between 7 hours and 32 hours using a 64-bit Windows 8-based workstation with 2× Intel Xeon E5-2620 2.00 GHz CPU and 32 GB of RAM.

The average effective strains and stresses for muscle, fat, and skin tissues (calculated in Pascals) were compared among all the model variants. For fat tissue, strain and stress data were collected only from fat elements below the imaginary horizontal line passing through the point of intersection between the fat, muscle, and bone regions. For skin and muscle tissues, strain and stress data were collected and stored automatically by means of the FE modeling software from all the elements belonging to the skin and gluteus maximus muscle. The average effective strains and stresses were normalized with respect to the reference model variant 1 (see Table 1) in order to facilitate comparisons between simulation cases using Excel software (Microsoft Corp, Seattle, WA).

Results

Comparisons of the effective stress distributions, reported in Pascals, in the gluteus maximus muscle when seated on an ACB cushion between the reference anatomy (variant 1) and 4 cases of a gradual increase in fat mass (model variants 3,5,7,9) are shown in Figure 2. Stresses in muscle tissue for the simulated sitting on the ACB cushion and different fat mass conditions (as indicated in Figure 2) were in the range of 0–0.12 Pa. Consistent with previous studies,^30,31,34 stress concentrations appeared in muscle tissue near the tip of the IT (see Figure 2), and peak strains appeared in fat tissue between the gluteus muscle and the skin. In all simulation cases (nondiabetic and diabetic), average effective strains and stresses in muscle tissue increased in value and in size of the affected tissue areas with the increase in fat mass (see Figures 2, 3a, 4a). Specifically, in the most extreme case of 40% increased fat mass with healthy tissue conditions, average effective strains and stresses in muscle tissue increased by 15% and 30%, respectively; the distribution of stress is shown in Figure 2. 

A comparison of the effective stress distributions in skin tissues when seated on an ACB cushion across all the model variants is shown in Figure 5 (quantitative trends of effects of increased fat mass and diabetic tissue conditions on skin tissue strains and stresses were reported in the C panels of Figures 3 and 4, respectively). In all of the simulated anatomies and in both nondiabetic and diabetic cases, the skin tissue was affected similarly to muscle, with a substantial increase in effective stresses with the increase in fat mass (see Figures 4c, 5). Interestingly, the average effective strains and stresses in fat tissues were only mildly affected by the increased fat mass (ie, within a ±20% range). However, differences between nondiabetic and diabetic tissue properties had a more pronounced effect on fat tissue strains (ie, exceeding a ±20% change) than on muscles and skin (see Figure 3). 

In the simulation cases that incorporated diabetic (stiffer) tissue conditions, the average effective stresses in skin ranged between 0 and 0.5 Pa, which was the same range that had been calculated for the nondiabetic skin (see Figure 5). However, as diabetic fat and skin tissues become stiffer due to the disease, the effective strains in fat and skin tissues decreased with respect to the nondiabetic cases (see Figure 3b,c). Although the stiffness of skeletal muscle tissues has not been reported to be directly affected by diabetes, muscle tissue in the simulations was shown to be subjected to lower effective stresses in the diabetic cases, as shown in Figure 4a. 

Discussion

The authors’ previous work^16,33 demonstrated strains and stresses in the weight-bearing soft tissues of the buttocks increase considerably with the increase in BMI or fat mass in the buttocks. Sopher and Gefen¹⁶ used a set of FE model variants to investigate how variations in BMI influence strain and stress distributions in the buttocks when a person is seated on flat stiff versus soft supports. Recently, Shoham et al³³ used the same method to explore how variations in fat mass, coupled with intramuscular fat infiltration and muscular atrophy, affect the loads in the soft tissues of the buttocks on a contoured foam cushion fitted for the patient close to the time of the injury. Both studies reported a considerable increase in peak strains and stresses in gluteal muscle tissues, as well as increased volumetric exposures to critical levels of strains and stresses in the gluteus with an increased BMI or fat mass.

It is critically important to state that in the aforementioned previous studies^16,21 about PU and DTI risks that obese individuals who sit on foam cushions, either flat foams or contoured foams, were consistently found to develop tissue stresses in the order of fPa. In this study using an ACB cushion, even the most extreme obese and diabetic conditions resulted in substantially lower tissue stresses with respect to the extents of increase in tissue stresses reported in the literature for obese individuals sitting on foam cushions or even for nonobese individuals sitting on foams, as mentioned previously. Hence, the potential biomechanical protective effect of ACB cushions still applies for obese and diabetic body and tissue conditions (see Figure 2).    

The current study also found an ACB cushion is able to keep the effective average strain and stress values from exceeding a +20% increase (see Figures 3a, 4a) for up to +20% increase in fat mass, which is equivalent in this model to reaching a BMI of 30 (the obesity threshold).¹⁶ The +20% increase in tissue strains and stresses on the ACB cushion when reaching obesity is a relatively moderate increase with respect to the previous findings,¹⁶ where the same extent of increase in fat mass had substantially more profound effects when sitting on flat foam supports (which required quantification using a logarithmic scale). Again, even after a 20% rise, tissue stresses on the ACB cushion are still substantially lower than those developing while sitting on flat foams and ill-fitting contoured foam cushions.^30,34

To be cautious, and given the known limitations of computer simulations in biomechanical research, morbidly obese patients always should be considered as being at a high risk for DTI on any cushion because their body weight deforms their internal soft tissues to such a great extent.¹⁶ However, based on the above discussion, in less severe cases (eg, patients who are overweight and obese class I according to the definitions of the WHO used by the US National Institutes of Health,²² including those who exhibit diabetic tissue conditions), the present data suggest these patients may experience enhanced tissue protection from an ACB cushion with respect to flat or contoured foam cushions. 

Although many clinicians may consider diabetes a risk factor for PUs due to impaired blood perfusion and sensation, based on their clinical experience, they have found the altered mechanical properties of collagen-rich connective tissues (eg, skin and subcutaneous fat) also seem to play an important role in the etiology of PUs and DTIs in patients with diabetes.²⁸ The locally increased soft tissue stiffness in skin and fat imposes the risk of elevated tissue stresses while also subjecting nearby tissue segments to an increased risk of deformation-inflicted injury (adjacent tissue regions need to deform more in order to compensate for the lack of deformability of the tissue sites more affected by the disease). Locally increased tissue deformations may be particularly dangerous in diabetes because these local deformations may distort, obstruct, or occlude capillaries and other microvessels that could compromise the performance of the vasculature and lymphatics in the affected sites in a situation where perfusion and tissue repair capacities often already are poor. Although average tissue strains decreased when (stiffer) diabetic tissue properties were considered in the current study (see Figure 3), localized tissue deformations and strains actually may rise at certain times because diabetes may not have a uniform homogeneous effect on tissues. Specifically, the slight decrease in strains and stresses found in the muscle tissue is likely due to an effective stiffening of the entire buttocks structure, which shields the muscle (but increases the stresses in fat and skin) when diabetes is present.

Unlike flat foam cushions, which offer low immersion and envelopment and zero adaptability as shown in previous biomechanical modeling work,²⁹ and contoured foam cushions, which are custom-fitted to the patient at a specific time-point but then become less effective and may even endanger tissue viability as the body changes after the fitting as indicated by computer simulations,³³ ACB cushions offer adjustability as well as adaptability. The ACB technology provides these adjustability and adaptability characteristics by conforming to the contours of the body and keeping this conformation ongoing even if the body contours change or if tissue stiffness properties are pathologically altered. Hence, an ACB cushion is able to conform to a wide variety of anatomical and physiological structures and changes in the bodies of patients. In previous biomechanical modeling studies,^31,34 ACB cushions were shown to have the ability to accommodate disuse-related anatomical changes in the hard and soft tissues of the buttocks and also protect tissues when deep or superficial scars already exist. The present study expands the authors’ previous investigations; specifically, it illustrates the potential of the ACB cushion technology to protect tissues of individuals who are obese and diabetic.

The recommendation to use a soft, thick cushion on the wheelchair for PU and DTI prevention is a consensus in the medical and biomechanical literature.³⁹ However, this recommendation is typically given in general (and sometimes even in vague) terms without specific indications for subgroups with known or suspected risk factors. In the current authors’ work, it has been observed a clinician who needs to decide which cushion to prescribe makes that decision based on experience and “clinical judgment” or experience combined with pressure mapping (but pressure mapping is limited to quantifying skin pressures per se). Although clinical experience should never be underestimated, the field of PU prevention needs more quantitative decision-making tools, in addition to pressure mapping, now that the current understanding is PUs form as a result of sustained deep tissue deformations and loads. Many clinicians want to make evidence-based decisions regarding prescriptions of cushions to individuals. In this context, while clinicians commonly (and rightfully) assume patients who are obese and have diabetes are at an increased risk for PUs and DTIs, no specific recommendations are available regarding the types of cushion technologies that can better protect these patients.

Limitations

Computational FE modeling is currently the only feasible method for correlating cushion design features (eg, technology, shape, and material types and composition) with internal strains and stresses in the weight-bearing soft tissues of the seated buttocks and the corresponding risk for sitting-related PUs and DTIs.^19,40 Nevertheless, computer modeling and simulations always involve limitations stemming from inherent assumptions and simplifications or omissions. First, the mechanical properties of the tissues were selected, as in most computational models, based on animal studies. Given the focus in this study is not on transient biomechanical phenomena in sitting, such as macro- and micro-movements, tissues are assumed to be hyperelastic rather than viscoelastic — that is, their mechanical stiffness is assumed to be time-independent — but this assumption is adequate because sitting is described as lasting tens of minutes to hours, which is longer than the transient stiffness changes associated with viscoelasticity.¹⁶ Additionally, the reference anatomical variant is of a person with a SCI rather than a healthy individual. As soon as 1 year following the injury, the reference MRI slice shows some degree of disuse-induced muscular atrophy associated with the SCI. Furthermore, reducing the 3D physical conditions to a slice model imposes additional limitations because the actual 3D mechanical interaction between the buttocks and the cushion are not considered, particularly out-of-plane forces. Finally, the changes in fat mass were introduced artificially under the assumption the volume of fat tissue in the buttocks increases proportionally to the increase in body weight, which is not necessarily the case. However, the authors were encouraged to see despite the limitations of FE modeling, the wound prevention community is now adopting FE as a tool for evaluating the efficacy of prevention technologies.⁴¹ Essentially, the international wound prevention industry is catching up with more mature medical device industries such as orthopedic implants or cardiovascular devices, where use of FE modeling for evaluating designs and efficacies is well-established.

Conclusion

The present study shows the tested ACB cushion was able to keep the effective average strain and stress values from increasing substantially as the amount of body fat increased or as diabetic tissue conditions developed. Thus, in theory, wheelchair users who are obese and diabetic may benefit from using an ACB cushion, because the results of this study suggest this may minimize the already increased mechanical strains and stresses in the weight-bearing soft tissues in the buttocks. Prospective clinical studies are needed to increase understanding about the risk factors of both obesity and diabetes mellitus for the development of PUs and DTIs. In addition, robust preclinical comparative studies may facilitate the development of complete, evidence-based guidelines for prescribing different cushion technologies depending on the individual risks for PUs and DTI. n

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Potential Conflicts of Interest: This research project is supported by a grant from ROHO, Inc, Belleville, IL aimed at developing computational models for evaluating the effects of cushioning materials and designs on buttocks tissues during weight bearing. Dr. Gefen is the Chair of ROHO’s Scientific Advisory Board. Ms. Kopplin is employed by ROHO, Inc.

Ms. Levy is a doctoral student, Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel. Ms. Kopplin is the Senior Director of Efficacy and Research, ROHO, Inc, Belleville, IL. Dr. Gefen is a Professor in Biomedical Engineering, Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University. Please address correspondence to: Prof. Amit Gefen, Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel; email: gefen@eng.tau.ac.il.