Negative-pressure wound therapy with instillation combines periodic instillation of a solution and negative pressure. This therapy is designed to be applied over a wound surface in a similar way to standard negative-pressure wound therapy, with the additional component of instilling a selected solution over the wound surface for a preprogrammed period. Fleischmann et al. in 1998 described this concept using a polyvinyl alcohol sponge, drainage tubes, and vacuum pump as an adjunct therapy for a variety of acutely and chronically infected wounds.1 They alternated two different antiseptic solutions, neomycin/bacitracin and polyhexanidum.
Since this early publication, there have been a variety of reports using many different instillation solutions. Predominantly, the solutions reported in the literature are considered antimicrobial, such as hypochlorite, silver nitrate, dilute povidone-iodine, bacitracin, antibiotic cocktails, and polyhexanide.2–8 However, others report positive clinical outcomes using 0.9% normal saline despite its lack of antimicrobial activity.9,10 A prospective, randomized comparison of the effectiveness or efficacy has never been reported. Thus, it is not clear whether an antimicrobial solution is required to maximize the effects of negative-pressure wound therapy with instillation in the adjunctive treatment of wounds. The primary goal of this study was to compare the outcomes of 0.9% normal saline and 0.1% polyhexanide plus 0.1% betaine with negative-pressure wound therapy with instillation for the adjunctive treatment of infected wounds.
PATIENTS AND METHODS
This is a single-institution, prospective, randomized, comparative effectiveness clinical study examining the outcomes for negative-pressure wound therapy with instillation using normal saline versus 0.1% polyhexanide plus 0.1% betaine. Patients admitted to a tertiary wound referral academic hospital with an infected wound requiring surgical débridement in the operating room and who consented to participate were enrolled in this study. All patients were excisionally débrided in the operating room in the customary fashion using sharp technique by four surgeons within 48 hours of admission (P.J.K., C.E.A., J.S.S., and K.K.E.). Devitalized and infected tissue was removed, and tunnels and abscess pockets were explored and decompressed. Pulsatile irrigation was performed on the wound using approximately 3 liters of 0.9% normal saline. After irrigation, the area was redraped in sterile fashion and a new set of sterile instruments were used for hemostasis and further débridement if needed. Negative-pressure wound therapy with instillation was then applied to the wound surface. Patients were then readmitted to the inpatient floor for medical monitoring and management. All patients received qualitative culture sensitivity–driven parenteral or oral antibiotics. Patients were brought back to the operating room serially every 2 to 4 days for débridement. The final operation was performed after resolution of the infection based on the surgeon’s judgment influenced by the following: scant or no growth on the postdébridement qualitative cultures taken from the prior operating room visit, clinical signs of infection clearance from the wound bed and surrounding tissue, and normalization of laboratory markers of infection. This final procedure was primary closure of the wound, local or free flap coverage, application of a xenograft or a split-thickness skin graft, or débridement alone based on the surgeon’s judgment. The primary team then discharged patients with follow-up in the outpatient wound center clinic.
After patients consented to participate in the study, the patients were randomized into the normal saline or the 0.1% polyhexanide plus 0.1% betaine group immediately before the first operation. Randomization was performed a priori by a research assistant using a simple scheme of 1:1 allocation using a random number generator producing a list of 100 discrete spreadsheet cells, with 1 representing normal saline and 2 representing 0.1% polyhexanide plus 0.1% betaine (Excel; Microsoft Corp., Redmond, Wash.). The negative-pressure wound therapy with instillation device (V.A.C. Ulta System with Veraflo; Acelity, San Antonio, Texas) was applied in the operating room in the customary fashion. The device settings were preprogrammed for 20 minutes of dwelling of solution and 2 hours of negative pressure. The solution was contained in a 1-liter bottle labeled with the assigned solution. The normal saline group solution was an isotonic 0.9% saline and the 0.1% polyhexanide plus 0.1% betaine solution was Prontosan (B. Braun, Bethlehem, Pa.). The investigators or patients were not blinded to the treatment once applied. A new, sterile drape and foam were applied at each operating room visit and a new bottle of solution was hung if necessary.
Study data that were collected included the following: (1) subject demographics, (2) comorbidities and smoking history, (3) wound location and cause, and (4) surrogate wound outcomes. The surrogate wound outcome endpoints consisted of the following: (1) number of operating room visits, (2) length of hospital stay in days, (3) time to final surgical procedure during the admission in days, (4) the proportion (percentage) of wounds closed/covered during the admission, and (5) the proportion (percentage) of wounds that remained closed or covered approximately 30 days after hospital discharge. Both intention-to-treat and per-protocol statistical analysis was performed on the demographics and outcomes for the two cohorts. Chi-square test was performed for analysis on proportions as represented by percentages. Means were statistically compared with a t test (p < 0.05 indicates statistical significance). This study was approved by the Georgetown University Medical Center Institutional Review Board (no. 2013-0865). Patients were not compensated for their participation in this study.
A total of 123 patients were assessed for eligibility. Twenty-three patients were excluded, with five patients not meeting the eligibility criteria and 18 refusing to participate. A total of 100 patients were randomized and enrolled in this study. For the intention-to-treat analysis, there were 49 patients in the normal saline cohort and 51 patients in the 0.1% polyhexanide plus 0.1% betaine cohort. For the per-protocol analysis, there were 42 patients in the normal saline cohort and 41 patients in the 0.1% polyhexanide plus 0.1% betaine cohort (total attrition rate, 17 percent). Seven patients were removed in the normal saline cohort and 10 patients were removed from the 0.1% polyhexanide plus 0.1% betaine cohort for one of the following reasons: (1) greater than 30-day length of stay (normal saline, n = 2; 0.1% polyhexanide plus 0.1% betaine, n = 3), (2) lost to follow-up after discharge (normal saline, n = 4; 0.1% polyhexanide plus 0.1% betaine, n = 5), or (3) had less than two visits to the operating room (normal saline, n = 1; 0.1% polyhexanide plus 0.1% betaine, n = 2) (Fig. 1).
Demographics were similar in each cohort for both the intention-to-treat and per-protocol analyses, with the only statistically significant difference being more male and fewer female patients in the 0.1% polyhexanide plus 0.1% betaine cohort compared with the normal saline cohort (p = 0.004) (Table 1). There was also no statistically significant difference in comorbidities including smoking history between the two cohorts for both the intention-to-treat and per-protocol analyses. There was no statistically significant difference in the wound location or wound cause for both the intention-to-treat and per-protocol analyses between the two cohorts (Tables 2 and 3).
The outcome data reveal no statistically significant difference between the normal saline and 0.1% polyhexanide plus 0.1% betaine cohorts for the number of operating room visits, length of hospital stay, proportion of wounds closed/covered, and proportion of wounds that remained closed at the 30-day follow-up for both the intention-to-treat and per-protocol analyses (Table 4). There was a statistically significant difference between the normal saline and the 0.1% polyhexanide plus 0.1% betaine cohorts for the time to final surgical procedure [intention-to-treat, 5.73 (SD, 3.75) and 7.73 (SD, 5.49), respectively, p = 0.038; per-protocol, 5.57 (SD, 3.61) and 7.46 (SD, 4.42), respectively, p = 0.035].
Negative-pressure wound therapy with instillation is an adjunctive therapy commonly used for wounds with a history of acute or chronic infection. Thus, defining the most effective selection of a topical solution for negative-pressure wound therapy with instillation is logical. The published clinical literature on this topic predominantly report and encourage the use of antimicrobial solutions.1–3,5–8,11,12 Specifically, 0.1% polyhexanide plus 0.1% betaine has been studied extensively as having a broad spectrum of activity and being well tolerated in both solution and gel formulations.13–19 Animal models also validate the use of antiseptics for negative-pressure wound therapy with instillation. Phillips et al., in a porcine explant Pseudomonas aeruginosa biofilm wound model of negative-pressure wound therapy with instillation, report no colony-forming unit log reduction for normal saline but report a 4-log reduction for 0.1% polyhexanide plus 0.1% betaine.20 Davis et al., in an in vivo Pseudomonas aeruginosa–inoculated porcine wound model, also reported a trend for a greater reduction in bacterial counts for 0.1% polyhexanide plus 0.1% betaine compared with normal saline.21 An international consensus article led by the study authors also preferentially recommended the use of antiseptics with negative-pressure wound therapy with instillation.22 In a noncomparative observational study, Lehner et al. report artificial joint replacement salvage rate of 86.4 percent (19 of 22) in the environment of acute infection and an 80 percent (eight of 10) salvage rate in the environment of a chronic infection using 0.04% polyhexanide.6 The authors published a 142-patient retrospective, comparative cohort study reporting the effectiveness of negative-pressure wound therapy with instillation with 0.1% polyhexanide plus 0.1% betaine compared with negative-pressure wound therapy.23 We reported that the number of operating room visits, length of hospital stay, time to final surgical procedure, and the proportion of wounds closed was superior for the negative-pressure wound therapy with instillation of 0.1% polyhexanide plus 0.1% betaine cohort compared with negative-pressure wound therapy. The vast majority of the publications on negative-pressure wound therapy with instillation with antiseptics are small case studies, case series, and expert opinion using various antiseptic and antibiotic solutions.5,7,8,11 There is a paucity of robust studies examining the outcomes of negative-pressure wound therapy with instillation, and inconsistency as to the optimal solution choice. Nevertheless, there is a clear bias toward the use of antiseptics.
This is the first randomized, prospective, comparative effectiveness study examining the outcomes with the use of negative-pressure wound therapy with instillation using two different solutions. The results of this study suggest that the outcomes following the use of negative-pressure wound therapy with instillation using normal saline are comparable to those of 0.1% polyhexanide plus 0.1% betaine. The only difference in outcomes is the time to final surgical procedure, which interestingly favored the normal saline cohort. Brinkert et al. also report positive outcomes for the use of normal saline with negative-pressure wound therapy with instillation.9 They report a wound closure rate of 98 percent in their case series of 131 patients with a variety of infected and contaminated wounds. This study may have been biased by the fact that there are few choices available to the authors for instillation solution selection, and normal saline was a default choice. Furthermore, 35 percent of patients received standard negative-pressure wound therapy before they received negative-pressure wound therapy with instillation, and 48.8 percent received negative-pressure wound therapy after receiving negative-pressure wound therapy with instillation, which may have skewed their results.
We used surrogate outcome endpoints to determine the effect of negative-pressure wound therapy with instillation on wounds. Thus, the direct effectiveness/efficacy of negative-pressure wound therapy with instillation with either solution cannot be definitely established with our results. However, our surrogate outcome endpoints of number of operating room visits, length of hospital stay, time to final surgical procedure, proportion of closed/covered wounds, and proportion of wounds that remain closed at the 30-day follow-up are relevant to the inpatient surgical management of infected wounds. These surrogate outcome endpoints reflect both clinical and economic realities. Another important variable that was not reported concerned the qualitative cultures taken before and after débridement at each operating room visit. We did report these data in our retrospective study but elected not to include the results in this study because of the difficulty in interpretation and variability of the microbiology culture results. We do not have strong confidence in qualitative culture results. The results may reflect inconsistent technique, prior antibiotic therapy, and institutionally established selective growth of specific bacterial species. For this study and as part of our routine clinical decision-making algorithm, we take into account the quality of the wound (color, odor, and pliability), serologic markers, radiographic findings, histologic reports, and qualitative cultures.
There are other significant potential flaws to our study that may impact the interpretation of our results. First, there is an ingrained institutional bias for aggressive serial excisional débridement. Therefore, the reliance on an antiseptic solution between operating room visits may be less important in our institution. Second, there was no control group used in this study, so we cannot determine whether the results reflect the experimental intervention of negative-pressure wound therapy with instillation. In other words, we cannot definitively determine whether these subjects would have had similar outcomes without the use of negative-pressure wound therapy with instillation. Third, investigator bias may have also skewed the results. From our prior published work, we observed that 0.1% polyhexanide plus 0.1% betaine resulted in good outcomes. Thus, potential candidates for this study may have been excluded because of the chance that the patient may have been randomized to the normal saline group. Every attempt was made to include all patients that met the very broad eligibility criteria, but the worst wounds or sickest patients may have been excluded from this study. However, this would have affected the cohorts equally. Thus, the principal focus of this study to compare solutions is uncontaminated. Finally, this was not a blinded study. Thus, investigator bias may have also influenced the decision by the surgeon that the wound was sufficiently prepared for closure or coverage. Again, this bias would have favored 0.1% polyhexanide plus 0.1% betaine based on prior experience. However, the 30-day follow-up data showed no difference in proportion of closed wounds. This implies that we did not favor one solution or another because, if we did bias for faster closure, we would most likely have seen a lower proportion of closed or covered wounds at the 30-day follow-up for the 0.1% polyhexanide plus 0.1% betaine cohort. Furthermore, the number of operating room visits was not different between the two cohorts. This indicates that closure/coverage decisions were similar in both groups.
Another limitation of this study is its overall study design. This study is best defined as an effectiveness study rather than an efficacy study. Although conducted in a randomized, prospective fashion, the broad eligibility criteria encompassing all wound causes, wound sizes, and anatomical locations preclude our study from being identified as a typical comparative efficacy study. Thus, the reader should acknowledge this lack of homogeneity of the study population and lack of adherence to the rules that govern a classic efficacy study design. However, we believe these results are meaningful because they reflect a real-world application of this type of therapy.
Our data suggest that the choice of solution may not be critical to the success or failure of this adjunctive therapy. One possible contribution to the positive clinical results may be related to a fundamental concept of negative-pressure wound therapy. Morykwas et al. reported that intermittent negative pressure improves local tissue perfusion, thus creating a more ideal environment for wound healing compared with continuous negative pressure.24,25 Negative-pressure wound therapy with instillation inherently provides intermittency because of the periods of solution dwell. As an aside, many wound care providers use the continuous setting for negative-pressure wound therapy for a variety of pragmatic reasons, including the concern for leaks during intermittent periods of no negative pressure. Perhaps the positive effect observed with negative-pressure wound therapy with instillation reflects this intermittent negative-pressure application phenomenon rather than anything to do with instillation of a solution. A more recent publication by Lessing et al. reported that negative-pressure wound therapy with instillation with normal saline significantly increases granulation thickness by almost 2 mm over intermittent or continuous negative pressure in an animal model.26 Thus, intermittency does not appear to be the sole reason for negative-pressure wound therapy with instillation efficacy. The mechanism(s) of action of negative-pressure wound therapy with instillation appears to be more complicated and elusive. The choice of solution may play a role, but other factors including the mechanical effect of fluid dynamics disrupting biofilm formation and the removal of inflammatory factors may also be important. Further work is needed to elucidate the mechanism of action of negative-pressure wound therapy with instillation to identify key contributors to positive outcome.
Our results provide important information regarding the choice of instillation solutions for negative-pressure wound therapy with instillation. Specifically, our data suggest that normal saline may be as effective as 0.1% polyhexanide plus 0.1% betaine when used as the solution for negative-pressure wound therapy with instillation. However, because of the limitations of our study as discussed above, definitive conclusions cannot be drawn. Ultimately, clinical effects, spectrum of activity, safety, and cost will be the driving factors for the choice of instillation solution. Normal saline conforms well to most of the above criteria despite its lack of direct antimicrobial activity.
Mathew Snow, D.P.M., Brian Derner, B.A., and Zinnia Rocha, B.A., assisted in data compilation. They received no compensation for their assistance. Written permission was obtained from Mathew Snow, D.P.M., Brian Derner, B.A., and Zinnia Rocha, B.A., for the above statements.
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