Chronic Wound: Manage Topical Negative Pressure - Dissertation Example

Chronic wounds are becoming more commonly managed using topical negative pressure. The evidence supporting the device’s clinical use is evaluated in this literature review. Randomized controlled trials (RCTs) were searched from the PubMed database, and one meta-analysis, five were systematic reviews, and three RCTs were obtained, and three systematic reviews plus one RCT were discussed in detail. In effect, 23 primary trials were looked at. Only a few of these studies reported statistically better improvements in time to wound healing as well as volume and size of wound for the participants treated with TNP, as compared to those managed with conventional dressing. Assessment of the effects on secondary outcomes did not show significant difference between TNP and control. However, the high number of methodological issues make most of these studies of poor quality, compromised validity, and high potential for bias. Thus, future RCTs should be large-scale, blinded, and with intention-to-treat analysis to make its findings significant. CHAPTER 1 Introduction Chronic wounds Wounds are said to be chronic if they take a long time to heal, if they fail to heal despite treatment, or recur (Azad and Nishikawa, 2002; Ubbink, et al., 2008). Werdin, et al. (2009) defines it as wounds that are persisting for more than or equal to three months. 1. Causes All wounds have a potential to become chronic, and as such should be treated based on their etiology, either venous insufficiency, arterial perfusion, or unrelieved pressure. Poor nutrition, immunosuppression, and infection further promote the progression of wounds to chronic state. The most common chronic wounds are located at the lower extremity, and are caused by vascular pathology or diabetes (Werdin, et al., 2009). Because those in the elderly population are the ones more prone to have such factors, chronic wounds are mostly found among the geriatrics, together with individuals with multiple health problems (Azad and Nishikawa, 2002). 2. Pathogenesis Wound healing occurs through a cascade of hemostasis, inflammation, proliferation and remodelling. Chronic wounds, start as acute wounds, although they become trapped in the inflammatory phase, and are thus persistently red, swollen, painful, and fluid-filled. The persistence of inflammation is sometimes promoted by the presence of bacteria in the wound site. At this time, the most common genes expressed were for cell death. The senescent cells persisting in chronic wounds make fibroblasts irresponsive to growth hormone, making the wound incapable of traversing through the next steps of the cascade (Leffler, et al., 2011). 3. Principle of treatment The Wound Healing Society has suggested the TIME acronym to guide healthcare providers in managing chronic wounds. The first letter represents “Tissue”, which means that treatment should first involve removal of impediments to healing, such as devascularized tissue, necrotic material, and excessive bacteria. These can be done through surgical debridement, mechanical debridement by curettage or waterjet, application of enzymatic agents like collagenase and papain-urea derivatives, dressings with autolytic hydrocolloid material, as well as biological interventions like infestation with maggots. Currently, there is still no definitive evidence that supports the use of a single form of debridement, although surgical debridement is generally regarded as fast and effective. Next, “Infection” should be managed through topical or systemic antibiotics. Surgical debridement also decreases bacterial load considerably. Then, “moisture” should be provided to prevent friction and resulting pain in the area. Many dressings, hydrocolloids, paraffin gauze and saline-moistened dressing, are being used to give a moist environment for the wound. Finally, letter E is for “Edge of the wound”, which means that the quality of wound edge should be monitored to assess the progress of healing. It should be determined whether the ulcer size is decreasing (Werdin, et al., 2009). While the TIME process is in progress, addressing the cause of the wound, by controlling blood sugar among diabetic patients, bed turning for those suffering from pressure ulcers, and revascularization among patients with vascular problems, should hasten the healing process (Werdin, et al., 2009). If this still does not lead to definitive wound healing, surgical closure or flap transfer can be performed (Leffler, et al., 2011). If a chronic wound is successfully treated, its recurrence should be prevented by compression therapy for pressure ulcers, clopidogrel for arterial ulcers, off-loading for neuropathic ulcers, and pressure relief for pressure sores (Werdin, et al., 2009). Topical negative pressure (TPN) 1. Description of technique TPN, also known as sub-atmospheric pressure, sealed surface wound suction, vacuum sealing, and foam suction dressing, is the application of negative pressure or suction force. This is done by inserting a drainage tube embedded in the open-pore wound dressing, which is made up of polyurethane ether and secured with transparent adhesive drape (Azad and Nishikawa, 2002; Ubbink, et al., 2008). Commercially available devices such as vacuum assisted closure (VAC) pump manufactured by Kinetic Concepts, Inc. (KCI), as well as wall suction or surgical drainage bottles can be used to apply TPN. Those available in the market tend to be more reliable, since they deliver controlled pressure, and they have safety features. A negative pressure or suction force is then applied through the tube. Currently, there is no standard regimen tested to work best in healing chronic wounds. Regimens thus differ based on amount of negative pressure, application of continuous or intermittent pressure cycle, and frequency of dressing changes (Azad and Nishikawa, 2002). Pressure applied is also modified from -50, 000 mmHg to -125 mmHg, although the upper boundary is the advised amount of negative pressure, based on the technique’s testing on swine models (Ubbink, et al., 2008). TPN is associated with accelerated healing rates, reduced nursing time and decreased hospital stay. A 2006 systematic review of RCTs and non-randomized studies provide evidence that TNP improves wound healing with minimal complications. However, other systematic reviews, which looked into the findings of RCTs, case series and basic science studies, found that there is relative lack of evidence supporting the benefits of TNP (Ubbink, et al., 2008). TPN is more expensive than conventional wound dressings, and may thus be difficult for hospitals and nursing homes to use such technique for chronic wounds (Azad and Nishikawa, 2002). Evidence from high quality studies is thus necessary to promote the clinical use of TPN. 2. Mechanism of action Although the mechanism of action is still not clearly elucidated, the application of negative pressure is thought to decrease the excess interstitial fluid surrounding the wound. The exudate compresses surrounding microcirculation, decreases oxygen, nutrient and waste product transport to and from the site, and promotes bacterial growth. By removing this fluid, blood, which transports oxygen and nutrients to tissues, has better access to the site. In addition, better circulation also allows the transport of waste products away from the wound. Improvement of surrounding vasculature is important in chronic wounds caused by vascular pathologies and diabetes, which causes chronic wounds through the abnormalities in vessels. The infiltration of active pro-inflammatory cells and factors, as well as oxygenation, should enhance wound healing (Plikaitis, 2006). Indeed, the availability of oxygen was shown to affect gene expression (Leffler, et al., 2011). Aside from this mechanism, it is also suggested that TNP decreases the bacterial load of the wound. Using animal models, it was demonstrated that deliberately infected wounds treated with TNP had a lower bacterial load compared to wounds not treated with TNP. Bacteria releases toxins that injure tissues, and it uses up the nutrients that should have been used for healing (Azad and Nishikawa, 2002; Ubbink, et al., 2008). Finally, the negative pressure causes the wound edges to appose and to develop microdeformations, which stimulates angiogenesis and tissue growth (Plikaitis, 2006). In vitro, the stretch resulting from TNP causes differences in gene expression of fibroblasts. A glaring difference after 7 days of TNP treatment is the increase in number of expressed genes to almost 12 times that observed from an untreated wound. These genes were found to be coding for structural proteins, such as epiphycan, that facilitate proliferation and remodelling. Also up-regulated in TNP-treated chronic wounds are those implicated in macrophage signalling. These inflammatory cells synthesize and release growth factors In contrast, cell adhesion proteins are down-regulated upon TNP therapy, thus promoting cell migration, which is important in the formation of granulation tissue (Leffler, et al., 2011). Literature Review Search strategy This study used the PubMed search engine to look for clinical trials on the effects of TNP on chronic wounds. The search was conducted using the Medical Subject Heading (MeSH) topic “Negative Pressure Wound Therapy” AND “chronic wound” as keywords. These should be present in the titles or abstracts. Inclusion criteria Out of all the list of journal articles gathered after the search, the ones included in this study are based in the following inclusion criteria. 1) Human participants 2) English 3) Randomized controlled trials (RCTs), or meta-analysis or systematic reviews on RCTs Journal articles that qualify the inclusion criteria were obtained for further assessment. Outcome of literature search There were 943 articles that can be found using the Mesh term. nine of these satisfied the inclusion criteria. One was meta-analyses, five were systematic reviews, and three were RCTs. Three systematic reviews and one primary study were discussed in detail in the second chapter. Validity of the study and potential for bias Quality of evidence was first evaluated by determining the validity of the study. Randomization, concealment, blinding, and the number of samples were looked at to assess the studies’ potential for bias. High quality of evidence can be found on those that are valid and with minimal potential for bias. Data analysis As adapted from the systematic reviews of Ubbink, et al. (2008 and 2011), primary, such as rate of healing and size of wound or any measure of wound healing, and secondary outcomes, like length of hospitalization, quality of life and adverse events, were watched out for. Continuous data expressed as mean with standard deviation, and dichotomous results stated either as relative risk, absolute risk, numbers needed to treat or numbers needed to harm were also obtained. Chapter 2: Methodological issues in research As of 2011, there is still lack of high quality evidence that supports the use of TNP in clinical setting. There is no better way of demonstrating its effectiveness in treating humans in the clinical setting than through a clinical trial. This systematic review of RCTs is thus conducted to answer the research question, “For individuals with chronic wounds, does TNP improve wound healing time and proportion of wounds completely healed than other treatment options?” The prevalence of systematic reviews of RCTs 1. A systematic review on 13 RCTs comparing TNP to controls (Armstrong and Lavery, 2005; Braakenburg, et al., 2006; Eginton, et al., 2003; Etoz, Ozgenel and Ozcan, 2004; Ford, et al., 2002; Jeschke, et al., 2004; Joseph, et al., 2000; Llanos, et al., 2006; McCallon, et al., 2000; Moisidis, et al., 2004; Moues, et al., 2004, 2005, 2007; Vuerstack, et al., 2006; Wanner, et al., 2003) was conducted by Ubbink, et al. (2008). Additional details on 7 of these studies were published in 2011. Databases looked at were Cochrane Wounds Group Specialised Register, Central Register of Controlled Trials (CENTRAL) of the Cochrane Library, Ovid Medline, Ovid Embase and Ovid CINAHL, and the search was limited to articles published from 1950 to December 2007. Publications were also sought from VAC manufacturers. TNP was compared with either gauze soaked in 0.9% saline or Ringer’s solution or hydrocolloid gel plus gauze (Armstrong and Lavery, 2005; Braakenburg, et al., 2006; Ford, et al., 2002; Vuerstack, et al., 2006). Primary, such as rate of healing and size of wound or any measure of wound healing, and secondary outcomes, like length of hospitalization, quality of life and adverse events, were watched out for. Assessment of articles, from selection to data synthesis, was conducted by two independent authors. Any disagreements were resolved through a discussion. These studies looked into the effects of TNP and controls on chronic wounds, diabetic wounds, pressure ulcers, skin grafts, and acute wounds. The variety of wound types made meta-analysis inapplicable. The number of participants ranged between 10 and 162. True randomization was done in only three studies, and concealment was uncertain in over half the trials. In addition, the nature of intervention made blinding impossible. Amount of negative pressure applied was also not standard, as one study used 150 mmHg, while another set it at 100 mmHg. It should also be noted that more than half of the found trials received their funding from KCI, while the others did not declare their sources of funding. Based on the review of these studies, it was found that TNP did not allow significantly faster healing rate. One study reported that a significantly greater proportion of TNP patients (78%) had reduced wound volume, as compared to just 30% in the gauze group (Joseph, et al., 2000). However, no standard deviations were reported for both of these studies, and the analysis could not be statistically validated. In the study by Eginton, et al. (2003), significant difference in mean % reduction of volume and depth were found between TNP and topical gel, although this study only used 7 participants to test TNP. Other studies measuring wound surface area did not find statistically significant difference between TNP and gauze, or cannot be verified because no standard deviations were reported. It was also found that TNP-treated chronic and diabetic wounds appeared ready for closure surgery 1 to 10 days earlier than those treated with controls. Because of its subjectivity, this data was ignored by the authors of the review. Glaringly, intention-to-treat analysis was done in just 6 of these studies. Meanwhile, Looking at secondary outcomes, one study determining differences in number of complications did not find any significant finding. Data on pain, quality of life, adverse events, and costs were either statistically insignificant or unverifiable. All seven trials were randomized, and were done with the consent of their participants, although none blinded the patients and healthcare providers. Only three concealed allocation, either through random number generator, envelope, or computer randomization. Again, the lack of concealment made the occurrence of selection bias was highly likely. Two trials each had treatment and control groups with dissimilar baseline characteristics. Another two did not declare the baseline characteristics of their participants. In terms of data analysis, only one of seven trials conducted intention-to-treat analysis. Thus, the data of other trials may have been overestimated. The variety of endpoints, comparator treatments and subgroup analysis used by these RCTs also prohibited meta-analysis. According to the authors of the review, it can be said that the quality of the clinical trials on TNP were poor, as they had small sample sizes, vague treatment allocation, short duration of follow-up, and non-blinding. These limitations could have contributed significantly to the observation that a lot of data were statistically inconclusive. Non-blinding also increases the potential for bias, especially with regards to quality-of-life assessment. In addition, clinically relevant outcomes, such as quality of life, adverse effects, and pain, were either ignored or reported using a clinically invalid method of measurement. The absence of intention-to-treat analysis in more than half of the reviewed trials made it difficult to objectively determine the balance between benefit and cost of TNP. Edema and bacterial counts, which, as discussed earlier, should have also been determined based on the suggested mechanisms of action of TNP (Ubbink, et al., 2008; Ubbink, et al., 2011). 2. A similar systematic review was conducted in 2011 by a completely different set of authors. Similarly, they found that the 9 RCTs (Blume, et al., 2008; Chio and Agrawal, 2010; Keskin, et al., 2008; Stannard, et al., 2009; Bee, et al., 2008; Mody, et al., 2008; Perez, et al., 2010; Saaiq, et al., 2010; Sepulveda, et al., 2009) on treatment of acute or chronic wounds that they were able to obtain from PubMed and Conchrane Library Databases did not show resounding positive results. Only two trials found statistically significant benefit of TNP. As can be seen, the RCTs assessed in this systematic review were not included in the previously mentioned reviews by Ubbink, et al. (2008 and 2011), although these studies also used conventional dressings, generally saline-soaked gauze as controls. It is also important to note that this review also included RCTs studying the effectiveness of makeshift TNP systems that were not commercially available, such as negative pressure generate by a suction pump for chest drainage, a central vacuum system, or Redon bottles (Bee, et al., 2008; Mody, et al., 2010; Perez, et al., 2010; Saaiq, et al., 2010 and Sepulveda, et al., 2009). Interestingly, all trials that studied the commercial TNP systems were conducted in the USA, which implies that these systems are unavailable or too expensive in developing countries. Peinemann and Sauerland (2011) also reported that there is a significant number of trials on which nothing has been published make any finding by published RCTs prone to publication bias. Two separate individuals also conducted the review, and differences in opinion were discussed further to arrive at a common decision. Randomization was detailed in seven of the nine RCTs reviewed, although concealment was not discussed in more than half of these trials. Interestingly, blinding was performed by Sepulveda, et al. (2009). This was the first time that an RCT was found to do so. As such it was the only one among those reviewed by Peinemann and Sauerland (2011) that was assessed to have a low potential for bias. Complete wound closure, either through raw data or Kaplan-Meier estimator, was the primary outcome looked at in this review. Just like in previous systematic reviews by Ubbink, et al., no meta-analysis was performed, because of the heterogeneity of RCTs. Secondary outcomes, particularly adverse events, such as death, secondary amputations, fistula formation, and wound infection, as well as health-related quality of life, were obtained. Interestingly, time to complete wound closure and reduction in wound size were considered secondary outcomes. The primary outcome being looked for was reported in only five of the nine new trials. Only two (Blume, et al., 2008; Saaiq, et al., 2010) of the five studies reported significance in the difference of number of patients with complete wound closure. Three (Blume, et al., 2008; Perez, et al., 2010; and Sepulveda, et al., 2009) of the four trials reporting on time to wound closure showed statistical significance of difference between two groups. Blume, et al. (2008) also showed statistically significant difference in the reduction in wound size. On the other hand, differences in wound complications between treatment groups were statistically insignificant. The study by Keskin, et al. (2008), revealed that those assigned to TNP group had significantly greater fear of treatment, due to possible pain, for example, than those in the control group. Stannard, et al. (2009) was the only one among the nine who investigated health-related quality of life using questionnaires, and found significant improvement in the physical health of those who were given TNP. In six of the nine trials, 20% of their randomized participants were dropped out from evaluation, thus no intention-to-treat analysis was done for these RCTs. Biochemical parameters as outcomes 3. The prospective randomized study of Moues, et al. (2008) thus looked into the differences in the concentrations of albumin, pro- and activated matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1), as well as MMP-9/TIMP-1 ratio of the fluids collected from 33 wounds being treated with TNP (n=15) or conventional gauze therapy (n=18). Because of the prospective nature of this study, the group size was small. In addition, the heterogeneity of the study population, in terms of the chronicity of wound, for example, might result to inconclusive findings. Conventional gauze therapy was described as moist gauze application at least twice a day, depending on the productivity of the wound. Moistening agents were either 0.9% saline, 0.2% nitrofurazone, 1% acetic acid solution, or 2% sodium hypochlorite. Which agent to use depended on degree of contamination, bacterial species, and amount of debris. Similarly, TNP therapy was also described. It consisted of polyurethane foam dressing of pore size measuring 400-600 µm, and a continuous negative pressure of 125 mmHg. No significant difference in albumin concentration was found between TNP and conventional therapy immediately after treatment, although there were significantly lower levels of pro-MMP-9 and total MMP-9/TIMP-1 ratio in TNP-treated wounds than those applied with gauze 10 days post-therapy. These findings were verified, because the values were expressed as mean and standard deviation. Looking deeper into its methods, patients were randomly assigned, and the allocation was concealed using a closed envelope. It was not mentioned if blinding and seeking informed consent was done. The wounds were debrided of necrotic tissue before application of assigned therapy. Upon measurement of albumin, MMP-9 and TIMP-1 after debridement, the values did not differ significantly between treatment groups. Similarly, the baseline characteristics did not significantly differ between TNP-treated and conventionally-treated groups. They were also subdivided into acute or chronic wounds. Acute wounds were defined as existing for less than a month, acquired either through infection or operative procedure, and with signs of normal wound healing. On the other hand, chronic wounds were those existing for more than a month. These wounds were further sub-categorized into pressure ulcers, chronic non-healing wounds, and infected non-healing wounds without tendency toward normal wound healing. Starting from the initiation of therapy, wound fluid was collected daily for 10 days using sterile filters. Quantitative measurements of pro-MMP-9 and TIMP-1 were performed in duplicate using enzyme-linked immunosorbent assay, albumin concentration were determined using turbidimetric immunoassay, while active MMP-9 was measured using Biotrak Activitiy Assay System. Another replicate could have been added to improve the precision of the measurements. Conclusion In total, 23 primary experiments were covered in this paper. Although most of the reviewed trials reported no significant difference between treatment groups in terms of time needed for wound closure, three of the four more recent RCTs reported significantly lower time needed for those treated with TNP than those receiving conventional treatment. However, all RCTs looking into complications of TNP and control did not find statistically significant difference between the treatment groups. Despite the promising findings of some of the RCTs reviewed, there were many problems in terms of their quality, validity and potential for bias. Current RCTs on TNP are few and of poor quality, which was compromised because of small sample sizes, poor concealment and impossibility of blinding. This might have caused the lack of significance of most of these studies’ findings. Differences in the characteristics of wounds being treated, the amount of pressure applied, and the heterogeneity of TNP systems also made comparison of data from different RCTs impossible. Data analysis was also poor in these studies, as continuous data sometimes lacked standard deviation, while dichotomous ones rarely have ITT analysis. All of these contributed to the difficulty in making a meta-analysis of these RCTs. The lack of intention-to-treat analysis might have been caused by the high proportion of drop-outs, as observed in some of the RCTs. Finally, publication bias is a significant consideration when assessing the evidence regarding the effectiveness of TNP. Chapter 3: Summary and Conclusion More healthcare providers and hospitals, especially in the developed countries, apply TPN for the management of chronic wounds. Among the 23 primary trials looked at in this literature review of three systematic reviews and one RCT, only a few of these studies reported statistically better improvements in time to wound healing as well as volume and size of wound for the participants treated with TNP, as compared to those managed with conventional dressing. Assessment of the effects on secondary outcomes did not show significant difference between TNP and control. However, methodological issues, such as small sample size, poor concealment of allocation, non-blinding, statistically useless data, and lack of intention-to-treat analysis, make most of these studies of poor quality, compromised validity, and high potential for bias. Although identifying the definite mechanism of action of TNP, such as that done by Moes, et al. (2008) is also important, future researches should focus on providing sound evidence on the clinical use of TNP. Thus, future RCTs should be large-scale, blinded, and with intention-to-treat analysis to make its findings significant. References Azad, S. and Nishikawa, H., 2002. Topical negative pressure may help chronic wound healing. BMJ, 324, pp. 1100. Leffler, M., Derrick, K. L., McNulty, A., Malsiner, C., Dragu, A., and Horch, R. E., 2011. Changes of anabolic processes at the cellular and molecular level in chronic wounds under topical negative pressure can be revealed by transcriptome analysis. J Cell Mol Med, 15(7), pp. 1564-1571. Moues, C. M., van Toorenenbergen, A. W., Heule, F., Hop, W. C., and Hovius, S. E. R., 2008. The role of topical negative pressure in wound repair: Expression of biochemical markers in wound fluid during wound healing. Wound Rep Reg, 16, pp. 488-494. Peinemann, F. and Sauerland, S., 2011. Negative pressure wound therapy—systematic review of randomized controlled trials. Dtsch Arztebl Int, 108(22), pp. 381-389. Plikaitis, C. M. and Molnar, J. A., 2006. Subatmospheric pressure wound therapy and the vacuum-assisted closure device: basic science and current clinical successes. Expert Review of Medical Devices, 3(2), pp. 175–184. Ubbink, D. T., Westerbos, S. J., Evans, D., Land L., and Vermeulen, H., 2011. Topical negative pressure for treating chronic wounds (Review). The Cochrane Library, 2, pp. 1-33. Ubbink, D. T., Westerbos, S. J., Nelson, E. A., and Vermeulen, H., 2008. A systematic review of topical negative pressure therapy for acute and chronic wounds. BJS, 95, pp. 685-692. Werdin, F., Tennenhaus, M., Schaller, H., and Rennekampff, H., 2009. Evidence-based Management Strategies for Treatment of Chronic Wounds. Eplasty, 9, pp. 169-179. Read More