Multidisciplinary Expert Consensus Statements and Recommendations for Use of Hypochlorous Acid as a Solution for Negative Pressure Wound Therapy With Instillation

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HOCl is a weak acid that is endogenously produced by leukocytes and is part of the host defense response against pathogens (bacteria, viruses, yeast, fungus).^1,2 The mechanism of action is through pathogen cell death via disruption of the cell membrane/wall via oxidation, as well as inhibition of ribonucleic acid and DNA synthesis.^2-6 HOCl is an oxidizing agent that oxidizes many chemical moieties associated with microbe survival. Its potential toxicity is modulated in human tissue via protective mechanisms that are likely associated with the evolutionary process. In other words, the effect of endogenous HOCl on native cells is well regulated during the inflammatory response against pathogens.^3,4 In fact, HOCl may have a beneficial effect on fibroblast and keratinocyte activity within a wound environment.^7,8 HOCl-containing aqueous solutions have also been demonstrated to mechanically disrupt exopolymeric matrix of bacteria.⁵ In clinical use for many years, HOCl-preserved cleansers have demonstrated no cellular toxicity, and have demonstrated rapid onset of cleansing/desloughing action.^4,9-12 pHAp has a pH within the range of 3.5 to 5.5, which is ideal for wound healing and is associated with the status of a wound as it changes from a chronic state to a healing state.^13-15 When dissolved in water, HOCl partially dissociates and becomes hypochlorite (0.03%). An example of a commercially available cleanser that contains HOCl is Vashe (Urgo Medical North America; pHAp hereinafter) (330 ppm stabilized pHAp). HOCl is an inherently unstable molecule unless it is stabilized using advanced methods. Some solutions of HOCl are so unstable that they must be refrigerated, used in situ, or stored in glass bottles.

The current report discusses a stabilized HOCl solution that can be stored for 18 months at ambient temperatures. Stabilization generally utilizes measured amounts of naturally occurring inorganic compounds that provide ionic strength, as well as pH that is both associated with the long-term packaged stability consistent with other HOCl solutions used in wound care and compatible with the ingress tube used with NPWTi-d (or NPWTi).

NPWTi-d combines traditional NPWT with preprogrammed and periodic instillation of a solution that dwells within the foam and on the wound surface (V.A.C. Veraflo; 3M).¹⁶ This method has been proposed to provide the dual benefit of the positive effects of negative pressure on the wound surface, including exudate removal, micro- and macro-deformation, and neovascularization, as well as the positive effects of a topical solution, which can promote solubilization of nonviable tissue and a decrease in bacterial bioburden.^17-22 This technology has slowly gained acceptance as an adjunct treatment option for complex infected and noninfected wounds, for wound bed preparation for closure or coverage, and for secondary healing in a variety of wound etiologies and anatomic locations.²³

A meta-analysis performed by Gabriel et al²⁴ reported that NPWTi-d was favored over other wound therapies, including traditional NPWT, as demonstrated by fewer surgeries, fewer days until wounds were ready for closure or coverage, reduced bacterial count, and an overall decrease in total therapy days. A multicenter prospective randomized controlled trial conducted by Kim et al²⁵ reported that patients in the traditional NPWT group were 3 times more likely to be rehospitalized after discharge compared with patients in the NPWTi-d group. Further, NPWTi-d has been reported to decrease the overall economic burden of inpatient wound care by reducing the length of hospitalization and number of surgeries.^26,27

A variety of instillate solutions have been used with NPWTi-d.^28,29 The choice of solution has largely been driven by clinician familiarity, access, and cost rather than demonstrated clinical superiority of a particular option. It is important to acknowledge that wound irrigation solutions and cleansers preserved with antimicrobial ingredients are considered by the United States Food and Drug Administration to be medical devices, in which the formal role of the antimicrobial component is that of a preservative. To date, only 1 study has directly compared 2 solutions used in conjunction with NPWTi-d in a prospective, randomized fashion. Kim et al³⁰ reported no difference in clinical surrogate outcomes in number of operations, length of hospitalization, time to wound readiness for closure or coverage, and 30-day closure rates between PHMB and 0.9% normal saline. That study has been misinterpreted to imply that normal saline is "as good" as any antiseptic or preserved wound cleanser. The study involved a surgically intensive approach with surgical serial wide excisional debridement. Thus, it is possible that an antiseptic solution may have had no added benefit in this situation. Further, the antiseptic agent PHMB has demonstrated cytotoxic effects, which may inadvertently enhance the perceived equivalency of normal saline.^31,32 Kim et al³⁰ concluded, "ultimately, clinical effects, spectrum of activity, safety, and cost will be the driving factors for the choice of instillation solution." The Kim et al study has poor external validity because it may lack applicability in cases in which wounds may not be effectively debrided due to the lack of surgeon availability, surgeon ability, facility limitations, scope of practice, and other factors. In these cases, use of an antiseptic or preserved wound cleanser with NPWTi-d may yield better outcomes.

In case studies and case series, NPWTi-d with pHAp has been reported to expedite wound conversion to a positive state (eg, ready for wound coverage, closure, or secondary healing) in complex wounds in a variety of anatomic locations.^33-37 To date, there are no large comparative retrospective or prospective studies examining the clinical benefits of this combination. In a small (n = 24), retrospective comparative observational study of NPWTi-d with pHAp vs NPWTi-d with 0.9% sodium chloride in patients with complex, infected, or contaminated wounds, Alberto et al³⁸ reported that the NPWTi-d with pHAp group trended toward fewer surgeries, fewer days to wound closure, and reduced length of hospitalization. An economic study of these data reported an overall cost savings of 56% with the use of pHAp compared with 0.9% sodium chloride.³⁹

There has been an evolution of thought amongst experts in NPWTi-d in favor of the use of pHAp. Six expert panel publications on the topic of NPWTi-d were published between 2013 and 2020.^28,29,40-43 The earlier articles, published in 2013, 2015, and 2016, did not include pHAp as a recommended solution choice.^28,40-42 The 2018 consensus document was the first to add pHAp as a recommended solution,⁴³ culminating in the most recent consensus publication in 2020, in which 91% (10 of 11) of the international multidisciplinary expert panel members recommended the use of pHAp.²⁹ This greater recognition of pHAp may have correlated with greater access to the solution and/or with greater knowledge of its advantages. Regardless, the use of pHAp in conjunction with
NPWTi-d continues to grow.

The purpose of this consensus document is to provide guidance based on the responses of a panel of multidisciplinary experts for the specific use of pHAp in conjunction with NPWTi-d.

The majority of the multidisciplinary expert clinician panel met in person in April 2023 in Washington, D.C., USA, after which all the members of the panel corresponded through written and verbal communications. The panel members were identified and selected by the primary author (P.J.K.) as clinical experts in pHAp, NPWTi-d, and the management of complex wounds. The in-person meeting focused on the general framework for the current article as well as consensus topics to include in it. The panel comprised 15 members from the disciplines of plastic surgery (n = 6), nursing/nurse practitioner (n = 4), trauma/general surgery (2), podiatric surgery (n = 1), vascular surgery (n = 1), and infectious diseases (n = 1). The panelists represent the major geographic areas of the United States (east, west, central, north, south), 1 region in France, and 1 province in Canada. They also represent rural and urban hospitals, as well as academic institutions. One panel member (L.T.) provided comments on the manuscript but did not participate in the survey.

A written survey of 10 declarative statements was distributed electronically to the panel with a request for a binary answer of either "agree" or "disagree" with each statement as well as a section for comments about each statement. These statements, which attempt to capture the scope of use of NPWTi-d with pHAp, were designed by the primary author (P.J.K.) and agreed upon by the panelists. Responses were tallied and the comments collated. The survey results are represented as fractional proportion as well as percentage agreement or disagreement. The comments were reviewed, and common themes concerning each respective statement are also presented.

The results of the 10 declarative consensus statements as well as synthesized comments are presented, along with the proportion of agreement and percentage agreement or disagreement (Table).

Consensus Statement 1: pHAp is the primary option as an instillate solution for NPWTi-d.

Thirteen panelists (93%) agreed with this statement. Panelists commented on the safety and efficacy profile of pHAp and the observed clinical benefits in wound bed preparation. Further, the relatively lower cost of pHAp compared with other antiseptics was noted, as was its wide availability. However, 1 panelist identified the need for a large prospective comparative study, or alternatively, a robust registry, to demonstrate its superiority over other solutions. Given the challenge of conducting large-scale prospective controlled trials in the context of extreme variability in wound types, underlying comorbidities, and infection status, registries may be the preferred option and are recommended in the future.

Consensus Statement 2: pHAp can have detrimental degradative effects on the foam dressings used for NPWTi-d.

No panelists (0%) agreed with this statement. All panelists reported they had never experienced this event. No published reports have demonstrated such degradation of the foam dressing. The in vitro material compatibility of the foam dressing and pHAp has been examined and has supported these observations (written communication on September 8, 2019, with Kinetic Concepts Inc/3M).

Consensus Statement 3: There are the same indications and contraindications for the use of pHAp and NPWTi-d when used independently or in combination.

Twelve panelists (86%) agreed with this statement, which addresses whether there are altered properties of using pHAp in combination with NPWTi-d. It is important to remember that when these options are used independently, the mechanism of action and the treatment goals for the choice of one or the other are different for pHAp and NPWTi-d. For example, pHAp utilizes chemical interactions to affect bacteria, whereas NPWTi-d uses mechanical properties. The majority of panelists commented that the clinician should apply the same safety principles to the combination of NPWTi-d with pHAp. One panelist stated that anatomic location of the wound may prohibit use of pHAp or NPWTi-d. However, this panelist conceded that this is not a strict indication or contraindication and that clinical decision-making is clinician- and patient-specific.

Consensus Statement 4: Early initiation (at the time of initial contact in the care setting) rather than delayed initiation of NPWTi-d with pHAp is recommended.

Although there was nearly complete agreement with this statement (13 of 14 panelists [93%]), there were several comments on specific conditions in which application of NPWTi-d should be delayed, such as necrotizing fasciitis and other rapidly evolving conditions for which close monitoring is warranted. In these situations, pHAp-soaked gauze dressing is recommended until the acute event has resolved. Preclinical research has demonstrated that pHAp is not dissipated quickly in contact with gauze (written communication on July 21, 2023, with Urgo Medical North America). The panelists also commented that recent prior excisional debridement, particularly in the operating room, may result in a greater effect of NPWTi-d with pHAp.

Consensus Statement 5: NPWTi-d with pHAp should be used only in cases of heavy bioburden where complete surgical excisional debridement is not possible.

No panelists (0%) agreed with this statement. They commented that the criteria for use of NPWTi-d with pHAp are broad. This combination has been commonly used as an adjunct when excisional debridement is performed as well as when excisional debridement is not performed. There may be an added benefit of combined excisional debridement and NPWTi-d with pHAp in heavily contaminated wounds with heavy bioburden.

Consensus Statement 6: More rapid cycling (shorter dwell time and negative pressure time) of NPWTi-d is recommended when pHAp is used.

Three panelists (21%) agreed with this statement. Most panelists commented that there is no observed added benefit of more rapid cycling. A longer rather than a shorter dwell time may be more beneficial to bacteria reduction due to longer contact time with the wound surface as a result of the antimicrobial pharmacokinetic contact time/kill curves of pHAp. Theoretically, the hydrodynamic effect through more rapid cycling imparted by NPWTi-d may provide added benefit of debris detachment and evacuation. However, for the less-experienced user, changing the default setting (10 minutes of dwell, 3.5 hours of negative pressure at −125 mm Hg) on the NPWTi-d device can cause confusion and lead to frequent need for adjustment. There are no published data that suggest that variations in cycling result in superior or inferior clinical results. There are practical concerns as well, including the need for more solution over the length of the therapy, which will require more frequent changes of both the pHAp cleanser container and the pump egress canister, thereby increasing the cost.

Consensus Statement 7: pHAp always requires a separate ingress and egress ports when used with NPWTi-d.

Two panelists (14%) agreed with this statement. The typical NPWTi device components include a pump, tubing, SensaT.R.A.C. Pad (3M), and an adhesive drape. The single TRAC pad consists of a single access point on the interface between the tubing and the foam surface with the ingress and egress ports within millimeters of each other. Another option is the use of the VeraT.R.A.C. Duo Tube Set (3M), which can be placed remotely from each other at a distance decided by the user. Most of the panelists reported that a 2 TRAC pad setup, with 1 port for solution ingress and 1 port for egress of solution into the canister, is not necessary.

There are anecdotal reports of observed crystallization/precipitation of pHAp loosened debris (whose volume in these reported cases is generally reported to be higher than with 0.9% normal saline) that leads to blockage alarms on the NPWTi-d device when using a single TRAC pad. No data, either in vivo or in vitro, have addressed this observation, and the majority of the panel's observations are inconsistent with those who have anecdotally reported this so-called blockage event. Internal testing (written communication on July 21, 2023, with Urgo Medical North America) shows that pHAp itself does not chemically crystalize or precipitate. It is possible that the observed blockage is a result of a greater degree of solubilization imparted by pHAp of nonviable tissue being evacuated out of the single TRAC pad where the ingress and egress ports are in close proximity. The panelists observed that, compared with antiseptics, preserved wound cleansers, and 0.9% normal saline, pHAp is associated with a greater degree of visible debris in the NPWTi-d egress canister. This may be the result of pHAp's ability to disrupt biomatter (written communication on July 21, 2023, with Urgo Medical North America). The panelists believe that a greater degree of visible debris may be a positive marker of the additional or incremental disruptive activity of pHAp compared with 0.9% normal saline or other cleansers that do not contain HOCl. The panelists commented that if possible, adequate excisional debridement of the wound should be performed if there is a concern for potential blockage with use of a single ingress/egress port. As stated previously, however, the majority of the panelists have not observed an increase in blockage alarms with the single TRAC pad design even when excisional debridement was not performed.

Consensus Statement 8: pHAp is the preferred solution when the large-perforated (reticulated) foam dressing is not available.

Five panelists (36%) agreed with this statement. One innovation of NPWTi-d is a perforated/reticulated foam design (V.A.C. Veraflo Cleanse Choice Dressing; 3M). The design allows for tangential and vertical forces imparted on the wound surface, theoretically allowing for mechanical "scrubbing" of the wound surface.⁴⁴ The panelists provided various comments in regard to Statement 8. Many noted that this novel foam design has not been seen to enhance the observed clinical outcomes when pHAp is used in combination with NPWTi-d. Other panelists do recommend the use of this reticulated foam when available, but they state that it is not absolutely necessary. Perhaps the addition of pHAp allows NPWTi-d to overcome any potential limitation of the traditional foam design. It is clear that the large-perforated foam design is growing in popularity and is often preferred over traditional foam designs. It is possible that the combination of NPWTi-d with pHAp with the large-perforated foam may lead to even greater benefits. However, there are no current comparative data to support this hypothesis. Studies are needed to directly compare this novel foam with the traditional foam design.

Consensus Statement 9: NPWTi-d with pHAp is safe when used in a wound that has deep exposed structures including deep fascia, ligament, tendon, capsule, cartilage, and bone.

All panelists (100%) agreed with this statement, with all reporting no hesitation in the use of NPWTi-d with pHAp in the management of wounds with deep exposed structures. For any product, it is important to review the safety data enclosed in the package insert. The panelists commented that the safety profile of pHAp supports its use in these deep exposed structures. When using fluids, it is always important to explore all tunnels where the fluid may become sequestered. Some panelists recommended applying a nonadherent contact layer onto the surface of these deep exposed structures if the user has concerns about direct application of NPWTi-d with pHAp onto them. It is the opinion of the primary author (P.J.K.) that the use of a nonadherent contact layer may decrease the overall effectiveness and efficiency of NPWTi-d with pHAp by creating an unnecessary barrier at the interface between the wound surface and the foam, albeit with no deleterious effects on the tissue. However, there is no evidence to support this contention.

Consensus Statement 10: NPWTi-d with pHAp provides more efficiency and effectiveness for wound bed preparation than if used independent of one another.

All panelists (100%) agreed with this statement. It is generally accepted that, independently, pHAp and NPWTi-d are safe and effective. When used in combination there may be a greater synergistic effect, and the 2 technologies appear to be quite compatible. pHAp is designed to efficiently affect pathogen removal and assist in mechanical disruption of biomatter via its HOCl-laden proprietary formulation, while NPWTi-d is designed to convert the wound to a prohealing trajectory through various mechanical submechanisms, including by detaching and removing nonviable tissue by mechanically scrubbing the surface of the wound and removing this debris through a fluid medium. The panelists commented that NPWTi-d with pHAp appears to be an ideal combination for converting the wound bed to a stage at which surgical coverage or closure can be considered. Alternatively, NPWTi-d with pHAp can be used in the acute stage of wound care until the patient can be discharged for secondary healing over time.

Although panelist comments about Statement 7 indicate that the majority of expert panelists have not had issues with blockage causing alarms, perhaps due to their complete familiarity with the nuances with the 2 technologies, there are anecdotal reports that instillation with pHAp solubilizes a high volume of nonviable wound debris that can adhere to the foam dressing and the negative pressure tubing and ports. These alarms have several negative consequences; they are annoying to the patient and clinician, the NPWTi-d pauses, and they are challenging for providers to troubleshoot, all of which may lead to discontinuation of the NPWTi-d. Identification of the type of blockage alarm is important; the pump is programmed to self-diagnose and identify whether the blockage is on the instill port or the negative pressure port.

The simplest and definitive resolution to this potential issue is to use the 2 TRAC pad setup as previously discussed. An alternative strategy is to start the pump in the negative pressure cycle rather than in an instillation phase. It is important to note that the NPWTi-d pump default setting is to start in the instillation (dwell) phase; thus, the pump settings need to be changed manually. Additionally, if the wound is believed to have a large amount of wound debris that may pass through the foam and tubing system, the port locations on the dressing can be moved preemptively before a blockage potentially develops. For example, at 24 hours, the clinician can pause therapy and move the ports to another location while trying to stay off seams and areas with uneven topography. The clinician must remember to repair the location where the port originated with an additional drape. This "clip and move" technique is easy and pain-free for the patient, taking only minutes to complete.

Adequate solution volume to bathe the entirety of the wound surface maximizes the effect of NPWTi-d. Although an automated software upgrade has been introduced in 2022, its volume recommendation may underestimate the amount of solution needed in larger wounds.⁴⁵ If the 2 TRAC pad setup is selected, pad location can be selected to optimize the use of gravity. Examples include the patient with a vertical component to the dressing (eg, an ambulatory patient with a leg wound), or the patient in the intensive care unit who is in a fixed supine position in whom a portion of the wound is closer to the bed surface. In these situations, the clinician may elect to place the ingress port at the lowest point and the egress point at the highest point. In this way, the solution is more likely to come into contact with the entirety of the wound surface because there is always a baseline of a low level of negative pressure pulling the fluid toward the egress port, even during the negative pressure phase.

It is important to periodically examine the canister contents. The clinician should evaluate the contents for thick exudate and/or larger debris fragments. Methods to circumvent the potential for a blockage alarm are to increase the volume of instillation solution per dwell cycle or increase the frequency cycling. Either method in isolation or in combination may assist the passage of debris into the cannister and help avoid clumping of the debris at the foam-tubing interface. As stated previously, the simplest solution to a potential blockage problem is to initiate and continue therapy using a 2 TRAC pad setup.

There are no uniquely different recommendations for the pump device settings when pHAp is used in combination with NPWTi-d. The default preprogrammed factory settings on the negative pressure pump provide a sufficient baseline. Individual clinician experience and patient circumstance may dictate changes in pressure, negative pressure time, and/or solution dwell time. Data are insufficient to support so-called dose-response recommendations. The 2020 expert panel recommendations on NPWTi-d provide further guidance.²⁹

As with all expert consensus statements, the recommendations reflect individual experiences rather than the results of a well-designed clinical study. Each expert panelist has biases based on their training, discipline, individual experiences, and interpretation of the published literature. It is also important to note that all the panelists are active users of and content experts on the use of NPWTi-d with pHAp. Thus, the panel members' support for this therapy is not surprising. However, the nature of an expert panel obviously necessitates active users who support the therapy in question.

The panel associated with the current report is the largest and most diverse multidisciplinary panel to address the topic of NPWTi-d with pHAp. Although there were differences in agreement for the 10 statements, these differences appear to reflect individual preferences rather than issues of safety or effectiveness. NPWTi-d with pHAp imparts a beneficial effect on wound bed preparation to achieve a positive state for wound closure or coverage or for secondary wound healing. Independently, NPWTi-d and pHAp each has demonstrated benefit; when used in combination, they may have an even greater synergistic effect. Theoretically, the mechanism of action for the combination of NPWTi-d with pHAp includes the following: (1) the softening or solubilization of nonviable tissue through dwelling of pHAp, (2) the hydrodynamic effect of pHAp flowing onto the wound surface and exiting from the wound surface, and (3) the mechanical contraction and expansion of the foam dressing when negative pressure is applied and then relieved. Although the exact mechanism of action of NPWTi-d with pHAp has yet to be elucidated, the clinical response is clear. Future research and more robust data are needed to test the statements drafted by this panel and to further study the safety and efficacy of NPWTi-d with pHAp.

Authors: Paul J. Kim, DPM, MS¹; Luis Fernandez, MD²; Mary Ann Obst, RN, BSN, CCRN, CWON³; Abigail Chaffin, MD, CWSP⁴; Elizabeth Faust, MSN, CRNP, CSWS, CWOCN-AP, MAPWCA⁵; John Lantis, MD⁶; Kara Couch, MS, CRNP, CWCN-AP⁷; Michael Desvigne, MD, CWS⁸; Mark Suski, MD, CWSP⁹; Neilendu Kundu, MD¹⁰; Marc Mathews, MD, MS¹¹; Richard Simman, MD¹²; Christine Murphy, PhD, RN, WOCC¹³; Natalie E. Nierenberg, MD, PhD¹⁴; and Luc Téot, MD, PhD¹⁵

Affiliations:¹Department of Plastic Surgery, Department of Orthopedic Surgery, The University of Texas Southwestern, Dallas, TX; ²Trauma Surgery, Professor, Department of Surgery, Division of Trauma Surgery/Surgical Critical Care, The University of Texas Health Science Center at Tyler, Tyler, TX; ³Department of Surgery, Regions Hospital, St Paul, MN; ⁴Division of Plastic and Reconstructive Surgery, Department of Surgery, Tulane University School of Medicine, New Orleans, LA; ⁵Department of Plastic Surgery - Wound Care, Reading Hospital, West Reading, PA; ⁶Icahn School of Medicine at Mount Sinai West, New York, NY; ⁷The George Washington University Hospital, Washington, DC; ⁸Abrazo Arrowhead Hospital, Glendale, AZ; ⁹Center for Advanced Wound Healing, Los Robles Regional Medical Center, Thousand Oaks, CA; ¹⁰Department of Plastic Reconstructive Surgery, Mercy Health, Cincinnati, OH; ¹¹Department of Surgery, The University of Arizona, Tucson, AZ; ¹²Division of Plastic Surgery, The University of Toledo College of Medicine and Life Sciences, Toledo, OH; ¹³Ottawa Hospital Limb Preservation Centre, Ottawa, Ontario, Canada; ¹⁴Department of Geographic Medicine and Infectious Diseases, Tufts University School of Medicine, Boston, MA; ¹⁵Department of Plastic Surgery, Montpellier University Hospital, Montpellier, France

Disclosures: The following authors disclose a financial relationship with Urgo Medical North America: Kim, Fernandez, Obst, Chaffin, Faust, Lantis, Couch, Desvigne, Suski, Mathews, Simman, Téot, Murphy, and Nierenberg. The following authors disclose a financial relationship with 3M: Kim, Fernandez, Obst, Chaffin, Faust, Lantis, Couch, Desvigne, Suski, Mathews, Simman, Téot, and Nierenberg. This manuscript was independently written and analyzed but was financially supported by Urgo Medical North America.

Correspondence: Paul J. Kim, DPM; Paul.Kim@UTSouthwestern.edu

Manuscript Accepted: March 7, 2024