Ischemic wounds can be difficult to treat due to their slow, stagnant healing. These wounds often increase in size and require lower-extremity bypass to heal. If patients are not bypass candidates, however, their prognosis is fair, at best. Poor prognosis is associated with comorbidities such as diabetes mellitus 1 and end-stage renal disease, which are related to small-vessel angiopathy and peripheral neuropathy.
In many clinical centers, surgical revascularization is the standard treatment for patients with ischemic ulcers of the lower extremity. However, patients with diabetes mellitus or end-stage renal disease, with or without vasculopathy, often are not operative candidates due to poor outflow vessel runoff or high operative risk. Many patients who are not ideal candidates for vascular reconstruction ultimately require lower-extremity amputation.
High-voltage pulsed current (HVPC) has been used by practitioners to augment the healing rate of nonischemic chronic wounds with few adverse effects, based on prospective randomized clinical trials 2–5 and a recent meta-analysis. 6 The salutary effect reported for HVPC has been attributed, at least in part, to the increased blood flow to wounds. Many clinical and in vivo studies 7–12 have reported increased blood flow to tissue from electrotherapy.
Increased skin microperfusion is observed in response to a family of electrotherapy signals characterized by short pulse duration (<500 microseconds [μs]), low repetition rate (<100 pulses per second [PPS]), high amplitude (>100 milliampere [mA]), and direct coupling. 13 Of these direct-coupled electrical stimulation signals, HVPC is the best studied in terms of chronic wound healing. The HVPC signal is produced by devices that are classified by the Food and Drug Administration (FDA) as powered muscle stimulators. 14 The FDA allows manufacturers to claim 6 indications for use of powered muscle stimulators, one of which is to improve local blood flow. Although increased blood flow to muscle is implied, an HVPC device might reasonably be utilized to improve local blood flow to ischemic ulcers because muscle cells near the ischemic wound are likely stimulated by electrotherapy. In the event a wound has no adjacent muscle, electrotherapy may still be applied off-label; health care providers may prescribe reasonable off-label applications as part of their practice. 15
HVPC may enhance physiologic processes associated with wound healing, including enhanced fibroblast proliferation, 16 enhanced collagen synthesis, 17,18 and resolution of edema. 19 Although these mechanisms have been tested in a normal oxygen tension environment, wound healing is impaired under hypoxic conditions. 20 If circulation cannot be significantly improved by surgery or angioplasty, microcirculation may be improved by HVPC. HVPC delivers an electrical signal that has distinct positive and negative polarity resulting from monophasic (twin-peaked) pulses. 13 HVPC and other electrotherapeutic signals have been observed to increase microcirculation slowly, approaching normal over a number of treatment sessions. Increases in perfusion with electrical stimulation have been observed following ischemic transtibial incisions, 21 breast flap reconstructions, 11 and infrapopliteal wounds. 22
Bilateral segmental systolic pressure measured by volume plethysmography (pulse-volume recording [PVR]) is an important means to determine arterial flow. One limitation of segmental systolic pressure, however, is incompressibility of leg arteries caused by calcification of the tunica media; this is particularly apparent in patients with ischemic wounds secondary to diabetes or chronic renal disease. Because segmental systolic pressure may be limited in its ability to predict healing in patients with these conditions, 23 transcutaneous oxygen (TcPo2) levels may be used to determine local microcirculation. TcPo2 has positive predictive value in wound healing. 23–25 It measures absolute, rather than relative, oxygen partial pressure in the dermis. 26 In prospective trials, TcPo2 has been an independent predictor of future lower-extremity amputation. 26–29 Perilesion measurements may be ischemic (TcPo2 <20 mm Hg), intermediate (TcPo2 >20 mm Hg and <40 mm Hg) or normal (TcPo2 >40 mm Hg). Ischemic wounds have a guarded prognosis for complete closure under the best circumstances. 23
A 6-subject case series suggested that HVPC induces a slow, persistent increase in TcPo2 in the vicinity of critically ischemic malleolar or inframalleolar skin lesions. 30 In the study, all patients had diabetes mellitus, 2 had type 1 diabetes, and none were candidates for invasive revascularization at the time electrotherapy was initiated. As electric stimulation continued for weeks or months, microcirculation improved, which may have resulted in improved outcomes. Although 2 patients underwent amputation, 4 patients healed. As expected, wounds that eventually healed initially deteriorated but tended to change to a positive healing rate when perilesion TcPo2 exceeded 20 mm Hg. Thereafter, these wounds closed at a predictable rate, suggesting that electrotherapy improves periwound microcirculation of ischemic inframalleolar skin lesions.
Although hypothesis testing must be asserted with caution for retrospective clinical case series, the present study intended to confirm that HVPC enhances healing of chronic ischemic wounds, in part by increasing microcirculation over time. To do this, the records of 22 patients with arteriosclerosis and high-risk nonsurgical ischemic wounds who were treated in a wound clinic were retrospectively reviewed and analyzed. All patients were treated with standard care for ischemic wounds; half were also treated with electrotherapy. Although surgical treatment is considered the primary option for patients with ischemic wounds at the authors’ facility, these patients were poor surgical candidates; standard care, therefore, was conservative (described below).
Charts of patients who presented with malleolar and inframalleolar ischemic wounds, who were seen between 1996 and 2001 in the Comprehensive Chronic Wound Clinic at the University of Pennsylvania Health System, Philadelphia, PA, were retrospectively reviewed for potential inclusion in the study. Patients were drawn from the facility’s wound care population and were evaluated for the clinical appropriateness of HVPC treatment. If patients were not candidates for HVPC, they received only standard care. 31
Criteria for inclusion in the study included (1) periwound TcPo2 (or closest available site) less than 20 mm Hg, (2) ischemic ulcers located only on the periankle or distal (because edema associated with more proximal leg ulcers could artificially lower TcPo2), (3) the presence of arteriosclerotic disease confirmed by a test other than TcPo2 (eg, PVR, magnetic resonance angiography, or contrast angiography), (4) wounds ischemic 6 weeks or longer after onset (because low TcPo2 due to trauma and/or infection resolves within days or weeks), (5) wounds that had TcPo2 assessed at some point between initial evaluation and 1 year following initial evaluation, (6) wound age of 6 weeks or more (chronic wound); a wound could initially be evaluated before 6 weeks, allowing the inclusion of acute ischemic postsurgical wounds that rapidly increased in size and that had electrotherapy urgently started, and (7) wounds that were followed actively for at least 4 weeks, allowing all conservative treatments to be implemented and followed. Patients had to be compliant with treatment, using electrotherapy 5 to 7 days per week, to be included in the analysis; outcomes were not further analyzed according to number of days per week HVPC was performed.
A wound was actively followed beginning with an initial evaluation and prescription of treatment through continuation of treatment for at least 4 weeks. Quantitative wound area and oxygenation were described from initial evaluation to either amputation, discharge, or 1-year posttreatment. Patients discharged before 1 year of treatment were followed by telephone or via hospital chart to determine qualitative wound status (healed or not healed) and amputation status at the 1-year point.
Exclusion criteria included (1) patients who were good candidates for arterial bypass or angioplasty, regardless of whether previous bypass had been attempted or completed; (2) wounds with active abscess or cellulitis because systemic infection would independently delay healing and lower TcPo2; (3) patients with extensive, rapidly expanding gangrene or gangrene involving an entire digit because of presumed marginal prognosis; (4) patients with an urgent need for amputation because any conservative treatment would be poorly advised; (5) patients with poor short-term survival prognosis, such as those with extensive, marginally compensated, and worsening multisystem disease, because of ethical concerns about unnecessary treatment; (6) active smokers because of the confounding negative influence of smoking on microcirculation; (7) patients with extensive periwound scaring (eg, from multiple prior healing attempts) because of the potential disruption of microcirculation caused by scars; (8) patients with uncomplicated venous insufficiency for which compression is indicated, including hyperpigmentation, lipodermatosclerosis, a leg wound with a red wound base, and edema, which may cause artifical decrease in TcPo2; and (9) patients with pacemakers because of possible interference of HVPC with the paced signal.
Of some 300 patients in the facility’s database, approximately 30 had wounds on the ankle and below and had periwound TcPo2 less than 20 mm Hg at some time during their course of treatment. Of the 30 subjects, 2 were rejected due to concurrent cigarette smoking; 1 for periwound scarring; 1 because the wound healed within 6 weeks after onset; 1 had TcPo2 less than 20 mm Hg, but the measurement was obtained after the 1-year observation period; and 1 because the wound was followed less than 4 weeks. Two subjects who had electrotherapy performed less than 5 days per week were also not included in the study: 1 was dispensed a machine but electrotherapy was not performed, and the other had HVPC performed by an outpatient physical therapist 3 days per week and was referred to another facility after 12 weeks. This resulted in 22 patients who met the study criteria. Four of 6 patients who were included in a previously published case series of HVPC 30 met the criteria to be included in this study.
The study had no wound size inclusion requirements. In addition, wounds with tendon or bone at the base were included, even though granulation tissue has poor healing potential in this situation; empirically, healing over tendon and bone has been noted with use of HVPC. Inframalleolar skin wounds could have a black, yellow, or red base. Plantar ulcers over weight-bearing bony prominences were included, as long as there was underlying ischemia and arteriosclerosis that could explain failure to heal, despite the patient employing maximal pressure-relief strategies.
For this retrospective analysis, the group that received only standard care served as the control group. Because of wide variability between initial evaluation and the start of HVPC treatment (0 to 90 days), the first day of HVPC therapy was defined as t = 0. For 10 of 11 subjects, the t = 0 “benchmark” was the day HVPC started at home 5 to 7 days per week (by history). For the eleventh subject, HVPC started in a skilled nursing facility at 4 to 6 days per week (week 0 to 2), then 5 to 7 days per week at home (weeks 3 to 19), then 3 days per week (week 20 on).
For the standard care group, t = 0 was defined as the date of initial wound evaluation plus 28 days. This number was chosen because it is the median time interval between initial evaluation and the start of HVPC treatment and offers a comparable pretreatment period for both groups.
The electrotherapy technique utilized in this study has been previously described. 30 A PGS 3000 handheld device (Universal Technology Systems, Inc, Jacksonville, FL) was used to provide HVPC, which was set to 80 to 330 volts peak amplitude, up to 100 PPS, for treatments of approximately 1 hour per day, 5 to 7 days per week. The 100-cm2 dispersive electrode was positioned proximally on the treated lower extremity. Active electrodes were placed directly over the wound and delivered electrical current to the tissue through a sterile conductive hydrocolloid sheet (Vigilon; Bard Medical Division, Covington, GA). After education, electrotherapy was applied daily at home by the patient, caregiver, or visiting nurse. Compliance with daily electrotherapy treatment was confirmed by patient reports at subsequent visits and as independently reported by a visiting nurse. No formal or objective means to ensure compliance was established. Once initiated, daily HVPC sessions continued uninterrupted until the wound healed or the patient was lost to follow-up or referred to another provider.
Standard wound care
All subjects received conventional wound care, 31 including (1) protection of ischemic skin lesions from mechanical trauma using padding and from excessive pressure and shear using padding and protection (eg, nonadherent gauze pads, ABD pads, Kerlix and DH walker); (2) silver sulfadiazine ointment applied to black or yellow eschar; (3) antibiotic ointment or hydrocolloid applied to granulating wound base to maintain a moist environment 32; (4) application of topical PDGF-BB (becaplermin [Regranex]; Ortho-McNeil, Raritan, NJ) if perilesion TcPo2 was greater than 30 mm Hg 33; (5) periodic sharp debridement of nonischemic wounds 34; (6) visiting nurse follow-up 35 for patient- and caregiver-performed wound care at home; and (7) ongoing management of medical comorbidities by primary care physicians and appropriate internal medicine specialists.
Pressure and shear have an independent influence on wound healing, especially on ischemic wounds. In the standard care group, 3 ischemic, neuropathic wounds located directly on the plantar surface received 4 to 12 weeks of total contact casting coupled with a high level of vigilance. 36 Total contact casting distributes weight over the entire plantar foot within a cast and typically yields better healing outcomes for well-perfused neuropathic wounds than complete off-loading. Total contact casting did not lead to pressure necrosis in any case.
Wound selection and measurement
Several subjects had more than 1 wound at and distal to the ankle. In this situation, the largest wound was defined as the index wound and was measured. In some cases, the index wound became 2 wounds as it healed. In that scenario, both areas were summed to find the index wound area. In all cases in which the index wound healed, other wounds open at the same time as the index wound healed as well.
Wound areas were determined by digital planimetry, which reports excellent intrarater and interrater reliability and concurrent validity compared with other objective methods of determining wound area. 37 For each determination, wound edges were outlined on an acetate sheet; the edges were then traced using a digital artpad (Model ET-0405-L1; Wacom Company, LTD, Taiwan) into ImageJ (version 1.09y; developed at National Institutes of Health, available at http://rsb.info.nih.gov/-image), from which areas were calculated. The average of 2 area calculations was recorded as the wound area. Using this method, intrarater and interrater reliability were both 0.99, exceeding published figures.
To measure TcPo2, 3 calibrated electrodes were coated with contact solution and affixed to a subject’s skin by circular double-sided tape. One electrode was placed on the periwound skin or as close as possible to the ischemic area; the second was placed within 10 cm of the wound on nearby skin (ie, on the plantar arch or dorsum of the foot); and the third electrode was placed on a farther-removed, well-perfused area (ie, the upper leg). If 2 electrodes were the same distance from the wound, both values were averaged. For example, if a wound on the hallux was so extensive that TcPo2 could not be measured, 2 electrodes were placed on the dorsal and plantar forefoot 2 cm from the wound and were averaged. Other details of the TcPo2 technique, including reliability, are reported elsewhere. 30 The repeatability of this technique on a subject with normal microcirculation is good. 30
Peripheral arterial disease
For inclusion in the study, patients had to have ipsilateral lower-extremity peripheral arterial disease confirmed by surgical history or a diagnostic test. Acceptable diagnostic studies included PVR from an accredited vascular laboratory, 1.5 Tesla magnetic resonance angiography, 38,39 or conventional contrast angiography that showed peripheral arterial disease proximal to the level of the ulcer.
Nonparametric statistics were used throughout. For individual patients, the observation period was 1 year from the start of HVPC plus standard care or 1 year plus 28 days for those who received standard care only. The 28-day period was defined as equivalent to the period before electrotherapy for the HVPC group. For both groups, the end of the pretreatment period was defined as t = 0. The number of wounds healed by t = 0 + 1 year was compared between groups, employing a 2-way contingency table by the Fisher exact test. To perform statistics on the healing rate for individual patients, the investigators constructed wound area versus time plots. From these plots, wound areas were determined by interpolation at 4-week intervals. From interpolated data, wound area descriptive statistics (means and standard deviations) and inferential statistics (Mann-Whitney test) were calculated between groups. The maximum periwound TcPo2 between groups was compared before and after t = 0, also employing the Mann-Whitney test. For a single group, the Wilcoxon signed rank test was used to compare periwound TcPo2 before and after t = 0, using paired data. All analyses were performed by Statview (SAS Institute, Inc, Cary, NC).
Over 4 years, 11 subjects satisfied the study’s entry criteria (Table 1) and received electrotherapy and standard care; a matched cohort of 11 patients received standard care only (Table 2). Those receiving standard care only did not start HVPC because treatment began before electrotherapy became available in the clinic (n = 5), subjects were unable or refused to perform the daily electrotherapy protocol at home (n = 3), electrotherapy was denied by insurance (n = 1), or the subject had a pacemaker, which is a relative contraindication for electrotherapy (n = 2).
The HVPC group and standard care group were similar in age (67 ± 15 and 71 ± 15, respectively), ratio of men to women (7:4 and 6:5, respectively), and percentage with diabetes mellitus (82%). The ratio of patients with type 1 to type 2 diabetes was slightly lower for the HVPC group (3:6) than the standard care group (4:5). Internists managed blood glucose levels of subjects with diabetes and visiting nurses provided diabetic teaching. Control of blood glucose, determined by reliable history, was adequate for 20 of 22 subjects. Two patients in the standard care group had inadequate control of blood glucose levels, one due to mild cognitive deficits and inconsistent family support, the other due to brittle type 1 diabetes.
Four patients in the HVPC group and 2 in the standard care group had a history of end-stage renal disease. All were receiving hemodialysis 3 times per week, except for 1 subject in the HVPC group who had a functioning renal allograft.
At t = 1 year, 1 subject in the HVPC group had died, compared with 3 subjects in the standard care group. Mortality for the standard care group tended to be higher. Of those subjects alive after 1 year, 1 subject in the HVPC group had a major amputation, compared with 2 subjects in the standard care group. Of the subjects who died, 1 additional major amputation occurred in each group during the observation year, yielding 2 major amputations for the HVPC group and 3 for the standard care group. Although sample size was small, there was a slight tendency toward improved limb salvage for the HVPC group.
Black eschar is usually a sign of ischemia; a red base is consistent with granulation and, rarely, minimal hypoxia. At both initial assessment and the start of HVPC, wounds treated with HVPC plus standard care had a more ischemic appearance. Fifty percent of HVPC-treated wounds had black eschar covering the wound (or bone in 1 case), 42% were covered in yellow slough, and 8% had a red base. Eight percent of wounds in the standard care group had black eschar, 42% were covered in yellow slough, and 50% had a red base. On initial evaluation, HVPC-treated wounds tended to be larger than wounds treated with standard care only (12.1 ± 21.1 cm2 vs 3.1 ± 5.0 cm2, respectively). In addition, HVPC-treated wounds were younger than wounds treated with standard care only (4 ± 2 months vs 9 ± 5 months, respectively). Several wounds selected for HVPC treatment emerged from intact skin and became full-thickness wounds 20 to 100 days prior to the start of HVPC treatment. Between initial wound evaluation and the start of electrotherapy, however, wound area in the HVPC-treated wounds remained stable (12.1 ± 21.1 cm2 and 12.5 ± 20.6 cm2, respectively) for the month (29 ± 32 days; median, 28 days; range, 0 to 100 days).
Including only subjects who were alive at the end of the observation period, 29% of wounds in the standard care group healed at t = 1 year compared with 90% of wounds that received HVPC plus standard care. This difference was significant (Fischer exact test, P <.05;Table 3).
Cumulative healing rate
If wound area is plotted against time in days, there appears to be an overall decrease in area with time for the HVPC group. In addition, 1 of 11 wounds exceeded twice its area at the start of electrotherapy. This wound closed within 32 weeks of starting HVPC. However, for the group receiving standard care only, 5 of 11 wounds exceeded twice their initial size, with none closing within the 1-year observation period.
The tendency for wounds in the standard care group to increase in size is demonstrated by a negative healing rate (Figure 1), compared with a positive healing rate for the HVPC group. For the HVPC group, all wounds closed by 32 weeks after the start of HVPC. For the standard care group, however, mean wound area increased more than 3 times the initial area by 16 weeks. At each 4-week interval from 20 through 52 weeks, the group means are significantly different (P <.05; Mann-Whitney test).
Prior to starting the protocol, periwound TcPo2 for the HVPC and standard care groups was ischemic (5 ± 8 vs 8 ± 7 mm Hg, respectively). After treatment began (t ≥0 weeks), maximum periwound TcPo2 for the HVPC group tended to rise out of the ischemic range and was higher than for the standard care group (26 ± 20 vs 13 ± 12 mm Hg, respectively). This difference was not significant (Mann-Whitney test). However, a paired comparison of maximum periwound TcPo2 for the HVPC group before and after the start of electrotherapy showed a significant difference (Wilcoxon signed rank test, paired data, P <.05;Figure 2). Electrotherapy tended to have a positive effect on perfusion of initially ischemic ulcers.
This report presents retrospective outcome data for patients with high-risk ischemic wounds who were treated with HVPC plus standard care compared with patients treated with standard care alone. Compared with standard care alone, HVPC plus standard care was associated with a significant decrease in wound area (P <.05) from 20 to 52 weeks after the start of electrotherapy. At the 1-year follow-up point, there were more healed wounds in the HVPC group (Fisher exact test;P <.05). Although fewer amputations occurred in the HVPC group, limb salvage data must be interpreted with caution because of the small number of subjects in the amputation subgroup. These positive indices of healing with potential for limb salvage may be partially related to improvement in periwound oxygenation. For the HVPC group, TcPo2 tended to improve after the start of electrical stimulation.
Any observational retrospective study could be criticized as having selection bias to favor the treated group. Unblinded investigators could conceivably select subjects for a treatment group who have a better prognosis of success. Bias may also occur from developing entry criteria a postiori, which could favor the treated group’s outcome. In addition, patients not selected for treatment may be less adherent with other standard therapies.
In this study, 2 patients in the standard care group historically had inadequate control of blood glucose; however, if the 2 patients are excluded from the data set, the conclusions do not change. The HVPC group’s mean wound area for weeks 20 through 52 after the start of electrical stimulation and the tabulated 1-year outcomes were still significantly improved.
Wounds treated with electrical stimulation tended to be more severely ischemic and acute than wounds treated with standard care alone. At the time that electrotherapy was initiated, TcPo2 tended to be lower for the HVPC group than for the standard care group. In fact, many wounds in the HVPC group had expanding cutaneous gangrene, requiring urgent intervention. Specifically, 50% of 11 wounds in the HVPC group had evidence of cutaneous gangrene, compared with 8% of wounds in the standard care group. The standard care group had smaller, longer-lasting wounds. These factors suggest that, on average, the HVPC group had more severely ischemic and unstable wounds.
It could reasonably be asked whether anyone would subject himself or herself to the rigors of daily electrotherapy application. The electrotherapy described in this study is a complex, intensive treatment, with results achieved slowly. Although the technique may be considered too challenging and timeconsuming to perform at home, most patients who agreed to treatment with electrical stimulation and all patients whose wounds reached 50% closure were able to participate during an extended period, with good compliance. Adherence was likely improved by the flexible treatment schedule; patients could perform electrotherapy at any time of day. Often, visiting nurses participated in treatment, taking stress off family members who participated in care. One patient who was given the alternative of having a bilateral amputation and permanent functional loss stated that the electrotherapy protocol was an excellent choice, given his options.
These results expand the published findings of a clinical case series, 30 which reported that HVPC plus standard care is associated with increased periwound TcPo2 over weeks of treatment to the point where wounds are no longer ischemic. In that study, TcPo2 increased with every ischemic wound that healed. Although not systematically studied, this TcPo2 increase was empirically durable and stable after healing. Because the present study represents a post hoc analysis of observational data, generalizing these clinical findings to the total population of ischemic wounds is not possible. However, the improved outcome data for the HVPC group cannot be attributed only to careful application of conservative wound healing strategies and/or the resolution of inflammation because both groups received standard care.
Physiologically, HVPC may facilitate reoxygenation and healing of ischemic wounds secondary to increased perfusion. After periwound TcPo2 approaches normal, any additional benefit of HVPC is unclear. The literature provides little guidance in this area; therefore, HVPC was applied 1 hour per day until complete closure or as long as tolerated. Reasonably, it could be argued that the longer electrotherapy is applied after TcPo2 returns to near-normal, the less important it may be when compared with conservative wound care alone or with surgical strategies, such as skin grafting.
Nevertheless, HVPC may promote wound healing by means other than an increase in perfusion, before or after TcPo2 normalizes, including enhanced fibroblast proliferation, 16 enhanced collagen synthesis, 17,18 and resolution of edema. 19 These mechanisms are consistent with positive results from clinical trials in which electrotherapy was applied to nonischemic chronic wounds. 2–5
In the present study, the dosimetry of HVPC was similar to what was applied to subjects in a clinical case series 3: 1250 microcoulombs/second, which is 2- to 4-fold higher than what is effective for nonischemic wound healing. The questions related to effective dose-response for HVPC are complex and are discussed elsewhere. 16 At present, dose-response data are not available to draw any conclusions about HVPC usage more than 1 hour per day.
If HVPC enhances microcirculation, the mechanism or mechanisms that underlie the effect remain unclear, but may relate to release of nitric oxide within ischemic tissue. Nitric oxide protects against reperfusion injury and is a vasodilator. 8,40,41
The next step is to replicate the findings of this observational study in a prospective trial that is randomized, blinded, and sham-controlled. 2,3 Patients consenting to be part of the trial must be willing to defer electrical stimulation for a controlled period, during which time their wounds could worsen. Therefore, only stable wounds without expanding gangrene should be randomized to the control arm and the study should be limited in duration (eg, 14 weeks). If the control arm is limited to 14 weeks and unstable wounds are not included in the power analysis, approximately 50 subjects (excluding dropouts) would be necessary to show statistically significant changes in wound area at the 14-week time point.
This research demonstrates that HVPC plus standard care promotes healing of inframalleolar ischemic skin lesions in subjects with peripheral arterial disease who are poor candidates for vascular reconstruction and have threatened limb loss. For the HVPC group, microperfusion tended to improve relative to pretreatment, suggesting that HVPC promotes healing at least partially by means of microperfusion increase. A controlled clinical trial is needed to confirm these encouraging, but speculative, positive clinical findings.
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