Hyperbaric Oxygen Therapy DoesNot Reduce Indications forAmputation in Patients WithDiabetes With Nonhealing Ulcersof the Lower Limb: A Prospective,Double-Blind, RandomizedControlled Clinical TrialDiabetes Care 2016;39:392–399 | DOI: 10.2337/dc15-2001

OBJECTIVE

Hyperbaric oxygen therapy (HBOT) is used for the treatment of chronic diabeticfoot ulcers (DFUs). The controlled evidence for the efficacy of this treatment islimited. The goal of this study was to assess the efficacy of HBOT in reducing theneed for major amputation and improving wound healing in patients with diabetesand chronic DFUs.

RESEARCH DESIGN AND METHODS

Patients with diabetes and foot lesions (Wagner grade 2–4) of at least 4 weeks’duration participated in this study. In addition to comprehensive wound care,participants were randomly assigned to receive 30 daily sessions of 90 min ofHBOT (breathing oxygen at 244 kPa) or sham (breathing air at 125 kPa). Patients,physicians, and researchers were blinded to group assignment. At 12 weeks post-randomization, the primary outcome was freedom from meeting the criteria foramputation as assessed by a vascular surgeon. Secondary outcomes were mea-sures of wound healing.

RESULTS

One hundred fifty-seven patients were assessed for eligibility, with 107 randomlyassigned and 103 available for end point adjudication. Criteria for major amputa-tion were met in 13 of 54 patients in the sham group and 11 of 49 in the HBOTgroup (odds ratio 0.91 [95% CI 0.37, 2.28], P = 0.846). Twelve (22%) patients in thesham group and 10 (20%) in the HBOT group were healed (0.90 [0.35, 2.31], P =0.823). All other indices of wound healing were also not statistically significantlydifferent between groups.

CONCLUSIONS

HBOT does not offer an additional advantage to comprehensive wound care inreducing the indication for amputation or facilitating wound healing in patientswith chronic DFUs.

1Toronto General Hospital, University HealthNetwork, Toronto, ON, Canada2Department of Clinical Epidemiology & Biosta-tistics, Faculty of Health Sciences,McMaster Uni-versity, Hamilton, ON, Canada3Programs for Assessment of Technology inHealth, St. Joseph’s Healthcare Hamilton, Ham-ilton, ON, Canada

Corresponding author: Ludwik Fedorko, ludwik.fedorko@uhn.ca.

Received 11 September 2015 and accepted 4December 2015.

Clinical trial reg. no. NCT00621608, clinicaltrials.gov.

© 2016 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered.

Ludwik Fedorko,1 James M. Bowen,2,3

Wilhelmine Jones,1 George Oreopoulos,1

Ron Goeree,2,3 Robert B. Hopkins,2,3 and

Daria J. O’Reilly 2,3

392 Diabetes Care Volume 39, March 2016

EPIDEM

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Patients with diabetes are at high risk oflower-limb amputation because of thehigh incidence of chronic lower-extremitywounds or diabetic foot ulcers (DFUs)(1,2). Diabetic peripheral neuropathywith loss of protective sensation, periph-eral artery disease, limited foot mobility,and foot deformities are themainetiologicreasons for difficulties in the preventionand treatment of DFUs (3). Nonhealingwounds pose a continuous risk of gan-grene, local and systemic infection, sep-sis, and death as well as a decline inquality of life (4). Defining the most ef-fective treatment strategies is essentialto reducing the burden of this disease(1). Hyperbaric oxygen therapy (HBOT)has been used as an adjuvant treatmentfor difficult-to-heal chronic diabetic footwounds; however, most evidence for itsefficacy is based on observational cohortstudies or open-label randomized trials(5–9). HBOT requires significant patienttime and financial commitment comparedwith conventional wound care withoutHBOT. An HBOT regimen for DFUs usu-ally consists of 30–60 daily sessions ofoxygen under pressure in a dedicatedhyperbaric chamber (200–250 kPa).This regimen is in sharp contrast to con-ventional wound care, which usually in-volves much fewer visits to treatingphysicians. Patient compliance, abilityto pay, or reimbursement coveragecreates a significant bias in observationalstudies. Therefore, placebo and largeparticipation effects associated withHBOTmake providing an identical woundcare environment for bothHBOTand con-trol groups in open-label randomized orobservational trials impossible (10). Thequestion remains whether the reportedbenefits of HBOT in patients with DFUscan be attributed specifically to HBOT.Two double-blind placebo controlled

trials have been reported (11,12). Onestudy included 16 patients (8 patientsper arm), and the other analyzed datafrom 94 patients (49 in HBOT and 45 insham) (12). Both studies reported benefi-cial effects on healing but no reduction inamputation rates. A large retrospectivestudy in .700 patients receiving HBOTthat used propensity score methodsfound no benefit of HBOT and possiblyan increased risk of amputation in pa-tients treated with HBOT (13). However,many factors affect the actual indicationsfor amputation. These factors includephysician practice patterns; the extent

of tissue loss; presenceor absenceof localand systemic infection; patient prefer-ences; cultural, socioeconomic, and insur-ance status; ability to obtain support andprosthetic devices; and timely access tosurgical care (14,15). Therefore, efficacyof HBOT for amputation-sparing effectsremains largely unsubstantiated.

We report the results of a double-blind, placebo-controlled clinical trialof HBOT in patients with chronic DFUsreceiving comprehensive wound carein a single community-based clinic. Theprimary goal of the trial was to assessthe efficacy of HBOT in reducing indica-tions for amputation (rather than ampu-tation events themselves) in patientswith diabetes and chronic ulcers of thelower limb who also receive compre-hensive wound care as outlined in Lipskyet al. (16). We also determined whetherHBOT significantly improves selected in-dicators of wound healing.

RESEARCH DESIGN AND METHODS

Trial DesignThe general design of this trial is de-scribed elsewhere (17). Briefly, thestudy was a single-center, double-blind,placebo-controlled randomized clinicaltrial. Patients with diabetes and chronicwounds of the lower limb were ran-domly assigned to receive either HBOTor sham HBOT in addition to compre-hensive wound care. Two parallel re-search ethics board approvals for theprotocol were obtained at both thesponsor’s (data handling and analysisgroup) and the site investigators’ insti-tutions. The trial was registered beforeparticipant enrollment.

ParticipantsInclusion criteria were patients $18years of age with type 1 or 2 diabetesreferred to a community-based specializedwound care and hyperbaric treatmentclinic for the treatment of a lower-limbwound (Wagner grade 2, 3, or 4) (18)persisting for a minimum of 4 weeks. Allpatients received prior wound care.

Exclusion criteria were any conditionsprecluding safe treatment in a hyperbaricchamber (see full list in O’Reilly et al.[17]), impending urgent amputationdue to ongoing or exacerbated infection,exposed calcaneus bone with no pros-pect of weight-bearing potential even ifthe defect was healed, and patients withmajor large-vessel, peripheral arterial

disease who were possible candidatesfor revascularization by open surgery orendovascular procedure (as assessed bythe vascular surgeon) or those who hadundergone such a procedure within thepast 3 months.

Sample SizeSample size was estimated on the basisof a review of the medical literature ofpreviously published randomized con-trolled trial evidence on the event ratesof the primary outcome (i.e., major am-putation) in HBOT and standard caregroups. Accordingly, a sample size of47 patients for each group (94 in total)was calculated to provide 90% power fordetecting a difference of 28% in the in-cidence ofmajor amputation (i.e., 39.29%in the placebo group and 11.54% in theHBOT group) between the two groupsby a two-sided test for equality (17).Anticipatinga20%drop-out rate, thesam-ple sizewas increased to 118 participants,or59 ineach studyarm[i.e., 94 / (1–0.20)=118].

Randomization and AllocationConcealmentA computerized block randomizationschedule with a multiple block size offour was used. All clinical and researchpersonnel as well as patients wereblinded to treatment allocation. Onlythe technician controlling the hyper-baric oxygen chamber was aware ofgroup allocation for each patient, whichwas maintained in sequential uniqueopaque envelops opened as partici-pants were randomly assigned. The con-cealment was extended through thecompletion of the data analysis. Thegroups were only identified as group 1or group 2 until the analysis of primaryand secondary outcomes on an intention-to-treat (ITT) basis was completed.

Interventions

HBOT

Study participants entered the hyper-baric chamber 5 days per week for6 weeks (30 sessions). HBOT consisted ofbreathing oxygen for 90min at 244 kPa ofpressure, with 5-min intervals of breath-ing air for every 30 min of oxygen. Shamsessions consisted of breathing air at;125 kPa of pressure (equivalent tobreathing 27% O2 by face mask) on thesame schedule. This minimum pressurewas required to create a sensation ofbeing pressurized and depressurized

care.diabetesjournals.org Fedorko and Associates 393

identical to the active treatment groupto keep the patients blinded to the allo-cation. Monoplace chambers (Pan-America Hyperbarics Inc., Richardson,TX) were used. Patients were followedfor 6 weeks after the end of hyperbaricsessions and returned to the clinic ev-ery week for wound assessment andtreatment.

Wound Care and Dressings

Weekly clinical assessments for 12weeks included comprehensive woundcare. Care was provided by the multidis-ciplinary team led by the wound carephysician at the study site to includeinfection control, debridement, pre-scriptions for offloading devices, andadvanced wound care dressings.

Data CollectionData to evaluate wound healing werecollected at screening, at baseline, andweekly throughout the treatment andfollow-up phases. At the end of thestudy period, the participating blindedvascular surgeon determined whetheramputation (major or minor) was indi-cated. Participant clinical data togetherwith digital photographs of the studywound progress were presented to thevascular surgeon. The surgeon had fulldiscretion on a case-by-case basis aboutwhether the status of the wound couldbe assessed through the digital photog-raphy and clinical information alone (asvalidated by Wirthlin et al. [19] andHoughton et al. [20]) or whether an ad-ditional patient visit was required. Otherdata were collected through interview,physical and biological measurements,and validated data collection instru-ments. Data were collected prospectivelythroughout the study and maintained iniDataFax (DF/Net Research, Hamilton,ON, Canada) at the study coordinatingcenter at St. Joseph’sHealthcareHamilton.

Outcomes

Primary Outcome

The primary outcomewas freedom fromhaving or meeting the criteria for ampu-tation (below-knee or metatarsal level)in patients at 12 weeks from initiation oftreatment. The vascular surgeon’s deci-sion was based on the following criteriafor amputation:

1. Lack of significant progress in woundhealing over the follow-up period,which indicated ongoing risk of

severe systemic infection related tothe wound

2. Persistent deep infection involvingbone and tendons (antibiotics required,hospitalization required, pathogeninvolved)

3. Inability to bear weight on the af-fected limb

4. Pain causing significant disability

Secondary Outcomes

Secondary outcomes were measures ofwound healing. Wound healing wasassessed in three ways: wound measure-ments, changes in wound assessmentscores, and wound classification.Wound Measurements. Wound size wasmeasured in two ways: manual mea-sures of wound width at each weeklyvisit and computerized woundmeasure-ments of wound surface area and perim-eter from high-resolution calibrateddigital photographs. Changes in woundsizes were calculated based on changesin wound width, surface area changefrom baseline, and linear advancementof the wound edge (LAWE) (21–23). Thevalues were averaged at baseline,6 weeks (end of HBOT), and 12 weekswhen the primary end point was reached.The WoundAreas computer program(Biomedical Consultants Group, www.bimeco.org) was used for digital mea-surements. These values were then usedto calculate the LAWE over time by usingthe modified Gillman equation (21) asshown in Eq. 1:

ðA1 2A0Þ ððP0 1 P1Þ=2Þ�tð120Þ

�(Eq. 1)

where A denotes area, P denotes woundperimeter, and t denotes the time intervalbetween measurements.Wound Assessment. The Bates-Jensenwound assessment tool (24) wasused weekly to measure progress onulcer healing. This tool assesses 13wound characteristics, with eachitem scored on a 1–5 scale (maximumscore 65). The individual scores aresummed for a total score. The higher thetotal score, the more severe the woundstatus.Wound Classification. Each study partici-pant’s wound was classified weekly withthe Wagner classification score (18,24).TheWagner system places the ulcer intoone of six categories, grading them from0 (preulcer) to 5 (amputation required).At 12weeks, participantwounds classified

as Wagner grade 0 or 1 were consideredhealed.

Solicited and unsolicited adverseevents were also captured during thetreatment phase. Solicited adverse effectsrecordedwere barotrauma, seizure, visualchanges, and psychologic intolerance.

Statistical MethodsFor the primary outcome of meeting cri-teria for or undergoing an amputation,univariable logistic regression was used.The primary outcome was analyzed onan ITT basis for all participants. The lastobservation carried forward was used forpatients who did not have 12-week data.

Secondary outcomes included theprogress of wound healing assessed bymanually measured ulcer width becausethis measure is less sensitive to the ab-solute size of the wound (21), surfacearea, LAWE, complete healing, andBates-Jensen wound assessment score.ANCOVA was used to determine a sta-tistically significant difference betweentreatment received on changes in man-ual ulcer width, digital surface area, andLAWE and the Bates-Jensen wound as-sessment score, controlling for baselinewound size. For manual ulcer width, dig-ital surface area, and LAWE, the meanwound measurements were obtained at6 and 12 weeks for each group, and thegroup mean changes from baselinewere compared. For any missing valuesat 6 and 12 weeks, we used the valueobtained within 1 week. The number ofwounds healed at 12 weeks by treat-ment group was analyzed by univariablelogistic regression. The adverse eventswere compared by treatment allocationby using the x2 statistic.

All primary statistical analyses wereconducted on an ITT basis in accordancewith the 2010 Consolidated Standardsof Reporting Trials (CONSORT) state-ment (25). Missing data were imputedby the last observation carried forward,where appropriate. A post hoc analysiswas also performed on participants whoreceived at least 27 of the planned 30treatments or inwhom thewoundhealedbefore having 30 treatments and wasconsidered a per-protocol analysis.

RESULTS

Enrollment and PatientCharacteristicsBetween September 2009 and May2012, 157 patients were assessed for

394 Hyperbaric Oxygen in Diabetic Foot Ulcer Diabetes Care Volume 39, March 2016

eligibility, and 107 were randomized(Fig. 1). One participant was improperlyrandomized, and three withdrew theirconsent after randomization (one inthe sham group and two in the HBOTgroup) and did not receive the allo-cated treatment. Six in the sham groupand 10 in the HBOT group discontinuedstudy participation. After two treat-ments of HBOT, sepsis complicatedwith Guillain-Barre syndrome developedin one participant in the HBOT group, re-quiring hospitalization, and six HBOTgroup participants were unable to toleratethe chamber sessions as opposed to one inthe sham group. As a result, 103 patientswere included in the ITT analysis (54 in thesham group and 49 in the HBOT group).

Despite randomization, HBOT groupparticipants had diabetes for a longerperiod than those in the sham group(19.1 vs. 12.4 years, respectively). Therewere also more patients with type 1diabetes in the HBOT group than in thesham group (Table 1). More men wererandomly assigned to the sham groupthan to the HBOT group (70.4% vs.63.3%, respectively), with an averageage of 62 years and 61 years, respec-tively. HbA1c was similar between thegroups. The mean number of days withthe index wound was 336 (min, max 28,3,650) in the sham group and 235 days(28, 1,080) in the HBOT group. Themeanindex ulcer surface area was 6.1 and5.1 cm2 in the sham and HBOT groups,

respectively, with most of the woundsclassified as Wagner grade 2 and 3. Thebaseline Bates-Jensenwound assessmentscores were similar in both groups.

TreatmentForty-one (76%) participants in thesham group and 30 (61%) in the HBOTgroup completed at least 30 treatments.Four (7%) and 10 (20%) participants re-ceived ,11 treatment sessions in thesham and HBOT groups, respectively.More participants in the HBOT groupdiscontinued treatment early (n = 10[20%]) than those in the sham group(n = 6 [11%]). Most of the discontinua-tions in the HBOT group were due toparticipants being unable to toleratethe chambers (n = 6) compared withonly one participant in the sham group(Fig. 1). One patient in the sham groupdiscontinued because of the need foramputation.

Primary Outcome: Meeting Criteria ofNeed for Amputation or UndergoingAmputationIn the ITT analysis, a nonsignificant dif-ference was found for HBOT, with 11(22.5%) HBOT group participantsand 13 (24.1%) sham group partici-pants meeting the criteria for major am-putation (odds ratio [OR] 0.91 [95% CI0.37, 2.28], P = 0.846) at the end ofthe 12-week study period (Table 2). Thepercentageof amputations recommendedof any type (major or minor) was 51% inthe HBOT group and 48% in the shamgroup (1.12 [0.52, 2.43], P = 0.771). Thehypothesized benefit of HBOT was a re-duction in indication for amputation of28%, and the results indicated a differ-ence of ,3 percentage points. Beyondthe adjudicated indication for amputa-tions, only one actual amputation oc-curred during the 12-week study period,and this was the removal of a toe in asham group participant.

Ten of the 11 participantswho receivedHBOT treatment and met the criteria formajor amputation were recommendedto have a below-knee amputation, andall of those assessed to require majoramputation in the sham group (n = 13)were recommended to have below-kneeamputation. Fourteen (28.6%) and 13(24.1%) participants were adjudicatedto undergo minor amputations in theHBOT and sham groups, respectively(1.26 [0.52, 3.04], P = 0.605).Figure 1—CONSORT diagram. Tx, treatment.

care.diabetesjournals.org Fedorko and Associates 395

Forty-eight sham group participantsand 39 HBOT group participants whocompleted at least 27 of the 30 plannedtreatments or healed without discontin-uation or withdrawal had end point data(Table 2). A per-protocol post hoc

analysis of these groups revealed similarproportions of participants meeting thecriteria for major amputation (20.5%and 22.9% in the HBOT and shamgroups, respectively [0.87 (95% CI 0.31,2.43), P = 0.787]) (Table 2).

Secondary Outcomes

Wound Measurements

No significant difference was found at12 weeks in the reduction in manualwidth or digital surface area after con-trolling for baseline wound size. The re-duction in manual width was slightlygreater in the sham group, with amean difference of 0.12 cm (95% CI20.46, 0.22, P = 0.491). The adjusted12-week reduction in digital surfacearea was 1.9 cm2 in the HBOT groupand 1.8 cm2 in the sham group for anadjusted mean difference of 0.037 cm2

(95% CI21.11, 1.19, P = 0.949) (Table 2).No significant difference was found be-tween the HBOT and sham groups withrespect to LAWE for weeks 0–6 (meandifference 20.002 cm/week [95% CI20.016, 0.013], P = 0.817) or weeks 6–12 (mean difference 20.0003 cm/week[95% CI 20.012, 0.015], P = 0.970)(Table 3 and Fig. 2).

Wound Assessment

The Bates-Jensen wound assessmentscore was similar for ulcers at baselinein both groups (mean score 34 of a pos-sible 65). Wounds in the sham groupimproved by 7.5 points compared with7.0 points in the HBOT group. These dif-ferences were not statistically signifi-cant (mean difference 0.53 points [95%CI 22.58, 3.64], P = 0.735) (Table 3 andFig. 2).

Wound Classification

At 12 weeks, the percentage of partic-ipants whose wounds were healed was20% and 22% in the HBOT and shamgroups, respectively (OR 0.90 [95% CI0.35, 2.31], P = 0.823) (Table 3 andFig. 2).

Adverse EventsOne patient in the HBOT group experi-enced an episode of congestive heartfailure, and there were 12 reports ofan inability to equalize middle ear pres-sure during treatment (3 in sham and 9in HBOT). Four participants in the HBOTgroup and 2 in the sham group experi-enced a hypoglycemic episode duringthe study. Other adverse events aresummarized in Table 4.

CONCLUSIONS

The amputation-sparing effects of HBOThave been reported in two open-labelstudies (5,8). The current study did notdemonstrate an advantage of HBOTcombined with comprehensive wound

Table 1—Baseline patient characteristics

HBOT (n = 49) Sham (n = 54)

Age (years) 61 (12) n = 47 62 (12)

Male sex 31 (63) 38 (70)

HbA1c (%) 8.27 (1.92), n = 43 8.03 (2.05), n = 51

BMI (kg/m2) 31.1 (6.8) 29.8 (5.0)

Diabetes duration (years) 19.1 (11.5) 12.4 (10.0)

Type 1 diabetes (n) 6 1

Type 2 diabetes (n) 43 53

Hypertension 32 (65.3) 41 (75.9)

Current smoker 24 (49.0) 30 (55.6)

Hyperlipidemia 33 (67.3) 39 (72.2)

Statins 33 (65.0) 32 (51.0)

History of stroke 4 (8.2) 4 (7.4)

Previous peripheral artery revascularization 6 (12.2) 7 (13.0)

Previous amputation 3 (6) 4 (7)

Manual length (cm) 2.5 (1.8) 2.5 (1.9)Min, max 0.5, 8.9 0.5, 10.5

Manual width (cm) 1.5 (1.0) 1.7 (1.2)Min, max 0.5, 4.5 0.3, 5

Manual depth (mm) 0.6 (1.3) 0.6 (0.7)Min, max 0.0, 9.0 0.0, 4.5

Digital wound area (cm2) 3.8 (4.8) 3.6 (5.7)Min, max 0.0, 19.6 0.1, 26.9

No. of days with ulcer 235 (227) 336 (528)Min, max 28, 1,080 28, 3,650

Wagner grade1 0 (0) 0 (0)2 23 (46.9) 23 (42.6)3 22 (44.9) 29 (53.7)4 4 (8.2) 2 (3.7)5 0 (0) 0 (0)

Bates-Jensen wound assessment score 34.2 (5.2) 34.3 (4.3)

Data are mean (SD) or n (%) unless otherwise indicated.

Table 2—Summary of the results for indication for amputation

HBOT Sham OR (95% CI) P value

Adjudicated indication for amputation (ITT)n 49 54Major 11 (22.5) 13 (24.1) 0.91 (0.37, 2.28) 0.846Minor 14 (28.6) 13 (24.1) 1.26 (0.52, 3.04) 0.605Total 25 (51.0) 26 (48.1) 1.12 (0.52, 2.43) 0.771

Adjudicated indication for amputation(per protocol)*

n 39 48Major 8 (20.5) 11 (22.9) 0.87 (0.31, 2.43) 0.787Minor 9 (23.1) 9 (18.8) 1. 30 (0.46, 3.68) 0.621Total 17 (43.6) 20 (41.7) 1.08 (0.46, 2.54) 0.857

Data are n (%) unless otherwise indicated. HBOT is reference. *At least 27 HBOT treatments orhealed without discontinuation or withdrawal.

396 Hyperbaric Oxygen in Diabetic Foot Ulcer Diabetes Care Volume 39, March 2016

care compared with wound care alonein reducing indications for amputationsin patients with DFUs.That we did not use actual amputa-

tion rates in this placebo-controlled trialmay be considered a limitation. How-ever, the rate, timing, and decision toamputate are highly variable (15) andinfluenced by a number of factors (14,26).As a result, to reduce this variability, we

decided to have a blinded experiencedvascular surgeon adjudicate the woundsfor amputation. This procedure replacedall the variable biases with a consistentbias of a single expert-observer for allparticipants.

The adjuvant HBOT care providedno incremental benefit in improvingmeasures of wound healing. These re-sults are in contrast to several cohort

(7,26–28) and open-label randomizedtrials (5,6,8,9) where no sham placebowas used. The study by Duzgun et al.(8), one of the largest trials published,often is quoted as the justification forHBOT utility in treating diabetic wounds(29). However, these results should beinterpreted with caution because it isdifficult to explain (outside the obser-vational bias) a zero healing rate (with-out surgery) in a random cohort of 50control group patients with Wagnergrade 2–4 DFUs over a .1-year periodas opposed to the 66% healed in theHBOT group (8). This finding is not con-sistent with reported healing rates ofnonhyperbaric wound care facilities(13,30).

Two randomized placebo-controlledtrials of HBOT for the treatment of DFUshave been published (11,12). Abidia et al.(11) reported on eight patients pergroup and showed a significant differ-ence in the reduction of wound size at6 weeks in favor of the HBOT group. Inthe larger trial by Londahl et al. (12), theauthors chose complete healing of theulcer as the primary outcome without apredetermined time point at 3-monthintervals up to 1 year. Although a cleartrend favoring healing in the HBOTgroup was observed, statistical signifi-cance was reached at 9 and 12 months.Both trials reported surprisingly lowhealing rates in the placebo groups.Londahl et al. reported only 3% at3months (as estimated fromthepublishedfigure), and Abidia et al. reported a com-plete lack of healing within the placebogroup (Wagner grade 1 and 2 ulcers only,0 of 8) at 1 year.

These poor healing rates in the pla-cebo arms are not consistent with theavailable literature (3,13) and may ac-count for an apparent benefit of HBOT.Both studies (11,12) used sham treat-ment, which is not benign and possiblyinterferes with the healing rate of thewounds in the control arm, thereforefavoring the HBOT group. The placebotreatment in both studies comprised30–40 repetitive hyperbaric air expo-sures to 250 kPa (;50 ft water depthequivalent) for 90 min each. Safety ofnot only 1 but also 40 cumulative hyper-baric air exposures in elderly patientswith diabetes and peripheral arterialdisease has never been experimentallyevaluated or modeled. This type of pla-cebo can only be considered as extreme

Table 3—Summary of results for wound healing

HBOT Sham

Mean difference(HBOT 2 sham)

(95% CI) P value

Wound measurement12-week reduction in

manual width (cm)0.57 (0.13) 0.69 (0.12) 20.12 (20.461, 0.223) 0.491

12-week reduction indigital surfacearea (cm2)

1.9 (0.42) 1.8 (0.39) 0.037 (21.113, 1.187) 0.949

LAWE (cm/week)Weeks 0–6 0.013 (0.005) 0.015 (0.006) 20.002 (20.016, 0.013) 0.817Weeks 6–12 0.026 (0.005) 0.026 (0.006) 20.0003 (20.012, 0.015) 0.970

Wound healingWounds healed, n (%) 10 (20) 12 (22) 0.90 (0.35, 2.31)a 0.823

Bates-Jensen woundassessmentscore

Baselineb 34.2 (5.2) 34.3 (4.3)End pointb 27.2 (7.8) 26.8 (9.0)Difference 27.0 (1.13) 27.5 (1.08) 0.53 (22.58, 3.64) 0.735

Data are mean (SE) unless otherwise indicated. HBOT is reference. aOR (95% CI). bMean (SD).

Figure 2—Graphical representation of changes in wound status. A: Wound edge advancement.B: Width reduction. C: Digital surface area. D: Bates-Jensen wound assessment score. Data aremean (95% CI). H, HBOT group; S, sham group.

care.diabetesjournals.org Fedorko and Associates 397

with regard to decompression stress. Itseffects on vascular function in this vul-nerable patient population are the leastunknown. Clear evidence indicates thatsingle, shorter exposures of healthyyoung divers to compressed air atslightly higher pressures are associatedwith evidence of significant gas emboliin venous circulation, proinflammatorychanges in peripheral blood, and in-creases of indirect markers of endothe-lial injury (31–33). Therefore, the onlytwo previously published randomizedplacebo-controlled trials do not satisfycriteria for an inert placebo, and theirresults should not be used in evaluatingthe efficacy of HBOT for treatment ofDFUs.The major benefit of the current

study is that the sham treatment groupair pressure exposure was limited to125 kPa absolute pressure so that ongo-ing decompression stress and its possi-ble negative effects on wound healingcould be avoided in the sham group. An-other possible limitation of the study isthe relatively short follow-up time of 12weeks. Efficacy within a similar timeframe has been demonstrated in severalcomparably sized trials of other treat-ment modalities for DFUs (34–36).Kessler et al. (9) reported that the great-est rate of wound surface area reductionhappened within the first 2 weeks ofHBOT. Reduction in the wound sizewithin the first 4 weeks of treatment isan excellent predictor of overall healing

(23). Had HBOT had a significant influ-ence on accelerating the healing process,we should have been able to observedifferences between the groups withinthe first 3 months of treatment and dur-ing the follow-up phase.

The present patient population in-cluded individuals with peripheral arte-rial disease who had either undergoneprevious vascular intervention or werenot candidates for such therapy, similarto the Londahl et al. study (12). It re-flects the actual pattern of patient re-ferrals for HBOT. Moreover, 50% ofpatients with DFUs have a significantneuroischemic component to theirulcers (37).

The current results agree with a largemulticenter retrospective cohort studyby Margolis et al. (13). The authorsused a propensity score matchingmethod to reduce the bias associatedwith retrospective data (793 patientstreated with HBOT vs. 5,466 patientstreated with standard therapies). Thestudy failed to find a beneficial treat-ment effect of HBOT regardless ofwound size and actually found higherrates of amputation in the HBOT cohort.

The current study did not find a signifi-cant benefit associated with adjuvantHBOT. A subset of diabetic lower-extremitywounds may benefit from HBOT; how-ever, until such a subset can be confirmedto exist in future studies, we cannot rec-ommend the use of adjuvant HBOT forreducing indications for amputation or

for facilitating healing in this patientpopulation.

Funding. This study was funded by an uncon-ditional researchgrant fromtheOntarioMinistryof Health and Long-Term Care (06129).Duality of Interest. No potential conflicts ofinterest relevant to this article were reported.Author Contributions. L.F. and D.J.O. contrib-uted to the study design, data research andcollection, andwriting, review, andeditingof themanuscript. J.M.B. and W.J. contributed to thestudy design, data research and collection, andreview and editing of the manuscript. G.O.contributed to the data research and collectionand review and editing of the manuscript. R.G.contributed to the study design and review andediting of the manuscript. R.B.H. contributed tothe data verification, statistical analysis, andreview and editing of the manuscript. L.F. isthe guarantor of this work and, as such, had fullaccess to all the data in the study and takesresponsibility for the integrityof thedataand theaccuracy of the data analysis.Prior Presentation. Parts of this study werepresentedduringaproandcondebate lecturebyL.F. at the 75th Scientific Sessions of the Amer-ican Diabetes Association, Boston,MA, 5–9 June2015, and during a lecture by L.F. at the DiabeticFoot Global Conference (DFCON 2013), Los An-geles, CA, 21–23 March 2013.

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Table 4—AEs occurring during the HBOT study

HBOT (n = 49)Totalevents

Control(n = 54)

Totalevents P value

Solicited AEsAcute respiratory distress 0 0 0 0Pneumothorax 0 0 0 0Convulsion/seizure 0 0 0 0Barotraumas 4 (8.2) 5 3 (5.6) 3Visual changes 4 (8.2) 4 3 (5.6) 3Total solicited AEs 8 (16.3) 9 6 (11.1) 6 0.441

Unsolicited AEsUnable to equalize ears 5 (10.2) 9 0 (0) 0Anxiety, chest pain 2 (4.1) 2 0 (0) 0Nausea 4 (8.2) 5 2 (3.7) 2Hypo/hyperglycemia 4 (8.2) 4 2 (3.7) 2Wound infection 2 (4.1) 2 1 (1.9) 1Pain postmyringotomy 1 (2.0) 1 0 (0) 0Congestive heart failure 1 (2.0) 1 0 (0) 0Total unsolicited AEs 13 (26.5) 24 5 (9.3) 5 0.021

Total any AEs 20* (40.1) 33 11 (20.4) 11

Data are n (%) or n. AE, adverse event. *Patients reported more than one AE.

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