hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes 9

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Hyperbaric Oxygen Therapy FacilitatesHealing of Chronic Foot Ulcers in Patients

With DiabetesMAGNUSLONDAHL, MD1PERKATZMAN, MD, PHD1

ANDERSNILSSON, MD2CHRISTERHAMMARLUND, MD, PHD3

OBJECTIVE Chronic diabetic foot ulcers are a source of major concern for both patientsand health care systems. The aim of this study was to evaluate the effect of hyperbaric oxygentherapy (HBOT) in the management of chronic diabetic foot ulcers.

RESEARCH DESIGN AND METHODS The Hyperbaric Oxygen Therapy in Diabet-ics with Chronic Foot Ulcers (HODFU) study was a randomized, single-center, double-blinded,placebo-controlled clinical trial. The outcomes for the group receiving HBOT were comparedwith those of the group receiving treatment with hyperbaric air. Treatments were given in amulti-place hyperbaric chamber for 85-min daily (session duration 95 min), five days a week foreight weeks (40 treatment sessions). The study was performed in an ambulatory setting.

RESULTS Ninety-four patients with Wagner grade 2, 3, or 4 ulcers, which had beenpresent for3 months, were studied. In the intention-to-treat analysis, complete healing of theindex ulcer was achieved in 37 patients at 1-year of follow-up: 25/48 (52%) in the HBOT groupand 12/42 (29%) in the placebo group (P 0.03). In a sub-analysis of those patients completing35 HBOT sessions,healing of the index ulcer occurred in 23/38 (61%) in the HBOT group and10/37 (27%) in the placebo group (P 0.009). The frequency of adverse events was low.

CONCLUSIONS The HODFU study showed that adjunctive treatment with HBOT facil-itates healing of chronic foot ulcers in selected patients with diabetes.

Diabetes Care33:9981003, 2010

D

iabetic foot ulcers are a common

and serious complication of diabe-tes (1,2). Treatment often requireslong-term hospital admissions and fre-quent outpatient visits. Furthermore, lossof mobility poses a great burden on thepatient and the health care system (3). Atcenters of excellence, 1935% of ulcersare reported as nonhealing (46). Thus,despite improvements in healing diabeticfoot ulcers, there is still a need for newtreatment strategies and methods.

Systemic hyperbaric oxygen therapy(HBOT) has been proposed as a medicaltreatment for diabetic foot ulcers (7).

HBOT has been demonstrated to have an

antimicrobial effect and to increase oxy-

genation of hypoxic wound tissues (810). This enhances neutrophil killingability, stimulates angiogenesis, and en-hances fibroblast activity and collagensynthesis (9,11,12). Thus, theoretically,HBOT could improve the healing of isch-emic foot ulcers in patients with diabetes.HBOT has been advocated and adoptedby a number of centers even though theevidence of its effectiveness is limited(1316). The first published double-blinded, randomized, controlled trial by

Abidia et al. (17) in 2003 suggested thebenefit of HBOT, but the study was small

and included only patients with Wagner

grade 1 and 2 ulcers. Therefore, the clin-ical utility of HBOT in treating diabeticfoot ulcers was not established. The finalconclusion of an analysis completed in2004 by the Cochrane Collaborationfound that further research was neededand the need for larger randomized pla-cebo-controlled studies was highlighted(13).

The aim of the Hyperbaric OxygenTreatment in Diabetic Patients withChronic Foot Ulcers (HODFU) study wasto evaluate if adjunctive treatment with

HBOT, when compared with treatmentwith hyperbaric air (placebo), would haveany therapeutic effect on chronic foot ul-cers in patients with diabetes.

RESEARCH DESIGN AND

METHODS This study was initi-ated, designed, and performed by the au-thors. A steering committee was in chargeof organization, data handling, and gen-eral conduct of the study. A blinded clin-ical event committee evaluated andclassified all reported events as well as

clinical outcome. The protocol was ap-proved by the ethics committee at theLund University.

The HODFU study was a random-ized, single-center, double-blinded, pla-c e bo-c ont rol le d c l inic a l t r ia l t ha tevaluated the effect of HBOT on ulcerhealing in patients with diabetes andchronic foot ulcers. The outcomes for thegroup receiving HBOT were comparedwith those of the group receiving treat-ment with hyperbaric air. The study de-sign and rationale were reported in detail

previously (18).All patients had diabetes and at leastone full-thickness wound below the anklefor 3 months. They were previouslytreated at a diabetes foot clinicfor a periodof no 2 months. All patients were as-sessed by a vascular surgeon at the time ofinclusion and only patients with adequatedistal perfusion or nonreconstructableperipheral vascular disease were includedin the study. Patients having an acute footinfection were included when the acutephase was resolved. Oral or local antibi-otic treatment did not exclude patients

From the 1Institution for Clinical Sciences in Lund, Lund University, Lund, Sweden; the 2Department ofInternal Medicine, Angelholm Hospital, Angelholm, Sweden; and the 3Department of Anesthesiology,Helsingborg Hospital, Helsingborg, Sweden.

Corresponding author: Magnus Londahl, [email protected] 20 September 2009 and accepted 12 January 2010.DOI: 10.2337/dc09-1754Clinical trial reg. no. NCT00953186, clinicaltrials.gov. 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

See accompanying editorial, p. 1143.

C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c hO R I G I N A L A R T I C L E

998 DIABETESCARE, VOLUME33, NUMBER5, MAY2010 care.diabetesjournals.org


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from study participation. Exclusion crite-ria for study participation were contrain-dications for hyperbaric treatment (severeobstructive pulmonary disease, malig-nancy, and untreated thyrotoxicosis),current drug or alcohol misuse, vascularsurgery in the lower limbs within the lasttwo months, participation in another

study, or suspected poor compliance. Allparticipants provided written informedconsent.

ProceduresPatients were stratified based upon arte-rial toe blood pressure (35 mmHg vs.35 mmHg) before being randomly as-signed to either of the treatment arms.Randomization was done in blocks of 10using sealed envelopes.

The study was performed in an am-bulatory setting. Treatment sessions were

given in a multi-place hyperbaric cham-ber five days per week for eight weeks (40treatment sessions). The treatment periodcould be extended to 10 weeks, but thenumber of treatments was not allowed toexceed 40. An HBOT session included aperiod of compression in air for 5 min,followed by a treatment period at 2.5 at-mospheres absolute (ATA) for 85 min,and then a decompression period of 5min. Patients from both groups could betreated in the same session as study gaseswere administered by masks and air or100% oxygen entered the chamber

through separate double-blinded pipes(19). Study treatment was given as an ad-

junct to regular treatment at the multidis-ciplinary diabetes foot clinic, whichincluded treatment of infection, revascu-larization, debridement, off-loading, andmetabolic control according to high inter-national standards (18). Investigators didnot intervene in the daily routine clinicalmanagement of the patients. Outcomeswere measured every first week duringthe treatment period (first 810 weeks)and then at three-month intervals. Ulcers

were graded using the Wagner classifica-tion system and ulcer areas were mea-sured using Visitrak Digital (Smith &Nephew, Hull, England) (20).

End pointsThe primary end point was healing of theindex ulcer. The index ulcer was definedas the ulcer with the largest area and aduration of at least three months at thetime of inclusion. An ulcer was consid-ered healed when it was completely cov-ered by epithelial regeneration andremained so until the next visit in the

study. Wagner grade 4 ulcers were con-sidered healed when the gangrene hadseparated and the ulcer below was com-pletely covered by epithelial regeneration.If a patient died during the follow-up pe-riod, he/she was censored at the time ofthe death. If a major amputation (above

ankle amputation) was required, the ulcerwas considered not to have healed. Sec-ondary end points reported in this paperare major amputations and death.

Statistical analysisThe treatment code was not broken untilthe last patient had completed the 1-yearfollow-up visit.

Statistical evaluation was initially per-formed as an intention-to-treat analysis.

An analysis was also performed on thosepatients who received 35 treatments(per protocol analysis). Categorical vari-

ables were analyzed using contingency ta-bles (Fisher exact test) and continuousvariables using Mann-Whitney Utest. Atwo-sidedP value 0.05 was consideredstatistically significant. Statistical analysiswas performed using Statistica software,version 8.0 (Statsoft, Tulsa, OK).

RESULTS

Enrollment and basal characteristicsof the patientsDuring theinclusion period, a total of 164eligible participants were registered: 23(14%) did not consent to participation,47 (29%) were excluded according to thestudy protocol, and 94 (57%) underwentrandomization (Fig. 1).

The two groups had similar charac-teristics at baseline (Table 1). The medianulcer duration was 10 months and the

Figure 1Study flow chart of the HODFU study. COPD, chronic obstructive pulmonary disease.

Londahl and Associates

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median ulcer area was 3 cm2. A majorityof index ulcers were classified as Wagnergrade 3 and 4 (20). Vascular surgery waspreviously performed in the affectedlower limb in 55% of the participants.

TreatmentFifty-four (57%) patients completed all

40 treatment sessions, and 75 (80%)completed 35 sessions. Nine patientscompleted10 treatment sessions, andthe remaining 10 patients completed be-tween 14 and 28 sessions. Early treatmenttermination was due to claustrophobia intwo patients and worsening medical con-dition in nine patients (two deaths, twomajor amputations, and five hospitaliza-tions). Eight patients decided to withdrawfrom the study.

Open vascular surgery in the affectedlower limb was not performed on any

study participant during the 1st year afterinclusion, whereas percutaneous translu-minal angioplasty (PTA) was carried outin 10 patients (Table 2).

Effect on ulcer healingIn the intention-to-treat analysis, com-plete healing of the index ulcer wasachieved in 37 patients at 1-year of fol-low-up in 25/48 (52%) in the HBOTgroup and 12/42 (29%) in the placebogroup (P 0.03). In the per-protocolanalysis, complete healing of the index ul-cer occurred in 23/38 (61%) in the HBOT

group and 10/37 (27%) in the placebogroup (P 0.009) (Fig. 2). The largestdifferences in healing rates betweengroups were seen at the nine-month fol-low-up. Numbers needed to treat to avertnonhealing of a chronic foot ulcer were4.2 and 3.1 according to the intention-to-treat and per-protocol analysis, respec-tively. During the 1st-year of follow-up,new ulcers developed in nine patients inthe HBOT group and eight patients in thecontrol group.

Effects on amputation and deathFour participantsone in the HBOTgroup and three in the placebo groupdied during their 1st year in the study.The patient in the HBOT group receivedeight treatments and died of multiple or-gan failure 20 days after inclusion. Shewas 87-years-old and had a medical his-tory including severe peripheral arterydisease, neuropathy, myocardial infarc-tion, and heart failure. In the placebogroup, the causes of death were myocar-dial infarction in two patients (at 162 daysafter 39 treatments and 218 days after 22

Table1Basal patient characteristics at randomization. Lowerextremity data are givenonly

for index ulcer limb. Categorical variables are given as percent and continuous variables asmedians and ranges

HBOT Placebo

Number of patients 49 45Age (years) 69 (3795) 68 (2886) n.s.

Females (%) 22 16 n.s.Smoking habits 61 69 n.s.

Current (%) 22 29 n.s.Previous (%) 41 38 n.s.

Pack-years (nonsmokers excluded) 26 (147) 25 (473) n.s.Mobility

Walking without support (%) 43 44 n.s.Walking with support (%) 38 31 n.s.

Wheelchair (%) 18 24 n.s.Diabetes duration (years) 20 (163) 23 (354) n.s.

Diabetes type 1/2 (%) 24/76 42/58 n.s.Glycated hemoglobin (%)* 7.8 (4.211.0) 8.1 (5.012.5) n.s.

Hemoglobin (g/l) 127 (95156) 123 (95160) n.s.Creatinine (mol/l) 104 (52804) 101 (48687) n.s.

C-reactive protein (mg/l) 8 (1161) 7 (149) n.s.Leukocyte count (109/l) 8.5 (3.713.1) 7.7 (1.913.8) n.s.

Concomitant diagnosesHypertension (%) 76 73 n.s.

Hyperlipidemia (%) 88 87 n.s.Myocardial infarction (%) 25 33 n.s.

Stroke (%) 16 16 n.s.

Congestive heart failure (%) 35 27 n.s.Atrial fibrillation (%) 25 33 n.s.

Nephropathy (%) 90 80 n.s.Dialysis (%) 6 7 n.s.

Renal transplant (%) 4 2 n.s.Prior major amputation (%) 14 7 n.s.

Prior minor amputation (%) 32 47 n.s.Charcot foot (%) 4 9 n.s.

MedicationInsulin (%) 90 91 n.s.

Metformin (%) 10 13 n.s.Sulfonylurea (%) 12 16 n.s.

Statin (%) 69 60 n.s.Aspirin (%) 63 56 n.s.

Clopidrogel (%) 8 13 n.s.Warfarin (%) 18 24 n.s.

ACE-inhibitor or ARB (%) 69 74 n.s.

-blocker (%) 39 40 n.s.

Diuretics (%) 67 51 n.s.Antibiotics, oral (%) 65 73 n.s.

Antibiotics, intravenous (%) 0 0 n.s.Index ulcer size (cm2) 3.1 (0.655) 2.8 (0.639) n.s.

Ulcer duration (months) 9 (344) 10 (339) n.s.Wagner classification

Grade 1 (%) 0 0 n.s.Grade 2 (%) 24 27 n.s.

Grade 3 (%) 51 62 n.s.

Grade 4 (%) 24 11 n.s.Grade 5 (%) 0 0 n.s.

Index ulcer locationToe (%) 35 47 n.s.

(continued)

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treatments) and sepsis derived from aninfected foot ulcer in one patient (at 144days after 40 treatments).

Three major amputations were per-formed in the HBOT group as comparedwith one in the placebo group within the1st year. In the HBOT group, two of thethree amputations were done within 2months after inclusion and the third wasdone at 191 days. The amputation in theplacebo group was performed 98 days af-ter inclusion. All four patients had an ar-terial toe blood pressure 15 mmHg inthe affected lower limb. Two of these ul-cers were classifiedas Wagner grade 4 andtwo were classified as grade 3 ulcers (20).Four minor amputations were performedin each group during the 1st year of

follow-up.

Adverse reactionsAll toge ther 3,225 treatment sessionswere given in the HODFU study. As dis-

cussed above, one fatal outcome was seenin the HBOT group during the treatmentperiod, and a relation between HBOT andthis fatal outcome cannot be excluded. Inthe placebo group, one patient was hos-pitalized for 24 h after temporarily losingconsciousness after a treatment session.

Hypoglyc e mia (sympt oms a ndblood-glucose 3.0 mmol/l) within 6 hafter treatment occurred in two and fourpatients in the HBOT and placebo groups,respectively (n.s.). One of the patients inthe HBOT group was hospitalized due tothe event.

One patient in the HBOT group en-dured barotraumatic otitis. Another fourpatients, two in each group, required my-ringotomy with tube placement due to

pain caused by the inability to equilibrateair pressure through the eustachian tube.

In the HBOT group, treatment-related dizziness was seen in one patientand the worsening of cataracts in another.

Onecase of minor head injury occurred inthe placebo group after a fall inside thehyperbaric chamber. Oxygen toxicity,seizures, or pneumothorax were not seen.

CONCLUSIONS T h e p r es e ntstudy supports the concept that adjunc-

tive treatment with HBOT enhances footulcer healing in selected patients with di-abetes. Accordingly, in our patients withlong-standing chronic ulcers at 1-year fol-low-up, HBOT doubled the number ofhealed ulcers as compared with adjunc-tive treatment with hyperbaric air used asplacebo.

In this study, arterial toe blood pres-sure was not a discriminating factor forbeneficial effect of HBOT (data notshown). Patients with arterial toe bloodpressureas low as 5 mmHg did healin theHBOT group, and we could not identify alower level of arterial toe blood pressurefor nonhealing. Ulcer healing rate in theplacebo group might be lower than ex-pected, probably mainly reflecting a longprestudy period of failure to heal.

Our findings are in agreement withthose reported in previous randomizedstudies focused on ulcer healing by Abidiaet al. (17), Duzgun et al. (21), Kessler etal.(22), and Kalani et al. (23). Abidia et al.evaluated the effect of HBOT comparedwith hyperbaric air in a double-blindstudy of ischemic Wagner grade 1 and 2

ulcers. In that study of 18 patients, a non-significant improvement of healing ratefollowing HBOT was seen after six weeks,which reached statistical significance at1-year follow-up. In the unblinded, ran-

Table 1Continued

HBOT Placebo

Plantar forefoot (%) 27 24 n.s.Middle foot (%) 14 13 n.s.

Heel (%) 16 7 n.s.Malleoli (%) 6 7 n.s.

Dorsal (%) 2 0 n.s.Peripheral circulation

Previous vascular surgery (%) 57 49 n.s.Toe blood pressure (mmHg) 50 (5130) 55 (15160) n.s.

Toe blood pressure 60 mmHg (%) 57 57 n.s.Toe blood pressure 35 mmHg (%) 33 29 n.s.

*Glycated hemoglobin recalculated to % in Diabetes Control and Complications Trial standard, aboveankle amputation, angiotensin II receptor blocker. n.s., not significant.

Table 2 PTA was performed in 10 patients during the first year of follow-up. Baseline arterial toe blood pressure, number of treatment

sessions given, and ulcer outcome are specified for those patients

PTA intervention (months

after randomization)

Total number of

HBOT treatments

Arterial toe blood

pressure at inclusion

Outcome of index

ulcer Amputation

HBOT Group

3 40 15 mmHg Unhealed Above ankle amputation

at 7 months6 40 25 mmHg Healed at 6 months Toe amputation at 8

months7 38 20 mmHg Unhealed Toe amputation at 10

months7 40 30 mmHg Healed at 3 months No

7 38 40 mmHg Healed at 12 months No8 40 20 mmHg Unhealed No

Placebo Group

2 40 20 mmHg Unhealed No

3 37 45 mmHg Unhealed No6 38 50 mmHg Unhealed No

7 38 25 mmHg Healed at 9 months No




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domized study by Duzgun et al., the effectof HBOT was compared with standardtherapy in 100 patients with a foot ulcer

duration of at least four weeks. During amean follow-up period of 92 weeks, pri-mary healing was achieved in 66% of pa-tients receiving HBOT compared with 0%following standard therapy (21). In therandomized trial by Kessler et al., the ef-fect of two daily 90-min sessions of HBOTfive days a week for two weeks was com-pared with regular treatment in 28 hospi-talized patients with neuropathic Wagnergrade 1 to 3 ulcers (22). After two weeksof treatment, the reduction in ulcer areawas doubled in the HBOT group (P 0.037). However, this improvement dis-

appeared during the next two weeks offollow-up. The study by Kalani et al. in-cluded 38 patients with ischemic ulcerswithout full-thickness gangrene. Afterthree years, 76% of the 17 patients receiv-ing HBOT had healedtheir ulcers to intactskin compared with 48% of those givenconventional treatment. However, thesedata should be interpreted with caution asthe randomization procedure was notsustained through the study (23).

In contrast to our findings, somestudies have shown the beneficial effect of

HBO T in pre ve nt ing a mput a t ions(8,21,23). Our study had insufficientpower to analyze the rate of major ampu-tations, which were only performed dueto life-threatening infection and refrac-tory pain. In the studies by Faglia et al.(8), Kalani et al. (23), and Duzgun et al.(21), amputation rates were substantiallyhigher than in our study, suggesting thesestudies used other indications for majoramputation (i.e., long-term unhealed ul-cers) (8,21,23). This might indirectly bemirrored in toe blood pressure levels thatwere 15 mmHg in our amputated pa-

tients compared with 42 30 mmHg inthe study by Kalani et al. (23). Also, apossible bias effect cannot be excluded in

open studies where the investigator maybe involved in the decision to amputate.Although 50% of our patients had

had at least one previous vascular inter-vention at the time of randomization andthe need foror possibility ofvascularsurgical intervention had been excludedat time of inclusion, PTA was performedin 10 patients (11%) within one year ofrandomization. This partly reflects a gen-eral problem in evaluating the effects ofdifferent treatment methods for diabeticfoot ulcers and is not unique for ourstudy. For instance in the study by Fagliaet al. (8), vascular surgical interventionwas performed in 38% of the patientsduring the follow-up period. The impli-cations of these interventions on studyoutcome have been debated (24). In ourstudy, however, PTA intervention cannotexplain thehigher ulcer healing rate in theHBOT group as only three ulcers, one ofwhich was in the placebo group, healedfollowing PTA.

The frequency (6%) of middle earbarotrauma or the need for myringotomywith tube placement was not higher in

our study population of relatively old pa-tients with severe cardiovascular diseaseand neuropathy compared with previ-ously reported data in younger patients(25). In our treatment schedule, an HBOTsession included a period of compressionin air for 5 min, followed by a treatmentperiod at 2.5 ATA for 85 min, and then adecompression period of 5 min. Thisschedule has been shown to be safe forscuba divers and our study showed it tobe safe in our diabetic foot ulcer popula-tion where 3,225 treatments were given

without decompression sickness, sei-zures, or pneumothorax.

In conclusion, the HODFU study, adouble-blinded, randomized, placebo-controlled trial, showed that adjunctivetreatment with HBOT facilitates healingof chronic foot ulcers in selected patientswith diabetes.

Acknowledgments This study was sup-ported by unrestricted grants from ThelmaZoegas Foundation, Region Skne Founda-tion, and the medical faculty of LundUniversity.

No potential conflicts of interest relevant tothis article were reported.

This study waspublished in abstract form atthe 16th International Congress on Hyper-baric Medicine, Beijing, China, 26 29 Octo-ber 2008; the European Committee forHyperbaric Medicines Oxygen & InfectionConference, Stockholm, Sweden, 79 May

2009; the 19th European Wound Manage-ment Association Conference, Helsinki, Fin-land, 2022 May 2009; and the 7th DiabeticFoot Study Group Conference, Bled, Slovenia,2528 September 2009.

The authors thank Dr. John Jeffery for sci-entific advice and help with the English text;Dr. Thomas Kjellstrom and Dr. Jan Apelqvistfor helpful support; and registered nurse Car-ina Johansson and assistant nurses Gisela To-rildsson and Magnus Andersson at theHyperbaric Unit and research nurses AnneliSvensson and Lisbeth Lundell at the ResearchUnit at Helsingborg Hospital for collaborationand invaluable help.

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