Re: Re: Lipsky full article on HBOT and diabetic ulcers

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(used under appropriate fair use provisions of the U.S. and international

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Hyperbaric Oxygen Therapy for Diabetic Foot Wounds

Has hope hurdled hype?

A. Lipsky, MD, FACP, FIDSA, FRCP1 and R. Berendt, BM, BCH, FRCP2

1University of Washington, VA Puget Sound, Seattle, Washington;

2Bone Infection Unit, Nuffield Orthopaedic Centre NHS Trust, Oxford, U.K.

Corresponding author: A. Lipsky,dblipsky@....

“One must always hope when one is desperate, and doubt when one hopes.â€

Gustave Flaubert.

Hyperbaric oxygen therapy (HBOT) has been promoted as an effective treatment for

diabetic foot wounds, and the first controlled trial for this indication was

reported (in Diabetes Care) over 20 years ago (1). Advocates have suggested that

the experimentally demonstrated effects of HBOT on improving wound tissue

hypoxia, enhancing perfusion, reducing edema, downregulating inflammatory

cytokines, promoting fibroblast proliferation, collagen production, and

angiogenesis make it a useful adjunct in clinical practice for “problem

wounds,†such as diabetic foot ulcers (2,3). HBOT is also touted for

eradicating difficult to treat soft tissue and bone infections by mechanisms

that include killing microorganisms, improving leukocyte and macrophage

function, and enhancing the effect of antimicrobials (4). If realized

clinically, these beneficial effects, although requiring expensive technology,

might powerfully reduce the risk of lower-extremity amputation in diabetic

patients with foot wounds. Thus, rigorously assessing the clinical effectiveness

of HBOT in diabetic foot ulceration is an important enterprise. But, because

both patients and clinicians are strongly motivated to avoid the devastating

outcome of amputation, there is a high potential for bias in poorly designed

trials. Proof of benefit requires properly conducted clinical trials that

minimize the possibility that preexisting prejudices will influence the

allocation of patients, diligence of foot care, or other key management

decisions.

Most of the published reports on the effect of HBOT for treating diabetic foot

wounds have been case series or nonrandomized trials with major methodological

limitations. Although these are a poor source of evidence, the consistency of

positive results is noteworthy. More recently, several randomized controlled

trials have been conducted. A Cochrane database systematic review published in

2004 concluded, based on results from four such trials, that “HBOT

significantly reduced the risk of major amputation and may improve the chance of

healing at 1 year†but, “… the small number of studies … modest numbers

of patients, methodological and reporting inadequacies … demand a cautious

interpretation†(5). A more recent systematic review and meta-analysis that

included 10 studies (6 of which were not randomized, controlled trials)

concluded that HBOT reduces the risk of amputation (odds ratio 0.24, seven

studies) and increases the likelihood of wound healing (odds ratio 10.0, six

studies) (6).

But there are concerns. HBOT is available in only a minority of communities, is

very expensive (a full course of treatment in the U.S. typically costs $50,000

[Medicare] to $200,000 [private pay]), and is time-consuming (an average of 60

total hours in the chamber). Limited economic analyses using the flawed primary

clinical data have suggested, however, that HBOT is potentially cost-effective

(7,8) or even cost-saving (9). The more skeptical view is best summarized in a

counterpoint commentary (10) on hyperbaric oxygen treatment for diabetic foot

wounds published 4 years ago that concluded “[it] is time that the advocates

of this therapy organized large, randomized, placebo-controlled trials to

provide definitive answers to the questions: which, if any, patients would

benefit from HBOT for a diabetic foot wound, and how great is any measurable

benefit?†Have there been investigations designed to answer these questions

published since that challenge, and, specifically, has the study from Lund,

Sweden, by Löndahl et al. (11) in this issue ofDiabetes Care provided the proof

that HBOT naysayers are seeking?

One new study that addressed this issue by Duzgun et al. (12) was published in

2008. This randomized trial compared the effects of HBOT with standard wound

care alone on 100 patients with a diabetic foot ulcer that had not responded to

a month of appropriate treatment. They found that HBOT was associated with

statistically significantly higher rates of wound healing (66% vs. 0%), lower

rates of operative interventions (debridement, amputation, or skin flap or

graft; 16% vs. 100%), and fewer lower extremity amputations (8% vs. 82%). This

study, in common with most others previously published, had several important

limitations, including a lack of investigator or patient blinding, minimal

descriptions of the types of wounds enrolled, and disparities in treatment

allocation that were presumed to be by chance. Nevertheless, it provided useful

data and increased by two-thirds the number of patients on which the previously

cited Cochrane systematic review of HBOT for diabetic wounds reported.

The study by Löndahl et al. (11) builds on work their team began in the early

1990s, when they demonstrated in a randomized controlled study of 16 nondiabetic

patients with a nonischemic chronic leg ulcer, that HBOT significantly reduced

the size of the wounds during a 6-week observation period (13). This study,

unlike all previous ones except that by Abidia et al. (9), was double-blinded;

all enrolled patients were treated in a multiplace hyperbaric chamber, but the

masks for half the subjects delivered air while those for the other half

delivered 100% oxygen. This method, although technically complex, allowed for a

placebo-controlled and blinded evaluation of HBOT, thus eliminating many of the

potential confounders that plagued other trials. Fortunately, the investigators

kept this design for the current trial in patients with diabetic foot ulcers. In

this study, the authors enrolled 94 diabetic patients with a foot ulcer (Wagner

grades 2–4) that had been present for at least 3 months and who did not need

or could not have reconstructive vascular surgery. They excluded only those

patients for whom HBOT was contraindicated or who had a substance abuse problem

and stratified enrolled patients by their arterial toe blood pressure.

Hyperbaric sessions were given for 8 to10 weeks (aiming for 40 sessions), in

conjunction with appropriate foot care provided by a multidisciplinary diabetic

foot clinic. The primary end point was ulcer healing, properly defined as

complete epithelial regeneration, and patients were followed for a year.

Patients randomized to the two treatment groups were similar at baseline; of

note is that over half had previously had vascular surgery to the affected lower

limb. It was disappointing that only 56% of eligible patients were enrolled, and

only 57% of those enrolled completed the 40 treatments (although most had at

least 35).

The results of the Löndahl study clearly support the benefit of HBOT. Complete

ulcer healing at the 1-year follow-up was noted in significantly more

HBOT-treated than hyperbaric air- treated patients (52% vs. 29% [P = 0.03] in

the intention-to-treat analysis, and 61% vs. 27% [P = 0.009] in the per-protocol

analysis). The number needed to treat to avert nonhealing was only 4.2 (3.1 in

the per-protocol analysis). Among their secondary outcomes, the rates during the

study period of major amputation (∼4%) and death (∼7%) were relatively low

(for these elderly diabetic patients with a high prevalence of comorbidities)

and were similar for the two groups. Although patients with infected wounds

(presumably including osteomyelitis) could be enrolled, and ∼70% of the

patients were receiving oral antibiotic therapy at the time of enrollment, the

authors, unfortunately, did not comment on the rates or speed of resolution of

infection in the two groups. The rate of adverse reactions to hyperbaric therapy

in this study was notable; one patient died (in the HBOT group, possibly related

to treatment), 5% had significant barotrauma, and 6% had symptomatic

hypoglycemia (one of whom was hospitalized), a known potential risk of HBOT.

The authors of this study are certainly to be commended on the strong study

design they used—it was fully blinded and placebo-controlled, with concealed

allocation that was maintained until the end of a 1-year follow-up period, the

exclusion criteria were limited, and patients were stratified by arterial

vascular status. The number of patients enrolled was larger than any but the

methodologically inferior study by Duzgun et al. (12). There were, however, some

important limitations. Only 55% of potentially eligible patients were available

for analysis at the 1-year follow-up. The Wagner system used to grade wound

severity, while also used in previous HBOT studies and by Medicare to determine

eligibility for treatment, has largely been superseded by other systems that

provide more information (14,15). We are given no information regarding how many

patients in each group had osteomyelitis, a clinically important variable that

was neither a reason for exclusion nor used for stratification of enrolled

patients. The enrolled patients were relatively unique in some ways: the mean

age was a decade older than in most studies of patients with diabetic foot

ulcers, all had ulcers that had failed prolonged attempts at treatment, and most

had previously had vascular surgery on the affected leg. The description of the

severity of infection in the two groups, or how HBOT affected the resolution of

infection, was inadequate. There were too few amputations to judge the effect of

HBOT on this crucial end point. No data supporting the statement that arterial

toe blood pressure did not predict outcomes were provided, and transcutaneous

oxymetry would have been a better means of determining adequacy of wound

perfusion and oxygenation than toe pressures (16). Finally, the authors made no

attempt to address the cost-effectiveness of this expensive technology.

What are we to conclude about the place of HBOT in treating patients with

diabetic foot wounds? It seems clear that in a center of excellence of both HBOT

and diabetic foot care, like the one in Lund, HBOT can help heal refractory

wounds. It is unnecessary for the great majority of patients, however, who will

respond to appropriate wound care (cleansing, debridement, off-loading,

antimicrobials, as needed). But, for chronic diabetic foot wounds that are not

responding to months of appropriate therapy, the present study, together with

most of those previously published, suggests that HBOT improves long-term

healing. Although HBOT is approved in the U.S. for treatment of chronic

osteomyelitis, there is little published support for this treatment for treating

infectious complications in the diabetic foot. The potential benefit of HBOT

comes at a high financial cost; it would be reasonable for payers to ask if

treating four patients to deliver one additional healed ulcer at 1 year is

cost-effective. Further randomized controlled trials would, of course, be

welcomed. In light of the expense of conducting properly designed clinical

trials, alternative methods of assessment, such as theoretical modeling, may be

helpful (17).

The study by Löndahl et al., standing on the shoulders of previous trials, has

placed HBOT on firmer ground. While this article may not be the one to untie the

purse strings of health care payment agencies, it does provide cause for hope

and serves to prove that large, properly designed trials are both possible and

necessary. Key issues that we must yet address to better understand the place of

HBOT in treating diabetic foot wounds include developing robust criteria to

determine which patients are likely to benefit, determining at what point in

their treatment HBOT should be considered (or abandoned), and deciding which

treatment protocols are most appropriate (18). This landmark study at last

demonstrates not only that answering these questions is possible using standards

of evidence appropriate for the 21st century, but that seeking the answers to

these questions is no longer of interest only to the hyperbaric industry. The

answers are important for, and eagerly awaited by, all “stakeholders†in the

diabetic foot world.

No potential conflicts of interest relevant to this article were reported.

© 2010 by the American Diabetes Association.

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On Feb 17, 2011, at 8:33 AM, hbotforhealth wrote:

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> Please post the full text of the article.

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