Response to Comments on Fedorko et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392–399


RESPONSE TO COMMENTS ON FEDORKO ET AL.

Hyperbaric Oxygen Therapy Does Not
Reduce Indications for Amputation in
Patients With Diabetes With Nonhealing
Ulcers of the Lower Limb: A Prospective,
Double-Blind, Randomized Controlled
Clinical Trial. Diabetes Care
2016;39:392–399
Diabetes Care 2016;39:e136–e137 | DOI: 10.2337/dci16-0006

We welcome this opportunity to re-
spond to the comments (1–3) regarding
our study (4). There are a few common
themes that we would like to clarify. The
first theme is around the criticism of us-
ing “meeting criteria for amputation” in-
stead of “amputation event.” It is ideal
to use more final patient outcomes in all
research; however, the sample size and
time needed to recruit and follow pa-
tients of sufficient duration to observe
final events is often prohibitive. This is
the reason why intermediate markers
and outcomes are used in many disease
areas, including diabetes. In addition, fi-
nal events like amputations may be an
inappropriate outcome in small, ran-
domized controlled trials (RCTs) where
other factors may confound the true
treatment effect. For example, patient
cultural preferences, psychological
trauma, and procedure-booking logis-
tics (among other factors) frequently
override medical advice about whether
and when the limb should be ampu-
tated. This (extrinsic to disease) variabil-
ity precludes using actual amputation
event as a consistent outcome mea-
sure unless a very large sample and long
follow-uptimesareused.Thisisimpractical

and prohibitively costly in placebo-
controlled hyperbaric treatment trials.
However, Margolis et al. (5) have done
it elegantly in a study of different de-
sign. This multicenter observational
cohort with propensity score matching
methodology showed no amputation-
sparing effect or improved wound heal-
ing in over 700 patients treated with
hyperbaric oxygen therapy (HBOT)
matched with over 5,000 patients re-
ceiving standard wound care. By using
the strength of a large sample of pa-
tients, this study was able to corrobo-
rate the findings we observed in our
smaller RCT.

A second criticism theme was around
the fact that the “meeting criteria for
amputation”outcomewas assessed solely
on the basis of the digital photography, a
method of validation that is not valid or
validated (2,3). This criticism is simply
incorrect and misleading. As described
in the RESEARCH DESIGN AND METHODS section
of our article (4), at the primary end
point of the study the wound care
nurse presented both clinical case in-
formation and all patient photographs
to the same vascular surgeon who eval-
uated patients prior to enrollment. The

surgeon had a choice (at his discretion)
to see the patient in person prior to
adjudication. This method of adjudica-
tion for indications to amputate has
been previously formally validated in
direct comparison with personal visits
(see refs. 19 and 20 in RESEARCH DESIGN AND
METHODS) (4).

Löndahl et al. (1) also questioned the
validity of our results because of small
differences in patient demographics and
shorter follow-up times between our
and their (Swedish) study (6). This criti-
cism is unfounded, as one would expect
to see some differences in demograph-
ics across countries and between popu-
lations due to higher rates of diabetes
and obesity in North America. Our follow-
up time is consistent with several RCTs
of other diabetic foot ulcer (DFU)
treatment modalities with positive out-
comes within 12 weeks (refs. 34–36) (4).
There is also very good evidence that
the healing rate during the first 4 weeks
of treatment is a strong predictor of
wound healing (ref. 23) (4). If anything,
our results have more relevance to
North American populations.

Also, contrary to the assertion by
Löndahl et al. (1), transcutaneous oxygen

1Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, Toronto, ON, Canada
2Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, ON, Canada
3Programs for Assessment of Technology in Health Research Institute, St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada
4Division of Vascular Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada

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

© 2016 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.

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

Wilhelmine Jones,1

George Oreopoulos,4 Ron Goeree,2,3

Robert B. Hopkins,2,3 and

Daria J. O’Reilly2,3

e136 Diabetes Care Volume 39, August 2016

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http://crossmark.crossref.org/dialog/?doi=10.2337/dci16-0006&domain=pdf&date_stamp=2016-07-06
mailto:ludwik.fedorko@uhn.ca


pressure measurement (TcPO2) has
very poor negative predictive value
(7), which limits its clinical/research
usefulness.
It is disappointing that Huang (3) as-

serts “methodological errors” seemingly
without carefully reading our article. It
is simply unprofessional to criticize an
article in a letter to the editor simply
because of the preconceived notions
of treatment benefit without even
reading the methods of an article.
First, actual amputations were reported
(see RESULTS). Second, off-loading (as re-
quired, and as tolerated) was used (see
RESEARCH DESIGN AND METHODS). Third, we have
clearly stated that Wagner grade 1
wounds “were considered healed” for
the purposes of analysis (see RESEARCH
DESIGN AND METHODS). Fourth, the primary
outcome was assessed at 12 weeks;
therefore, the rate of actual amputa-
tion after the final adjudication point
is irrelevant to the study methodology
(see RESEARCH DESIGN AND METHODS).
Contrary to the assertion by Murad

(2), there are no known contraindica-
tions to HBOT specific to Wagner grade
2 ulcers. We are dismayed at his un-
precedented statement that our study
was “not patient-centered” and “did
not add any new information” because
we did not exclude patients with Wag-
ner grade 2 wounds. One should not
confuse Undersea and Hyperbaric
Medical Society (UHMS) guidelines (8)
alignment with U.S. Centers for Medi-
care & Medicaid Services (CMS) reim-
bursement policies with scientific
evidence. Virtually all RCTs of HBOT to
date have included patients with Wag-
ner grade 2 DFU. In this study, we
painstakingly assessed a wide range of
patient-centered outcomes. We did not
see differences in any outcome mea-
sures of wound healing rates, quality
of life, or independent living between
the groups.
Löndahl et al. (1) also refer to the crit-

ical issue of an inappropriate placebo
used in their double-blind RCT (6), which
we discussed in our article, as “irrelevant,”
a “‘bubble’ theory” and “of no value.”

Huang (3) dismisses our concerns
(while agreeing at the same time) that
the placebo used by Löndahl et al. (6)
was not inert. This study (6) is widely
quoted and is used in multiple meta-
analysis and reviews (including UHMS
guidelines) as important level 1 positive
evidence for efficacy of HBOT for DFU
treatment. Hyperbaric chambers were
originally invented to treat “bends”
caused by nitrogen bubbles, not to
cause them. We stand by our opinion
that the placebo used in the study by
Löndahl et al. (6) was not a placebo
but a nonbenign exposure of control
group subjects. “Placebo” patients were
subjected to 40 daily 90-min air com-
pressions to 2.5 atmosphere absolute.
Such compressed air exposure is be-
yond the time limits of the generally
accepted civilian no-decompression
tables (9), putting patients at significant
risk of evolving intravascular gaseous
nitrogen bubbles. These tables were
never tested for repetitive exposures
in elderly, sick people with poor periph-
eral circulation. Therefore, this study
regimen may have been associated
with observed delayed wound healing
and with higher 3-year mortality in the
placebo group, as was reported by
Löndahl et al. in an abstract form (10).
It may also conceivably explain why we
were not able to reproduce positive re-
sults of the study by Löndahl et al. (6) in
our placebo-controlled trial.

Hyperbaric oxygen is a drug delivered
in a large pill called a hyperbaric cham-
ber. After several decades of use, it has
to be held to the same standards as are
applied to other expensive drugs. We
were more disappointed than anybody
else when we analyzed the data and re-
viewed it critically in the context of liter-
ature. However, as of now, the best
available evidence does not provide sup-
port for use of HBOT in the patients with
chronic diabetic wounds to facilitate heal-
ing or prevent the need for amputations.

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

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clinical trial. Diabetes Care 2016;39:392–399
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clinical trial. Diabetes Care 2016;39:392–399
(Letter). Diabetes Care 2016;39:e133–e134.
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