Correspondence:
David Juurlink
Sunnybrook Health Science Centre G-106
2075 Bayview Avenue
Toronto Ontario
Canada M5N 1P6
T: 416 480 4835
E:
david.juurlink@ices.on.ca
Disagreement about the role of hyperbaric oxygen (HBO) for carbon
monoxide (CO) poisoning is nothing new, but there are several related
points on which most everyone will agree. First, CO is an insidious and
globally significant poison, killing upwards of 40,000 people and
sickening perhaps a million others around the world each year.(1) This
fact alone highlights why resolving disagreement about its treatment
should be a priority. Second, absent a clear exposure history, the
diagnosis of CO poisoning can be challenging because symptoms are
nonspecific, ranging from headache, fatigue and nausea to chest pain,
dyspnea, confusion and coma. Third, removal from exposure and
administration of supplemental oxygen are the cornerstones of treatment,
although it warrants mention that even oxygen itself has not been
rigorously evaluated as a therapy.(2) Fourth—and this is an especially
important point—the pathophysiology of CO poisoning is more complex
than generally appreciated. While it is widely known that CO displaces
oxygen from hemoglobin and shifts the oxygen-hemoglobin dissociation
curve to the left, impairing peripheral oxygen delivery, it also
generates reactive oxygen species,(3) inhibits cellular respiration by
binding to mitochondrial heme, and directly peroxidates brain lipids,
leading to neuroinflammation.(4)
Clinicians who treat CO poisoning know that supplemental oxygen hastens
the elimination of carboxyhemoglobin, and that HBO hastens it further
yet. The elimination half-life of carboxyhemoglobin while breathing room
air averages about 6 hours, falling to around 75 minutes when breathing
100% oxygen (“normobaric oxygen”, NBO) and about 22 minutes when
breathing 100% oxygen at 3 atmospheres.(5) But because clinicians tend
to anchor their diagnostic and mechanistic thinking around
carboxyhemoglobin, it can be tempting to infer that HBO must be
beneficial simply because it promotes carboxyhemoglobin elimination.
This reasoning oversimplifies CO poisoning, reducing it to a functional
anemia akin to methemoglobinemia and discounting entirely its other
mechanisms of toxicity.
Is hastening the elimination of carboxyhemoglobin intuitively appealing?
Of course. But neither the carboxyhemoglobin concentration itself nor
the rate of its disappearance is a clinical outcome. The
carboxyhemoglobin concentration should be viewed in much the same way as
an LDL-cholesterol concentration: a laboratory value that can be useful
for diagnosis and lowered by medical intervention. In patients with CO
poisoning, the goal of treatment is not simply lowering that number; the
goal is the reduction of morbidity. And in the case of CO poisoning,
morbidity is chiefly neurologic.
At issue, then, is whether HBO reduces the risk of neurologic sequelae
compared to standard treatment with 100% oxygen. And it is on this
point where champions and skeptics of HBO disagree.
As with any medical intervention, there is only one way to establish
whether HBO does what is claimed of it: through well-designed randomized
controlled trials (RCTs). The clinical utility of HBO simply cannot be
divined from a collection of cases,(6) and certainly not from
observational studies, which are easy to perform but hopelessly
undermined by selection bias and information bias when the issue is one
of treatment effects. The fact that observational studies cannot
quantify the utility of HBO has not, however, stopped researchers from
trying. Several such studies have been published using administrative
data, generating conflicting results(7, 8) along with estimates of
effect size that are frankly impossible. Simply put, database studies
purporting to evaluate the effect of HBO are not to be taken seriously.
What then do the available RCTs tell us about the value of HBO in CO
poisoning? Regrettably, not much. The strengths and weaknesses of the
various trials have been reviewed in detail by Buckley and
colleagues.(9, 10) But in a commentary advocating against the routine
use of HBO, it’s worth focusing specifically on the RCTs widely regarded
as demonstrating its benefit.
The first of these, published in 1995 by Thom and colleagues,(11)
involved 65 patients with mild to moderate CO poisoning presenting
within 6 hours. Patients received either 100% oxygen at ambient
pressure until asymptomatic (n=32) or HBO for two hours (n=33), by which
time symptoms had resolved in all patients. The primary outcome was
delayed neuropsychologic sequelae (DNS), defined as new symptoms
developing after oxygen therapy plus deterioration from baseline
in one or more neuropsychologic subtests. (The concept of delayed
neurologic sequelae—symptoms developing after a period of
normalcy—will become especially relevant later in this commentary).
After excluding five patients lost to follow-up, Thom and colleagues
identified DNS in 7 of 30 patients treated with NBO and 0 of 30 patients
treated with HBO (P<0.05).
Setting aside the small size of the trial, three aspects warrant special
emphasis. First, treatment allocation was not concealed; patients and
investigators alike knew who had spent time in a chamber and who had
not. Second, as Buckley has observed, outcomes were assessed by
“clinicians who had been on the record for many years in support of HBO
for CO poisoning.”(9) Third, in 1992 the investigators presented an
interim analysis of the study, reporting DNS in 4 of 29 subjects treated
with NBO and 0 of 29 subjects treated with HBO (along with a P value of
<0.005, a clear statistical impossibility.)(12) Thereafter,
the trial was terminated after recruitment of just seven additional
patients, with all three subjects newly recruited to the NBO arm
developing DNS. Termination at this stage is remarkable if not curious.
While this pattern of outcomes in the NBO arm before and after the
interim analysis could conceivably represent the play of chance
(P=0.007; Fisher’s exact test), termination at this stage greatly
exaggerated the apparent treatment effect. Moreover, the investigators
did not adjust for multiple comparisons. Had they done so, the trial’s
overall result would not have been statistically significant.
The second positive trial—indeed, the one typically cited as
definitive by proponents of HBO for CO poisoning—was published by
Weaver and colleagues in 2002.(13) At first blush, the appeal of this
study is evident: it was a multicentre randomized trial published in the
New England Journal of Medicine, it enrolled 152 patients with a range
of poisoning severity, it employed “sham dives” in which subjects in
the control (NBO) arm received 100% oxygen in a hyperbaric chamber, and
outcome assessors were blind to treatment allocation. The study also
suggested an impressive effect of HBO: at six weeks, cognitive sequelae
were identified in 25% of those treated with HBO compared with 46% of
those treated with NBO.
But scratch beneath the surface and several problems with the study
quickly become evident. A detailed exposition of these is given by
Buckley and colleagues,(9) with the key elements being baseline
imbalance between treatment groups, a high likelihood of unblinding,
biased handling of missing data, and repeated alterations of the primary
outcome.
In the study by Weaver and colleagues, important differences between
treatment groups were evident at baseline, with those in the NBO arm
having far longer average exposure to CO (22 vs. 13 hours) and nearly
four times the prevalence of cerebellar dysfunction (15% vs. 4%) than
those in the HBO arm. The latter observation is especially relevant
because two of the six neuropsychological tests defining the primary
outcome involved “trail-making”, which might be sensitive to
clinically evident cerebellar signs. This apparent failure of
randomization is compounded by the virtual certainty of unblinding: in
the first interim analysis, the investigators reported that one group of
patients was four times more likely than the other to be intolerant of
the hyperbaric chamber.(14) There can only be one interpretation of
this. Indeed, in the final publication, failure to complete the chamber
sessions was much more common in the HBO group (18.4%) than the NBO
group (3.9%).
Biased handling of missing data is apparent in the imputation of
neurologic sequelae to patients with no outcome data at 6 weeks,
including 4 of 76 patients (5.3%) in the NBO group and 1 of 76 patients
(1.3%) in the HBO group. The wellbeing of these five patients was by
definition unknown, and imputing the presence of neurologic sequelae
necessarily inflated the apparent effect of treatment.
But arguably the most serious problem with the Weaver study is the
evolution of the primary outcome over time, from one seemingly destined
to show no benefit from HBO to one that did. The investigators’ own
writings from make this clear. Their original intent, reported in the
first interim analysis presented in 1995, was to evaluate the effect of
HBO on the incidence of delayed neurologic sequelae, defined
exclusively by neuropsychiatric testing.(14) They reaffirmed this that
same year, writing “Our major question is, does HBO reduce the
incidence of delayed neurologic sequelae (DNS)?”(15) Yet nowhere in the
final publication were rates of DNS reported. Instead, the eventual
primary outcome consisted simply of “cognitive sequelae,” defined
using less stringent neuropsychiatric test cutoffs than originally
planned, and newly incorporating nonspecific symptoms in its definition.
In essence, a secondary outcome was elevated to primary, while the
original primary outcome was simply discarded.
The investigators’ decision to change the primary outcome has never been
publicly acknowledged, let alone justified. Confronted on this point
years later, leaders in the field of hyperbaric medicine have repeatedly
chosen to sidestep the issue rather than address it.(16, 17)
Notwithstanding its shortcomings, the study by Weaver et. al continues
to be portrayed as definitive evidence of the benefit of HBO in CO
poisoning.(18) For a moment, set aside the various concerns—the
baseline differences between groups, the early unblinding, the dubious
handling of missing data, and alteration of the primary outcome—and
consider the following question: Despite these limitations, all of which
favour the active treatment arm, what do the study’s findings suggest
about the objective effects of HBO in patients with CO poisoning? The
figure below, reproduced from Buckley et al.(9), give us some idea.