Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial
Carlos D Scheinkestel, Michael Bailey, Paul S Myles, Kerry Jones, D
James Cooper, Ian L Millar and David V Tuxen
MJA 1999; 170: 203-210
For editorial comment, see Moon & DeLong
Objective: To assess neurological sequelae in
patients with all grades of carbon monoxide (CO) poisoning after
treatment with hyperbaric oxygen (HBO) and normobaric oxygen (NBO).|
Design: Randomised controlled double-blind trial,
including an extended series of neuropsychological tests and sham
treatments in a multiplace hyperbaric chamber for patients treated
Setting: The multiplace hyperbaric chamber at the
Alfred Hospital, a university-attached quarternary referral
centre in Melbourne providing the only hyperbaric service in the
State of Victoria.
Patients: All patients referred with CO poisoning
between 1 September 1993 and 30 December 1995, irrespective of
severity of poisoning. Pregnant women, children, burns victims and
those refusing consent were excluded.
Intervention: Daily 100-minute treatments with
100% oxygen in a hyperbaric chamber -- 60 minutes at 2.8 atmospheres
absolute for the HBO group and at 1.0 atmosphere absolute for the NBO
group -- for three days (or for six days for patients who were
clinically abnormal or had poor neuropsychological outcome after
three treatments). Both groups received continuous high flow oxygen
Main outcome measures: Neuropsychological
performance at completion of treatment, and at one month where
Results: More patients in the HBO group required
additional treatments (28% v. 15%, P = 0.01 for all patients;
35% v. 13%, P = 0.001 for severely poisoned patients). HBO
patients had a worse outcome in the learning test at completion of
treatment (P = 0.01 for all patients; P = 0.005 for
severely poisoned patients) and a greater number of abnormal test
results at completion of treatment (P = 0.02 for all patients;
P = 0.008 for severely poisoned patients). A greater
percentage of severely poisoned patients in the HBO group had a poor
outcome at completion of treatment (P = 0.03). Delayed
neurological sequelae were restricted to HBO patients (P =
0.03). No outcome measure was worse in the NBO group.
Conclusion: In this trial, in which both groups
received high doses of oxygen, HBO therapy did not benefit, and may
have worsened, the outcome. We cannot recommend its use in CO
Carbon monoxide (CO) poisoning is one of the most common lethal
poisonings,1 with neurological or
psychiatric sequelae occurring in up to 67% of survivors.2|
Treatment with hyperbaric oxygen (HBO) is recommended because it
reduces carboxyhaemoglobin (COHb) dissociation half-life from
more than four hours at room air or 45 minutes on 100% oxygen to 23
minutes at 2.5 atmospheres absolute (ATA).3 Carbon monoxide also
inhibits cellular respiration by binding to cytochrome oxidase, a
component of the mitochondrial electron transport
chain.4 Hyperbaric oxygen enhances
the dissociation of CO from this enzyme.5
Despite these physiological effects, it has not been established in
humans that HBO either improves survival or decreases
neuropsychological deficits. Much of the evidence that HBO is more
efficacious than normobaric oxygen (NBO) therapy in humans arises
from isolated case reports,6-8 uncontrolled clinical
non-randomised13 and unblinded
series9,11,13-20 and incomplete
assessment of outcome (no neuropsychological testing).9,11,15-18
All reported non-randomised studies have suggested benefit from
HBO. Of the four published randomised studies, two report benefit
from HBO12,14 and two report no
benefit15,17 (Box 1). Three
restricted entry to mildly poisoned patients, while the
fourth15 included severely
poisoned patients, but did not allocate any to NBO treatment. None of
the randomised studies blinded patients by using sham treatments for
NBO, only one blinded outcome assessment12 and only one used
neuropsychological tests to assess outcome.14
Hence, the benefit of HBO in CO poisoning has been
questioned1,2,21-27 and remains
unproven. We therefore performed a randomised double-blind trial in
patients with all grades of CO poisoning, comparing HBO and NBO (with
sham treatments for the NBO group), and using an extended series of
neuropsychological tests to assess both persistent and delayed
neurological sequelae (PNS and DNS).
The multiplace chamber at the Alfred Hospital, a
university-attached quarternary referral centre, provides the
only hyperbaric service in the State of Victoria (population, 4.5
million; area, 228 000 km2). Between 1 September 1993
and 30 December 1995, most CO-poisoned and all severely poisoned
patients were referred for treatment. We included all referred
patients, irrespective of severity of poisoning. Patients were
excluded if they were pregnant, children, burns victims or if they did
not consent. Informed consent to enter the trial was requested from
patients with a Mini-mental score >2428 and from the next of kin for
those obtunded or with a score ≤24.
The Alfred Hospital's Ethics Committee approved the trial,
conditional on an independent blinded interim analysis after
recruitment of 50 patients (using a stopping rule of P <
0.001); this allowed continuation of enrolment to completion.
Randomisation and blinding||
Patients were randomly allocated to HBO or NBO treatment. To ensure a
similar distribution of causes and severity of poisoning in both
groups, patients were first stratified into four groups (suicide
versus accidental, then mechanically ventilated versus
non-ventilated). A hyperbaric technician then allocated patients
to treatment groups by opening envelopes chosen from random blocks,
each with equal numbers of HBO and NBO selections.
To minimise the impact of the trial on daily practice, we used cluster
randomisation for patients who presented simultaneously from the
same CO exposure, allocating them all to the same treatment group.
Cluster randomisation accounted for the difference in numbers
between HBO and NBO groups. As patients presenting simultaneously
could be uniquely identified by having identical measurements for
three continuous baseline severity measurements (exposure time,
time to COHb measurement and time to treatment), any effects due to
cluster randomisation could be controlled and adjusted for by
including these variables in the generalised linear model.
The hyperbaric technicians and nursing staff had knowledge of the
treatment group but patients and outcome assessor did not.
Before arrival at Alfred Hospital, non-intubated patients received
high flow oxygen by non-occlusive facemask and intubated patients
received 100% oxygen. All patients were admitted to hospital,
received three treatments on a once-daily basis and continuous
oxygen by non-occlusive facemask at 14 L/min (100% oxygen for
ventilated patients) between treatments.
Patients randomised to NBO therapy were treated for 100 minutes in the
multiplace chamber with 100% oxygen at 1.0 atmosphere absolute
(ATA). Non-ventilated patients used an occlusive facemask attached
via a non-rebreathing valve to a Laerdal adult ventilation bag (1.6 L)
with an oxygen reservoir (2.6 L; Armund S Laerdal, Stavanger,
Norway). The chamber door was closed and the chamber flushed with air
regularly to simulate pressurisation, but the chamber was not
pressurised (sham treatment).
HBO patients received 100% oxygen by hood, occlusive facemask or
mechanical ventilator in the hyperbaric chamber for 100 minutes (60
minutes at 2.8 ATA).
After the third treatment, patients were reassessed medically and
underwent full neuropsychological assessment. Patients who were
clinically abnormal or had poor neuropsychological outcome
received three further treatments and received high flow oxygen
Patient assessment at entry included length of CO exposure, COHb
level, time from end of exposure to COHb measurement and to treatment,
Mini-mental score and clinical effects of poisoning (Box 2).
We then assessed patients at completion of treatment (three or six
treatments), and, wherever possible, at one month.
We attempted to quantify deficits known to occur in CO poisoning by
assessing attention, information processing, memory and learning.
A clinical psychologist trained in neuropsychological assessment
of brain-injured patients performed all tests at completion of
treatment and at follow-up. Computerised testing was used to
standardise administration and data-recording procedures and
The tests used were the digit span subtest of the Wechsler Adult
Intelligence Scale -- Revised,29 comprising (i) Digit
span forward and (ii) Digit span backwards (in which
patients are asked to repeat a series of numbers read to them), which
measures immediate auditory-verbal memory span, working memory and
attention; computerised reaction-time tests,30 consisting of
(iii) Simple reaction time (in which subjects are requested
to press the space bar on a computer keyboard as soon as they see
anything appear on the screen) to give a basal measure of alertness or
arousal, and (iv) Choice reaction time (which requires
subjects to ignore stimuli in a centre box and to respond selectively
to the word "SEVEN" as it appears around the periphery of the computer
screen) to test selective attention (reaction time was tested
because it can show diffuse cerebral dysfunction, and because
processing speed is considered to underlie attention
deficits31); (v) a score on
the Rey auditory verbal learning test, in which a 15-word list
(List A) is presented over five learning trials, followed by an
interference trial (List B), after which (vi) Short term free
recall is tested without any further presentation of the word
list, and (vii) Long term free recall is tested 20 minutes
later (this provides a measure of learning across trials, and
retention of information following short and long delay
Raw scores of these seven neuropsychological tests were converted to
z scores ([score - mean in normal population] / standard
deviation), and then t scores (McCall's T; an adjusted
z score so that the mean is 50 and the standard deviation is
10).33 Age-based and
education-based norms were used where available to calculate
A t score more than one standard deviation below the mean was
considered abnormal, and two or more abnormal scores constituted a
Patients with poor outcome at hospital discharge were considered to
have persistent neurological sequelae (PNS). Delayed neurological
sequelae (DNS) were defined as morbidity found at follow-up that was
not obvious at hospital discharge, or deterioration of
neuropsychological subtest scores by more than one standard
Statistical analyses were made using mixed linear models to adjust
for all baseline covariants (age, sex, suicide attempt, COHb level,
time to COHb level, duration of exposure, time to treatment, and
presence of other drugs). Data were presented as mean and SD, median
and interquartile range (IQR) or number and per cent. Continuous data
were first assessed for normality and then analysed by unpaired
two-tailed Student's t-test, or Wilcoxon rank sum test.
Proportions were compared with chi-squared tests (with Yates'
correction), or Fisher's exact test, as appropriate, with multiple
logistic regression being used to adjust for confounding factors. We
calculated odds ratios and 95% confidence intervals (95% CI) for the
difference between proportions. The 95% CI for the difference
between means and P values were calculated after adjustment
for baseline covariants. All statistical analyses were performed
Two hundred and thirty patients with CO poisoning were referred for
treatment. Thirty-nine were excluded (one child, eight burns
victims, and 30 who refused consent) and treated with HBO. Thus, 191
patients entered the trial (Box 2). Based on the most sensitive
neuropsychological test (Short reaction time), with 191
patients and a significance level of 0.05, we had greater than 99%
power to detect a 10% difference between groups (ie, 408 seconds v. 450
seconds; SD, 63 seconds) (Clinical Trials Design Program, Biosoft,
The groups (104 HBO patients, 87 NBO patients) were comparable in age,
sex, incidence of suicide attempt, mechanical ventilation,
Mini-mental score, and other markers of severity, including loss of
consciousness (coma). Forty-four per cent of patients who had
attempted suicide (44% HBO and 44% NBO) also had evidence of
self-administration of drugs or alcohol.
Most of our patients (73%) had severe CO poisoning, defined by any of
the following before or on arrival at Alfred Hospital: a Mini-mental
score ≤24, COHb level >30%, confusion, focal neurological
deficits, loss of consciousness, electrocardiogram
abnormalities, arrhythmias, pulmonary oedema, metabolic
acidosis, hypotension, convulsions, and cardiac arrest. All
mechanically ventilated patients met the criteria of severe
Overall mortality was 3%, and the incidence of PNS was 71% at hospital
discharge and 62% at follow-up, with no significant differences
between the HBO and NBO groups (Box 3).
A smaller proportion of NBO patients than HBO patients were
considered to be medically or neuropsychologically impaired after
three treatments and thus received additional treatments (all
patients, 15% v. 28%, P = 0.01; severely poisoned patients,
13% v. 35%, P = 0.001).
The only statistically significant difference between groups in
neuropsychological performance was in the learning test at
completion of treatment (Boxes 3 and 4); this was in favour of the NBO
group for both all patients (P = 0.01) and severely poisoned
patients (P = 0.005).
NBO patients had a significantly lower number of abnormal test
results at completion of treatment (all patients, 3.4 v. 2.7,
P = 0.02; severely poisoned patients, 3.7 v. 2.6, P =
0.008) and, for those severely poisoned, there were fewer NBO
patients with a poor outcome (85% v. 65%; P = 0.03).
All five relapses (DNS) occurred in HBO patients (P = 0.03) at a
median of 40 days (IQR, 29-81 days) after initial treatment; these
patients then received a mean 4.5 (SD, 2.5) additional treatments.
Although three of these patients improved with further treatments,
all DNS patients had a poor outcome after re-treatment, with a mean 6.3
(SD, 1.2) abnormal test results.
The evaluation at completion of treatment showed no difference in
outcome between the HBO and NBO groups for patients:
- treated within four hours of exposure;
- with severe poisoning and treated within four hours of exposure;
- who required ventilation; and
- who were accidentally poisoned (as opposed to those who attempted
Only 46% of patients attended the one-month follow-up. Thus, the
numbers in subgroups of interest at one month were small, but showed no
difference in any test between HBO and NBO groups.
Ten patients had chamber-related complications; seven HBO patients
experienced ear barotrauma, one HBO patient developed oxygen
toxicity (convulsions) and two patients (one HBO and one NBO)
developed severe claustrophobia. The incidence of such
complications was thus 9% for HBO and 1% for NBO treatment.
In patients with acute CO poisoning, we found no benefit and possible
adverse effects of HBO therapy compared with three days of high-flow
NBO. Our multiple comparisons between groups may have produced type 1
errors, and some differences may be spurious. However, differences
were consistent and all suggested a more detrimental outcome in the
HBO group. Despite multiple comparisons, we found no evidence to
support HBO therapy. Our findings thus contrast with those of all
other published studies, which have suggested benefit or lack of
benefit, but never detriment, from HBO therapy (Box 1). To explain
this, careful comparison with previous studies is required.
No previous study has compared HBO with NBO in severely poisoned
patients. Unlike the non-randomised studies (Box 1) which used HBO
for all severely poisoned patients and NBO only for mildly poisoned
patients,9,13,16,18-20 all patients
in our study were randomised. Of the randomised studies (Box 1), three
included patients with mild CO poisoning only12,14,17 (two showing
benefit and one no benefit from HBO),17 while the fourth compared
one versus two HBO treatments for severely poisoned
Whereas most CO poisoning in the northern hemisphere occurs as a
result of heating accidents, in Australia most results from suicide
attempts. Not only had a high proportion of our patients (69%)
attempted suicide, but, as in other studies,9,35 many (44%) had ingested
other drugs. Stratified randomisation equalised this factor
between groups and hence could not account for lack of benefit in the
Further, the six potential factors thought to influence baseline
severity (listed in the Methods) were subsequently adjusted for in
the generalised linear modelling process. This adjustment also
accounted for the small imbalances in the data resulting from cluster
Although COHb level is often used as an indicator of the severity of CO
poisoning and to determine need for HBO,12-16,20 our findings and
other reviews9,14,18,24,36-40 have shown
no relationship between COHb level and outcome.
COHb level depends on CO exposure, time elapsed to measurement and
whether or not oxygen has been given. The low COHb levels in our study
(HBO 20.5%; NBO 22%) reflect the delay to the measurement and use of
high flow oxygen before measurement. Most previous studies did not
report time to measurement and used isolated COHb levels to compare
severity of poisoning between groups.12-16,20 Our multivariate
analysis showed no correlation between outcome and COHb level even
when taking the time to measurement into account. The low COHb levels
do not explain the lack of benefit of HBO.
Animal studies5 reporting beneficial
effects of HBO given immediately after CO exposure cannot readily be
extrapolated to clinical practice because treatment delay is to be
expected in all clinical scenarios. Our study had a geometric mean
treatment delay of 7.1 hours (95% CI, 1.9-26.5 hours), which is longer
than in others,14,16,20 but well within
entry criteria limits of most studies that report treatment
delay15,17,39 (Box 1).
Some authors have suggested that the benefits of HBO diminish with
treatment delay,12,41 that more than six
hours' delay increases DNS and mortality,9 and that treatment delay is
associated with increased neuropsychological
Other studies have found treatment delay to be
unimportant,42 while some case
studies43 and small case
series7 report HBO benefit
regardless of treatment delays ranging from days to months. Most
North American hyperbaric facilities surveyed in 1995 treated
CO-poisoned patients who had neurological deficits despite
presentation delays ranging from six hours to 56 days,44 and HBO has
been advocated for DNS occurring weeks after initial
In our study, analysis of patients commencing
treatment within four hours (all patients or severely poisoned only)
showed no differences in outcome between HBO and NBO. We also analysed
time to treatment in quartiles (<3, 3-6, 6-12 and >12 hours) and found no
difference in outcome between HBO and NBO. Further, multivariate
regression analysis did not identify delay in treatment as a
predictor of poor outcome. Thus, there was no evidence that delay to
treatment might explain the lack of benefit from HBO.
There are no universally accepted recommendations for depth of
pressurisation or duration of hyperbaric treatment for CO poisoning
(Box 1). The only studies of the benefit of multiple treatments
reached contradictory conclusions.13,15,38 Raphael et
found no difference in recovery at one month among 286 patients with
transient loss of consciousness who received either one or two HBO
treatments 12 hours apart. Gorman and Runciman reviewed 13 case
series involving 3441 patients and concluded that HBO at 2-3 ATA for
1-2 hours on three or more occasions achieved the lowest mortality,
PNS and DNS.38|
Based on the conclusions of Gorman and Runciman, our study was
designed to provide maximum advantage for HBO, with a daily 60-minute
treatment at 2.8 ATA on three consecutive days. Because the required
dose of NBO for treating CO poisoning is unknown, to ensure we did not
undertreat patients, and to maximise similarity of treatment in HBO
and NBO groups, all our patients received a treatment on at least three
consecutive days and continuous oxygen by non-occlusive facemask at
14 L/min between treatments.
Compared with most previous studies, we performed more treatments,
of longer duration, at higher ATA and in conjunction with prolonged
high flow oxygen therapy between treatments (Box 1). Our HBO group
received oxygen therapy equating to approximately 35.7
COHb-dissociation half-lives, while the NBO group received the
equivalent of 28.5 COHb-dissociation half-lives.
Most other studies have used total oxygen doses of less than 7.0
COHb-dissociation half-lives,9,12,14,15,17 with two
series using up to 18 COHb-dissociation half-lives.13,16
It is possible that some of the reported beneficial effects of HBO are
purely oxygen-dose related, and that adequate NBO, as given in our
study, may achieve the same result. This is supported by an
uncontrolled study in which a single HBO treatment had no benefit over
NBO, but two or more HBO treatments of 60 minutes at 2.8 ATA resulted in
significantly less PNS at hospital discharge and DNS at one month
(P < 0.005).13
The apparent worse outcome in our HBO group may also be oxygen-dose
related, with higher doses of oxygen adding no further benefit and
possibly causing adverse effects. Hampson et al45 (discussing
seizures rather than neuropsychological sequelae) have suggested
that CO-poisoned patients are at greater risk of brain injury because
of the higher ATA used in treatment, concomitant use of other drugs and
toxins (particularly in patients who have attempted suicide), as
well as the underlying CO poisoning.
Assessment of outcome||
Abnormalities of the basal ganglia, subcortical white matter and
hippocampus are the most consistent neuropathological findings in
victims of CO poisoning42,46 and are associated
with deficits of attention, information processing and
memory.47 These deficits can be
easily missed on casual assessment or simple neurological
examination unless specifically targeted. Studies that did not use
neuropsychological assessments9,12,15 reported a lower
incidence of PNS than those that did,48 including our study.
Appropriately targeted neuropsychological assessment provides
the most objective, reliable and sensitive evaluation of outcome
after CO poisoning,24,49,50 and in studies that
did not report these data9,12,15-17 it is possible
that significant adverse effects were missed, making resulting
The Carbon monoxide neuropsychological screening battery
(CONSB)50 does not adequately
measure memory, which may be impaired following CO
poisoning.47 The neuropsychological
tests we used were therefore more comprehensive than the CONSB, very
sensitive to the deficits known to occur in CO poisoning and were
computerised (thus increasing objectivity). Further, as one
clinical psychologist performed all our testing, interviewer bias
Because a full pretreatment neuropsychological assessment was not
practical, a Mini-mental examination was used as our baseline
neuropsychological assessment, as it gives a global assessment of
severity of cerebral injury. Although not ideal, it had the
advantages that (i) it could readily be performed by the assessing
doctor and quantified, (ii) it enabled us to determine which patients
were capable of giving informed consent, and (iii) as it was tested on
presentation, completion of treatment and at follow-up, patients
served as their own "controls".
Our definition of an abnormal test result (>1 SD below the mean)
would have included 16% of normal patients. This definition was
deliberately chosen to be sensitive to small group differences. We
defined a poor outcome as at least two test scores more than one
standard deviation below the mean, which would have included less
than 2.6% of normal patients. While it is possible that the true
incidence of poor outcome or PNS may therefore be slightly lower than
we report, the important analyses in making the group comparisons
were based on the raw data.
Non-randomised studies (Box 1) suggest beneficial effects of HBO,
but only two13,20 used
neuropsychological tests. One used extensive neuropsychometric
evaluation at the one-month review,13 but no evaluation before
or at completion of treatment. The other used the CONSB before
treatment whenever possible,20 but not after treatment.
Of the randomised studies (Box 1), one supplemented clinical
assessments with electroencephalogram and cerebral blood flow
reactivity to acetazolamide,12 but the clinical
relevance of these is uncertain, as the abnormal results were found in
patients who were clinically normal. Another used the CONSB, but only
after completion of treatment and if patients were "fatigued", the
tests were performed in the patients' homes within 12 hours, and a
three-month review was only a telephone interview. The lack of
baseline assessment, the variable circumstances of immediate
outcome assessment and the restricted assessment of delayed outcome
greatly limit the interpretation of the findings.
Insensitive assessments and lack of blinding may also have missed
important differences and created bias in these randomised studies.
Our high rate of PNS (compared with previous studies) is probably
attributable to our high proportion of severe poisonings (73%) and
suicide attempts (69%, likely to be associated with depression and
possibly a poor outcome on neuropsychological testing), as well as
the comprehensive neuropsychological testing we employed. A type 1
error resulting from multiple testing may have contributed, as well
as our cautious definition of PNS (≥2 test scores <1 SD below
the mean). The rate of DNS in our study (2.6%) is lower than in most
previous reports9,13,16,17,51 (especially
given our higher proportion of severe poisonings) and possibly the
result of effective treatment with higher doses of oxygen.
Our findings differ from those of most published series (Box 1).
Although all the non-randomised studies9,11,13,16,18-20 have
reported benefit from HBO, none had a control group of matching
severity, most had no neuropsychological assessment, and all had low
doses of oxygen (brief treatment times) in the NBO groups.
With these significant limitations, it is not possible to rely on
the conclusions of these studies nor to compare them with adequately
conducted randomised trials.
None of the four randomised trials included pretreatment or
follow-up neuropsychological assessments or sham
treatment of the NBO group (our study is unique in doing this). Three
did not have blinded outcome assessments. Both randomised trials
that concluded there was benefit from HBO12,14 studied only patients
with mild CO poisoning, thereby excluding the patients in whom the
effects of HBO might be most important. The other two found no benefit
in HBO and support our findings.15,17 Mathieu et al found a
significantly different incidence of neurological sequelae
between HBO and NBO at three-month review (9.5% v. 15%; P =
0.016), but not at completion of treatment, one month, six months or 12
months.17 Raphael et al randomised
only mildly poisoned patients,15 and both treatment
regimens used (HBO and NBO) have been criticised.38
Interim results (61 patients) of a United States randomised
controlled trial enrolling all patients, irrespective of severity
of poisoning and also using sham normobaric treatments, found no
difference in PNS between NBO and HBO.52 Of the four published
randomised studies, the two small ones12,14 reported a benefit
from HBO, whereas the two larger studies15,17 did not. If our study is
included, three studies involving 1395 patients have now shown no
benefit for HBO, compared with two studies involving 91 patients
which showed a benefit. Thus, it appears that much of the evidence
supporting HBO for CO poisoning is flawed.
Although our multiple tests increased the likelihood of a type 1
error, as the main outcome measures (the number of abnormal tests and a
"poor outcome") were based on combining all tests we have minimised
the chance of a spurious result.
Despite repeated efforts, only 46% of patients attended for
follow-up. This low rate was probably affected by many of our patients
having characteristics associated with suicide attempts and
depression, many being referred from distant locations, and lack of
incentive. However, the follow-up rate was equal in both groups, and
evenly distributed across subgroups.
Our follow-up assessment was more comprehensive than in all but one
other study,13 but failed to show benefit
Others studies have had significant non-attendance rates at delayed
review of 11%-47%.12-15,19,48 Most studies do
not quote the "drop-out" rate.9,16-18,20
Our prospective, randomised controlled trial of CO-poisoned
patients of all severities attempted to address the shortcomings of
previous studies by incorporating sham treatments for the NBO group,
blinded outcome assessment and extensive neuropsychological
assessment. Our HBO protocol was designed to provide the maximum
potential advantage for HBO therapy based on currently available
knowledge. When compared with three days of normobaric oxygen, we
could find no evidence that treatment with HBO was beneficial to
outcome and therefore do not recommend its use.
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(Received 25 Mar, accepted 1 Dec, 1998)
Alfred Hospital, Melbourne, VIC.
Carlos D Scheinkestel, FRACP, DipDHM, Deputy Director,
Department of Intensive Care and Hyperbaric Medicine, and Head,
General Intensive Care Unit;
Paul S Myles, MD, FANZCA, Head of
Research, Department of Anaesthesia and Pain Management;
Cooper, MD, FRACP, Head, Trauma Intensive Care Unit;
Millar, FAFOM, DipDHM, Head, Hyperbaric Medicine;
Tuxen, MD, FRACP, Director, Department of Intensive Care and
Department of Epidemiology and Preventive Medicine, Monash
University, Melbourne, VIC.
Michael Bailey, BSc, MSc(Stat), Statistical Consultant.
School of Psychological Science, La Trobe University, Melbourne,
Kerry Jones, BBSc(Hons), MPsych, Psychologist, and PhD
Reprints: Dr C D Scheinkestel, Department of Intensive Care
and Hyperbaric Medicine, Alfred Hospital, Commercial Road,
Prahran, Melbourne, VIC 3181.
Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>".
|1: Published trials of carbon monoxide poisoning treated with hyperbaric oxygen (HBO) and normobaric oxygen (NBO)|
|Study||Patients included||No. HBO patients||No. NBO patients||Blinded||Neuropsychological tests|
| Roche et al11||All||20||20||No||No|
| Mathieu et al16||All||203||27||No||No|
| Myers et al20||All||131||82||No||Yes|
| Willms et al18||All||72||46||No||No|
| Goulon et al9||All||273||29||No||No|
| Gorman et al13||All||92||8||No||Yes|
| Ely et al19||All||4||26||No||No|
| Raphael et al15||Non-comatose|
| Thom et al14||Mildly poisoned||33||32||No||Yes|
| Ducasse et al12||Non-comatose||13||13||Yes||No|
| Mathieu et al17||Non-comatose||299||276||No||No|
| This study*||All||104||87||Yes||Yes|
|Study||Number of treatments||Maximum ATA||Time at maximum ATA (min)||Entry criteria time to treatment (h)||Actual time to treatment (h)||HBO benefit reported|
| Roche et al11||1-10||2.5||60||?||?||Yes|
| Mathieu et al16||1-5||2.5||90||?||~4||Yes|
| Myers et al20||?||1.8-2.0||46||?||1-1.5||Yes|
| Willms et al18||3||2.5||?||?||?||Yes|
| Goulon et al9||2||2||90||?||?||Yes|
| Gorman et al13||1, 2, >2||2.8||60||?||?||Yes|
| Ely et al19||1||2.5||120||?||?||Yes|
| Raphael et al15||1|
1 v. 2
| Thom et al14||1|
| Ducasse et al12||1||?||?||?||~1||Yes|
| Mathieu et al17||1||2.5||90||12||?||No|
| This study*||≥3||2.8||60||<24||7.1|
(95% CI, 1.9-26.5)
ATA = atmospheres absolute; HBO = hyperbaric oxygen; NBO = normobaric oxygen; ? = not reported; ~ = approximately.
* Our study was the only one listed in which there were sham treatments for NBO patients.
|2: Patient characteristics and description of severity of carbon monoxide poisoning for patients treated with hyperbaric oxygen (HBO) and normobaric oxygen (NBO)|
|HBO (n = 104)||NBO (n = 87)||P|
| Age||37.8 (35.1-40.5)||34.8 (32.0-37.6)||0.13+|
| Male||89 (86%)||67 (77%)||0.13++|
| Suicide attempt||68 (65%)||63 (72%)||0.3++|
| Ventilated||20 (19%)||16 (18%)||0.88++|
| Exposure time (h)||2.6 (2.0-3.2)||2.5 (1.9-3.1)||0.87+|
| Time to carboxyhaemoglobin level (h)*||3.2 (2.6-3.8)||2.6 (2.1-3.1)||0.11+|
| Carboxyhaemoglobin level (%)||20.5 (18.0-23.0)||22.0 (19.6-24.4)||0.39+|
| Time to treatment (h)*||7.5 (6.6-8.6)||6.6 (5.7-7.5)||0.16+|
| Mini-mental score||27.0 (26.1-27.9)||26.4 (25.4-27.4)||0.27+|
| No. with criteria for severe poisoning||72 (69%)||67 (77%)||0.23++|
| Coma||53 (51%)||49 (56%)|
| Acidosis||11 (11%)||13 (15%)|
| Focal neurological deficits||9 (9%)||6 (7%)|
| Electroencephalogram changes||7 (7%)||9 (10%)|
| Hypotension||3 (3%)||2 (2%)|
| Arrhythmias||2 (2%)||7 (8%)|
| Pulmonary oedema||2 (2%)||1 (1%)|
| Convulsions||1 (1%)||3 (3%)|
| Cardiac arrest||1 (1%)||1 (1%)|
| Headache||55 (53%)||38 (44%)|
| Fatigue||47 (45%)||38 (44%)|
| Difficulty in thinking||46 (44%)||37 (43%)|
| Dizziness||38 (37%)||21 (24%)|
| Nausea||38 (37%)||25 (29%)|
| Acute confusional state||20 (19%)||10 (11%)|
| Paraesthesiae||11 (11%)||6 (7%)|
| Visual disturbance||9 (9%)||4 (5%)|
| Palpitations||8 (8%)||3 (3%)|
| Chest pain||7 (7%)||3 (3%)|
| Tinnitus||4 (4%)||2 (2%)|
| Abdominal pain||3 (3%)||0|
| Diarrhoea||2 (2%)||2 (2%)|
Figures are number (%) or mean (95% CI). HBO = hyperbaric oxygen; NOB = normobaric oxygen. *Geometric mean; +t test; ++chi-squared test.
|3: Neuropsychological outcome for all patients treated with hyperbaric oxygen (HBO) and normobaric oxygen (NBO)|
|HBO (n = 104)||NBO (n = 87)||Difference (95% CI) in favour of HBO*||P|
|At end of treatment|
| No. requiring >3 treatments||29 (28%)||13 (15%)||OR 2.8 (1.3-6.2)++||0.01++|
| Deaths||3 (3%)||3 (3.4%)||0.96++|
|Average neuropsychological test results+|
| Simple reaction time (s)||385||375||-10 (-50 to 30)||0.63s|
| Choice reaction time (s)||10.4||11.1||-0.7 (-1.9 to 0.5)||0.25s|
| Digit span forward (no. digits recalled)||8.2||8.1||0.1 (-9 to 1.1)||0.87s|
| Digit span backwards (no. digits recalled)||5.3||5.6||-0.3 (-1.1 to 0.5)||0.55s|
| Rey auditory verbal learning test (score)||42.2||47.7||-5.5 (-9.8 to -1.2)||0.01s|
| Short term free recall (no. objects)||3.2||3||-0.2 (-1.1 to 0.7)||0.54s|
| Long term free recall (no. objects)||4.4||4.2||-0.2 (-1.5 to 1.1)||0.76s|
| Improvement in Mini-mental score||0||0.7||-0.7 (-2.7 to 1.3)||0.53s|
|Average number of abnormal tests ||3.4||2.7||-0.7 (-1.3 to -0.1)||0.02s|
|Poor outcome (PNS)||0.74||0.68||OR 1.7 (0.8-4.0)++||0.19++|
|Relapse (DNS)||5 (4.8%)||0||0.03**|
Figures are number (%) or mean (95% CI). HBO = hyperbaric oxygen; NBO = normobaric oxygen; OR = odds ratio; PNS = persistent neurological sequelae (>2 abnormal test results); DNS = delayed neurological sequelae.
*After adjustment for age, sex, suicide attempt, carboxyhaemoglobin (COHb) level, time to measurement of COHb level, duration of exposure, time to treatment, presence of other drugs; +See Methods section for description of neuropsychological tests; ++chi-squared test; sF-test; **Fisher's exact test.
|4: Characteristics of 139 patients with severe carbon monoxide poisoning, and the neurophysiological outcome for this subgroup|
|HBO (n = 72)||NBO (n = 67)||Difference (95% CI) in favour of HBO*||P*|
| Age||38.6 (35.2-42.0)||36.7 (33.5-39.9)||0.42**|
| Male||60 (83%)||55 (82%)||0.99s|
| Suicide||55 (76%)||54 (81%)||0.69++|
| Ventilated||20 (28%)||16 (24%)||0.74s|
| Exposure time (h)||2.5 (1.9-3.1)||2.2 (1.6-2.8)||0.45**|
| Time to carboxyhaemoglobin level (h)+||2.9 (2.3-3.7)||2.2 (1.9-2.7)||0.07**|
| Carboxyhaemoglobin level (%)+||23.0 (19.8-26.2)||22.9 (22.0-25.8)||0.94**|
| Time to treatment (hours)||7.3 (6.3-8.5)||6.1 (5.4-6.9)||0.08**|
| Mini-mental score||25.6 (24.3-26.9)||25.8 (24.5-27.1)||0.8**|
|At end of treatment|
| No. requiring >3 treatments||25 (35%)||9 (13%)||OR 5.4 (2.0-14.8)||0.001s|
| Deaths||3 (4.2%)||3 (4.5%)||OR 1.0 (0.2-6.0)||0.97s|
|Average neuropsychological test results+|
| Simple reaction time (s)||410||377||-33 (-72 to 6.0)||0.01ss|
| Choice reaction time (s)||9.9||10.7||-0.8 (-2.4 to 0.8)||0.32ss|
| Digit span forward (no. digits recalled)||7.9||8||-0.1 (-1.3 to 1.1)||0.91ss|
| Digit span backwards (no. digits recalled)||5||5.5||-0.5 (-1.6 to 0.6)||0.35ss|
| Rey auditory verbal learning test (score)||42||49.2||-7.2 (-12.2 to -2.2)||0.005ss|
| Short term free recall (no. objects)||4||3.5||-0.5 (-1.7 to 0.7)||0.43ss|
| Long term free recall (no. objects)||4.6||5.2||0.6 (-1.1 to 2.3)||0.47ss|
| Improvement in Mini-mental score||2||1.6||0.4 (-0.2 to 2.8)||0.71ss|
|Average number of abnormal tests||3.7||2.6||-1.1 (-1.9 to -0.3)||0.008ss|
|Poor outcome (PNS)||0.85||0.65||OR 3.6 (1.1-11.9)||0.03s|
Figures are number (%) or mean (95% CI). HBO = hyperbaric oxygen; NBO = normobaric oxygen; OR = odds ratio; PNS = persistent neurological sequelae (>2 abnormal test results); DNS = delayed neurological sequelae.
*After adjustment for age, sex, suicide attempt, carboxyhaemoglobin (COHb) level, time to measurement of COHb level, duration of exposure, time to treatment, presence of other drugs; +Geometric mean (95% CI); ++See Methods section for description of neuropsychological tests; schi-squared test; **t-test; ssF-test.