Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial

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 observations,^9-11 small,¹² non-randomised¹³ and unblinded series^9,11,13-20 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 HBO^12,14 and two report no benefit^15,17 (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 questioned^1,2,21-27 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 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.  

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.  

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 between treatments.  

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 increase objectivity.

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 periods³²).

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 t scores.

A t score more than one standard deviation below the mean was considered abnormal, and two or more abnormal scores constituted a poor outcome.

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 deviation.  

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 poisoning.

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 suicide).

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.

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 HBO group.

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 randomisation.  

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.  

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 sequelae.¹³

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 exposure.^20,44

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.  

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.  

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 data^9,12,15-17 it is possible that significant adverse effects were missed, making resulting conclusions unreliable.

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 was eliminated.

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 two^13,20 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 findings differ from those of most published series (Box 1).

Although all the non-randomised studies^{9,11,13,16,18-20} 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 HBO^12,14 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 ones^12,14 reported a benefit from HBO, whereas the two larger studies^15,17 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.  

Our follow-up assessment was more comprehensive than in all but one other study,¹³ but failed to show benefit for HBO.

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

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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, VIC.
Kerry Jones, BBSc(Hons), MPsych, Psychologist, and PhD student.

Reprints: Dr C D Scheinkestel, Department of Intensive Care and Hyperbaric Medicine, Alfred Hospital, Commercial Road, Prahran, Melbourne, VIC 3181.
Email: cdschATozemail.com.au

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