Scheinkestel 1999.

Methods	Prospective double‐blind RCT of HBO vs. NBO. Cluster randomisation for patients presenting simultaneously. Allocation through sealed opaque envelopes, not sequentially numbered. Patients and outcome assessor blind to allocation, technicians and nurses not. Stratified by vent/non‐vent and suicide vs. accidental exposure.
Participants	230 patients sequentially referred to single centre in Australia. Inclusion: all referred. Excluded (n=39): children, burn victims, pregnant, refusal of consent. Two groups similar for all important variables. 89% male, coma in 50.6%, average COHb 21%. Large number of suicide attempts (69%), co‐intoxication (44%), and severe poisonings (73%).
Interventions	All patients given high‐flow O2 prior to randomisation. Randomized to daily treatment (for 3 days) with HBO (100 minutes; 60 minutes at 2.8 ATA) vs. NBO (100 minutes of 100% O2 at 1 ATA) as a sham dive. All patients received 100% oxygen via mask continuously between sessions (i.e. 100% oxygen for more than 2 days). After third treatment, patients with deficits were treated again, with high‐flow oxygen in between. 3 additional courses of original therapy given to 28% HBO and 15% NBO because of "poor outcome".
Outcomes	191 randomised (104 HBO and NBO 87, discrepancy due to cluster.) No mortality difference at discharge. Poor follow‐up attendance (46%) at one month. Objective outcome data at 1 month post‐treatment were not presented but it was stated that they "showed no difference in any test". Communication with the authors clarified that 34/52 were symptomatic in HBO arm vs. 20/34 symptomatic in NBO arm at 4 weeks (p=NS) and this is the outcome we include in this meta‐analysis.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Quote: "Patients were randomly allocated to HBO or NBO treatment" Quote: "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."
Allocation concealment?	Unclear risk	Quote: "We used cluster randomisation for patients who presented simultaneously from the same CO exposure, allocating them all to the same treatment group". Comment: It is unclear whether the randomisation of the cluster took place after the first person was enrolled (which would have likely meant there was no allocation concealment for all others in the cluster) or whether the entire cluster was screened for eligibility and consented prior to randomisation of the entire cluster which would have preserved allocation concealment.
Blinding? All outcomes	Low risk	Quote: "The hyperbaric technicians and nursing staff had knowledge of the treatment group but patients and outcome assessor did not." Comment: 8 patients had complications apparently related to HBO. It is likely this would have effectively unblinded the analysis. The authors do not discuss whether the patient or physician was also unblinded in these cases, or whether the patients completed the assigned therapy. No attempt was described to assess whether the sham therapy was successful in maintaining blinding.
Incomplete outcome data addressed? All outcomes	Unclear risk	Quote: "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". "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." "Poor outcome (PNS) HBO: 0.74 (of 104) NBO: 0.68 (of 87), OR: 1.7 (0.8‐4.0) P=0.19". Comment: No sensitivity analysis performed. Exact numbers for which assumptions are made are unclear from the final report.
Free of selective reporting?	High risk	Quote: "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)" Quote: "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." Comments: Several of these and other conclusions in text were based upon analysis of individual neuropsychological test results in one sub‐group. However, there was no adjustment for multiple comparisons leading to a high likelihood of a Type I error. There was no pre‐specified primary outcome in the paper. The focus of most of the analysis on early outcomes (immediately post‐treatment) contrasted with their stated aim to "to assess both persistent and delayed neurological sequelae (PNS and DNS)" and is likely to have been driven by necessity given the low follow up (and therefore post hoc).
Free of other bias?	Unclear risk	Intention to treat/Power/Premature stopping‐ Quote: "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)" Quote: "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 (i.e., 408 seconds v. 450 seconds; SD, 63 seconds)" Interim analysis abstract (introduction) Quote: "Ethics Committee required an interim analysis of this prospective single blind study (with outcome assessor also blind to group identity) after 100 patients, to ensure early detection of any adverse outcomes." (145 patients recruited at this analysis, No P value presented) Interim analysis abstract (results) Quote: "For the same exposure, time to treatment, time to CO level, CO level, initial mini‐mental, signs and symptoms, the NBO group required less treatments and had a better outcome" "Sub‐analysis of severe CO poisoning (56 HBO, 50 NBO) showed HBO group had more severe exposure and worse outcome" Interim analysis abstract (conclusions) Quote:"Interim analysis by major categories and sub‐categories showed no difference in outcome for NBO and HBO treated groups." Comment: The power calculation appears to be retrospective so it is unclear whether the trial was completed as planned or stopped prematurely, based on these results of the interim analysis.