Randomised control trial
Dgillali Annane, Karim Chadda, Philippe Gajdos, Marie-Claude Jars-Guincestre, Sylvie Chevret, Jean-Claude RaphaelHyperbaric oxygen therapy for acute domestic carbon monoxide poisoning: two randomized controlled trials
Intensive Care Medicine
12/2/10;486-92
- Submitted by:Landen Rentmeester - Emergency Medicine Resident Physician
- Institution:Grand Rapids Medical Education Partners/ Michigan State University College of Human Medicine
- Date submitted:3rd May 2011
1
Objectives and hypotheses
1.1
Are the objectives of the study clearly stated?
The objectives of the study are clear: "Hence, we compared NBO to HBO in patients with transient loss of consciousness, and, in comatose patients, NBO with one or two HBO sessions." "The primary end point was complete recovery as defined above. Secondary end points were 1 month rates of PNS, DNS, and proportion of patients who resumed their former occupational activity. Tertiary endpoints included difference in carboxyhemoglobin levels before/after treatment completion and adverse events."
2
Design
2.1
Is the study design suitable for the objectives
The study design is suitable for the objectives. Patients were randomized to HBO therapy vs. NBO therapy in one group and were randomized to HBO of one particular length plus NBO vs. HBO of a different length plus NBO.
2.2
Who / what was studied?
Patients poisoned by CO
2.3
Was this the right sample to answer the objectives?
This appears to be the right sample to study this question. Clear inclusion and exclusion criteria were explained, and terms defined.
2.4
Is the study large enough to achieve its objectives? Have sample size estimates been performed?
Sample sizes for trial A and B were calculated separately. In trial A, assuming an 1 month recovery rate of 40% in the reference group (A0), 245 patients were needed per treatment arm to detect an absolute difference of at least 15% in recovery rates with a type I error of 0.05 and a type II error of 0.10 using a two-sided test. In trial B, the number of patients per treatment arm required to detect a 15% difference between the two treatments was 240 assuming 35% recovery rates in the reference group (B1), a type I error of 0.05, and a type II error of 0.10 using a two-sided test. Thus, the total number of patients required was 970 patients, 490 in trial A and 480 in trial B.
The trial was terminated prematurely after the interim analysis (January 2000), based on a total of 385 patients, showing that, in comatose patients (trial B), the 1 month complete recovery rate was lower in the ‘‘two HBO sessions’’ arm compared to the ‘‘one HBO session’’ arm (47 vs. 68%, p = 0.007). Furthermore, in trial A patients, recovery rates were close (61% in control arm vs. 58% in experimental arm), suggesting futility of treatment continuation. Accordingly, the authors decided to terminate trial A also.
The trial was terminated prematurely after the interim analysis (January 2000), based on a total of 385 patients, showing that, in comatose patients (trial B), the 1 month complete recovery rate was lower in the ‘‘two HBO sessions’’ arm compared to the ‘‘one HBO session’’ arm (47 vs. 68%, p = 0.007). Furthermore, in trial A patients, recovery rates were close (61% in control arm vs. 58% in experimental arm), suggesting futility of treatment continuation. Accordingly, the authors decided to terminate trial A also.
2.5
Were all subjects accounted for?
Of the 179 patients included in trial A, 6 had coma before admission; these misclassified patients were kept in trial A for analysis. Eighty-six patients were then allocated to NBO alone (A0 arm) and 93 to NBO plus one HBO session (A1 arm). Of 179 patients, 174 had normal con- sciousness at randomization, and 5 had confusion. At 1 month, 26 patients (14.5%) were lost to follow-up. Complete recovery rates were roughly the same in both arms [61% compared with 58%; p = 0.87; OR = 0.90 (CI, 0.47–1.71)] (Table 2).
Unexpectedly, of the 170 patients evaluated at 1 month, in the experimental arm (2 HBO sessions), the full recovery rate was significantly lower than in the control arm (47 vs. 68%; p = 0.007). This difference remained statistically significant in favor of the control arm, whe- ther lost to follow-up patients were treated as failures or as successes, and after adjustment of prognostic factors (Table 3). Of note, when examining all possible alloca- tions of cases with missing outcome, differences werenever in favor of HBO therapy (Table 3). Finally, there were more patients with PNS at 1 month in the ‘‘two HBO sessions’’ group (Table 3).
Unexpectedly, of the 170 patients evaluated at 1 month, in the experimental arm (2 HBO sessions), the full recovery rate was significantly lower than in the control arm (47 vs. 68%; p = 0.007). This difference remained statistically significant in favor of the control arm, whe- ther lost to follow-up patients were treated as failures or as successes, and after adjustment of prognostic factors (Table 3). Of note, when examining all possible alloca- tions of cases with missing outcome, differences werenever in favor of HBO therapy (Table 3). Finally, there were more patients with PNS at 1 month in the ‘‘two HBO sessions’’ group (Table 3).
2.6
Were all appropriate outcomes considered?
Patients were followed-up to 1 month after randomization. At 1 month, patients completed a self-assessment questionnaire with yes/no items about headaches, tiredness, memory impairment, difficulty in concentrating, difficulty in sleeping, visual disorders, and new difficulties with social or professional activities. They underwent a thorough physical examination at the ICU outpatient clinic by one intensive care physician qualified in neurology who remained blinded to patients’ treatment arm. In patients who could not come back to the hyperbaric center, the 1-month visit was performed by patient’s general practitioner.
The authors aimed at identifying symptom-free patients. They found a higher rate of minor symptoms than did earlier studies [14, 15], supporting the sensitivity of physical examination by an intensive care physician qualified in neurology.
The authors aimed at identifying symptom-free patients. They found a higher rate of minor symptoms than did earlier studies [14, 15], supporting the sensitivity of physical examination by an intensive care physician qualified in neurology.
2.7
Has ethical approval been obtained if appropriate?
The study was approved by the ethics committee of the Socie ́te ́ de Re ́animation de Langue Franc ̧aise. Patients were recruited between October 1989 and January 2000 at Raymond Poincare ́ Teaching Hospital, Garches, France. Written informed consent was obtained from patients or their relatives.
2.8
Were the patients randomised between treatments?
Yes
2.9
How was randomisation carried out?
Eligible patients were classified by attending physicians into those who experienced transient loss of conscious- ness (malaise, syncope; trial A) or coma as confirmed by a household member or a rescuer (trial B). Patients were randomized (1:1) by using numbered sealed envelopes. An independent statistician prepared a computer-gener- ated allocation sequence for each trial (A and B).
2.10
Are the outcomes clinically relevant?
Yes, the study points out how previous studies utilized neuro-psychologic testing which would include subclinical neuro-odeficits, where as the focus of their study was to determine clinically relevant deficits at one month follow up.
3
Measurement and observation
3.1
Is it clear what was measured, how it was measured and what the outcomes were?
At 1 month, patients completed a self-assessment questionnaire with yes/no items about headaches, tiredness, memory impairment, difficulty in concentrating, difficulty in sleeping, visual disorders, and new difficulties with social or professional activities. They underwent a thorough physical examination at the ICU outpatient clinic by one intensive care physician qualified in neurology who remained blinded to patients’ treatment arm. In patients who could not come back to the hyperbaric center, the 1-month visit was performed by patient’s general practitioner.
3.2
Are the measurements valid?
Yes
3.3
Are the measurements reliable?
The crude 1-month recovery rate in patients who had experienced only transient loss of consciousness was very similar to previous reports [4]. Severe neurological deficits and death were infrequent regardless of HBO therapy. These findings confirmed the reliability of the definitions discriminating between patients with and without coma.
3.4
Are the measurements reproducible?
Regardless of the method used to treat missing values, sensitivity analyses never favored HBO treatment. These findings are in line with the higher rate of neurological deficits with HBO reported in another trial of 191 patients, most of whom were suicide attempts
3.5
Were the patients and the investigators blinded?
An independent statistician prepared a computer-generated allocation sequence for each trial (A and B).
At one month follow up they underwent a thorough physical examination at the ICU outpatient clinic by one intensive care physician qualified in neurology who remained blinded to patients’ treatment arm.
At one month follow up they underwent a thorough physical examination at the ICU outpatient clinic by one intensive care physician qualified in neurology who remained blinded to patients’ treatment arm.
4
Presentation of results
4.1
Are the basic data adequately described?
Of the 179 patients included in trial A, 6 had coma before admission; these misclassified patients were kept in trial A for analysis. Eighty-six patients were then allocated to NBO alone (A0 arm) and 93 to NBO plus one HBO session (A1 arm). Of 179 patients, 174 had normal con- sciousness at randomization, and 5 had confusion. At 1 month, 26 patients (14.5%) were lost to follow-up. Complete recovery rates were roughly the same in both arms [61% compared with 58%; p = 0.87; OR = 0.90 (CI, 0.47–1.71)] (Table 2).
Unexpectedly, of the 170 patients evaluated at 1 month, in the experimental arm (2 HBO sessions), the full recovery rate was significantly lower than in the control arm (47 vs. 68%; p = 0.007). This difference remained statistically significant in favor of the control arm, whe- ther lost to follow-up patients were treated as failures or as successes, and after adjustment of prognostic factors (Table 3).
Unexpectedly, of the 170 patients evaluated at 1 month, in the experimental arm (2 HBO sessions), the full recovery rate was significantly lower than in the control arm (47 vs. 68%; p = 0.007). This difference remained statistically significant in favor of the control arm, whe- ther lost to follow-up patients were treated as failures or as successes, and after adjustment of prognostic factors (Table 3).
4.2
Were groups comparable at baseline?
In each trial, treatment arms were well matched (Table 1).
4.3
Are the results presented clearly, objectively and in sufficient detail to enable readers to make their own judgement?
Yes
4.4
Are the results internally consistent, i.e. do the numbers add up properly?
Yes
4.5
Were side effects reported?
In trial A, NBO was stopped prematurely in one patient in the experimental arm because of a panic attack. HBO was stopped prematurely in seven patients in trial B, four in the control arm, and three in the experimental arm because of claustrophobia (n = 4), otalgia (n = 2), and seizures (n = 1). Barotrauma was confirmed for six patients in trial B, four in the control arm, and two in the experimental arm.
5
Analysis
5.1
Are the data suitable for analysis?
yes
5.2
Are the methods appropriate to the data?
yes
5.3
Are any statistics correctly performed and interpreted?
Statistical analysis was performed on an intention-to-treat basis. The same statistical analysis procedure was carried out separately in trials A and B. First, non-parametric Wilcoxon rank sum tests and Fisher’s exact tests were used to compare treatment arms at baseline. Then, complete recovery rates in the two treatment arms were compared by Fisher’s exact test. Odds ratio (OR) with 95 percent confidence interval (95% CI) was computed from logistic models to estimate the strength of the association between the randomly allocated treatment and the com- plete recovery rate. Finally, secondary end points were compared using Fisher’s exact tests (severe neurological impairment, return to work after 1 month, and treatment-related adverse events) and non-parametric Wilcoxon rank sum test (change in carboxyhemoglobin from baseline to treatment completion). Absolute and relative changes in carboxyhemoglobin levels were evaluated.
6
Discussion
6.1
Are the results discussed in relation to existing knowledge on the subject and study objectives?
Yes, the results are discussed in context with other trials that had similar results as well as opposite results
6.2
Is the discussion biased?
It does not appear biased, however it does appear there are more patients that ended up in the B1 arm of the trial compared to the B0 arm who required mechanical ventilation
7
Interpretation
7.1
Are the authors' conclusions justified by the data?
From there data, definitions, and findings on follow up it appears that conclusions drawn are justified
7.2
What level of evidence has this paper presented? (using CEBM levels)
2a
7.3
Does this paper help me answer my problem?
The paper adds information to answering the question in general, but it does not definitively answer the question.
8
Implementation
8.1
Can any necessary change be implemented in practice?
Due to the conflicting nature of studies in this topic, change in practice may not occur until overwhelming evidence arises supporting one treatment or the other.
8.2
What aids to implementation exist?
Adequate study design, observation for clinically apparent outcome over subclinical deficits
8.3
What barriers to implementation exist?
Conflicting results of studies, each providing sound evidence to their results