Volume 170 Issue 5

Research 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 Abstract - Introduction - Methods - Results - Discussion - Conclusion - References - Authors' details - - More articles on Anaesthesia and intensive care Abstract 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 with NBO. 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 between treatments. Main outcome measures: Neuropsychological performance at completion of treatment, and at one month where possible. 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 poisoning. Introduction 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.2Treatment 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 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). Methods 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. Interventions 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 between treatments. Outcome measures 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 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. Statistical analyses 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 using SAS.34 Results 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, Cambridge, UK). 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. Discussion 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. Baseline severity 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 patients.15Whereas 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. Carboxyhaemoglobin level 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. Treatment delay 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 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. Oxygen dose 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 al15 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.38Based 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 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 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. Study outcomes 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. Delayed review 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 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 Conclusion 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. References Meredith T, Vale A. Carbon monoxide poisoning. BMJ 1988; 2 96(6615): 77-79. Tibbles PM, Perrotta PL. Treatment of carbon monoxide poisoning: a critical review of human outcome studies comparing normobaric oxygen with hyperbaric oxygen. 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Anaesth Intens Care 1991; 19: 506-511. Norkool DM, Kirkpatrick JN. Treatment of acute carbon monoxide poisoning with hyperbaric oxygen: a review of 115 cases. Ann Emerg Med 1985; 14: 1168-1171. Choi IS. Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neurol 1983; 40: 433-435. Origani G, Michael M, Tuscano R, Arghetti S. Outcome of patients suffering from CO poisoning. Undersea Hyperb Med 1996. 23 Suppl: 83. Pracyk JB, Stolp BW, Fife CE, et al. Brain computerized tomography after hyperbaric oxygen therapy for carbon monoxide poisoning. Undersea Hyperb Med 1996; 22: 1-7. Samuels AH, Vamos MJ, Taikato MR. Carbon monoxide, amnesia and hyperbaric oxygen therapy. Aust N Z J Psychiatry 1992; 26: 316-319. Hampson NB, Dunford RG, Kramer CC, Norkool DM. Selection criteria utilized for hyperbaric oxygen treatment of carbon monoxide poisoning. J Emerg Med 1995. 13: 227-231. Hampson NB, Simonson SG, Kramer CC, Piantadosi CA. Central nervous system oxygen toxicity during hyperbaric treatment of patients with carbon monoxide poisoning. Undersea Hyperb Med 1996; 23: 215-219. Miura T, Mitoma M, Kawai R, Harada K. CT of the brain in acute carbon monoxide intoxication: characteristic features and prognosis. Am J Neuroradiol 1985; 6: 739-742. La Plane D, Baulac M, Widlocher D, Dubois B. Pure psychic akinesia with bilateral lesions of basal ganglia. J Neurol Neurosurg Psychiatry 1984; 47: 377-385. Hopkins RO, Weaver LK. Long-term outcome in subjects with carbon monoxide poisoning. Undersea Hyperb Med 1994; 21 Suppl: 17. Starkstein SE, Berthier ML, Leigurada R. Psychic akinesia following bilateral pallidal lesions. Int J Psychiatry Med 1989; 19: 155-164. Messier LD, Myers RAM. A neuropsychological screening battery for emergency assessment of carbon monoxide-poisoned patients. J Clin Psychol 1991; 47: 675-684. Hopkins RO, Weaver LK. Does late repetitive hyperbaric oxygen improve delayed neurologic sequelae associated with carbon monoxide poisoning? Undersea Biomed Res 1991; 18 Suppl: 34. Weaver LK, Hopkins RO, Larson-Lohr V, et al. Double-blind, controlled, prospective, randomized clinical trial (rct) in patients with acute carbon monoxide (CO) poisoning: outcome of patients treated with normobaric oxygen or hyperbaric oxygen -- an interim report. Undersea Hyperb Med 1995; 22 Suppl: 14. (Received 25 Mar, accepted 1 Dec, 1998) Authors' details 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; D James Cooper, MD, FRACP, Head, Trauma Intensive Care Unit; Ian L Millar, FAFOM, DipDHM, Head, Hyperbaric Medicine; David V Tuxen, MD, FRACP, Director, Department of Intensive Care and Hyperbaric Medicine. 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 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>". <URL: http://www.mja.com.au/> 1: Published trials of carbon monoxide poisoning treated with hyperbaric oxygen (HBO) and normobaric oxygen (NBO)StudyPatients includedNo. HBO patientsNo. NBO patientsBlindedNeuropsychological testsNon-randomised Roche et al11All2020NoNo Mathieu et al16All20327NoNo Myers et al20All13182NoYes Willms et al18All7246NoNo Goulon et al9All27329NoNo Gorman et al13All928NoYes Ely et al19All426NoNoRandomised Raphael et al15Non-comatose Severely poisoned173 145170 141No NoNo No Thom et al14Mildly poisoned3332NoYes Ducasse et al12Non-comatose1313YesNo Mathieu et al17Non-comatose299276NoNo This study*All10487YesYesStudyNumber of treatmentsMaximum ATATime at maximum ATA (min)Entry criteria time to treatment (h)Actual time to treatment (h)HBO benefit reportedNon-randomised Roche et al111-102.560??Yes Mathieu et al161-52.590?~4Yes Myers et al20?1.8-2.046?1-1.5Yes Willms et al1832.5???Yes Goulon et al92290??Yes Gorman et al131, 2, >22.860??Yes Ely et al1912.5120??YesRandomised Raphael et al151 1 v. 22 2120 12012 12? ?No No Thom et al141 2.8 230 90 <6 ~1 Ducasse et al121???~1Yes Mathieu et al1712.59012?No This study*≥32.860<247.1 (95% CI, 1.9-26.5)NoATA = 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)PDemographic characteristics Age37.8 (35.1-40.5)34.8 (32.0-37.6)0.13+ Male89 (86%)67 (77%)0.13++ Suicide attempt68 (65%)63 (72%)0.3++Baseline severity Ventilated20 (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 score27.0 (26.1-27.9)26.4 (25.4-27.4)0.27+ No. with criteria for severe poisoning72 (69%)67 (77%)0.23++Signs Coma53 (51%)49 (56%) Acidosis11 (11%)13 (15%) Focal neurological deficits9 (9%)6 (7%) Electroencephalogram changes7 (7%)9 (10%) Hypotension3 (3%)2 (2%) Arrhythmias2 (2%)7 (8%) Pulmonary oedema2 (2%)1 (1%) Convulsions1 (1%)3 (3%) Cardiac arrest1 (1%)1 (1%)Symptoms Headache55 (53%)38 (44%) Fatigue47 (45%)38 (44%) Difficulty in thinking46 (44%)37 (43%) Dizziness38 (37%)21 (24%) Nausea38 (37%)25 (29%) Acute confusional state20 (19%)10 (11%) Paraesthesiae11 (11%)6 (7%) Visual disturbance9 (9%)4 (5%) Palpitations8 (8%)3 (3%) Chest pain7 (7%)3 (3%) Tinnitus4 (4%)2 (2%) Abdominal pain3 (3%)0 Diarrhoea2 (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*PAt end of treatment No. requiring >3 treatments29 (28%)13 (15%)OR 2.8 (1.3-6.2)++0.01++ Deaths3 (3%)3 (3.4%)0.96++Average neuropsychological test results+ Simple reaction time (s)385375-10 (-50 to 30)0.63s Choice reaction time (s)10.411.1-0.7 (-1.9 to 0.5)0.25s Digit span forward (no. digits recalled)8.28.10.1 (-9 to 1.1)0.87s Digit span backwards (no. digits recalled)5.35.6-0.3 (-1.1 to 0.5)0.55s Rey auditory verbal learning test (score)42.247.7-5.5 (-9.8 to -1.2)0.01s Short term free recall (no. objects)3.23-0.2 (-1.1 to 0.7)0.54s Long term free recall (no. objects)4.44.2-0.2 (-1.5 to 1.1)0.76s Improvement in Mini-mental score00.7-0.7 (-2.7 to 1.3)0.53sAverage number of abnormal tests 3.42.7-0.7 (-1.3 to -0.1)0.02sPoor outcome (PNS)0.740.68OR 1.7 (0.8-4.0)++0.19++Relapse (DNS)5 (4.8%)00.03**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 subgroupHBO (n = 72)NBO (n = 67)Difference (95% CI) in favour of HBO*P*Demographic characteristics Age38.6 (35.2-42.0)36.7 (33.5-39.9)0.42** Male60 (83%)55 (82%)0.99s Suicide55 (76%)54 (81%)0.69++Baseline severity Ventilated20 (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 score25.6 (24.3-26.9)25.8 (24.5-27.1)0.8**At end of treatment No. requiring >3 treatments25 (35%)9 (13%)OR 5.4 (2.0-14.8)0.001s Deaths3 (4.2%)3 (4.5%)OR 1.0 (0.2-6.0)0.97sAverage neuropsychological test results+ Simple reaction time (s)410377-33 (-72 to 6.0)0.01ss Choice reaction time (s)9.910.7-0.8 (-2.4 to 0.8)0.32ss Digit span forward (no. digits recalled)7.98-0.1 (-1.3 to 1.1)0.91ss Digit span backwards (no. digits recalled)55.5-0.5 (-1.6 to 0.6)0.35ss Rey auditory verbal learning test (score)4249.2-7.2 (-12.2 to -2.2)0.005ss Short term free recall (no. objects)43.5-0.5 (-1.7 to 0.7)0.43ss Long term free recall (no. objects)4.65.20.6 (-1.1 to 2.3)0.47ss Improvement in Mini-mental score21.60.4 (-0.2 to 2.8)0.71ssAverage number of abnormal tests3.72.6-1.1 (-1.9 to -0.3)0.008ssPoor outcome (PNS)0.850.65OR 3.6 (1.1-11.9)0.03sFigures 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.

Carlos D Scheinkestel · Michael Bailey · Paul S Myles · Kerry Jones · Ian L Millar · David V Tuxen

ADRAC An adverse reaction to the herbal medication milk thistle (Silybum marianum) MJA 1999; 170: 218-219 Introduction - Case - Comment - References - - More articles on Complementary medicine Introduction There is widespread use of herbal and other complementary medicines in Australia.1 Many people believe that these products are "natural" and therefore free from side effects, but this is not necessarily the case. Various adverse reactions can occur.2 A recent publication has suggested that adverse drug reactions to herbal remedies are even more under-reported than those to conventional over-the-counter (OTC) medicines.3 The Adverse Drug Reactions Advisory Committee (ADRAC) receives and analyses reports of adverse drug reactions to complementary medicines as well as to prescribed and OTC medications, and has published reports on adverse reactions to royal jelly, chaparral and Kombucha tea.4-7 Case A report of a severe reaction in association with milk thistle has recently been received. A 57-year-old woman presented with a two-month history of intermittent episodes of sweating, nausea, colicky abdominal pain, fluid diarrhoea, vomiting, weakness and collapse. The episodes could last up to 24 hours, but she felt completely well between attacks. The episodes were not related to food or to any obvious activity. She had been taking ethinyloestradiol and amitriptyline. The patient had no abnormalities on examination, with a regular pulse rate of 80 beats/minute and only a 6 mmHg postural drop in blood pressure. Neurological examination was normal. Differential diagnoses considered were phaeochromocytoma, carcinoid syndrome and thyrotoxicosis. She was admitted to hospital for investigation one day after an attack. Investigations revealed an initial minor elevation of urea and haemoglobin level, and raised white cell count, which were believed to be due to dehydration and reverted to normal without therapy. All other tests, including thyroid function, blood glucose level, urinary free catechol level and 5-hydroxyindolacetic acid levels, were normal and her erythrocyte sedimentation rate was 15 mm/hour. She was then questioned further about any changes to her routine in the previous two months. She admitted that she had started taking Microgenics Herbals Milk Thistle Vegicaps (Aust L 56929; Optimum Healthcare Pty Ltd) for headaches and liver cleansing exactly two months previously. On the day before admission to hospital she had taken a capsule a few hours before the onset of symptoms. On reflection, she thought that all the attacks had occurred after taking the capsules. She ceased taking milk thistle and had no further symptoms. A few weeks later she took another capsule and experienced a violent reaction similar to the one causing hospital admission. Comment Milk Thistle Vegicaps contain Silybum marianum (commonly known as milk thistle), a plant which is native to southern Europe, southern Russia, Asia Minor and North Africa. It now grows naturally in Australia, but the drug is largely obtained from cultivated plants. The active constituents of Silybum marianum fruit include a group of flavonolignans known collectively as silymarin.8 Silymarin consists of four isomers, with silybin accounting for 50% of the total. These substances have been studied both in vitro and in vivo and found to have antioxidant properties and to protect against light-induced skin cancer.9,10 They are also hepatoprotective in rodents. In humans, silymarin has been used to protect against poisoning with the toxic mushroom Amanita phalloides, and as both prophylaxis and treatment for liver disease.11 Silymarin has been studied in a number of prospective clinical trials.12,13 Its efficacy in liver disease is still debated, but a recent overview indicated that no serious side effects have been reported.14The present case report describes a severe and time-associated reaction to milk thistle capsules confirmed on rechallenge. It is, however, quite possible that the problem was caused not by silybin, but by some other substance contained in the capsules. Drew and Myers point out a number of ways in which medications can cause problems because of extrinsic effects unrelated to the intended active ingredient.2 These idiosyncratic reactions are just as likely to occur with complementary medicines as with more conventional medications. ADRAC has received only two previous reports in association with milk thistle. In one, an 83-year-old man was found to be thrombocytopenic. The relation with taking milk thistle was uncertain. In the other report, a woman developed abdominal pains, nausea, listlessness and insomnia after taking milk thistle. The important message for health professionals is to take a full drug history from patients, particularly when unusual symptoms occur. It is necessary to ask directly about herbal and alternative substances as well as prescribed and OTC medications. If there is any suspicion that an adverse drug reaction has occurred it should be reported to ADRAC on a "blue card", where it will be reviewed by the Committee, collated and compared with other reactions related to complementary medicines. References McLennan AH, Wilson DH, Taylor AW. Prevalence and cost of alternative medicine in Australia. Lancet 1996; 347: 569-572. Drew AK, Myers SP. Safety issues in herbal medicine: implications for the health professions. Med J Aust 1997; 166: 538-541. Barnes J, Mills SY, Abbot NC, et al. Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol 1998; 45: 496-500. Bullock RJ, Rohan A, Straatmans J-A. Fatal royal jelly-induced asthma [letter]. Med J Aust 1994; 160: 44. Smith BC, Desmond PV. Acute hepatitis induced by ingestion of the herbal medication chaparral [case report]. Aust N Z J Med 1993; 23: 526. ADRAC. Harmless herbals? Aust Adv Drug React Bull 1993; 12: 11. ADRAC. Kombucha tea. Aust Adv Drug React Bull 1997; 16: 6. Bisset NG, Wichtl M. Herbal drugs and phytopharmaceuticals. A handbook for practice on a scientific basis. Boca Raton, Fla: CRC Press, 1994; 121-125. Basaga H, Poli G, Tekkaya C, Aras I. Free radical scavenging and antioxidative properties of silibin complexes on microsomal lipid peroxidation. Cell Biochem Funct 1997; 15: 27-33. Katiyar SK, Norman NJ, Muktar H, Agarwal R. Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst 1997; 89: 556-566. Hruby K, Csomos G, Furhmann M, Thaler H. Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 1983; 2: 183-195. Ferenci P, Frank H, Benda L, et al. Treatment with silymarin decreases mortality in patients with cirrhosis of the liver. Hepatology 1984; 4: 1093. Pares A, Planas R, Torres M, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomised and multicentre trial. J Hepatol 1998; 28: 615-621. Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1998; 93: 139-143. Adverse Drug Reactions Advisory Committee PO Box 100, Woden, ACT 2606 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>". <URL: http://www.mja.com.au/>

Viewpoint The force of numbers: why hepatitis C is spreading among Australian injecting drug users while HIV is not The hepatitis C virus requires expanded strategies to control its spread Nick Crofts, Campbell K Aitken, John M Kaldor Reader response added, 6 July 1999, with reply from the authors. MJA 1999; 170: 220-221 Introduction - References - Authors' details - - More articles on Drugs and alcohol Introduction The hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) are both bloodborne viruses, are both spread through needle-sharing and other practices of injecting drug users (IDUs), and both represent serious health risks for Australian IDUs. Despite these similarities, in Australia the epidemiology of these viruses differs greatly. The prevalence of HCV among IDUs is about 65%, whereas that of HIV is less than 3%; this difference is mirrored by their respective incidences, about 15% per year for HCV and less than 1% per year for HIV.1,2 While new HIV diagnoses in heterosexual IDUs are rare, estimates of new HCV infections in the same group range from 6000 to 10 000 per year.1Should we conclude from these differences that our current approaches to prevention of bloodborne viruses among IDUs (which are based on the harm-reduction philosophy and include needle and syringe distribution, methadone maintenance therapy, peer education and advocacy) are ineffective? This is unlikely for two reasons. Firstly, HIV has a very low incidence in Australian IDUs, but continues to spread rapidly among IDUs in many parts of the United States and in other populations lacking equally comprehensive prevention strategies. Secondly, there have been dramatic declines in transmission of other viruses (hepatitis B and D) among Australian IDUs since the mid 1980s.1 The effectiveness of just one element of our harm reduction programs -- needle and syringe exchange -- has been well demonstrated,3 and is supported by an American study which found that IDUs in needle exchange programs were seven times less likely to be exposed to HCV than those who were not.4 Can the difference be explained by HCV spreading in a different manner to HIV? Sexual transmission of HCV is rare5 and is unimportant epidemiologically, while the reverse applies for HIV. Both viruses are transmitted between IDUs by blood contact. The determinants of the epidemics are background virus prevalence, virus infectiousness and the existence of behaviour that permits spread. Sharing needles and syringes is generally acknowledged as the most important means of spread between IDUs, and has consistently been found to be the major association with HCV transmission among IDUs worldwide. Since the early 1980s, in response to the threat of HIV infection, there have been substantial declines in needle-sharing among Australian IDUs. About 13% of IDUs in Melbourne reported having shared a needle and syringe in the preceding month in 1994, compared with 38% in 1989.6 Nevertheless, it remains a problem, and higher proportions of IDUs who share needles and syringes are found among substantial minority groups, such as Vietnamese migrants and prisoners.6,7 There is emerging evidence of the importance of blood contact between IDUs in ways other than sharing needles and syringes. Videotapes of groups of IDUs reveal many opportunities for exposure to viruses through blood contaminating equipment other than needles and syringes. This includes swabs, spoons, water vials and tourniquets, as well as fingers, other body parts and surfaces in the immediate environment.1 For example, a user applying a tourniquet to a partner's arm might deposit a tiny smear of blood on skin which is subsequently punctured by a needle, or wipe blood from an injection site and let the swab fall onto a communal tabletop. The risk associated with such behaviour is greater for HCV than for HIV, because the higher infectiousness of HCV8 means smaller amounts of blood can efficiently transmit the infection. Two studies have attempted to quantify IDUs' risk of HCV transmission in the absence of needle-sharing: one found an incidence of about 4% per year among those who reported never sharing needles and syringes, compared with about 17% per year among those who did;9 the second, 11.9% compared with 30.2%.10 Both studies potentially suffered from misclassification bias, with some of those reporting never sharing actually having shared. Such bias would exacerbate the difference between the two incidences, further supporting the conclusion that the majority of HCV infections among Australian IDUs are associated with needle-sharing. Risky behaviour permits the blood contact necessary for both HCV and HIV transmission, and the higher infectiousness of HCV undoubtedly explains some of the difference in incidence. Background viral prevalence is the other critical factor. HCV prevalence is now so high that even very occasional sharing of needles and syringes carries an extreme risk of HCV infection, to which must be added the unknown but non-negligible risk due to "environmental" contamination. With a low-prevalence virus such as HIV, high-risk behaviour must be far more frequent and prevalent in a population before the risks of transmission become large enough to sustain continued spread. Given the much higher infectiousness of HCV per contact episode and its much higher prevalence in Australian IDUs relative to HIV, the difference in incidence comes down to the force of numbers. The Table combines background prevalences of HCV and HIV, estimates of infectiousness, and carrier rates to illustrate the difference in infection risk encountered by IDUs in Australia. On the basis of these crude estimates, an IDU sharing a needle used by another IDU of unknown infection status is at somewhere between 150 and 800 times higher risk of infection with HCV than HIV. Despite this somewhat sobering picture, it should be noted that there are tentative indications that HCV incidence in Australian IDUs has been declining in recent years. Modelling has suggested that incidence may have fallen from around 18% per year before 1987 to around 12% per year thereafter;1 a Victorian cohort study found a decline from 16.6 cases per 100 person-years in 1990-91 to 8.1 per 100 person-years in 1994-95, matched by declines in behavioural risk;9 and HCV prevalence among IDUs tested for the first time at a methadone maintenance program in Melbourne decreased from 75% in 1992 to 50% in 1995.12 The conclusion from all these considerations is that control of the HCV epidemic requires more intense concentration on reducing needle-sharing and other risky behaviour, and will require a greater effort to decrease incidence than HIV has. This has been seen with HIV infection among IDUs in other countries -- epidemics which have reached high prevalences have proven much harder to control than epidemics which have not taken off before interventions began. Further decreases in needle-sharing will require increased support for accepted programs (increased funding and reach of needle exchange programs, pharmacy sales, peer education) as well as consideration of new strategies. These should urgently include needle exchange programs in prisons (where needle-sharing is the norm)13 and youth training centres, safe injecting spaces, special programs for Aboriginal IDUs and people of non-English-speaking background, and deregulation of supply of needles and syringes so they can be purchased from outlets such as service stations and convenience stores. Other strategies, such as promoting transition to the smoking rather than injecting of illicit drugs, are worth further research and consideration. Finally, the importance of hygiene with regard to injecting environments and conditions must be strongly and routinely stressed. Without serious commitment to new and expanded strategies -- especially needle exchange -- the HCV epidemic will continue, with its high and growing toll of illness and cost. References Crofts N, Jolley D, Kaldor J, et al. The epidemiology of HCV infection among injecting drug users in Australia. J Epidemiol Community Health 1997; 51: 692-697. National Centre in HIV Epidemiology and Clinical Research. HIV/AIDS and related diseases in Australia: annual surveillance report, 1998. Sydney: National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, 1998. Hurley SF, Jolley DJ, Kaldor JM. Effectiveness of needle-exchange programs for prevention of HIV infection. Lancet 1997; 349: 1797-1800. Hagan H, Des Jarlais DC, Friedman SR, et al. Reduced risk of hepatitis B and hepatitis C among injection drug users in the Tacoma Syringe Exchange Program. Am J Public Health 1995; 85: 1531-1536. Wyld R, Robertson JR, Brettle RP, et al. Absence of hepatitis C virus transmission but frequent transmission of HIV-1 from sexual contact with doubly-infected individuals. J Infect 1997; 35:163-166. Crofts N, Webb-Pullman J, Dolan K. An analysis of trends over time in social and behavioural factors related to the transmission of HIV among injecting drug users and prison inmates. Canberra: AGPS, 1996. Louie RL, Krouskos D, Gonzalez M, Crofts N. Vietnamese-speaking injecting drug users in Melbourne: the need for harm reduction programs. Aust N Z J Public Health 1998; 22: 481-484. Patz JA, Jodrey D. Occupational health in surgery: risks extend beyond the operating room. Aust N Z J Surg 1995; 65: 627-629. Crofts N, Aitken CK. Incidence of bloodborne virus infection and risk behaviours in a cohort of injecting drug users in Victoria, 1990-1995. Med J Aust 1997; 167: 17-20. van Beek I, Dwyer R, Dore GJ, et al. Infection with HIV and hepatitis C among injecting drug users in a prevention setting: retrospective cohort study. BMJ 1998; 317: 433-437. MacDonald M, Wodak AD, Ali R, et al. HIV prevalence and risk behaviour in needle exchange attenders: a national study. The Collaboration of Australian Needle Exchanges. Med J Aust 1997; 166: 237-240. Crofts N, Nigro L, Oman K, et al. Methadone maintenance and hepatitis C virus infection among injecting drug users. Addiction 1997; 92: 999-1005. Crofts N, Thompson S, Wale E, Hernberger F. Risk behaviours for blood-borne viruses in a Victorian prison. Aust N Z J Criminol 1996; 29: 20-28. Authors' details Centre for Harm Reduction, Macfarlane Burnet Centre for Medical Research, Fairfield, VIC. Nick Crofts, MB BS, Director; Campbell K Aitken, PhD, Senior Research Officer. National Centre in HIV Epidemiology and Clinical Research, Darlinghurst, NSW. John M Kaldor, PhD, Deputy Director. Reprints will not be available from the authors. Correspondence: Dr N Crofts, Centre for Harm Reduction, Macfarlane Burnet Centre for Medical Research, PO Box 254, Fairfield, VIC 3078. Email: croftsATburnet.edu.au 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>". <URL: http://www.mja.com.au/> Estimated percentage probabilities of infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) associated with a single injection with a needle previously used by an Australian injecting drug user (IDU) of unknown infection status HIV HCV IDU population prevalence estimates9,11 (A)2.1% 62.4% Carrier rates1 (B)100% 80% Needlestick infection probability estimates8 (C) High Low 0.4% 0.3% 10.0% 2.7% Probability of infection (A x B x C)High Low 0.0084% 0.0063% 4.9% 1.3% Ratio of probabilities (HCV/HIV)High Low 778 155 Back to text Reader response to this article, 6 July 1999: The "IDU population prevalence" and "needlestick infection probability" of HCV versus HIV (62% versus 2.5% and some 0.3% versus 5.0%) make it clear why HCV is progressing in such a spectacular fashion in the IDU population. The differences of "carrier rates" (80% versus 100%) are almost inconsequential. If IDUs were to have their communual injecting sessions with partners who were also HCV-negative, there would be no easy way for them to get infected. This implies that IDUs should be encouraged to find out their own HCV-status and get tested regularly. Injecting partners should be encouraged to find out the HCV-status of each other. The parallels with HIV are clear. What this excellent article did not mention was that injecting partners are already self-selecting for HIV - they choose partners who are likely to be also HIV-negative. This would go a long way towards explaining why "new HIV diagnoses in heterosexual IDUs are rare". Alfred Nassim 50 Sloane Street London SW1X 9SN England Authors' reply, 6 July 1999: There is anecdotal evidence that injecting drug users (IDUs) may be discriminating in relation to their own and others HIV status in some situations; for instance, if sharing of injecting equipment is unavoidable (as in prison), and one person is known to be infected with HIV, that person will go last with the needle and syringe. We are not aware of any published research evidence supporting the existence or prevalence of these behaviours. As to public health authorities promoting this behaviour as a strategy for IDUs uninfected with the hepatitis C virus (HCV) to protect themselves against infection, we remain unconvinced. Firstly, networks of IDUs are determined by other and potentially more powerful forces than knowledge of each other's HCV status. Secondly, prevalence of HCV in most IDU networks is so high as to make such a strategy impracticable. Lastly, this strategy raises the possibility of fostering yet more discrimination against HCV-infected IDUs, perhaps even within their own social networks. A corollary of this approach is that HCV-infected IDUs should only inject with each other, which raises the possibility of reinfection with different genotypes - unless the strategy is reduced to the absurd level of injecting only with others of the same genotype. As with HIV, effective public health strategies will rest on an acceptance of everyone being responsible for their own safety, and action to ensure that this is in fact possible for everyone. Dr Nick Crofts Dr Campbell Aitken Professor John Kaldor Back to top of article. Back to top of reader's response.

Nick Crofts · Campbell K Aitken · John M Kaldor

Medicine and the Law Confidentiality and the courts There is a general belief that, once in the witness box, doctors are compelled to reveal confidential information about their patients if asked by counsel. Where no issue of public interest is involved, a medical witness should ask the court to rule in its inherent discretion that the information sought is confidential and privileged. Paul Gerber MJA 1999; 170: 222-224 Introduction - The judge's discretion - When confidentiality may be ignored - Conclusion - References - Authors' details - - More articles on Law Introduction It is said that there is no rule of law which permits a doctor in court proceedings (except in Victoria, Tasmania and the Northern Territory) to refuse to give evidence or disclose information merely because it was supplied to him or her in confidence. The Evidence Acts of the Commonwealth (which applies also in the Australian Capital Territory) and of New South Wales provide that evidence is admissible if "relevant in a proceeding".1 Therefore, except in Victoria, Tasmania and the NT, the law stands in stark contrast with the code of ethics that has stood unchallenged since the days of Hippocrates. This code demands that whatever is revealed in the doctor-patient relationship "ought not to be spoken abroad", although this obligation of confidentiality was diluted in the Australian Medical Association's revised Code of Ethics in 1996.2 In contrast, the law recognises that a party to a marriage is not compellable to disclose a communication made to the other during the marriage, relying on the fundamental right of spouses to confide in each other freely without interference from the law. Likewise, a member of the clergy may refuse to divulge a religious confession to a court in NSW, the ACT and a federal court, but not elsewhere. Client legal professional privilege is justified on the basis that it promotes candour and trust between lawyer and client. Yet nothing is more calculated to destroy candour and trust in the doctor-patient relationship than making a medical witness compellable. But is it the law? My purpose in this article is to clarify the law and to argue that in some circumstances a doctor can, and should, seek the inherent discretion of the court for a claim of privilege. If this is granted, evidence otherwise relevant may be withheld from the court. When in doubt, medical witnesses should voice their concern to the judge and request a ruling. The judge's discretion A judge, being master of his or her own court, has a residual discretion to disallow certain evidence to be given. This discretion will only be exercised where non-disclosure will not result in concealing a crime or endangering the health of others, where the public interest in discovering the truth cannot be advanced as legitimately prevailing over the betrayal of a medical confidence, or where the probative value is substantially outweighed by the danger that the evidence might be unfairly prejudicial to a party. A good starting point is an early decision of the English Court of Appeal in which Lord Denning MR noted: The only profession that I know which is given the privilege from disclosing information to a court of law is the legal profession, and then it is not the privilege of the lawyer but of his client. Take the clergyman, the banker or the medical man. None of these is entitled to refuse to answer when directed to by a judge. Let me not be mistaken. The judge will respect the confidences which each member of these honourable professions receives in the course of it, and will not direct him to answer unless not only it is relevant but also it is a proper, and indeed, necessary question in the course of justice to be put and answered. A judge is the person entrusted, on behalf of the community, to weigh these conflicting interests -- to weigh on the one hand the respect due to confidence in the profession and on the other hand the ultimate interest of the community in justice being done.3 Lord Justice Donovan arrived at a similar conclusion, finding that it would be wrong to hold that a judge should invariably be required to order that the question be answered, and to punish a refusal to answer once it is shown that the question is technically admissible.3 On the same facts, the Full Court of the Supreme Court of New South Wales held in Re Buchanan that: It has never been suggested that, if the question is relevant and proper, any further discretion remains in the trial judge as to whether or not the witness should be compelled to answer, and if it did it is difficult to see upon what material it could be exercised. . . . litigants cannot be constrained by private codes of strangers.4 However, the Full Court went on to add this rider -- that there may be circumstances: ...impossible to define in advance arising out of an infinite number of facts and circumstances which a court encounters which may lead a judge to conclude more harm than good would result from compelling disclosure.4 Both the above cases, involving newspaper journalists claiming to protect their sources, are readily distinguishable from that of the doctor whose disclosure may contain no element of public interest-- for example, medical evidence in divorce proceedings, which is of interest only to the parties and of no concern to the general public -- in which case a judge may be more readily inclined to exercise a discretion in favour of a medical witness. Whatever discretion a court may have in not compelling disclosure of confidential information, it will not be exercised where withholding evidence may protect a criminal or endanger public health. In Hunter v Mann,5 Dr Mann had treated the driver of a stolen vehicle and his passenger after they were involved in an accident. Although Dr Mann advised his patients to go to the police, he did not seek their consent to identify them to the authorities. When a police officer asked for the name and/or address of the man and his passenger, Dr Mann refused to give the information as he considered it confidential, following the British Medical Association code of conduct for members. This code included the principle that a doctor should refrain from voluntarily disclosing to a third party information which he or she learned directly or indirectly in his or her professional relationship with a patient, subject to exceptions, including: "(1) the patient gives his consent; (2) the information is required by law". The prosecutor alleged that Dr Mann was guilty of an offence under the Road Traffic Act 1972 (UK), and the doctor was convicted. An appeal was dismissed, although the judge added this rider: I accept that the doctor ... has no right to refuse to disclose confidential information in the course of judicial or quasi-judicial proceedings; but I also accept that the judge in certain circumstances, and in the exercise of his judicial discretion, may refuse to compel the doctor to do so.5 When confidentiality may be ignored The Australian Medical Association's revised Code of Ethics recognises that in some circumstances medical confidentiality may be ignored, although it would have been more helpful if the guidelines had been more specific. A doctor is entitled -- and indeed bound -- to disclose confidential information where a failure to do so would constitute a threat to public or private interests. Suppose a patient confesses to his psychiatrist that he intends to kill his girlfriend. If the psychiatrist takes this threat seriously, can it possibly be suggested that he or she is not duty bound to alert the authorities? This situation did occur in the United States; the patient did kill his girlfriend and the psychiatrist's employer was held vicariously liable for the girl's death.6The different States and Territories have various reporting laws, dealing with matters such as child abuse, fitness to hold a driving licence, and notifiable diseases, which require medical practitioners to provide certain information to relevant authorities. Child abuse is notifiable in all States and Territories except South Australia and Queensland. South Australia imposes a duty on doctors, opticians and physiotherapists to inform the relevant traffic authorities if they have reasonable cause to believe that a person whom they have examined suffers from a disability such that, if driving a motor vehicle, he or she would be likely to endanger the public.7 New South Wales merely provides immunity from suit for medical practitioners if they provide advice to the Roads and Traffic Authority about a patient's fitness to drive a motor vehicle or fly an aircraft;8 Victoria, Queensland, Western Australia and Tasmania are silent on the matter. In the absence of mandatory reporting requirements, I suggest that a doctor is nonetheless under a positive duty to inform the relevant authorities where he or she reasonably suspects that a patient suffers from a psychiatric or other medical disorder which may pose a threat to that person or to the lives or safety of others. For example, the patient may be a train driver suffering from a serious heart condition who refuses to give up his job, or may suffer from a communicable disease (whether notifiable or not) which poses a health risk to others, including his or her partner. Where practical or meaningful, the patient's permission to disclose the information should be sought, and, if permission is refused, the patient should be warned that the information will be passed on to the relevant authority. But taking such a course of action may result in legal action. In 1983, a general practitioner in New Zealand had been treating a bus driver who had had a coronary bypass and whose heart condition was unstable. The doctor advised the man to give up driving, but the patient refused. On learning that the man proposed to take a group of schoolchildren on an excursion in his bus, the doctor informed the traffic authorities that, in his opinion, the man was unfit to drive and was a danger to the public. The bus driver brought legal proceedings against the doctor, resulting in an award of damages, severe censure by the New Zealand Medical Council,9 and the doctor's suicide. However, it is most unlikely that an Australian court would award damages in similar circumstances, if only because the bus driver would be unable to prove a "loss" recognised at law. Another New Zealand case, Furniss v Fitchett (Box), undoubtedly represents the current law in Australia. According to this case, the duty of care is dependent on the foreseeability of the harm in suit.10 Conclusion Doctors should always seek judicial guidance before answering any question in court involving confidential information about a patient. Where a party causes a subpoena duces tecum to be issued to a medical practitioner, calling for all records relating to a patient to be produced, these documents must be produced to the court. It is then for the court to decide whether the documents may be inspected by the parties or their advisers. As a matter of law, medical records cannot be adduced in evidence except when proved by the doctor, and it is at that point that the doctor should seek to invoke the court's discretion, pleading confidentiality of the material unless waived by the patient. If the judge rules against the doctor, the choice is between compliance and prison, although a fine is more likely. Medical defence organisations will fund a doctor's resistance to the disclosure of confidential medical information. However, if the judge compels disclosure and the doctor refuses to comply, any fine is unlikely to be covered by the doctor's indemnity -- idealism is rarely rewarded. Where there is little conflict on medical evidence, a patient's notes may be produced to the court by agreement and admitted into evidence without the doctor being present, after affording the patient the opportunity to claim privilege. Doctors would be well advised to explore this option in appropriate cases. It provides an alternative to waiting needlessly in court in the many cases where a medical witness is not called, either because after a conference with counsel the medical evidence is thought to be unhelpful, or because the case is settled just before or during the hearing. Finally, a word of warning. A doctor unhappy to provide records or give evidence must not take the law into his or her own hands. When in doubt, consult your medical defence organisation. References Evidence Act 1995 (Cwlth), sec 55; Evidence Act 1995 (NSW), sec 55. Australian Medical Association. AMA Code of Ethics. Canberra: AMA, 1996. Attorney-General v Mulholland [1963] 2 QB 477. Re Buchanan [1964-5] NSWR 1379. Hunter v Mann [1974] QB 767. Tarasoff v Regents of the University of California 529 P 2d 253 (1974). Motor Vehicle Act 1959 (SA), sec 148. Traffic Act 1909 (NSW), sec 17A. Duncan v Medical Practitioners Disciplinary Committee [1986] 1 NZLR 513. Furniss v Fitchett [1958] NZLR 396. Author's details University of New South Wales (ATAX), Sydney, NSW. Paul Gerber, LLB, DJur, Professor of Law. Reprints will not be available from the author. Correspondence: Professor P Gerber, GPO Box 9955, Brisbane, QLD 4001. Make a comment 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>". <URL: http://www.mja.com.au/> Furniss v Fitchett Dr Fitchett, a GP in New Zealand, was the medical attendant of both Mrs Furniss and her husband. In about 1956, Mrs Furniss began to think that her husband was poisoning her and that he was mentally unsound. She told Dr Furniss that her husband was cruel to her and even violent. These suspicions and charges were without foundation, but led to domestic discord, which affected the health of the husband. The husband consulted a solicitor about a separation and/or whether his wife could be certified. During a subsequent consultation with Dr Fitchett, the husband, in a distraught state, asked the doctor to provide a medical report on his wife. Dr Fitchett, "after deep thought", wrote and signed a document, to be given to the husband's solicitor, which, after listing a series of symptoms, stated that the doctor considered that the wife "exhibits symptoms of paranoia and should be given treatment for same if possible. An examination by a psychiatrist would be needed to fully diagnose her case and its requirements." Some 12 months later, this document came to light in proceedings by Mrs Furniss against her husband for separation and maintenance. The lady may have exhibited symptoms of paranoia, but she recognised a good claim against a doctor. Her action against Dr Fitchett in damages succeeded.10 Chief Justice Barrowclough held that the doctor should reasonably have foreseen that the contents of the report were likely to come to his patient's knowledge and that she would be likely to suffer hurt as the result of his action. In these circumstances, there arose a duty of care on his part to prevent the foreseeable harm which the circulation of such a report would cause, notwithstanding that the certificate was true and accurate. Back to text

Paul Gerber