- Email: [email protected]
High-dose pralidoxime for organophosphorus poisoning
Correspondence
probability of a favourable treatment result for a randomly selected member of one group over a member of the other, calculated as 0·53 and 0·68 (for “deaths” and “intubation during admission”, respectively),3 suggests otherwise. The mortality treatment effect also seems fragile: a minimum change in the number of deaths (two and seven vs one and eight) renders the mortality effect non-significant. The results of this trial have limited applicability to late presentation (in our centre only 15% reach hospital within 6 h), when oxime therapy can be potentially harmful owing to acetylcholinesterase ageing.2 Median initial 24-h atropine requirements (6 mg treatment group, 30 mg control group) compared with reported requirements in oxime-treated organophosphorus poisoning4 and mean atropine use during resuscitation (23·4 mg5), suggest mild intoxication in the Pawar study, as do the small recorded poison volumes (median 15 mL, lowest 5 mL). Thus physicians should continue to use judgment regarding oxime use in severe organophosphorus poisoning and in late presentation where the evidence for benefit is not shown. We declare that we have no conflict of interest.
*John Victor Peter, John L Moran, Thambu David Sudarsanam, Petra Graham [email protected] Department of Medical Intensive Care (JVP) and Department of Medicine (TDS), Christian Medical College and Hospital, Vellore 632 004, India; Department of Intensive Care Medicine, Queen Elizabeth Hospital, Woodville, South Australia, Australia (JLM); and CSIRO Mathematical and Information Sciences, North Ryde, New South Wales, Australia (PG) 1
2
3
1426
Pawar KS, Bhoite RR, Pillay CP, Chavan S, Malshikare DS, Garad MS. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial. Lancet 2006; 368: 2136–41. Peter JV, Moran JL, Graham P. Oxime therapy and outcomes in human organophosphate poisoning: an evaluation using meta-analytic techniques. Crit Care Med 2006; 34: 502–10. Colditz GA, Miller JN, Mosteller F. Measuring gain in the evaluation of medical technology: the probability of a better outcome. Int J Technol Assess Health Care 1988; 4: 637–42.
4
5
Cherian AM, Peter JV, Samuel J, et al. Effectiveness of P2AM (PAM-Pralidoxime) in the treatment of organophosphate poisoning (OPP): a randomized, double blind, placebo controlled clinical trial. J Assoc Physicians India 1997; 45: 22–24. Eddleston M, Buckley NA, Checketts H, et al. Speed of initial atropinisation in significant organophosphorus pesticide poisoning—a systematic comparison of recommended regimens. J Toxicol Clin Toxicol 2004; 42: 865–75.
Kirti Pawar and colleagues report that high-dose pralidoxime infusion in patients with organophosphorus pesticide poisoning is associated with a positive clinical outcome. This surprising conclusion contradicts previously published evidence.2 First, the case fatality rates in the study group and the control group (1% vs 8%) are much lower than in a systematic review of two clinical trials (182 people): 22% versus 14% and 29% versus 5%, respectively.2 Also, the median atropine dose needed to dry the tracheobronchial tree in the study and control groups (6 mg and 30 mg, respectively) within 24 h of admission was much smaller than that in a previous trial.3 Of note, although Pawar and colleagues enrolled only mildly poisoned patients, they intubated a much larger proportion of them (study group, 64%; control group, 88%) than the authors of a previous study (23%).4 The report does not explain these contradictions. Second, the study patients were asked to buy pralidoxime at a cost of about US$400 for the first 48 h, an amount “far beyond the capacity of most patients in rural Asia” in Pawar and colleagues’ words. We believe that study patients should not pay for trial medications and are surprised that the local ethics committee ignored this fact. Finally, because there was no blinding, as the trial advanced and the data accrued, Pawar and colleagues were aware that the study group was doing significantly better than the control group (one death vs eight deaths). Did Pawar and colleagues share this fact with the participants who were enrolled late in the study? Was it ethical to continue the trial despite this observation?
We declare that we have no conflict of interest.
Rajnish Joshi, *S P Kalantri [email protected] Department of Medicine, Mahatma Gandhi Institute of Medical Sciences Sevagram, Maharashtra 442102, India (RJ, SPK); and Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA (RJ) 1
1
2
3
4
Pawar KS, Bhoite RR, Pillay CP, Chavan S, Malshikare DS, Garad MS. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial. Lancet 2006; 368: 2136–41. Buckley NA, Eddleston M, Szinicz L. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst Rev 2005; 1: CD005085. Cherian AM, Peter JV, Johnson S, et al. Effectiveness of oximes (PAM- Pralidoxime) in the treatment of organophosphorus poisoning (OPP) a randomised, double blind placebo controlled clinical trial. J Assoc Physicians India 1997; 45: 22–24. Eddleston M, Eyer P, Worek F, et al. Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet 2005; 366: 1452–59.
Kirti Pawar and colleagues1 show that a high-dose regimen of pralidoxime reduces the need for intubation, the duration of mechanical ventilation, and the amount of atropine required to offset the muscarinic consequences of organophosphorus poisoning. Some issues warrant additional information before a therapeutic approach that is neither cheap nor innocuous is translated into everyday practice.2 Since the main clinically relevant outcome of the study is the need for intubation, it is crucial to detail indications of such a decision, particularly in an open-label trial such as this. The general intubation criteria provided in the Methods section should have been adapted to the specific condition of organophosphorus poisoning. Intubation in such patients is usually indicated by acute respiratory failure induced by organophosphorus poisoning itself (depression in respiratory centres, bronchorrhoea, or bronchospasm).3 Intubation is also done to protect the airways. The beneficial effects of oximes are expected to reduce organophosphorus-related respiratory failure. Accordingly, the respective www.thelancet.com Vol 369 April 28, 2007
probability of a favourable treatment result for a randomly selected member of one group over a member of the other, calculated as 0·53 and 0·68 (for “deaths” and “intubation during admission”, respectively),3 suggests otherwise. The mortality treatment effect also seems fragile: a minimum change in the number of deaths (two and seven vs one and eight) renders the mortality effect non-significant. The results of this trial have limited applicability to late presentation (in our centre only 15% reach hospital within 6 h), when oxime therapy can be potentially harmful owing to acetylcholinesterase ageing.2 Median initial 24-h atropine requirements (6 mg treatment group, 30 mg control group) compared with reported requirements in oxime-treated organophosphorus poisoning4 and mean atropine use during resuscitation (23·4 mg5), suggest mild intoxication in the Pawar study, as do the small recorded poison volumes (median 15 mL, lowest 5 mL). Thus physicians should continue to use judgment regarding oxime use in severe organophosphorus poisoning and in late presentation where the evidence for benefit is not shown. We declare that we have no conflict of interest.
*John Victor Peter, John L Moran, Thambu David Sudarsanam, Petra Graham [email protected] Department of Medical Intensive Care (JVP) and Department of Medicine (TDS), Christian Medical College and Hospital, Vellore 632 004, India; Department of Intensive Care Medicine, Queen Elizabeth Hospital, Woodville, South Australia, Australia (JLM); and CSIRO Mathematical and Information Sciences, North Ryde, New South Wales, Australia (PG) 1
2
3
1426
Pawar KS, Bhoite RR, Pillay CP, Chavan S, Malshikare DS, Garad MS. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial. Lancet 2006; 368: 2136–41. Peter JV, Moran JL, Graham P. Oxime therapy and outcomes in human organophosphate poisoning: an evaluation using meta-analytic techniques. Crit Care Med 2006; 34: 502–10. Colditz GA, Miller JN, Mosteller F. Measuring gain in the evaluation of medical technology: the probability of a better outcome. Int J Technol Assess Health Care 1988; 4: 637–42.
4
5
Cherian AM, Peter JV, Samuel J, et al. Effectiveness of P2AM (PAM-Pralidoxime) in the treatment of organophosphate poisoning (OPP): a randomized, double blind, placebo controlled clinical trial. J Assoc Physicians India 1997; 45: 22–24. Eddleston M, Buckley NA, Checketts H, et al. Speed of initial atropinisation in significant organophosphorus pesticide poisoning—a systematic comparison of recommended regimens. J Toxicol Clin Toxicol 2004; 42: 865–75.
Kirti Pawar and colleagues report that high-dose pralidoxime infusion in patients with organophosphorus pesticide poisoning is associated with a positive clinical outcome. This surprising conclusion contradicts previously published evidence.2 First, the case fatality rates in the study group and the control group (1% vs 8%) are much lower than in a systematic review of two clinical trials (182 people): 22% versus 14% and 29% versus 5%, respectively.2 Also, the median atropine dose needed to dry the tracheobronchial tree in the study and control groups (6 mg and 30 mg, respectively) within 24 h of admission was much smaller than that in a previous trial.3 Of note, although Pawar and colleagues enrolled only mildly poisoned patients, they intubated a much larger proportion of them (study group, 64%; control group, 88%) than the authors of a previous study (23%).4 The report does not explain these contradictions. Second, the study patients were asked to buy pralidoxime at a cost of about US$400 for the first 48 h, an amount “far beyond the capacity of most patients in rural Asia” in Pawar and colleagues’ words. We believe that study patients should not pay for trial medications and are surprised that the local ethics committee ignored this fact. Finally, because there was no blinding, as the trial advanced and the data accrued, Pawar and colleagues were aware that the study group was doing significantly better than the control group (one death vs eight deaths). Did Pawar and colleagues share this fact with the participants who were enrolled late in the study? Was it ethical to continue the trial despite this observation?
We declare that we have no conflict of interest.
Rajnish Joshi, *S P Kalantri [email protected] Department of Medicine, Mahatma Gandhi Institute of Medical Sciences Sevagram, Maharashtra 442102, India (RJ, SPK); and Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA (RJ) 1
1
2
3
4
Pawar KS, Bhoite RR, Pillay CP, Chavan S, Malshikare DS, Garad MS. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial. Lancet 2006; 368: 2136–41. Buckley NA, Eddleston M, Szinicz L. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst Rev 2005; 1: CD005085. Cherian AM, Peter JV, Johnson S, et al. Effectiveness of oximes (PAM- Pralidoxime) in the treatment of organophosphorus poisoning (OPP) a randomised, double blind placebo controlled clinical trial. J Assoc Physicians India 1997; 45: 22–24. Eddleston M, Eyer P, Worek F, et al. Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet 2005; 366: 1452–59.
Kirti Pawar and colleagues1 show that a high-dose regimen of pralidoxime reduces the need for intubation, the duration of mechanical ventilation, and the amount of atropine required to offset the muscarinic consequences of organophosphorus poisoning. Some issues warrant additional information before a therapeutic approach that is neither cheap nor innocuous is translated into everyday practice.2 Since the main clinically relevant outcome of the study is the need for intubation, it is crucial to detail indications of such a decision, particularly in an open-label trial such as this. The general intubation criteria provided in the Methods section should have been adapted to the specific condition of organophosphorus poisoning. Intubation in such patients is usually indicated by acute respiratory failure induced by organophosphorus poisoning itself (depression in respiratory centres, bronchorrhoea, or bronchospasm).3 Intubation is also done to protect the airways. The beneficial effects of oximes are expected to reduce organophosphorus-related respiratory failure. Accordingly, the respective www.thelancet.com Vol 369 April 28, 2007