- Email: [email protected]
Multiple-dose activated charcoal in yellow oleander poisoning – Authors' reply
Correspondence
We declare that we have no conflict of interest.
*M Eddleston, A H Dawson, N A Buckley [email protected] South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka 1
2
3
4
5
de Silva HJ, Wijewickrema R, Senanayake N. Does pralidoxime affect outcome of management in acute organophosphorus poisoning? Lancet 1992; 339: 1136–38. 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. Pawar KS, Bhoite RR, Pillay CP, Chavan SC, Malshikare DS, Garad SG. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial. Lancet 2006; 368: 2136–41. Eyer P, Buckley NA. Pralidoxime for organophosphate poisoning. Lancet 2006; 368: 2110–11. Eddleston M, Szinicz L, Eyer P, Buckley N. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. Q J Med 2002; 95: 275–83.
Multiple-dose activated charcoal in yellow oleander poisoning Michael Eddleston and colleagues (Feb 16, p 579)1 report the results of an unblinded study in which they found that multiple-dose activated charcoal did not reduce mortality in patients with yellow oleander poisoning. This finding is at variance with the results of our large investigator-blinded study in which multiple-dose activated charcoal significantly reduced mortality.2 www.thelancet.com Vol 371 June 28, 2008
The generally accepted case-fatality rate from yellow oleander poisoning is 10%.3 Mortality in patients who were given a single dose of activated charcoal by Eddleston and colleagues was only 4·7%. They calculated the sample size to detect whether multiple-dose activated charcoal can reduce case fatality from 10% to 7%, with a significance of 5% and a power of 80%. To detect a comparable 30% reduction in the event rate from 4·7% to 3·3%, they would have required more than 3000 patients in each group. With the numbers they reported for the multiple-dose and single-dose groups of 541 and 549, respectively, their study would only have had a power of 18% to detect such a difference. There are differences between the two studies that also warrant comment. We continued multiple-dose activated charcoal for 72 h, in view of the long half-lives of oleander glycosides (median 43 h4), compared with only 24 h by Eddleston and colleagues. Although most deaths occur in the first 24 h (87% in Eddleston and colleagues’ study vs 66% in ours), we found that the frequency of life-threatening cardiac arrhythmias increased significantly after 24 h in the placebo group. In our study, trial staff directly observed patients, ensuring adherence to treatment in all cases. Eddleston and colleagues estimated adherence in only 25% and found that it fell from 80% with the first dose to 60% by the sixth dose. Poor adherence could have reduced the effectiveness of charcoal. There were also differences in the criteria for entry. We restricted enrolment to those who presented within 24 h of ingestion, whereas Eddleston and colleagues included those presenting up to 72 h after ingestion, thus increasing the possibility of recruiting more survivors. Eddleston and colleagues also included less severely ill patients (excluding those with Glasgow coma scale scores <13). Eddleston and colleagues have previously noted that activated charcoal
could have clinical benefits in patients with yellow oleander poisoning,4 and we do not believe that they would want the results of their present study used to support a policy of withholding from such patients a simple, effective, inexpensive remedy, and one that they have also clearly shown is exceptionally safe. We declare that we have no conflict of interest.
*H Asita de Silva, Arunasalam Pathmeswaran, David G Lalloo, H Janaka de Silva, Jeffrey K Aronson [email protected] University of Kelaniya, Ragama, Sri Lanka (HAdS, AP, HJdS); Liverpool School of Tropical Medicine, Liverpool, UK (DGL); and University of Oxford, Oxford, UK (JKA) 1
2
3
4
Eddleston M, Juszczak E, Buckley NA, et al, for the Ox-Col Poisoning Study collaborators. Multiple-dose activated charcoal in acute selfpoisoning: a randomised controlled trial. Lancet 2008; 371: 579–87. de Silva HA, Fonseka MM, Pathmeswaran A, et al. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. Lancet 2003; 361: 1935–38. Eddleston M, Ariaratnam CA, Meyer WP, et al. Epidemic of self-poisoning with seeds of the yellow oleander tree (Thevetia peruviana) in northern Sri Lanka. Trop Med Int Health 1999; 4: 266–73. Roberts DM, Southcott E, Potter JM, Roberts MS, Eddleston M, Buckley NA. Pharmacokinetics of digoxin cross-reacting substances in patients with acute yellow oleander (Thevetia peruviana) poisoning, including the effect of activated charcoal. Ther Drug Monit 2006; 28: 784–92.
Authors’ reply Retrospective reworking of power calculations is a flawed method to determine whether an important difference has been missed.1 For that, the 95% CI of the observed difference is the best guide. In this case, our results suggest that a true reduction in mortality of more than 2·5% with activated charcoal is highly unlikely. The largest difference between our study and that by Asita de Silva and colleagues is a higher mortality in their control group, rather than a lower mortality in their treated group. This finding would seem to suggest that they obtained a chance or exaggerated treatment effect when they saw a 5·5% difference. Meta-analysis of
Science Photo Library
not reflect the situation in most hospitals that see poisoned patients in rural Asia. Their hospital largely admits referred patients and provides a very high standard of care. Their intensivecare unit is well resourced, with dedicated intensive-care consultants, nurses, and physiotherapists. As a private tertiary care hospital receiving patients who have survived at least 8 h after poisoning and been fit for transfer, they see few patients who die within a few hours of cardiovascular shock or cholinergic crises.
2171
Correspondence
Science Photo Library
their 400 patients2 with the relevant 1089 patients in our trial3 showed no significant difference to support the use of charcoal. The longer course of charcoal given by de Silva and colleagues is unlikely to be relevant. Most deaths in our study occurred within 24 h of admission, precluding a significant effect of longer administration on the primary outcome. By contrast, de Silva and colleagues found an increase in fatal dysrhythmias more than 24 h after admission (about 34 h after poisoning). A possible reason for these late deaths is the very high doses of atropine (eg, up to 6 mg in boluses over 15–30 min) that they state were given to patients with pulse rates less than 50–60 bpm. This treatment would probably cause ileus (prolonging exposure to oleander), increase myocardial workload, and lead to life-threatening complications such as hyperthermia and delirium. De Silva and colleagues imply that our lack of study blinding is a shortcoming. However, blinding is less important than allocation concealment,4 especially when death is the primary outcome. Furthermore, we supervised 100% of doses and formally measured adherence in more than 3500 doses—12·3% of patients receiving multiple doses completely refused their sixth dose.5 We assume that de Silva and colleagues also had a similar proportion of patients who objected to further doses, or who were vomiting or moribund, and are not convinced that their research assistants would have been able to fully “ensure adherence in all cases”. We agree that charcoal should be of benefit from a theoretical perspective and we have shown that it is safe. However, we stand by our statement that “the combined evidence does not suggest a major effect of charcoal in oleander poisoning”. We declare that we have no conflict of interest.
*M Eddleston, E Juszczak, N A Buckley, for the South Asian Clinical Toxicology Research Collaboration [email protected]
2172
Scottish Poisons Information Bureau, New Royal Infirmary, 51 Little France, Edinburgh EH16 4SA, UK (ME); Centre for Statistics in Medicine, Wolfson College, University of Oxford, Oxford, UK (EJ); and Department of Clinical Pharmacology and Toxicology, Australian National University Medical School, Canberra, ACT, Australia (NAB) 1
2
3
4
5
Goodman SN, Berlin JA. The use of predicted confidence intervals when planning experiments and the misuse of power when interpreting results. Ann Intern Med 1994; 121: 200–06. de Silva HA, Fonseka MMD, Pathmeswaran A, et al. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. Lancet 2003; 361: 1935–38. Eddleston M, Juszczak E, Buckley NA, et al, for the Ox-Col Poisoning Study collaborators. Multiple-dose activated charcoal in acute selfpoisoning: a randomised controlled trial. Lancet 2008; 371: 579–87. Wood L, Egger M, Gluud LL, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 2008; 336: 601–05. Mohamed F, Senarathna L, Azher S, Sheriff MHR, Buckley NA, Eddleston M. Compliance for single and multiple dose regimens of superactivated charcoal: a prospective study of patients in a clinical trial. Clin Toxicol 2007; 45: 132–35.
The UK medical workforce: sleepwalking into isolation? The UK was set on the path towards self sufficiency in producing its own medical workforce in 1997 when the government decided to expand medical school places. Such expansion was necessary to reduce reliance on overseas-trained personnel. The poaching of health-care staff has been identified as a major impediment to developing and maintaining health services in developing countries. But, as with all policies, there are consequences. For many years, in the health sector, the UK maintained its influence and connections around the world. Since the inception of the National Health Service (NHS), health professionals from across the globe have come to the UK to train and to work. But, will this continue? The abolition of permit-free training in April, 2006, and the replacement of the Highly Skilled Migrant Programme with a
points-based system have made it very difficult for doctors from outside the European Economic Area to come to the UK for training. We are already seeing doctors and governments overseas looking elsewhere for postgraduate training opportunities. This situation could cost the UK dearly in the long term. Within a generation it will have lost much of its network across the world. Young doctors trained in the UK have often become the future leaders in their own countries and have maintained links based on contacts and experience within the UK. Also, to run a health service with a multicultural and mobile population, which characterises today’s UK, health-care staff need exposure to new or different methods of training and knowledge of global health issues. Ways need to be found to ensure that the UK is able to continue to offer reasonable periods of clinical training (up to 24 months) to nonUK citizens, whether that be through Royal Colleges Sponsorship Schemes or other mechanisms. To do this, commitments, support, and input will be needed from the Department of Health, Postgraduate Deaneries, Royal Colleges, NHS Trusts, and the profession as a whole. At the same time, with the advent of more prescriptive training curricula and close scrutiny by the Postgraduate Medical Education Training Board, it has become increasingly hard for UK doctors-in-training to spend a period of time overseas. Obtaining approval for in-programme or out-ofprogramme experience is lengthy and bureaucratic. Cross-cultural richness is of great benefit to the UK and we must maintain strong and responsive international links or risk isolation. We declare that we have no conflict of interest.
*Matthew Foster, Salman Rawaf, Michael Pelly, Ian Gilmore [email protected] Royal College of Physicians, 11 St Andrews Place, Regent’s Park, London NW1 4LE, UK
www.thelancet.com Vol 371 June 28, 2008
We declare that we have no conflict of interest.
*M Eddleston, A H Dawson, N A Buckley [email protected] South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka 1
2
3
4
5
de Silva HJ, Wijewickrema R, Senanayake N. Does pralidoxime affect outcome of management in acute organophosphorus poisoning? Lancet 1992; 339: 1136–38. 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. Pawar KS, Bhoite RR, Pillay CP, Chavan SC, Malshikare DS, Garad SG. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial. Lancet 2006; 368: 2136–41. Eyer P, Buckley NA. Pralidoxime for organophosphate poisoning. Lancet 2006; 368: 2110–11. Eddleston M, Szinicz L, Eyer P, Buckley N. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. Q J Med 2002; 95: 275–83.
Multiple-dose activated charcoal in yellow oleander poisoning Michael Eddleston and colleagues (Feb 16, p 579)1 report the results of an unblinded study in which they found that multiple-dose activated charcoal did not reduce mortality in patients with yellow oleander poisoning. This finding is at variance with the results of our large investigator-blinded study in which multiple-dose activated charcoal significantly reduced mortality.2 www.thelancet.com Vol 371 June 28, 2008
The generally accepted case-fatality rate from yellow oleander poisoning is 10%.3 Mortality in patients who were given a single dose of activated charcoal by Eddleston and colleagues was only 4·7%. They calculated the sample size to detect whether multiple-dose activated charcoal can reduce case fatality from 10% to 7%, with a significance of 5% and a power of 80%. To detect a comparable 30% reduction in the event rate from 4·7% to 3·3%, they would have required more than 3000 patients in each group. With the numbers they reported for the multiple-dose and single-dose groups of 541 and 549, respectively, their study would only have had a power of 18% to detect such a difference. There are differences between the two studies that also warrant comment. We continued multiple-dose activated charcoal for 72 h, in view of the long half-lives of oleander glycosides (median 43 h4), compared with only 24 h by Eddleston and colleagues. Although most deaths occur in the first 24 h (87% in Eddleston and colleagues’ study vs 66% in ours), we found that the frequency of life-threatening cardiac arrhythmias increased significantly after 24 h in the placebo group. In our study, trial staff directly observed patients, ensuring adherence to treatment in all cases. Eddleston and colleagues estimated adherence in only 25% and found that it fell from 80% with the first dose to 60% by the sixth dose. Poor adherence could have reduced the effectiveness of charcoal. There were also differences in the criteria for entry. We restricted enrolment to those who presented within 24 h of ingestion, whereas Eddleston and colleagues included those presenting up to 72 h after ingestion, thus increasing the possibility of recruiting more survivors. Eddleston and colleagues also included less severely ill patients (excluding those with Glasgow coma scale scores <13). Eddleston and colleagues have previously noted that activated charcoal
could have clinical benefits in patients with yellow oleander poisoning,4 and we do not believe that they would want the results of their present study used to support a policy of withholding from such patients a simple, effective, inexpensive remedy, and one that they have also clearly shown is exceptionally safe. We declare that we have no conflict of interest.
*H Asita de Silva, Arunasalam Pathmeswaran, David G Lalloo, H Janaka de Silva, Jeffrey K Aronson [email protected] University of Kelaniya, Ragama, Sri Lanka (HAdS, AP, HJdS); Liverpool School of Tropical Medicine, Liverpool, UK (DGL); and University of Oxford, Oxford, UK (JKA) 1
2
3
4
Eddleston M, Juszczak E, Buckley NA, et al, for the Ox-Col Poisoning Study collaborators. Multiple-dose activated charcoal in acute selfpoisoning: a randomised controlled trial. Lancet 2008; 371: 579–87. de Silva HA, Fonseka MM, Pathmeswaran A, et al. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. Lancet 2003; 361: 1935–38. Eddleston M, Ariaratnam CA, Meyer WP, et al. Epidemic of self-poisoning with seeds of the yellow oleander tree (Thevetia peruviana) in northern Sri Lanka. Trop Med Int Health 1999; 4: 266–73. Roberts DM, Southcott E, Potter JM, Roberts MS, Eddleston M, Buckley NA. Pharmacokinetics of digoxin cross-reacting substances in patients with acute yellow oleander (Thevetia peruviana) poisoning, including the effect of activated charcoal. Ther Drug Monit 2006; 28: 784–92.
Authors’ reply Retrospective reworking of power calculations is a flawed method to determine whether an important difference has been missed.1 For that, the 95% CI of the observed difference is the best guide. In this case, our results suggest that a true reduction in mortality of more than 2·5% with activated charcoal is highly unlikely. The largest difference between our study and that by Asita de Silva and colleagues is a higher mortality in their control group, rather than a lower mortality in their treated group. This finding would seem to suggest that they obtained a chance or exaggerated treatment effect when they saw a 5·5% difference. Meta-analysis of
Science Photo Library
not reflect the situation in most hospitals that see poisoned patients in rural Asia. Their hospital largely admits referred patients and provides a very high standard of care. Their intensivecare unit is well resourced, with dedicated intensive-care consultants, nurses, and physiotherapists. As a private tertiary care hospital receiving patients who have survived at least 8 h after poisoning and been fit for transfer, they see few patients who die within a few hours of cardiovascular shock or cholinergic crises.
2171
Correspondence
Science Photo Library
their 400 patients2 with the relevant 1089 patients in our trial3 showed no significant difference to support the use of charcoal. The longer course of charcoal given by de Silva and colleagues is unlikely to be relevant. Most deaths in our study occurred within 24 h of admission, precluding a significant effect of longer administration on the primary outcome. By contrast, de Silva and colleagues found an increase in fatal dysrhythmias more than 24 h after admission (about 34 h after poisoning). A possible reason for these late deaths is the very high doses of atropine (eg, up to 6 mg in boluses over 15–30 min) that they state were given to patients with pulse rates less than 50–60 bpm. This treatment would probably cause ileus (prolonging exposure to oleander), increase myocardial workload, and lead to life-threatening complications such as hyperthermia and delirium. De Silva and colleagues imply that our lack of study blinding is a shortcoming. However, blinding is less important than allocation concealment,4 especially when death is the primary outcome. Furthermore, we supervised 100% of doses and formally measured adherence in more than 3500 doses—12·3% of patients receiving multiple doses completely refused their sixth dose.5 We assume that de Silva and colleagues also had a similar proportion of patients who objected to further doses, or who were vomiting or moribund, and are not convinced that their research assistants would have been able to fully “ensure adherence in all cases”. We agree that charcoal should be of benefit from a theoretical perspective and we have shown that it is safe. However, we stand by our statement that “the combined evidence does not suggest a major effect of charcoal in oleander poisoning”. We declare that we have no conflict of interest.
*M Eddleston, E Juszczak, N A Buckley, for the South Asian Clinical Toxicology Research Collaboration [email protected]
2172
Scottish Poisons Information Bureau, New Royal Infirmary, 51 Little France, Edinburgh EH16 4SA, UK (ME); Centre for Statistics in Medicine, Wolfson College, University of Oxford, Oxford, UK (EJ); and Department of Clinical Pharmacology and Toxicology, Australian National University Medical School, Canberra, ACT, Australia (NAB) 1
2
3
4
5
Goodman SN, Berlin JA. The use of predicted confidence intervals when planning experiments and the misuse of power when interpreting results. Ann Intern Med 1994; 121: 200–06. de Silva HA, Fonseka MMD, Pathmeswaran A, et al. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. Lancet 2003; 361: 1935–38. Eddleston M, Juszczak E, Buckley NA, et al, for the Ox-Col Poisoning Study collaborators. Multiple-dose activated charcoal in acute selfpoisoning: a randomised controlled trial. Lancet 2008; 371: 579–87. Wood L, Egger M, Gluud LL, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 2008; 336: 601–05. Mohamed F, Senarathna L, Azher S, Sheriff MHR, Buckley NA, Eddleston M. Compliance for single and multiple dose regimens of superactivated charcoal: a prospective study of patients in a clinical trial. Clin Toxicol 2007; 45: 132–35.
The UK medical workforce: sleepwalking into isolation? The UK was set on the path towards self sufficiency in producing its own medical workforce in 1997 when the government decided to expand medical school places. Such expansion was necessary to reduce reliance on overseas-trained personnel. The poaching of health-care staff has been identified as a major impediment to developing and maintaining health services in developing countries. But, as with all policies, there are consequences. For many years, in the health sector, the UK maintained its influence and connections around the world. Since the inception of the National Health Service (NHS), health professionals from across the globe have come to the UK to train and to work. But, will this continue? The abolition of permit-free training in April, 2006, and the replacement of the Highly Skilled Migrant Programme with a
points-based system have made it very difficult for doctors from outside the European Economic Area to come to the UK for training. We are already seeing doctors and governments overseas looking elsewhere for postgraduate training opportunities. This situation could cost the UK dearly in the long term. Within a generation it will have lost much of its network across the world. Young doctors trained in the UK have often become the future leaders in their own countries and have maintained links based on contacts and experience within the UK. Also, to run a health service with a multicultural and mobile population, which characterises today’s UK, health-care staff need exposure to new or different methods of training and knowledge of global health issues. Ways need to be found to ensure that the UK is able to continue to offer reasonable periods of clinical training (up to 24 months) to nonUK citizens, whether that be through Royal Colleges Sponsorship Schemes or other mechanisms. To do this, commitments, support, and input will be needed from the Department of Health, Postgraduate Deaneries, Royal Colleges, NHS Trusts, and the profession as a whole. At the same time, with the advent of more prescriptive training curricula and close scrutiny by the Postgraduate Medical Education Training Board, it has become increasingly hard for UK doctors-in-training to spend a period of time overseas. Obtaining approval for in-programme or out-ofprogramme experience is lengthy and bureaucratic. Cross-cultural richness is of great benefit to the UK and we must maintain strong and responsive international links or risk isolation. We declare that we have no conflict of interest.
*Matthew Foster, Salman Rawaf, Michael Pelly, Ian Gilmore [email protected] Royal College of Physicians, 11 St Andrews Place, Regent’s Park, London NW1 4LE, UK
www.thelancet.com Vol 371 June 28, 2008