- Email: [email protected]
Artesunate for severe malaria in African children
Correspondence
newborn resuscitation. Certain kinds of inhaled gas (eg, nitric oxide) have been shown to reduce the pulmonary hypertension that is common during the fetal–neonatal transition period of full-term or late-preterm neonates selectively and effectively.3 Should such gases be considered for integration into oxygen therapy for newborn resuscitation to maximise net gain? We declare that we have no conflicts of interest.
*Bing Hou, Zhi-Wei Xu, Lai-Shuan Wang [email protected] State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China (BH, ZWX); and Department of Neonatology, Children’s Hospital of Fudan University, Shanghai, China (LSW) 1
2
3
Saugstad OD. Resuscitation of newborn infants: from oxygen to room air. Lancet 2010; 376: 1970–71. Kattwinkel J, Perlman JM, Aziz K, et al. Neonatal resuscitation: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics 2010; 126: e1400–13. American Academy of Pediatrics Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics 2000; 106: 344–45.
Author’s reply Bing Hou and colleagues raise some timely questions about the use of oxygen or air for newborn resuscitation. After my Comment was accepted, the International Liaison Committee on Resuscitation stated in their 2010 guidelines for newborn resuscitation that “it is best to begin with air rather than 100% oxygen”.1 In our first clinical studies with air versus 100% oxygen,2 we showed that it is possible to resuscitate with air, having oxygen as a backup and switching to oxygen after 90 s in the absence of a satisfactory response to air. Oxygenation depends, however, largely on lung surface area so it is not appropriate to start giving oxygen until appropriate attempts have been made to aerate the lung. Only in a few cases should oxygen be given. There are no solid data to guide us as to which oxygen concentrations www.thelancet.com Vol 377 April 2, 2011
should be used in each case. I and many others have for years recommended that oxygen supplementation should be guided by pulse oximeters, provided a pulse oximeter with proper technology is available. Reference values for oxygen saturations the first minutes after birth have been published.3 Some have suggested using these references as a guide.4 Until more data are available, we should provide 100% oxygen if there is a need for chest compressions or drugs, and subsequently wean down oxygen as quickly as possible. What about high altitude? Gonzales and Salirrosas5 showed that oxygen saturation is significantly higher in infants born at sea level (Lima, 150 m above sea level) than in infants born at a higher altitude (Cerro de Pasco, 4340 m) from 1 min to 24 h after birth. Until specific data are available from high-altitude areas, I recommend starting resuscitation with air, being prepared to add oxygen in selected cases. In most cases the pulmonary arterial pressure decreases satisfactorily with air resuscitation. To my knowledge there are no data to show that mixing nitric oxide with air during resuscitation of neonates is beneficial. This question should be addressed in an appropriately designed randomised controlled trial. Until data are available to show a potential shortterm and long-term benefit of adding nitric oxide to the resuscitation gas, such a practice is in my opinion not recommendable. I declare that I have no conflicts of interest.
Ola Didrik Saugstad [email protected] Department of Paediatric Research, Oslo University Hospital, Rikshospitalet, University of Oslo, 0027 Oslo, Norway 1
Perlman JM, Wyllie J, Kattwinkel J, et al, for the Neonatal Resuscitation Chapter Collaborators. Part 11: neonatal resuscitation. 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2010; 122 (suppl 2): S516–38.
2
3
4
5
Saugstad OD, Rootwelt T, Aalen O. Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: the Resair 2 study. Pediatrics 1998; 102: e1. Dawson JA, Kamlin CO, Vento M, et al. Defining the reference range for oxygen saturation for infants after birth. Pediatrics 2010; 125: e1340–47. Vento M, Saugstad OD. Oxygen supplementation in the delivery room: updated information. J Pediatr 2011; 158 (suppl 2): e5–7. Gonzales GF, Salirrosas A. Arterial oxygen saturation in healthy newborns delivered at term in Cerro de Pasco (4340 m) and Lima (150 m). Reprod Biol Endocrinol 2005; 3: 46.
Artesunate for severe malaria in African children The report by Arjen Dondorp and colleagues (Nov 13, p 1647)1 on the use of artesunate in the treatment of severe malaria in African children provides some hope for a cheap and improved management of severe malaria in African children. However, the case definition for severe malaria leaves a crucial question unanswered. The definition of severe malaria in malaria-endemic regions with high prevalence of asymptomatic parasitaemia and comorbid conditions remains contentious. The heterogeneity of disease transmission in these settings might have been partly overcome by the application of a parasite density threshold, but the case definition for severe malaria would have been substantially improved by excluding children with meningitis, bacteraemia, and pneumonia.2 Inclusion of these children in the analysis could confound the interpretation of the results. The innate antimicrobial activity of artesunate might have contributed to its superior efficacy over quinine, which has only antiparasitic activity. Given that as many as 20% of children with severe malaria could be bacteraemic,3 and the absence of efficacy data in patients with exclusive 1153
Correspondence
malaria parasitaemia with symptoms, the question of the true efficacy of this agent in severe malaria could still be open. For practical implementation, it would now be important to address the question of whether artesunate be used as a sole agent in the management of “severe malaria” in patients who may have malaria parasitaemia with undiagnosed bacteraemia. I declare that I have no conflicts of interest.
Stephen K Obaro [email protected] Michigan State University, East Lansing, MI 48824, USA 1
2
3
Dondorp AM, Fanella CI, Hendriksen ICE, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010; 376: 1647–57. Bejon P, Berkley JA, Mwangi T, et al. Defining childhood severe falciparum malaria for intervention studies. PLoS Med 2007; 4: e251. Berkley JA, Lowe BS, Mwangi I, et al. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med 2005; 352: 39–47.
Authors’ reply
Corbis
Stephen Obaro argues that children with a diagnosis of meningitis, bacteraemia, and pneumonia should have been excluded from the AQUAMAT trial, since their inclusion would have confounded the interpretation of the results. This is easier said than done. Inclusion of all severely ill children with a positive rapid test for falciparum malaria reflects the “real life” situation in African hospitals. The signs and symptoms of severe malaria overlap with those of other common severe febrile illnesses including pneumonia, meningitis, and bacterial septicaemia. Furthermore, African children with slide-proven severe malaria commonly have concomitant bacteraemia (4·6–11·7%).1–4 Given the limited sensitivity of conventional blood culture, the real proportion might indeed be as high as 20%. Introduction of a parasite density threshold does not exclude concomitant sepsis, since severe malaria in itself is a risk factor for invasive bacterial infection. Since bacteraemia 1154
confers a 2·5–8·5-fold increased risk of death in children with severe malaria, and the artemisinins do not have substantial antimicrobial effects, the inclusion of children with concomitant invasive bacterial infection in our trial will have diluted the lifesaving benefit of artesunate over quinine. This dilution might be an important contributor to the lower relative risk of death for artesunate versus quinine in African children (23%) than in Asian adults (35%) since bacteraemia is much less common in adults with severe malaria. The high incidence of concomitant bacterial infection does raise the important question of whether all children with a diagnosis of severe falciparum malaria should also receive a broad-spectrum parenteral antibiotic such as a third-generation cephalosporin. We declare that we have no conflicts of interest.
Arjen M Dondorp, Caterina I Fanello, Lorenz von Seidlein, Nicholas P J Day, *Nicholas J White [email protected] Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (AMD, CIF, NPJD, NJW); Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK (AMD, CIF, NPJD, NJW); and Menzies School of Health Research, Casuarina, NT, Australia (LvS) 1
2
3
4
Berkley J, Mwarumba S, Bramham K, Lowe B, Marsh K. Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg 1999; 93: 283–86. Berkley JA, Bejon P, Mwangi T, et al. HIV infection, malnutrition, and invasive bacterial infection among children with severe malaria. Clin Infect Dis 2009; 49: 336–43. Were T, Davenport GC, Hittner JB, et al. Bacteremia in Kenyan children with malaria presenting at a rural hospital in a holoendemic Plasmodium falciparum transmission area. J Clin Microbiol 2010; published online 24 Nov. DOI:10.1128/JCM.01864-10. Nadjm B, Amos B, Mtove G, et al. WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: a prospective study. BMJ 2010; 340: c1350.
Department of Error Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377: 42–51—In this Article (Jan 1), the conflicts of interest statement for JVC should have stated that JVC has done consultancy for Roche, received payment for educational presentations from Roche, received honoraria and grants from Roche, served as an investigator in Roche-funded research, and received travel grants from Roche. These corrections have been made to the online version as of April 1, 2011. Sengupta A, Prasad V. Towards a truly universal Indian health system. Lancet 2011; 377: 702–03—The print version of this Comment (Feb 26) contained the wrong DOI. The correct DOI is 10.1016/S01406736(10)62043-0. The online version of the Comment is correct. Reddy KS, Patel V, Jha P, et al, for The Lancet India Group for Universal Healthcare. Towards achievement of universal health care in India by 2020: a call to action. Lancet 2011; 377: 760–68—The print version of this Series paper (Feb 26) should have referred readers to DOI:10.1016/S0140-6736(10)62041-7 under the “See Online/Comment” information. The online version of the paper is correct.
www.thelancet.com Vol 377 April 2, 2011
newborn resuscitation. Certain kinds of inhaled gas (eg, nitric oxide) have been shown to reduce the pulmonary hypertension that is common during the fetal–neonatal transition period of full-term or late-preterm neonates selectively and effectively.3 Should such gases be considered for integration into oxygen therapy for newborn resuscitation to maximise net gain? We declare that we have no conflicts of interest.
*Bing Hou, Zhi-Wei Xu, Lai-Shuan Wang [email protected] State Key Laboratory of Proteomics, Beijing Institute of Radiation Medicine, Beijing, China (BH, ZWX); and Department of Neonatology, Children’s Hospital of Fudan University, Shanghai, China (LSW) 1
2
3
Saugstad OD. Resuscitation of newborn infants: from oxygen to room air. Lancet 2010; 376: 1970–71. Kattwinkel J, Perlman JM, Aziz K, et al. Neonatal resuscitation: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics 2010; 126: e1400–13. American Academy of Pediatrics Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics 2000; 106: 344–45.
Author’s reply Bing Hou and colleagues raise some timely questions about the use of oxygen or air for newborn resuscitation. After my Comment was accepted, the International Liaison Committee on Resuscitation stated in their 2010 guidelines for newborn resuscitation that “it is best to begin with air rather than 100% oxygen”.1 In our first clinical studies with air versus 100% oxygen,2 we showed that it is possible to resuscitate with air, having oxygen as a backup and switching to oxygen after 90 s in the absence of a satisfactory response to air. Oxygenation depends, however, largely on lung surface area so it is not appropriate to start giving oxygen until appropriate attempts have been made to aerate the lung. Only in a few cases should oxygen be given. There are no solid data to guide us as to which oxygen concentrations www.thelancet.com Vol 377 April 2, 2011
should be used in each case. I and many others have for years recommended that oxygen supplementation should be guided by pulse oximeters, provided a pulse oximeter with proper technology is available. Reference values for oxygen saturations the first minutes after birth have been published.3 Some have suggested using these references as a guide.4 Until more data are available, we should provide 100% oxygen if there is a need for chest compressions or drugs, and subsequently wean down oxygen as quickly as possible. What about high altitude? Gonzales and Salirrosas5 showed that oxygen saturation is significantly higher in infants born at sea level (Lima, 150 m above sea level) than in infants born at a higher altitude (Cerro de Pasco, 4340 m) from 1 min to 24 h after birth. Until specific data are available from high-altitude areas, I recommend starting resuscitation with air, being prepared to add oxygen in selected cases. In most cases the pulmonary arterial pressure decreases satisfactorily with air resuscitation. To my knowledge there are no data to show that mixing nitric oxide with air during resuscitation of neonates is beneficial. This question should be addressed in an appropriately designed randomised controlled trial. Until data are available to show a potential shortterm and long-term benefit of adding nitric oxide to the resuscitation gas, such a practice is in my opinion not recommendable. I declare that I have no conflicts of interest.
Ola Didrik Saugstad [email protected] Department of Paediatric Research, Oslo University Hospital, Rikshospitalet, University of Oslo, 0027 Oslo, Norway 1
Perlman JM, Wyllie J, Kattwinkel J, et al, for the Neonatal Resuscitation Chapter Collaborators. Part 11: neonatal resuscitation. 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2010; 122 (suppl 2): S516–38.
2
3
4
5
Saugstad OD, Rootwelt T, Aalen O. Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: the Resair 2 study. Pediatrics 1998; 102: e1. Dawson JA, Kamlin CO, Vento M, et al. Defining the reference range for oxygen saturation for infants after birth. Pediatrics 2010; 125: e1340–47. Vento M, Saugstad OD. Oxygen supplementation in the delivery room: updated information. J Pediatr 2011; 158 (suppl 2): e5–7. Gonzales GF, Salirrosas A. Arterial oxygen saturation in healthy newborns delivered at term in Cerro de Pasco (4340 m) and Lima (150 m). Reprod Biol Endocrinol 2005; 3: 46.
Artesunate for severe malaria in African children The report by Arjen Dondorp and colleagues (Nov 13, p 1647)1 on the use of artesunate in the treatment of severe malaria in African children provides some hope for a cheap and improved management of severe malaria in African children. However, the case definition for severe malaria leaves a crucial question unanswered. The definition of severe malaria in malaria-endemic regions with high prevalence of asymptomatic parasitaemia and comorbid conditions remains contentious. The heterogeneity of disease transmission in these settings might have been partly overcome by the application of a parasite density threshold, but the case definition for severe malaria would have been substantially improved by excluding children with meningitis, bacteraemia, and pneumonia.2 Inclusion of these children in the analysis could confound the interpretation of the results. The innate antimicrobial activity of artesunate might have contributed to its superior efficacy over quinine, which has only antiparasitic activity. Given that as many as 20% of children with severe malaria could be bacteraemic,3 and the absence of efficacy data in patients with exclusive 1153
Correspondence
malaria parasitaemia with symptoms, the question of the true efficacy of this agent in severe malaria could still be open. For practical implementation, it would now be important to address the question of whether artesunate be used as a sole agent in the management of “severe malaria” in patients who may have malaria parasitaemia with undiagnosed bacteraemia. I declare that I have no conflicts of interest.
Stephen K Obaro [email protected] Michigan State University, East Lansing, MI 48824, USA 1
2
3
Dondorp AM, Fanella CI, Hendriksen ICE, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010; 376: 1647–57. Bejon P, Berkley JA, Mwangi T, et al. Defining childhood severe falciparum malaria for intervention studies. PLoS Med 2007; 4: e251. Berkley JA, Lowe BS, Mwangi I, et al. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med 2005; 352: 39–47.
Authors’ reply
Corbis
Stephen Obaro argues that children with a diagnosis of meningitis, bacteraemia, and pneumonia should have been excluded from the AQUAMAT trial, since their inclusion would have confounded the interpretation of the results. This is easier said than done. Inclusion of all severely ill children with a positive rapid test for falciparum malaria reflects the “real life” situation in African hospitals. The signs and symptoms of severe malaria overlap with those of other common severe febrile illnesses including pneumonia, meningitis, and bacterial septicaemia. Furthermore, African children with slide-proven severe malaria commonly have concomitant bacteraemia (4·6–11·7%).1–4 Given the limited sensitivity of conventional blood culture, the real proportion might indeed be as high as 20%. Introduction of a parasite density threshold does not exclude concomitant sepsis, since severe malaria in itself is a risk factor for invasive bacterial infection. Since bacteraemia 1154
confers a 2·5–8·5-fold increased risk of death in children with severe malaria, and the artemisinins do not have substantial antimicrobial effects, the inclusion of children with concomitant invasive bacterial infection in our trial will have diluted the lifesaving benefit of artesunate over quinine. This dilution might be an important contributor to the lower relative risk of death for artesunate versus quinine in African children (23%) than in Asian adults (35%) since bacteraemia is much less common in adults with severe malaria. The high incidence of concomitant bacterial infection does raise the important question of whether all children with a diagnosis of severe falciparum malaria should also receive a broad-spectrum parenteral antibiotic such as a third-generation cephalosporin. We declare that we have no conflicts of interest.
Arjen M Dondorp, Caterina I Fanello, Lorenz von Seidlein, Nicholas P J Day, *Nicholas J White [email protected] Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (AMD, CIF, NPJD, NJW); Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK (AMD, CIF, NPJD, NJW); and Menzies School of Health Research, Casuarina, NT, Australia (LvS) 1
2
3
4
Berkley J, Mwarumba S, Bramham K, Lowe B, Marsh K. Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg 1999; 93: 283–86. Berkley JA, Bejon P, Mwangi T, et al. HIV infection, malnutrition, and invasive bacterial infection among children with severe malaria. Clin Infect Dis 2009; 49: 336–43. Were T, Davenport GC, Hittner JB, et al. Bacteremia in Kenyan children with malaria presenting at a rural hospital in a holoendemic Plasmodium falciparum transmission area. J Clin Microbiol 2010; published online 24 Nov. DOI:10.1128/JCM.01864-10. Nadjm B, Amos B, Mtove G, et al. WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: a prospective study. BMJ 2010; 340: c1350.
Department of Error Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377: 42–51—In this Article (Jan 1), the conflicts of interest statement for JVC should have stated that JVC has done consultancy for Roche, received payment for educational presentations from Roche, received honoraria and grants from Roche, served as an investigator in Roche-funded research, and received travel grants from Roche. These corrections have been made to the online version as of April 1, 2011. Sengupta A, Prasad V. Towards a truly universal Indian health system. Lancet 2011; 377: 702–03—The print version of this Comment (Feb 26) contained the wrong DOI. The correct DOI is 10.1016/S01406736(10)62043-0. The online version of the Comment is correct. Reddy KS, Patel V, Jha P, et al, for The Lancet India Group for Universal Healthcare. Towards achievement of universal health care in India by 2020: a call to action. Lancet 2011; 377: 760–68—The print version of this Series paper (Feb 26) should have referred readers to DOI:10.1016/S0140-6736(10)62041-7 under the “See Online/Comment” information. The online version of the paper is correct.
www.thelancet.com Vol 377 April 2, 2011