- Email: [email protected]
Artesunate versus quinine for severe falciparum malaria
Correspondence
ambulatory outcomes. So, if anything, the shorter intervals in our surgical group might have introduced a bias against surgery. Ian Kunkler speculates that more patients in the radiotherapy alone group might have had MSCC due to compression by bone rather than by soft tissue. Compromise of the spinal cord by bone was included in the definition of “unstable spine” used in this trial as a stratification factor. There were equal numbers with unstable spines in each treatment group. Furthermore, when we did a multivariate analysis with an unstable spine as a prognostic factor, it did not prove to be significant either overall or within each treatment group. A further review of our data specifically to answer this question showed no significant difference in the distribution of spinal cord compression due to bone versus soft tissue impingement. Kunkler also suggests that non-neurological factors rather than treatment effect were responsible for the poor results in the radiation-alone group. The differences in 30-day morbidity and mortality were overwhelmingly due to the secondary effects of not being able to walk (eg, deep vein thrombosis or infection). Since ambulation was the factor that was most influenced by surgical treatment, these problems were ultimately related to neurological factors. We think that neither hypothesis suggested by Kunkler is the best explanation for the results of the study. The difference in outcomes between the two treatment groups is almost certainly due to the fact that surgery was simply a better treatment, allowing patients to remain ambulatory for longer. These patients were less susceptible to the secondary effects of paraplegia. We declare that we have no conflict of interest.
*Roy A Patchell, Phillip A Tibbs, William F Regine [email protected] Division of Neurosurgery, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536, USA (RAP, PAT); and Department of
110
Radiation Oncology, University of Maryland Medical School, Baltimore, MD, USA (WFR) 1
2
Helweg-Larsen S, Sorensen PS, Kreiner S. Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients. Int J Radiat Oncol Biol Phys 2000; 46: 1163–69. Loblaw DA, Smith K, Lockwood G, Laperriere N. The Princess Margaret Hospital Experience of malignant spinal cord compression. Proc Am Soc Clin Oncol 2003; 22: 119 (abstr 477).
Artesunate versus quinine for severe falciparum malaria The South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT; Aug 27, p 717)1 represents the first clinical trial to show an improvement in mortality from severe malaria, a notable achievement that encourages further studies in sub-Saharan Africa. Interestingly, only 3% of patients receiving quinine were seen to become hypoglycaemic after entry. This low rate might represent prevention of hypoglycaemia by appropriate replenishment of glucose, but it is more likely to reflect underdiagnosis for several reasons. As suggested by the investigators, clinical signs of hypoglycaemia are often absent in severe malaria. In comparable studies (table),2,3 hypoglycaemia complicated about 25% of severe malaria cases after quinine, suggesting that in SEAQUAMAT quinineinduced hypoglycaemia might have remained undiagnosed and consequently untreated. Under-recognition of this complication could have disproportionately increased mortality in quinine recipients to a potentially sig-
nificant level. Using predicted rates of postadmission hypoglycaemia of 25% and 10% for severe malaria patients receiving quinine and artesunate, respectively, we calculate that 116 and 45 cases of hypoglycaemia, respectively, could have been undiagnosed (an excess of 71 cases in the quinine group). The potential contribution of these cases to excess deaths in the quinine group is clearly substantial. In adults, quinine-induced hypoglycaemia typically occurs at least 24–48 h after admission4 when peripheral insulin resistance might be decreasing and when excess deaths began to accumulate in SEAQUAMAT. Artesunate has proved itself better than quinine in SEAQUAMAT, but given the possibility of undetected but treatable quinine toxicity, assessment of the contribution of superior antimalarial efficacy of artesunate to improved survival could be difficult. It would be valuable to understand the reasons why hypoglycaemia might have been underestimated here, particularly if these reasons vary between sites. These considerations are especially relevant to populations in whom the risk of hypoglycaemia is even higher, such as children with severe malaria. Future trials comparing quinine and artesunate might need to implement additional procedures for prevention, detection, and treatment of hypoglycaemia. We declare that we have no conflict of interest.
Charles J Woodrow, Timothy Planche, *Sanjeev Krishna [email protected]
Drugs and Artemisinin derivative group route of administration
Quinine group
Deaths Hypoglycaemia Hypoglycaemia Deaths Hypoglycaemia Hypoglycaemia at admission after admission at admission after admission Hien2
IM artemether, IM quinine Newton3 IM artesunate, IM quinine SEAQU- IM artesunate, 1 IM quinine AMAT
36/284 23/284 (8%) (13%) 7/59 1/59 (1%) (12%) 107/730 8/730 (1%) (15%)
31/284 (11%) 47/276 18/276 (7%) (17%) 6/59 (10%) 12/54 0/54 (22%) 6/730 (1%) 164/731 17/731 (3%) (22%)
69/276 (25%) 15/54 (28%) 19/731 (3%)
Table: Rate of death and hypoglycaemia in randomised controlled trials comparing parenteral artemisinin derivatives and quinine in adults with severe malaria
www.thelancet.com Vol 367 January 14, 2006
Correspondence
1
2
3
4
SEAQUAMAT Group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717–25. Hien TT, Day NP, Nguyen HP, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996; 335: 76–83. Newton PN, Angus BJ, Chierakul W, et al. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis 2003; 37: 7–16. White NJ, Warrell DA, Chanthavanich P, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 1983; 309: 61–66.
The report by the South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group1 is an impressive display of intravenous artesunate’s superiority over intravenous quinine in southeast Asia, at least with respect to cure and survival. However, the paper does raise concern over the neurotoxicity of the artemisinins. Since coma recovery times are not specifically reported in the paper, the times to speak, sit, and eat are taken as indicators of coma recovery. No significant differences were found in these recovery times between the two treatment groups. This finding is in the face of quinine’s reduced powers in the region, as stated by the SEAQUAMAT group: “There is evidence of a decline in the efficacy of the drug in southeast Asia, in terms of parasite and fever clearance in uncomplicated malaria and coma recovery times in severe malaria”. The question the SEAQUAMAT report raises is this: is artesunate’s inability to wake patients up faster a sign of occult neurotoxicity? There are theoretical grounds to believe that this might be so. First, the neurotoxic potential of artemisinins is well known,2 with characteristic brainstem lesions the hallmark. Second, treating severe falciparum malaria with intravenous artesunate, Davis and colleagues3 found indications that artesunate’s main metabolite, dihydroartemisinin, accumulates in cerebrospinal fluid; the mean dihydroartemisinin concentration found by Davis and colleagues was www.thelancet.com Vol 367 January 14, 2006
0·031 mg/L (0·11 mol/L). Referenced to dihydroartemisinin’s effect on neurite sprouting by neuroblastoma cells in culture, this concentration was interpreted at the time as being subtoxic.4 Later work by Schmuck and colleagues,5 however, which examined dihydroartemisinin’s toxicity to in vitro neural networks, showed exquisite sensitivity to dihydroartemisinin by brainstem neurons. The “no effect concentration” for neuronal ATP depletion found by Schmuck and colleagues was less than 0·001 mg/L—ie, more than 30 times less than the concentration in cerebrospinal fluid shown in malaria patients by Davis and colleagues. It has been shown that the artemisinins induce oxidative stress in brainstem neurons, with collapse of the mitochondrial membrane potential and loss of activity in superoxide dismutase—an enzyme that protects against oxidative stress;5 a 400% increase in reactive oxygen species was noted at a dihydroartemisinin concentration of 0·01 mg/L; ATP depletion is probably part of these processes. Strikingly, the sensitivity of cortical neurons to dihydroartemisinin is an order of magnitude less than that of brainstem nuclei, offering a credible explanation as to why the lesions so characteristic of artemisinin neurotoxicity preferentially locate themselves in the brainstem. Although the SEAQUAMAT report reassures over artemisinin efficacy, it increases concerns over safety. I have been reimbursed by numerous manufacturers of antimalarials for attending conferences, speaking, and consulting. I am married to a former Novartis employee formerly associated with artemetherlumefantrine.
Stephen Toovey [email protected] Academic Centre for Travel Medicine and Vaccines, Royal Free Travel Health Centre, London NW3 2PF, UK 1
2
3
SEAQUAMAT Group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717–25. Park BK, O’Neill PM, Maggs JL, Pirmohamed M. Safety assessment of peroxide antimalarials: clinical and chemical perspectives. Br J Clin Pharmacol 1998; 46: 521–29. Davis TME, Binh TQ, Ilett KF, et al. Penetration of dihydroartemisinin into cerebrospinal fluid after administration of intravenous artesunate in
4
5
severe falciparum malaria. Antimicrob Agents Chemother 2003; 47: 368–70. Smith SL, Sadler CJ, Dodd CC, et al. The role of glutathione in the neurotoxicity of artemisinin derivatives in vitro. Biochem Pharmacol 2001; 61: 409–16. Schmuck G, Roehrdanz E, Haynes RK, Kahl R. Neurotoxic mode of action of artemisinin. Antimicrob Agents Chemother 2002; 46: 821–27.
Authors’ reply Quinine stimulates the pancreatic cells to release insulin, and can cause hypoglycaemia.1 In the acute phase of severe malaria, this effect is often attenuated, presumably because of -cell dysfunction. Blood glucose was not monitored routinely after admission in the SEAQUAMAT study (as indeed in most tropical hospitals), although facilities for checking glucose frequently were available in three of the four study centres. If there was an unexplained clinical deterioration and blood glucose could not be checked, glucose was given parenterally. As we stated in our paper, hypoglycaemia was still probably underestimated, but there are several reasons why this is unlikely to have contributed significantly to the large difference in mortality between artesunate and quinine. First, more than half the 1461 patients enrolled were conscious. Loss of consciousness more than 24 h after admission, as would be expected in severe iatrogenic (ie, quinine-induced hyperinsulinaemic) hypoglycaemia, occurred in only 63 of these patients (35 on quinine and 28 on artesunate; relative risk 1·3, 95% CI 0·8–2·1, p=0·27). Second, late hyperinsulinaemic hypoglycaemia does not carry the same mortality as admission hypoglycaemia. Hypoglycaemia documented on admission with severe malaria and usually accompanied by lactic acidosis carries a very poor prognosis.1 In the absence of quinine pretreatment, plasma insulin concentrations are appropriately suppressed. Although late hypoglycaemia was still associated with death in the SEAQUAMAT study (relative risk 2·2, 95% CI 1·3–3·6, p=0·005), in the quinine group, mortality was not significantly higher in those with late
Rights were not granted to include this image in electronic media. Please refer to the printed journal
111
Science Photo Library
Division of Cellular and Molecular Medicine, Centre for Infection, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK
ambulatory outcomes. So, if anything, the shorter intervals in our surgical group might have introduced a bias against surgery. Ian Kunkler speculates that more patients in the radiotherapy alone group might have had MSCC due to compression by bone rather than by soft tissue. Compromise of the spinal cord by bone was included in the definition of “unstable spine” used in this trial as a stratification factor. There were equal numbers with unstable spines in each treatment group. Furthermore, when we did a multivariate analysis with an unstable spine as a prognostic factor, it did not prove to be significant either overall or within each treatment group. A further review of our data specifically to answer this question showed no significant difference in the distribution of spinal cord compression due to bone versus soft tissue impingement. Kunkler also suggests that non-neurological factors rather than treatment effect were responsible for the poor results in the radiation-alone group. The differences in 30-day morbidity and mortality were overwhelmingly due to the secondary effects of not being able to walk (eg, deep vein thrombosis or infection). Since ambulation was the factor that was most influenced by surgical treatment, these problems were ultimately related to neurological factors. We think that neither hypothesis suggested by Kunkler is the best explanation for the results of the study. The difference in outcomes between the two treatment groups is almost certainly due to the fact that surgery was simply a better treatment, allowing patients to remain ambulatory for longer. These patients were less susceptible to the secondary effects of paraplegia. We declare that we have no conflict of interest.
*Roy A Patchell, Phillip A Tibbs, William F Regine [email protected] Division of Neurosurgery, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536, USA (RAP, PAT); and Department of
110
Radiation Oncology, University of Maryland Medical School, Baltimore, MD, USA (WFR) 1
2
Helweg-Larsen S, Sorensen PS, Kreiner S. Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients. Int J Radiat Oncol Biol Phys 2000; 46: 1163–69. Loblaw DA, Smith K, Lockwood G, Laperriere N. The Princess Margaret Hospital Experience of malignant spinal cord compression. Proc Am Soc Clin Oncol 2003; 22: 119 (abstr 477).
Artesunate versus quinine for severe falciparum malaria The South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT; Aug 27, p 717)1 represents the first clinical trial to show an improvement in mortality from severe malaria, a notable achievement that encourages further studies in sub-Saharan Africa. Interestingly, only 3% of patients receiving quinine were seen to become hypoglycaemic after entry. This low rate might represent prevention of hypoglycaemia by appropriate replenishment of glucose, but it is more likely to reflect underdiagnosis for several reasons. As suggested by the investigators, clinical signs of hypoglycaemia are often absent in severe malaria. In comparable studies (table),2,3 hypoglycaemia complicated about 25% of severe malaria cases after quinine, suggesting that in SEAQUAMAT quinineinduced hypoglycaemia might have remained undiagnosed and consequently untreated. Under-recognition of this complication could have disproportionately increased mortality in quinine recipients to a potentially sig-
nificant level. Using predicted rates of postadmission hypoglycaemia of 25% and 10% for severe malaria patients receiving quinine and artesunate, respectively, we calculate that 116 and 45 cases of hypoglycaemia, respectively, could have been undiagnosed (an excess of 71 cases in the quinine group). The potential contribution of these cases to excess deaths in the quinine group is clearly substantial. In adults, quinine-induced hypoglycaemia typically occurs at least 24–48 h after admission4 when peripheral insulin resistance might be decreasing and when excess deaths began to accumulate in SEAQUAMAT. Artesunate has proved itself better than quinine in SEAQUAMAT, but given the possibility of undetected but treatable quinine toxicity, assessment of the contribution of superior antimalarial efficacy of artesunate to improved survival could be difficult. It would be valuable to understand the reasons why hypoglycaemia might have been underestimated here, particularly if these reasons vary between sites. These considerations are especially relevant to populations in whom the risk of hypoglycaemia is even higher, such as children with severe malaria. Future trials comparing quinine and artesunate might need to implement additional procedures for prevention, detection, and treatment of hypoglycaemia. We declare that we have no conflict of interest.
Charles J Woodrow, Timothy Planche, *Sanjeev Krishna [email protected]
Drugs and Artemisinin derivative group route of administration
Quinine group
Deaths Hypoglycaemia Hypoglycaemia Deaths Hypoglycaemia Hypoglycaemia at admission after admission at admission after admission Hien2
IM artemether, IM quinine Newton3 IM artesunate, IM quinine SEAQU- IM artesunate, 1 IM quinine AMAT
36/284 23/284 (8%) (13%) 7/59 1/59 (1%) (12%) 107/730 8/730 (1%) (15%)
31/284 (11%) 47/276 18/276 (7%) (17%) 6/59 (10%) 12/54 0/54 (22%) 6/730 (1%) 164/731 17/731 (3%) (22%)
69/276 (25%) 15/54 (28%) 19/731 (3%)
Table: Rate of death and hypoglycaemia in randomised controlled trials comparing parenteral artemisinin derivatives and quinine in adults with severe malaria
www.thelancet.com Vol 367 January 14, 2006
Correspondence
1
2
3
4
SEAQUAMAT Group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717–25. Hien TT, Day NP, Nguyen HP, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996; 335: 76–83. Newton PN, Angus BJ, Chierakul W, et al. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis 2003; 37: 7–16. White NJ, Warrell DA, Chanthavanich P, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 1983; 309: 61–66.
The report by the South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group1 is an impressive display of intravenous artesunate’s superiority over intravenous quinine in southeast Asia, at least with respect to cure and survival. However, the paper does raise concern over the neurotoxicity of the artemisinins. Since coma recovery times are not specifically reported in the paper, the times to speak, sit, and eat are taken as indicators of coma recovery. No significant differences were found in these recovery times between the two treatment groups. This finding is in the face of quinine’s reduced powers in the region, as stated by the SEAQUAMAT group: “There is evidence of a decline in the efficacy of the drug in southeast Asia, in terms of parasite and fever clearance in uncomplicated malaria and coma recovery times in severe malaria”. The question the SEAQUAMAT report raises is this: is artesunate’s inability to wake patients up faster a sign of occult neurotoxicity? There are theoretical grounds to believe that this might be so. First, the neurotoxic potential of artemisinins is well known,2 with characteristic brainstem lesions the hallmark. Second, treating severe falciparum malaria with intravenous artesunate, Davis and colleagues3 found indications that artesunate’s main metabolite, dihydroartemisinin, accumulates in cerebrospinal fluid; the mean dihydroartemisinin concentration found by Davis and colleagues was www.thelancet.com Vol 367 January 14, 2006
0·031 mg/L (0·11 mol/L). Referenced to dihydroartemisinin’s effect on neurite sprouting by neuroblastoma cells in culture, this concentration was interpreted at the time as being subtoxic.4 Later work by Schmuck and colleagues,5 however, which examined dihydroartemisinin’s toxicity to in vitro neural networks, showed exquisite sensitivity to dihydroartemisinin by brainstem neurons. The “no effect concentration” for neuronal ATP depletion found by Schmuck and colleagues was less than 0·001 mg/L—ie, more than 30 times less than the concentration in cerebrospinal fluid shown in malaria patients by Davis and colleagues. It has been shown that the artemisinins induce oxidative stress in brainstem neurons, with collapse of the mitochondrial membrane potential and loss of activity in superoxide dismutase—an enzyme that protects against oxidative stress;5 a 400% increase in reactive oxygen species was noted at a dihydroartemisinin concentration of 0·01 mg/L; ATP depletion is probably part of these processes. Strikingly, the sensitivity of cortical neurons to dihydroartemisinin is an order of magnitude less than that of brainstem nuclei, offering a credible explanation as to why the lesions so characteristic of artemisinin neurotoxicity preferentially locate themselves in the brainstem. Although the SEAQUAMAT report reassures over artemisinin efficacy, it increases concerns over safety. I have been reimbursed by numerous manufacturers of antimalarials for attending conferences, speaking, and consulting. I am married to a former Novartis employee formerly associated with artemetherlumefantrine.
Stephen Toovey [email protected] Academic Centre for Travel Medicine and Vaccines, Royal Free Travel Health Centre, London NW3 2PF, UK 1
2
3
SEAQUAMAT Group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717–25. Park BK, O’Neill PM, Maggs JL, Pirmohamed M. Safety assessment of peroxide antimalarials: clinical and chemical perspectives. Br J Clin Pharmacol 1998; 46: 521–29. Davis TME, Binh TQ, Ilett KF, et al. Penetration of dihydroartemisinin into cerebrospinal fluid after administration of intravenous artesunate in
4
5
severe falciparum malaria. Antimicrob Agents Chemother 2003; 47: 368–70. Smith SL, Sadler CJ, Dodd CC, et al. The role of glutathione in the neurotoxicity of artemisinin derivatives in vitro. Biochem Pharmacol 2001; 61: 409–16. Schmuck G, Roehrdanz E, Haynes RK, Kahl R. Neurotoxic mode of action of artemisinin. Antimicrob Agents Chemother 2002; 46: 821–27.
Authors’ reply Quinine stimulates the pancreatic cells to release insulin, and can cause hypoglycaemia.1 In the acute phase of severe malaria, this effect is often attenuated, presumably because of -cell dysfunction. Blood glucose was not monitored routinely after admission in the SEAQUAMAT study (as indeed in most tropical hospitals), although facilities for checking glucose frequently were available in three of the four study centres. If there was an unexplained clinical deterioration and blood glucose could not be checked, glucose was given parenterally. As we stated in our paper, hypoglycaemia was still probably underestimated, but there are several reasons why this is unlikely to have contributed significantly to the large difference in mortality between artesunate and quinine. First, more than half the 1461 patients enrolled were conscious. Loss of consciousness more than 24 h after admission, as would be expected in severe iatrogenic (ie, quinine-induced hyperinsulinaemic) hypoglycaemia, occurred in only 63 of these patients (35 on quinine and 28 on artesunate; relative risk 1·3, 95% CI 0·8–2·1, p=0·27). Second, late hyperinsulinaemic hypoglycaemia does not carry the same mortality as admission hypoglycaemia. Hypoglycaemia documented on admission with severe malaria and usually accompanied by lactic acidosis carries a very poor prognosis.1 In the absence of quinine pretreatment, plasma insulin concentrations are appropriately suppressed. Although late hypoglycaemia was still associated with death in the SEAQUAMAT study (relative risk 2·2, 95% CI 1·3–3·6, p=0·005), in the quinine group, mortality was not significantly higher in those with late
Rights were not granted to include this image in electronic media. Please refer to the printed journal
111
Science Photo Library
Division of Cellular and Molecular Medicine, Centre for Infection, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK