Artemether

Editorials

Plasmodium falciparum malaria kills over 5,000 people every day. Most of these deaths are in African children but many are in nonimmune adults. With an incubation period of approximately 2 weeks, and ever increasing air travel, malaria in travelers may present to medical attention in temperate non-endemic countries. The diagnosis is often delayed, increasing the probability of progression to severe malaria and death. In this issue of AJRCCM (pp. 684-689), Bruneel and colleagues report their experience in the management of severe falciparum malaria at the Hopital Bichat-Claude Bernard in Paris (1). Between 1988 and 1999 they admitted 188 adult patients with severe malaria to their intensive care unit. This is the largest single center experience of managing severe malaria in recent years from a nonendemic country. It shows what can be achieved with modern intensive care, something that is unfortunately seldom possible in resource-limited tropical countries. None of the 95 patients with less severe malaria died, and the mortality in the 93 patients with strictly defined severe malaria was 11%. This is low by comparison with previous series of severe malaria from malaria-endemic areas, where the reported mortality has ranged from 10 to 40%, with lower figures reflecting a broader definition of severity rather than better management (2). The largest series of adults with severe falciparum malaria reported previously was a randomized, double-blind comparison of artemether and quinine in 560 Vietnamese patients (3). Of 276 quinine recipients, 47 died (17%) compared with 10 of 93 (11%) in the Paris series (p = 0.2). Comparison of blood lactate, an excellent overall measure of disease severity (2, 4), depth of coma, and degree of renal impairment suggests that there were no great differences in the overall severity of disease between the two studies.

Two factors are likely to contribute significantly to the low mortality reported in the Paris series. Both have important cost implications for developing countries. The first is early renal replacement. Recent studies have shown a significantly lower mortality with hemofiltration compared with peritoneal dialysis in sepsis or malaria-related acute renal failure (5). Metabolic acidosis resulting both from lactic acidosis and acute renal failure is a major cause of death in severe malaria (4). Peritoneal dialysis provides much slower correction of metabolic abnormalities than hemofiltration. Hemodialysis should be similar to hemofiltration in its efficiency. In the Paris series, 27 of 29 patients requiring renal replacement were treated with hemodialysis, whereas in the Vietnamese series the majority received peritoneal dialysis. The second major factor is mechanical ventilation; 43% of the severely ill patients in the Paris series were ventilated, whereas this is unavailable in most hospitals in endemic areas. Patients with severe falciparum malaria may die of acute respiratory arrest (2). The risk is increased by phenobarbitone (20 mg/kg loading dose)-an otherwise effective method of preventing convulsions in cerebral malaria (6). This suggests pathologic dysfunction of the respiratory centers in severe malaria, which could be pre-empted by mechanical ventilation. The pathogenesis of this problem is not fully understood. Although brain swelling is common in cerebral malaria, it results largely from intravascular space occupation provided by the large biomass of sequestered parasitized erythrocytes and not from cerebral edema (7). Tentorial or foramen magnum herniation is an unusual finding at autopsy in endemic areas. In contrast, cerebral edema was present in 4 of 10 fatal cases in the Paris series (although in 2, septic shock was a confounder), and in 1 there was herniation. One avoidable situation in which a lethal rise in intracranial pressure may occur is transient hypercapnia. Patients with severe falciparum malaria are acidotic (4) and compensate by hyperventilation. The low-normal Pa^sub (CO^sub 2^)^ maintains cerebral vasoconstriction. Even brief carbon dioxide retention, leading to cerebral vasodilatation, may result in a catastrophic rise in intracranial pressure. The engorged brain, full of static adherent parasitized erythrocytes and encased by the rigid cranium, has little space for further expansion. Intubation of patients with severe falciparum malaria must be done smoothly and rapidly to avoid this lethal scenario. Adults with severe falciparum malaria may also develop acute pulmonary edema associated with normal pulmonary arterial occlusion pressures (2, 8). As in other causes of acute respiratory distress syndrome, the mortality is high. In the current series, 5 of 10 fatal cases had pulmonary edema compared with only 5 (6%) of the 83 survivors. The Vietnamese series is probably generally representative of adult severe malaria in endemic countries; of the 83 patients who died, 35 had terminal respiratory arrest and 12 had pulmonary edema. Early positivepressure ventilation may prevent some of these deaths.

In the Paris series, 24 patients received inotropic support because of shock; 16 received dopamine, and 8 received epinephrine and/or norepinephrine, although epinephrine administration is a potent cause of lactic acidosis in severe malaria (8). Dopamine is often recommended because of its renal vasodilator effects, although direct hemodynamic studies of renal blood flow and metabolism in severe malaria provide no evidence that this is beneficial (9). Communityacquired bacterial coinfections occurred in 13 patients (14%), including 4 of 10 fatal cases. There were also 34 episodes of nosocomial infections in 23 (25%) patients. Severe falciparum malaria increases susceptibility to bacterial infections. Indeed, in African children there may be overlap between the presentations of bacterial sepsis and severe malaria (10). Any patient who deteriorates suddenly and unexpectedly while receiving intensive care for severe malaria should have hypoglycemia excluded, cultures taken, and broad-spectrum antibiotic treatment started (2).

These are good results, but could they have been even better? The mortality of untreated severe falciparum malaria probably approaches 100%. Specific antimalarial treatment with quinine reduces mortality up to 90%. No adjuvant has proved beneficial (11) (many have proved harmful!). But quinine may not be the best antimalarial treatment. There is increasing evidence that the artemisinin derivatives are better. In the recent individual patient data, meta-analysis of 1,919 adults and children entered into randomized comparisons of artemether and quinine, mortality was significantly lower in artemether-treated adults (12). Artemether is administered as an oil-based intramuscular injection. Its intrinsic advantage over quinine is blunted by slow and erratic absorption. Artesunate, a water-soluble artemisinin derivative that can be given by intravenous or intramuscular injection, is theoretically preferable. These potent antimalarials are easier to administer and safer than quinine as they do not cause hyperinsulemic hypoglycemia-a major complication of quinine treatment (3). But they are not available in most temperate countries. If they do become generally available, the mortality of severe malaria may be reduced even lower than the 11% achieved by the excellent team at the Hopital Bichat-Claude Bernard.

References

1. Bruneel F, Hocqueloux L, Alberti C, Wolff M, Chevret S, Bedos J-P, Durand R, Le Bras J, Regnier B, Vachon F. The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults. Am J Respir Crit Care Med 2003;167:684-689.

2. World Health Organization. Severe falciparum malaria. Trans R Soc Trop Med Hyg 2000;94:1-90.

3. Hien TT, Day NPJ, Phu NH, Mai NTH, Chau TTH, Loc PP, Sinh DX, Chuong LV, Vinh H, Waller D, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996;335:76-83.

4. Day NP, Phu NH, Mai NT, Chau TI, Loc PP, Chuong LV, Sinh DX, Holloway P, Hien TT, White NJ. The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit Care Med 2000; 28:1833-1840.

5. Phu NH, Hien TT, Mai NTH, Chau TTH, Chuong LV, Loc PP, Winearls CG, Farrar JJ, White NJ, Day NPJ. Hemofiltration and peritoneal dialysis in infection associated acute renal failure in Vietnam. N Engl J Med 2002;347:895-902.

6. Crawley J, Waruiru C, Mithwani S, Mwangi I, Watkins W, Ouma D, Winstanley P, Peto T, Marsh K. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. Lancet 2000;355:701-706.

7. Looareesuwan S, Wilairatana P, Krishna S, Kendall B, Vannaphon S, Viravan C, White NJ. Magnetic resonance imaging of the brain in cerebral malaria. Clin Infect Dis 1995;21:300-309.

8. Day NPJ, Phu NH, Bethell DB, Mai NTH, Chau TTH, Hien TT, White NJ. The effects of dopamine and adrenaline infusions on acid-base balance and systemic haemodynamics in severe infection. Lancet 1996; 348:219-223.

9. Day NP, Phu NH, Mai NT, Bethell DB, Chau TT, Loc PP, Chuong LV, Sinh DX, Solomon T, Haywood G, et al. Effects of dopamine and epinephrine infusions on renal hemodynamics in severe malaria and severe sepsis. Crit Care Med 2000;28:1353-1362.

10. Berkley J, Mwarumba S, Bramham K, Lowe B, Marsh K. Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg 1999;93:283-286.

11. White NJ. Not much progress in treatment of cerebral malaria. Lancet 1998;352:594-595.

12. The Artemether-Quinine Meta-analysis Study Group. A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg 2001;95:637-650.

DOI: 10. 1164/rccm.2212001

NICHOLAS J. WHITE, D.Sc., M.D.

Faculty of Tropical Medicine

Mahidol University

Bangkok, Thailand

Copyright American Thoracic Society Mar 1, 2003
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