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close this bookGuidelines for the Treatment of Malaria (WHO; 2006; 266 pages) View the PDF document
View the documentGlossary
View the documentAbbreviations
open this folder and view contents1. Introduction
View the document2. The clinical disease
open this folder and view contents3. Treatment objectives
open this folder and view contents4. Diagnosis of malaria
open this folder and view contents5. Resistance to antimalarial medicines9
open this folder and view contents6. Antimalarial treatment policy
open this folder and view contents7. Treatment of uncomplicated P. Falciparum malaria10
close this folder8. Treatment of severe falciparum malaria14
View the document8.1 Definition
View the document8.2 Treatment objectives
View the document8.3 Clinical assessment
View the document8.4 Specific antimalarial treatment
View the document8.5 Practical aspects of treatment
View the document8.6 Follow-on treatment
View the document8.7 Pre-referral treatment options16
View the document8.8 Adjunctive treatment
View the document8.9 Continuing supportive care
View the document8.10 Additional aspects of clinical management
View the document8.11 Treatment during pregnancy
View the document8.12 Management in epidemic situations
View the document8.13 Hyperparasitaemia18
open this folder and view contents9. Treatment of malaria caused by P. vivax, P. ovale or P. malariae19
View the document10. Mixed malaria infections
open this folder and view contents11. Complex emergencies and epidemics
open this folder and view contentsAnnexes
 

8.4 Specific antimalarial treatment

It is essential that antimalarial treatment in full doses is given as soon as possible in severe malaria. Two classes of drugs are currently available for the parenteral treatment of severe malaria: the cinchona alkaloids (quinine and quinidine) and the artemisinin derivatives (artesunate, artemether and artemotil). Although there are a few areas where chloroquine is still effective, parenteral chloroquine is no longer recommended for the treatment of severe malaria because of widespread resistance. Intramuscular sulfadoxine- pyrimethamine is also not recommended.

8.4.1 Quinine

Quinine treatment for severe malaria was established before modern trial methods were developed. Several salts of quinine have been formulated for parenteral use, but the dihydrochloride is the most widely used. Peak concentrations following intramuscular quinine in severe malaria are similar to those following intravenous infusion. Pharmacokinetic modelling studies suggest that a loading dose of quinine of twice the maintenance dose (i.e. 20 mg salt/kg bw) reduces the time to reach therapeutic plasma concentrations. After the first day of treatment, the total daily maintenance dose of quinine is 30 mg salt/kg bw (usually divided into three equal administrations at 8 h intervals).

EVIDENCE: trials on dosage and route of administration of quininea

Interventions: high first dose of quinine (loading dose 20 mg/kg bw) compared with non-loading dose regimen

Summary of RCTs: a systematic review of two small trials showed shorter parasite and fever clearance time with high first-dose regimens but the trials were too small to show an impact on mortality.

Pharmacokinetic studies: a 20 mg salt/kg bw loading dose results in effective blood levels of quinine being reached by the end of a 4-h infusion or within 4 h of i.m. administration. If a loading dose is not given, therapeutic concentrations may not be reached in the first 12 h of treatment.

Basis of decision: pharmacokinetic studies.


Recommendation: use a loading dose of quinine of 20 mg salt/kg bw.

Interventions: quinine i.m. compared with quinine by i.v. infusion

Summary of RCTs: one small trial of limited power did not demonstrate large differences.

Expert comment: peak plasma concentrations are similar for both routes of administration. However, quinine i.m. may be erratically absorbed in severe malaria, particularly in patients with shock.

Basis of decision: pharmacokinetic studies.


Recommendation: rate-controlled i.v. infusion is the preferred route of quinine administration, but if this cannot be given safely, then i.m. injection is a satisfactory alternative.

Interventions: quinine, rectal compared with quinine by i.m or i.v. infusion

Summary of RCTs: one systematic review of 8 trials detected no difference in effect on parasites, clinical illness between the rectal group and either i.m or i.v. groups. Some studies however excluded patients with severe malaria.

Expert comment: quinine dihydrochloride is locally irritant, quinine gluconate is less irritant.

Basis of decision: systematic review.


Recommendation: there is insufficient evidence to recommend rectal administration of quinine unless parenteral administration is not possible and no other effective options are available.

 

a See also Annex 9.1-9.3.


8.4.2 Artemisinin derivatives

Various artemisinin derivatives have been used in the treatment of severe malaria including artemether, artemisinin (rectal), artemotil and artesunate. The pharmacokinetic properties of artesunate are superior to those of artemether and artemotil as it is water soluble and can be given either by intravenous or intramuscular injection. Randomised trials comparing artesunate and quinine from South-East Asia show clear evidence of benefit with artesunate. In the largest multi-centre trial, which enrolled 1461 patients (including 202 children <15 years old), mortality was reduced by 34.7% compared to the quinine group. The results of this and smaller trials are consistent and suggest that artesunate is the treatment of choice for adults with severe malaria.

There are, however, still insufficient data for children, particularly from high transmission settings to make the same conclusion. An individual patient data meta-analysis of trials comparing artemether and quinine showed no difference in mortality in African children.

Although artesunate has better pharmacokinetic properties than artemether or artemotil, there are relatively few published comparative clinical trials. Concerns have been raised, regarding the possibility that the intrinsic benefits of artemether as an antimalarial may have been negated by its erratic absorption following intramuscular injection. Artemotil is very similar to artemether, but very few trials have been conducted.

EVIDENCE: trials of treatment of severe malaria with artemisinin derivatives compared to quininea

Interventions: AS i.v. compared with quinine i.v. infusion

Summary of RCTs: multi-centre trials enrolling 1461 patients, with mortality in the AS vs QN being 15% vs 22%. There was a relative reduction in mortality of 34.7% (95% CI: 18.5-47.6%; p = 0.002) in the AS group. QN was associated with hypoglycaemia (RR: 3.2, p = 0.009). Clear evidence of mortality benefit with artesunate.

Expert comment: trials mainly in Asian adults, more information needed in children in higher transmission settings. There are no RCTs comparing AS with artemether i.m.

Basis of decision: RCT


Recommendation: AS is the recommended first choice in areas of low-malaria transmission.

Interventions: artemether i.m. compared with quinine i.v. infusion

Summary of RCTs: systematic review of 11 RCTs; analysis across all trials showed lower mortality with artemether, but this was not significant in an analysis of adequately concealed trials (RR: 0.8; 95% CI: 0.52-1.25). Within these, in an individual patient data analysis of 1919 adults and children, the odds ratio for deaths in artemether recipients was 0.8 (95% CI: 0.62-1.02). In the prospectively defined subgroup analysis of adults with multisystem failure, there was a significant difference in mortality in favour of artemether.

Expert comment: artemether i.m. is erratically absorbed in severe malaria particularly in patients with shock.

Basis of decision: systematic review.


Recommendation: artemether i.m. is an acceptable alternative to quinine i.v. infusion.

Interventions: artemotil i.m. compared with quinine by i.v. infusion

Summary of RCTs: systematic review of two trials; the trials had insufficient power to show a difference.

Expert comment: insufficient clinical trials and pharmacokinetic data to warrant a recommendation.

Basis of decision: systematic review.


Recommendation: do not use artemotil unless alternatives are not available.

Interventions: artemisinin derivatives, rectal, compared with quinine by i.v. infusion

Summary of RCTs: systematic review of three trials; the trials had insufficient power to show a difference.

However, rectal artesunate has superior effect in reducing parasite densities compared to quinine (i.v. or i.m.) at 12 and 24 hours after administration.

Expert comment: pharmacokinetic studies suggest highly variable but adequate absorption of rectal artemisinin and rectal artesunate. Rectal formulations have been developed for pre-referral use.

Basis of decision: systematic review.


Recommendation: use artemisinins rectally for complete treatment only when parenteral antimalarial treatment is not possible.

 

a See also Annex 9.4-9.7.


8.4.3 Quinidine

Quinidine commonly causes hypotension and concentration-dependent prolongation of ventricular repolarization (QT prolongation). Quinidine is thus considered more toxic than quinine and should only be used if none of the other effective parenteral drugs are available. Electrocardiographic monitoring and frequent assessment of vital signs are required if quinidine is used.

Summary of recommendations on the treatment of severe malaria

RECOMMENDATIONS

LEVEL OF EVIDENCE

Severe malaria is a medical emergency.

After rapid clinical assessment and confirmation of the diagnosis, full doses of parenteral antimalarial treatment should be started without delay with whichever effective antimalarial is first available.

E

Artesunate 2.4 mg/kg bw i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day is the recommended choice in low transmission areas or outside malaria endemic areas

S

For children in high transmission areas, the following antimalarial medicines are recommended as there is insufficient evidence to recommend any of these antimalarial medicines over another for severe malaria:

- artesunate 2.4 mg/kg bw i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day;

- artemether 3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day;

- quinine 20 mg salt/kg bw on admission (i.v. infusion or divided i.m. injection), then 10 mg/kg bw every 8 h; infusion rate should not exceed 5 mg salt/kg bw per hour.

S, T, O, E

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