Advance 1: Improvements in the treatment of severe
malaria
In the two largest randomized controlled trials conducted in patients
hospitalised with severe falciparum malaria artesunate was shown to
reduce mortality substantially. The mortality reduction (95% confidence
interval) was 34.7% (18·5 to 47·6%) in Southeast Asian adults and
children and 22.5% (8·1 to 36·9%) in African children (3,4) (Figure
1). In African children it can be difficult to distinguish severe
malaria from bacterial sepsis with incidental parasitaemia. In those
children with a high likelihood of having severe malaria based on
parasite biomass estimation the reduction in mortality was the same
(i.e. one third) as observed in the Asian series (5). Artesunate was
also better tolerated (less hypoglycaemia) and easier to administer
(intravenous injection rather than controlled rate infusion, and no pain
and local toxicity following intramuscular injection) than the previous
“gold-standard” treatment quinine. Importantly there were also less
neurological sequelae in the survivors so lives were not saved at the
expense of neurological deficits. Artemether is nearly as active as
artesunate in-vitro against P. falciparum but, being an
oil-based intramuscular injection, is slowly and erratically absorbed
from the intramuscular injection site in-vivo (particularly in shocked
patients) (6). In contrast the water soluble artesunate is rapidly and
reliably absorbed. This probably explains why the severe malaria
mortality following artemether is higher than that following artesunate
treatment (7,8). Community based pre-referral rectal artesunate was also
shown to reduce malaria attributable mortality by 25% in children
unable to take oral antimalarial medications (9) Since these trials
reported artesunate has become the generally recommended first line
treatment for severe malaria (1) and usage has increased substantially,
although unfortunately quinine is still the only available parenteral
antimalarial in some malaria endemic areas.
Following drug administration the DHA derivatives are rapidly and
reliably converted back to DHA in-vivo which is then very rapidly
eliminated (t1/2 < 1 hour) mainly by
glucuronidation (10), yet they are highly efficacious when given once
daily (11). The main pathological process in severe falciparum malaria
is the sequestration of erythrocytes containing mature forms of the
parasite in the vascular beds of vital organs (5,12). This reduces
microcirculatory blood flow and probably markedly disturbs endothelial
function. The key pharmacodynamic effect of the artemisinin derivatives,
which mediates the life-saving advantage over quinine, is their action
in killing the younger circulating stages of P. falciparum before
they sequester (12). Unfortunately, this property is reduced markedly in
artemisinin resistance.
Apart from the prompt initiation of renal replacement therapies
(preferably haemofiltration) in acute kidney injury (12,13), no adjuvant
therapies have proved beneficial and many (including aspirin,
corticosteroids, heparin, mannitol, high dose phenobarbitone, anti-TNF
antibody and rapid fluid loading) were found to be harmful in severe
malaria (12,14).