OTHER ADJUNCTIVE THERAPIES
The malaria literature contains many small trials of potential adjunctive therapies for severe malaria. Most of these
studies to date have been underpowered, and in a recent
review many were found to have “inadequate methodological
quality.”49 In many cases, meta-analyses have been conducted
with multiple small trials in attempts to make sense of the
data, but still the power was usually insufficient to draw conclusions. An exception is the placebo-controlled trial of antiTNF trial in the Gambia reported in 1996, which recruited 610
patients, 124 of whom died. There was no mortality difference
and a suggestion of an increased incidence of sequelae in the
treatment group.50 The classic 1982 dexamethasone study
from Thailand on the other hand, although well-conducted
and the largest study ever in severe malaria at the time (N ס
100), is underpowered by today’s standards and may conceal
a type II error.51 A meta-analysis combining it with the second malaria steroid trial from Indonesia concluded that there
was insufficient power to exclude a mortality effect either
way.52,53 A meta-analysis of trials on the use of iron chelators
also concluded that, although no clear benefit was demon-strated, there is not enough data to draw a definitive conclusion.54
Exchange blood transfusion is a popular adjunctive
therapy, particularly in well-resourced settings. There are a
number of rationales for its use in severe malaria, including
removal of parasitized erythrocytes, removal of cytokines and
other soluble toxins and mediators, and improving the rheology of the blood unparasitized erythrocytes by replacing unparasitized erythrocytes with reduced deformability.55 However, no adequately powered randomized controlled clinical
trial has been performed, and a meta-analysis of small studies
and case series showed no clear benefit (although the transfused patient group was significantly sicker than the control
group).56
Two adjuvant candidates aimed at the disease process in
general are the antioxidant N-acetylcysteine (NAC) and the
antihelminthic drug levamisole. NAC has been the subject of
several small studies, in one of which it was shown to increase
lactate clearance.57 Levamisole, which inhibits binding of
parasitized erythrocytes to CD36 in vitro and in uncomplicated malaria58 has not yet been trialed in severe malaria.59