The Management of Patients with Severe Malaria

Nicholas Day* and Arjen M. Dondorp

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and the Centre for Tropical Medicine, Nuffield Department of
Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Abstract. Severe malaria is a global problem, claiming at least 1 million lives annually. Few adequately powered
clinical studies have been directed at improving the management of severe malaria over the years, but this situation is
slowly changing. The antimalarial treatment of severe disease is being transformed by the development and deployment
of the water-soluble artemisinin derivative artesunate. Parenteral artesunate is now the treatment of choice in low-
transmission areas and in the 2nd and 3rd trimesters of pregnancy, and research is underway into whether it should
replace quinine as the treatment of choice in African children. Development of good manufacturing practice (GMP)
formulations should make parenteral artesunate more widely available in the near future. The development of artesu-
nate suppositories offers another exciting prospect, the ability to treat patients with severe disease in remote rural
settings, delaying the evolution of disease and buying them time to reach a health care facility. No adjunctive therapy
has been shown to improve the outcome of severe malaria, but most studies have been underpowered. Future trials of
interventions shown to be promising in pilot studies should be large and adequately powered. This will require multi-
center designs and necessitate close collaboration between groups, as well as agreement on the research agenda. We
suggest a list of candidate interventions for debate.
INTRODUCTION
Falciparum malaria remains a major cause of morbidity and
mortality throughout the tropical world, with as many as 500
million cases annually causing 13 million deaths.
1
Most cases
of malaria are uncomplicated and can be treated successfully
with appropriate oral antimalarial drugs. However, in a pro-
portion of patients, particularly in nonimmune individuals
and/or where treatment has been delayed or ineffective drugs
(chloroquine in most areas of the world) or substandard coun-
terfeited drugs given, life-threatening severe disease can
evolve requiring hospitalization, parenteral antimalarial
therapy, and the treatment of complications. Severe malaria is
often a multisystem disorder, presenting with multiple com-
plications, each requiring specific management. In most of the
malaria-endemic world, sophisticated intensive care facilities
are not available and treatment is necessarily resource-
limited. The mortality associated with severe malaria remains
high, ranging from 10% to 50% depending on the setting. In
this context, the main objective of the management of severe
malaria is to prevent the patient from dying. Prevention of
long-term sequelae and recrudescence (the usual primary
endpoint of antimalarial trials in uncomplicated malaria) are
secondary objectives.
The World Health Organization coordinated the produc-
tion of guidelines for the management of severe and compli-
cated malaria in 1990 and again in 2000, which also contain
strict definitions of severe malaria, useful for standardizing
clinical research.
2,3
More recently, in 2006, WHO published
evidence-based guidelines for the treatment of malaria, which
include extensive advice on the management of severe ma-
laria as well as a clinically useful distillation of the WHO
severe malaria definitions (Table 1).
4
Unfortunately, the clinical evidence base on which to base
guidelines is small, as most of the clinical trials on severe
malaria management have been either negative, underpow-
ered, or both. Until the SEAQUAMAT trial in 2005, no pro-
posed intervention in severe malaria had ever been shown to
reduce mortality. This review will briefly recapitulate the evi-
dence for current best practice but will also concentrate on
the many gaps in our knowledge and how they might be ad-
dressed.
INITIAL ASSESSMENT AND MANAGEMENT
Severe malaria is a medical emergency. Initial management
is based on that of any acutely and severely ill patient. The
initial rapid clinical assessment should focus on the airway
and circulation and include assessments of conscious level,
respiratory status, and state of hydration. Hypoglycemia
should be ruled out or, if the patient is comatose, treated
empirically. Convulsions, which can present with subtle symp-
toms, especially in children, should be treated promptly. In-
travenous rehydration should be commenced if indicated,
oxygen given if there is clinical or blood gas evidence of res-
piratory distress or hypoxia, and an appropriate antimalarial
drug administered. If the presence of severe malaria is sus-
pected (Table 1), the patient should be transferred to the
highest level of care available (preferably an intensive care
unit).
2,4
In areas of high transmission, peripheral parasitemia is
common and relatively uninformative unless very high, and
other common infections may produce clinical pictures simi-
lar to the spectrum of syndromes produced by severe malaria.
In cases with impaired consciousness, a lumbar puncture
should be performed to exclude meningitis
5
and the possibil-
ity of bacterial sepsis considered in all seriously ill individuals.
Blood cultures are rarely available in endemic areas, but
where they have been done systematically, bacteremias were
found in a significant proportion of clinically severe patients
with parasitemia.
6,7
Clearly if there are focal signs suggesting
a bacterial infection (such as pneumonia), broad-spectrum
antibiotic cover should be given. However, at present there is
no robust method of excluding bacterial sepsis in patients
with parasitemia and severe malaria in high-transmission
areas. In the absence of such a test, a strong case can be made
* Address correspondence to Nicholas Day, Wellcome Trust
Mahidol UniversityOxford Tropical Medicine Programme, Faculty
of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road,
Bangkok, 10400, Thailand. E-mail: [email protected]
Am. J. Trop. Med. Hyg., 77(Suppl 6), 2007, pp. 2935
Copyright 2007 by The American Society of Tropical Medicine and Hygiene
29
for a broader use of empirical antibiotics (in addition to the
antimalarials), although so far no clinical trials have ad-
dressed this issue.
ANTIMALARIAL TREATMENT
For most of the last 300 years, the cinchona alkaloid qui-
nine has been the drug of choice for severe malaria. In the
1950s, it was supplanted by the synthetic 4-aminoquinoline
antimalarial chloroquine, but with the inexorable worldwide
rise of chloroquine resistance, quinine returned to widespread
use in the last decades of the 20th century. The situation is
now rapidly changing once more with the rediscovery and
development by Chinese scientists of the artemisinin deriva-
tives, the most rapidly acting of all antimalarial drugs.
Quinine. Parenteral quinine remains at present the drug of
choice for treating severe malaria in African children. Be-
cause of its cardiotoxicity, intravenous infusion should be car-
ried out over 4 hours. Where intravenous infusion is not prac-
tical, quinine can be given by deep intramuscular injection,
although this can cause sterile abscesses, which in turn have
been associated with a lethal form of tetanus.
8
Injection into
the buttocks can also cause sciatic nerve damage. Quinine is
a relatively toxic drug with a narrow therapeutic ratio. Qui-
nine-induced hyperinsulinemic hypoglycemia is a particular
problem in patients with severe malaria, especially during
pregnancy, and is impossible to diagnose clinically in the al-
ready unconscious patient.
9,10
Frequent monitoring of blood
glucose concentrations is therefore essential. It is also impor-
tant that parasitocidal drug levels are obtained as quickly as
possible, so in patients who have not been given recent (< 24
hours before admissions) doses of quinine, an initial loading
dose of 20 mg/kg should be administered.
11
The total appar-
ent volume of distribution of quinine and its systemic clear-
ance are both reduced in proportion to disease severity, and
in severe malaria the dose should be reduced by one-third
after 48 hours if there is no clinical improvement or if there is
renal failure.
12
Artemisinin derivatives. The artemisinin derivatives are the
most exciting recent development in the treatment of severe
malaria. They are rapidly parasitocidal, andcrucially unlike
quininethey kill young circulating parasites before they se-
quester in the deep microvasculature. To examine whether
these advantages over quinine could be translated into a re-
duction in severe malaria mortality, between 2003 and 2005,
1461 patients (including 202 children) in 4 south and south-
east Asian countries were recruited into SEAQUAMAT
(South and Southeast Asian Quinine versus Artesunate in
severe Malaria Trial), the largest ever clinical drug trial in
severe malaria.
13
Mortality in those randomized to artesunate
was 15% (107 of 730) compared with 22% (164 of 731) in
quinine recipients; a relative reduction of 34.7% (95% CI
18.547.6%; P 0.0002). The NNT (Number Needed to
Treat to save one life) was 11.1 (95% CI 5.8121) in Bang-
ladesh, 12.6 (7.3 to 45) in Burma, 16.6 in Indonesia, and 21.2
in India. The mortality difference was particularly marked in
those patients with large numbers of circulating young para-
sites, consistent with the hypothesis that artesunates advan-
tage lies in its ability to kill young parasites before they se-
quester (unpublished observations). As a result of the
SEAQUAMAT study, parenteral artesunate is now recom-
mended by WHO as the drug of choice for the treatment of
severe malaria in low-transmission areas and in the second
and third trimesters of pregnancy (Table 2).
4
The current recommendation for treating severe malaria
patients in high-transmission areas is either quinine or an
artemisinin derivative. This patient group consists mainly of
African children, who bear the largest part of the global ma-
laria disease burden and for whom the potential advantage
for parenteral artesunate is not as clear-cut as in southeast
Asian adults. Severe malaria in children progresses more rap-
idly than in adults, leaving a smaller time window for the
killing of young parasites by artesunate to deliver a clinical
advantage. In the 1980s and 1990s under WHO oversight, a
number of studies were carried out in both Africa and Asia
comparing quinine with artemether, a lipid-soluble artemi-
sinin derivative administered intramuscularly (it can also be
given rectally, but not intravenously). An individual patient
data meta-analysis showed that, whereas overall there was no
significant difference in mortality between the two drugs
[14% vs. 17%, odds ratio (95% confidence interval) 0.8 (0.62
to 1.02), P 0.08], there was substantial heterogeneity in the
treatment effect; in the Asian patients (mainly adults), arte-
mether was associated with a modest, but significantly lower
mortality than quinine [OR (99% CI) 0.59 (0.35 to 1.01), P
0.012], but this effect was not seen in African patients (mainly
children).
14
Intramuscular artemether has since been shown
to be erratically absorbed (unlike intramuscular artesunate,
which was rapidly absorbed and quickly hydrolyzed to DHA);
it is unclear whether artemethers lack of effect on mortality
in African children is due to this or to the absence of a true
difference in efficacy between quinine and the artemisinin
derivatives in African childhood severe malaria
15,16
; hence
the need for evidence from randomized clinical trials compar-
ing quinine and artesunate in African children. AQUAMAT
(African Quinine versus Artesunate in severe Malaria Trial),
a multicenter study based on the SEAQUAMAT design, is
currently underway. This trial plans to recruit 5,306 patients
by 2010, and is powered to detect a 25% reduction in mor-
tality from 8% to 6%.
The only widely available parenteral artesunate formula-
tion is made by Guilin Pharmaceutical factory in China. Al-
TABLE 1
WHO criteria for severe malaria
One or more of the following clinical or laboratory features
Clinical manifestations
Prostration
Impaired consciousness
Respiratory distress (acidotic breathing)
Multiple convulsions
Circulatory collapse
Pulmonary edema (radiological)
Abnormal bleeding
Jaundice
Hemoglobinuria
Laboratory test
Severe anemia
Hypoglycemia
Acidosis
Renal impairment
Hyperlactatemia
Hyperparasitemia
Taken from WHO Guidelines for the Treatment of Malaria. (WHO, Geneva Switzerland:
2006). Full details of the definitions can be found in WHO severe falciparum malaria
(Trans R Soc Trop Med Hyg 2000; 94 (Suppl. 1): 190).
DAY AND DONDORP 30
though it is effective (it was used in the SEAQUAMAT
study) and is registered in many countries, it is manufactured
to Chinese GMP (Good Manufacturing Practice) standards
and is not yet international GMP certified (although there
are plans for this). It is currently particularly difficult to treat
severe malaria in the United States, as both parenteral arte-
sunate and quinine are unlicensed, and intravenous quinidine,
the mainstay of severe malaria therapy in the U.S., is increas-
ingly unavailable as its use in cardiology declines.
17
A new
GMP formulation of artesunate is being developed by the
U.S. Army and will hopefully obtain FDA approval in the
next year or so.
Animal toxicity studies have raised concerns about possible
neurotoxicity with high doses of the artemisinin derivative
drugs, but so far, despite widespread use, neurotoxicity has
not been reported in humans.
18,19
The animal neurotoxicity
appears particularly related to high sustained levels produced
by administration of lipophilic artemisinin derivatives such as
artemether, which suggests that if a problem with neurotox-
icity did exist (and there is no evidence of this to date), then
water-soluble derivatives such as artesunate would be much
safer.
20
Animal studies have also shown some reproductive
toxicity, with fetal resorption in rats and rabbits.
21,22
There is
no evidence that this occurs in humans, but such a problem
would by its nature be difficult to detect. As severe malaria is
a potentially fatal illness for the mother, until further evi-
dence becomes available, the 2006 WHO guidelines regard
both quinine and artesunate as treatment options in the first
trimester (Table 2).
4
Artesunate suppositories. Most patients with malaria in the
rural tropics live far from the nearest health clinic or hospital,
and many develop severe disease and die before reaching a
health facility where parenteral treatment can be given. De-
ployment of artesunate suppositories in rural areas offers the
prospect of effective early treatment of malaria, preventing
clinical deterioration and buying time to reach a hospital. The
use of suppositories containing artemisinin or one of its de-
rivatives for the treatment of severe malaria in both adults
and children was pioneered in Viet Nam in the early
1990s.
23,24
Subsequently, the WHO sponsored the develop-
ment of GMP-manufactured rectal artesunate capsules, which
appear to be reasonably well absorbed and are effective for
the treatment of moderately severe malaria.
2528
A large
phase III study of early deployment has been completed and
will report soon, and it appears likely that rectal artesunate
will obtain U.S. FDA registration in the near future.
1
Home-
or village-based deployment of rectal artesunate in rural areas
of the tropics may play an important role in reducing malaria-
associated morbidity and mortality. Further research needs to
be conducted on how best to achieve this, in particular, at
what level to deploy the suppositories (family, village health
worker, etc.), whether they will be socially and culturally ac-
ceptable, and assessment of practical problems concerning
their administration (early passing of suppository, multiple
dosing, potential paradoxical delays in referral, etc.). As a
high proportion of sick individuals will have severe bacterial
sepsis rather than severe malaria, the question of antibiotic
cover arises. A suppository containing both artesunate and an
antibiotic (preferably one with some antimalarial activity)
may be the next logical step and is currently the subject of
preliminary research into its feasibility.
SUPPORTIVE CARE AND MANAGEMENT
OF COMPLICATIONS
Good nursing care is essential in the management of severe
malaria, with particular attention to fluid balance, manage-
1
On June 21, 2007, the U.S. FDA approved an Investigational New
Drug protocol that will allow the Centers for Disease Control and
Prevention to make intravenous artesunate available to clinicians
who request it for patients who have severe malaria.
TABLE 2
Extracts from current WHO guidelines for the treatment of severe malaria
4
(reproduced with permission)
Summary of recommendations on the treatment of severe malaria Level of evidence
Severe malaria is a medical emergency. After rapid clnical 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 body weight (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
Summary of recommendations on pre-referral treatment for severe falciparum malaria
The following may be given:
Artesunate or artemisinin by rectal administration T, E
Artesunate or artemether i.m. E
Quinine i.m. O, E
Recommendation for treatment for severe falciparum malaria in pregnant women
Use the parenteral antimalarial treatment locally available for severe malaria in full doses. Where available, AS is the first
and artemether the second option in the second and third trimesters. In the first trimester, until more evidence becomes
available, both artesunate and quinine may be considered as options.
E
* Levels of evidence: S, formal systematic reviews, such as a Cochrane Review, including more than one randomized controlled trial; T, comparative trials without formal systematic review;
O, observational studies (e.g., surveillance or pharmacological data); E, expert opinion/consensus.
MANAGEMENT OF SEVERE MALARIA 31
ment of the unconscious patient, and detection of potentially
lethal complications such as hypoglycemia.
Coma. In Western ICUs, mechanical ventilation is often
used in the unconscious cerebral malaria patient to protect
the airway, although its efficacy in terms of prevention of
mortality and sequelae has not been proven.
29
In a small
study of Kenyan children with cerebral malaria and raised
intracranial pressures, mannitol, an anti-osmotic agent, was
successful in reducing intracranial pressure for short peri-
ods,
30
but no convincing clinical evidence exists to support its
routine use.
Convulsions. Seizures in cerebral malaria should be treated
with rectal diazepam, intravenous lorazepam, paraldehyde, or
other standard anticonvulsants, after high-flow oxygen and
appropriate airway management have been initiated.
31
Pro-
phylactic phenobarbitone was shown to reduce seizure inci-
dence in adult cerebral malaria, but a study in children using
a single intramuscular dose of 20 mg/kg reduced seizures but
increased mortality, possibly through respiratory depression
caused by an interaction with diazepam.
32,33
Prophylactic an-
ticonvulsive therapy is therefore currently not recommended.
Acute renal failure. Whereas in African children malaria-
associated acute renal failure is extremely rare, it is a rela-
tively common complication of severe malaria in nonimmune
adults and children. It has an untreated mortality of > 70%
and should be treated with adequate renal replacement
therapypreferably by hemofiltration when available, as this
has been shown to be superior to peritoneal dialysis in terms
of mortality and cost-effectiveness.
34,35
The role of hemodi-
alysis has not been assessed in a randomized trial, but it is
likely to be superior to peritoneal dialysis in the hemodynami-
cally stable patient.
Hemodynamic shock. Shock in severe malaria (algid ma-
laria) carries a high mortality in both adults and chil-
dren.
29,36
It should be treated initially with oxygen and fluids
(with monitoring of central venous pressure if available),
though, as in children, it is unclear how aggressive the volume
expansion should be in terms of safety and effectiveness. Mas-
sive hemorrhage, from the gastrointestinal tract or rarely a
ruptured spleen, should be excluded. A septic screen includ-
ing blood cultures should be performed and appropriate
broad-spectrum antibiotics administered to cover the possi-
bility of bacterial sepsis. If inotropes are necessary, dopamine
has been used safely in malaria, and dobutamine and norepi-
nephrine may also be used though there is little experience
with them in severe malaria.
37
Epinephrine should be avoided
as it induces serious lactic acidosis.
38
Fluid resuscitation. The role of aggressive fluid resuscita-
tion in the management of severe malaria, particularly in chil-
dren, is unclear and currently controversial. The debate cen-
ters around whether hypovolemia plays an important role in
the pathophysiology of severe malaria, causing poor tissue
perfusion, leading to anaerobic glycolysis and consequent aci-
dosis. Advocates of aggressive fluid repletion suggest that the
standards of care applied in resource-rich settings for severely
ill children with bacterial sepsis should be extrapolated to
severe malaria, while those against argue that there is no
evidence that severe dehydration occurs in severe malaria and
are concerned that overzealous rehydration may lead to pul-
monary and cerebral edema.
3941
There is at present insuffi-
cient evidence either way, as all clinical studies conducted so
far have been small and unsatisfactory.
42
A large multicenter
clinical trial is planned that will hopefully provide some an-
swers, but in the meantime, intravenous fluid regimens should
be guided by clinical judgment and, if available, by central
venous pressure monitoring.
Acidosis. Metabolic acidosis, a common complication of se-
vere malaria, is strongly associated with fatal outcome in both
adults and children.
43,44
Lactic acid is an important contribu-
tor, but impaired renal bicarbonate handling and the presence
of other as yet unidentified acids also play major roles.
45
Dichloroacetate (which stimulates pyruvate dehydrogenase)
has been shown to reduce plasma lactate in severe malaria,
but to have no effect on pH, possibly because of the multi-
factorial etiology of the acidosis.
46,47
Hemofiltration has been
shown to rapidly eliminate acidosis in malaria patients with
renal failure, even in the presence of lactic acidosis.
35
Early
hemofiltration may be a useful strategy in patients with aci-
dosis and renal impairment who have not yet developed es-
tablished renal failure, but this has not yet been evaluated in
a clinical trial.
Anemia. This is present in almost all patients with severe
malaria but occurs most prominently in young children. Ben-
efits of blood transfusion should outweigh the risks (espe-
cially of HIV and other pathogens). There is no clear evi-
dence supporting specific hemoglobin cut-off levels, and a
number of figures are quoted in reviews and guidelines. In
adults, the threshold for blood transfusion is commonly set at
a hematocrit < 20%. Clinical evidence from Kenya has led to
proposed threshold hemoglobin levels for African children of
5 g/dL if there is co-existing respiratory distress, impaired
consciousness, or hyperparasitemia or at an absolute cut-off
of 4 g/dL.
48
ARDS. This feared complication has a high mortality rate
and can develop several days after admission and onset of
treatment. Clinical research is needed into both the patho-
physiology and treatment of this condition. The etiology is
poorly understood, and treatment in malaria is currently
based on expert opinion and extrapolation from studies on
ARDS associated with other conditions.
OTHER ADJUNCTIVE THERAPIES
The malaria literature contains many small trials of poten-
tial 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 con-
clusions. An exception is the placebo-controlled trial of anti-
TNF 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
100), is underpowered by todays standards and may conceal
a type II error.
51
A meta-analysis combining it with the sec-
ond 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-
DAY AND DONDORP 32
strated, there is not enough data to draw a definitive conclu-
sion.
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 rheol-
ogy of the blood unparasitized erythrocytes by replacing un-
parasitized erythrocytes with reduced deformability.
55
How-
ever, 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 trans-
fused 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 uncompli-
cated malaria
58
has not yet been trialed in severe malaria.
59
FUTURE DIRECTIONS
The evidence base for the treatment of severe malaria is
lamentably small given the global importance of the disease
and the number of deaths it causes. Fewer than 10,000 pa-
tients have ever been randomized into treatment trials of se-
vere malaria, an astonishingly small figure given the 10 mil-
lion cases of severe malaria annually and our inadequate
knowledge of how it should best be managed. Clearly, under-
funding has played a major role in the past, but in recent years
this problem has begun to be addressed as the global com-
munity has started making major investments in tackling the
main infectious-disease killers. There has been an associated
slow but steady development of clinical research capacity in
the malaria-endemic world, and although there is a long way
to go, it is for the first time becoming practical to conduct
large, adequately powered clinical trials of candidate treat-
ments for severe malaria. Major funding and logistical chal-
lenges are still associated with such projects, and research
capacity building has to be an integral part of the planning.
The considerable problem of agreeing on the research agenda
must also be kept in mind, as only a limited number of such
multicenter trials can be conducted at any one time. Only by
forming multinational collaborations can we hope to address
important clinical research questions with sufficient statistical
power.
Which new treatments or clinical management strategies
warrant assessment in these multi-center studies? In Table 3
we list a number of candidates along with a subjective assess-
ment of the evidence supporting their inclusion and the level
of controversy such a trial is likely to generate. Several have
been mentioned already in this review, whereas others are
more speculative and may require study in smaller trials with
surrogate marker endpoints before a larger study can be jus-
tified. This is necessarily a personal list, and we are sure to
have omitted a number of worthy contenders. The main ob-
jective is to stimulate debate and, ultimately, some degree of
agreement. This is a prerequisite for the development of col-
laborations and networks to carry out the studies.
Received January 19, 2007. Accepted for publication October 1,
2007.
N.D. and A.D. are funded by the Wellcome Trust.
Acknowledgments: We thank Professor Nicholas White for helpful
discussions.
Authors addresses: Nicholas Day and Arjen M. Dondorp, Wellcome
TrustMahidol UniversityOxford Tropical Medicine Programme,
Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi
Road, Bangkok, 10400, Thailand, Telephone: +66 2 3549172, Fax: +66
2 3549169 and Centre for Tropical Medicine, Nuffield Department of
Clinical Medicine, John Radcliffe Hospital, University of Oxford,
Oxford, U.K, E-mail: [email protected].
REFERENCES
1. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI, 2005. The
global distribution of clinical episodes of Plasmodium falci-
parum malaria. Nature 434: 214217.
2. World Health Organization Communicable Diseases Cluster,
2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg
94 (Suppl 1): S190.
3. World Health Organization Division of Control of Tropical Dis-
eases, 1990. Severe and complicated malaria. Trans R Soc Trop
Med Hyg 84 (Suppl 2): 165.
4. World Health Organization, 2006. Guidelines for the Treatment of
Malaria. Geneva: WHO.
5. Berkley JA, Mwangi I, Mellington F, Mwarumba S, Marsh K,
1999. Cerebral malaria versus bacterial meningitis in children
with impaired consciousness. Q J Med 92: 151157.
TABLE 3
Suggested list of candidate interventions in severe malaria
Candidate intervention
Scientific
rationale
Evidence from
previous studies Practicality
Potential impact in
resource-poor settings Controversy
Status
(September 2007)
Parenteral artesunate vs. quinine in African children ***** ***** ***** ***** ** Underway
Aggressive fluid resuscitation in children *** *** *** **** ***** Funded
Levamisole **** *** **** ***** ** Pilot
Exchange blood transfusion ***** *** * * *** No plans
Empirical antibiotics in high-transmission areas ***** **** ***** ***** *** No plans
Dichloroacetate **** *** ** *** **** No plans
Early vs. standard hemofiltration *** **** * * *** No plans
N-acetylcysteine **** *** ** ** ** No plans
Ventilation and sedation ***** **** * * *** No plans
Mannitol in cerebral malaria ** * *** *** **** No plans
Optimal fluid management in adults **** ** *** **** *** No plans
Feeding strategies **** * **** **** *** No plans
* Very little; *****very much.
MANAGEMENT OF SEVERE MALARIA 33
6. Berkley J, Mwarumba S, Bramham K, Lowe B, Marsh K, 1999.
Bacteraemia complicating severe malaria in children. Trans R
Soc Trop Med Hyg 93: 283286.
7. Evans JA, Adusei A, Timmann C, May J, Mack D, Agbenyega T,
Horstmann RD, Frimpong E, 2004. High mortality of infant
bacteraemia clinically indistinguishable from severe malaria. Q
J Med 97: 591597.
8. Yen LM, Dao LM, Day NP, Waller DJ, Bethell DB, Son LH,
Hien TT, White NJ, 1994. Role of quinine in the high mortality
of intramuscular injection tetanus. Lancet 344: 786787.
9. White NJ, Warrell DA, Chanthavanich P, Looareesuwan S, War-
rell MJ, Krishna S, Williamson DH, Turner RC, 1983. Severe
hypoglycemia and hyperinsulinemia in falciparum malaria. N
Engl J Med 309: 6166.
10. White NJ, Miller KD, Marsh K, Berry CD, Turner RC, William-
son DH, Brown J, 1987. Hypoglycaemia in African children
with severe malaria. Lancet 1: 708711.
11. White NJ, Looareesuwan S, Warrell DA, Warrell MJ, Chantha-
vanich P, Bunnag D, Harinasuta T, 1983. Quinine loading dose
in cerebral malaria. Am J Trop Med Hyg 32: 15.
12. Krishna S, White NJ, 1996. Pharmacokinetics of quinine, chloro-
quine and amodiaquine. Clinical implications. Clin Pharma-
cokinet 30: 263299.
13. Dondorp A, Nosten F, Stepniewska K, Day N, White N, 2005.
Artesunate versus quinine for treatment of severe falciparum
malaria: a randomised trial. Lancet 366: 717725.
14. ArtemetherQuinine Meta-analysis Study Group, 2001. A meta-
analysis using individual patient data of trials comparing arte-
mether with quinine in the treatment of severe falciparum ma-
laria. Trans R Soc Trop Med Hyg 95: 637650.
15. Murphy SA, Mberu E, Muhia D, English M, Crawley J, Waruiru
C, Lowe B, Newton CR, Winstanley P, Marsh K, Watkins
WM, 1997. The disposition of intramuscular artemether in chil-
dren with cerebral malaria; a preliminary study. Trans R Soc
Trop Med Hyg 91: 331334.
16. Hien TT, Davis TM, Chuong LV, Ilett KF, Sinh DX, Phu NH,
Agus C, Chiswell GM, White NJ, Farrar J, 2004. Comparative
pharmacokinetics of intramuscular artesunate and artemether
in patients with severe falciparum malaria. Antimicrob Agents
Chemother 48: 42344239.
17. Magill A, Panosian C, 2005. Making antimalarial agents available
in the United States. N Engl J Med 353: 335337.
18. Brewer TG, Peggins JO, Grate SJ, Petras JM, Levine BS, Weina
PJ, Swearengen J, Heiffer MH, Schuster BG, 1994. Neurotox-
icity in animals due to arteether and artemether. Trans R Soc
Trop Med Hyg 88 (Suppl 1): S33S36.
19. Hien TT, Turner GD, Mai NT, Phu NH, Bethell D, Blakemore
WF, Cavanagh JB, Dayan A, Medana I, Weller RO, Day NP,
White NJ, 2003. Neuropathological assessment of artemether-
treated severe malaria. Lancet 362: 295296.
20. Nontprasert A, Pukrittayakamee S, Dondorp AM, Clemens R,
Looareesuwan S, White NJ, 2002. Neuropathologic toxicity of
artemisinin derivatives in a mouse model. Am J Trop Med Hyg
67: 423429.
21. Clark RL, White TE, A Clode S, Gaunt I, Winstanley P, Ward
SA, 2004. Developmental toxicity of artesunate and an arte-
sunate combination in the rat and rabbit. Birth Defects Res B
Dev Reprod Toxicol 71: 380394.
22. White TE, Bushdid PB, Ritter S, Laffan SB, Clark RL, 2006.
Artesunate-induced depletion of embryonic erythroblasts pre-
cedes embryolethality and teratogenicity in vivo. Birth Defects
Res B Dev Reprod Toxicol 77: 413429.
23. Hien TT, Arnold K, Vinh H, Cuong BM, Phu NH, Chau TT, Hoa
NT, Chuong LV, Mai NT, Vinh NN, et al., 1992. Comparison
of artemisinin suppositories with intravenous artesunate and
intravenous quinine in the treatment of cerebral malaria. Trans
R Soc Trop Med Hyg 86: 582583.
24. Cao XT, Bethell DB, Pham TP, Ta TT, Tran TN, Nguyen TT,
Pham TT, Nguyen TT, Day NP, White NJ, 1997. Comparison
of artemisinin suppositories, intramuscular artesunate and in-
travenous quinine for the treatment of severe childhood ma-
laria. Trans R Soc Trop Med Hyg 91: 335342.
25. Sabchareon A, Attanath P, Chanthavanich P, Phanuaksook P,
Prarinyanupharb V, Poonpanich Y, Mookmanee D, Teja-
Isavadharm P, Heppner DG, Brewer TG, Chongsuphajaisid-
dhi T, 1998. Comparative clinical trial of artesunate supposi-
tories and oral artesunate in combination with mefloquine in
the treatment of children with acute falciparum malaria. Am J
Trop Med Hyg 58: 1116.
26. Barnes KI, Mwenechanya J, Tembo M, McIlleron H, Folb PI,
Ribeiro I, Little F, Gomes M, Molyneux ME, 2004. Efficacy of
rectal artesunate compared with parenteral quinine in initial
treatment of moderately severe malaria in African children
and adults: a randomised study. Lancet 363: 15981605.
27. Karunajeewa HA, Reeder J, Lorry K, Dabod E, Hamzah J, Page-
Sharp M, Chiswell GM, Ilett KF, Davis TM, 2006. Artesunate
suppositories versus intramuscular artemether for treatment of
severe malaria in children in Papua New Guinea. Antimicrob
Agents Chemother 50: 968974.
28. Simpson JA, Agbenyega T, Barnes KI, Di Perri G, Folb P,
Gomes M, Krishna S, Krudsood S, Looareesuwan S, Mansor S,
McIlleron H, Miller R, Molyneux M, Mwenechanya J, Navar-
atnam V, Nosten F, Olliaro P, Pang L, Ribeiro I, Tembo M,
van Vugt M, Ward S, Weerasuriya K, Win K, White NJ, 2006.
Population pharmacokinetics of artesunate and dihydroarte-
misinin following intra-rectal dosing of artesunate in malaria
patients. PLoS Med 3: e444.
29. Gerardin P, Rogier C, Ka AS, Jouvencel P, Diatta B, Imbert P,
2007. Outcome of life-threatening malaria in African children
requiring endotracheal intubation. Malar J 6: 51.
30. Newton CR, Crawley J, Sowumni A, Waruiru C, Mwangi I, En-
glish M, Murphy S, Winstanley PA, Marsh K, Kirkham FJ,
1997. Intracranial hypertension in Africans with cerebral ma-
laria. Arch Dis Child 76: 219226.
31. Maitland K, Nadel S, Pollard AJ, Williams TN, Newton CR,
Levin M, 2005. Management of severe malaria in children:
proposed guidelines for the United Kingdom. BMJ 331: 337
343.
32. Crawley J, Waruiru C, Mithwani S, Mwangi I, Watkins W, Ouma
D, Winstanley P, Peto T, Marsh K, 2000. Effect of phenobar-
bital on seizure frequency and mortality in childhood cerebral
malaria: a randomised, controlled intervention study. Lancet
355: 701706.
33. White NJ, Looareesuwan S, Phillips RE, Chanthavanich P, War-
rell DA, 1988. Single dose phenobarbitone prevents convul-
sions in cerebral malaria. Lancet 2: 6466.
34. Trang TT, Phu NH, Vinh H, Hien TT, Cuong BM, Chau TT, Mai
NT, Waller DJ, White NJ, 1992. Acute renal failure in patients
with severe falciparum malaria. Clin Infect Dis 15: 874880.
35. Phu NH, Hien TT, Mai NT, Chau TT, Chuong LV, Loc PP,
Winearls C, Farrar J, White N, Day N, 2002. Hemofiltration
and peritoneal dialysis in infection-associated acute renal fail-
ure in Vietnam. N Engl J Med 347: 895902.
36. Tran TH, Day NP, Nguyen HP, Nguyen TH, Tran TH, Pham PL,
Dinh XS, Ly VC, Ha V, Waller D, Peto TE, White NJ, 1996.
A controlled trial of artemether or quinine in Vietnamese
adults with severe falciparum malaria. N Engl J Med 335: 76
83.
37. Bruneel F, Gachot B, Timsit JF, Wolff M, Bedos JP, Regnier B,
Vachon F, 1997. Shock complicating severe falciparum malaria
in European adults. Intensive Care Med 23: 698701.
38. Day NP, Phu NH, Bethell DP, Mai NT, Chau TT, Hien TT,
White NJ, 1996. The effects of dopamine and adrenaline infu-
sions on acidbase balance and systemic haemodynamics in
severe infection. Lancet 348: 219223.
39. Planche T, Onanga M, Schwenk A, Dzeing A, Borrmann S,
Faucher JF, Wright A, Bluck L, Ward L, Kombila M, Krem-
sner PG, Krishna S, 2004. Assessment of volume depletion in
children with malaria. PLoS Med 1: e18.
40. Planche T, 2005. Malaria and fluidsbalancing acts. Trends Para-
sitol 21: 562567.
41. Maitland K, 2006. Severe malaria: lessons learned from the man-
agement of critical illness in children. Trends Parasitol 22: 457
462.
42. Day N, 2006. Fluid resuscitation in malaria: the need for new
randomised clinical trials. PLoS Clin Trials 1: e24.
43. Krishna S, Waller DW, ter Kuile F, Kwiatkowski D, Crawley J,
Craddock CF, Nosten F, Chapman D, Brewster D, Holloway
PA, et al., 1994. Lactic acidosis and hypoglycaemia in children
DAY AND DONDORP 34
with severe malaria: pathophysiological and prognostic signifi-
cance. Trans R Soc Trop Med Hyg 88: 6773.
44. Day NP, Phu NH, Mai NT, Chau TT, Loc PP, Chuong LV, Sinh
DX, Holloway P, Hien TT, White NJ, 2000. The pathophysi-
ologic and prognostic significance of acidosis in severe adult
malaria. Crit Care Med 28: 18331840.
45. Dondorp AM, Chau TT, Phu NH, Mai NT, Loc PP, Chuong LV,
Sinh DX, Taylor A, Hien TT, White NJ, Day NP, 2004. Uni-
dentified acids of strong prognostic significance in severe ma-
laria. Crit Care Med 32: 16831688.
46. Krishna S, Supanaranond W, Pukrittayakamee S, Karter D, Sup-
putamongkol Y, Davis TM, Holloway PA, White NJ, 1994.
Dichloroacetate for lactic acidosis in severe malaria: a phar-
macokinetic and pharmacodynamic assessment. Metabolism
43: 974981.
47. Agbenyega T, Planche T, Bedu-Addo G, Ansong D, Owusu-
Ofori A, Bhattaram VA, Nagaraja NV, Shroads AL, Hender-
son GN, Hutson AD, Derendorf H, Krishna S, Stacpoole PW,
2003. Population kinetics, efficacy, and safety of dichloroac-
etate for lactic acidosis due to severe malaria in children. J Clin
Pharmacol 43: 386396.
48. World Health Organization, 2001. The Prevention and Manage-
ment of Severe Anaemia in Children in Malaria-Endemic Re-
gions of Africa: A Review of Research. Geneva: WHO.
49. Enwere G, 2005. A review of the quality of randomized clinical
trials of adjunctive therapy for the treatment of cerebral ma-
laria. Trop Med Int Health 10: 11711175.
50. van Hensbroek MB, Palmer A, Onyiorah E, Schneider G, Jaffar
S, Dolan G, Memming H, Frenkel J, Enwere G, Bennett S,
Kwiatkowski D, Greenwood B, 1996. The effect of a mono-
clonal antibody to tumor necrosis factor on survival from child-
hood cerebral malaria. J Infect Dis 174: 10911097.
51. Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intara-
prasert R, Bunnag D, Harinasuta T, 1982. Dexamethasone
proves deleterious in cerebral malaria. A double-blind trial in
100 comatose patients. N Engl J Med 306: 313319.
52. Hoffman SL, Rustama D, Punjabi NH, Surampaet B, Sanjaya B,
Dimpudus AJ, McKee KT Jr, Paleologo FP, Campbell JR,
Marwoto H, et al., 1988. High-dose dexamethasone in quinine-
treated patients with cerebral malaria: a double-blind, placebo-
controlled trial. J Infect Dis 158: 325331.
53. Prasad K, Garner P, 2000. Steroids for treating cerebral malaria.
Cochrane Database Syst Rev CD000972.
54. Smith HJ, Meremikwu M, 2003. Iron chelating agents for treating
malaria. Cochrane Database Syst Rev CD001474.
55. Powell VI, Grima K, 2002. Exchange transfusion for malaria and
Babesia infection. Transfus Med Rev 16: 239250.
56. Riddle MS, Jackson JL, Sanders JW, Blazes DL, 2002. Exchange
transfusion as an adjunct therapy in severe Plasmodium falci-
parum malaria: a meta-analysis. Clin Infect Dis 34: 11921198.
57. Watt G, Jongsakul K, Ruangvirayuth R, 2002. A pilot study of
N-acetylcysteine as adjunctive therapy for severe malaria. Q J
Med 95: 285290.
58. Dondorp AM, Silamut K, Charunwatthana P, Chuasuwanchai S,
Ruangveerayut R, Krintratun S, White NJ, Ho M, Day NPJ,
2007. Levamisole inhibits sequestration of infected red blood
cells in patients with falciparummalaria. J Int Dis 196: 460466.
59. Yipp BG, Robbins SM, Resek ME, Baruch DI, Looareesuwan S,
Ho M, 2003. Src-family kinase signaling modulates the adhe-
sion of Plasmodium falciparum on human microvascular en-
dothelium under flow. Blood 101: 28502857.
MANAGEMENT OF SEVERE MALARIA 35