The New England Journal o f Me di c i ne
Review Article
Current Concepts
T HE T REATMENT OF M ALARIA
N.J. WHITE, D.SC., M.D.
M
ALARIA is the worlds most important
parasitic infection. Although it has been
eradicated from temperate zones, increas-
ing numbers of travelers from temperate areas each
year visit tropical countries, where the disease re-
mains a major cause of morbidity and death. The
treatment of malaria has changed over the past two
decades in response to declining drug sensitivity in
Plasmodium falciparum and a resurgence of the dis-
ease in tropical areas. This review will concentrate on
the practical aspects of treatment.
DIAGNOSIS
Patients with malaria usually present with nonspe-
cific and irregular fever, chills, headache, and ma-
laise. Vomiting occurs in approximately 20 percent
of patients, and mild diarrhea in less than 5 percent.
As the disease progresses, the spleen enlarges and
the patient becomes anemic. Malaria is so common
that any patient who has been in a malarious area in
the previous two months (usual incubation period,
two weeks) should be considered to have malaria
until it has been proved otherwise. The blood tests
show a normal white-cell count and mild thrombo-
cytopenia. The diagnosis is confirmed by microsco-
py of stained thin and thick blood films, at a mag-
nification of 1000. The intraerythrocytic parasites
should be identified (if the species is uncertain, it
should be considered to be P. falciparum) and
counted.1 In severe malaria, the developmental stage
of the parasites and the percentage of neutrophils
containing malarial pigment should also be noted.
The prognosis worsens with increasing parasite
From the Faculty of Tropical Medicine, Mahidol University, Bangkok,
Thailand; the Wellcome Trust Clinical Research Unit, Centre for Tropical
Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam; and the Centre
for Tropical Medicine, Nuffield Department of Clinical Medicine, John
Radcliffe Hospital, Headington, Oxford, United Kingdom. Address reprint
requests to Prof. White at the Faculty of Tropical Medicine, 420/6 Rajvithi
Rd., Mahidol University, Bangkok 10400, Thailand.
1996, Massachusetts Medical Society.
800  Sep tem b er 1 2 , 1 9 9 6
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counts, more mature parasites, and more neutro-
phils containing pigment (Table 1).2 A negative
blood smear makes the diagnosis very unlikely, but
if there is still uncertainty the test should be repeat-
ed every 12 hours for 48 hours. A simple test strip
for finger-prick blood samples, which uses a mono-
clonal antibody to the P. falciparum histidine-rich
protein 2, has a diagnostic sensitivity similar to that
of microscopy.3
UNCOMPLICATED MALARIA
The treatment of malaria depends on the severity
of the infection, the patients age, the degree of
background immunity (if any), the likely pattern of
susceptibility to antimalarial drugs, and the cost and
availability of such drugs. For this reason, recom-
mendations vary according to geographic region and
should be under constant review.4
The three so-called benign malarias, P. vivax,
P. malariae, and P. ovale, should all be treated with
chloroquine. High-grade resistance to chloroquine
in P. vivax has been reported from Oceania,5,6 but
elsewhere the parasite remains generally sensitive and
responds rapidly. Chloroquine is usually well tolerat-
ed, although it commonly produces pruritus in dark-
skinned patients, and in the treatment of acute ma-
laria it may cause nausea, dysphoria, and very rarely,
a transient neuropsychiatric syndrome or cerebellar
dysfunction. Recent studies have shown that the tra-
ditional 3-day course of treatment of 25 mg (base)
per kilogram of body weight (10 mg per kilogram
initially, 10 mg per kilogram at 24 hours, and 5 mg
per kilogram at 48 hours) can be compressed into 36
hours for convenience (Table 2).8 A two-week course
of primaquine is also required to treat infections with
P. vivax and P. ovale in order to eradicate forms of
the parasite (hypnozoites) that survive in the liver
(radical cure). This prevents relapse in the majority
of cases. Primaquine may cause nausea and abdomi-
nal pain, particularly if taken on an empty stomach,
and more important, oxidant hemolysis with methe-
moglobinemia, anemia, and sometimes hemoglobin-
uria. Patients with a deficiency of glucose-6-phos-
phate dehydrogenase are particularly vulnerable to
oxidant hemolysis, and primaquine is contraindicated
in patients with severe variants of the deficiency. In
places where mild variants of glucose-6-phosphate
dehydrogenase deficiency are common, primaquine
(0.8 mg of base per kilogram; adult dose, 45 mg)
should be given once a week for six weeks for a rad-
ical cure.4 In areas where malaria is endemic and re-
infection is common, a radical cure with primaquine
is not indicated.
 CURRENT CONCEPTS
TABLE 1. FEATURES INDICATING
A POOR PROGNOSIS IN SEVERE MALARIA.
Clinical features
Impaired consciousness*
Repeated convulsions (3 in 24 hr)
Respiratory distress (rapid, deep, labored, stertorous
breathing)
Substantial bleeding
Shock
Biochemical features
Renal impairment (serum creatinine, 3 mg/dl
[265 mmol/liter])
Acidosis (plasma bicarbonate, 15 mmol/liter)
Jaundice (serum total bilirubin, 2.5 mg/dl [43
mmol/liter])
Hyperlactatemia (venous lactate, 45 mg/dl [5
mmol/liter])
Hypoglycemia (blood glucose, 40 mg/dl [ 2.2
mmol/liter])
Elevated aminotransferase levels (3 times normal)
Hematologic features
Parasitemia (500,000 parasites/mm3 or 10,000
mature trophozoites and schizonts/mm3)
5% of neutrophils contain malaria pigment
*The deeper the coma, the worse the prognosis.
The combination of deep jaundice and renal fail-
ure is particularly grave.
Trophozoites are mature parasites in which pig-
ment is visible under light microscopy.2
The choice of treatment for P. falciparum de-
pends on the parasites sensitivity to antimalarial
drugs in the area where the infection was acquired.
Known sensitive infections (e.g., those from North
Africa, Central America north of the Panama Canal,
Haiti, or the Middle East) should be treated with
chloroquine. Where there is low-grade resistance to
chloroquine, amodiaquine (35 mg of base per kilo-
gram over a period of three days) is a more effective
alternative.9 Chloroquine-resistant infections in
most of Africa and some parts of Asia and South
America usually respond to a single-dose combina-
tion of a long-acting sulfonamide (usually sulfadox-
ine) and pyrimethamine. Although both amodi-
aquine and sulfadoxinepyrimethamine are well
tolerated in treatment, neither should be used as a
prophylactic drug, because of potential toxicity
(amodiaquine can be associated with agranulocyto-
sis and hepatitis, and sulfadoxinepyrimethamine
can be associated with exfoliative dermatitis, hepati-
tis, and blood dyscrasias). Unfortunately, resistance
to sulfadoxinepyrimethamine has developed rapidly
in many areas (particularly in South America and
Southeast Asia). For multidrug-resistant P. falcipa-
rum, the choice for treatment is mefloquine, halo-
fantrine, or quinine with tetracycline. Clindamycin is
used with quinine in some countries; three-day com-
bination regimens have proved effective in areas of
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endemic disease,10 but there is insufficient evidence
of their effectiveness in nonimmune patients.
Mefloquine is cleared slowly (elimination half-life,
two to three weeks),11 and a course of treatment
comprises one or two doses (Table 2). Mefloquine
is relatively well tolerated, although nausea, vomit-
ing, giddiness, weakness, dysphoria, feelings of dis-
sociation, clouding of consciousness, and nightmares
are all common. More serious self-limiting neuro-
psychiatric reactions have been reported in 0.5 to
1 percent of Europeans and Africans, but in approx-
imately 0.1 percent of Southeast Asian patients.12,13
Although vomiting in the first hour after adminis-
tration is more common in children, the other ad-
verse effects of mefloquine are more common in
adults.14
Halofantrine is more active and better tolerated
than mefloquine,15 but its oral bioavailability is poor
and variable (although it is increased by the con-
sumption of fat). Halofantrine induces a concentra-
tion-dependent delay in atrioventricular conduction
and ventricular repolarization16 that has cast a shad-
ow over its future role. Halofantrine should not be
given to patients with an abnormally long corrected
QT interval or those taking drugs likely to prolong
it (Table 2).16 Neither halofantrine nor mefloquine
should be used to treat early recrudescences (within
28 days of treatment) of malaria after primary mef-
loquine treatment, because their respective cardiac
and central nervous system effects are increased.
Treatment with oral quinine or quinidine is not
well tolerated. These venerable compounds are ex-
tremely bitter and often induce the complex of cin-
chonism (nausea, dysphoria, tinnitus, and high-tone
deafness). Fortunately, more serious toxic reactions
are rare. Although the combination of quinine with
tetracycline or doxycycline remains more than 85
percent effective nearly everywhere,17 compliance
with the seven-day courses of treatment required for
resistant P. falciparum infections is poor.
The derivatives of artemisinin (qinghaosu) ob-
tained from qinghao, or sweet wormwood (Arteme-
sia annua), and developed as pharmaceutical agents
in China, are the most rapidly acting of all antima-
larial drugs. These drugs are not registered and there-
fore not generally available in many countries, but
they have been used extensively for the treatment
of drug-resistant falciparum malaria in China and
Southeast Asia. In both severe and uncomplicated
malaria they have given faster relief of fever and con-
siderably faster clearance of parasites than other an-
timalarial agents, without evident toxicity.18,19 Three
compounds have been used: the parent, artemisinin,
and two more active derivatives (a water-soluble
hemisuccinate, artesunate, and an oil-soluble ether,
artemether), both of which are metabolized to a bi-
ologically active metabolite, dihydroartemisinin.18
Indeed, artesunate can be considered a prodrug for
Vol ume 335 Numbe r 11  801
 The New England Journal o f Me di c i ne

TABLE 2. RECOMMENDED DOSES OF ANTIMALARIAL DRUGS FOR THE TREATMENT OF MALARIA IN ADULTS AND CHILDREN.*

ORAL TREATMENT FOR PARENTERAL TREATMENT

DRUG UNCOMPLICATED MALARIA FOR SEVERE MALARIA

Drug-sensitive malaria
Chloroquine 10 mg base/kg followed either by 10 mg base/kg at 24 hr 10 mg base/kg by constant-rate infusion over 8 hr followed
and 5 mg base/kg at 48 hr or by 5 mg base/kg at 12, 24, by 15 mg base/kg over 24 hr, or 3.5 mg base/kg by in-
and 36 hr (total dose, 25 mg base/kg). For P. vivax or tramuscular or subcutaneous injection every 6 hr (total
P. ovale, add primaquine (0.25 mg base/kg daily) for dose, 25 mg base/kg).
14 days for radical cure.
Sulfadoxinepyrimethamine 20 mg sulfadoxine and 1 mg of pyrimethamine/kg in a single
oral dose (usual adult dose, 3 tablets; 1 tablet  500 mg sul-
fadoxine and 25 mg pyrimethamine).
Drug-resistant malaria
Mefloquine For people with some background immunity, 15 mg base/kg
in a single dose. For people without immunity or in areas of
mefloquine resistance, give second dose (10 mg base/kg)
824 hr later. In U.S., 1 tablet  228 mg base; elsewhere,
1 tablet  250 mg base.
Quinine 10 mg salt/kg every 8 hr for 7 days, combined with tetracy- 20 mg of dihydrochloride salt/kg by intravenous infusion
cline (4 mg/kg four times daily) or doxycycline (3 mg/kg over 4 hr followed by 10 mg/kg infused over 28 hr
once daily) for 7 days. Clindamycin (10 mg/kg twice every 8 hr.**
daily for 37 days) is an alternative to tetracycline.
Quinidine 10 mg base/kg infused at a constant rate over 1 hr followed
by 0.02 mg/kg/min, with electrocardiographic
monitoring.
Halofantrine 8 mg/kg repeated at 6 and 12 hr. Repeat the regimen 1 wk
later in people without immunity.
Artesunate In combination with a total of 25 mg of mefloquine/kg, give 2.4 mg/kg intravenously or intramuscularly initially, fol-
a total of 1012 mg/kg in divided doses over 35 days lowed by 1.2 mg/kg at 12 and 24 hr, then 1.2 mg/kg
(e.g., 4 mg/kg daily for 3 days or 4 mg/kg followed by 1.5 daily. Artesunic acid (60 mg) is dissolved in 0.6 ml of 5%
mg/kg/day for 4 days). If used alone, the same total dose sodium bicarbonate, diluted to 35 ml with 5% dextrose,
is given over 7 days (usually 4 mg/kg initially followed by and given by intravenous bolus or intramuscular injection.
2 mg/kg on days 2 and 3 and 1 mg/kg on days 47). 1 ampule  60 mg.
1 tablet  50 mg.
Artemether Same regimen as for artesunate. 1 capsule  40 mg. 3.2 mg/kg intramuscularly initially, followed by 1.6 mg/kg
daily. Not to be given intravenously. 1 ampule  80 mg.

*If there is any doubt concerning the drug sensitivity of the parasite, the infection should be considered to be resistant. Antimalarial doses are generally
recommended in terms of the base form of the drug, but the drugs are often dispensed in salt form. This gives rise to confusion; prescribers should make
clear to nurses and pharmacists which they mean.
Oral treatment should be substituted as soon as the patient can take tablets by mouth.
Either chloroquine phosphate (250 mg of the salt equals 156 mg of the base) or chloroquine sulfate (200 mg of the salt equals 147 mg of the base)
may be used. If neither is available, then hydroxychloroquine (200 mg of the salt equals 155 mg of the base) may be substituted.
For primaquine phosphate, 26.3 mg of the salt equals 15 mg of the base. In Oceania and Southeast Asia the dose should be 0.33 mg of base per
kilogram.
The combination is currently recommended in the United States only for self-treatment of presumptive malaria (not prophylaxis) by travelers.
Neither tetracycline nor doxycycline should be given to pregnant women or children less than eight years old.
**Alternatively, 7 mg of salt per kilogram can be infused over a period of 30 minutes, followed by 10 mg of salt per kilogram over a period of 4 hours.7
Quinine dihydrochloride is not available in the United States.
Halofantrine should not be taken with fatty foods and should not be given to patients with preexisting cardiac-conduction defects, those who have a
long QT interval, those who have received mefloquine within the previous 28 days, or those who are taking drugs known to prolong the QT interval (i.e.,
quinine, quinidine, chloroquine, tricyclic antidepressants, neuroleptic drugs, terfenadine, or astemizole). Halofantrine is not available in the United States.
This drug is not available in the United States.

dihydroartemisinin. In some parts of Southeast Asia Children and Pregnant Women

(particularly the eastern and western borders of
Thailand) where the failure rates of treatment with
high-dose mefloquine alone in falciparum malaria
now exceed 40 percent, oral artesunate given for
three to five days in combination with mefloquine
still remains highly effective.20,21 When used alone
(for example, for the treatment of recrudescence af-
ter treatment with mefloquine), the artemisinin de-
rivatives should be given for seven days.
Children tolerate antimalarial drugs relatively well.
Mefloquine is not recommended for children who
weigh less than 15 kg, but this is a policy of caution
based on limited published data. Experience sug-
gests that children are at no additional risk, although
infants are more likely to vomit the drug.13,14 Pri-
maquine should not be given to pregnant women or
newborn babies because of the risk of hemolysis.
Chloroquine, sulfadoxinepyrimethamine, quinine,

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 CURRENT CONCEPTS
and quinidine are considered safe in therapeutic dos-
es in all trimesters of pregnancy, although there is a
theoretical risk of kernicterus if sulfadoxine is given
in the third trimester. There is also evidence that
mefloquine is safe in the second and third trimesters.
Although there is little information on the use of
the artemisinin derivatives in pregnancy, the general
consensus is that they too should be used if they are
indicated (i.e., for mefloquine-resistant falciparum
malaria), except in early pregnancy, when alternative
treatment (quinine) is still preferred.22 Apart from
primaquine and halofantrine (for which there are no
data), the other antimalarial agents can all be used
in women who are breast-feeding.
There are no pediatric formulations of mefloquine,
the artemisinin derivatives, primaquine, or in many
countries, quinine or chloroquine. Quinine, and par-
ticularly chloroquine, are dangerous in overdoses,
and should be stored in childproof containers. When
treating children, particular care should be taken to
ensure that the correct doses are given and retained.
Early vomiting is common, particularly after the ad-
ministration of mefloquine or quinine to infants,
and is more likely in children with high fever. Pa-
tients should be cooled with acetaminophen, fan-
ning, and sponging with tepid water before they re-
ceive oral antimalarial treatment, and they should
then be observed for one hour. If vomiting occurs
within 1 hour, the full dose should be repeated (with
mefloquine, we repeat half the initial dose if the
child vomits between 30 and 60 minutes after ad-
ministration). If vomiting occurs after one hour, it
is not necessary to readminister the drugs.
Postural hypotension is common in uncomplicated
malaria and is exacerbated by the quinoline antima-
larial agents. Febrile patients, both adults and chil-
dren, should be kept in a horizontal position, and
great care should be taken if they get up rapidly from
their beds. Mothers should be discouraged from car-
rying febrile babies vertically immediately after par-
enteral quinine or chloroquine has been given.
SEVERE P. FALCIPARUM MALARIA
Management
Although infections with P. vivax, P. ovale, or
P. malariae are very rarely fatal, an infection with
P. falciparum may progress rapidly to a lethal multi-
system disease. The clinical manifestations of severe
malaria depend on age.23 Hypoglycemia, convul-
sions, and severe anemia are relatively more common
in children24,25; acute renal failure, jaundice, and pul-
monary edema are more common in adults. Cere-
bral malaria (with coma), shock, and acidosis, which
often terminate in respiratory arrest, may occur at
any age. The state of hydration of patients on admis-
sion is quite variable; the dividing line between over-
hydration and underhydration is thin. Adults in par-
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ticular may have noncardiogenic pulmonary edema
and are vulnerable to fluid overload, yet dehydration
and hypovolemia contribute to hypotension and
shock (particularly in children) and may hasten acute
renal failure arising from acute tubular necrosis (par-
ticularly in adults).26 After rehydration, the central
venous pressure should be maintained at approxi-
mately 5 cm of water (pulmonary-artery occlusion
pressure, less than 15 mm Hg). When hypercatabol-
ic acute renal failure develops with other evidence of
vital-organ dysfunction, dialysis or hemofiltration
should be started quickly. Renal function (restora-
tion of urine flow to more than 20 ml per kilogram
per day) returns after a median of four days, al-
though some patients will require dialysis for more
than a week.
Hypoglycemia occurs in approximately 8 percent
of adults27 and 25 percent of children.24,28 After re-
hydration, a maintenance infusion of 5 to 10 percent
glucose should be given to all patients, but the
blood glucose level should still be checked frequent-
ly. Unconscious patients with cerebral malaria should
be kept on their sides, and a lumbar puncture should
be performed to rule out bacterial meningitis. The
incidence of seizure ranges from more than 80 per-
cent in infants to less than 20 percent in adults.
Many of these seizures are focal, and the signs may
be subtle in an unconscious patient. Seizures should
be treated promptly with intravenous benzodiaz-
epines. Use of prophylactic intramuscular phenobar-
bital reduces the incidence of seizure, but the opti-
mal dose remains to be determined. Hemolysis is
extensive, and anemia develops rapidly. Blood should
be transfused if the hematocrit falls below 20 per-
cent. In Africa, where blood free of viral pathogens
is in short supply, it has been recommended that the
threshold for transfusion be a hemoglobin level of
less than 5 g per deciliter if there is respiratory dis-
tress, and less than 3 g per deciliter if there is not.29
A transfusion of fresh blood is preferable, particularly
if there is marked bleeding due to disseminated intra-
vascular coagulation (found in approximately 5 per-
cent of adults with severe malaria) or to stress ulcer-
ation.
Bacterial infections are common. Pneumonia is
likely if the duration of coma exceeds three days; uri-
nary tract infections may complicate the drainage of
indwelling catheters; and spontaneous (usually gram-
negative) septicemia may occur occasionally. System-
ic salmonella infections may develop in patients with
otherwise uncomplicated malaria.30 If the condition
of a patient with severe malaria deteriorates sudden-
ly without an evident cause, hypoglycemia should be
ruled out; blood cultures should be performed, and
empirical treatment with broad-spectrum antimicro-
bial agents started. Vital signs, including a patients
coma score, urine output, blood glucose level, and
if possible, lactate level, arterial pH, and blood gas
Vol ume 335 Numbe r 11  803
 The New England Journal of Me di c i ne
levels, should be monitored as frequently as possible.
The parasite count should be measured at least twice
a day in all patients. If the parasite count has not fall-
en by at least 75 percent 48 hours after the start of
treatment, it should be rechecked, and if confirmed,
a different antimalarial agent should be used.
Treatment
Chloroquine
In the few remaining places where there is not
widespread resistance to the drug, parenteral chloro-
quine should be given,31 but if there is any uncertain-
ty about resistance, then quinine or quinidine should
be used. Chloroquine should be given by controlled-
rate intravenous infusion and never by intravenous
injection. Intramuscular or subcutaneous administra-
tion is a satisfactory alternative: absorption is rapid;
bioavailability exceeds 80 percent, even in severe ma-
laria; and the injections are not painful.32 Provided it
does not enter the circulation too rapidly, either be-
cause the intravenous infusion is too fast or because
the dose given in an intramuscular or subcutaneous
injection is too large (more than 3.5 mg of base per
kilogram), hypotension will not occur and parenteral
chloroquine is very well tolerated.
Quinine and Quinidine
The alkaloids from the bark of the cinchona tree
still constitute the mainstay of the antimalarial phar-
macopeia, as they have for over three centuries.
Quinidine, the dextrorotatory diastereoisomer, is
more active than quinine, but it is also more car-
diotoxic and more expensive. In the United States
parenteral quinidine is recommended for severe ma-
laria, because of its wide availability as an antiar-
rhythmic agent.33 Elsewhere, quinine is used. The
cinchona alkaloids are effective against all species of
malaria including chloroquine-resistant strains of
P. falciparum.23 Both quinine and quinidine have
narrow therapeutic ratios, although serious cardio-
vascular or nervous system toxic effects during anti-
malarial treatment are most unusual. Quinine and
quinidine should be given by intravenous infusion
never by bolus injection, which can lead to fatal
hypotension. The principal adverse effect of these
drugs in severe malaria is hyperinsulinemic hypogly-
cemia.27,34 Iatrogenic hypoglycemia usually develops
after at least 24 hours of treatment and is a particu-
lar problem in pregnant women.35 Quinidine has ef-
fects similar to quinines on insulin secretion but a
fourfold greater effect on the heart.36 Electrocardio-
graphic monitoring is required so that infusion rates
can be reduced if the corrected QT interval is pro-
longed by more than 25 percent of the base-line val-
ue. Routine electrocardiographic monitoring is un-
necessary when quinine is used in patients with
previously normal hearts.
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The pharmacokinetic properties of the cinchona
alkaloids are altered considerably in malaria, with a
contraction in the volume of distribution and a re-
duction in clearance that is proportional to the se-
verity of disease.37 Consequently, doses should be
reduced by 30 to 50 percent after the third day of
treatment to avoid accumulation of the drugs in pa-
tients who remain seriously ill. Binding to plasma
proteins, principally to a1-acid glycoprotein, is in-
creased in malaria (from approximately 80 percent
to 90 percent for quinine).38,39 This explains why
plasma quinine levels that have been associated with
blindness and deafness after self-poisoning (more
than 10 mg per liter), although common during the
treatment of severe malaria, do not cause such ad-
verse effects. The therapeutic range for the unbound
drug, which depends on the sensitivity of the infect-
ing malaria parasites to the drug, has not been de-
fined precisely but probably lies between 0.8 and
2 mg per liter, corresponding to total plasma con-
centrations of approximately 4 to 8 mg per liter for
quinidine and 8 to 20 mg per liter for quinine.
When intravenous infusions cannot be given, qui-
nine dihydrochloride, diluted to between 60 and
100 mg per milliliter, should be administered by
deep intramuscular injection to the anterior thigh;
the initial loading dose should be divided, with half
injected in each leg. The intramuscular bioavailabil-
ity of quinine is good (approximately 90 percent)
even in severe malaria.40,41 Injections of undiluted
quinine (300 mg per milliliter) are painful and occa-
sionally produce sterile abscesses.
Artemisinin
Artesunate is unstable in solution and is therefore
dispensed as a dry powder of artesunic acid, together
with an ampule of 5 percent sodium bicarbonate so-
lution. The powder and liquid are mixed, and the so-
dium artesunate solution is given by intravenous or
intramuscular injection. Artemether is more stable
than artesunate. It is formulated in peanut oil and
given by intramuscular injection. In recent studies42
rectal suppositories of artemisinin have proved as ef-
fective as the parenteral drugs. Thus, effective drug
treatment for severe malaria can be given in rural set-
tings even if injections cannot. Artemisinin and its
derivatives have a broader window period of effec-
tiveness than other antimalarial agents during the
48-hour asexual life cycle of the parasite.43 Antipara-
sitic effects on the younger ring-form parasites lead
to their clearance and prevent development to the
more mature pathogenic forms that induce the par-
asitized erythrocytes to adhere to uninfected cells
(rosetting) or to vascular endothelium (cytoadher-
ence).44 Artesunate is the most rapidly acting of the
available compounds, possibly because it is immedi-
ately bioavailable (as dihydroartemisinin) after intra-
venous injection, and it is absorbed rapidly after oral
 CURRENT CONCEPTS
or intramuscular administration. In two recent, large
comparative studies of patients with severe falcipa-
rum malaria (which together enrolled over 1000 pa-
tients), treatment with intramuscular artemether ac-
celerated parasite clearance but slightly prolonged
recovery from coma, and it did not reduce mortality
significantly in comparison with quinine.45,46 The re-
sults of these trials confirm that artemether is an ac-
ceptable and well-tolerated alternative to quinine in
severe malaria, but a final assessment with respect to
mortality should await a systematic overview of these
and other recently completed studies. Over a million
patients have been treated with the artemisinin deriv-
atives. No serious toxicity has been reported.18,22
However, in experiments with animals, artemether,
the closely related compound arteether, and the me-
tabolite dihydroartemisinin have induced a consis-
tent, but unusual, selective pattern of damage to
some of the brain-stem nuclei.47 The relevance of
these findings to their use in humans is unresolved
but remains a cause of concern.
Ancillary Treatment
Many ancillary treatments have been suggested
and tried in severe malaria, but none have been
shown unequivocably to affect outcome. Only an-
tipyretics (acetaminophen), anticonvulsants (pro-
phylactic phenobarbital), and exchange transfusion
have been supported by sufficient evidence to war-
rant their use.23,48,49 Exchange transfusion should be
performed if there are adequate facilities, the patient
is seriously ill, and the parasitemia exceeds 15 percent.
Exchange should still be considered with para-
sitemia in the range of 5 to 15 percent if there are
other signs of poor prognosis (Table 1). The roles of
antibody against tumor necrosis factor, deferoxamine,
mannitol, prostacyclin, dextran, pentoxifylline, and
acetylcysteine in the treatment of malaria are unclear;
aspirin and hyperimmune serum have been shown to
confer no benefit, and heparin, cyclosporine, and
high-dose corticosteroids are probably harmful.
THE FUTURE
Mother Nature gave us the cinchona alkaloids and
qinghaosu. World War II led to the introduction of
chloroquine, chloroguanide (proguanil), and even-
tually, amodiaquine and pyrimethamine. The war in
Vietnam brought mefloquine and halofantrine. These
drugs are all we have available now to treat malaria.
It is difficult to see where the next generation of an-
timalarial drugs will come from. Even though malar-
ia now affects about 250 million people and kills be-
tween 1 million and 2 million children each year,
there is little pharmaceutical-industry interest in de-
veloping new antimalarial drugs; the risks are great,
but the returns on investment are low. Much of the
worlds malaria occurs in countries with an annual
per capita expenditure on health of less than $10. If
The New England Journal of Medicine
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drug resistance in P. falciparum continues to increase
at the current rate, malaria may become untreatable
in parts of Southeast Asia by the beginning of the
next millennium.
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