Page 996 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 78: Severe Malaria 727

artemether—and the cinchona alkaloids—quinine and quinidine. for the treatment of severe malaria did not show a significant difference
Parenteral sulphadoxine-pyrimethamine and chloroquine are no longer in mortality between these drugs. 61
useful because of global widespread resistance. In comparative studies Until artesunate becomes more widely available, parenteral quinine
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with quinine, parenteral artesunate has significantly reduced mortality will remain the most widely used drug for the treatment of severe
in both adults and children. Parenteral artesunate is recommended by malaria, including in several nonendemic countries. In order to obtain
the WHO as the first-line treatment of severe malaria in both adults parasitocidal blood levels rapidly and safely, it is essential to give the first
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and children, irrespective of the endemic setting. quinine dose in the loading form of 20 mg salt/kg, except in patients who
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The artemisinins or qinghaosu compounds are derived from the have received quinine in the 24 hours before admission. 62,63 The loading
plant Artemisia annua. They all contain an unusual chemical structure dose is followed by an 8-hourly dose of 10 mg salt/kg. Because of its
consisting of a sesquiterpene within which is a unique endoperoxide cardiotoxicity, intravenous infusions should be administered over 2 to
bridge that is essential for its biological activity. Derivatives of artemis- 4 hours. A shorter loading dose regimen can be used with rate controlled
inin, which is the parent compound extracted from plants, are made by infusion pumps.
simple chemical modifications. 54 If intravenous infusion is not practicable, quinine can be given by
Artemisinins are potent and rapidly acting blood schizonticides deep intramuscular injection into the anterior thighs. Quinine solutions
against all Plasmodium species. They have an unusually broad activity are relatively concentrated (300 mg/mL) so they should be diluted (1 : 1
against asexual parasites, killing all stages from young rings to schiz- vol : vol) in saline and the loading dose should be divided and given in
onts. This property distinguishes them from all other antimalarials, two sites, based on studies in children. Injection into the buttocks can
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and is probably the pharmacodynamic basis for artesunate’s superiority cause sciatic nerve damage.
in the treatment of severe malaria, since it prevents the maturation of Quinine is a relatively toxic drug with a narrow therapeutic ratio.
ring form parasites to the more pathogenic trophozoite and schizont Quinine-induced hyperinsulinemic hypoglycemia is a particular prob-
forms, which sequester in the microcirculation of vital organs. lem in patients with severe malaria, especially during pregnancy, and
9,10
Artemisinin and its derivatives are generally safe and remarkably well is impossible to diagnose clinically in the already unconscious patient.
tolerated. Reported side effects include dizziness, tinnitus, reticulo- Frequent monitoring of blood glucose concentrations is therefore
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cytopenia, dose-dependent neutropenia, and elevated liver enzyme essential. The total apparent volume of distribution of quinine and its
values. Although electrocardiographic abnormalities, including pro- systemic clearance are both reduced in proportion to disease severity,
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longation of the QT interval, have been mentioned in some reports, and in severe malaria the dose should be reduced by one-third after
significant QT prolongation was not observed in severe malaria 48 hours if there is no clinical improvement or if there is renal failure. 62,63
patients treated with parenteral artesunate. Potentially serious adverse Quinidine has long been the only readily available parenteral antima-
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effects reported with this class of drugs are type 1 hypersensitivity larial to treat severe malaria in the USA. Quinidine is a diastereomer
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reactions in approximately 1 in 3000 patients and dose-dependent of quinine but is more toxic, commonly causing hypotension and con-
neutropenia. The artemisinins are considered safe in the second and centration-dependent prolongation of ventricular repolarization (QT
third trimesters of pregnancy. prolongation). Administration requires electrocardiographic monitor-
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Artesunate is a water-soluble artemisinin derivative that acts as a pro- ing and frequent assessment of vital signs. With the availability of bet-
drug for dihydroartemisinin (DHA); both have antimalarial activity. ter alternatives, it can no longer be recommended for the treatment of
54
Artesunate has a plasma elimination half-time of a few minutes, and DHA severe malaria.
has reliable bioavailability after intramuscular administration, reaching ■ TREATMENT OF CONCOMITANT DISEASES
of ~45 minutes. Artesunate can be given intravenously over 2 minutes. It
peak levels within 20 to 40 minutes in children and adults. The African children with slide proven severe malaria have concomitant
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recommended dose is 2.4 mg/kg immediately followed by the same dose bacteremia in 4.6% to 7.8% of cases. Given the limited sensitivity of
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at 12 hours, 24 hours, and then daily until oral medication can be taken blood culture, the real number of children with concomitant bacteremia
reliably. Oral follow-on treatment is most easily given as a full course might be at least twice as high. This group represents children in high
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of an artemisinin combination therapy such as artemether-lumefantrine. transmission areas where background peripheral blood parasitemia is
There have been two large trials comparing artesunate with quinine common and a positive blood slide can thus be an incidental finding in
for the treatment of severe malaria. The Asian SEAQUAMAT trial in a child with sepsis. However, severe malaria in itself is also a risk factor
mainly adult patients with severe malaria found a 35% reduction in for invasive bacterial infection such as pneumonia or bacteremia with
inhospital mortality in favor of intravenous artesunate, which was not non-Salmonella typhi. Blood cultures should therefore be collected in
at the expense of an increase in neurological sequelae. In the African all patients with severe malaria, although this is often not feasible in
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AQUAMAT trial in pediatric severe malaria, mortality was 23% lower settings with limited resources harboring the majority of the world’s
in patients treated with parenteral artesunate, also with no difference in malaria cases. In addition to antimalarial treatment, every patient with
severe neurological sequelae between treatment groups. Hypoglycemia a proven diagnosis of severe malaria should also be considered for
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was more frequent with quinine treatment in both studies. Availability treatment with empiric broad-spectrum antibiotics until culture results
of quality assured parenteral artesunate compliant with strict Good become available.
manufacturer obtained WHO prequalification for their parenteral ■ ADJUVANT THERAPIES
Manufacturing Practice was a problem until 2010. In that year, a Chinese
artesunate product. It is expected that this will facilitate registration of Many adjunctive treatments have been tried, often in underpowered
the product in both malaria endemic and nonendemic countries. In clinical trials, but none have convincingly improved survival in severe
addition, the Walter Reed Army Institute in the USA has developed a malaria. Exchange blood transfusion is a popular adjunctive therapy,
formulation of intravenous artesunate, which is available for compas- particularly in well-resourced settings. There are a number of reasons
sionate use within the USA. for its use in severe malaria, including rapid removal of parasitized
Artemether is an oil-soluble artemisinin derivative. The parenteral erythrocytes, removal of cytokines and other soluble toxins and media-
formulation of artemether can only be administered by intramuscular tors, and improving the rheology of the blood by replacing unparasitized
route and the recommended dose is 3.2 mg/kg on admission followed erythrocytes having reduced deformability by fresh red cells and replen-
by a 24-hourly dose of 1.6 mg/kg. Intramuscular artemether has shown ishment of some plasma components. A meta-analysis of small studies
erratic bioavailability in patients with severe malaria, with very low and case series has failed to show clear benefit. We consider erythrocy-
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plasma levels in a subset of patients. This probably explains why a topheresis in patients who are severely ill with multiorgan involvement
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meta-analysis of randomized trials comparing artemether with quinine and with relatively high parasitemias (>5%).

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