SEVERE AND COMPLICATED MALARIA6,7 Unless P. falciparum
malaria is promptly diagnosed and treated the clinical picture may deteriorate rapidly, often with catastrophic consequences. Severe malaria is defined as parasitaemia of higher than 5%, a haemoglobin of <6 g/dl, spontaneous hypoglycaemia or major organ dysfunction - particularly cerebral malaria.
SYMPTOMS A
patient with severe and complicated malaria may present with impaired consciousness (but rousable), extreme weakness and jaundice. In addition, the following complications may arise:
* cerebral malaria, defined as unrousable coma not attributable to any other cause * generalised seizures * hyperpyrexia
* renal failure * hypoglycaemia * fluid, electrolyte and acid-base disturbance * disseminated intravascular coagulation
* pulmonary oedema and adult respiratory distress syndrome * circulatory collapse and shock ("algid malaria") * hyperparasitaemia
* malarial haemoglobinuria * hepatic impairment * secondary bacterial infections * normocytic anaemia
It is important to appreciate that these severe manifestations can occur alone, or more commonly in combination in the same patient. Children, pregnant women,
immunocompromised, splenectomised and non-immune patients are of especially high risk.
TREATMENT Supportive management, preferably in an Intensive Care Unit, is critical in severe malaria.
Exchange transfusion has gained acceptance as an adjunct to conventional therapy in patients with heavy parasitaemia (more than 10% red blood cells parasitised) and organ dysfunction.
However, the indications for use, mechanism of action and optimal method of exchange remain contentious.15
The treatment regimens for the treatment of severe and complicated malaria are given in Table 2. Quinine Quinine is the drug of choice for the treatment of complicated/severe falciparum malaria. See "quinine" under uncomplicated malaria for possible adverse effects of quinine.Oral quinine therapy is recommended if the
patient is still capable of swallowing. The initial doses of quinine may be administered intravenously if the patient is vomiting. If the patient cannot take quinine orally, it must
be given intravenously. If quinine cannot be administered intravenously, it may be administered in the same dosage by intramuscular injection [IM] (half dose in each anterior thigh).
For IM use, quinine should be diluted in normal saline to a concentration of 60 mg/ml. This concentration appears to be less irritant than the undiluted concentration of 300 mg/ml.
Loading dose
In severe malaria an initial loading dose must be given by slow intravenous infusion. The dosage is quinine dihydrochloride salt (20 mg/kg body weight) in 5% dextrose saline (5-10
ml/kg body weight depending on the patient's fluid balance) intravenously, over 4 hours.A loading dose of quinine should not be used if the patient has received
quinine or quinidine in the preceding 24 hours or mefloquine in the preceding 7 days. In patients requiring more than 48 hours of parenteral therapy, the patient should be reassessed
and the serum quinine levels be checked. Some patients (e.g. those with impaired renal function) require a reduction in maintenance quinine dihydrochloride salt to 5-7 mg/kg every 8
hours. Maintenance dose Eight (8) hours after starting the loading dose, a maintenance dose of quinine dihydrochloride salt 10 mg/kg in dextrose saline diluted as above
over 4 hours must be given. The maintenance dose should be repeated every 8 hours until the patient can take oral medication (usually after 48 hours).
The total duration of treatment with quinine is 7 days, or longer until a blood smear is negative. Combination of quinine and doxycycline (or sulfadoxine-pyrimethamine If the patient contracted the malaria infection in a country with suspected quinine resistance (e.g. South America and Asia), the addition of a
second antimalarial is indicated. Anecdotal evidence suggests that partial resistance to quinine in sub-Saharan Africa is increasing, although published reports are currently
infrequent. Quinine therapy must then be combined with 7 days of daily doxycycline, or a stat dose (3 tablets) of sulfadoxine-pyrimethamine, once the patient can swallow.
The doxycycline or sulfadoxine-pyrimethamine should be added 2-3 days after initiation of quinine to ensure that possible adverse effects from the quinine are not confused with
those of the second agent. The doxycycline should be continued for longer than 7 days if the patients smear remains positive on the seventh day. Doxycycline Doxycycline, as well as the closely related
compounds, tetracycline and minocycline, have a potent but slow action against the asexual blood stages of P. falciparum.
It is also active against the primary intrahepatic stages of P. falciparum. Because of its slow onset of action, it should never be used as monotherapy in treating malaria.
15 Doxycycline should not be used for children under 8 years of age or during pregnancy. Sulfadoxine-Pyrimethamine
It should not be used alone for treatment of severe or complicated malaria. See "sulfadoxine-pyrimethamine
" under uncomplicated malaria for possible
adverse effects of the drug. Alternative treatment If there is a poor response to quinine in severe and complicated malaria, the additional use of halofantrine, mefloquine or artemisinin
may be considered in a referral center. All of these have significant restrictions to their use. The prescriber should also be aware of possible drug-drug interactions between quinine
and mefloquine or halofantrine. Halofantrine Some failures of halofantrine have been attributed to its poor and variable absorption. To prevent toxicity, halofantrine should be administered on
an empty stomach, as its administration with a fatty meal has been shown to increase the rate of absorption six-fold. A significant breakthrough rate after the recommended three
dose regimen necessitates an additional course one week after the initial therapy, especially in non-immune patients.Halofantrine should not be administered after
mefloquine was taken for chemoprophylaxis or treatment due to the additive cardiotoxicity. A number of authors have demonstrated that halofantrine induces consistent dose-related
lengthening of the PR and QT intervals.16,17
Because of the variable bioavailability and cardiotoxicity, halofantrine should only be used as emergency treatment in patients known to have normal QT intervals. Mefloquine
Mefloquine is not registered in South Africa for treatment of malaria and should only be used for prophylaxis. It should only be considered as treatment when multi-drug resistance,
including quinine resistance, is proven.While severe adverse events in a prophylactic setting are rare, neuropsychiatric adverse effects, including psychotic episodes,
depression and anxiety have been reported. Neuropsychiatric toxicity appears to be approximately sixty times more probable after treatment doses than after prophylactic doses of
mefloquine11. The drug has a long and variable elimination half-life ranging from 13 to 26 days and thus for those using mefloquine prophylaxis, malaria treatment with
halofantrine should be avoided and treatment with mefloquine should be administered only under close medical supervision because of the possibility of added toxicity. Artemisinin16,18,19
Artemisinin's use should be restricted to treating travellers returning from south-east Asia with multi-drug-resistant P. falciparum
infection, which does not respond to quinine therapy. However, widespread, uncontrolled or irregular use is likely to lead to the development of resistance to this drug. The World Health Organization has therefore developed guidelines to ensure effective treatment and reduce the emergence of artemisinin resistance.
In South Africa, artemisinin is only available on a named-patient basis, and this requires special clearance from the Medicines Control Council. There is no consensus
yet on the most appropriate treatment duration and dose. GENERAL MANAGEMENT OF SEVERE MALARIA7 The following measures should be applied in the management of all patients with clinically diagnosed or suspected severe or complicated
malaria:* If parasitological confirmation of malaria is not readily available, a blood film should be made and treatment started on the basis of the clinical
presentation. * Antimalarial chemotherapy must be given parenterally (intravenous or intramuscularly). Oral treatment should be substituted as soon as possible. * Doses must be calculated on a mg/kg of body weight basis. It is therefore important, whenever possible, to weigh the patient. This is particularly important for
children. * Do not confuse the doses of salt and base. Quinine doses are usually prescribed as salt (10 mg of salt = 8.3 mg of base). Chloroquine, quinidine and
mefloquine are commonly prescribed as base. * Good nursing care is vital. *
If an intensive care unit (ICU) is available, patients should be admitted. If no ICU is available, the patient should be nursed at the highest available level of care.* If fluids are being given intravenously, careful attention should be paid to fluid balance to avoid over- and underhydration. * A rapid initial check of
blood glucose level and frequent monitoring for hypoglycaemia are important, when possible. Otherwise glucose should be given. * Unconscious patients should
receive meticulous nursing care. Indwelling urinary catheters should be removed as soon as they are no longer necessary.
* Other treatable causes of coma should be excluded (by lumbar puncture) or covered by treatment.
* Frequent monitoring of the therapeutic response, both parasitaemic and clinical, is important. * Look for and manage any complicating or associated infections. * Monitor urine output constantly and look for the appearance of haemoglobinuria. * Regular monitoring of the core temperature, respiration rate, blood
pressure, level of consciousness and other vital signs is mandatory. * Reduce high body temperatures (> 39o
C by vigorous tepid sponging and fanning. Antipyretics may also be given. * Blood cultures should be taken if the patient goes into shock while undergoing treatment. * Laboratory measurements should include regular checks of erythrocyte volume fraction (haematocrit), glucose, urea or creatinine, and electrolytes.
* Administer an anticonvulsant prophylactically e.g. thenobarbital.
* Drugs that increase the risk of gastro-intestinal bleeding (aspirin, corticosteroids) should be avoided as far as possible. The guidelines are endorsed by the Medical Association of South Africa. |
