Malaria is a mosquito-borne protozoal infection caused in humans by four species of Plasmodium: P. falciparum, P. vivax, P. malariae, or P. ovale.1 Only P. falciparum causes life-threatening malaria, but other species can cause severe illness in debilitated individuals. Plasmodium sporozoites, inoculated by female Anopheles mosquitoes during their blood meal, invade hepatocytes where they mature into schizonts, and after 6 to 16 days rupture to release merozoites into the bloodstream. In the cases of P. vivax and P. ovale,
some sporozoites remain dormant in the liver for months or years in the form of hypnozoites, and can give rise to relapsing infections months or even years later. Plasmodium falciparum and P. malariae may persist as inapparent low-grade parasitemias to cause symptomatic recrudescences. However, these species do not persist in the liver. The erythrocytic cycle consists of invasion, development from rings to mature pigmented multinucleated schizonts, and rupture with release of 4 to 32 merozoites, depending on the species. These invade erythrocytes to produce repeated cycles of infection, or develop into male and female gametocytes. Merozoites cannot reinvade the liver from the blood. Erythrocytes containing mature trophozoites and schizonts of P. falciparum are sequestered in the tissues. Gametocytes taken up by mosquitoes complete a sexual cycle producing sporozoites which are injected with the mosquito's saliva during a blood meal. The usual intervals between the mosquito bite and the appearance of parasitemia are 10 days for P. falciparum, 8 to 13 days for P. vivax, 9 to 14 days for P. ovale, and 15 to 16 days for P. malariae. Minimal intervals between the bite and first symptom (incubation period) are a few days longer.
Malaria is endemic throughout tropical countries except in Pacific Islands east of Vanuatu (Fig. 58-1). P. falciparum is the most common cause of malaria in Africa, Haiti, some parts of South America, Southeast Asia, and New Guinea, but is now absent from Europe. Plasmodium vivax has been the dominant species in most parts of the Indian subcontinent where there is now a resurgence of P. falciparum; it is replaced by P. ovale in West Africa, but occurs with varying frequency throughout other parts of the malaria endemic area. P. malariae infections are widespread but usually infrequent.
Distribution of malaria in the world.
Children who grow up in endemic areas eventually acquire, through frequent infections, immunity to symptoms and severe malaria.1 In these regions, severe disease is confined to infants and young children. This immunity lapses in those who move outside the endemic area for several years. Thus Asian or African immigrants living in Europe or North America may become susceptible to symptomatic malaria by the time they return home on vacation. Outside the endemic areas, autochthonous malaria may occur in those living around international airports or in immigrant communities. Malaria can be transmitted by transfusion of blood products and bone marrow, by transplanted organs and contaminated needles (for example, among intravenous and subcutaneous drug abusers), and transplacentally (congenital malaria). Nosocomial outbreaks have followed contamination of intravenous lines and contrast medium, and administration of drugs.
So far, eighteen human genetic polymorphisms have been associated with resistance to malaria.2 These include thalassemias, hemoglobins S, E, and C, South East Asian ovalocytosis, glucose-6-phosphate dehydrogenase (G6PD) deficiency, interferon-α and -γ receptors, toll-like receptor 4, and for vivax malaria, the Duffy blood group. The highest frequencies of these resistance genes occur in intensely malarious areas.
Symptoms and pathologic changes are attributable to the asexual erythrocytic cycle and to secondary activation of macrophages and the immune system. A malarial toxin, released at schizont rupture, stimulates macrophages to release interleukin-1, tumor necrosis factor-α (TNF-α), and other cytokines. Cytoadherence to the wall of venules by erythrocytes containing mature trophozoites and schizonts plays an important role in producing organ and tissue dysfunction. The molecular basis of cytoadherence is the binding of malarial antigens expressed on the erythrocyte surface (notably the diverse and variable adhesive antigens, PfEMP1) to endothelial receptors such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), E-selectin, chondroitin-4-sulfate and hyaluronic acid (on placental villi), membrane glycoprotein CD36, or the multifunctional adhesive glycoprotein thrombospondin.1 Sequestration of parasitized erythrocytes is most marked in brain, kidney, gut, placenta, skeletal muscle, liver, bone marrow, and retina.2–4 The resulting stagnation of blood flow causes hypoxia and anaerobic glycolysis with increased lactic acid production.5
Pathophysiology of Specific Organ and Tissue Dysfunctions
Anemia results principally from hemolysis of parasitized erythrocytes and perhaps some immune hemolysis. Enhanced splenic removal of nonparasitized erythrocytes and dyserythropoiesis may contribute. Intravascular hemolysis and hemoglobinuria in patients with inherited erythrocytic enzyme defects such as G6PD deficiency is commonly associated with the use of oxidant antimalarial drugs such as primaquine and chloroquine. Classic blackwater fever has been attributed to quinine-related immune hemolysis, but the evidence is inconclusive. Thrombocytopenia results from splenic sequestration or immune destruction; there is no evidence of reduced marrow production. There is evidence of disseminated intravascular coagulation (DIC) in about 15% of severe cases. Neurologic symptoms (cerebral malaria) are attributable to sequestration of parasitized erythrocytes in venules with some inflammatory change, especially in children. Plasma concentrations of TNF-α correlate directly with severity and incidence of neurologic sequelae.6 In human cerebral malaria, permeability of the blood-cerebrospinal fluid barrier is only mildly deranged. Cerebral edema does not explain coma. Acute pulmonary edema may be precipitated by fluid overload, but is more commonly associated with normal or low pulmonary artery wedge pressures and resembles acute respiratory distress syndrome. Leukocyte sequestration in the pulmonary capillaries resembles experimental “endotoxin lung.” Hypoglycemia may result from quinine- or quinidine-induced hyperinsulinemia or from inhibition of hepatic gluconeogenesis by TNF-α, in association with appropriately low plasma insulin levels. Renal and hepatic dysfunction result from vasoconstriction and vascular obstruction by sequestered parasitized erythrocytes.1,7Shock (algid malaria) is frequently associated with secondary gram-negative rod septicemia, but may also arise in patients with acute pulmonary edema, dehydration, lactic acidosis, hypoglycemia, and hemorrhagic shock following gastrointestinal hemorrhage or splenic rupture.
The shortest interval between the infecting mosquito bite and the first symptom is 7 days. This fact may be useful in excluding the diagnosis of malaria in patients who fall ill too soon after entering a malarial endemic region. More than 80% of patients with imported falciparum malaria become ill within 1 month of leaving the endemic area, whereas only a few percent present between 3 and 12 months or longer after leaving. None of the symptoms of malaria is specific. The illness may start with headache, a fever, a chill, tiredness, or lethargy. Backache, myalgias, postural syncope, prostration, vomiting, and diarrhea are common. Physical signs include anemia, jaundice, and tender hepatosplenomegaly. An absence of focal symptoms, lymphadenopathy, and rash (other than herpes labialis) help distinguish malaria from some other fevers. The classical tertian or subtertian fever (a fever spike every 36 or 48 hours) is rarely seen, and even the classic “paroxysm” (chill, hot phase, and diaphoresis) is uncommon.1,8
Life-threatening falciparum malaria is defined by the presence of any of the features listed in Table 58-1.9 There are age and geographic variations in the frequency of these different features. In most parts of the world, cerebral malaria is the most familiar manifestation of severe malaria in adults, but jaundice is more common in Vietnam and Papua New Guinea, and in African children acidotic breathing is more common.1,9
Table 58–1. Severe Manifestations of Falciparum Malaria in Adults and Children |Favorite Table|Download (.pdf)
Table 58–1. Severe Manifestations of Falciparum Malaria in Adults and Children
|Clinical Manifestations||Laboratory Findings|
|Prostration||Severe anemia (hemoglobin <5 g/dL or hematocrit <15%)|
|Impaired consciousness (cerebral malaria)||Hypoglycemia (blood glucose <2.2 mmol/L or 40 mg/dL)|
|Respiratory distress (acidotic breathing)||Acidosis (plasma bicarbonate <15 mmol/L or base excess >–10)|
|Multiple convulsions||Hyperlactatemia (>5 mmol/L)|
|Pulmonary edema||Renal impairment|
Cerebral malaria10,11 should be considered in any acutely febrile patient, possibly exposed to P. falciparum infection, whose level of consciousness is impaired. A typical history would be that after a few days of febrile symptoms, coma developed insidiously or suddenly with a generalized convulsion. An immediate trial of antimalarial chemotherapy is warranted in such patients even if parasitemia is not evident in the peripheral blood smear. A strict definition of cerebral malaria (essential for comparative clinical trials) demands unrousable coma (Glasgow Coma Scale score ≤11), the demonstration of asexual P. falciparum parasitemia, and the exclusion of other causes of coma, especially of bacterial meningitis and locally prevalent viral encephalitides.9,12
Other clinical features of cerebral malaria include seizures (which may be subclinical in children),13 dysconjugate gaze, forcible jaw closure and tooth grinding (bruxism), signs of a symmetrical upper motor neuron lesion (with extensor plantar responses and absent superficial reflexes), and abnormal extensor or flexor posturing (decerebrate/decorticate rigidity). Retinal hemorrhages, and the less frequent exudates and papilledema, carry a severe prognosis. Survivors recover consciousness within a few days and are usually free of neurologic sequelae (but see discussion of children below). Psychiatric manifestations (brief reactive psychosis), involuntary (extrapyramidal) movements, and focal convulsions without loss of consciousness are seen but are uncommon. Delayed and reversible postmalaria ataxia has been described, especially in South Asia, but is not usually associated with cerebral malaria or severe disease.1,10
Renal functional impairment of some degree occurs in about a third of adult patients with severe falciparum malaria.14 Acute tubular necrosis develops in a minority. Acute renal failure is a feature of classic blackwater fever.
Acute pulmonary edema is often fatal. It is associated with hyperparasitemia, renal failure, lactic acidosis, use of excessive parenteral fluid replacement, and parturition. It has been rarely reported in vivax and ovale malarias (see below).15
Hypoglycemia is increasingly recognized. Symptoms of hypoglycemia may be confused with those of malaria itself, and so hypoglycemia must be specifically excluded in all patients with impaired consciousness, abnormal posturing, convulsions, shock, tachypnea, and in pregnant women in whom there is evidence of fetal distress. Hypoglycemia commonly develops as a complication of treatment with cinchona alkaloids (quinine and quinidine), which induce hyperinsulinemia, even in convalescence, particularly in pregnant women who may be asymptomatic, and in adults and children with hyperparasitemia and other features of severe disease.
Shock (algid malaria) may complicate severe malaria itself or be a result of simple dehydration or acute hemorrhage, but in many patients there is superimposed gram-negative septicemia. Cardiac arrhythmias and myocardial failure are extremely rare.
Bleeding, coagulopathy, and DIC are found in about 15% of nonimmune travelers with severe falciparum malaria. Thrombocytopenia is common in both falciparum and vivax malarias; its degree is not related to prognosis.
Acidosis, usually resulting from lactic acid accumulation, presents with rapid deep respirations in severely ill patients.
Massive intravascular hemolysis and hemoglobinuria in patients with normal erythrocyte enzymes has been termed “blackwater fever.” This puzzling syndrome is associated with intermittent use of quinine, mild or absent parasitemia, fever, loin pain, vomiting, diarrhea, polyuria followed by oliguria and passage of black urine, tender hepatosplenomegaly, profound anemia, and deep jaundice.
Hepatic dysfunction is manifested by deep jaundice with a major component of conjugated bilirubin, prolonged prothrombin time, increased concentrations of serum aminotransferases (rarely more than 3 to 5 times greater than normal), and a low or falling serum albumin.
Severe falciparum malaria in children1,16,17 is found in endemic regions of the tropics, where children under the age of 5 years are the most vulnerable. The history may be very short with less than 24 hours between the first feverish symptom and loss of consciousness. Generalized and subclinical convulsions are common.13 There is evidence of raised intracranial pressure (cerebrospinal fluid [CSF] opening pressure at lumbar puncture is elevated), brain swelling (confirmed by computed tomography [CT] or magnetic resonance imaging [MRI]), and in some cases neurologic signs suggesting cerebral and brain stem herniation.17A syndrome of metabolic acidosis, respiratory distress, and profound anemia carries a particularly bad prognosis.16 Jaundice, renal failure, hemostatic abnormalities, and pulmonary edema are much less common than in adults, but hypoglycemia is very common. The incidence of persistent neurologic sequelae after childhood cerebral malaria may exceed 10%.
The mortality of severe falciparum malaria ranges from 10% to 50%. In a recent report of imported cases of malaria managed in a European ICU, the mortality was 11%.18 However, in adults, impaired consciousness alone, without evidence of other organ or tissue dysfunctions, carries a good prognosis.12,18
Initial febrile and influenza-like symptoms associated with other Plasmodium species are as unpleasant as in falciparum malaria. The fever in untreated vivax and ovale malarias has a tertian periodicity (fever spike every 48 hours), and in P. malariae infection has quartan periodicity (every 72 hours). Vivax and ovale malarias may relapse 8 years or longer after the initial infection, and malarial infection may recrudesce for 50 years or more.
If, in a patient whose blood film shows only parasites of P. vivax, P. ovale, or P. malariae, there are clinical features of severe disease, inapparent mixed infection with P. falciparum should be suspected and the patient treated accordingly. Rapid antigen detection tests specific for P. falciparum can be useful in this situation (see below). However, Plasmodium vivax and P. ovale malarias can cause increased pulmonary capillary permeability, and on rare occasions, even clinically apparent pulmonary edema.15 Fatal splenic rupture has been described in vivax, and some debilitated children or adults have died of severe anemia. P. malariae malaria may prove severe or even fatal in immunocompromised patients who acquire the infection by transfusion. P. malariae infection is an important cause of nephrotic syndrome, especially in Africa.
Impact of Other Conditions on Disease Severity
Malaria is more severe in pregnant women, especially in the third trimester, and even women with acquired malarial immunity become newly vulnerable to severe disease during their first pregnancy. Splenic dysfunction predisposes to severe disease with high parasitemia with schizonts, and other mature forms may be present in the peripheral blood smear. An interaction between human immunodeficiency virus (HIV) immunosuppression and malaria has so far been demonstrated only in pregnant women, who show higher parasitemias, and in their babies, who suffer higher perinatal mortality. Although sickle cell trait partially protects against falciparum (but not ovale) malaria, malaria may be disastrous in children with sickle cell disease.
In a case of suspected malaria, the most urgent investigation is confirmation of diagnosis by microscopy or rapid antigen detection (see below). Other useful laboratory tests include a full blood count to detect anemia, thrombocytopenia (also common in vivax malaria), and neutrophil leukocytosis (of prognostic significance); examination of a thin blood film to detect malarial pigment in leukocytes (see below); measurement of plasma electrolytes (hyponatremia, hypophosphatemia, and hypocalcemia are reported); blood urea, creatinine, creatine kinase (for evidence of rhabdomyolysis), bilirubin, albumin, aminotransferases, lactate dehydrogenase and other serum enzymes (evidence of hepatic dysfunction); blood glucose; arterial blood gases, pH, bicarbonate and lactate (of prognostic significance); rapid urine testing for blood, hemoglobin, and myoglobin, and microscopy (sediment typical of acute glomerulonephritis); and, in cases of cerebral malaria, lumbar puncture and examination of CSF to exclude a bacterial, viral, fungal, or protozoal meningoencephalitis.1
The chest radiograph may show pulmonary edema or an incidental pneumonia or, if clear, supports the diagnosis of “acidotic breathing” in a hyperventilating patient. Electrocardiography (ECG) may confirm an arrhythmia or conduction defect attributable to quinine or quinidine. Abdominal ultrasound may show hepatosplenomegaly or evidence of splenic rupture. Electroencephalography may reveal subclinical seizure activity.13
CT and MRI scans have been reported in patients with cerebral19,20 and noncerebral malaria.21 Abnormalities include diffuse cerebral edema, focal hemorrhagic and nonhemorrhagic infarcts in various parts of the brain, subarachnoid hemorrhage, areas of hypoattenuation, and symmetrical infarction of the thalamus and cerebellum in adults who died of cerebral malaria.21 Not all those with cerebral malaria showed evidence of cerebral edema, and the prognosis was better in patients with normal scans.
Malaria must be included in the differential diagnosis of any acutely ill, febrile patient with an appropriate travel history.
Exposure can occur during a brief stopover in a malarious area, even if the ultimate destination was malaria-free. Routes of infection other than mosquito bites must be considered, such as blood transfusions and needlestick injuries and other nosocomial parenteral exposures to blood products. A diagnosis of malaria is more likely if the patient took no precautions against mosquito bites and no antimalarial chemoprophylaxis (or took the drugs irregularly or stopped them prematurely). The differential diagnosis of malaria includes other acute infections that cause chills and rigors, especially those that do not cause focal signs or symptoms (e.g., influenza enteric fevers or brucellosis); jaundice (e.g. viral hepatitis, leptospirosis, and relapsing fevers); hemorrhage (e.g., viral hemorrhagic fevers or hepatic failure); hyperpyrexia (e.g., heatstroke, neuroleptic malignant syndrome, malignant hyperthermia, or thyroid storm), gastrointestinal symptoms (e.g., gastroenteritis, traveler's diarrhea, or salmonellosis); and encephalopathy (e.g., viral, bacterial, fungal, or protozoal encephalitides, heat stroke, or metabolic coma).
Rapid antigen detection tests employing monoclonal antibodies to P. falciparum histidine-rich protein 2 and lactate dehydrogenase have proved to be sensitive and specific screening tests.
Microscopic diagnosis, which remains the gold standard, is achieved by examining conventional hematologic thin blood smears and thick films (a simple concentration method), preferably made at the bedside using blood straight from the patient that has not been stored with anticoagulant. Wright, Field, Leishman, and Giemsa stains are suitable (Fig. 58-2). Parasites should be counted in relation to erythrocytes or leukocytes in the same field, and the parasite concentration (per microliter) calculated from total erythrocyte or leukocyte counts. Blood examinations should be repeated at least every 12 hours, as parasitemia may fluctuate. Blood sampling need not be timed to coincide with a fever spike or paroxysm. There is no advantage in using venous or arterial blood instead of blood obtained by finger prick. Blood smears should be examined at 12-hour intervals (minimum) after starting treatment until parasitemia has disappeared for at least 24 hours. Malaria parasites may not be seen or recognized in travelers who are taking antimalarial drugs prophylactically. For this reason, such drugs should be stopped immediately, in the interest of making a diagnosis. Peripheral parasitemia may sometimes be undetectable in patients subsequently found (at autopsy) to have parasitized erythrocytes sequestered in their brains, and so a therapeutic trial of antimalarial drugs should be considered if there is clinical suspicion of severe malaria. The presence of gametocytes indicates recovery from infection; their morphology distinguishes falciparum from other malarias. Malarial pigment may be found in circulating leukocytes; its density is of prognostic value.
Plasmodium falciparum hyperparasitemia in a thin blood film from a patient with cerebral malaria. (Copyright D.A. Warrell.)
Management of Severe Malaria
Severe malaria is nearly always the result of P. falciparum infection. Because the disease can evolve rapidly, with sudden clinical deterioration and successive involvement of many vital organs and tissues, severe falciparum malaria is a medical emergency that should ideally be managed in an ICU.
Initial Clinical Assessment and Management
The clinical history, taken from the patient or accompanying friends and relatives, should include precise details (times and places) of travel to the tropics, preventive methods, recent antimalarial therapy or prophylaxis, and previous attacks of malaria. A history of ominous events such as convulsions, drowsiness, diminishing urine output, black urine, and psychosis should be elicited. It is important to know whether a female patient is pregnant. In severely ill patients, a rapid initial examination should be carried out to exclude other diagnoses (e.g., meningitis) and to detect life-threatening complications such as pulmonary edema, renal failure, shock, and hypoglycemia. In patients with malarial parasitemia, the physician must keep an open mind about other disease processes, especially in residents of the malarious zone in whom parasitemia may be irrelevant to their current illness. Initial investigations must include a parasite count (which is of prognostic importance), hematocrit, full blood count, and measurement of electrolytes, blood urea, and creatinine (Table 58-2). Frequent measurement of the blood glucose concentration is most important. It can be checked rapidly and repeatedly at the bedside using one of the many commercially available methods. The blood should be cultured. In patients with respiratory distress, arterial pH, blood gas tensions, bicarbonate, and lactic acid concentrations should be measured. In patients with impaired consciousness and other neurologic signs, lumbar puncture is important to exclude treatable meningoencephalitides. The usual precautions should be observed before carrying out a lumbar puncture: search for clinical evidence of raised intracranial pressure, lateralizing neurologic signs, and signs of imminent coning, local skin sepsis, etc. If there is any doubt, a CT or nuclear magnetic resonance (NMR) scan should be performed first. Lumbar puncture is safe in adult patients with cerebral malaria. However, African children may show progressive signs of cerebral compression and raised intracranial pressure, and some authorities recommend delaying lumbar puncture for 24 hours and giving presumptive antimicrobial treatment against bacterial meningitis.17 In cerebral malaria the CSF is usually normal. However, a mild lymphocyte pleocytosis (up to about 15 cells/μL) and mildly raised total protein concentration are found occasionally. Low or undetectable CSF glucose concentration indicates hypoglycemia. CSF opening pressure was normal in 80% of Thai adults with cerebral malaria, but was elevated in Kenyan children.17
Table 58–2. Initial Management of Patients with Severe Malaria |Favorite Table|Download (.pdf)
Table 58–2. Initial Management of Patients with Severe Malaria
|1. Clear and maintain airway.|
|2. Position semiprone or on side.|
|3. Weigh the patient, calculate drug dosage.|
|4. Start antimalarial chemotherapy.|
|5. Make rapid clinical assessment.|
|6. Take blood for diagnostic smear, monitoring of blood sugar (rapid “stix” method), hematocrit, and other laboratory tests.|
|7. Exclude or treat hypoglycemia.|
|8. Assess state of hydration.|
|9. Consider need for additional drugs (antimicrobials, vitamin K, etc).|
|10. Measure and monitor urine output. If necessary, insert urethral catheter. Measure urine specific gravity and sodium concentration.|
|11. Plan first 8 hours of intravenous fluids, including diluent for antimalarial drug, glucose therapy, and blood transfusion.|
|12. Consider inserting central venous pressure or pulmonary artery catheter to monitor fluid replacement.|
|13. If rectal temperature exceeds 39°C, remove patient's clothes, tepid sponge, fan, use hypothermia mattress, and consider antipyretic (acetaminophen).|
|14. Do lumbar puncture to exclude meningitis. Consider other infections.|
In patients with proven or suspected severe falciparum malaria, appropriate parenteral chemotherapy (usually with licensed quinine or quinidine) must be started immediately. Artemisinin derivatives such as artesunate, artemether (which has proved as effective as quinine in the treatment of cerebral and severe falciparum malaria),22 or arteether, may be available for treatment on a named-patient basis. Delay in diagnosis and treatment and the use of inappropriate antimalarial drugs account for most cases of fatal imported malaria.
In severely ill patients, chloroquine-resistant P. falciparum infection should be assumed. Recommended parenteral regimens for treatment of severe malaria are summarized in Table 58-3.
Table 58–3. Severe Falciparum Malaria: Antimalarial Chemotherapy |Favorite Table|Download (.pdf)
Table 58–3. Severe Falciparum Malaria: Antimalarial Chemotherapy
|1. Quinine: 7 mg dihydrochloride salt/kg (loading dose) IV by infusion pump over 30 minutes followed immediately by 10 mg salt/kg (maintenance dose) diluted in 10 mL/kg isotonic fluid by IV infusion over 4 hours, repeated every 8–12 hours until the patient can swallow,c then quinine tablets,b approx. 10 mg salt/kg every 8 hours to complete 7 days of treatment.25|
|2. Quinine: 20 mg dihydrochloride salt/kg (loading dose)a by IV infusion over 4 hours, then 10 mg salt/kg over 4 hours, every 8–12 hours until patient can swallow,c then quinine tablets,b to complete 7 days of treatment.24|
|3. Quinidine: 15 mg base/kg (equivalent to 20 mg/kg of quinidine gluconate) (loading dose)a by IV infusion over 4 hours, then 7.5 mg base/kg over 4 hours, every 8–12 hours until patient can swallow,c then quinine tabletsb to complete 7 days of treatment.23|
|4. Artesunate: (reconstitute with 5% bicarbonate immediately before injection) 2.4 mg/kg (loading dose) by IV (bolus) or IM injection, followed by 1.2 mg/kg daily as a single dose for a minimum of 3 days or until patient can take oral therapy or another effective antimalarial.1|
: 3.2 mg/kg (loading dose) by IM injection, followed by 1.6 mg/kg daily for a minimum of 3 days or until patient can take oral treatment or another effective antimalarial.1|
Cinchona Alkaloids (Quinine and Quinidine)
Quinine remains effective in the treatment of severe falciparum malaria. In the United States quinidine23 is supplied by the Centers for Disease Control and Prevention in Atlanta, Georgia, whose 24-hour malaria hotline telephone number is (404) 332-4555. Quinine and quinidine should never be given by intravenous push or bolus injection, but should be administered by slow, controlled-rate intravenous infusion using an intravenous drip with a metered chamber or an infusion pump. Unless the patient has been given quinine, quinidine, or mefloquine within the previous 12 hours, an initial loading dose should be used so that therapeutic blood concentrations can be achieved rapidly.23–25
The initial dose should not be reduced in pregnant women26 or in patients with renal and hepatic dysfunction, but the maintenance dose should be reduced after 48 hours of parenteral treatment, unless the patient can continue treatment by the oral route. The dose should also be reduced if at any stage the plasma concentration exceeds 15 mg/L (45 mmol/L). In patients treated with quinidine, the ECG should be monitored for QTc prolongation, and blood pressure measured every 30 minutes during the initial loading dose infusion.23
TOXICITY OF CINCHONA ALKALOIDS Plasma concentrations of cinchona alkaloids above about 5 mg/L are associated with cinchonism: giddiness, tinnitus, high-tone deafness, tremors, blurred vision, nausea, and vomiting. Concentrations above 20 mg/L may cause blindness, deafness, hypotension, ECG abnormalities, and central nervous system depression. However, most patients with malaria are more tolerant of high plasma concentrations than uninfected patients who take overdoses of these drugs, due to binding of quinine by acute phase reactive proteins, especially α1-acid glycoprotein. Quinidine more than quinine causes prolongation of the QTc interval and QRS complex, but this is rarely associated with dysrhythmia or hypotension unless the drugs are given too rapidly. The most frequent important side effect of quinine and quinidine is hypoglycemia, which may occur at any stage of treatment and may cause recurrent neurologic symptoms in patients who appear to have recovered from cerebral malaria. Normal therapeutic doses can be used safely even in the third trimester of pregnancy.26 In these patients it is important to assess uterine activity and fetal heart rate before starting quinine, to avoid confusing the effects of malaria and high fever per se from those of the drug.26 In severe quinine toxicity (following oral or parenteral administration), quinine elimination can be increased by oral or nasogastric administration of activated charcoal.27
Artemisinin Derivatives (Artesunate, Artemether, and Arteether)
These compounds are convenient to administer, rapidly clear parasitemia, and have proved safe in clinical use. Large comparative studies have demonstrated that they reduce case fatality of cerebral and severe falciparum malaria at least as effectively as quinine.22 They are particularly valuable where quinine resistance is emerging and in patients with recurrent quinine-induced hypoglycemia.
Artesunate, a water soluble preparation for intravenous injection, is inherently unstable in aqueous solution, but can be made up with 5% bicarbonate immediately before use. Artemether is an oily suspension for intramuscular injection which is licensed for use in a number of countries (but not the United States, Canada, or the United Kingdom). Arteether, a virtually identical compound, is being prepared for registration in the United States. Artemether and arteether have proved to be neurotoxic and fetotoxic in animals, but these effects have never been observed in tens of thousands of human patients monitored during and after treatment with these drugs.
Supportive Care of Patients with Severe Falciparum Malaria
Hyperpyrexia can cause febrile convulsions in children, fetal distress in pregnant women, and when sustained at core temperatures above 40°C, irreversible neurologic damage. Core temperature should be monitored, and when necessary the patient should be tepid-sponged and fanned, placed on a hypothermia mattress, or given an antipyretic (e.g., acetaminophen).
Generalized or covert seizures are common, especially in children. These must be controlled rapidly with appropriate anticonvulsants such as diazepam. Single-dose phenobarbital prophylaxis effectively reduces the incidence of generalized convulsions in adult and childhood cerebral malaria, but in a large randomized, placebo-controlled trial in African children, excess mortality was associated with this treatment, and thus it is not recommended.28 Cerebral edema does not require treatment in adult patients with cerebral malaria. However, in African children with cerebral malaria, intracranial pressure is commonly raised, and in those who are deteriorating, intravenous infusion of mannitol 1 g/kg over 20 minutes should be considered.17 Most of the ancillary treatments for cerebral malaria advocated in the past, including dexamethasone, have proved ineffective and potentially dangerous.12,29,30
Anemia is an inevitable consequence of severe malaria. If transfusion becomes necessary, packed red blood cells should be used while the patient is carefully monitored for evidence of incipient pulmonary edema. Diuretics, such as intravenous furosemide, may be required to reduce the risk of fluid overload. Children with profound malarial anemia may present in shock with tachycardia and tachypnea. Hypovolemia and metabolic (lactic) acidosis are usually the main problems requiring urgent correction. Blood transfusion may have little permanent effect in raising the hematocrit of patients with severe malaria because of the greatly reduced survival of even nonparasitized erythrocytes.31
The possibility of hypoglycemia in patients with severe or deteriorating symptoms must constantly be borne in mind. Frequent monitoring of the blood glucose is essential. Intravenous 50% dextrose (25 to 50 mL) should be tried if hypoglycemia is suspected or proved.
Metabolic (Lactic) Acidosis
Metabolic (lactic) acidosis results from impaired tissue perfusion caused by hypovolemia and microvascular obstruction, reduced hepatic clearance of lactate, and in patients with a large parasite burden, from the parasites' lactic acid production. Tissue perfusion and oxygenation should be improved by correcting hypovolemia, clearing the airway, increasing the inspired oxygen concentration, and providing mechanical ventilatory support if necessary. The treatment of gram-negative bacteremia, a frequently associated complication, should be considered as well. Use of epinephrine as a pressor agent may increase lactic acidosis, an effect not seen with dopamine.32
Disseminated Intravascular Coagulation
Severe DIC with spontaneous bleeding and fibrin deposition in the lungs and other tissues is occasionally seen (for treatment of DIC see Chap. 69).
Disturbances of Fluid and Electrolyte Balance
Patients with severe falciparum malaria are commonly dehydrated and hypovolemic on admission to the hospital as a result of decreased fluid intake, increased insensible losses through sweating and hyperventilation during febrile episodes, gastrointestinal fluid losses (vomiting and diarrhea), and sometimes during the diuretic phase of recovery from acute renal failure. These patients require parenteral fluid replacement, but this must be carefully controlled or else the increases in pulmonary capillary permeability may lead to acute and catastrophic pulmonary edema. A central venous or pulmonary artery catheter should be inserted. For correction of hyponatremia, hypocalcemia, hypophosphatemia, and hyper- or hypokalemia, see Chap. 76.
This may be associated with high central venous and pulmonary wedge pressures (caused by volume overload and/or anemia), or with low pressures as in acute respiratory distress syndrome from other causes. Mechanical ventilation may be required.18 See Chaps. 36 and 38 for a discussion of the management of these complications.
Oliguria may be prerenal—caused by volume depletion—or attributable to direct renal injury.14 If dialysis is indicated (see Chap. 75), hemofiltration has proved more effective than peritoneal dialysis.18,33
Hemoglobinuria and Blackwater Fever
Intravascular hemolysis may be associated with acute renal failure. To protect the kidney from “pigment nephropathy,” hypovolemia and acidosis must be corrected. Mannitol diuresis is recommended by some nephrologists. Packed red blood cells should be transfused to maintain the hematocrit above 20%. Despite the unproven suspicion that quinine may be responsible for the massive intravascular hemolysis of blackwater fever, treatment with cinchona alkaloids should not be stopped unless an alternative drug such as an artemisinin derivative is available.
Mortality generally increases with parasitemia, exceeding 50% at parasitemias above 500,000/μL. It has been suggested that exchange transfusion, by reducing the burden of parasitemia more rapidly than chemotherapy alone, might reduce mortality, although the introduction of artemisinin derivatives that clear parasitemia very rapidly may weaken the argument for this intervention. Other theoretical advantages of exchange transfusion include the removal of harmful metabolites, toxins, and mediators, and the replenishment of normal red blood cells, platelets, clotting factors, and other depleted blood constituents. However, these potential advantages must be weighed against potential dangers, such as electrolyte disturbances (hypocalcemia and hyperkalemia), cardiovascular complications, line infections, and contamination of transfused blood with blood-borne pathogens, notably HIV, human T-lymphocyte virus-1, hepatitis viruses, and protozoa. In more than 200 reported cases, red blood cell exchange achieved rapid reduction in parasitemia, which in some cases was accompanied by evidence of clinical improvement.34 Exchange transfusion should be considered for nonimmune travelers who are severely ill, who have deteriorated on optimal chemotherapy, or who have parasite densities above 10% of circulating erythrocytes.1
This life-threatening complication may occur in vivax or falciparum malaria. It must be suspected and excluded in patients who develop abdominal pain and shock. Ultrasound is useful for detecting free blood in the peritoneum and a tear in the splenic capsule. Invasive techniques such as needle aspiration of the peritoneal cavity, laparoscopy, or laparotomy may be required.