Treatment of Severe Falciparum Malaria

Treatment of severe falciparum malaria
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Official reprint from UpToDate www.uptodate.com 2012 UpToDate

Author Terrie E Taylor, DO Disclosures Last literature review version 19.3: Setembro 2011 | This topic last updated: Outubro 28, 2011 INTRODUCTION Malaria is endemic throughout most of the tropics. Of the approximately 3 billion people living in 108 countries who are exposed, approximately 243 million will develop symptomatic malaria annually [1]. Most of these are attributable to P. falciparum (90 percent), but P. vivax and P. knowlesi can also cause severe disease [2,3]. Around 863,000 deaths are caused by malaria each year; over 80 percent of the deaths occur among children in sub-Saharan Africa. Severe malaria is acute malaria with major signs of organ dysfunction and/or high level of parasitemia. In endemic areas, young children and pregnant women are at high risk for severe malaria. Older children and adults develop partial immunity after repeated infections; these groups are thus at relatively low risk for severe disease. Travelers to areas where malaria is endemic generally have no previous exposure to malaria parasites and so are at high risk for severe disease. Management of patients with severe malaria presents a broad array of clinical challenges given the complex pathophysiology of the infection involving multiple organ systems. These challenges are increased manyfold in endemic areas where access to diagnostic and therapeutic tools may be limited. Nevertheless, it is possible to provide excellent care for these patients. The approach to treatment of severe falciparum malaria will be reviewed here. Issues related to management in both endemic and nonendemic areas will be addressed. The treatment of nonsevere malaria is discussed separately. (See "Treatment of uncomplicated falciparum malaria".) DEFINITION Severe malaria is generally defined as acute malaria with high levels of parasitemia (>5 percent) and/or major signs of organ dysfunction (table 1) [4-6]: Altered consciousness with or without convulsions Deep breathing, respiratory distress (acidotic breathing, costal indrawing, use of accessory muscles, nasal alar flaring) Metabolic acidosis (plasma bicarbonate M 15 mmol/L or whole blood lactate >5 mmol/L) Circulatory collapse Pulmonary edema or acute respiratory distress syndrome (ARDS) Renal failure, hemoglobinuria ("blackwater fever") Clinical jaundice Disseminated intravascular coagulation Severe anemia Hypoglycemia The clinical manifestations of severe malaria vary with age and geography. In areas where malaria is endemic, young children (ages 2 to 5 years) are at high risk for severe malaria, as are pregnant women. Older children and adults develop partial immunity to febrile malaria episodes (but not to malaria infection) after repeated infection [7], and thus are at relatively low risk for severe disease. Travelers to areas where malaria is endemic generally have no previous exposure to malaria parasites and so are at high risk for progression to severe disease if infected with P. falciparum [8,9]. For this reason, it is important to consider malaria in the differential diagnosis of all febrile patients with a history of travel to areas where the disease is endemic. Seizures and severe anemia are relatively more common in children, whereas hyperparasitemia, acute renal failure, and jaundice are more common in adults. Cerebral malaria (with coma), shock, acidosis and respiratory arrest may occur at any age [10]. The clinical manifestations of malaria are discussed in further detail separately. (See "Clinical manifestations of malaria".) DIAGNOSIS The diagnosis of malaria infection and the degree of parasitemia are established by blood smear. In general, the heavier the parasitemia, the sicker the patient, but there are many asymptomatic patients with high parasitemia, and patients with severe malaria can present with low density infection. Other techniques for diagnosis for malaria are discussed in detail separately. (See "Diagnosis of malaria".) CLINICAL MANAGEMENT General principles Death due to severe malaria can occur within hours of presentation, so prompt assessment and initiation of antimalarial therapy are essential. Patients should be evaluated with attention to findings consistent with malaria as well as additional and/or alternative causes of presenting symptoms. A full neurologic assessment should be performed, including assessment of the Blantyre coma score for children (table 2); the Glasgow coma scale is suitable for adults (table 3). Temperature, heart rate and rhythm, respiratory rate and rhythm, blood pressure oxygen saturation, and weight should be noted, as should capillary refill and degree of pallor. (See "Stupor and coma in adults" and "Evaluation of stupor and coma in children".) Of primary importance in the treatment of malaria is the provision of prompt, effective therapy and concurrent supportive care to manage life-threatening complications of the disease. Supportive measures (eg, oxygen, ventilatory support, cardiac monitoring, and pulse oximetry) should be instituted as needed. During this time, intravenous catheters should be placed and fingerprick blood samples should be obtained for laboratory tests needed immediately. Point-of-care testing machines can be used for rapid determination of hematocrit [packed cell volume (PCV) or hemoglobin (HemoCue)], glucose, and lactate. Parasitemia can also be determined quickly but requires a microscope. Additional tests can be done if/when indicated: electrolytes, full blood count, type and cross, blood culture, and clotting studies. Unconscious patients should have a lumbar puncture to rule out concomitant bacterial meningitis in the absence of contraindications (eg, papilledema). These tasks should overlap with institution of antimalarial treatment as well as other ancillary therapies as needed (including anticonvulsants, intravenous glucose and fluids, antipyretics, antibiotics, and blood transfusion). Repeat clinical assessments should be performed every two to four hours for prompt detection and management of complications (in an intensive care setting, if possible). If the coma score decreases after initiation of treatment, investigations should focus on the possibility of seizures, hypoglycemia, or worsening anemia. Repeat laboratory assessments of parasitemia, hemoglobin/hematocrit, glucose, and lactate should be performed in 6 hour intervals. A flow chart summarizing the vital information may be used to guide management decisions [11] (table 4). Section Editor Johanna Daily, MD, MSc Deputy Editor Elinor L Baron, MD, DTMH
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Careful observation and thoughtful responses to changes in clinical status are the most important elements in looking after patients with severe malaria. Patients can make remarkable recoveries, and the time and effort to address the components of clinical care described in the following sections can reap tangible rewards in a relatively short period of time. Antimalarial therapy There are two major classes of drugs available for parenteral treatment of severe malaria: the cinchona alkaloids (quinine and quinidine) and the artemisinin derivatives (artesunate, artemether and artemotil) [4]. Data comparing quinine and artemisinins suggest that intravenous artesunate is preferable for treatment of adults and children with severe falciparum malaria (in areas where intravenous artesunate of reliable quality is readily available) [4,12]. If intravenous artesunate is not an option, intravenous quinine (or quinidine in the United States) remains the drug of choice. Artemisinins Artemisinin derivatives clear parasitemia more rapidly than quinine. They are active against a broader life-cycle range of blood stage parasites than quinine and they are active against gametocytes [13,14]. Artemisinin derivatives include artesunate, artemether and artemotil. Artesunate is the preferred artemisinin; clinical experience with artemether and artemotil drugs is limited and they should not be used for treatment of severe disease. Artesunate is the preferred therapy for treatment of severe falciparum malaria in adults and children in areas where intravenous artesunate is available [4,12]. This approach is based on data suggesting that artesunate is superior to intravenous quinine for treatment of adults in Asia and children in Africa with severe malaria: Among 1461 patients in Bangladesh, India, Indonesia, and Myanmar randomized to receive artesunate or quinine, lower mortality was observed among those who received artesunate (15 versus 22 percent, respectively; risk reduction 34 percent) [15]. The life saving impact of artesunate was noted among patients who survived more than 24 hours after starting treatment. Artesunate was well tolerated, while quinine was associated with a threefold increased risk of hypoglycemia. Among 5425 children in Africa with severe malaria randomized to receive therapy artesunate or quinine, lower mortality was observed among those who received artesunate (8.5 versus 10.9 percent, respectively; risk reduction 22.5 percent) [12]. The life saving impact of artesunate was apparent throughout the course of treatment. Hypoglycemia was less frequent in the artesunate group than the quinine group (1.8 versus 2.8 percent). There were no differences in the rate of neurological sequelae between the two groups. A meta-analysis of seven randomized trials compared the survival rates among recipients of parenteral quinine and artesunate; artesunate was superior with respect to mortality (overall odds ratio 0.69, 0.57-0.84, p<0.00001), and there was no significant heterogeneity between results from Africa and Asia [12]. Intravenous artesunate of reliable quality is not yet available in many countries; in these areas, quinine remains the treatment of choice. In the United States intravenous artesunate is not approved by the Food and Drug Administration but is available for use under an investigational protocol by enrollment with the Centers for Disease Control (CDC Malaria Hotline: (770) 488-7788 Monday-Friday 8a to 4:30p EST; (770) 488-7100 after hours, weekends and holidays) [16]. Eligible patients include those with parasitemia 5 percent and/or other signs of severe malaria, as well as those with uncomplicated malaria who require parenteral therapy due to intolerance of oral medications. The CDC also requires that artesunate be available at least as rapidly as quinidine or that there be quinidine intolerance, failure or contraindication [16]. (See 'Quinine/quinidine' below.) Artesunate is the most rapidly acting of the artemisinin compounds because of its water solubility. Administration of intravenous artesunate consists of 2.4 mg/kg as first dose, followed by 2.4 mg/kg at 12 and 24 hours, followed by 2.4 mg/kg once daily (table 5) [4,13]. Following four doses of intravenous artesunate, oral antimalarial treatment may be administered if the patient is able to tolerate oral therapy. Intravenous therapy for more than three days may be indicated in very ill patients. Artesunate can also be administered intramuscularly, orally, or via rectal suppository [17]. (See 'Completing therapy' below and 'Prereferral treatment' below.) Artesunate dosing need not be adjusted for hepatic or renal failure, nor for concomitant or previous therapy with other medications (including mefloquine, quinine, or quinidine) [13]. The most common adverse effects associated with artemisinins include nausea, vomiting, anorexia and dizziness, although these may be due to malaria rather than drug toxicity. There is no convincing evidence of neurotoxic effects in humans due to oral or intravenous artemisinins, although neurotoxicity has been described in animals and attributed to fat soluble artemisinins more frequently than to artesunate [18]. Limited data are available on the use of artesunate for severe malaria during pregnancy. (See 'Pregnancy' below.) Emergence of artemisinin resistance is an important concern, and combination of artemisinins with other active agents may protect against the development of resistance to individual drugs [19]. Pending further data, use of intravenous artesunate monotherapy remains appropriate for treatment of severe malaria. After the patient is no longer critically ill, oral combination therapy is typically used to complete the course of treatment. (See 'Completing therapy' below.) Quinine/quinidine Intravenous quinine remains the treatment of choice for areas where intravenous artesunate of reliable quality is not readily available. In the United States, parenteral quinine was withdrawn by the CDC in 1991; intravenous quinidine is available for treatment of severe malaria [20]. Quinine (or quinidine) should be administered by intravenous infusion beginning with an initial loading dose (table 5): Intravenous quinine dihydrochloride 20 mg salt/kg (in 5 percent dextrose) loading dose over 4 hours, followed by 20 to 30 mg salt/kg divided into two to three equal administrations of 10 mg salt/kg (over 2 hours) at 8 or 12 hour intervals (maximum 1800 mg salt/day). Solutions diluted to 60 mg/mL quinine dihydrochloride are less painful than more concentrated preparations [21]. Intravenous quinidine gluconate 10 mg salt/kg loading dose (maximum 600 mg salt) in normal saline over 1 hour, followed by 0.02 mg/kg/minute continuous infusion. If intravenous infusions cannot be given, quinine can be administered via intramuscular injection. Two injections of 10 mg/kg quinine (diluted to 60 to 100 mg/mL) should be administered 4 hours apart. The anterior thigh is preferred over the gluteal region to minimize the risk of sciatic nerve damage. Both quinine and quinidine can act as pancreatic secretagogues, leading to hyperinsulinemic hypoglycemia. Other toxic effects include tinnitus, reversible hearing loss, nausea, vomiting, dizziness, and visual disturbances. Quinidine can cause QT prolongation and should be administered with electrocardiographic monitoring [22]. Infusions should be done with care and the rate should be reduced if the corrected QT interval becomes prolonged by more than 25 percent of the baseline value. Such monitoring is not necessary in the setting of quinine administration in patients without cardiac abnormalities. (See "Major side effects of quinidine".) The approach to parenteral treatment with quinine (or quinidine) depends on the clinical circumstances (table 5). For patients with malaria acquired in SE Asia, parenteral treatment with quinine (or quinidine) should be combined with one of the following: doxycycline, tetracycline or clindamycin (table 5). For children with malaria acquired in Africa, clinical management consists of administering parenteral quinine (at least three doses) until the child can swallow,
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followed by oral therapy with an artemisinin combination drug. (See 'Completing therapy' below.)
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Prereferral treatment The risk of death due to severe malaria is greatest in the first 24 hours of illness. In rural endemic areas where patients with severe malaria cannot begin intravenous therapy immediately, patients should be treated with a prereferral dose of intramuscular or intrarectal therapy and triaged to an acute care facility. Options include intramuscular administration of quinine or an artemisinin, or rectal administration of artesunate. A single artesunate rectal suppository pending transport has been demonstrated to reduce mortality. This was illustrated in a randomized trial of over 12,000 patients in rural Bangladesh, Ghana and Tanzania with suspected severe malaria [17]. Dosing consisted of 100 mg for children 6 months to 6 years of age and 400 mg for patients >6 years. Mortality was significantly lower among those who received prereferral rectal artesunate than among those who received placebo (1.9 versus 3.8 percent, respectively; risk ratio 0.49, 95 percent CI 0.32-0.77). If referral is impossible, intramuscular or rectal treatment should be continued until the patient can tolerate oral medication, at which point a full course of oral therapy should be administered. Completing therapy In general, the total duration of therapy with quinine/quinidine for severe malaria is 7 days. The total duration of therapy with artemisinin based therapy is 3 days. After the acute stage of illness has been treated with parenteral therapy and the patient can swallow, a course of oral therapy should be administered based on known susceptibility data to complete the treatment course. In general, the class of agent administered parenterally may be used for oral completion of therapy when feasible. Patients receiving parenteral quinine/quinidine can be transitioned to oral quinine, and those receiving parenteral artemisinin therapy can be transitioned to oral artemisinin combination chemotherapy. Patients completing oral quinine treatment should also receive a second agent. Options for coadministration with quinine include 7 days of doxycycline or tetracycline (or clindamycin for children or pregnant women) (table 5). Options for oral artemisinin combination therapy are outlined in detail separately. (See "Treatment of uncomplicated falciparum malaria".) Alternatively, a full course of treatment with atovaquone-proguanil or mefloquine may be administered as for uncomplicated malaria (table 6). Regimens containing mefloquine should be avoided if the patient presented with altered consciousness, since there is an increased incidence of neuropsychiatric toxic effects associated with mefloquine following cerebral malaria. Respiratory status Hypoxemia and rales are not common in the setting of severe malaria; the presence of either should raise suspicion for a concomitant lower respiratory tract infection [23]. Pulmonary edema may develop, particularly in the settings of renal impairment or severe malarial anemia. Acute respiratory distress syndrome (ARDS) can also complicate severe malaria. The approach to ventilatory management ranges from supplemental oxygen to mechanical ventilation with positive end expiratory pressure (PEEP). (See "Mechanical ventilation in acute respiratory distress syndrome".) Deep breathing (Kussmaul respirations) is a clinical indicator of metabolic acidosis and is associated with a worse outcome in patients with falciparum malaria [24]. Often deep breathing is associated with hyperlactatemia, although a study of 3248 Tanzanian children noted that among the 164 deaths, 45 children with admission blood glucose concentrations >5 mmol/L had no evidence of deep breathing/respiratory compensation [25]. This same study confirmed previous findings of the prognostic significance of hyperlactatemia; that association was even more pronounced in children with severe nonmalarial illness. Neurologic status The standard clinical case definition of cerebral malaria includes the following criteria [4]: Blantyre coma score 2 (table 2) P. falciparum parasitemia (any density) No other identifiable cause of coma (eg, hypoglycemia, meningitis, or a post-ictal state) [4]. The histologic hallmark of cerebral malaria is cerebral sequestration of parasitized erythrocytes. Autopsy-based studies have demonstrated that cerebral malaria may be incorrectly diagnosed (based on the clinical case definition) in about 25 percent of cases [26,27]. Rather, the most reliable clinical indicator for cerebral malaria in patients who meet the standard clinical case definition (above) is the presence of one or more elements of malaria retinopathy: white-centered hemorrhages (figure 1A), vessel changes (figure 1B), and whitening in areas of the retina (figure 1C) [28,29]. The role of cerebral edema in the pathogenesis of cerebral malaria is uncertain. In an Indian trial in which 126 adults with cerebral malaria were randomized to treatment with intravenous mannitol or placebo, there was no evidence of benefit for mannitol, even though 63 percent of participants had evidence of cerebral edema on CT scan [30]. An autopsy study of 20 Vietnamese adults with fatal malaria showed no association between clinical coma and postmortem evidence of edema and compromised vascular integrity on histopathology [31]. Clinical evaluation Clinical evaluation includes full physical exam, a complete neurologic examination, calculation of Blantyre coma score, and funduscopic evaluation. Patients with altered sensorium should undergo lumbar puncture (in the absence of contraindications) to exclude concomitant bacterial meningitis. Blantyre coma score The Blantyre coma score is a clinical indicator of severity in children with altered consciousness due to malaria (table 2) [32]. It was developed based on modifications of Glasgow coma score because some key Glasgow indicators are not appropriate for evaluation of altered consciousness in pediatric malaria. Examples include eye opening in response to pain (open-eyed children can be in coma) and verbal response to pain (many children with severe malaria are not yet able to speak) [33]. The Blantyre coma score is outlined in the Table (table 2). Fully conscious children score 5; children who do not respond to painful stimuli score 0. Blantyre coma score 2 is associated with high risk of mortality [33]. Among 2030 children admitted to a pediatric ward in Malawi with Blantyre coma score 2, the mortality in children with a score of 0, 1 or 2 on admission was 34.2, 16.7 and 10.4 percent, respectively. Patients meeting the standard clinical case definition of cerebral malaria had overall mortality of 17.8 percent. (See 'Neurologic status' above.) The Blantyre coma score should be reassessed at regular intervals following initiation of therapy. A decrease should prompt reevaluation for seizures (including consideration of unwitnessed or subclinical events), anemia, and hypoglycemia. Funduscopic exam Malarial retinopathy is pathognomonic for cerebral malaria in patients who satisfy the standard clinical case definition [34]. The optic fundi should be evaluated following instillation of mydriatics for pupillary dilatation. Examination should be performed via direct ophthalmoscope (which provides magnification) and indirect ophthalmoscope (which provides three-dimensional perspective and wide field of view). Features of malarial retinopathy include white-centered hemorrhages, vessel changes, and whitened areas of the retina (figure 1A-C) [28]. Lumbar puncture Patients with altered sensorium should undergo lumbar puncture (in the absence of contraindications) to exclude concomitant bacterial meningitis. If clinical instability or papilledema on ocular fundus examination preclude lumbar puncture, presumptive antibiotic therapy for
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bacterial meningitis should be initiated. (See "Lumbar puncture: Indications, contraindications, technique, and complications in children" and "Lumbar puncture: Technique; indications; contraindications; and complications in adults".) In patients with cerebral malaria, the mean opening pressure is about 16 cm of CSF. Laboratory examination may be normal or may demonstrate slightly elevated total protein level and cell count. In a study comparing CSF findings from 12 children with cerebral malaria and 14 children with presumed viral encephalitis, patients with cerebral malaria had lower white cell count, glucose, and protein levels [35]. Children with malaria had a mean white cell count of 0 cells/microL (range 0 to 4 cells/microL); children with viral encephalitis had a mean white cell count of 4 cells/microL (range 0 to 9 cells/microL). A CSF glucose concentration below 3.4 mmol/L (61 mg/dL) was the best discriminator of cerebral malaria from presumed viral encephalitis. Seizure management Seizures occur in up to 70 percent of children with severe malaria; subclinical seizures occur in 15 to 20 percent of cases [34,36]. In an African study comparing 132 pediatric survivors of retinopathy-positive cerebral malaria with age-matched controls, epilepsy or other neurobehavioral sequelae were observed in nearly one-third of patients [34]. These observations suggest that enhanced seizure control may improve longterm outcomes. Seizures may be generalized or focal, and the clinical signs may be subtle (nystagmus, irregular respirations, hypoventilation, or a drop in the Blantyre coma score). It is also important to evaluate for causes of seizure besides cerebral malaria (eg hypoglycemia, fever) and to treat accordingly as outlined in the following sections. Benzodiazepines are useful first line agents for seizure treatment. Diazepam (0.4 mg/kg) can be administered intravenously or per rectum; lorazepam (0.1 mg/kg) can be administered intravenously or intraosseously. These doses can be repeated once if seizures do not cease within 5 minutes of the initial dose. Benzodiazepines should not be combined due to risk of respiratory depression. If seizures are not controllable with benzodiazepines, other options include phenobarbitone (phenobarbital 15 to 20 mg/kg, slow IV push) or phenytoin (18 mg/kg diluted in 100 mL normal saline, infused over 20 minutes). (See "Management of status epilepticus in children".) If seizures recur, repeat single doses of benzodiazepine may be administered. Alternatively, maintenance doses of phenobarbital (5 to 15 mg/kg/day, administered orally, via NG tube, or via slow IV push in divided doses every 12 hours) or phenytoin (5 mg/kg/day IV) may be initiated. (See "Management of status epilepticus in children".) For many years paraldehyde was used as an intramuscular injection to treat seizures in the setting of severe malaria (0.2 to 0.4 mL/kg); its chief advantage is that it does not cause respiratory suppression. The cost of this agent has increased dramatically, and it is therefore out of reach for many formularies in malaria-endemic areas. Patients with severe malaria should not receive routine seizure prophylaxis in the absence of clinical seizure activity. In a study of 340 children with cerebral malaria randomized to receive phenobarbital (20 mg/kg) or placebo upon admission to hospital, the mortality in the phenobarbital group was significantly higher than the placebo group (18 versus 8 percent) [37]. Anemia and coagulopathy Removal of infected and uninfected erythrocytes from the circulation is associated with rapid development of anemia. Patients with severe anemia may present with or without altered consciousness. In endemic areas hemoglobin concentration may decrease gradually over the course of repeated malaria infections, so patients can be fully alert with hemoglobin concentrations of 2 to 3 g/dL (hematocrit <10 percent). Evaluation for pallor of the conjunctivae, nailbeds, and palms can provide a rough estimate of the degree of anemia, since blood vessels in these areas are close to the surface (figure 2). (See "Anemia in malaria".) Hemoglobin concentration and hematocrit are routinely measured components of complete blood counts, but this may not be available in resource limited settings or the results may not be available in a timely manner. In such circumstances the hematocrit can be measured on a fingerprick sample of blood collected into a heparinized capillary tube and centrifuged using a handheld mechanical device (figure 3). Alternatively, the hemoglobin concentration can be determined from fingerprick samples of blood collected into cuvettes. This method is more expensive than "spinning a hematocrit" but can be performed readily near the bedside. Transfusion In areas where malaria and HIV are common infections, blood transfusion is associated with important risks. Most blood banks in endemic areas screen for HIV, hepatitis B, and syphilis, although such screening may miss HIV infected donors who have not yet mounted a detectable serologic response to the infection. Logistical constraints including limited blood supplies, and nurse staffing should also be considered. In endemic areas, a single unit of blood may be typed and cross-matched for several children, such that each receives an aliquot from the same unit. Such infusions require careful attention for prompt discontinuation to ensure that no more than the intended volume is transfused. For these reasons, transfusion should be reserved for patients with dire prognoses -- eg, patients with altered consciousness, high output heart failure, respiratory distress, cool peripheries, hyperlactatemia, and/or high density parasitemia. Laboratory parameters of concern include low hemoglobin concentration (4 to 5 g/dL) or low hematocrit (10 to 15 percent) [38]. The degree of anemia and the level of parasitemia may be useful parameters for predicting the need for a blood transfusion and for determining the volume of blood to transfuse, but there have been no conclusive studies in this area. In general, 10 mL/kg of packed red blood cells or 20 mL/kg of whole blood transfused over 2 to 4 hours is appropriate. Blood should be typed and cross-matched prior to infusion. Blood transfusions are generally well tolerated in the setting of severe malaria since patients are relatively hypovolemic; diuretics are rarely needed. Monitoring of hemoglobin concentration or hematocrit should continue until the parasitemia clears, since repeat transfusion may be required. Exchange transfusion has been proposed as a means of removing infected red blood cells from the circulation, thereby lowering the parasite burden and replacing with unparasitized cells. However, we do not favor this approach as there is no consensus on the indications, approach, benefits, or risks of this procedure. The WHO guidelines indicate that it is not possible to make any recommendations regarding the use of exchange transfusion based on the available evidence [4]. The CDC recommends consideration of exchange transfusion for patients with parasite density of >10 percent with end organ complications [39]. Coagulopathy Clinically evident disseminated intravascular coagulation in the setting of severe malaria is rare (<5 percent), but profound thrombocytopenia is common, and the microcirculation in many organs is occluded by fibrin thrombi [26]. The approach to this complication is discussed in detail separately. (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults" and "Disseminated intravascular coagulation in infants and children".) Fluids and nutrition Hypoglycemia Hypoglycemia (traditionally defined as blood glucose <40 mg/dL or <2.2 mmol/L) is a common complication of malaria and a marker of severe disease [40,41]. It should be suspected in any patient who is comatose or who deteriorates suddenly.
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In a prospective study of 437 children in Mali with presumed severe malaria (85 percent of whom had microscopic evidence of P. falciparum infection), a significant difference in admission glucose concentration was observed between those who died and those who survived (median 4.6 versus 7.6 mmol/L, P <0.001) [42]. Children with initial blood glucose concentrations <2.2 mmol/L were classified as hypoglycemic, those between 2.2 and 4.4 mmol/L were classified as low glycemia, those between 4.4 and 8.3 mmol/L were categorized as normoglycemia, and those with concentrations >8.3 mmol/L were classified as hyperglycemia. The case fatality rates for hypoglycemia, low glycemia, normal glycemia and hyperglycemia were 61, 46, 13, and 7 percent, respectively. The adjusted odds ratio was 0.75 (0.64 to 0.88) for case fatality for each 1 mmol/L increase in admission blood glucose concentration, suggesting that the traditional cut-off of 2.2 mmol/L may be too low for adequate sensitivity in the setting of pediatric cerebral malaria. The pathogenesis of hypoglycemia is not fully understood; it may be related to parasite glucose consumption and/or impaired host gluconeogenesis [41]. Malnutrition, adrenal insufficiency and hyperinsulinemia are not likely causes of hypoglycemia [41]. In addition to primary hypoglycemia, administration of quinine or quinidine (insulin secretagogues) can cause iatrogenic hypoglycemia [43,44]. Hypoglycemia with artesunate therapy is less common than with quinine or quinidine. Clinical manifestations of hypoglycemia include seizure and altered consciousness, although these are not reliable clinical indicators and blood glucose concentration should be assessed as part of routine evaluation. In resource limited settings this may be performed via fingerprick samples of whole blood on indicator strips (with or without handheld glucometers). Hypoglycemic patients should have intravenous access established promptly, followed by administration of initial bolus of dextrose (0.25 g/kg of body weight). This is usually achieved with 2.5 mL/kg of 10 percent dextrose solution, since extravasation of higher concentrations of glucose can cause severe tissue damage. Blood glucose measurement after 15 minutes should be repeated, with administration of repeat boluses until the patient is normoglycemic. If glucose measurement is not possible, comatose patients with parasitemia at the time of initial assessment should receive a bolus of 2.5 mL/kg of 10 percent dextrose solution. (See "Approach to hypoglycemia in infants and children".) Maintenance intravenous fluids should contain at least 5 percent dextrose; patients with recurrent hypoglycemia should receive 10 percent dextrose (10 percent dextrose can be prepared quickly by withdrawing 100 mL from a one liter bag of a 5 percent dextrose solution and replacing it with 100 mL of a 50 percent dextrose solution). Patients presenting with normoglycemia can develop hypoglycemia during the course of treatment. In addition, those managed promptly for hypoglycemia at presentation can have subsequent recurrent hypoglycemia. Therefore, blood glucose should be monitored closely during the course of illness with prompt management as outlined above. Volume management The intravascular volume status in the setting of severe malaria is uncertain; there are data to both support and refute the presence of hypovolemia in the setting of severe malaria infection [45,46]. Adults with malaria appear to be more vulnerable to fluid overload than children; there is a thin line between underhydration (and thus worsening renal impairment) and overhydration (and risking pulmonary and cerebral edema). Therefore, fluid requirements should be assessed on an individual basis. Reliable markers of intravascular volume depletion in patients with severe malaria include cool peripheries, delayed capillary refill, low venous pressure and low urine output. Deep breathing (reflecting lactic acidosis) may also be a reasonable indicator of hypovolemia. Clinical symptoms of hypovolemia frequently resolve with blood transfusion (when warranted). When transfusion is not indicated, data suggest that repeated boluses of normal saline or albumin may be counterproductive [47]. In a large study involving 3141 African children with severe infection and impaired consciousness and/or increased work of breathing as well as evidence of impaired perfusion (over half of whom had malaria), patients who received saline or albumin bolus had higher mortality at 48 hours than patients who received no bolus (10.6 and 10.5 percent versus 7.3 percent, respectively) [47]. Therefore, aggressive fluid resuscitation and specific treatment for acidosis are of uncertain benefit in these settings. Some data suggest that volume resuscitation with crystalloid is favorable over colloid, although it is uncertain whether crystalloid increases risk of exacerbating cerebral edema in the setting of a fragile blood-brain barrier [48,49]. In the setting of acute renal failure, institution of renal replacement therapy is appropriate if feasible. Hemofiltration is associated with lower mortality than peritoneal dialysis; there have been no comparative trials of hemofiltration and hemodialysis. (See "Renal replacement therapy (dialysis) in acute kidney injury (acute renal failure) in adults: Indications, timing, and dialysis dose".) Maintenance fluids Maintenance intravenous fluids should include 5 percent dextrose. The rate of fluid administration should be determined by weight. Patients weighing 1 to 10 kg should receive fluids at a rate of 4 mL/kg/hour. For patients weighing 10 to 20 kg, patients should receive 40 mL per hour for the first 10 kg PLUS 2 mL/kg/hour for each kg above 10 kg. For patients who weigh more than 20 kg, patients should receive 60 mL per hour for the first 20 kg PLUS 1 mL/kg/hour for every kg above 20 kg [50]. At body weights above 80 kg, the contribution of water to total body weight falls, so these methods would significantly overestimate the fluid requirements. Total maintenance needs are generally capped near 2.5 liters daily. Intravenous fluid support should be continued until oral intake is tolerated. (See "Maintenance fluid therapy in children".) Most hospitals in endemic areas do not have infusion pumps, and intravenous fluids are usually available in one liter bags only. Therefore, fluid delivery can be difficult to monitor and there is real risk of iatrogenic volume overload. To prevent this problem, interposition of a burette (or "drip chamber") between the patient and the bag may be placed for monitoring IV fluid administration. A chamber is filled with a known amount of fluid (generally 2 hours' worth), labeled with tape, and the drip rate is set. In this way, providers can tell at a glance if the infusion is proceeding as scheduled (figure 4). Nutrition Nutritional supplementation should be provided by nasogastric tube (NG) for patients with prolonged coma who are unable to eat and drink within 24 to 48 hours. (See "Enteral nutrition in infants and children".) In most endemic areas no commercially prepared enteral products are available; substitutes (such as "eggnog" containing eggs, milk, sugar and oil) or high calorie drinks may be used. The volumes calculated for intravenous fluids can be administered via NG; the intravenous fluid infusion rate should be decreased accordingly. Most patients are able to eat and drink within 5 to 7 days. (See "Oral rehydration therapy".) Fever High fevers (>38.5C) are common in the setting of malaria infection and may reflect the host response to endogenous pyrogens released at the time of schizont rupture [51]. The optimal approach to treatment of fever is uncertain, although use of antipyretics in patients with high fever is appropriate given the association between high fever and convulsions [4]. Aggressive temperature control may help reduce long-term neurologic outcomes in pediatric patients with retinopathy-positive cerebral malaria [34]. Paracetamol (acetaminophen; 15 mg/kg every 6 hours; maximum dose 1000 mg) is a reasonable antipyretic agent; oral therapy can be used for patients able to swallow. Otherwise, suppository formulations are acceptable [4]. If fever persists, ibuprofen (10 mg/kg every 6 hours; maximum dose 1200 mg per day) can be administered (orally, via nasogastric tube, or intravenously) alone or on an alternating schedule with paracetamol every 3 hours. Bacterial infection Bacteremia is an important contributor to morbidity and mortality in the setting of severe malaria, and severe anemia has been implicated as a primary risk factor for nontyphoidal Salmonella septicemia [52,53]. A comprehensive study of bacteremia in Kenya identified falciparum infection as a major risk factor for bacteremia with multiple organisms [54]. When the prevalence of malaria parasitemia was 29 percent, 62 percent of bacteremia cases were attributable to malaria; the prevalence of bacteremia declined in parallel with the prevalence of malaria infection. (See "Approach to the patient with nontyphoidal Salmonella in a stool culture".)
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The approach to empiric antibiotic therapy in the setting of severe malaria is contentious. Bacterial infection should be suspected in patients with severe anemia together with signs or symptoms of sepsis (hypotension, cool extremities, delayed capillary refill, hyperlactatemia). In such cases, blood cultures should be obtained and broad spectrum antibiotic therapy with activity against gram-negative bacilli should be initiated. PREGNANCY Pregnant women are more likely to develop severe P. falciparum malaria than other adults, particularly in the second and third trimesters. Complications such as hypoglycemia and pulmonary edema are more common than in nonpregnant individuals. Maternal mortality can approach 50 percent, and fetal death and premature labor are common. Prompt antimalarial therapy and supportive care should be administered as outlined in the preceding sections. If there is a choice of therapy available, artesunate or artemether are preferred over quinine in the second and third trimesters since quinine is associated with recurrent hypoglycemia [4]. In the first trimester, either artemisinins or quinine are acceptable choices; during this period the risk of hypoglycemia associated with quinine is lower and the uncertainties regarding the safety of artemisinins are greater. Other issues related to malaria and pregnancy are discussed in detail separately (see "Treatment and prevention of malaria in pregnancy"). SUMMARY AND RECOMMENDATIONS Severe malaria is acute malaria with major signs of organ dysfunction and/or high level of parasitemia (table 1). In endemic areas, young children and pregnant women are at high risk for severe malaria. Older children and adults develop partial immunity after repeated infections and therefore are at relatively low risk for severe disease. Travelers to areas where malaria is endemic generally have no previous exposure to malaria parasites and so are at high risk for severe disease. (See 'Definition' above.) The diagnosis of malaria infection and the degree of parasitemia are established by blood smear. In general, the heavier the parasitemia, the sicker the patient, but there are many asymptomatic patients with high parasitemia, and patients with severe malaria can present with low density infection. (See 'Diagnosis' above.) For treatment of nonpregnant adults and children with severe falciparum malaria, we suggest intravenous artesunate (in areas where intravenous artesunate of reliable quality is readily available), rather than intravenous quinine (table 5) (Grade 2A). For treatment of pregnant women with severe falciparum malaria in the second and third trimesters we suggest intravenous artesunate (in areas where intravenous artesunate of reliable quality is readily available) (table 5) (Grade 2B). For treatment of pregnant women with severe falciparum malaria in the first trimester we suggest intravenous quinine (Grade 2B). (See 'Pregnancy' above.) The total duration of therapy with quinine/quinidine for severe malaria is 7 days. The total duration of therapy with artemisinin based therapy is 3 days. After the acute stage of illness has been treated with parenteral therapy and the patient can swallow, a complete course of oral therapy (selected on the basis of known parasite drug susceptibility or national treatment guidelines) should be administered (table 5). (See 'Completing therapy' above.) We recommend administration of pre-referral treatment to patients in rural endemic areas with suspected severe malaria who cannot begin intravenous therapy immediately (Grade 1A). (See 'Prereferral treatment' above.) Death due to severe malaria can occur within hours of presentation, so prompt assessment and initiation of antimalarial therapy are essential, followed by concurrent supportive care to manage life-threatening complications of the disease: Pulmonary complications of severe malaria include pulmonary edema, acute respiratory distress syndrome, and lower respiratory tract infection. Management requirements may range from supplementary oxygen to mechanical ventilation. (See 'Respiratory status' above.) Neurologic complications include altered sensorium, seizure and coma. Clinical evaluation includes full physical examination, calculation of Blantyre coma score (table 2), funduscopic exam and lumbar puncture. Seizures should be managed as outlined above. (See 'Neurologic status' above.) Hematologic complications include severe anemia and coagulopathy. Decisions regarding transfusion should be tailored to individual patient circumstances. (See 'Transfusion' above.) Hypoglycemia (blood glucose <40 mg/dL or <2.2 mmol/L) is a common complication of malaria and a marker of severe disease; it should be suspected in any patient who deteriorates suddenly. Hypoglycemic patients should have intravenous access established promptly followed by administration of 50 percent dextrose (1 mL/kg) with repeat blood glucose measurement after 15 minutes. (See 'Hypoglycemia' above.) Hypovolemia should be assessed on an individual basis. Adults with malaria appear to be more vulnerable to fluid overload than children; there is a thin dividing line between underhydration (and thus worsening renal impairment) and overhydration (and risk of pulmonary and cerebral edema). (See 'Volume management' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. World Malaria Report 2008, Geneva, World Health Organization, 2009. 2. Baird JK. Severe and fatal vivax malaria challenges 'benign tertian malaria' dogma. Ann Trop Paediatr 2009; 29:251. 3. Cox-Singh J, Hiu J, Lucas SB, et al. Severe malaria - a case of fatal Plasmodium knowlesi infection with post-mortem findings: a case report. Malar J 2010; 9:10. 4. WHO guidelines for the treatment of malaria. Geneva, World Health Organization, 2010. http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf (Accessed on December 30, 2010). 5. White NJ. The treatment of malaria. N Engl J Med 1996; 335:800. 6. Crawley J, Chu C, Mtove G, Nosten F. Malaria in children. Lancet 2010; 375:1468. 7. Bejon P, Warimwe G, Mackintosh CL, et al. Analysis of immunity to febrile malaria in children that distinguishes immunity from lack of exposure. Infect Immun 2009; 77:1917. 8. Mali S, Steele S, Slutsker L, et al. Malaria surveillance--United States, 2006. MMWR Surveill Summ 2008; 57:24. 9. Phillips A, Bassett P, Zeki S, et al. Risk factors for severe disease in adults with falciparum malaria. Clin Infect Dis 2009; 48:871. 10. Dondorp AM, Lee SJ, Faiz MA, et al. The relationship between age and the manifestations of and mortality associated with severe malaria. Clin Infect Dis 2008; 47:151. 11. Taylor T, Olola C, Valim C, et al. Standardized data collection for multi-center clinical studies of severe malaria in African children: establishing the
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SMAC network. Trans R Soc Trop Med Hyg 2006; 100:615.
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12. Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010; 376:1647. 13. Rosenthal PJ. Artesunate for the treatment of severe falciparum malaria. N Engl J Med 2008; 358:1829. 14. ter Kuile F, White NJ, Holloway P, et al. Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. Exp Parasitol 1993; 76:85. 15. Dondorp A, Nosten F, Stepniewska K, et al. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366:717. 16. New Medication for Severe Malaria Available Under an Investigational New Drug Protocol. MMWR Surveill Summ 2007; 56:769. http://www.cdc.gov/mmWR/preview/mmwrhtml/mm5630a5.htm (Accessed February 20, 2009). 17. Gomes MF, Faiz MA, Gyapong JO, et al. Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial. Lancet 2009; 373:557. 18. Nontprasert A, Pukrittayakamee S, Nosten-Bertrand M, et al. Studies of the neurotoxicity of oral artemisinin derivatives in mice. Am J Trop Med Hyg 2000; 62:409. 19. Noedl H, Se Y, Schaecher K, et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 2008; 359:2619. 20. Treatment with Quinidine Gluconate of Persons with Severe Plasmodium falciparum Infection: Discontinuation of Parenteral Quinine. MMWR Morb Mortal Wkly Rep 1991; 40(RR-4):21. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/00043932.htm (Accessed February 25, 2009). 21. The complete drug reference 36th edition [online]. Sweetman, SC (Ed), London, Pharmaceutical Press. Available at: http://www.medicinescomplete.com/ (Accessed March 5, 2009). 22. White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis 2007; 7:549. 23. Bassat Q, Machevo S, O'Callaghan-Gordo C, et al. Distinguishing Malaria from Severe Pneumonia among Hospitalized Children who Fulfilled Integrated Management of Childhood Illness Criteria for Both Diseases: A Hospital-Based Study in Mozambique. Am J Trop Med Hyg 2011; 85:626. 24. Marsh K, Forster D, Waruiru C, et al. Indicators of life-threatening malaria in African children. N Engl J Med 1995; 332:1399. 25. Hendriksen IC, Mtove G, Pedro AJ, et al. Evaluation of a PfHRP2 and a pLDH-based rapid diagnostic test for the diagnosis of severe malaria in 2 populations of African children. Clin Infect Dis 2011; 52:1100. 26. Taylor TE, Fu WJ, Carr RA, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 2004; 10:143. 27. Lewallen S, White VA, Whitten RO, et al. Clinical-histopathological correlation of the abnormal retinal vessels in cerebral malaria. Arch Ophthalmol 2000; 118:924. 28. Beare NA, Taylor TE, Harding SP, et al. Malarial retinopathy: a newly established diagnostic sign in severe malaria. Am J Trop Med Hyg 2006; 75:790. 29. Beare, NA, Harding, SP, Taylor, TE, et al. Perfusion abnormalities in children with cerebral malaria and malarial retinopathy. J Inf Dis, in press. 30. Mohanty S, Mishra SK, Patnaik R, et al. Brain swelling and mannitol therapy in adult cerebral malaria: a randomized trial. Clin Infect Dis 2011; 53:349. 31. Medana IM, Day NP, Sachanonta N, et al. Coma in fatal adult human malaria is not caused by cerebral oedema. Malar J 2011; 10:267. 32. Newton CR, Chokwe T, Schellenberg JA, et al. Coma scales for children with severe falciparum malaria. Trans R Soc Trop Med Hyg 1997; 91:161. 33. Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med 1989; 71:441. 34. Birbeck GL, Molyneux ME, Kaplan PW, et al. Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study. Lancet Neurol 2010; 9:1173. 35. Jakka SR, Veena S, Atmakuri RM, Eisenhut M. Characteristic abnormalities in cerebrospinal fluid biochemistry in children with cerebral malaria compared to viral encephalitis. Cerebrospinal Fluid Res 2006; 3:8. 36. Crawley J, Smith S, Muthinji P, et al. Electroencephalographic and clinical features of cerebral malaria. Arch Dis Child 2001; 84:247. 37. Crawley J, Waruiru C, Mithwani S, et al. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. Lancet 2000; 355:701. 38. Bojang KA, Palmer A, Boele van Hensbroek M, et al. Management of severe malarial anaemia in Gambian children. Trans R Soc Trop Med Hyg 1997; 91:557. 39. Zucker JR, Campbell CC. Malaria. Principles of prevention and treatment. Infect Dis Clin North Am 1993; 7:547. 40. White NJ, Miller KD, Marsh K, et al. Hypoglycaemia in African children with severe malaria. Lancet 1987; 1:708. 41. Taylor TE, Molyneux ME, Wirima JJ, et al. Blood glucose levels in Malawian children before and during the administration of intravenous quinine for severe falciparum malaria. N Engl J Med 1988; 319:1040. 42. Willcox ML, Forster M, Dicko MI, et al. Blood glucose and prognosis in children with presumed severe malaria: is there a threshold for 'hypoglycaemia'? Trop Med Int Health 2010; 15:232. 43. White NJ, Warrell DA, Chanthavanich P, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 1983; 309:61. 44. Limburg PJ, Katz H, Grant CS, Service FJ. Quinine-induced hypoglycemia. Ann Intern Med 1993; 119:218. 45. Maitland K, Levin M, English M, et al. Severe P. falciparum malaria in Kenyan children: evidence for hypovolaemia. QJM 2003; 96:427. 46. Planche T, Onanga M, Schwenk A, et al. Assessment of volume depletion in children with malaria. PLoS Med 2004; 1:e18. 47. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011; 364:2483. 48. Brown H, Hien TT, Day N, et al. Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol Appl Neurobiol 1999; 25:331. 49. Maitland K, Pamba A, English M, et al. Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Clin Infect Dis 2005; 40:538. 50. Duke T, Molyneux EM. Intravenous fluids for seriously ill children: time to reconsider. Lancet 2003; 362:1320. 51. Hensmann M, Kwiatkowski D. Cellular basis of early cytokine response to Plasmodium falciparum. Infect Immun 2001; 69:2364. 52. Berkley J, Mwarumba S, Bramham K, et al. Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg 1999; 93:283. 53. Bronzan RN, Taylor TE, Mwenechanya J, et al. Bacteremia in Malawian children with severe malaria: prevalence, etiology, HIV coinfection, and outcome. J Infect Dis 2007; 195:895. 54. Scott JA, Berkley JA, Mwangi I, et al. Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study. Lancet 2011; 378:1316.
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GRAPHICS
Features indicating a poor prognosis in severe malaria
Clinical features
Impaired consciousness* Repeated convulsions (3 in 24 hr) Respiratory distress (rapid, deep, labored breathing) Substantial bleeding Shock
Biochemical features
Renal impairment (serum creatinine, >3 mg/dl [>265 mol/liter]) Acidosis (plasma bicarbonate, <15 mmol/liter) Jaundice (serum total bilirubin, >2.5 mg/dl [>43 mol/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 percent of neutrophils contain malaria pigment * The deeper the coma, the worse the prognosis. The combination of deep jaundice and renal failure is particularly grave. Trophozoites are mature parasites in which pigment is visible under light microscopy. Reproduced with permission from: White NJ. Current concepts: The treatment of malaria. N Engl J Med 1996; 335:800. Copyright 1996 Massachusetts Medical Society. All rights reserved.
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Blantyre coma score

Score
Eye movement Watches or follows Fails to watch or follow Best motor response Localizes painful stimulus Withdraws limb from painful stimulus No response or inappropriate response Best verbal response Cries appropriately with pain, or, if verbal, speaks Moan or abnormal cry with pain No vocal response to pain Total 2 1 0 2 1 0 1 0
Fully conscious children score 5; children who do not respond to painful stimuli score 0. Response to pain should be assessed via firm nailbed pressure, sternal pressure, and pressure over the supraorbital ridge. Blantyre coma score 2 is associated with mortality.
Molyneux, ME, Taylor, TE, Wirima, JJ, Borgstein, A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med 1989; 71:441.
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Glasgow coma scale

Eye opening Spontaneous Response to verbal command Response to pain No eye opening Best verbal response Oriented Confused Inappropriate words Incomprehensible sounds No verbal response Best motor response Obeys commands Localizing response to pain Withdrawal response to pain Flexion to pain Extension to pain No motor response 6 5 4 3 2 1 5 4 3 2 1 4 3 2 1
The GCS is scored between 3 and 15, 3 being the worst, and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury; a score of 9 to 12 correlates with moderate injury; and a score of 8 or less represents severe brain injury.
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Observations chart malaria

Observations chart
Time Other times (cross out above line) Hours since admission Convulsions: Y/N Coma score: Motor Verbal Eye Coma score total Vomiting/diarrhoea: Y/N Drinking/feeding: Y/N Dehydration (0, +, ++) Pallor: Y/N Cyanosis: Y/N Passing urine: Y/N Pulse rate/min Respiratory rate/min Blood pressure systolic/diastolic Temperature: 40 39 38 37 36 Temperature recorded (axillary/rectal) Oxygen Y/N (litres/min) Oxygen saturation (without O2) Blood: Glucose Lactate Lab results: PCV MPs (+, ++, +++, ++++, +++++) Observer's initials Courtesy of Terrie Taylor, DO.
Day: 6a 8a 10a 12a 2p 4p
Date: 6p 8p 10p 12m 2a 4a
Day: 6a 8a 10a 12a 2p 4p
Date: 6p 8p 10p 12m 2a 4a
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Therapeutic options for parenteral treatment of severe malaria*

I. Artemisinin derivative
Artesunate 2.4 mg/kg intravenously as first dose, followed by 2.4 mg/kg at 12 and 24 hours, followed by 2.4 mg/kg once daily
II. Quinine or quinidine

Quinine dihydrochloride Quinidine gluconate 16.7 mg base/kg (= 20 mg salt/kg) in 5 percent dextrose loading dose over 4 hours, followed by 25 mg base/kg/day (20 to 30 mg salt/kg/day) divided into 2 to 3 equal administrations of 8.35 mg base/kg (= 10 mg salt/kg) over 2 hours at 8 or 12 hr intervals (maximum 1800 mg salt/day) 6.25 mg base/kg (= 10 mg salt/kg) loading dose intravenously (maximum 600 mg salt) in normal saline over 1-2 hrs, followed by 0.0125 mg base/kg/min (= 0.02 mg salt/kg/minute) continuous infusion for at least 24 hours Alternative: 15 mg base/kg (= 24 mg salt/kg) loading dose intravenously in normal saline over 4 hrs, followed by 7.5 mg base/kg (= 12 mg salt/kg) infused over 4 hrs every 8 hrs, starting 8 hrs after the beginning of the loading dose PLUS* one of the following: Doxycycline, Tetracycline or Clindamycin Doxycycline Tetracycline Clindamycin Adults: 100 mg orally twice daily. Children: 2.2 mg/kg (up to 100 mg) orally twice daily. Intravenous dosing acceptable if oral medication not tolerated; switch to oral dosing once patient is able to swallow. Treatment course is 7 days. Adults: 250 mg orally four times daily. Children: 25 mg/kg/day (up to 1000 mg) divided into 4 equal doses. Treatment course is 7 days. Adults and children: 20 mg base/kg/day orally (maximum 1800 mg) divided into 3 equal doses. Treatment course is 7 days.
* In general, parenteral therapy is administered for severe disease. Once the patient is able to tolerate oral medications, treatment may be completed orally. Options include: 1. Parenteral artesunate followed by atovaquone-proguanil (for adults: 4 adult tabs orally for 3 days), mefloquine (for adults: 750 mg salt orally as initial dose followed by 500 mg salt orally 6 to 12 hrs later), doxycycline or clindamycin. 2. Parenteral quinine (or quinidine) with doxycycline, tetracycline or clindamycin (7 days therapy total); this is common practice for patients with malaria acquired in SE Asia, if artesunate is not available. 3. Parenteral quinine (at least three doses) until the patient is able to swallow, followed by oral therapy with an artemisinin combination drug such as artemetherlumefantrine (3 days therapy total; see separate table summarizing oral artemisinin combination therapy); this is common practice for children with malaria acquired in Africa, if artesunate is not available. Artesunate can also be administered intramuscularly, orally, or via rectal suppository (100 mg for children 6 months to 6 years of age; 400 mg for children >6 years). In the United States intravenous artesunate is not approved by the Food and Drug Administration but is available for emergency use under an investigational protocol by enrollment with the Centers for Disease Control (CDC). Artesunate is unstable in solution so is dispensed as a dry powder of artesunic acid together with an ampule of diluent (5 percent sodium bicarbonate solution or sodium phosphate solution as supplied by US CDC). The powder and liquid are mixed to provide a concentration of 10 mg/mL; the artesunate solution should be administered within one hour of preparation. Once the patient has received four doses of intravenous artesunate and is able to swallow, the treatment can be completed with a course of an active oral antimalarial drug based on known susceptibility data. Important adverse effects include hypoglycemia, QT prolongation, tinnitus, reversible hearing loss, nausea, vomiting, dizziness and visual disturbances. To avoid cardiotoxicity, a loading dose of quinine/quinidine should not be administered to patients who received mefloquine or other quinine derivatives within the previous 12 hours. Quinine should be given by rate controlled intravenous infusion and never by intravenous injection (which can be lethal). Quinine can also be administered via intramuscular injection if intravenous infusions cannot be given: two injections of 10 mg/kg quinine (diluted to 60 mL) should be administered four hours apart. The anterior thigh is preferred over the gluteal region to minimize the risk of sciatic nerve damage. In the United States, intravenous quinidine is available for treatment of severe malaria. Quinidine can cause QT prolongation and should be administered by rate controlled intravenous infusion with continuous electrocardiographic and hemodynamic monitoring in an intensive care unit. Quinidine may be significantly absorbed to PVC tubing; tubing length should be minimized to approximately 12 inches. Clindamycin should be administered for pregnant women; doxycycline and tetracycline are contraindicated. CDC Malaria Hotline: (770) 488-7788 MondayFriday 8a to 4:30p EST; (770) 488-7100 after hours, weekends and holidays.
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Guidelines for treatment of uncomplicated P. falciparum malaria (or species not identified)
Recommended drug and adult dose Recommended drug and pediatric dose (pediatric dose should NEVER exceed adult dose)
Chloroquine-resistant or unknown resistance* All malarious regions except those specified as chloroquine-sensitive listed below. Middle Eastern countries with chloroquine-resistant P. falciparum include Iran, Oman, Saudi Arabia, and Yemen.
A. Artemisinin combination therapy Artemether + lumefantrine (Coartem) Administration consists of combination tablets (1 tablet = 20 mg artemether and 120 mg lumefantrine). A 3 day treatment schedule with a total of 6 oral doses is recommended based on weight (5 - <15 kg: 1 tablet per dose, 15 - <25 kg: 2 tablets per dose, 25 - <35 kg: 3 tablets per dose, 35 kg: 4 tablets per dose). The patient should receive the initial dose, followed by the second dose 8 hours later, then 1 dose po bid for the following 2 days.
Artesunate + amodiaquine Administration consists of separate scored tablets containing 50 mg of artesunate and 153 mg base of amodiaquine. The recommended treatment is 4 mg/kg of artesunate and 10 mg/kg of amodiaquine given once a day for 3 days.
Artesunate + mefloquine Administration consists of separate scored tablets containing 50 mg of artesunate and 250 mg base of mefloquine, The recommended treatment is 4 mg/kg of artesunate given once a day for 3 days and 25 mg base/kg of mefloquine (usually split over 2 or 3 days to reduce vomiting and optimize absorption). This may be achieved either as 15 mg/kg (usually on the second day) followed by 10 mg/kg one day later, or as 8.3 mg/kg per day for 3 days.
Artesunate + sulfadoxine-pyrimethamine Administration consists of separate scored tablets containing 50 mg of artesunate, and tablets containing 500 mg of sulfadoxine with 25 mg of pyrimethamine. The total recommended treatment is 4 mg/kg of artesunate given once a day for 3 days and a single administration of sulfadoxine-pyrimethamine (25/1.25mg base/kg) on day 1. B. Atovaquone-proguanil (Malarone) Adult tab = 250 mg atovaquone/100 mg proguanil 4 adult tabs po once daily x 3 days B. Atovaquone-proguanil (Malarone) Adult tab = 250 mg atovaquone/100 mg proguanil Peds tab = 62.5 mg atovaquone/25 mg proguanil 5-8 kg: 2 peds tabs po once daily x 3 days 9-10 kg: 3 peds tabs po once daily x 3 days 11-20 kg: 1 adult tab po once daily x 3 days 21-30 kg: 2 adult tabs po once daily x 3 days 31-40 kg: 3 adult tabs po once daily x 3 days >40 kg: 4 adult tabs po once daily x 3 days C. Quinine sulfate PLUS one of the following: Doxycycline, Tetracycline, or Clindamycin Quinine sulfate: 542 mg base (=650 mg salt) po tid x 3 or 7 days PLUS one of the following: Doxycycline: 100 mg po bid x 7 days Tetracycline: 250 mg po four times daily x 7 days Clindamycin: 20 mg base/kg/day (up to 1.8 grams) po divided tid x 7 days Sulfadoxine-pyrimethamine: single dose of 25/1.25 mg base/kg on day 1. D. Mefloquine (Lariam and generics) Mefloquine + artesunate (dosing as above) Mefloquine +/- doxycycline Mefloquine: 684 mg base (=750 mg salt) po as initial dose, followed by 456 mg base (=500 mg salt) po given 6-12 hours after initial dose. Total dose = 1250 mg salt. PLUS Doxycycline: 100 mg po bid Mefloquine: 13.7 mg base/kg (=15 mg salt/kg) po as initial dose, followed by 9.1 mg base/kg (=10 mg salt/kg) po given 6-12 hours after initial dose. Total dose = 25 mg salt/kg. PLUS Doxycycline: 2.2 mg/kg po every 12 hours C. Quinine sulfate PLUS one of the following: Doxycycline, Tetracycline, or Clindamycin Quinine sulfate: 8.3 mg base/kg (=10 mg salt/kg) po tid x 3 or 7 days PLUS one of the following: Doxycycline: 2.2 mg/kg po every 12 hours x 7 days Tetracycline: 6.25 mg/kg po every 6 hours x 7 days Clindamycin: 6.7 mg base /kg po every 8 hours x 7 days Sulfadoxine-pyrimethamine: single dose of 25/1.25 mg base/kg on day 1.
Chloroquine-sensitive Central America west of Panama Canal; Haiti; the Dominican Republic; and most of the Middle East. Infections acquired in Korea and the states of the former Soviet Union have been uniformly caused by P. vivax to date and should therefore be treated as chloroquine-sensitive infections.
Chloroquine (Aralen and generics) 600 mg base (=1000 mg salt) po immediately, followed by 300 mg base (=500 mg salt) po at 6, 24, and 48 hours. Total dose: 1500 mg base (=2500 mg salt). OR Hydroxychloroquine (Plaquenil and generics) 620 mg base (=800 mg salt) po immediately, followed by 310 mg base (=400 mg salt) po at 6, 24, and 48 hours. Total dose: 1550 mg base (=2000 mg salt). Chloroquine (Aralen and generics) 10 mg base/kg po immediately, followed by 5 mg base/kg po at 6, 24, and 48 hours. Total dose: 25 mg base/kg. OR Hydroxychloroquine (Plaquenil and generics) 10 mg base/kg po immediately, followed by 5 mg base/kg po at 6, 24, and 48 hours. Total dose: 25 mg base/kg.
po: orally; bid: twice daily; tid: three times daily. * NOTE: There are 4 options (A, B, C, or D) available for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum. The US Centers for Disease Control (CDC) recommends options A (artemether-lumefantrine), B, and C equally. The World Health Organization (WHO) recommends option A as the
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first line treatment for uncomplicated malaria. For option C, because there is more data on the efficacy of quinine in combination with doxycycline or tetracycline, these treatment combinations are generally preferred to quinine in combination with clindamycin. In addition, option C has higher incidence of adverse effects than options A or B. Because of a higher rate of severe neuropsychiatric reactions seen at treatment doses, option D (mefloquine) is recommended only when the other options cannot be used. Take with food or whole milk. If patient vomits within 30 minutes of taking a dose, then they should repeat the dose. It is also acceptable to take one half of the dose twice daily. US manufactured quinine sulfate capsule is only available in a 324 mg (salt) strength; therefore 2 capsules should be sufficient for adult dosing. Pediatric dosing may be difficult due to unavailability of non-capsule forms of quinine in the United States. Doxycycline and tetracycline are not indicated for use in children less than 8 years old. For children less than 8 years old with chloroquine-resistant P. falciparum, atovaquone-proguanil and artemether-lumefantrine are recommended treatment options; mefloquine can be considered if no other options are available. For children less than 8 years old with chloroquine-resistant P. vivax, mefloquine is the recommended treatment. If it is not available or is not being tolerated and if the treatment benefits outweigh the risks, atovaquone-proguanil or artemether-lumefantrine should be used instead. For infections acquired in Southeast Asia, quinine treatment should continue for 7 days. For infections acquired elsewhere, quinine treatment should continue for 3 days. Treatment with mefloquine is not recommended in persons who have acquired infections from Southeast Asia due to drug resistance. Treatment with mefloquine as a single agent is acceptable in low endemic areas as the likelihood of spread and maintenance of drug resistant parasites is low. However, in highly endemic areas combination therapy is important to prevent emergence of resistance. Adapted from United States Centers for Disease Control guidelines for treatment of malaria: http://www.cdc.gov/malaria/pdf/treatmenttable.pdf (Accessed June 18, 2009). CDC Malaria Hotline: (770) 4887788 Monday-Friday 8 am to 4:30 pm EST - (770) 488-7100 after hours, weekends and holiday.
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White-centered hemorrhages
White-centered hemorrhages in the optic fundi of patients with cerebral malaria. The image on the right is from a patient with hemorrhages and whitening (prominently seen around the macula). Courtesy of Susan Lewallen
and Nicholas Beare.
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Vessel changes in optic fundi
Vessel changes in the optic fundi of patients with cerebral malaria. Vessels which are normally red in color become orange or yellow because they contain parasitized red cells. The parasite consumes some of the hemoglobin in solution, so those red cells become less red. In the image on the left, all three features of malarial retinopathy are present (whitecentered hemorrhages, vessel changes and whitening in areas of the retina). Courtesy of Susan Lewallen and Nicholas Beare.
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Retinal whitening
Whitening, a change seen in areas of the retina in patients with cerebral malaria. This mosaic-like appearance is the result of capillary non-perfusion. In the image on the lower right, the pathological whitening is in the perimacular area, similar to the upper, left image. The extra-macular changes are a reflections from flash on the fundus camera. Courtesy of
Susan Lewallen and Nicholas Beare.
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Palmar pallor in a patient with severe anemia
The anemic child's palm is cradled in the palm of the less anemic mother. Courtesy of Terrie Taylor, DO.
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Microhematocrit determination
The capillary tube is plugged at one end and centrifuged (left). The proportion of blood volume occupied by red cells can be readily determined by eye in a microhematocrit reader (right). Courtesy of
Nathaniel Duke.
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IV fluids malaria
Courtesy of Nathaniel Duke.
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Treatment of Severe Falciparum Malaria

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Treatment of Severe Falciparum Malaria

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Treatment of severe falciparum malaria

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