Treatment of severe falciparum malaria

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Treatment of severe falciparum malaria
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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Treatment of severe falciparum malaria

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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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A decrease should prompt reevaluation for seizures (including consideration of unwitnessed or subclinical events).29]. (See "Treatment of uncomplicated falciparum malaria".2. In general. The total duration of therapy with artemisinin based therapy is 3 days. In an Indian trial in which 126 adults with cerebral malaria were randomized to treatment with intravenous mannitol or placebo. and whitening in areas of the retina (figure 1C) [28. The Blantyre coma score is outlined in the Table (table 2). Options include intramuscular administration of quinine or an artemisinin. calculation of Blantyre coma score.Treatment of severe falciparum malaria followed by oral therapy with an artemisinin combination drug. the mortality in children with a score of 0. Mortality was significantly lower among those who received prereferral rectal artesunate than among those who received placebo (1.9 versus 3.8 percent. Clinical evaluation — Clinical evaluation includes full physical exam. After the acute stage of illness has been treated with parenteral therapy and the patient can swallow. patients should be treated with a prereferral dose of intramuscular or intrarectal therapy and triaged to an acute care facility. 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. and whitened areas of the retina (figure 1A-C) [28]. Ghana and Tanzania with suspected severe malaria [17]. and those receiving parenteral artemisinin therapy can be transitioned to oral artemisinin combination chemotherapy. Rather. 45 children with admission blood glucose concentrations >5 mmol/L had no evidence of deep breathing/respiratory compensation [25]. In rural endemic areas where patients with severe malaria cannot begin intravenous therapy immediately. Patients completing oral quinine treatment should also receive a second agent. that association was even more pronounced in children with severe nonmalarial illness. meningitis. Options for coadministration with quinine include 7 days of doxycycline or tetracycline (or clindamycin for children or pregnant women) (table 5). even though 63 percent of participants had evidence of cerebral edema on CT scan [30]. Funduscopic exam — Malarial retinopathy is pathognomonic for cerebral malaria in patients who satisfy the standard clinical case definition [34].7 and 10. particularly in the settings of renal impairment or severe malarial anemia. (See "Mechanical ventilation in acute respiratory distress syndrome".) Alternatively.49. children who do not respond to painful stimuli score 0.4 percent. Options for oral artemisinin combination therapy are outlined in detail separately. intramuscular or rectal treatment should be continued until the patient can tolerate oral medication. risk ratio 0. This was illustrated in a randomized trial of over 12. 16. 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]. Among 2030 children admitted to a pediatric ward in Malawi with Blantyre coma score ≤2. anemia. The role of cerebral edema in the pathogenesis of cerebral malaria is uncertain. and hypoglycemia.77).com/contents/treatment-of-severe-falciparum-malaria?view=print Página 3 de 21 . or a post-ictal state) [4]. 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). Patients receiving parenteral quinine/quinidine can be transitioned to oral quinine.) 11/01/12 16:38 Prereferral treatment — The risk of death due to severe malaria is greatest in the first 24 hours of illness. since there is an increased incidence of neuropsychiatric toxic effects associated with mefloquine following cerebral malaria. a course of oral therapy should be administered based on known susceptibility data to complete the treatment course. If clinical instability or papilledema on ocular fundus examination preclude lumbar puncture.27].) The Blantyre coma score should be reassessed at regular intervals following initiation of therapy. a complete neurologic examination. there was no evidence of benefit for mannitol. hypoglycemia.uptodate. Patients meeting the standard clinical case definition of cerebral malaria had overall mortality of 17. Features of malarial retinopathy include white-centered hemorrhages.8 percent. respectively. a full course of treatment with atovaquone-proguanil or mefloquine may be administered as for uncomplicated malaria (table 6). and funduscopic evaluation. although a study of 3248 Tanzanian children noted that among the 164 deaths. the total duration of therapy with quinine/quinidine for severe malaria is 7 days. 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). (See 'Neurologic status' above. (See 'Completing therapy' below. falciparum parasitemia (any density) No other identifiable cause of coma (eg. The approach to ventilatory management ranges from supplemental oxygen to mechanical ventilation with positive end expiratory pressure (PEEP). vessel changes (figure 1B). 1 or 2 on admission was 34. Regimens containing mefloquine should be avoided if the patient presented with altered consciousness. Often deep breathing is associated with hyperlactatemia. Pulmonary edema may develop. or rectal administration of artesunate. Lumbar puncture — Patients with altered sensorium should undergo lumbar puncture (in the absence of contraindications) to exclude concomitant bacterial meningitis. 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. the class of agent administered parenterally may be used for oral completion of therapy when feasible.32-0. Patients with altered sensorium should undergo lumbar puncture (in the absence of contraindications) to exclude concomitant bacterial meningitis. A single artesunate rectal suppository pending transport has been demonstrated to reduce mortality. respectively. Dosing consisted of 100 mg for children 6 months to 6 years of age and 400 mg for patients >6 years. 95 percent CI 0. Acute respiratory distress syndrome (ARDS) can also complicate severe malaria. If referral is impossible. vessel changes. the presence of either should raise suspicion for a concomitant lower respiratory tract infection [23].) Deep breathing (Kussmaul respirations) is a clinical indicator of metabolic acidosis and is associated with a worse outcome in patients with falciparum malaria [24]. Fully conscious children score 5. Respiratory status — Hypoxemia and rales are not common in the setting of severe malaria. Completing therapy — In general. presumptive antibiotic therapy for http://www. This same study confirmed previous findings of the prognostic significance of hyperlactatemia. Blantyre coma score — The Blantyre coma score is a clinical indicator of severity in children with altered consciousness due to malaria (table 2) [32]. at which point a full course of oral therapy should be administered. Neurologic status — The standard clinical case definition of cerebral malaria includes the following criteria [4]: Blantyre coma score ≤2 (table 2) P.000 patients in rural Bangladesh. Blantyre coma score ≤2 is associated with high risk of mortality [33]. 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]. The histologic hallmark of cerebral malaria is cerebral sequestration of parasitized erythrocytes.

Exchange transfusion has been proposed as a means of removing infected red blood cells from the circulation. and treatment of disseminated intravascular coagulation in adults" and "Disseminated intravascular coagulation in infants and children". irregular respirations. Most blood banks in endemic areas screen for HIV. In general. maintenance doses of phenobarbital (5 to 15 mg/kg/day. but there have been no conclusive studies in this area. the mean opening pressure is about 16 cm of CSF. However. and nurse staffing should also be considered.1 mg/kg) can be administered intravenously or intraosseously. subclinical seizures occur in 15 to 20 percent of cases [34. a single unit of blood may be typed and cross-matched for several children. 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". (See "Management of status epilepticus in children". or a drop in the Blantyre coma score). approach. Blood should be typed and cross-matched prior to infusion. such that each receives an aliquot from the same unit. lorazepam (0.) If seizures recur. The approach to this complication is discussed in detail separately. hepatitis B. since blood vessels in these areas are close to the surface (figure 2). and it is therefore out of reach for many formularies in malaria-endemic areas.4 mg/kg) can be administered intravenously or per rectum. 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]. contraindications. respiratory distress. hyperlactatemia. other options include phenobarbitone (phenobarbital 15 to 20 mg/kg.eg. These doses can be repeated once if seizures do not cease within 5 minutes of the initial dose. and complications in adults".com/contents/treatment-of-severe-falciparum-malaria?view=print Página 4 de 21 . Anemia and coagulopathy — Removal of infected and uninfected erythrocytes from the circulation is associated with rapid development of anemia. Laboratory examination may be normal or may demonstrate slightly elevated total protein level and cell count. the mortality in the phenobarbital group was significantly higher than the placebo group (18 versus 8 percent) [37]. but profound thrombocytopenia is common. nailbeds. In a study of 340 children with cerebral malaria randomized to receive phenobarbital (20 mg/kg) or placebo upon admission to hospital. In a study comparing CSF findings from 12 children with cerebral malaria and 14 children with presumed viral encephalitis. thereby lowering the parasite burden and replacing with unparasitized cells. patients with cerebral malaria had lower white cell count.2 mmol/L) is a common complication of malaria and a marker of severe disease [40. or risks of this procedure. Alternatively. Patients with severe anemia may present with or without altered consciousness. diagnosis. It should be suspected in any patient who is comatose or who deteriorates suddenly. and/or high density parasitemia. These observations suggest that enhanced seizure control may improve longterm outcomes. Logistical constraints including limited blood supplies. administered orally. 10 mL/kg of packed red blood cells or 20 mL/kg of whole blood transfused over 2 to 4 hours is appropriate. Seizure management — Seizures occur in up to 70 percent of children with severe malaria. benefits. and the clinical signs may be subtle (nystagmus. A CSF glucose concentration below 3. http://www. children with viral encephalitis had a mean white cell count of 4 cells/microL (range 0 to 9 cells/microL).) Fluids and nutrition Hypoglycemia — Hypoglycemia (traditionally defined as blood glucose <40 mg/dL or <2.36]. epilepsy or other neurobehavioral sequelae were observed in nearly one-third of patients [34]. cool peripheries. and complications in children" and "Lumbar puncture: Technique. Laboratory parameters of concern include low hemoglobin concentration (≤4 to 5 g/dL) or low hematocrit (≤10 to 15 percent) [38]. The cost of this agent has increased dramatically. Transfusion — In areas where malaria and HIV are common infections.Treatment of severe falciparum malaria 11/01/12 16:38 bacterial meningitis should be initiated. indications. Coagulopathy — Clinically evident disseminated intravascular coagulation in the setting of severe malaria is rare (<5 percent). infused over 20 minutes). contraindications.4 mmol/L (61 mg/dL) was the best discriminator of cerebral malaria from presumed viral encephalitis. the hemoglobin concentration can be determined from fingerprick samples of blood collected into cuvettes.2 to 0. diuretics are rarely needed. It is also important to evaluate for causes of seizure besides cerebral malaria (eg hypoglycemia. high output heart failure. via NG tube. Patients with severe malaria should not receive routine seizure prophylaxis in the absence of clinical seizure activity. and palms can provide a rough estimate of the degree of anemia. Seizures may be generalized or focal. The CDC recommends consideration of exchange transfusion for patients with parasite density of >10 percent with end organ complications [39].) For many years paraldehyde was used as an intramuscular injection to treat seizures in the setting of severe malaria (0. If seizures are not controllable with benzodiazepines.) In patients with cerebral malaria. and syphilis. 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. fever) and to treat accordingly as outlined in the following sections. Evaluation for pallor of the conjunctivae. In endemic areas. (See "Lumbar puncture: Indications. 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). since repeat transfusion may be required. This method is more expensive than "spinning a hematocrit" but can be performed readily near the bedside. Such infusions require careful attention for prompt discontinuation to ensure that no more than the intended volume is transfused. hypoventilation. we do not favor this approach as there is no consensus on the indications. so patients can be fully alert with hemoglobin concentrations of 2 to 3 g/dL (hematocrit <10 percent). but this may not be available in resource limited settings or the results may not be available in a timely manner. and the microcirculation in many organs is occluded by fibrin thrombi [26]. Benzodiazepines should not be combined due to risk of respiratory depression. technique. glucose. Monitoring of hemoglobin concentration or hematocrit should continue until the parasitemia clears. (See "Clinical features. and protein levels [35]. Diazepam (0. repeat single doses of benzodiazepine may be administered.uptodate. Children with malaria had a mean white cell count of 0 cells/microL (range 0 to 4 cells/microL). For these reasons. slow IV push) or phenytoin (18 mg/kg diluted in 100 mL normal saline.41]. its chief advantage is that it does not cause respiratory suppression.4 mL/kg). blood transfusion is associated with important risks. although such screening may miss HIV infected donors who have not yet mounted a detectable serologic response to the infection. (See "Anemia in malaria". Alternatively. Benzodiazepines are useful first line agents for seizure treatment.) Hemoglobin concentration and hematocrit are routinely measured components of complete blood counts. transfusion should be reserved for patients with dire prognoses -. Blood transfusions are generally well tolerated in the setting of severe malaria since patients are relatively hypovolemic. In endemic areas hemoglobin concentration may decrease gradually over the course of repeated malaria infections. patients with altered consciousness. In an African study comparing 132 pediatric survivors of retinopathy-positive cerebral malaria with age-matched controls.

and the drip rate is set. suppository formulations are acceptable [4]. When the prevalence of malaria parasitemia was 29 percent.Treatment of severe falciparum malaria 11/01/12 16:38 In a prospective study of 437 children in Mali with presumed severe malaria (85 percent of whom had microscopic evidence of P.001) [42]. In this way. A comprehensive study of bacteremia in Kenya identified falciparum infection as a major risk factor for bacteremia with multiple organisms [54]. there are data to both support and refute the presence of hypovolemia in the setting of severe malaria infection [45.uptodate. there is a thin line between underhydration (and thus worsening renal impairment) and overhydration (and risking pulmonary and cerebral edema). 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. The case fatality rates for hypoglycemia. Clinical manifestations of hypoglycemia include seizure and altered consciousness.3 mmol/L were classified as hyperglycemia. Therefore. This is usually achieved with 2. oral therapy can be used for patients able to swallow. When transfusion is not indicated. For patients weighing 10 to 20 kg. 15 mg/kg every 6 hours. Hypoglycemia with artesunate therapy is less common than with quinine or quinidine. Intravenous fluid support should be continued until oral intake is tolerated. Adults with malaria appear to be more vulnerable to fluid overload than children. the prevalence of bacteremia declined in parallel with the prevalence of malaria infection. patients should receive 40 mL per hour for the first 10 kg PLUS 2 mL/kg/hour for each kg above 10 kg. Patients weighing 1 to 10 kg should receive fluids at a rate of 4 mL/kg/hour. (See "Renal replacement therapy (dialysis) in acute kidney injury (acute renal failure) in adults: Indications.49]. respectively.53].2 mmol/L were classified as hypoglycemic. and intravenous fluids are usually available in one liter bags only. delayed capillary refill. The pathogenesis of hypoglycemia is not fully understood. Hypoglycemic patients should have intravenous access established promptly. patients should receive 60 mL per hour for the first 20 kg PLUS 1 mL/kg/hour for every kg above 20 kg [50].) Fever — High fevers (>38. In addition.75 (0.2 and 4. aggressive fluid resuscitation and specific treatment for acidosis are of uncertain benefit in these settings. In addition to primary hypoglycemia. respectively) [47]. although it is uncertain whether crystalloid increases risk of exacerbating cerebral edema in the setting of a fragile blood-brain barrier [48. At body weights above 80 kg.3 mmol/L were categorized as normoglycemia.6 and 10. ibuprofen (10 mg/kg every 6 hours. Malnutrition. those between 2. although these are not reliable clinical indicators and blood glucose concentration should be assessed as part of routine evaluation. blood glucose should be monitored closely during the course of illness with prompt management as outlined above. 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 presenting with normoglycemia can develop hypoglycemia during the course of treatment. If fever persists. In the setting of acute renal failure.46]. The volumes calculated for intravenous fluids can be administered via NG. The optimal approach to treatment of fever is uncertain. administration of quinine or quinidine (insulin secretagogues) can cause iatrogenic hypoglycemia [43. Children with initial blood glucose concentrations <2. fluid requirements should be assessed on an individual basis.5 mL/kg of 10 percent dextrose solution. 46. milk. the intravenous fluid infusion rate should be decreased accordingly. low glycemia. P <0.5 percent versus 7. For patients who weigh more than 20 kg. The rate of fluid administration should be determined by weight. fluid delivery can be difficult to monitor and there is real risk of iatrogenic volume overload. Some data suggest that volume resuscitation with crystalloid is favorable over colloid. Otherwise. Reliable markers of intravascular volume depletion in patients with severe malaria include cool peripheries.25 g/kg of body weight).88) for case fatality for each 1 mmol/L increase in admission blood glucose concentration. the contribution of water to total body weight falls. low venous pressure and low urine output. labeled with tape. timing.2 mmol/L may be too low for adequate sensitivity in the setting of pediatric cerebral malaria. 13. To prevent this problem.) In most endemic areas no commercially prepared enteral products are available. maximum dose 1200 mg per day) can be administered (orally. and dialysis dose". A chamber is filled with a known amount of fluid (generally 2 hours' worth). Hemofiltration is associated with lower mortality than peritoneal dialysis. data suggest that repeated boluses of normal saline or albumin may be counterproductive [47]. followed by administration of initial bolus of dextrose (0. there have been no comparative trials of hemofiltration and hemodialysis. although use of antipyretics in patients with high fever is appropriate given the association between high fever and convulsions [4]. Therefore. Blood glucose measurement after 15 minutes should be repeated.) Maintenance fluids — Maintenance intravenous fluids should include 5 percent dextrose. Most patients are able to eat and drink within 5 to 7 days. If glucose measurement is not possible. or intravenously) alone or on an alternating schedule with paracetamol every 3 hours.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 5 de 21 . those between 4. providers can tell at a glance if the infusion is proceeding as scheduled (figure 4). since extravasation of higher concentrations of glucose can cause severe tissue damage. via nasogastric tube. substitutes (such as "eggnog" containing eggs. falciparum infection). comatose patients with parasitemia at the time of initial assessment should receive a bolus of 2. Deep breathing (reflecting lactic acidosis) may also be a reasonable indicator of hypovolemia.4 mmol/L were classified as low glycemia. patients who received saline or albumin bolus had higher mortality at 48 hours than patients who received no bolus (10. (See "Maintenance fluid therapy in children". and those with concentrations >8.5 liters daily. 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).6 versus 7. institution of renal replacement therapy is appropriate if feasible. interposition of a burette (or "drip chamber") between the patient and the bag may be placed for monitoring IV fluid administration. and 7 percent. it may be related to parasite glucose consumption and/or impaired host gluconeogenesis [41]. Therefore.6 mmol/L. Total maintenance needs are generally capped near 2. (See "Approach to the patient with nontyphoidal Salmonella in a stool culture". adrenal insufficiency and hyperinsulinemia are not likely causes of hypoglycemia [41]. and severe anemia has been implicated as a primary risk factor for nontyphoidal Salmonella septicemia [52.4 and 8.) Maintenance intravenous fluids should contain at least 5 percent dextrose.3 percent.) Most hospitals in endemic areas do not have infusion pumps. (See "Oral rehydration therapy".5 mL/kg of 10 percent dextrose solution. Bacterial infection — Bacteremia is an important contributor to morbidity and mortality in the setting of severe malaria. sugar and oil) or high calorie drinks may be used. Clinical symptoms of hypovolemia frequently resolve with blood transfusion (when warranted). so these methods would significantly overestimate the fluid requirements. Aggressive temperature control may help reduce long-term neurologic outcomes in pediatric patients with retinopathy-positive cerebral malaria [34]. suggesting that the traditional cut-off of 2. (See "Enteral nutrition in infants and children". (See "Approach to hypoglycemia in infants and children". normal glycemia and hyperglycemia were 61. The adjusted odds ratio was 0.) http://www.5ºC) 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]. those managed promptly for hypoglycemia at presentation can have subsequent recurrent hypoglycemia. Paracetamol (acetaminophen. Therefore. with administration of repeat boluses until the patient is normoglycemic. Volume management — The intravascular volume status in the setting of severe malaria is uncertain. In resource limited settings this may be performed via fingerprick samples of whole blood on indicator strips (with or without handheld glucometers). maximum dose 1000 mg) is a reasonable antipyretic agent.64 to 0.44]. a significant difference in admission glucose concentration was observed between those who died and those who survived (median 4. 62 percent of bacteremia cases were attributable to malaria.

Malaria in children. Risk factors for severe disease in adults with falciparum malaria. http://whqlibdoc. particularly in the second and third trimesters.Treatment of severe falciparum malaria 11/01/12 16:38 The approach to empiric antibiotic therapy in the setting of severe malaria is contentious. World Malaria Report 2008. Older children and adults develop partial immunity after repeated infections and therefore are at relatively low risk for severe disease.2 mmol/L) is a common complication of malaria and a marker of severe disease. 5. Baird JK. 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. 10. et al. In the first trimester. et al. Prompt antimalarial therapy and supportive care should be administered as outlined in the preceding sections. delayed capillary refill. Malaria surveillance--United States. et al. (See 'Definition' above. (See 'Neurologic status' above. we suggest intravenous artesunate (in areas where intravenous artesunate of reliable quality is readily available). 2006. followed by concurrent supportive care to manage life-threatening complications of the disease: Pulmonary complications of severe malaria include pulmonary edema. Nosten F. 77:1917. Mali S. et al.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 6 de 21 . The total duration of therapy with artemisinin based therapy is 3 days. but there are many asymptomatic patients with high parasitemia.) Neurologic complications include altered sensorium.) Death due to severe malaria can occur within hours of presentation. Complications such as hypoglycemia and pulmonary edema are more common than in nonpregnant individuals. et al. Ann Trop Paediatr 2009. Standardized data collection for multi-center clinical studies of severe malaria in African children: establishing the http://www. and fetal death and premature labor are common. Infect Immun 2009. seizure and coma. and lower respiratory tract infection. Olola C.pdf (Accessed on December 30. Lee SJ. REFERENCES 1. acute respiratory distress syndrome. Mackintosh CL. Clin Infect Dis 2008. Warimwe G. 29:251. (See 'Diagnosis' above. Lancet 2010. Maternal mortality can approach 50 percent. Bejon P. World Health Organization. 2. Adults with malaria appear to be more vulnerable to fluid overload than children. Crawley J. After the acute stage of illness has been treated with parenteral therapy and the patient can swallow. 9:10. If there is a choice of therapy available. MMWR Surveill Summ 2008. rather than intravenous quinine (table 5) (Grade 2A). (See 'Completing therapy' above. and patients with severe malaria can present with low density infection. 9. Severe and fatal vivax malaria challenges 'benign tertian malaria' dogma. For treatment of pregnant women with severe falciparum malaria in the first trimester we suggest intravenous quinine (Grade 2B). Hiu J.uptodate. there is a thin dividing line between underhydration (and thus worsening renal impairment) and overhydration (and risk of pulmonary and cerebral edema). White NJ. 2009.who. Phillips A.) For treatment of nonpregnant adults and children with severe falciparum malaria.a case of fatal Plasmodium knowlesi infection with post-mortem findings: a case report. Taylor T. 11. 47:151.) Use of UpToDate is subject to the Subscription and License Agreement. Chu C. 6. Geneva.) Hypovolemia should be assessed on an individual basis. 48:871. 8. PREGNANCY — Pregnant women are more likely to develop severe P. 57:24. Clin Infect Dis 2009. the sicker the patient. The treatment of malaria. Cox-Singh J. young children and pregnant women are at high risk for severe malaria. Geneva. calculation of Blantyre coma score (table 2).) Hematologic complications include severe anemia and coagulopathy. falciparum malaria than other adults. 2010). (See 'Volume management' above.int/publications/2010/9789241547925_eng. 4. Travelers to areas where malaria is endemic generally have no previous exposure to malaria parasites and so are at high risk for severe disease. Faiz MA. blood cultures should be obtained and broad spectrum antibiotic therapy with activity against gram-negative bacilli should be initiated. artesunate or artemether are preferred over quinine in the second and third trimesters since quinine is associated with recurrent hypoglycemia [4]. Dondorp AM. Steele S. Decisions regarding transfusion should be tailored to individual patient circumstances. Lucas SB. Valim C.) The total duration of therapy with quinine/quinidine for severe malaria is 7 days. Zeki S. 2010. funduscopic exam and lumbar puncture. 375:1468. Mtove G.) The diagnosis of malaria infection and the degree of parasitemia are established by blood smear. In such cases. In general. (See 'Prereferral treatment' above. the heavier the parasitemia. The relationship between age and the manifestations of and mortality associated with severe malaria. Clinical evaluation includes full physical examination. during this period the risk of hypoglycemia associated with quinine is lower and the uncertainties regarding the safety of artemisinins are greater. (See 'Respiratory status' above. SUMMARY AND RECOMMENDATIONS Severe malaria is acute malaria with major signs of organ dysfunction and/or high level of parasitemia (table 1). a complete course of oral therapy (selected on the basis of known parasite drug susceptibility or national treatment guidelines) should be administered (table 5). Bassett P. Bacterial infection should be suspected in patients with severe anemia together with signs or symptoms of sepsis (hypotension. In endemic areas. 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). Analysis of immunity to febrile malaria in children that distinguishes immunity from lack of exposure. Seizures should be managed as outlined above. Other issues related to malaria and pregnancy are discussed in detail separately (see "Treatment and prevention of malaria in pregnancy"). so prompt assessment and initiation of antimalarial therapy are essential. 335:800. N Engl J Med 1996. (See 'Pregnancy' above. World Health Organization. it should be suspected in any patient who deteriorates suddenly. 3. Severe malaria . (See 'Transfusion' above. cool extremities. WHO guidelines for the treatment of malaria. (See 'Hypoglycemia' 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). Malar J 2010. 7. Slutsker L.) Hypoglycemia (blood glucose <40 mg/dL or <2. hyperlactatemia). Management requirements may range from supplementary oxygen to mechanical ventilation. either artemisinins or quinine are acceptable choices. et al.

362:1320. 119:218. Cellular basis of early cytokine response to Plasmodium falciparum. 25:331. Stepniewska K. 366:717. Willcox ML. et al. et al. Schaecher K. 40:538. Trans R Soc Trop Med Hyg 1997. 50. Severe P. 91:557. Patnaik R. Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised. Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. 359:2619. 25. 355:701. Infect Dis Clin North Am 1993. Mohanty S.cdc. Ann Intern Med 1993. in press. Hensmann M. 378:1316. 28. Day NP. Evidence of artemisinin-resistant malaria in western Cambodia. Dicko MI. 18. Coma in fatal adult human malaria is not caused by cerebral oedema. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. 71:441. Campbell CC. 93:283. Exp Parasitol 1993. Schellenberg JA. Principles of prevention and treatment. et al. Am J Trop Med Hyg 2011. Fu WJ. 49. et al. Taylor TE. Boele van Hensbroek M.cdc. 9:1173. Warrell DA. Kiguli S.uptodate. 30. 100:615. Characteristic abnormalities in cerebrospinal fluid biochemistry in children with cerebral malaria compared to viral encephalitis. 376:1647. 40. 364:2483. case-control study and a longitudinal study. Perfusion abnormalities in children with cerebral malaria and malarial retinopathy. Management of severe malarial anaemia in Gambian children. Dondorp AM. New Medication for Severe Malaria Available Under an Investigational New Drug Protocol. et al. Lancet 2000. Schwenk A. Molyneux ME. Lancet Infect Dis 2007. Quinine-induced hypoglycemia. Available at http://www. 51. Katz H. Bojang KA. 14. Blood glucose levels in Malawian children before and during the administration of intravenous quinine for severe falciparum malaria. 24. White NJ. London. Medana IM. PLoS Med 2004. Lancet 2010. Clin Infect Dis 2005. N Engl J Med 1983. J Infect Dis 2007. randomised trial. White NJ. Lancet 2005. 29. Assessment of volume depletion in children with malaria. 10:143. Taylor TE. et al. Am J Trop Med Hyg 2006. Coma scales for children with severe falciparum malaria. Carr RA. falciparum malaria in Kenyan children: evidence for hypovolaemia. N Engl J Med 2008. 37. Newton CR. Nat Med 2004. Faiz MA. et al. 39. et al. 2009). Grant CS.htm (Accessed February 20.htm (Accessed February 25. Maitland K. 1:708. Chokwe T. Veena S. Birbeck GL. Berkley JA. Bacteremia in Malawian children with severe malaria: prevalence. Jakka SR. Nontprasert A. Wirima JJ. 7:547. http://www. The complete drug reference 36th edition [online]. et al. Se Y. et al. Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study. Waruiru C. 69:2364. Berkley J. Rosenthal PJ. Miller KD. 96:427.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 7 de 21 . Mwangi I. Treatment with Quinidine Gluconate of Persons with Severe Plasmodium falciparum Infection: Discontinuation of Parenteral Quinine. 7:549. et al. Smith S. Blood glucose and prognosis in children with presumed severe malaria: is there a threshold for 'hypoglycaemia'? Trop Med Int Health 2010. etiology. Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial. Trans R Soc Trop Med Hyg 2006. 33. Onanga M. Gyapong JO. 27. Beare NA. Scott JA. Opoka RO. et al. controlled intervention study. ter Kuile F. Trans R Soc Trop Med Hyg 1997. 15. 358:1829. Available at: http://www. Studies of the neurotoxicity of oral artemisinin derivatives in mice. Clin Infect Dis 2011. 195:895. Evaluation of a PfHRP2 and a pLDH-based rapid diagnostic test for the diagnosis of severe malaria in 2 populations of African children. 46. 19. et al. 56:769. HIV coinfection. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Day N. Lancet Neurol 2010.medicinescomplete. English M. Bronzan RN. 53:349. 26. Waruiru C. Mishra SK. Muthinji P. Lancet 2009. Cardiotoxicity of antimalarial drugs. N Engl J Med 2011. Arch Ophthalmol 2000. Service FJ. Marsh K. Clin Infect Dis 2011. Pukrittayakamee S. 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. Crawley J. Planche T. Machevo S. Harding. Forster M. 319:1040. Atmakuri RM. et al. Artesunate for the treatment of severe falciparum malaria. et al. 2009). SC (Ed). 91:161. 22. Electroencephalographic and clinical features of cerebral malaria. Marsh K. 52:1100. Lewallen S. TE. Taylor TE. Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based. Lancet 2003. et al. Hypoglycaemia in African children with severe malaria. 38. Wirima JJ. N Engl J Med 1988.com/ (Accessed March 5. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.gov/mmWR/preview/mmwrhtml/mm5630a5. et al. Molyneux ME. Palmer A. N Engl J Med 1995. 3:8. 31. Mortality after fluid bolus in African children with severe infection. 13. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. 47. Chanthavanich P. Malaria. et al. Brown H. et al. Lancet 1987. J Inf Dis. http://www. 20. Taylor. Gomes MF. Q J Med 1989. 23. 75:790. 11/01/12 16:38 12. Pedro AJ. Nosten-Bertrand M. Kaplan PW. 84:247. O'Callaghan-Gordo C. NA. Malarial retinopathy: a newly established diagnostic sign in severe malaria. 42. Intravenous fluids for seriously ill children: time to reconsider. and outcome. SP. N Engl J Med 2008. Borgstein A. Nosten F. Taylor TE. Fanello CI. White VA. Hendriksen IC. Sachanonta N. et al. Pamba A. Maitland K. et al. Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Forster D. 1:e18. Sweetman. Zucker JR. Mtove G. 45. Arch Dis Child 2001. Evidence of blood-brain barrier dysfunction in human cerebral malaria. Lancet 2011. 44. 41. Whitten RO. MMWR Morb Mortal Wkly Rep 1991. Hendriksen IC. et al. 32. 62:409. Kwiatkowski D. Trans R Soc Trop Med Hyg 1999. et al. et al. 309:61. Mithwani S. Am J Trop Med Hyg 2000. Infect Immun 2001. 36. et al. White NJ. Bacteraemia complicating severe malaria in children. Harding SP. Dondorp A. Cerebrospinal Fluid Res 2006. 10:267. 118:924. Mwarumba S. et al. 35. 17. 54. 43. Maitland K. QJM 2003. MMWR Surveill Summ 2007. Taylor TE. et al. Indicators of life-threatening malaria in African children. 52. 373:557. Hien TT. et al. et al. Holloway P. Levin M. Bramham K. 85:626. 15:232. Brain swelling and mannitol therapy in adult cerebral malaria: a randomized trial. et al. 2009). et al. Limburg PJ. Noedl H. Pharmaceutical Press.gov/mmwr/preview/mmwrhtml/00043932. 16. 53. Neuropathol Appl Neurobiol 1999. Duke T. Eisenhut M. 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http://www. All rights reserved. Reproduced with permission from: White NJ. labored breathing) Substantial bleeding Shock Biochemical features Renal impairment (serum creatinine. Copyright © 1996 Massachusetts Medical Society. >2. <15 mmol/liter) Jaundice (serum total bilirubin.000 mature trophozoites and schizonts/mm3)Δ ≥5 percent of neutrophils contain malaria pigment * The deeper the coma. <40 mg/dl [<2. 335:800.2 mmol/liter]) Elevated aminotransferase levels (>3 times normal) Hematologic features Parasitemia (>500. Current concepts: The treatment of malaria. Δ Trophozoites are mature parasites in which pigment is visible under light microscopy. >45 mg/dl [>5 mmol/liter]) Hypoglycemia (blood glucose.Treatment of severe falciparum malaria 11/01/12 16:38 GRAPHICS Features indicating a poor prognosis in severe malaria Clinical features Impaired consciousness* Repeated convulsions (≥3 in 24 hr) Respiratory distress (rapid. • The combination of deep jaundice and renal failure is particularly grave.000 parasites/mm3 or >10. deep.uptodate. N Engl J Med 1996. >3 mg/dl [>265 µmol/liter])• Acidosis (plasma bicarbonate. the worse the prognosis.5 mg/dl [>43 µmol/liter])• Hyperlactatemia (venous lactate.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 8 de 21 .

ME. and pressure over the supraorbital ridge. Borgstein.Treatment of severe falciparum malaria 11/01/12 16:38 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. A. 71:441. Wirima. children who do not respond to painful stimuli score 0. or. Blantyre coma score ≤2 is associated with mortality. Molyneux. TE. Q J Med 1989. Taylor. 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. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. JJ.uptodate. sternal pressure.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 9 de 21 . Response to pain should be assessed via firm nailbed pressure. http://www.

com/contents/treatment-of-severe-falciparum-malaria?view=print Página 10 de 21 . The components of the GCS should be recorded individually.Treatment of severe falciparum malaria 11/01/12 16:38 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. a score of 9 to 12 correlates with moderate injury. E2V3M4 results in a GCS score of 9. http://www. 3 being the worst.uptodate. and a score of 8 or less represents severe brain injury. best verbal response (V). It is composed of three parameters: best eye response (E). for example. A score of 13 or higher correlates with mild brain injury. and 15 the best. and best motor response (M).

Treatment of severe falciparum malaria 11/01/12 16:38 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. ++. +++++) Observer's initials Courtesy of Terrie Taylor.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 11 de 21 . 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 http://www. +++. ++) 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 (+. ++++.uptodate. +. DO.

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). followed by 2. followed by 7.uptodate. doxycycline and tetracycline are contraindicated. Parenteral quinine (or quinidine) with doxycycline. 3. 400 mg for children >6 years). Children: 25 mg/kg/day (up to 1000 mg) divided into 4 equal doses. • Artesunate can also be administered intramuscularly.5 mg base/kg (= 12 mg salt/kg) infused over 4 hrs every 8 hrs. Treatment course is 7 days. Intravenous dosing acceptable if oral medication not tolerated. Quinidine may be significantly absorbed to PVC tubing. parenteral therapy is administered for severe disease. the treatment can be completed with a course of an active oral antimalarial drug based on known susceptibility data. Options include: 1. ◊ Quinine should be given by rate controlled intravenous infusion and never by intravenous injection (which can be lethal). followed by oral therapy with an artemisinin combination drug such as artemetherlumefantrine (3 days therapy total. 2. followed by 2. nausea.4 mg/kg intravenously as first dose. if artesunate is not available.Treatment of severe falciparum malaria 11/01/12 16:38 Therapeutic options for parenteral treatment of severe malaria* I. Once the patient has received four doses of intravenous artesunate and is able to swallow. tetracycline or clindamycin (7 days therapy total). Adults and children: 20 mg base/kg/day orally (maximum 1800 mg) divided into 3 equal doses. Artemisinin derivative• Artesunate 2. a loading dose of quinine/quinidine should not be administered to patients who received mefloquine or other quinine derivatives within the previous 12 hours. The powder and liquid are mixed to provide a concentration of 10 mg/mL.2 mg/kg (up to 100 mg) orally twice daily. Treatment course is 7 days. treatment may be completed orally. Quinine or quinidineΔ Quinine dihydrochloride◊ Quinidine gluconate§ 16. doxycycline or clindamycin. tinnitus. (770) 488-7100 after hours. § In the United States. if artesunate is not available. followed by 0. http://www. starting 8 hrs after the beginning of the loading dose PLUS* one of the following: Doxycycline. or via rectal suppository (100 mg for children 6 months to 6 years of age. Parenteral artesunate followed by atovaquone-proguanil (for adults: 4 adult tabs orally for 3 days). CDC Malaria Hotline: (770) 488-7788 MondayFriday 8a to 4:30p EST. this is common practice for children with malaria acquired in Africa. ¥ Clindamycin should be administered for pregnant women. weekends and holidays. Once the patient is able to tolerate oral medications. The anterior thigh is preferred over the gluteal region to minimize the risk of sciatic nerve damage. 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).35 mg base/kg (= 10 mg salt/kg) over 2 hours at 8 or 12 hr intervals (maximum 1800 mg salt/day) 6.7 mg base/kg (= 20 mg salt/kg) in 5 percent dextrose loading dose over 4 hours. see separate table summarizing oral artemisinin combination therapy). mefloquine (for adults: 750 mg salt orally as initial dose followed by 500 mg salt orally 6 to 12 hrs later). vomiting.4 mg/kg once daily II.4 mg/kg at 12 and 24 hours. Parenteral quinine (at least three doses) until the patient is able to swallow. switch to oral dosing once patient is able to swallow.0125 mg base/kg/min (= 0. this is common practice for patients with malaria acquired in SE Asia. orally. Δ Important adverse effects include hypoglycemia. followed by 25 mg base/kg/day (20 to 30 mg salt/kg/day) divided into 2 to 3 equal administrations of 8.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 12 de 21 . Children: 2.02 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. QT prolongation. 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. reversible hearing loss. dizziness and visual disturbances. the artesunate solution should be administered within one hour of preparation. Adults: 250 mg orally four times daily. * In general. Treatment course is 7 days. tubing length should be minimized to approximately 12 inches. 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. intravenous quinidine is available for treatment of severe malaria. Tetracycline or Clindamycin Doxycycline Tetracycline Clindamycin¥ Adults: 100 mg orally twice daily. To avoid cardiotoxicity.25 mg base/kg (= 10 mg salt/kg) loading dose intravenously (maximum 600 mg salt) in normal saline over 1-2 hrs.

followed by 9. 25 . B. A 3 day treatment schedule with a total of 6 oral doses is recommended based on weight (5 . This may be achieved either as 15 mg/kg (usually on the second day) followed by 10 mg/kg one day later. Chloroquine (Aralen and generics) 600 mg base (=1000 mg salt) po immediately. 24. and tablets containing 500 mg of sulfadoxine with 25 mg of pyrimethamine. Total dose: 1550 mg base (=2000 mg salt). falciparum. B. Quinine sulfate PLUS one of the following: Doxycycline. 24.doxycycline ‡ Mefloquine: 684 mg base (=750 mg salt) po as initial dose. * NOTE: There are 4 options (A.2 mg/kg po every 12 hours C. and 48 hours. OR Hydroxychloroquine (Plaquenil and generics) 10 mg base/kg po immediately. and 48 hours.<25 kg: 2 tablets per dose. tid: three times daily.uptodate. Artesunate + amodiaquine Administration consists of separate scored tablets containing 50 mg of artesunate and 153 mg base of amodiaquine. PLUS Doxycycline: 2. followed by 456 mg base (=500 mg salt) po given 6-12 hours after initial dose. or as 8. 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. po: orally. 15 . Total dose = 25 mg salt/kg. Tetracycline◊. followed by 310 mg base (=400 mg salt) po at 6. PLUS Doxycycline: 100 mg po bid Mefloquine: 13. Artemisinin combination therapy Artemether + lumefantrine (Coartem) • Administration consists of combination tablets (1 tablet = 20 mg artemether and 120 mg lumefantrine). Total dose = 1250 mg salt. Atovaquone-proguanil (Malarone)• Adult tab = 250 mg atovaquone/100 mg proguanil Peds tab = 62. falciparum include Iran. Artesunate + sulfadoxine-pyrimethamine Administration consists of separate scored tablets containing 50 mg of artesunate.3 mg base/kg (=10 mg salt/kg) po tid x 3 or 7 days § PLUS one of the following: Doxycycline: 2. The World Health Organization (WHO) recommends option A as the http://www.8 grams) po divided tid x 7 days Sulfadoxine-pyrimethamine: single dose of 25/1.Treatment of severe falciparum malaria 11/01/12 16:38 Guidelines for treatment of uncomplicated P.25 mg/kg po every 6 hours x 7 days Clindamycin: 6. Infections acquired in Korea and the states of the former Soviet Union have been uniformly caused by P. Saudi Arabia. Mefloquine (Lariam and generics) ¥ Mefloquine + artesunate (dosing as above) Mefloquine +/.<35 kg: 3 tablets per dose. then 1 dose po bid for the following 2 days. or Clindamycin Quinine sulfate: 542 mg base (=650 mg salt)Δ 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. Chloroquine (Aralen and generics) 10 mg base/kg po immediately. bid: twice daily. 24. vivax to date and should therefore be treated as chloroquine-sensitive infections.1 mg base/kg (=10 mg salt/kg) po given 6-12 hours after initial dose. Artesunate + mefloquine Administration consists of separate scored tablets containing 50 mg of artesunate and 250 mg base of mefloquine. 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. and Yemen. Total dose: 1500 mg base (=2500 mg salt). ≥35 kg: 4 tablets per dose).2 mg/kg po every 12 hours x 7 days Tetracycline: 6. Haiti.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. and 48 hours. the Dominican Republic.3 mg/kg per day for 3 days.25 mg base/kg on day 1. followed by 5 mg base/kg po at 6. followed by the second dose 8 hours later. The recommended treatment is 4 mg/kg of artesunate and 10 mg/kg of amodiaquine given once a day for 3 days. The patient should receive the initial dose.7 mg base/kg (=15 mg salt/kg) po as initial dose. 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). Total dose: 25 mg base/kg. OR Hydroxychloroquine (Plaquenil and generics) 620 mg base (=800 mg salt) po immediately. B.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.25mg base/kg) on day 1. 24. followed by 5 mg base/kg po at 6. or D) available for treatment of uncomplicated malaria caused by chloroquine-resistant P.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 13 de 21 . Total dose: 25 mg base/kg. A. D. and 48 hours. Atovaquone-proguanil (Malarone)• Adult tab = 250 mg atovaquone/100 mg proguanil 4 adult tabs po once daily x 3 days B. Oman. or Clindamycin Quinine sulfate: 8.<15 kg: 1 tablet per dose. C. Quinine sulfateΔ PLUS one of the following: Doxycycline◊. Tetracycline. Chloroquine-sensitive Central America west of Panama Canal. and C equally. The US Centers for Disease Control (CDC) recommends options A (artemether-lumefantrine). Middle Eastern countries with chloroquine-resistant P. and most of the Middle East. followed by 300 mg base (=500 mg salt) po at 6.

atovaquone-proguanil and artemether-lumefantrine are recommended treatment options. If it is not available or is not being tolerated and if the treatment benefits outweigh the risks. CDC Malaria Hotline: (770) 4887788 Monday-Friday 8 am to 4:30 pm EST . weekends and holiday. these treatment combinations are generally preferred to quinine in combination with clindamycin. For infections acquired elsewhere.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 14 de 21 . For children less than 8 years old with chloroquine-resistant P. vivax.uptodate. then they should repeat the dose. Because of a higher rate of severe neuropsychiatric reactions seen at treatment doses. For children less than 8 years old with chloroquine-resistant P. ◊ Doxycycline and tetracycline are not indicated for use in children less than 8 years old. mefloquine is the recommended treatment.gov/malaria/pdf/treatmenttable. ¥ Treatment with mefloquine is not recommended in persons who have acquired infections from Southeast Asia due to drug resistance. atovaquone-proguanil or artemether-lumefantrine should be used instead. If patient vomits within 30 minutes of taking a dose. In addition.Treatment of severe falciparum malaria 11/01/12 16:38 first line treatment for uncomplicated malaria. • Take with food or whole milk. option C has higher incidence of adverse effects than options A or B. http://www. therefore 2 capsules should be sufficient for adult dosing. 2009). quinine treatment should continue for 7 days. mefloquine can be considered if no other options are available.pdf (Accessed June 18. § For infections acquired in Southeast Asia. Pediatric dosing may be difficult due to unavailability of non-capsule forms of quinine in the United States. in highly endemic areas combination therapy is important to prevent emergence of resistance. falciparum.cdc. option D (mefloquine) is recommended only when the other options cannot be used. Δ US manufactured quinine sulfate capsule is only available in a 324 mg (salt) strength. because there is more data on the efficacy of quinine in combination with doxycycline or tetracycline. ‡ 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. It is also acceptable to take one half of the dose twice daily. Adapted from United States Centers for Disease Control guidelines for treatment of malaria: http://www. quinine treatment should continue for 3 days.(770) 488-7100 after hours. For option C.

The image on the right is from a patient with hemorrhages and whitening (prominently seen around the macula).com/contents/treatment-of-severe-falciparum-malaria?view=print Página 15 de 21 .Treatment of severe falciparum malaria 11/01/12 16:38 White-centered hemorrhages White-centered hemorrhages in the optic fundi of patients with cerebral malaria. Courtesy of Susan Lewallen and Nicholas Beare. http://www.uptodate.

uptodate. http://www. Courtesy of Susan Lewallen and Nicholas Beare. vessel changes and whitening in areas of the retina). Vessels which are normally red in color become orange or yellow because they contain parasitized red cells. In the image on the left. The parasite consumes some of the hemoglobin in solution.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 16 de 21 . so those red cells become less red.Treatment of severe falciparum malaria 11/01/12 16:38 Vessel changes in optic fundi Vessel changes in the optic fundi of patients with cerebral malaria. all three features of malarial retinopathy are present (whitecentered hemorrhages.

This mosaic-like appearance is the result of capillary non-perfusion. the pathological whitening is in the perimacular area. a change seen in areas of the retina in patients with cerebral malaria. Courtesy of Susan Lewallen and Nicholas Beare.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 17 de 21 . similar to the upper. http://www.uptodate. In the image on the lower right. The extra-macular changes are a reflections from flash on the fundus camera. left image.Treatment of severe falciparum malaria 11/01/12 16:38 Retinal whitening Whitening.

uptodate.Treatment of severe falciparum malaria 11/01/12 16:38 Palmar pallor in a patient with severe anemia The anemic child's palm is cradled in the palm of the less anemic mother. DO.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 18 de 21 . Courtesy of Terrie Taylor. http://www.

uptodate. http://www.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 19 de 21 . Courtesy of Nathaniel Duke.Treatment of severe falciparum malaria 11/01/12 16:38 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).

http://www.uptodate.Treatment of severe falciparum malaria 11/01/12 16:38 IV fluids malaria Courtesy of Nathaniel Duke.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 20 de 21 .

Inc. All rights reserved.uptodate.utd.com/contents/treatment-of-severe-falciparum-malaria?view=print Página 21 de 21 .170. | Subscription and License Agreement Licensed to: Centro de Estudos Superiores Postitivo L | Support Tag: [ecapp1105p.14] http://www.34-34856A2F7F-184150.216.Treatment of severe falciparum malaria 11/01/12 16:38 © 2012 UpToDate.com-80.

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