Treatment of Severe Falciparum Malaria

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    Official reprint from UpToDatewww.uptodate.com

    2012 UpToDate

    Author

    Terrie E Taylor, DO

    Section Editor

    Johanna Daily, MD, MSc

    Deputy Editor

    Elinor L Baron, MD, DTMH

    Treatment of severe falciparum malaria

    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 willbe 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 athigh 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 caresetting, 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).

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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 severedisease.

    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 wassuperior with respect to mortality (overall odds ratio 0.69, 0.57-0.84, p

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    followed by oral therapy with an artemisinin combination drug. (See 'Completing therapy' below.)

    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 ofquinine 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 ofdoxycycline 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 with end organ

    complications [39].

    Coagulopathy Clinically evident disseminated intravascular coagulation in the setting of severe malaria is rare (

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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

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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 areaswhere 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

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    SMAC network. Trans R Soc Trop Med Hyg 2006; 100:615.

    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 treatmentof 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 MorbMortal 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 comatoseMalawian 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 forsevere 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, 2.5 mg/dl [>43 mol/liter])

    Hyperlactatemia (venous lactate, >45 mg/dl [>5 mmol/liter])

    Hypoglycemia (blood glucose, 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: Thetreatment 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 1

    Fails to watch or follow 0

    Best motor response

    Localizes painful stimulus 2

    Withdraws limb from painful stimulus 1

    No response or inappropriate response 0

    Best verbal response

    Cries appropriately with pain, or, if verbal, speaks 2

    Moan or abnormal cry with pain 1

    No vocal response to pain 0

    Total

    Fully conscious children score 5; children who do not respond to painful stimuli score 0. Response to pain should be assessed via firmnailbed 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 4

    Response to verbal command 3

    Response to pain 2

    No eye opening 1

    Best verbal responseOriented 5

    Confused 4

    Inappropriate words 3

    Incomprehensible sounds 2

    No verbal response 1

    Best motor response

    Obeys commands 6

    Localizing response to pain 5

    Withdrawal response to pain 4

    Flexion to pain 3

    Extension to pain 2

    No motor response 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 moderateinjury; and a score of 8 or less represents severe brain injury.

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    Observations chart malaria

    Observationschart

    Day: Date: Day: Date:

    Time 6a 8a 10a 12a 2p 4p 6p 8p 10p 12m 2a 4a 6a 8a 10a 12a 2p 4p 6p 8p 10p 12m 2a 4a

    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.

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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

    dihydrochloride16.7 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)

    Quinidine

    gluconate6.25 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 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.

    Tetracycline 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.

    Clindamycin 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 artemether-

    lumefantrine (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 Monday-Friday 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 doseRecommended 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 isrecommended based on weight (5 -

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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 DiseaseControl guidelines for treatment of malaria: http://www.cdc.gov/malaria/pdf/treatmenttable.pdf (Accessed June 18, 2009). CDC Malaria Hotline: (770) 488-

    7788 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 cerebralmalaria. The image on the right is from a patient with hemorrhages andwhitening (prominently seen around the macula). Courtesy of Susan Lewallenand Nicholas Beare.

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    Vessel changes in optic fundi

    Vessel changes in the optic fundi of patients with cerebral malaria. Vesselswhich are normally red in color become orange or yellow because theycontain parasitized red cells. The parasite consumes some of thehemoglobin in solution, so those red cells become less red. In the imageon the left, all three features of malarial retinopathy are present (white-

    centered hemorrhages, vessel changes and whitening in areas of theretina). Courtesy of Susan Lewallen and Nicholas Beare.

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    Retinal whitening

    Whitening, a change seen in areas of the retina in patientswith cerebral malaria. This mosaic-like appearance is the

    result of capillary non-perfusion. In the image on the lowerright, the pathological whitening is in the perimacular area,similar to the upper, left image. The extra-macular changesare a reflections from flash on the fundus camera. Courtesy ofSusan 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 lessanemic mother. Courtesy of Terrie Taylor, DO.

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    Microhematocrit determination

    The capillary tube is plugged at one end and centrifuged (left). Theproportion of blood volume occupied by red cells can be readilydetermined by eye in a microhematocrit reader (right). Courtesy ofNathaniel Duke.

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    IV fluids malaria

    Courtesy of Nathaniel Duke.

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