Navy Medical Department Guide to Malaria Prevention and Control

Chapter 4: Treatment

Department of the Navy
Bureau of Medicine and Surgery

Overview

After establishing the presence of a malaria infection, treatment should be initiated as soon as possible. Specific treatment regimen depends on whether the case is diagnosed as complicated or uncomplicated malaria. Severity of clinical illness and level of parasitemia determine this distinction. In addition, steps must be taken to identify the responsible species, and the area where transmission occurred as those factors influence treatment. Patients diagnosed with complicated malaria are at risk for morbidity and death. Prompt treatment minimizes this risk. If possible, treatment of malaria should be done in consultation with a physician trained and experienced in treatment, with access to a tertiary care center.

Choice of treatment regimen, drug type, and selection of oral or intravenous administration, is based on the above factors. Two types of drugs are used to treat malaria. Blood schizonticides, which attack parasites in red blood cells, are used in acute infection to prevent or terminate the clinical attack. Tissue schizonticides are medications that act on the exoerythrocytic parasite stages (forming merozoites and hypnozoites) in liver cells to prevent relapse. Treatment with tissue schizonticides, known as "radical" cure, is required for infections of P. vivax and P. ovale. An algorithm for malaria treatment is illustrated in Figure 4-1.

During treatment, patients must be monitored for response to therapy and complications from the infection or treatment. Repeated clinical assessment is important in cases of severe malaria, where early detection of complications and immediate intervention may be lifesaving.

Table 4-1. Uncomplicated Malaria Treatment

* contraindicated for use in pregnant or lactating women, and those at risk of cardiac arrhythmia

Treatment

Uncomplicated Malaria. Chloroquine remains the medication of choice for patients with P. vivax, P. ovale, P. malariae, and uncomplicated chloroquine-sensitive P. falciparum infections. Drugs and dosages for treatment of uncomplicated malaria are listed in Table 4-1. Chloroquine-resistant P. vivax has been reported in New Guinea, Indonesia, Myanmar, India, Irian Jaya, and the Solomon Islands; so it is important to consult with medical intelligence sources to obtain the latest information on drug resistance in the area of transmission. Chloroquine is safe, and the 3-day treatment course is well tolerated. If chloroquine therapy is not effective, or if infection was acquired in an area with chloroquine-resistant malaria, mefloquine is the next drug of choice, followed by quinine in combination with either doxycycline or pyrimethamine-sulfadoxine (Fansidar^R). Tetracycline may be used as an alternate to doxycycline. The regimen of tetracycline is an adult dose of 250 mg qid, and a pediatric dose of 5 mg/kg qid, not to exceed 250 mg qid. Doxycycline and tetracycline are not to be used in children under 8. For uncomplicated malaria, quinine can be given as a 3 day course, except in Southeast Asia where a 7 day course is required because of an increase in relative resistance to quinine.

Febrile, acutely ill patients are prone to vomiting anti-malarial drugs, which are very bitter tasting. Administer an antipyretic such as Tylenol^R (acetominophen). This eases symptoms and helps patients tolerate anti-malarial drugs. Patients continuing to vomit require treatment by injection, administration of crushed tablets via nasogastric tube, or suppository. After administering an effective dose by one of these routes, patients can usually complete their course of therapy by mouth.

Complicated Malaria. Complicated malaria is almost always due to P. falciparum, and is associated with a mortality rate between 15 and 25%. Its diagnosis is based on the severity of clinical manifestations and a parasitemia involving more than 1% or 2% of red blood cells. Patients presenting with any of the clinical manifestations listed in Table 4-2 should be treated for complicated malaria. Drugs and dosages for treatment of complicated malaria are listed in Table 4-3.

Treatment approach for complicated malaria is listed below:

• Start treatment as soon as diagnosis is suspected.

• Calculate dosage according to patient weight.

• Give medication intravenously.

• Give loading dose of medication (not indicated if patient has received quinine, quinidine, or mefloquine in the last 24 hours).

• Switch to oral medication as soon as patient can tolerate tablets, and response to treatment is confirmed.

• Observe patients carefully for drug toxicity and complications.

Patients with complicated malaria should be treated with intravenous quinidine (parenteral quinine has not been available in the U.S. since 1991). Intravenous quinine or quinidine are potent blood schizonticides, and therapeutic plasma concentrations can be quickly and safely achieved by administration of a loading dose. Loading doses have been shown to decrease the duration of fever, parasitemia, and coma, and should be given if the patient has not received quinine, quinidine, or mefloquine in the last 24 hours.

Loading doses of quinine or quinidine should be given followed by continuous infusion. Baseline blood pressure and ECG should be obtained before initiating therapy, and periodically throughout treatment. Therapy should be discontinued if systolic blood pressure persists below 80 mm Hg, if either the QRS interval widens greater than 50%, or the QT interval is greater than 50% of the preceding R-R interval; or if a cardiac arrhythmia arises.

Overdose of quinine or quinidine, particularly if too rapidly infused, can cause convulsions, hypotension, cardiovascular collapse, heart block, and ventricular fibrillation. If possible, plasma concentrations of quinidine or quinine should be monitored, and the maintenance dose should be reduced if plasma concentrations exceed 15 mg/l. The maintenance dose should be reduced to one-third to one-half after 48 hours to prevent accumulation and toxicity, unless the patient has improved and can tolerate oral medication. Therapeutic doses of both quinine and quinidine can cause hypoglycemia through stimulation of insulin release. Blood glucose should be monitored periodically during treatment.

Table 4-2. Manifestations of Complicated Malaria

Table 4-3. Regimens for treatment of Complicated Malaria

*delay initial dose until 12 hours after the last dose of quinidine or quinine

Intravenous therapy is continued until the patient is able to tolerate oral therapy. Regimens for oral therapy are given in Table 4-3. Tetracycline may be used as an alternate to doxycycline. The regimen of tetracycline is an adult dose of 250 mg qid, and a pediatric dose of 5 mg/kg qid, not to exceed 250 mg qid. Doxycycline and tetracycline are not to be used in children under 8.

Alternate treatments include intravenous chloroquine, intramuscular FansidarR, mefloquine or halofantrine tablets crushed and mixed with water given via nasogastric tube, or artemisinin derivatives. Intravenous chloroquine is less toxic than quinine or quinidine, but resistance to it is so prevalent that it is not used for treatment of severe malaria cases. This applies even to areas without resistant strains of malaria. If oral therapy with mefloquine is chosen to complete the recommended 7 days of therapy, delay the intial dose for 12 hours after the last dose of quinidine or quinine.

Halofantrine is a newly licensed drug developed by the Walter Reed Army Institute of Research. It should not be used in patients who developed P. falciparum infections while on mefloquine prophylaxis because parasite resistance to both drugs is similar. In addition, fatalities have occurred when halofantrine has been used for treatment in patients who received mefloquine prophylaxis.

Intramuscular Fansidar^R (a combination drug containing sulfadoxine and pyrimethamine) has been shown to clear parasitemia as quickly as chloroquine, but hypersensitivity reactions to sulfonamides are common and cause complications.

Artemisinin, a compound known as qinghaosu in China, has been used with great success there and in trials in Thailand. It is available as heterogeneous compounds in suppository, intravenous, and tablet forms.

"Radical" Cure. To prevent relapse, P. vivax and P. ovale infections need to be treated to eradicate tissue schizonts (persistent liver cell stages known as hypnozoites). This is known as "radical" cure, and currently the only available effective drug is primaquine. It is a potent oxidant, and can cause severe hemolytic anemia in G-6-PD deficient patients. Therefore, before treating with primaquine, the G-6-PD status of patients must be checked, and an appropriate dosage regimen selected. Radical cure dosage schedules are listed in Table 4-4.

 Table 4-4. Primaquine Treatment Regimens

* 1 tablet consists of 26.3 mg pimaquine phosphate, 15 mg primaquine base.

Treatment Management

Monitoring. Complicated malaria patients are at risk for sudden decompensation and need to be closely monitored. If possible, these patients should be transferred to facilities with an intensive care unit (ICU) or equivalent. Treatment should be supervised by a physician. Initial patient monitoring should be frequent (every 1 to 2 hours), until the patient improves. Parameters to monitor include:

• Vital signs (temperature, pulse, blood pressure, respiration)

• Parasite concentration.

• Urinary output.

• Serum electrolytes.

• Blood glucose.

• Hematocrit/hemoglobin.

• ECG (required for quinidine treatment).

Response to therapy is monitored by serial blood smears. Fewer parasites will be seen on successive smears if treatment is effective. If no improvement in clinical symptoms or decrease in parasitemia is seen in the first 24 to 48 hours of treatment, resistance should be assumed and treatment with an alternate drug should be initiated. Providers should be vigilant and monitor other parameters to identify the common complications of malaria: cerebral malaria, hypoglycemia, anemia, renal failure, pulmonary edema, concurrent bacterial infection, and over-hydration. Prompt initiation of supportive measures (intravenous hydration, glucose administration, oxygen therapy, blood transfusion, etc.) is important in reducing permanent injury and mortality.

Cerebral Malaria. Generalized seizures occur in more than 50% of patients with cerebral malaria, and can lead to sustained neurological deterioration or aspiration pneumonia. Patients with impaired consciousness should be placed in the lateral decubitis position. If patient is unconscious, intubation with an endotracheal tube or placement of a rigid oral airway is indicated to maintain the airway. Vital signs, level of consciousness (modified Glasgow coma scale, see Table 4-5), and seizures should be monitored and recorded frequently. Seizures must be treated promptly with a benzodiazepine drug (diazepam, chlormethiazole, or lorazepam). A nasogastric tube should be placed to lower risk of aspiration pneumonia.

Deepening coma or signs of cerebral herniation are indications for further assessment with computed tomography (CT) or magnetic resonance imaging (MRI). If such techniques are not available, therapy to lower intracranial pressure should be attempted. Acceptable treatment measures include intravenous mannitol, 1.5 mg/kg of 10-20% concentration given over 30 minutes, or hyperventilation to reduce arterial pCO2 below 4.0 pKa. Steroids have been proven ineffective when used in an attempt to lower intracranial pressure.

Seizures may be prevented with a single intramuscular dosage of phenobarbital sodium (loading dose 15-20 mg/kg, total dose 60-200 mg/kg/day). In an ICU, an alternate method is phenytoin, 10-15 mg/kg loading dose, followed by an adult maintenance dose of 100 mg every 6 hours. Plasma phenytoin concentration should be monitored daily.

Hypoglycemia. This complication should be suspected in any patient who becomes unresponsive. Frequent monitoring of blood glucose is necessary in complicated malaria, particularly during intravenous quinine or quinidine administration. Hypoglycemia can be caused by two mechanisms, stimulation of insulin release caused by quinine or quinidine therapy, or from consumption of glucose by large numbers of parasites. If available, give a therapeutic trial of 50% dextrose followed by continuous infusion of 5 or 10 % dextrose solution.

Table 4-5. Modified Glasgow Coma Scale

Pulmonary Edema. This complication results from either increased capillary permeability or fluid overload and resembles Adult Respiratory Distress Syndrome (ARDS). A patient with pulmonary edema needs treatment in an ICU, as positive pressure ventilation with positive end expiratory pressure/continuous positive airway pressure (PEEP/CPAP) is needed for adequate oxygenation. Fluid overload must be prevented by maintaining the central venous pressure between zero and 10-15 cm H2O. If an ICU setting is not available, oxygen should be delivered by the most effective means available, and a rapid acting diuretic such as furosemide should be given intravenously.

Renal Failure. Renal complications are seen in one third of adult patients with severe falciparum malaria. Most patients will respond to cautious re-hydration with an increase in urine output. Dialysis is indicated for hyperkalemia, uremia, metabolic acidosis, or pulmonary edema. Treatment of intravascular hemolysis (blackwater fever) involves correction of uremia with dialysis, and avoidance of fluid overload due to blood transfusion. In cases of renal failure due to massive hemolysis, blood transfusion is usually necessary to prevent death.

Anemia. In most cases no intervention beyond treatment of the malaria infection is required. Transfusion should be considered if the hematocrit drops below 20%, or if it is falling rapidly and associated with clinical distress. Clinical manifestations indicating need for transfusion include shock, cardiac failure, hypoxia, and extreme lethargy.

Transfusion has safely been used to correct anemia, but the volume given must be included in fluid balance calculations to prevent pulmonary edema. Diuretics (furosemide, 1-2 mg/kg) can be given to promote urine output to maintain fluid balance during transfusion. Plasma expanders (colloids), and administration of oxygen can be used if transfusion is not practical or available.

Exchange transfusion for treatment of hyperparasitemia has been used for approximately 70 patients. Though most showed clinical improvement during and after the procedure, it has not been proven superior to optimal anti-malarial medication treatment. Manual exchange transfusion (alternating phlebotomy with transfusion), or continuous cell separation (hemophoresis) are methods of exchange transfusion that have been used.

Septic Shock. Secondary bacterial infection is a frequent complication in severe malarial cases. Blood, urine, and CSF fluid, etc. should be routinely cultured. Broad-spectrum intravenous antibiotics combining an aminoglycoside and a later generation cephalosporin should be started immediately if a secondary bacterial infection is suspected. Other causes of shock to consider are hypovolemia from dehydration, pulmonary edema, or massive blood loss (gastrointestinal hemorrhage or ruptured spleen).

Ruptured Spleen. This potentially fatal complication should be considered in patients infected with P. vivax or P. falciparum. Clinical manifestations include complaints of abdominal pain, especially in the left upper quadrant, left shoulder pain, and hypotension without other signs of blood loss. Free blood in the peritoneal cavity or a torn splenic capsule can be detected by ultrasound or CT, and confirmed by needle aspiration of the peritoneal cavity. A trial of conservative management is currently recommended so the spleen and its immunological functions can be preserved. This includes blood transfusion, close observation in an ICU or equivalent setting, and rapid access to surgical consultation.

Pregnancy. Treatment is essential for pregnant women to save their lives and prevent miscarriages. Falciparum malaria is associated with low birth weight, fetal distress, premature labor, miscarriage, stillbirth, and hypoglycemia. Treat as for any adult, suspect hypoglycemia, and do not give tetracycline or halofantrine.

Pediatrics. Most of the 1 to 3 million deaths from malaria each year are children, primarily in Africa. Common complications are convulsions, coma, hypoglycemia, metabolic acidosis, and severe anemia. Severe jaundice, acute renal failure, and pulmonary edema are unusual. Children tolerate anti-malaria drugs well, and treatment is virtually the same as for adults with appropriate dosage adjustments. Tetracycline drugs cause defects in forming teeth and bone, and should not be given to children under 8 or 9 years.

Completion of Treatment

Complicated malaria should be treated for a total of 7 days. Mefloquine can be given as a single dose when oral drugs can be tolerated, since therapeutic blood levels last for a week. Dosages of other oral medications indicated after intravenous therapy are shown in Table 4-3.

Uncomplicated malaria requires 3 days of chloroquine treatment in susceptible infections. Oral mefloquine or halofantrine can be used in resistant cases. If P. vivax or P. ovale were identified or suspected, "radical" cure to eradicate hypnozoites is indicated. Table 4-4 lists appropriate dosages for patient G-6-PD status.

Follow Up and Prognosis

Once elimination of parasites has been documented on peripheral blood smears, routine repeat smears are not recommended. Patients should be advised that malaria relapse is possible despite thorough treatment. If presenting for care with a febrile illness within a year, they should be advised to inform their provider that they were recently treated for malaria and it should be considered a potential cause of their present illness.

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Operational Medicine 2001

Health Care in Military Settings

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