Go to Treatment of P. vivax / P. ovale / P. malariae | Treatment of Uncomplicated P. falciparum | Treatment of Severe Malaria
Aims of Treatment
| Aims | Causation | Therapy | Drugs |
| To alleviate symptoms | Symptoms are caused by blood forms of the parasite | Blood schizonticidal drugs | Chloroquine, quinine, artemisinin combinations |
| To prevent relapses | Relapses are due to hypnozoites of P. vivax/ P. ovale | Tissue schizonticidal drugs | Primaquine |
| To prevent spread | Spread is through the gametocytes | Gametocytocidal drugs | Primaquine for P. falciparum, Chloroquine for all other |
Thus, in effect, a blood schizonticidal drug and Primaquine should be administered to ALL types of malaria.
Principles of Treatment
Treatment of malaria depends on the following factors:
- Type of infection.
- Severity of infection.
- Status of the host.
- Associated conditions/ diseases.
Type of infection: Treatment obviously depends on the type of infection. Patients with P. falciparum malaria should be evaluated thoroughly in view of potential seriousness of the disease and possibility of resistance to anti malarial drugs.
P. vivax: Only Chloroquine 25 mg/kg + Primaquine for 14 days.
P. falciparum: Treat depending on severity & sensitivity; in most countries, artimisinin based combination therapy is recommended by the authorities. Primaquine as gametocytocidal is also recommended to prevent spread.
Mixed infections: Blood schizonticides as for P. falciparum and Primaquine as for P. vivax.
Severity of infection: All patients with malaria should be carefully and thoroughly assessed for complications of malaria. Acute, life-threatening complications occur only in P. falciparum malaria. Malaria is probably the only disease of its kind that can be easily treated in just 3 days, yet if the diagnosis and proper treatment are delayed, it can kill the patient very quickly and easily.
- All cases of severe malaria should be presumed to have P. falciparum malaria or treated as such.
- If there is any uncertainty about the drug sensitivity of the parasite, it is safer to treat these cases as chloroquine resistant malaria with drugs like quinine or artemisinin.
- All cases of severe malaria should be admitted to the hospital for proper evaluation, treatment and monitoring.
- All cases of severe malaria should be treated with injectable antimalarials (quinine, artemisinin derivatives) so as to ensure adequate absorption and plasma drug levels. Once the patientg is able to take oral medications, artimisinin combination therapy must be used as per recommendations.
- All associated conditions should be carefully assessed and treated.
Status of the host: Treatment of malaria is also dependent on host factors.
- Patient’s age and weight should be recorded so as to administer adequate doses of anti malarial drugs.
- Functional capacity- independent, dependent, bed ridden etc. All patients with severe prostration and who are looking ill should be admitted to a hospital and monitored.
- Patients with nausea and vomiting should be given anti emetic drugs to ensure adequate treatment. While high-grade fever frequently stimulates vomiting, this may be further aggravated by anti malarial drugs. Therefore it is better to avoid administration of oral antimalarials at the height of fever. One can wait for the fever to subside before taking the drugs. If the patient vomits within one hour of taking the anti malarial drugs, the same should be re-administered. In case of persistent vomiting, patient should be admitted and vomiting should be controlled with parenteral anti emetics. Parenteral anti malarials are needed only in cases of severe malaria or uncontrolled vomiting.
- Adequate hydration should be ensured.
Associated conditions/ diseases: Treatment of malaria may have to be modified due to certain associated conditions/ diseases. Therefore, all such should be carefully assessed before starting the patient on anti malarial treatment.
- Pregnancy: Treatment of malaria in pregnancy may prove to be difficult due to contra indication for use of certain antimalarials. Chloroquine can be used safely in all trimesters of pregnancy. Artemisinin is not shown to have any deleterious effects on the fetus in animal studies; however, it is not yet recommended for routine use in the first trimester, but can be safely used in the second and third trimesters. Quinine can be used in pregnancy, but one should be watchful about hypoglycemia. Whereas mefloquine is contraindicated in the first trimester of pregnancy, pyrimethamine/ sulphadoxine is contraindicated in the first and last trimesters. Halofantrine, tetracycline and doxycycline are absolutely contra indicated in pregnancy. Primaquine is also contra indicated in pregnancy, and therefore pregnant women with P. vivax malaria should be started on 500 mg of chloroquine weekly as suppressive chemoprophylaxis against relapse of malaria. [See Malaria in Pregnancy]
- Epilepsy: Malaria as well as anti malarials can trigger convulsions. Mefloquine is better avoided in these patients. See C.N.S. Disease and malaria
- Cardiac disease: High-grade fever of malaria can exacerbate left ventricular failure and therefore, in all such patients energetic management of malaria is called for. Fever should be controlled with anti-pyretics and tepid sponging. Chloroquine, artemisinin, pyrimethamine/ sulphadoxine, tetracyclines and primaquine can be safely used in these patients. Quinine can also be used carefully. Mefloquine and halofantrine are better avoided in patients with known cardiac illness. See C.V.S. Disease and malaria
- Hepatic insufficiency: None of the antimalarial drugs have any direct hepatotoxic effect. However, chloroquine is not advisable in patients with severe hepatic insufficiency. See liver disease and malaria
- Renal failure: The initial dose of antimalarial drugs need not be reduced in patients with renal failure. However, if the patient requires parenteral antimalarials even after three days and continues to be sick, then the dose can be reduced by one third to half of usual dose. See renal disease and malaria
- Dermatitis: Concomitant use of chloroquine with gold salts and phenyl butazone should be avoided because all the three can cause dermatitis.
Also see myasthenia gravis and malaria, anaesthesia and malaria, Diabetes and malaria
Modes of Treatment: Two important concepts in the treatment of malaria are suppressive and radical treatments.
Suppressive treatment: The symptoms of malaria can be alleviated by suppressing the erythrocytic stage of the parasitic development. Suppressive therapy involves administration of appropriate blood schizonticidal drugs. In all cases of non-falciparum malaria (P. vivax, P. ovale, P. malariae and P. knowlesi), it involves administration of chloroquine.
Presumptive treatment for malaria involves administration of blood schizonticidal drugs, such as chloroquine, to suspected cases of malaria, followed by full treatment after confirmation. This strategy has been abandoned in recent years. NVBDCP-India now recommends first loading dose of chloroquine only for those areas where neither microscopy nor RDTs are available within 24 hours.
Radical treatment: Radical treatment is administration of primaquine to all confirmed cases of malaria.
In P. vivax malaria, 2 weeks’ therapy with primaquine completely cures the infection in the host by its tissue schizonticidal activity and thereby prevents relapses.
In P. falciparum malaria, a single dose of primaquine destroys the gametocytes, thereby prevents the spread of the infection into the mosquito.
Therefore, administration of primaquine is a must in ALL proven cases of malaria, (a two weeks’ course in P. vivax malaria and a single dose in P. falciparum malaria).
All cases of P. vivax malaria and uncomplicated cases of P. falciparum malaria are treated with oral drugs. Chloroquine is the ONLY drug used for P. vivax malaria, because resistance to chloroquine in P. vivax malaria is almost unknown in most countries. In most parts of the world, P. falciparum is resistant to chloroquine, and the recommended treatment is artemisinin bases combinations. Primaquine should be used in P. vivax and P. ovale malaria for eradicating the persisting liver forms and in P. falciparum malaria to destroy the gametocytes, so as to prevent the spread of infection.
Scheme for the treatment of uncomplicated malaria [2]
Treatment of P. vivax, P. ovale, P. malariae and P. knowlesi Infections
P. vivax, the second most important species causing human malaria, accounts for about 40% of malaria cases worldwide and is the dominant malaria species outside Africa. It is prevalent in endemic areas in the Middle East, Asia, Oceania and Central and South America. In Africa, it is rare except in the Horn and it is almost absent in West Africa. The other two human malaria parasite species P. malariae and P. ovale are generally less prevalent but are distributed worldwide, especially in the tropical areas of Africa.[1-4] P. knowlesi is being increasingly reported from SE Asia region.[5]
Treatment of clinical infection:
P. vivax is generally very sensitive to chloroquine, although resistance is prevalent and increasing in some areas, notably Oceania, (Irian Jaya, Myanmar, Papua New Guinea and Vanuatu), Indonesia and Peru. Resistance to pyrimethamine has increased rapidly in some areas, and sulfadoxine-pyrimethamine is consequently ineffective. P. vivax is sensitive to all the other antimalarial drugs; it is more sensitive than P. falciparum to the artemisinin derivatives, and slightly less sensitive to mefloquine (although mefloquine is still effective). However, artesunate + sulfadoxine-pyrimethamine may not be effective against P. vivax in many areas owing to the resistance to pyrimethamine.[1-4]
Both P. ovale and P. malariae are regarded as very sensitive to chloroquine, although there is a single recent report of chloroquine resistance in P. malariae. These species are also susceptible to amodiaquine, mefloquine and the artemisinin derivatives.[1-4] P. knowlesi is sensitive to chloroquine, quinine, mefloquine and other conventional antimalarials. As P. knowlesi has no hypnozoites, primaquine is not necessary for its treatment. Therefore, the treatment of uncomplicated P. knowlesi infection is similar to P. malariae (i.e., chlorquine without primaquine). Severe infections due to P. knowlesi, should be treated as for severe P. falciparum infections, with artemisinin derivatives or quinine.[5]
Prevention of relapses:
P. vivax and P. ovale form hypnozoites, parasite stages in the liver that can result in multiple relapses of infection, weeks to months after the primary infection. Therefore, treatment of P. vivax and P. ovale infections should be aimed at curing both the blood stage and the liver stage infections, and thereby preventing both relapse and recrudescence. The only drugs with significant activity against the hypnozoites are the 8-aminoquinolines like primaquine. A combination of chloroquine + primaquine will therefore provide radical cure.
The frequency and pattern of relapses vary geographically. Whereas 50–60% of P. vivax infections in South- East Asia relapse, the frequency is lower in Indonesia (30%) and the Indian subcontinent (15–20%). Some P. vivax infections in the Korean peninsula have an incubation period of nearly one year. It appears that the total dose of 8-aminoquinoline given is the main determinant of curative efficacy against liver-stage infection. There is no evidence that the short courses of primaquine widely recommended (such as 5-day regimens) have any efficacy. Primaquine should be given for 14 days. The usual adult oral dose is 15 mg base (0.25 mg/kg bw per day) but in South-East Asia, particularly Indonesia, and in Oceania, higher doses (0.5 mg base/kg bw per day) are required. Primaquine causes abdominal discomfort when taken on an empty stomach; it should always be taken with food.
In low-transmission areas, the benefits of deploying primaquine are considered to exceed the risks, but in areas of sustained high transmission (such as on the island of New Guinea), P. vivax infection is very frequent, immunity is acquired, and the risks of widespread deployment of primaquine are considered to outweigh the benefits.
Primaquine is an oxidant and causes variable haemolysis in G6PD-deficient individuals. As primaquine is is eliminated rapidly, haemolysis is self-limiting provided no further medicine is taken. Screening for G6PD deficiency is not generally available outside hospitals, although rapid tests are under development. If a patient is known to be severely G6PD deficient, then primaquine should not be given. For the majority of patients with mild variants of the deficiency, primaquine should be given in a dose of 0.75 mg base/kg bw once a week for 8 weeks. If significant haemolysis occurs on treatment, then primaquine should be stopped.[1-4]
Treatment of P. vivax and P. ovale infections:
Chloroquine 25 mg base/kg bw divided over 3 days, combined with primaquine 0.25 mg base/kg bw, taken with food once daily for 14 days is the treatment of choice for chloroquine-sensitive infections. In Oceania and South-East Asia the dose of primaquine should be 0.5 mg/kg bw.[1-4]
| Treatment of Uncomplicated P. vivax, P. ovale, P. malariae and P. knowlesi Infections [1-5] | |||||
| Age in years | Dose of Chloroquine (as base) (Each 250 mg tablet contains 150 mg base and each 5 ml of suspension contains 50 mg base) |
Dose of Primaquine Once a day for 14 days (P. vivax and P. ovale only) |
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| 1st dose* (Tab) | 2nd dose (Tab) | 3rd dose (Tab) | 4th dose (Tab) | ||
| 0-1 | 75 mg (½) | 37.5 mg (¼) | 37.5 mg (¼) | 37.5 mg (¼) | Nil |
| 1-5 | 150 mg (1) | 75 mg (½) | 75 mg (½) | 75 mg (½) | 2.5 mg |
| 5-9 | 300 mg (2) | 150 mg (1) | 150 mg (1) | 150 mg (1) | 5 mg |
| 9-14 | 450 mg (3) | 225 mg (1½) | 225 mg (1½) | 225 mg (1½) | 10 mg |
| >14 | 600 mg (4) | 300 mg (2) | 300 mg (2) | 300 mg (2) | 15 mg |
| *1st dose of chloroquine should always be larger to obtain sufficient blood levels, in view of large volume of distribution. | |||||
For chloroquine-resistant vivax malaria, Amodiaquine (30 mg base/kg bw divided over 3 days as 10 mg/kg bw single daily doses) combined with primaquine should be given. Where ACT has been adopted as the first-line treatment for P. falciparum malaria, it may also be used for P. vivax malaria in combination with primaquine for radical cure. Artesunate + sulfadoxine-pyrimethamine is the exception as it will not be effective against P. vivax in many places.
P. malariae and uncomplicated P. knowlesi should be treated with the standard regimen of chloroquine as for vivax malaria, but it does not require radical cure with primaquine as no hypnozoites are formed in infection with this species.[1-4]
| Dose spacing for chloroquine | 1st dose | 2nd dose | 3rd dose | 4th dose |
| If the patient comes in the morning and treatment can be started by mid-day | Stat. | After 6 hours | After 24 hours | After 48 hours |
| If the patient comes in the afternoon and treatment is started by evening | Stat | After 12 hours | After 24 hours | After 36 hours |
| If the patient is coming from a far off place and /or if the MP test report is available only next day | Stat (as presumptive) | 2nd and 3rd doses together after 24 hours | After 48 hours | |
Parenteral Chloroquine: Parenteral chloroquine (rarely needed these days) may be needed in patients with drug sensitive malaria with persistent vomiting. It should never be used as a bolus injection.
| Intravenous infusion | 10 mg / kg (max.600mg) in isotonic fluid, over 8 hours; followed by 15 mg / kg (max.900mg) over 24 hours. |
| Intramuscular or subcutaneous injections | 3.5 mg of base/ kg (max.200 mg) every 6 hours or 2.5 mg of base/ kg (max.150mg) every 4 hours. (Intramuscular injection can cause fatal hypotension, especially in children) |
Treatment of Uncomplicated P. falciparum Malaria
Treatment of P. falciparum malaria depends on the severity of infection, status of the host and drug sensitivity pattern in the locality. In view of the potential seriousness of the infection and synergistic toxicity of antimalarial drugs, the drugs should be properly chosen right at the start of the treatment; changing the drugs or adding the drugs half-way through the treatment only complicates the issue and adds to the adverse effects of treatment.
Uncomplicated malaria is defined as symptomatic malaria without signs of severity or evidence of vital organ dysfunction.[1] Uncomplicated P. falciparum infection should be treated according to the sensitivity of the parasite at the area of acquiring the infection. To counter the threat of resistance of P. falciparum to monotherapies, and to improve treatment outcome, combinations of antimalarials are now recommended by WHO for the treatment of falciparum malaria.[1] Two or more blood schizontocidal drugs with independent modes of action and thus unrelated biochemical targets in the parasite are used and at present Artemisinin Combinations (ACTs) are the recommended treatments for uncomplicated falciparum malaria.[1]
Artemisinin-based Combination Therapy (ACT)
Artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) produce rapid clearance of parasitaemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10 000 in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100- to 1000-fold per cycle). Artemisinin and its derivatives are eliminated rapidly. When given in combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course of treatment with an artemisinin compound is required; but when given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective.[1]
Non-artemisinin based combinations (non-ACTs) include sulfadoxine–pyrimethamine with chloroquine (SP+CQ) or amodiaquine (SP+AQ). However, the prevailing high levels of resistance have compromised the efficacy of these combinations. There is no convincing evidence that SP+CQ provides any additional benefit over SP, so this combination is not recommended.[1]
The choice of ACT in a country or region is based on the level of resistance of the partner medicine in the combination. In areas of multidrug resistance (South-East Asia), artesunate +mefloquine or artemether-lumefantrine is recommended, while in Africa, artemether-lumefantrine, artesunate + amodiaquine or artesunate + sulfadoxine-pyrimethamine can be used. Amodiaquine + sulfadoxine-pyrimethamine may be considered as an interim option in situations where ACTs cannot be made available.[1]
The National Vector Borne Disease Control Programme (NVBDCP) of India recommends Artesunate + SP and Primaquine (0.75mg/kg as single dose on the second day; not to be given in pregnancy) as the first line treatment for all cases of P. falciparum malaria.
| Global Deployment of Artemisinin Combination Therapy [6] | |||
| ACT | Countries Using | Failure | Status |
| Artemether+Lumefantrine | 56 (Africa, SE Asia, Brazil, Venezuela) | 0.8%-13% | No more in Cambodia |
| Artesunate+Amodiaquine | 27 (Africa, Viet Nam, Indonesia) | >10% | Used only in countries with failure rate <10% |
| Artesunate+Mefloquine | 8 (S America, SE Asia) | <10% | |
| Artesunate+Sulfa-Pyrimethamine | 11 (India, Middle east) | 0-1.5% | No more used in NE India |
| Dihydroartemisinin+Piperaquine | 8 (China, SE Asia) | <10% | |
Artesunate + Sulfadoxine–Pyrimethamine
This is currently available as separate scored tablets containing 50 mg or 200mg of artesunate, and tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine. The total recommended treatment is 4 mg/kg bw of artesunate given once a day for 3 days and a single administration of sulfadoxine+pyrimethamine (25/1.25 mg base/kg bw) on day 1. This combination is sufficiently efficacious only where 28-day cure rates with sulfadoxine–pyrimethamine alone exceed 80%.[1]
Dosing of Artesunate + Sulfadoxine–Pyrimethamine
Directorate of NVBDCP. National Drug Policy on Malaria 2013 [See]
|
| Dose of Primaquine (Single dose, mg; on Day 2) | |||||
| Age (yrs) | 0-1 | 1-5 | 5-9 | 9-14 | >14 |
| Dose (mg, once on Day 2) | Nil | 7.5 | 15 | 30 | 45 |
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This is currently available as separate scored tablets containing 50 mg of artesunate and 153 mg base of amodiaquine, respectively. Co-formulated tablets are under development. The total recommended treatment is 4 mg/kg bw of artesunate and 10 mg base/kg bw of amodiaquine given once a day for 3 days. This combination is sufficiently efficacious only where 28-day cure rates with amodiaquine monotherapy exceed 80%.[1]
Artesunate + Mefloquine
This is currently available as separate scored tablets containing 50 mg of artesunate and 250 mg base of mefloquine, respectively. Co-formulated tablets are under development but are not available at present. The total recommended treatment is 4 mg/kg bw of artesunate given once a day for 3 days and 25 mg base/kg bw of mefloquine usually split over 2 or 3 days.[1]
Mefloquine is associated with an increased incidence of nausea, vomiting, dizziness, dysphoria and sleep disturbance in clinical trials, but these are seldom debilitating and in general has been well tolerated.[1]
Artemether-Lumefantrine
This is currently available as co-formulated tablets containing 20 mg of artemether and 120 mg of lumefantrine. The total recommended treatment is a 6-dose regimen of artemether-lumefantrine twice a day for 3 days.[1]
| Dose of Artemether + Lumefantrine Tablets[1] | ||
| Weight (kgs) | Age (years) | Dose (No. of 20/120mg tablet) Twice daily for 3 days |
| 5-14 | <3 | 20/120 (1 tablet) |
| 15-24 | ≥3-8 | 40/240 (2 tablets) |
| 25-34 | ≥9-14 | 60/360 (3 tablets) |
| >35 | >14 | 80/480 (4 tablets) |
| [Commercial packs containing 80mg artemether and 480 mg lumefantrine in a single pill are also available; the adult dose is one such tablet per day for 3 days] | ||
Dose of Blister Packs of Artemether-Lumefantrine Supplied by NVBDCP, India
Directorate of NVBDCP. National Drug Policy on Malaria 2013 [See]
Fat-containing food (like milk or butter) enhances the absorption of this ACT and is therefore recommended, particularly on the second and third days of treatment.
While the WHO recommends Artemether-lumefantrine in areas of multidrug resistance such as South-East Asia; the NVBDCP Drug Policy 2010 does not mention this ACT.[1,2] This ACT should not be used for treating P. vivax malaria.
Dihydroartemisinin plus Piperaquine
Dihydroartemsinin plus piperaquine (DHA+PPQ) has now been found to be as effective as other ACTs and therefore recommended for the treatment of uncomplicated falciparum malaria by the WHO. DHA+PPQ is currently available as tablets of fixed-dose combination containing 40 mg of DHA and 320mg of PPQ. The recommended dose is 4 mg/kg/day dihydroartemisinin and 18 mg/kg/day piperaquine once a day for 3 days.
Treatment in Pregnancy
The antimalarials considered safe in the first trimester of pregnancy are quinine, chloroquine, proguanil, pyrimethamine and sulfadoxine–pyrimethamine. Of these, quinine remains the most effective and can be used in all trimesters of pregnancy including the first trimester.[1]
There is increasing experience with artemisinin derivatives in the second and third trimesters and there have been no adverse effects on the mother or fetus. Therefore, artemisinin derivatives can be used to treat uncomplicated falciparum malaria in the second and third trimesters of pregnancy, but should not be the first choice in the first trimester. Mefloquine has been associated with an increased risk of stillbirth. Sulfadoxine–pyrimethamine is safe but may be ineffective in many areas because of increasing resistance. Clindamycin is also safe, but both medicines (clindamycin and the artemisinin partner) must be given for 7 days. Primaquine and tetracyclines should not be used in pregnancy. Amodiaquine, chlorproguanil-dapsone, halofantrine, lumefantrine and piperaquine have not been evaluated sufficiently to permit positive recommendations.[1] The NVDCP in India does not recommend artemisinin compounds in any trimester of pregnancy.[2]
Scheme for the treatment of malaria in pregnancy [2]
| Recommendations for Treatment of Uncomplicated P. falciparum Malaria in Pregnancy [1,2] | |
| First trimester | Quinine + Clindamycin for 7 days. |
| Second and third trimesters | ACT known to be effective in the country/region or artesunate + clindamycin to be given for 7 days or quinine + clindamycin to be given for 7 days. |
Lactating wome: Tetracyclines are contraindicated because of their effect on the infant’s bones and teeth.
For infants and young children, ACTs should be the first-line treatment.
For travellers returning to non-endemic countries, WHO recommends any of the following:
-
-
- Atovaquone–proguanil (15/6 mg/kg; usual adult dose, 4 tablets once a day for 3 days)
- Artemether–lumefantrine (adult dose, 4 tablets twice a day for 3 days)
- Quinine (10 mg salt/kg bw every 8 h) + doxycycline (3.5 mg/kg bw once a day) or clindamycin (10 mg/kg bw twice a day); all drugs to be given for 7 days
-
See CDC Guidelines for Treatment of Malaria in the United States[4]
Patients with HIV infection who develop malaria should receive standard antimalarial treatment regimens.
Patients who do not tolerate oral medications or who have high parasitemia can be managed as for severe falciparum malaria (see below)
Fever can be treated with antipyretics and, if necessary, tepid sponging. Care should be taken to ensure that the water is not too cool as, paradoxically, this may raise the core temperature by inducing cutaneous vasoconstriction. Paracetamol (acetaminophen) 15 mg/kg bw every 4 h is widely used; it is safe and well tolerated given orally or as a suppository. Ibuprofen (5 mg/kg bw) has been used successfully as an alternative. There has been some concern that antipyretics might attenuate the host defence against malaria, as their use is associated with delayed parasite clearance. However, this appears to result from delaying cytoadherence, which is likely to be beneficial. There is no reason to withhold antipyretics in malaria.[1]
Treatment of Severe Malaria
Plasmodium falciparum malaria is the cause of most of the mortality and morbidity in malaria, although, rarely, P. vivax or P. ovale also produce serious complications, debilitating relapses, and even death.
Severe malaria is a medical emergency and may rapidly progress to death without prompt and appropriate treatment.[7] The main objective of the treatment of severe malaria is to prevent the patient from dying; prevention of recrudescence, transmission or emergence of resistance and prevention of disabilities are secondary objectives. The mortality of untreated severe malaria can be 100%, but with antimalarial treatment, the overall mortality falls to 15–20%.[1] As death from severe malaria can occur within hours of admission to hospital or clinic, it is essential that therapeutic concentrations of antimalarial drugs are achieved as soon as possible[1] with intravenous antimalarials. Further, gastrointestinal intolerance and erratic intestinal absorption make the oral route of administration unreliable in these patients.[7] As resistance to antimalarial drugs can complicate matters further, proper choice of antimalarials to start the treatment is of utmost importance; changing the drugs or adding of drugs half-way through the treatment only complicates the issue and adds to the adverse effects of treatment.
Management of severe malaria comprises four main areas: clinical assessment of the patient, specific antimalarial treatment (regimen, follow-on treatment, pre-referral treatment, artimisinin, quinine/quinidine), adjunctive therapy and supportive care.[1]
A detailed clinical examination should be conducted, with particular note of the level of consciousness (the Glasgow coma scale is suitable for adults, and the simple Blantyre modification or children’s Glasgow coma scale for children). The airway should be secured in unconscious patients and breathing and circulation assessed. Body weight of the patient should be measured or estimated so as to calculate the dose of antimalarial drugs and fluids. An intravenous cannula should be inserted and blood should be taken for cross-match, full blood count, platelet count, clotting studies, blood culture and full biochemistry; immediate measurements of blood glucose (stick test), haematocrit/haemoglobin, parasitaemia and, in adults, renal function should also be done. Unconscious patients should have a lumbar puncture for cerebrospinal fluid analysis to exclude bacterial meningitis. The degree of acidosis is an important determinant of outcome; the plasma bicarbonate or venous lactate level should therefore be measured if possible. If facilities are available, arterial or capillary blood pH and gases should be measured in patients who are unconscious, hyperventilating or in shock. The assessment of fluid balance is critical in severe malaria. Respiratory distress, in particular with acidotic breathing in severely anaemic children, often indicates hypovolaemia and requires prompt rehydration and, where indicated, blood transfusion.
Specific antimalarial treatment:
After rapid clinical assessment and confirmation of the diagnosis, full doses of parenteral antimalarial treatment should be started without delay with whichever effective antimalarial that is first available.[1] Two classes of drugs are currently available for the parenteral treatment of severe malaria: the cinchona alkaloids (quinine and quinidine) and the artemisinin derivatives (artesunate, artemether and artemotil). Although there are a few areas where chloroquine is still effective, parenteral chloroquine is no longer recommended for the treatment of severe malaria because of widespread resistance. Intramuscular sulfadoxine– pyrimethamine is also not recommended.[1]
The WHO recommends intravenous artesunate as the treatment of choice for severe malaria in adults and children in areas of low transmission.[1] Data on children in high-transmission regions are limited, and the WHO recommends treatment with artesunate, artemether, or quinine. For severe malaria during pregnancy, additional data regarding the risks of artemisinins are needed. The WHO recommends artesunate or quinine during the first trimester and artesunate as the first-line therapy during the second and third trimesters.[1,8]
Scheme for the treatment of severe malaria [2]
| Treatment of Severe Malaria [1,4,7] | |
| First Drug | Follow-on Treatment (Full course of any ACT) |
| Artesunatea 2.4 mg/kg bw iv or im on admission; then at 12 h and 24 h, then once a day for at least 24 hours, followed by full course of ACT |
|
| OR Artemetherb 3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg bw per day for at least 24 hours, followed by full course of ACT |
|
| Quinineb,c 20 mg salt/kg bw on admission (iv infusion or divided im injection), then 10 mg/kg bw every 8 h; infusion rate should not exceed 5 mg salt/kg bw per hour; course for 3 days for malaria acquired in Africa and South America, 7 days for malaria acquired in SE Asia[4] | Doxycyclined 100mgs BID (2.2mg/kg BID for <45kgs[4]) for 7 days OR Clindamycin 20mg base/kg/day divided in three doses for 7 days[4] in pregnancye,f |
| Quinidine gluconatec 10 mg salt/kg (equivalent to 6.2 mg base/kg) iv infused over 1–2 hours, followed immediately by 0.02 mg/kg/min salt (equivalent to 0.0125 mg/kg/min base) continuous iv infusion; course for 3 days for malaria acquired in Africa and South America, 7 days for malaria acquired in SE Asia[4] | Doxycycline OR Clindamycin as above |
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Treatment response should be assessed by parasite count daily until clearance of all trophozoites is achieved. Parasitemia may rise during the first 12–24 hours, because available drugs do not inhibit schizont rupture and release of merozoites. Rising parasitemia beyond 36–48 hours after the start of antimalarial treatment indicates treatment failure, usually because of high-level drug resistance. Because nonimmune hosts may exhibit a high pretreatment total parasite burden, it may take up to 6 days to achieve complete elimination of P. falciparum trophozoites from the blood, even with fast-acting antimalarial agents (e.g. quinine, artemisinin derivatives). A rising gametocyte count does not indicate treatment failure.[7]
Follow-on treatment:[1]
Following initial parenteral treatment, once the patient can tolerate oral therapy, it is essential to continue and complete treatment with an effective oral antimalarial. Current practice is to continue the same medicine orally as given parenterally to complete a full 7 days of treatment. In non-pregnant adults, doxycycline is added to either quinine, artesunate or artemether and should also be given for 7 days. Doxycycline is preferred to other tetracyclines because it can be given once daily, and does not accumulate in renal failure. But as treatment with doxycycline only starts when the patient has recovered sufficiently, the doxycycline course finishes after the quinine, artemether or artesunate course. Where available, clindamycin may be substituted in children and pregnant women, as doxycycline cannot be given to these groups. Although following parenteral treatment with a full course of oral ACT (artesunate +amodiaquine or artemether-lumefantrine) is theoretically a good alternative, this has not been evaluated in clinical trials. The recommendation from experts’ opinion is to complete treatment in severe malaria following parenteral drug administration by giving a full course of combination therapy, ACT or quinine + clindamycin or doxycycline. Regimens containing mefloquine should be avoided if the patient presented initially with impaired consciousness. This is because of an increased incidence of neuropsychiatric complications associated with mefloquine following cerebral malaria.
Pre-referral treatment:[1]
The risk of death from severe malaria is greatest in the first 24 h, yet in most malaria endemic countries, the transit time between referral and arrival at appropriate health facilities is usually prolonged thus delaying the commencement of appropriate antimalarial treatment, during which time the patient may deteriorate or die. It is recommended that patients are treated with the first dose of one of the recommended treatments by the parenteral route if possible or by the intra-rectal route before referral (unless the referral time is very short).
This could be intramuscular artemether, artesunate or quinine, or a rectal formulation of artemisinin or artesunate.
The following may be given:
- Artesunate or artemisinin by rectal administration
- Artesunate or artemether im
- Quinine im
Pre-referral and continued treatment with rectal artemisinins
The administration of an artemisinin by the rectal route as pre-referral treatment is feasible even at the community level. There is insufficient evidence to show whether rectal artesunate is as good as intravenous or intramuscular options in the management of severe malaria. The recommendation, therefore, is to use artesunate or artemisinin suppositories only as pre-referral treatment and to refer the patient to a facility where complete parenteral treatment with artesunate, quinine or artemether can be instituted. If, however, referral is impossible, rectal treatment should be continued until the patient can tolerate oral medication, at which point a full course of the recommended ACT for uncomplicated malaria in the locality can be administered. Definitive therapy for malaria should be followed as soon as possible after the initial rectal administration.
Artemisinin suppositories are not widely available. Doses used have been variable and empiric: 10–40 mg/kg bw (at 0, 4 or 12, 24, 48 and 72 h). Some studies have given a maintenance dose of one- to two-thirds of the initial dose. Artesunate suppositories (data relate to a single suppository formulation) are given in a dose of 10 mg/kg bw daily. The individual suppositories contain either 50, 100 or 400 mg of artesunate.
The appropriate single dose of artesunate given by suppository should be administered rectally as soon as the presumptive diagnosis of severe malaria is made. In the event that an artesunate suppository is expelled from the rectum within 30 min of insertion, a second suppository should be inserted and, especially in young children, the buttocks should be held together, for 10 min to ensure retention of the rectal dose of artesunate.
| Dosage for initial (pre-referral) treatment in adult patients (aged ≥16 years) [1] | ||
| Weight (kg) | Artesunate dose | Regimen (single dose) |
| <40 | 10 mg/kg bw | Use appropriate no. of 100-mg rectal suppositories |
| 40–59 | 400 mg | One 400-mg suppository |
| 60–80 | 800 mg | Two 400-mg suppositories |
| >80 | 1200 mg | Three 400-mg suppositories |
For children: one or more artesunate suppositories inserted in the rectum as indicated in Table 6. The dose should be given once and followed as soon as possible by definitive therapy for malaria.
| Dosage for initial (pre-referral) treatment in children (aged 2–15 years) and weighing at least 5 kg | |||
| Weight (kg) | Age | Artesunate dose (mg) | Regimen (single dose) |
| 5–8.9 | 0–12 months | 50 | One 50-mg suppository |
| 9–19 | 13–42 months | 100 | One 100-mg suppository |
| 20–29 | 43–60 months | 200 | Two 100-mg suppositories |
| 30–39 | 6–13 years | 300 | Three 100-mg suppositories |
| >40 | >14 years | 400 | One 400-mg suppository |
Quinine
The intrarectal dose used in treatment trials in Africa was either 12 mg/kg bw quinine base every 12 h without a loading dose, or 8 mg/kg bw every 8 h, also without a loading dose. The retention and absorption of quinine is dependent on pH. Results with gluconate salts (pH 4.5) cannot be extrapolated to more acidic solutions (such as the dihydrochloride salt, pH 2).
Antimalarial drugs used in severe malaria:
Artemisinin Derivatives: Artemisinins, the most important new class of antimalarial agents, have the key advantage of rapid action against all of the erythrocytic stages of the parasite, including transmissible gametocytes, resulting in a rapid clinical benefit and decreased transmission of malaria.[8] Intravenous and intramuscular artemisinins have been highly efficacious for the treatment of severe malaria. Rectal administration is also effective and may be of value in settings with limited resources. In addition, there is currently limited, if any, resistance to artemisinins in malaria parasites. Although all artemisinins have rapid antiparasitic activity, they have short half-lives, such that the standard 3-day treatment course is commonly followed by recrudescence of infecting parasites and recurrent illness within days to weeks. To help prevent late recrudescences and the emergence of resistant parasites, these drugs should always be used in combination with a longer-acting agent.[8]
The first artemisinin to be studied in large clinical trials of severe malaria was artemether. Large randomized comparisons of intramuscular artemether and quinine in Gambian children and Vietnamese adults and a meta-analysis of individual data from 1919 patients in 11 trials of parenteral therapy identified no significant difference in efficacy between these agents. However, in the meta-analysis, the subgroup of adults had lower mortality when treated with artemether.[8]
Artesunate is dispensed as a powder of artesunic acid. This is dissolved in sodium bicarbonate (5%) to form sodium artesunate. The solution is then diluted in approximately 5 ml of 5% dextrose and given by intravenous injection or by intramuscular injection to the anterior thigh. The solution should be prepared freshly for each administration and should not be stored. Artemether and artemotil are dispensed dissolved in oil (groundnut, sesame seed) and given by i.m. injection into the anterior thigh.[1]
The efficacy of intramuscular artemether in severe malaria may be limited by varied absorption of this fat-soluble artemisinin derivative. Artesunate, which is water-soluble, has more reliable pharmacokinetic characteristics. A large, randomized comparison of intravenous artesunate and quinine in 1461 patients in Asia showed a significant survival benefit with artesunate. Mortality was 22% with quinine, as compared with 15% with artesunate, a risk reduction of 34.7%. Treatment with artesunate had a relatively mild side-effect profile; hypoglycemia was significantly more common with the use of quinine. A systematic review of five randomized trials comparing the efficacy of intravenous quinine with that of artesunate and one additional trial of intramuscular artesunate demonstrated the superiority of artesunate, with significant reductions in the risk of death (relative risk, 0.62), incidence of hypoglycemia, and parasite clearance time, as compared with quinine.[8] The Cochrane review on the Artemisinin derivatives for treating severe malaria concluded that the artemisinin drugs are no worse than quinine in preventing death in severe or complicated malaria and that no artemisinin derivative appears to be better than the others.[9] However, Artemisinin-based combination therapies are not yet available in the United States.
Cardiac monitoring is not mandatory during treatment with artesunate, and no serious toxic effects due to the drug are anticipated. Hypoglycemia is also less common with artesunate than quinine or quinidine; nonetheless, it is important to monitor the patient’s blood glucose level and provide supplementary glucose as needed. Artesunate dosages need not be changed because of hepatic or renal failure or concomitant or previous therapy with other medications, including previous therapy with mefloquine, quinine, or quinidine. There are no known interactions between artesunate and other drugs.[8]
The dosage of artemisinin derivatives does not need adjustment in vital organ dysfunction.[1]
After the acute stage of the illness, when the patient can tolerate oral medication, long acting antimalarials like doxycycline or, in children or pregnant women, clindamycin, or full courses of treatment with atovaquone–proguanil or mefloquine (although the neuropsychiatric toxic effects of mefloquine may be increased after cerebral malaria) should be given.[8]
Toxic effects have been reported less frequently with the artemisinins than with other antimalarial agents. The most common toxic effects that have been identified are nausea, vomiting, anorexia, and dizziness; these are probably due, in many patients, to acute malaria rather than to the drugs. More serious toxic effects, including neutropenia, anemia, hemolysis, and elevated levels of liver enzymes, have been noted rarely. Neurotoxicity is the greatest concern regarding artemisinins, since the administration of high doses in laboratory animals has led to severe and irreversible changes in the brain. Although neurologic findings are fairly common with acute malaria, there is no convincing evidence of neurotoxic effects resulting from standard oral or intravenous therapy with artemisinins.Limited data are available on the use of intravenous artesunate for severe malaria during pregnancy.[8]
Quinine and Quinidine: In most of the world, standard therapy for severe malaria has been intravenous or intramuscular quinine. In the United States, intravenous quinidine has been the standard therapy since 1991. That year, parenteral quinine was withdrawn by the CDC because quinidine had been shown to be more potent in vitro and highly effective against P. falciparum when used orally for uncomplicated disease or intravenously for severe falciparum malaria. However, quinine and quinidine are associated with considerable toxic effects, including tinnitus, reversible hearing loss, nausea, vomiting, dizziness, hypoglycemia, and visual disturbances. As compared with quinine, intravenous quinidine is associated with greater risks of cardiotoxic effects and hypotension and therefore requires continuous cardiac monitoring, with slowing or discontinuation of the infusion for prolongation of the QT interval. As the use of quinidine as an antiarrhythmic agent has decreased, its decreasing availability has also become a problem. The antimalarial efficacy of quinine has diminished in some areas, in particular Southeast Asia, suggesting partial resistance that may limit the drug’s efficacy against severe malaria.[8]
Whereas many antimalarials are prescribed in terms of base, for historical reasons quinine doses are often recommended in terms of salt (usually sulfate for oral use and dihydrochloride for parenteral use). Therefore, one should be clear whether the salt or base is being referred to while recommending the dose (doses with different salts must have the same base equivalents).[1]
Quinine must never be given by intravenous injection, as lethal hypotension may result. Quinine dihydrochloride should be given by rate-controlled infusion in saline or dextrose solutions at a rate not exceeding 5 mg salt/kg bw per hour. If this is not possible then it should be given by intramuscular injection to the anterior thigh, not the buttock (to avoid sciatic nerve injury). The first dose should be split, 10 mg/kg bw to each thigh. Undiluted quinine dihydrochloride at a concentration of 300 mg/ml is acidic (pH 2) and painful when given by intramuscular injection, so it is best either formulated or diluted to concentrations of 60–100 mg/ml for intramuscular injection. Gluconate salts are less acidic and better tolerated than the dihydrochloride salt when given by the intramuscular and rectal routes.[1]
As the first dose (loading dose) is the most important in the treatment of severe malaria, this should be reduced only if there is clear evidence of adequate pretreatment before presentation. Although quinine can cause hypotension if administered rapidly, and overdose is associated with blindness and deafness, these adverse effects are rare in the treatment of severe malaria. The dangers of insufficient treatment (i.e. death from malaria) exceed those from excessive treatment initially.
After the second day of parenteral treatment, if there is no clinical improvement the maintenance doses of quinine given by infusion should be reduced by one-third to avoid accumulation.[1] In renal failure (clearance <10 ml/min) and in dialysis patients, a normal loading dose should be administered, but the maintenance dose should be reduced by 30–50%. If hemodialysis is performed, quinine or quinidine should be administered after dialysis. Electrocardiographic monitoring is mandatory with quinidine infusion and with quinine infusion if the patient has acute renal failure. If the QRS complex lengthens by more than 25% beyond baseline or the QTc interval increases to more than 500 ms, the infusion should be slowed or discontinued.[7] Dosage adjustment by one-third is necessary in patients with hepatic dysfunction.[1]
Adjunctive treatment
Various adjunctive treatments for the complications of malaria may be needed to reduce the unacceptably high mortality of severe malaria.[1,8]
Patients with severe malaria often require care in an intensive care unit. Aggressive supportive care, including mechanical ventilation and hemofiltration or hemodialysis, can be instrumental in successful management of severe malaria. In technologically limited settings, high-quality nursing care, management of fluid balance, and control of seizures are helpful, although anticonvulsant agents that are respiratory depressants should be used with caution if mechanical ventilation is unavailable. Aggressive fluid resuscitation, blood transfusion for moderate anemia, exchange transfusion, and specific treatment for acidosis are of uncertain value. Bacterial infections can coexist with severe malaria, so blood cultures should be obtained from patients with shock or other signs of sepsis despite appropriate antimalarial therapy, and these patients should receive broad-spectrum antibiotic therapy. Although hypoglycemia is less common when artesunate is used rather than quinine or quinidine, it is important to monitor the patient’s blood glucose level and provide supplementary glucose as needed.[8]
| Immediate clinical management of severe manifestations and complications of falciparum malaria1 | |
| Manifestation/complication | Immediate management (in addition to antimalarial treatment) |
| Coma (cerebral malaria) | Maintain airway, place patient on his or her side, exclude other treatable causes of coma (e.g. hypoglycaemia, bacterial meningitis); avoid harmful ancillary treatment such as corticosteroids, heparin and adrenaline; intubate if necessary |
| Hyperpyrexia | Administer tepid sponging, fanning, cooling blanket and antipyretic drugs |
| Convulsions | Maintain airways; treat promptly with intravenous or rectal diazepam or intramuscular paraldehyde |
| Hypoglycaemia (blood glucose concentration of<2.2 mmol/l; <40 mg/100ml) | Check blood glucose, correct hypoglycaemia and maintain with glucose-containing infusion |
| Severe anaemia (haemoglobin <5 g/100ml or packed cell volume <15%) | Transfuse with screened fresh whole blood |
| Acute pulmonary oedema | Over-enthusiastic rehydration should be avoided so as to prevent pulmonary oedema. Prop patient up at an angle of 45o, give oxygen, give a diuretic, stop intravenous fluids, intubate and add positive end-expiratory pressure/continuous positive airway pressure in life-threatening hypoxaemia |
| Acute renal failure | Exclude pre-renal causes, check fluid balance and urinary sodium; if in established renal failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis. The benefits of diuretics/dopamine in acute renal failure are not proven |
| Spontaneous bleeding and coagulopathy | Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets if available); give vitamin K injection |
| Metabolic acidosis | Exclude or treat hypoglycaemia, hypovolaemia and septicaemia. If severe add haemofiltration or haemodialysis |
| Shock | Suspect septicaemia, take blood for cultures; give parenteral antimicrobials, correct haemodynamic disturbances |
| Hyperparasitaemia | Treat with artemisinins, intravenously or orally (See below) |
Supportive care:[1,7,10-12]
Vital signs, with an accurate assessment of respiratory rate and pattern, coma score, and urine output should be recorded as frequently as possible. Blood glucose should be checked, using rapid stick tests every 4 h if possible, particularly in unconscious patients.
Comatose patients should be placed in a semirecumbent position to reduce the risk for aspiration. Serum sodium concentration, arterial carbon dioxide tension, blood glucose, and arterial lactate concentration should be monitored frequently. The efficacy of hypertonic mannitol in treatment of cerebral edema is not proven.[7]
Seizures are common in cerebral malaria, particularly in children. Convulsions should be treated promptly with intravenous or rectal diazepam or intramuscular paraldehyde. In a large double-blind placebo-controlled evaluation of a single intramuscular injection of 20 mg/kg bw of phenobarbital (phenobarbitone) in children with cerebral malaria there was a reduction in seizures but a significant increase in mortality in phenobarbital recipients, resulting from respiratory arrest. Prophylactic anticonvulsants are not recommended.[1]
Fluid requirements should be assessed individually. Adults with severe malaria are very vulnerable to fluid overload and there is a thin dividing line between underhydration, and thus worsening renal impairment, and overhydration, with the risk of precipitating pulmonary oedema.[1] The intravascular volume should be maintained at the lowest level sufficient for adequate systemic perfusion.[7] If the patient becomes oliguric (<0.4 ml of urine/kg bw per hour) despite adequate rehydration, and the blood urea or creatinine are rising or already high, then fluids should be restricted to replace insensible losses only. Children, on the other hand, are more likely to be dehydrated and may respond well to a bolus of fluid. The fluid regimen must also be tailored around infusion of the antimalarial drugs. Central venous pressure should be maintained at 0–5 cm. If the venous pressure is elevated (usually because of excessive fluid administration), the patient should be nursed with the head raised at an angle of 45o and, if necessary, intravenous furosemide should be given. If available, heamofiltration should be started early for acute renal failure or severe metabolic acidosis unresponsive to rehydration.[1] In hypotension early use of inotropic support is indicated rather than overhydration. Negative fluid balance is critical to avoid exacerbating acute lung injury, but is balanced against the risk for precipitating acute renal failure[7]
Early institution of renal replacement therapy may avoid the development of ARDS. Patients with hypotension tolerate continuous renal replacement therapy better than conventional intermittent hemodialysis. In addition, a continuous regulation of body fluid avoids periods of volume overload and depletion.[7]
If blood glucose is <2.2 mmol/l (<40mg/dL), then hypoglycaemia should be treated immediately (0.3–0.5 g/kg bw of glucose). Hypoglycaemia should be suspected in any patient who deteriorates suddenly. Stick tests may overestimate the frequency of hypoglycaemia, so laboratory confirmation may be necessary.
Patients with acute pulmonary oedema should be nursed in an upright position and given oxygen, and filling pressures on the right side of the heart should be reduced with whichever treatments are available (loop diuretics, opiates, venodilators, venesection, haemofiltration, dialysis). The right-sided pressure should be reduced to the lowest level compatible with an adequate cardiac output.[1] The patient may need to be intubated because of impaired consciousness or because of acute lung injury. Mechanical ventilation with lower tidal volume improves the clinical outcome. A higher positive end-expiratory pressure may be needed to maintain optimal arterial oxygenation. In respiratory acidosis, the plateau pressure should be in excess of 25 cm H2O and the ventilator rate should be increased. Surfactant therapy, inhaled nitric oxide, and corticosteroids have no effect on survival or duration of ventilation in patients with ARDS.[7]
Fewer than 5% of patients with severe malaria develop clinically significant disseminated intravascular coagulation. These patients should be given fresh blood transfusions and vitamin K.
Patients with secondary pneumonia should be given empirical treatment with a third-generation cephalosporin, unless admitted with clear evidence of aspiration, in which case penicillin or clindamycin is adequate. Unexplained deterioration may result from a supervening bacterial infection. Children with persistent fever despite parasite clearance may have a systematic Salmonella infection, although in the majority of cases of persistent fever no other pathogen is identified after parasite clearance. Urinary tract infections are common in catheterized patients. Antibiotic treatments should take account of likely local antibiotic sensitivity patterns.
Other treatments:[1]
Many other supportive strategies and interventions have been proposed in severe malaria, but very few are supported by evidence of benefit, and many have proved harmful. Heparin, prostacyclin, deferoxamine, pentoxifylline, low molecular weight dextran, urea, high-dose corticosteroids, acetylsalicylic acid, deferoxamine, anti-tumour necrosis factor antibody, cyclosporin, dichloroacetate, adrenaline and hyperimmune serum have all been suggested – but none of these is recommended.
One systematic review on the use of corticosteroids in severe malaria found no significant difference in mortality but increased risk of gastrointestinal bleeding; therefore, corticosteroids should not be used in severe malaria.
Severe metabolic acidosis is common but apart from correction of hypovolaemia and anaemia, no specific treatment is of proven value. Significant electrolyte abnormalities are relatively unusual, and potassium supplementation is often not required in the acute phase. The optimum fluid resuscitation regimens, the thresholds for blood transfusion, the role of exchange transfusion, and the management of seizures remain areas of uncertainty. It is generally agreed that early ventilation for respiratory abnormalities and early management of renal failure or severe metabolic acidosis are beneficial. In acute renal failure, haemofiltration is associated with a lower mortality, and more rapid correction of biochemical abnormalities compared with peritoneal dialysis.
Blood transfusion:[1]
In high transmission settings, blood transfusion is recommended for children with a haemoglobin level of <5 g/100 ml (haematocrit <15%). In low-transmission settings, a threshold of 20% (haemoglobin 7 g/100ml) is recommended. These general recommendations still need to be tailored to the individual, as the pathological consequences of rapid development of anaemia are worse than those of acute on chronic anaemia, where there has been adaptation and a compensatory right shift in the oxygen dissociation curve.
Exchange blood transfusion (EBT)[1]
There have been many anecdotal reports and several series claiming benefit for EBT in severe malaria but no comparative trials, and there is no consensus on whether it reduces mortality or how it might work. It requires intensive nursing and a relatively large volume of blood, and carries significant risks. There is no consensus on the indications, benefits and dangers involved, or on practical details such as the volume of blood that should be exchanged. Therefore no recommendation regarding the use of EBT has been made by the WHO.
Treatment during pregnancy
Pregnant women, particularly in the second and third trimesters of pregnancy are more likely to develop severe malaria than other adults, often complicated by pulmonary oedema and hypoglycaemia. Maternal mortality is approximately 50%, which is higher than in non-pregnant adults. Fetal death and premature labour are common. The role of early Caesarean section for the viable live fetus is unproven, but is recommended by many authorities. Obstetric advice should be sought at an early stage, the paediatricians alerted, and blood glucose checked frequently. Hypoglycaemia should be expected and is often recurrent if the patient is receiving quinine. Severe malaria may also present immediately following delivery. Postpartum bacterial infection is a common complication in these cases. Falciparum malaria has also been associated with severe mid-trimester haemolytic anaemia in Nigeria. This often requires transfusion, in addition to antimalarial treatment and folate supplementation.
Parenteral antimalarials should be given to pregnant women with severe malaria in full doses without delay. Artesunate or artemether are preferred over quinine in the second and third trimesters because quinine is associated with recurrent hypoglycaemia. Recent evidence shows that in non pregnant adults with severe malaria in areas of low transmission, artesunate was superior to quinine, reducing mortality by 35% compared to quinine, which makes artesunate the preferred option in the second and third trimesters. In the first trimester, the risk of hypoglycaemia associated with quinine is lower, and the uncertainties over the safety of the artemisinin derivatives are greater. However, weighing these risks against the above evidence in favour of the efficacy of artesunate, and until more evidence becomes available, both artesunate and quinine may be considered as options. Treatment must not be delayed, so if only one of the drugs artesunate, artemether or quinine is available, it should be started immediately. The National vector Borne Disease Programme in India recommends quinine for the treatment of severe malaria in pregnancy.[2]
Management in epidemic situations:[1]
In epidemic situations, staff shortages and high workloads make intensive care monitoring difficult. Drug treatment should therefore be as simple and safe as possible, with simple dosing schedules and a minimum need for monitoring. As reconstitution of artesunate is a two step procedure and the dosing is twice a day, and as parenteral quinine requires either intravenous infusions or a three times a day intramuscular regimen, plus monitoring of blood glucose, the simple once a day regimens of intramuscular artemether is a suitable alternative for severe malaria in most epidemic situations, including in pregnant women in all trimesters. Artesunate suppositories may be appropriate in severely ill patients who are unable to swallow oral medication when intramuscular artemether (or quinine by intravenous infusion) is unavailable and in such cases, the patients should be moved as soon as possible to a facility where intramuscular or intravenous therapy can be started. When the patient cannot be moved, continued treatment with rectal artesunate is appropriate until oral drugs can be taken.
Hyperparasitaemia:[1]
Patients with high parasite counts are known to be at increased risk of dying, although the relationship between parasite counts and prognosis varies at different levels of malaria endemicity. Many hyperparasitaemic patients have evidence of vital organ dysfunction but there is a large subgroup in which no other manifestations of severe disease are present. These patients have symptoms and signs compatible with a diagnosis of uncomplicated malaria in association with a high parasite count (sometimes termed uncomplicated hyperparasitaemia). The relevance for treatment is firstly the increased risk of progressing to severe malaria, and secondly the generally higher treatment failure rates. This is of particular concern as resistance to antimalarials is most likely to arise in patients with heavy parasite burdens and little or no immunity. In a low-transmission area in north-west Thailand, the overall mortality of uncomplicated falciparum malaria was 0.1%, but in patients with parasitaemia of >4% it was 3%. In areas of moderate or high transmission, much higher parasitaemias are often well tolerated, however. There is not enough evidence to provide a firm recommendation on the definition of hyperparasitaemia, although ≥5% parasitaemia in a low-transmission setting and ≥10% in a higher transmission setting are commonly used.
The rapidity of action of the artemisinin derivatives makes them ideal drugs for the treatment of hyperparasitemia. Available evidence indicates that use of oral treatment under close supervision is effective in the treatment of patients with hyperparasitaemia who have no other features of severe malaria. Patients must be monitored closely for the first 48 h after the start of treatment and if there is concern or if the patient does not retain oral medication, parenteral treatment should be given without delay. Non-immune patients with parasitaemia of >20% should receive parenteral antimalarial treatment. Alternatively, the first dose of artemisinin derivative can be given parenterally or rectally to ensure adequate absorption, followed by a full course of ACT. Mefloquine, if used, should be given on days 2 and 3, rather than day 1, when it is better tolerated, with a lower incidence of early vomiting. The optimum duration of treatment for hyperparasitaemia is still unresolved. Data to support the suggestion that patients should be treated conservatively with 7 days of an artemisinin derivative, plus a full course of partner medicine (e.g. artesunate 7 days + mefloquine 25 mg/kg bw divided over 2 days) are lacking.
Treatment of severe vivax malaria:[1]
Although P. vivax malaria is considered to be a benign malaria, with a very low case-fatality ratio, it may still cause a severe and debilitating febrile illness. It can also very occasionally result in severe disease as in falciparum malaria. Severe vivax malaria manifestations that have been reported are cerebral malaria, severe anaemia, severe thrombocytopenia and pancytopenia, jaundice, spleen rupture, acute renal failure and acute respiratory distress syndrome. Severe anaemia and acute pulmonary oedema are not uncommon. The underlying mechanisms of severe manifestations are not well understood. Prompt and effective treatment and case management should be the same as for severe and complicated falciparum malaria.
References:
- Guidelines for the Treatment of Malaria. 2nd edn. WHO, Geneva, 2010. Available at http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf
- National Drug Policy on Malaria – 2013. Directorate of National Vector Borne Disease Control Programme. Govt. of India. New Delhi. 2013. Available at http://nvbdcp.gov.in/Doc/National-Drug-Policy-2013.pdf
- CDC. Treatment of Malaria (Guidelines for Clinicians). Available at http://www.cdc.gov/ malaria/resources/pdf/clinicalguidance.pdf
- CDC. Guidelines for Treatment of Malaria in the United States (Based on drugs currently available for use in the United States – updated Sep 23, 2011). Available at http://www. cdc.gov/malaria/resources/pdf/treatmenttable.pdf
- Wilairatana P, Krudsood S, Tangpukdee N. Management of P. knowlesi Malaria Without PCR Confirmation. Southeast Asian J Trop Med Public Health January 2010;41(1):19-21. Available at http://www.tm.mahidol.ac.th/seameo/2010-41-1/03-4750.pdf
- WHO. World Malaria Report 2014. WHO, Geneva. Available at http://apps.who.int/iris/bitstream/10665/144852/2/9789241564830_eng.pdf
- Andrej Trampuz, Matjaz Jereb, Igor Muzlovic, Rajesh M Prabhu. Clinical review: Severe malaria. Critical Care 2003;7:315-323 Available at http://ccforum.com/content/7/4/315
- Rosenthal PJ. Artesunate for the Treatment of Severe Falciparum Malaria. NEJM. 2008;358(17):1829-1836 Available at http://content.nejm.org/cgi/content/full/358/17/1829
- McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria. Cochrane Database Syst Rev. 2000;(2): CD000527. Availabe at http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD000527/frame.html
- World Health Organization: Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990;84(suppl 2):S1-S65.
- World Health Organization: Severe falciparum malaria. Trans R Soc Trop Med Hyg 2000;94(suppl 1):S1-S90.
- Management of Severe Malaria: A practical handbook. Third edition. World Health Organization. Geneva, 2012. Available at http://apps.who.int/iris/bitstream/10665/79317/1/9789241548526_eng.pdf
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