Andrej Trampuz; Matjaz Jereb; Igor Muzlovic; Rajesh M Prabhu

“ Metabolic acidosis and hypoglycemia are common systemic complications. Intravenous quinine and quinidine are the most widely used drugs in the initial treatment of severe falciparum malaria, whereas artemisinin derivatives are currently recommended for quinine-resistant cases. As soon as the patient is clinically stable and able to swallow, oral treatment should be given. The intravascular volume should be maintained at the lowest level sufficient for adequate systemic perfusion to prevent development of acute respiratory distress syndrome. Renal replacement therapy should be initiated early. ”

“ Persons with partial immunity can tolerate low parasitemia (<10 000 parasites/μl) without clinical symptoms [18] . Therefore, in a proportion of semi-immune individuals parasitemia may not be responsible for current signs and symptoms [ [6] . In 5–10% of patients with falciparum malaria, treatment failure will occur, with recurrence of symptoms usually within 1 month of treatment. A repeated blood smear examination at 7 and 28 days after completion of therapy is recommended to monitor for relapse of severe falciparum malaria [ [30] . ”

“ Exchange blood transfusion has been suggested for the treatment of patients with severe malaria and high parasitemia. For early diagnosis, it is paramount to consider malaria in every febrile patient with a history of travel in an area endemic for malaria.
Introduction
Malaria remains a devastating global health problem. Worldwide, an estimated 300–500 million people contract malaria each year, resulting in 1.5–2.7 million deaths annually [1] , [2] . ”

“ Once the parasite begins to divide, the trophozoites are called schizonts, consisting of many daughter merozoites (blood schizogony) . Eventually, the infected erythrocytes are lysed by the merozoites, which subsequently invade other erythrocytes, starting a new cycle of schizogony. The duration of each cycle in P. falciparum is about 48 hours. In non-immune humans, the infection is amplified about 20-fold each cycle. After several cycles, some of the merozoites develop into gametocytes, the sexual stage of malaria, which cause no symptoms, but are infective for mosquitoes [5] . ”

“ However, patients who received transfusions had higher parasitemia and were much more ill according to WHO criteria for severe malaria. Cytokines such as TNF-α and interleukin-1 probably contribute to the pathogenesis of severe malaria, and some authors have suggested that plasma exchange, plasmaphere-sis, and hemodialysis are effective alternatives to exchange transfusion [ [49] . ”

“ Because of the increase in global travel to and immigration of people from areas endemic for malaria, the incidence of imported cases of malaria in developed countries has risen. Approximately 10 000–30 000 travelers from industrialized countries are expected to contract malaria each year [ [3] . In addition, drug-resistant Plasmodium falciparum malaria continues to spread and at present involves almost all areas of the world. An increasing number of travelers are exposed to drug-resistant plasmodia. ”

“ The major complications of severe malaria include cerebral malaria, pulmonary edema, acute renal failure, severe anemia, and/or bleeding. Acidosis and hypoglycemia are the most common metabolic complications. ”

“ Death in patients with malaria is related to the level of parasitemia, with significant mortality when parasitemia exceeds 5% despite appropriate parenteral antimalarial therapy. Exchange transfusion may rapidly reduce parasitemia, decrease the risk for intravascular hemolysis, improve blood flow, decrease cytokines, and improve oxygen-carrying capacity. ”

“ From a practical standpoint, any alteration in mental status should be treated as cerebral malaria. A lumbar puncture should be performed to rule out bacterial meningitis. To distinguish cerebral malaria from transient postictal coma, unconsciousness should persist for at least 30 min after a convulsion. The deeper the coma, the worse is the prognosis. On examination, neurologic abnormalities resemble those of a diffuse symmetric encephalopathy, similar to a metabolic encephalopathy. Nuchal rigidity and focal neurologic signs are rare. ”

“ Signs and symptoms of malaria
The clinical symptoms of malaria are primarily due to schizont rupture and destruction of erythrocytes. Malaria can have a gradual or a fulminant course with nonspecific symptoms. The presentation of malaria often resembles those of common viral infections; this may lead to a delay in diagnosis [8] . The majority of patients experience fever (>92% of cases) , chills (79%) , headaches (70%) , and diaphoresis (64%) [ [9] . Other common symptoms include dizziness, malaise, myalgia, abdominal pain, nausea, vomiting, mild diarrhea, and dry cough. ”

“ Several hypotheses have been proposed to explain the pathophysiology of cerebral malaria, but none have been completely satisfactory. The excellent neurologic recovery argues against ischemia alone being the culprit. Raised intracranial pressure, at least in nonimmune adults, appears not to play an important role in the pathogenesis of cerebral malaria. ”

“ To prevent medication errors it is important to check whether the recommended dose relates to a base or salt. Patients with severe malaria should always receive a full treatment dose, including those with breakthrough malaria and those who received some prior antimalarial medication. ”

“ Malaria is caused by obligate intraerythrocytic protozoa of the genus Plasmodium. Humans can be infected with one (or more) of the following four species: P. falciparum, P. vivax, P. ovale, and P. malariae. Plasmodia are primarily transmitted by the bite of an infected female Anopheles mosquito, but infections can also occur through exposure to infected blood products (transfusion malaria) and by congenital transmission. In industrialized countries, most cases of malaria occur among travelers, immigrants, or military personnel returning from areas endemic for malaria (imported malaria) . ”

“ Delirium, agitation, and even transient paranoid psychosis may develop as the patient recovers consciousness. Apart from cerebral malaria, other neurologic sequelae can occur, such as cranial nerve abnormalities, extrapyramidal tremor, and ataxia. ”

“ Postural hypotension may be secondary to autonomic dysfunction. Severe hypotension can develop suddenly, usually with pulmonary edema, metabolic acidosis, sepsis, and/or massive hemorrhage due to splenic rupture or from the gastrointestinal tract.
Hematologic abnormalities
Severe anemia is more common in children in highly endemic areas due to repeated or chronic Plasmodium infections. Thrombocytopenia is common, but usually not associated with bleeding. Disseminated intravascular coagulation is reported in fewer than 10% of patients with severe malaria. ”

“ Both quinine and quinidine may cause cinchonism (bitter taste, dysphoria, tremor, tinnitus, reversible high-tone hearing loss, headache, nausea, vomiting, and abdominal pain) or pruritus, which should not lead to dose reduction. Both drugs have narrow therapeutic windows. Severe toxicities include cardiac arrhythmias, hypotension, blindness, deafness, and hyper-insulinemic hypoglycemia [ [12] , [33] .
An initial loading dose of quinine or quinidine should be administered as soon as possible, followed by the maintenance dose. ”

“ Side effects include nausea, vomiting, pruritus, and fever; bleeding and cardiac arrhythmias rarely occur. Despite reports of brainstem neurotoxicity with high doses in animal studies, this side effect has not been observed in humans to date. ”