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Patients with Malaria

Introduction

According to a report in the New York Times (June 6th two years of war have resulted in the deaths of more than 1.7 million people in the eastern Congo. The report, based on a study released by the International Rescue Committee in New York, indicates that about four times as many people have died in the area since August 1998 than would be expected under normal conditions (an additional 600,000 died of non war related causes). Although the majority of people have been able to escape death from the fighting, they die of hunger and malaria in the jungle. Out of the total 1.7 million deaths, 200,000 were due to violence. The Federal Centers for Disease Control and Prevention in Atlanta, extrapolated the results to the interior regions and neighboring provinces to consider a population base of 18 million in the sub Sahara area. Results show a startling increase in malaria and other infectious diseases, including cholera, meningitis, and polio, as health clinics and water and sewer systems are destroyed or abandoned. Because blood transfusions are often needed for malaria victims, the prevalence of HIV infection is also on the increase as there has been no blood tested in these areas since 1998.

Yet another study from the International Federation of Red Cross and Red Crescent Societies reported in the New York Times (International section, June 29th 2000, pA17), compared the death toll exerted by natural disasters and that attributable to AIDS, tuberculosis, and malaria. Mortality due to the three infectious diseases was 160 times greater than the number of people killed by earthquakes, cyclones, and floods in 1999. According to the federation’s “World Disasters Report,” an estimated 150 million people have died from these diseases since 1945 (thirteen million in 1999 alone) compared with 23 million in wars during the same period. The Red Cross has pinpointed climate change, growing urbanization, and environmental damage, coupled with little more than a facade of health systems, as causative factors for the increase in infectious disease. While wealthier countries spend about 6% of the gross domestic product on health care, poorer countries may contribute only 1%. As a result, malaria, once under control in countries like Azerbaijan and Tajikistan, has escalated.

Thus it is apparent that the annual global incidence of malaria is increasing due to the above-cited reasons, and also due the ban on the use of DDT for spraying, and the emergence of DDT resistant strains of the disease vector. While 3.5 billion (63% of the world’s population) live in malaria free areas, 29% live in parts where malaria is now increasing after having been reduced previously. (www.malaria.org.za/)

Over 300 million people contract the disease annually (five times as many as combined cases of TB, AIDS, measles and leprosy). Women are four times more likely to contract the disease and twice as likely to die if pregnant. Malaria is predominantly a disease of the third world with approximately 1 million deaths occurring annually in Africa alone, mostly in children under 5 years. Malaria transmission occurs in more than 100 countries throughout Africa, Asia, Latin America, and the Caribbean. It also occurs in non-endemic parts of the world, such as Britain and the US, as people travel to and from infected areas.

The direct and indirect costs of malaria in Africa alone are estimated to exceed $2 billion due to decreased productivity and increased health care costs.

Types of Infection

Malaria may occur in either acute or chronic forms and is caused by protozoa of the genus Plasmodium, which are obligate intracellular parasites. here are four species of Plasmodium, P falciparum, (causes 85% to 90% of cases in Africa, also occurs in SE Asia and South America), P vivax, (Asia and central Africa and America) P ovale (West and South Africa and West Pacific) and P malariae (infrequent). Almost all deaths and most complications result from P falciparum infection. However, mixed infections are possible. P falciparum can override other species, and when the primary protozoa are eradicated, the others, which have remained untreated, can flare up. While the incubation period is usually 7 to 14 days, the disease can remain dormant and appear many months after the initial infection.

Pathophysiology

The cycle of malarial infection in humans is sketched in Figure 1. Malaria is transmitted by the bite of an infected female Anopheles mosquito. In humans, the parasite multiplies in two stages, first in the liver and then in blood cells. Sporozoites, which form the infective stage of the parasite, are injected during feeding into the host’s blood stream. Many sporozoites enter the liver where asexual multiplication occurs to produce thousands of merozoites. (One parasite cell in the liver stage produces 10,000 in P vivax and 30,000 in P falciparum merozoites.) A tissue schizont is formed which ruptures 6 to 16 days after the initial infection and releases merozoites into the circulation. The merozoites then invade the erythrocytes forming trophozoites, which exist initially in small and rounded ring forms. After a period of growth (one parasite produces 12 to 32 new parasites), the parasites become irregular, adopt a crescent shape, and undergo nuclear division producing and releasing merozoites into the circulation. This process is continuously repeated. The liver stage of the parasite can become dormant, only to reemerge after 1 to 18 months (P vivax, P ovale). Recurrence in P falciparum (under one year), and P malariae (up to 50 years), is due to re-emergence of parasites living at very low levels in the blood.

After entering the human host, instead of dividing, some parasites form sexual cells called gametocytes. These cells are ingested by feeding mosquitoes and fertilized in the stomach to form ookinetes, which are forced through the gastric wall to the body cavity. Sporozoites develop and settle in the salivary glands, ready for injection back to the human host.

The primary event in the pathogenesis of clinical malaria was once thought to be adherence of trophozoite and schizont infected erythrocytes to capillary endothelium, a process known as sequestration. With maturation, red cells containing P falciparum parasites develop knolls that contain histidine-rich proteins. The phenomenon enhances microvascular obstruction and pathology produced by the parasites, and removes mature P falciparum from the circulation such that only early asexual erythrocyte stages such as rings are detected on peripheral blood smears.

Although sequestration is still believed to be a primary pathogenetic mechanism, the role of cellular mediators (cytokines) released from infected erythrocytes is now thought to be of equal or greater importance. Circulating levels of tumor necrosis factor (TNF) are elevated in patients with cerebral malaria and correlate with death. Massive release of TNF into systemic circulation can cause hypotension, lactic acidosis, septic shock, mucosal gut damage, increased pulmonary microvascular permeability and neutrophil aggregation in the lung. TNF also plays a key role in triggering the release of other cytokines, notably IL-1, IL-6, and IL-9.

A definitive diagnosis of malaria can be made only by detection of parasites in the peripheral blood. Thick blood films enable better detection than thin films at low levels of parasitemia but examination requires greater skill and there is a higher incidence of error. Errors in microscopy can occur, and patients in whom repeated blood films are negative despite a strong clinical suspicion of disease should have a fine needle bone marrow aspirate performed for diagnosis.

Clinical Features

The clinical features of uncomplicated malaria are generally non-specific, consisting of fever, malaise, weakness, chills, dizziness, diarrhea, myalgia, and headache. Presenting symptoms in children may include cough, tachypnea, and even convulsions. Hypoglycemia is not uncommon. Although a very high temperature (>40oC) is typically associated with malaria fever, it is remitting and the patient is often apyrexial when examined. Fever is probably due to release of toxins when infected cells rupture. Hepatomegaly or splenomegaly is found in approximately one third of patients. Anemia is caused by destruction of both infected and uninfected cells by the parasite. Renal failure develops when capillaries clot and kidneys can no longer filter toxic wastes.

It is of paramount importance to distinguish between patients with uncomplicated and severe malaria, as the latter are at considerable risk of dying and require meticulous preoperative assessment. Features indicative of severe disease are outlined in Table 1. Differential diagnosis should consider such diseases as influenza, typhoid, dengue fever, meningitis and septic shock.

Treatment

Antimalarial chemotherapy should be commenced at the earliest possible opportunity. Strong clinical suspicion of severe malaria warrants chemotherapy even if the initial blood smear is negative. Oral therapy is used for uncomplicated disease and intravenous therapy for severe malaria. Parenteral quinine remains the mainstay of treatment in severe falciparum malaria, particularly in chloroquine resistant areas. It is generally well tolerated. Commonly occurring side effects of quinine therapy include cinchonism and hypoglycemia, which can be attributed to enhanced stimulation of pancreatic insulin secretion. Signs of severe quinine toxicity are rare and include myocardial conduction abnormalities, hypotension, blindness, deafness, and coma. It is generally considered unjustifiable to stop treatment even in the presence of persistent side effects since the hazards of uncontrolled falciparum malaria far outweigh the lesser hazards of therapy. The administered dosage however, may have to be modified.

If parenteral quinine is not available then quinidine, the dextrotary optical isomer of quinine, is probably the next best choice. Quinidine is more readily available but is more toxic. Its efficacy has been well documented in Thailand where decreasing sensitivity to quinine has prompted a search for more potent agents. The major side effects of quinidine are cardiac conduction abnormalities related to a prolongation of the QTc interval. Chloroquine is the cheapest and most rapidly acting, and gives fast symptomatic relief. Resistance is common, however, and it does not eradicate the parasite. It may be used in conjunction with pyrimethamine-sulphadoxine (S-P), which is a convenient single dose treatment for uncomplicated malaria. Side effects include vomiting and skin rashes. Mefloquine is used to treat malaria resistant to chloroquine and S-P, and is expensive. Artemisinin, which includes the derivatives artesunate and artemether, and amodiaquine are used for uncomplicated malaria, resistant to other agents. As most common drugs deal with the blood phase of the infection, species that have dormant liver phases, (Vivax and Ovale), may not be eradicated. Primaquine is successful in removing hepatic residue.

The use of exchange transfusion for the treatment of cerebral malaria was first described by Gyr in 1974 and has since gained increasing acceptance as an adjunct to conventional drug therapy in severe or complicated cases. Although all previous reports of exchange transfusion have been essentially favorable there is still no trial data to conclusively support its use. Furthermore, the indications for its use, mechanism of action, and optimal method of exchange, remain unknown. Exchange transfusion offers a number of possible benefits when compared to conventional medical therapy. It facilitates a rapid reduction in parasite load over a short time without the accompanying hemolysis associated with medical treatment. A rapid reduction in parasitemia may halt the progression of deleterious pathophysiological changes in the microcirculation with a concomitant improvement in rheology, hemodynamics, and oxygen transport and reduction in cytokine release.

Almost all patients with P virax, P ovale or P malarial infection respond well to chloroquine and should make an uneventful recovery. In patients with P falciparum infection, the best prognostic indicator is the quantitative parasite count. Patients with 5% or greater parasitemia (>250,000 parasites per ml of blood) are at increased risk of severe complications. (The maximum parasite density achieved by P falciparum prior to death is 2 million parasites per ml or 40% infected red blood cells). These patients should be considered for exchange transfusion if there is no response to quinine or other commonly used agents in 12 to 24 hours.

Prophylaxis of malaria is very important and consists of chloroquin, mefloquine, doxycycline, primaquine, or hydroxychlorquine sulfate. The drugs are taken one week before arrival in the malaria risk area, once a week while in the region, and then once a week for 4 weeks after the return home. Minimal side effects are associated with this dosage regimen, and consist of nausea, headache, blurred vision, and itching. Chloroquine may worsen the symptoms of psoriasis. The drugs should be taken after eating.

Preoperative Considerations

Malaria is a multifactorial disease that is partially explained by the magnitude of the parasitemia. P falciparum can invade red cells of any age and produce unrestricted parasitemias involving more than 20% of uncirculating red cells. On the other hand, P virax and P ovale invade only young cells limiting parasitemia to <25,000 per cubic millimeter. P malarial attacks older red cells amounting to invasion of > 10,000 per cubic millimeter. Because of the repetitive nature of malaria, the immune response to infection is reduced and an inadequate host immune cycle develops.

As the pathology of severe malaria is that of a microvascular disease involving many organs, including the brain, lung and kidney, there are several complications that have a major effect on anesthetic care.

Central Nervous System

Coma as a result of cerebral malaria is the worst complication of P falciparum infection. Causes combine microvascular obstruction, hypoglycemia, and the effects of cytokines, especially TNF. Intracranial pressure may be very high and cerebral perfusion pressure greatly reduced. Cerebral autoregulatory mechanisms are frequently disturbed. Seizures may occur, especially in children. Adequate dilantin levels should be achieved. While general anesthesia and control of the airway are essential, the technique should focus on agents that cause least intracranial perturbations. Mannitol and furosemide should be available.

Cardiovascular System

Myocardial function is generally thought to be well preserved although hemodynamic data to support this belief is scanty. Early pathological studies have described blocking of the coronary vessels with parasites and pigments, fatty degeneration of the myocardium and myocardial changes similar to those found in diphtheritic myocarditis. In view of these findings it would be unreasonable to expect universally good myocardial function in patients with severe malaria, particularly since TNF acts as a direct myocardial depressant. Monitoring with a pulmonary artery catheter may be indicated. Myocardial function support including inotropes and even balloon counterpulsation may be indicated.

Pulmonary System

Pulmonary edema is a common complication of severe malaria, and once it has occurred is associated with a particularly grim prognosis. It is thought to result from fluid overload, increased plasma oncotic pressure, increased pulmonary capillary permeability, or a combination of these factors. Whilst there have been several reports of pulmonary edema occurring in the presence of a normal or low pulmonary capillary wedge pressure there is little doubt that iatrogenic fluid overload contributes substantially to the high mortality associated with this condition. The first clinical indication of impending pulmonary edema is usually an increase in the respiratory rate, which precedes the development of other ventilatory changes. Usually, hemodynamic measurements indicate that the pulmonary edema is of a noncardiogenic form. These findings, and the association with high TNF levels suggest that the pathogenesis of pulmonary edema may be similar to that of bacterial septicemia. Renal Function

Renal dysfunction in severe malaria is common and is usually due to acute tubular necrosis. Some patients may present with pre-renal failure and renal function may be restored to normal with rehydration. Renal failure is typically oliguric and is strongly associated with hyperparasitemia, jaundice, and hypovolemia. The mechanism by which renal dysfunction occurs remains uncertain. Sequestration of parasitized red cells occurs in the glomerular capillaries although it is not as pronounced as in other organs such as the brain.

Hematologic System

Anemia, an inevitable consequence of severe malaria, occurs due to destruction of red cells combined with marrow dysplasia and correlates with the degree of parasitemia and total serum bilirubin levels. Tumor necrosis factor may play a direct role in depressing erythropoiesis. Thrombocytopenia occurs commonly in both mild and severe falciparum malaria and is not particularly associated with disease severity. Furthermore it is not usually associated with bleeding or other abnormalities of coagulation. Clinically significant coagulopathies occur in only 5% of adult patients with cerebral malaria and occur mainly in individuals with no natural immunity. It is only this group that may require replacement of clotting factors. Blood transfusion should be considered if the hematocrit falls below 25% but caution should be taken as pulmonary edema may be precipitated. Hemodynamic monitoring with a pulmonary artery or central venous pressure cannula is advisable and will act as an invaluable guide to blood replacement and diuretic therapy.

Gastrointestinal Effects

Diarrhea is especially common in children with P falciparum infection. Postmortem studies have shown parasitized red cells in the microvasculature of the intestine. Dehydration, hypoglycemia, hypoproteinemia, electrolyte imbalance, and anemia are common complications.

Liver Function

Jaundice and deranged liver function tests are extremely common findings in patients with moderate and severe malaria. Generally, no specific treatment is required. Jaundice is usually non-obstructive and occurs as a consequence of intravascular hemolysis. Levels of both total and indirect bilirubin are elevated. Only when levels of bilirubin are very high, does hepatocyte dysfunction occur and levels of conjugated bilirubin rise. Decreased blood flow in the hepatoportal system has been demonstrated during severe malaria4 and it seems likely that this change reflects erythrocyte sequestration.

Hypoalbuminemia

Hypoalbuminemia is an almost universal finding in patients with severe malaria. Since malnutrition does not appear to increase susceptibility to severe falciparum malaria, hypoalbuminemia may be a dilutional effect reflecting an increased circulating plasma volume.

Hypoglycemia

Hypoglycemia occurs frequently in severe malaria. Patients particularly at risk include pregnant women and those in the hospital for more than 48 hours. Quinine is one of the most potent in vitro stimulants to pancreatic insulin secretion, and glucose consumption may be increased due to fever and infection. Impaired gluconeogenesis due to lactic acidosis, reduced hepatic blood flow, or endotoxemia may also contribute to hypoglycemia.

Assessment

Preoperative assessment should be directed towards determining the severity of the disease state (Table 1). The type of parasite and percentage parasitemia are useful indicators of severity. Non-immune patients, such as those normally living in non-endemic areas and those traveling without appropriate chemoprophylaxis, as in the current case, are at particular risk. The following biochemical tests are appropriate:

1. complete blood count

2. urea and creatinine levels

3. electrolyte determinations

4. glucose

5. coagulation profile

6. albumin

7. liver function tests

8. type and cross match for blood and blood products.

It is mandatory to ensure baseline blood samples have been assessed for liver function tests since these are invariably abnormal and accurate documentation is essential for both monitoring disease progression and for medico-legal reasons. Arterial blood gas analyses, electrocardiography, and chest radiograph should also be requested and interpreted.

Thrombocytopenia is such a common finding in severe malaria that platelet transfusion will almost always be required. Generally each unit of platelets increases the serum count by 5000 to 10000/mm. The minimum platelet count below which the risk of bleeding contraindicates surgery ranges from 50,000 to 75,000 mm3, with an upper level of 100,000mm. Other abnormalities of coagulation are unusual and other replacement factors are rarely necessary.

Careful assessment of the patient’s conscious level is essential and the Glasgow coma scale must be recorded. The patient with impaired neurological function preoperatively is likely to deteriorate postoperatively. Many centers perform exchange transfusion in severe falciparum malaria, and since this procedure is associated with an improved level of consciousness it should ideally be undertaken prior to administration of general anesthesia. As noted above, opinion is divided on the absolute indications for performing exchange transfusion, although the case presented here of a nonimmune patient with a marked parasitemia and confusion is representative of the type of patient who would most likely benefit.

Premedication and administration of sedative drugs is probably better omitted in all but uncomplicated cases of malaria and should certainly not be used in any patient presenting with drowsiness prior to securing the airway. Even slight respiratory depression will increase arterial carbon dioxide levels and cause cerebral vasodilation that may result in herniation in a patient in whom the intracranial pressure is already markedly elevated.

Anesthetic Plan

Abnormalities of hepatic function preclude the use of halothane, although inhalation agents with minimal degradation such as desflurane are acceptable. Atracurium or cis-atracurium because of Hoffman elimination, should be used as the relaxants of choice if there is preexisting renal dysfunction. The presence of thrombocytopenia advises against the use of a regional technique unless general anesthesia is absolutely contra-indicated or adequate platelet transfusion has been given.

Meticulous attention should be paid to fluid balance and central venous pressure monitoring employed for any procedure where fluid shifts may be anticipated. Several workers have suggested that the central venous pressure should not be allowed to rise above 5 cmH2O. Particular care should be taken not to administer any excess fluid as these patients are especially prone to develop fatal pulmonary edema. Blood loss during the procedure should be replaced preferably with whole blood to reduce the circulating parasite count and possibly also reduce levels of TNF.

Hypoglycemia associated with falciparum malaria is often refractory to treatment and an infusion of 10% dextrose together with regular assessment of blood glucose levels is advisable. To ensure adequate access to timely sampling, an arterial cannula should be inserted.

In addition to usual monitoring, temperature monitoring should be employed routinely for all cases, as patients frequently present preoperatively with temperatures in excess of 40oC. Any later concern regarding the possible onset of malignant hyperpyrexia may thus be obviated. A more recent study has emphasized the correlation between the unconsciousness produced by cerebral; malaria and general anesthesia as reflected in the auditory evoked response (AER). In a study of 6 patients with cerebral malaria, the early complex of the AER, Pa/Nb/Pc was clearly represented and was similar to the AER observed at light planes of general anesthesia. Similar changes were also seen on awakening from anesthesia and on reversal of coma. The AER showed an arousal effect on unresponsive patients on auditory stimulation. The authors felt that the AER might be a valuable monitoring tool for patients, unconsciousness from cerebral malaria.

Assessment of level of consciousness forms an important part of immediate postoperative care. Patients should not be discharged to the ward unless they are awake and alert and have regained or exceeded their preoperative level of consciousness. If total circulating albumin is reduced, decreased protein binding of drugs such as sodium thiopental may result, leading to prolonged unconsciousness, as more of the pharmacologically active agent is available.

Patients who are suffering from malaria may be receiving many medications. Dapsone is used to treat several systemic inflammatory diseases such as leprosy, lupus erythematosus, and pemphigus, and has also recently been used prophylactically alone or in combination against malaria and AIDS. Induction of general anesthesia may be complicated by methemoglobinemia, albeit an unusual side effect. Recognition and prompt therapy with intravenous methylene blue are, however, important.

Finally it should be remembered that malaria can be transmitted via needle-stick injury and universal precautions should be adopted including special care in disposing of sharps. However, post-transfusion malaria has never been a significant cause of blood recipient morbidity.

Management of the Case Presented

Examination of a peripheral blood film revealed infection with Plasmodium falciparum with a parasitemia of 50%. Antimalarial therapy was started immediately with quinine, sulphadoxine, and pyrimethamine. Because of the low hemoglobin and platelet counts, the patient was transfused with whole blood and platelets prior to surgery. MRI of the head indicated markedly raised intracranial pressure. Following intubation and sedation, an intracranial pressure (ICP) monitor was inserted. ICP was measured at 22mmHg. A Foley catheter was inserted and the patient given mannitol and furosemide. Anesthesia was continued with low dose isoflurane and fentanyl infusion. No muscle relaxants were required. The fracture was reduced according to surgical protocol. Postoperatively, the patient was monitored in the intensive care unit. ICP returned to normal within 24 hours and the trachea was extubated successfully. The patient made an uneventful recovery.

Conclusion

The presence of malaria should be suspected whenever a patient presents with otherwise unexplained fever, malaise, and history of recent travel in a country where malaria is endemic. The disease exerts multisystem pathologic effects. Careful preanesthetic evaluation, as well as preoperative documentation of laboratory abnormalities, is necessary. General anesthetic techniques are usually preferable to regional anesthesia.


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