FALCIPARUM MALARIA IN ICU

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1 18 : 2 FALCIPARUM MALARIA IN ICU Abstract Malaria since its inception in medical literature has always been a nightmare to the human race. Though currently we know that 4 species affect humans, recently a new species has been discovered, plasmodium knowlesi which also causes a significant disease in humans. P falciparum malaria exhibits varying clinical presentation ranging from a mild infection to a fulminant presentation viz cerebral malaria, acute renal failure, ALI/ARDS, severe anemia, hypoglcemia and coagulopathy. Untreated it leads to severe morbidity and mortality. Malaria is a global problem, creating a menacing health problem worldwide. The gravity of malaria is largely due to increased risk of transmission in areas where malaria control has declined with prevalence of drug resistance cases largely due to misuse/ indiscriminate use of antimalarial drugs creating drug resistant strains, increasing international travel and immigration of people from endemic areas. It is postulated that international travel and immigration would lead to approximately 10,000 to 30,000 travellers contracting malaria. Table 1 : WHO criteria for severe falciparum malaria. Cerebral Malaria Unarousable coma(gcs <11/15), with peripheral falciparum parasitemia after exclusion of other causes of encephalopathy. Severe anaemia Normocytic anemia with Hb < 5 gm/ dl, PCV <15% in presence of parasitemia >10000/ml. Respiratory distress Pulmonary oedema or ARDS, now Renal failure also include rapid laboured acidotic breathing. Hypoglycemia Circulatory collapse Urine output < 400 ml in 24 hours Coagulation failure and S. creatinine >3 mg/dl. Whole blood glucose <40 mg/dl. SABP <70mmHg. Spontaneous bleeding and/or laboratory evidence of DIC. Complicated Malaria Impaired consciousness of any degree, prostration, jaundice, Such patients should be managed as severe malaria, with parenteral antimalarials even though they may intractable vomiting, parasitemia 2% not meet with the criteria of severe in non immune individuals ie no disease. previous malaria. Ashit Bhagawati, Mumbai We know that there are 4 plasmodium species of malaria viz P Falciparum,P Vivax, P Ovale and P Malariae which infect human population. A fifth species P knowlesi has recently been identified as a clinically significant pathogen in humans. Almost all patients of severe malaria are caused by P falciparum, with a reasonably high degree of morbidity and mortality. Statistics have shown that notwithstanding the type of malaria, annual clinical caseload is estimated around million people/year, resulting in 1.5 to 2.7 million deaths annually. Almost all deaths are due to falciparum malaria. Rarely P vivax or P ovale cause serious morbidity and death. Among the case load of falciparum infection, 90% of the cases ocur in Africa, followed by Asia, with approximately 80% of cases occurring in India. Case fatality rates due to falciparum is steadily increasing in our country, with an estimated range between 10-50% of critically ill patients admitted in ICU of falciparum malaria. When one talks of severe falciparum malaria being admitted to ICU possibilities of cerebral malaria, acute renal dysfunction,,severe anemia, impending respiratory failure(acute Lung Injury/ARDS) and /or coagulation disorder immediately comes to our mind. In 2000 WHO revised the criteria to define severe falciparum to assist future clinical and epidemiological studies. Table 1. Pathogenesis Falciparum malaria, unlike other forms of malaria contributes to severe pathogenicity. Several reasons contribute to its increased pathogenicity. Unlike other species of malaria which infect either new or old RBC,P falciparum malaria is able to infect RBCs of any age, leading to high parasite burden and severe anaemia. Infection due to Falciparum malaria lead to membrane protrusions on the RBC surface hours after cell s invasion. The protrusions or knobs extrude a high molecular weight, antigenically variant, strain specific protein erythrocytic membrane adhesive protein(pfemp1) which facilitates adherence to receptors on the venular and capillary endothelium, a phenomenon termed as cytoadherence. PfEMP1 binds to ligands on endothelial cells, includ-

2 Medicine Update 2010 Vol. 20 RBC deformability Protrusions/knobs on RBC membrane Adhesion to the Venular Endothelium P. Falciparum Microvascular Sequestration of Parasitized RBC Infects RBC s of all ages High levels of Parasitemia Release of Inflammatory Mediators (TNF-α, interleukin - 1, kinins, etc.) Up regulate and activation of endothelial adhesion molecules, (Intracellular adhesion molecules, E-Selectin) Sluggish Flow Obstruction Impaired O 2 delivery ORGAN DYSFUNCTION Fig. 1 : Pathogenesis ing CD36, thrombospondin, vascular adhesion molecule-1 (VCAM-1),intracellular adhesion molecule -1 ( ICAM-1), and E-selectin. The infected RBCs thus stick inside and eventually block capillaries and venules. The parasitized RBCs may at times adhere to uninfected RBCs to form rosettes and to other parasitized RBCs (agglutination). This results in sequestration of RBCs containing mature form of the parasites in vital organs particularly the brain. This compromises the microcirculation and metabolism of the tissues causing ischemia leading to organ dysfunction/failure. The parasites also stimulate the production of high levels of cytokines, including TNF,interleukin-1 and kinnins. Merozoite surface antigens are also released from infected red blood cells by a poorly understood mechanism, which also induce cytokine production. These cytokines suppress production of RBCs, increase fever, induce nitric oxide production, leading to tissue damage. There is upregulation and activation of endothelial adhesion molecules increasing sequestration and adhesions to vascular endothelium. Eventually this leads to microvascular sequestration of parasitized RBCs, causing sluggish blood flow, obstructruction and impaired O2 delivery. The end result is organ dysfunction/ organ failure leading to morbidity or mortality. (Figure 1.) Approach to Management of Falciparum Malaria As mentioned in (Table 1), regarding presentation of falciparum malaria, it provides major challenge to the intensivist in management. Eradication of malaria with use of approved antimalarials may not pose a major issue as managing the complications of falciparum malaria. Approach to such patients would therefore include the following Table 2 Clinical presentation Assessment parameters Impaired Consciousness GCS 11 or Blantyre scale 3 Severe pallor Conjunctiva, tongue, lips and palm are pale Oliguria, Anuria/ARF Jaundice with evidence of other multiple organ dysfunction U/O <400ml/24hrs in adults Yellow discolouration of sclera Hypoglycemia Anxiety, sweating, Blood sugar<40mg/dl palpitations, altered sensorium, convulsions, shortness of breath. Hyperparasitemia Malarial index 20% in periphertal smear. Prostration Unable to sit, feed, walk stand unaided. strategy, 1. Clinical manifestations and their laboratory findings. 2. Diagnosis of malaria. 3. Treatment Clinical manifestations and laboratory findings. Severe falciparum malaria being admitted to ICU several possibilities come to our mind viz: cerebral malaria, acute renal dysfunction,,severe anemia, impending respiratory failure(acute Lung Injury/ARDS) and /or coagulation disorder, acidosis or acidemia, immediately comes to our mind. These presentations have their tell-tale laboratory findings, (Table 2). Detection of Malaria Laboratory parameters CSF normal Hb < 5gm/dl, PCV < 15% S creat >3 mg/dl in adults S bilirubin >3mg/dl Circulatory collapse SABP<70mmHg; with cold extremities & feeble pulse Metabolic acidosis Kussmaul s breathing ABG ph,7.35, plasma HC03 <15 mmol/l; venous lactate >5mmol/l ALI/ARDS Seizures Spontaneous bleeding Haemoglobinuria Tachypnea, dyspnoea, bilateral basal rales. Myoclonic jerks of the limbs, 2 or more convulsions in 24 hours. Various sites-viz: gums, DIC nose venepuncture sites, GI bleed Dark red or black coloured urine Xray Chest -Bilateral pulmonary infiltrates. CSF normal Urine positive for haemoglobin Besides clinical parameters, malaria can be detected in blood by light microscopy or immunological tests for parasite derived 862

3 Falciparum Malaria in ICU proteins (or rapid diagnostic tests:rdts). Giemsa or Field-stained thick and thin blood smears should be examined in all patients of suspected malaria. RDTs are recommended when microscopy is not available or inconclusive. These are based on detection of P falciparum specific circulating proteins in the whole blood. The commonly used proteins are histidine-rich protein-ii (PfHRP II or HRP-II) and the recently developed parasite lactate dehydrogenase (pldh). HRP-II detects antigen of live and dead parasites, while pldh can detect live parasites. Treatment General Measures Suspected patients of malaria should be subjected to a rapid solid assessment with emphasis of their neurological status, vital parameters and O2 saturation. Admit the patient in the intensive care unit. Donot wait for parasitological confirmation, if it is likely to get delayed. Start immediately on specific anti-malarial therapy on basis of clinical diagnosis. Give antimalarial therapy intravenously. If not possible give intramuscularly, provided platelet counts are adequate. Rectal suppository formulations of artemisinins are available and can be used when parenteral administration is not possible. Start oral antimalarials once patient can swallow and retain the tablets. Calculate dosage as mg/kg of body weight before administration of the medication. Provide proper general nursing care to the patient particularly if the patient is unconscious. Maintain ABC ie airway, breathing and circulation. Monitor vital parameters of the patient including O2 saturation. Measure core temperature of the patient. Reduce high body temperatures. Maintain proper intake /output chart. Watch for oliguria/ anuria. Insert a urinary indwelling catheter to monitor the hourly urine output by sterile precaution. Insert a feeding nasogastric tube, for medication administration, to check for upper GI bleeding and for providing feeds to the patient. Insert central venous pressure line for CVP monitoring, fluid administration to prevent over or under hydration. Check HGT levels at frequent intervals to prevent hypoglycaemia. Correct if hypoglycaemia developes. Maintain neurological assessment including Glasgow Coma Scale. Worsening of neurological parameters or development of seizures needs immediate medical attention. Monitor the therapeutic response, both clinical and parasitological, by regular observations and blood films. Monitor haematocrit values, Hb concentration, glucose, renal parameters, electrolytes and ABG at regular intervals. Avoid drugs that increase risk of gastrointestinal bleeding or cause nephrotoxicity. Antimalarials Anti malarials specific for falciparum malaria are administered. Monitor the therapeutic response, both clinical and parasitological, by regular observations and blood films. Chloroquine resistance is now global and hence it is advisable to treat all patients with severe malaria with artemisinin derivative with or without quinine. However the National Drug Policy on Malaria (2007) recommends that in severe and complicated cases of falciparum malaria, IV quinine is still the drug of choice. The revised guidelines released by WHO for treatment of Malaria recommend the use of artemisinin compounds for severe falciparum malaria. The drug offers a potent, rapid antimalarial activity with a wider therapeutic window along with an absence of clinically important drug resistance. The artemisinins kill all species of plasmodium that infect humans. The compound not only target the early ring stages of plasmodia, but also prevent maturation of ring stages, thereby inducing rapid clearance and reduction of cyto-adherence of the parasite. They are also effective against early gametocyte stages of development, thereby interfering with mosquito transmission. Unlike artemisinin derivatives, quinine has a narrow therapeutic window. It acts on the middle third life cycle of the parasite and does not prevent parasite maturation which cause cyto-adherence. Also significant toxic effects like cardiotoxicity, cinchonism, hyperinsulinemic, hypoglycaemia and painful local reactions post intramuscular administration is a cause for concern. Also recent studies particularly from South-East Asia, have shown reduced efficacy as well as resistance to quinine. The artemisinin compounds are available as artesunate, arteether, artemether, dihydroartemisinin, and artelinic acid. These drugs can be administered orally, parenterally and as rectal preparation. Both arteether and artemether are oil base preparation that release the drug erratically after im administration. Artesunate can be given IV, IM is rapidly and reliably absorbed with peak concentrations reached within I hour. As a result subsequent investigators have focussed their attention on water soluble and pharmacologically superior artesunate in severe malaria Studies have shown that it takes three life cycles (6 days) to completely eradicate all parasite forms. Needless to say the duration of the therapy therefore should be for seven days, as these drugs are rapidly eliminated from the body. Though artesunate is considered as first line of therapy, for treatment of severe malaria, in view of its pharmacokinetics, recrudescence of malaria may occur, it is always essential to use it in combination with another slower acting antimalarial agents. Recommended is a 7 day course of oral doxycycline or clindamycin when doxycycline 863

4 Medicine Update 2010 Vol. 20 is contraindicated as in children and pregnant women. Dose: Artesunate: 2.4mg/kg iv/im (0 hrs, 12 hrs, 24 hrs ) and then daily for 7 days. Quinine: IV 20mg/kg in 100ml of 25% dextrose as a loading dose over 3-4 hrs followed by 10mg/kg in 25% dextrose over 3-4 hrs 8hrly. IM dose is similar to IV dose. Oral dose is 10mg/kg 8hrly x 7 days. Monitor QTc interval. In pregnancy as first line, artesunate and quinine are considered. Artemether should be considered as second line option during second and third trimester of pregnancy. Artemether IM is an acceptable alternative to IV quinine. Artemotil is not recommended unless alternatives are not available. Rectal administration of artemisinins are suggested only when parenteral or oral administration of antimalarials is not possible. Management of Complications a. Cerebral Malaria Cerebral malaria is considered if persistent changes in sensorium is not attributed to bacterial meningitis or viral encephalitis. Variable presentation may occur viz: altered sensorium, insidious in onset or persistent coma after generalized seizure. Meningismus, opisthotonos and disconjugate gaze is frequently seen. Diffuse symmetric encephalopathy with frontal lobe signs may occur. Symmetric UMN signs are common. Hypotonia and acute cerebellar ataxia may occur occasionally. Both decorticate and decerebrate posturing may occur. Brain stem reflexes are usually intact. Fundoscopy may show retinal haemorrhages in 15% of cases. In 30-60% cases discrete spots of retinal opacification may be noted. Papilledema is rare in adults. In less then 5% patients fundoscopy may show cotton wool spots. Principles of management include; Meticulous nursing care of unconscious patient, with emphasis on ABC (airway, breathing and circulation). Maintain accurate record of intake and output. Insert a nasogastric feeding tube and urethral catheter using sterile technique. Record accurately vital parameters including O2 saturation. Maintain neurology charting, GCS score. Watch for convulsions. Treat convulsions as and when they occur using IV diazepam( 5-10 mg slowly)/midazolam( 4mg slowly). If persistent a infusion drip can be given. For repeated and uncontrolled convulsions phenytoin is used (15-20mg/kg IV slowly, followed by 5mg/kg iv 8hrly or 12hrly in divided dose as maintenance). Control pyrexia with tepid sponging and or use of paracetamol. Administer specific antimalarial drugs as mentioned earlier. Caution: Following drugs recommended earlier/used are now not considered to be of beneficial use and must be avoided. Corticosteroids, Anti-inflammatory drugs, Drugs for cerebral oedema (urea, mannitol), Low molecular weight dextran, Adrenaline and Heparin. Mortality is significantly higher in patients with cerebral malaria when associated with other complications, like acute renal failure, ALI/ARDS, jaundice etc. Hence it is mandatory to admit such patients in intensive care unit. b. Anaemia Anemia in malaria is caused by hemolysis due to destruction of parasitized RBC and inhibition of bone marrow production. Anaemia is best treated with pathogen free packed cell volume if PCV falls below 20% or Hb falls below 7gm/ dl. Prevent fluid overload by giving IV furosemide if patient s renal function is adequate and hemodynamically stable. Include the volume of blood transfused in the intake. Monitor Hb and PCV at regular intervals c. Acute Renal Failure Incidence of acute renal failure is approximately 30% of patients with cerebral malaria. Acute renal failure may occur simultaneously with other organ failure in which case the mortality risk is higher. It should be noted that ARF may progress as other disease manifestation may resolve. Contributory factors include: Hypovolemia, renal vasoconstriction, microvascular obstruction due to RBC sequestration interfering with renal microcirculatory flow and metabolism. Hemolysis causes pigment nephropathy. These eventually lead to renal ischemia, acute renal tubular necrosis and finally renal failure. This can be prevented by; Monitor CVP to maintain adequate hydration Monitor and maintain BP. According to BP and CVP either fluids or vasoactive drugs may be required to 864

5 Falciparum Malaria in ICU maintain hemodynamic stability. If fluid overload occurs, judicious use of diuretics (furosemide/torsemide) may be required. If after adequate hydration and hemodynamic stability is achieved, patient still remains oliguric/anuric with worsening renal biochemical parameters; hemodialysis or peritoneal dialysis is actively considered. Avoid administration of sodium-bicarbonate unless associated with severe life threatening acidosis. Caution: Nephrotoxic drugs should be avoided in these patients with renal dysfunction. Assessment of renal function must be done at regular intervals. d. Fluid and Electrolyte Imbalance Asssess for evidence of dehydration (hypovolemia) or circulatory overload as both are detrimental. Correct hypovolemia with fluid administration. Monitor CVP, BP and hourly urine output to assess hydration status. Improve oxygenation by clearing airway, increasing concentration of inspired oxygen. Provide artificial ventilation if required. e. Shock/Circulatory Collapse Some patients with malaria present in a state of circulatory collapse with a systolic BP of < 80 mmhg. Possible contributory factors are Spleenic rupture, Gram Negative Septicaemia, GI bleed, ALI/ARDS or Severe Metabolic Acidosis due to Acute Renal Failure. In these patients; Monitor CVP/BP (preferably intra arterial BP monitoring). Correct hypovolemia with appropriate fluid therapy, if present. If patient does not respond to adequate fluid therapy, and CVP is normal then use vasoactive drugs.(dopamine/noradrenaline). Look for possible sites of infection. Aspiration pneumonia should be considered in any unconscious patient with convulsions. Gram Negative Septicemia should be considered if patient is not responsive to specific antimalarial therapy or if patient deteriorates. Take appropriate Blood culture and start broad spectrum antibiotics. If spleenic rupture is confirmed, emergency spleenectomy is done with volume and blood replacement. f. Jaundice No specific treatment is required for treatment of jaundice. It is seldom fatal, unless associated high bilirubin values, renal failure and cerebral malaria. g. Hypoglycemia Hypoglycemia is an important complication of falciparum malaria. In severely ill patients, hypoglycaemia commonly occurs together with metabolic (lactic) acidosis and carries a poor prognosis. Caution should be exercised in patients on quinine therapy, since quinine induced hyperinsulinemia leads to hypoglycaemia. Equally susceptible are pregnant women, and patients with severe disease. Prevention/Correction of hypoglycaemia is essential particularly in patients on quinine/quinidine therapy. Monitor HGT values. If required administer 50 ml of 50% glucose solution followed by either 5% dextrose or 10% dextrose solution. h. ALI/ARDS(Non-Cardiogenic Pulmonary Oedema) Acute non cardiogenic pulmonary oedema is a fatal complication which occurs in severe falciparum malaria, with a mortality rate as high as 80%. It may also occur in vivax malaria. Pulmonary oedema may also occur due to inadvertent fluid overload. Management involves; Give high concentration of O2 by any convenient method, including mechanical ventilation. Prevent fluid overload. Give IV diuretics if evidence of fluid overload has occurred. If respiratory comprise continues to occur with deteriorating oxygen values on ABG and progressive bilateral diffuse infiltrations on Chest X-ray; Mechanical ventilation needs to be initiated using PEEP, including inverse ratio ventilation and low tidal volumes. i. Coagulopathy and DIC Normally thrombocytopenia occurs in malaria. Deranged liver function can lead to deficit in the production of coagulation factors and albumin. In severe malaria this leads to coagulopathy leading to DIC. Coagulation defects and severity of thrombocytopenia often correlate with the degree of parasitemia. Treat such patients with; Fresh blood transfusion, clotting factors or platelets as required. Give Vitamin K, 10 mg by slow IV injection. j. Hyperparasitaemia Hyperparasitaemia should be considered if parasite density exceeds > 5% in non immune subjects or > 20% in normal individuals. Management of these patients involve; Parenteral antimalarial therapy irrespective whether the the patient can take the medication orally. Even after optimal antimalarial therapy, condition de- 865

6 Medicine Update 2010 Vol. 20 teriorates, exchange transfusion with screened blood should be considered if facility is available. Conclusion Malaria continues to be a major problem in many countries of the world, affecting over 2400 million people the world over who are at risk of infection. Delay in treating P falciparum malaria, it can cause severe forms of the disease, with rapid deterioration in the patients condition and development of life threatening complications including mortality. References 1. Regional Guidelines for management of severe falciparum malaria in large hospitals. WHO October 2006, Regional office for South East Asia, New Delhi 2. Guidelines for diagnosis and treatment of Malaria in India Management of Severe Malaria; A practical handbook 2 nd edition WHO Geneva. 4. Artesunate as first line therapy for severe falciparum malaria: Ravikiran Sonawane, D R Karnad. pgs Critical care update Harrison,s Principles of Internal Medicine. 17 th edition. Chapter 203 pgs Pathologic Basis of disease. Robins and Cotran. 7 th edition. Chapter 8 Infectious disease, pgs

FACTS. Approximately 2.48 million malaria cases are reported annually from South Asia. Of Which 75% cases are contributed by India alone.

FACTS. Approximately 2.48 million malaria cases are reported annually from South Asia. Of Which 75% cases are contributed by India alone. MALARIA 2 FACTS Approximately 2.48 million malaria cases are reported annually from South Asia. Of Which 75% cases are contributed by India alone. The magnitude of the problem is further enhanced by P