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- severe
- Potentially lethal multi-system disease.
clinical manifestations depend on age. Hypoglycaemia, convulsions and severe
anaemia are relatively more common in children. Acute renal failure, jaundice
and pulmonary oedema are more common in adults
- cerebral malaria (ie malaria causing coma), shock, and acidosis, which often
terminate in respiratory arrest may occur at any age
Aetiology
- infection with P. falciparum
- for practical purposes does not occur with P.vivax, ovale and malariae
Epidemiology
- Asia, parts of Greece, Turkey, Middle East, Central & S. America
- people who live in an endemic area acquire a degree of immunity which
decreases with time
- high risk groups: travellers, emigrants returning home from a long spell
abroad whose immunity has elapsed, pregnant women, immunosuppressed
Pathogenesis
- not fully understood
- result of complex interactions within vasculature mediated by humoral,
vascular and haematological factors
- an immune mediated inflammatory reaction releases vasoactive products which
cause endothelial damage
- trophozoites within RBCs induce changes in RBCs as trophozoites mature that
makes them capable of adhering to vascular endothelium. Results in sequestration
of RBCs in small cerebral venules, microvascular congestion and tissue hypoxia
- not clear whether cerebral oedema plays a significant role
- hypoglycaemia is an important complication of cerebral malaria and may
contribute to decreased level of consciousness
Clinical features
- patients usually have been ill for days and are pyrexial
- however sometimes onset is abrupt and very ill patients may be hypothermic
Fluid balance
- state of hydration of patients on admission is quite variable
- thin dividing line between over and underhydration
- adults in particular may have noncardiogenic pulmonary oedema and are
vulnerable to fluid load
- dehydration and hypovolaemia contribute to hypotension and shock (particularly
in children) and may hasten acute renal failure (particularly in adults)
- when acute renal failure develops with other evidence of vital organ
dysfunction, renal replacement therapy should be started quickly
Hypoglycaemia
- approx 8% of adults and 25% of children
- after rehydration 5-10% glucose should be given to all patients
Haemolysis
- extensive and anaemia develops rapidly
- blood should be transfused if Hct < 20%
- transfusion of fresh blood preferable, particularly if there is marked
bleeding due to DIC (occurs in approx 5%) or stress ulceration
Cerebral malaria
- suspect any person from an endemic area with cerebral symptoms or signs of
having cerebral malaria
- conscious level always impaired
- evidence of an organic brain syndrome: hallucinations, delirium, psychosis; in
some complicated by motor signs and movement disorders
- +/- meningism and opisthotonus (NB bacterial and other forms of meningitis may
coexist with malaria and LP should be performed to exclude these)
- convulsions common. Incidence ranges from >80% in children to <20% in
adults
- failure to regain consciousness after 2 h after febrile convulsion in a child
should raise the suspicion of cerebral malaria
- consider cerebral venous thrombosis in patients with cerebral malaria who
have focal signs
Bacterial infections
- common
- pneumonia likely if duration of coma > 3 days
- UTI
- occasionally spontaneous (usually Gm -ve) septicaemia
- systemic salmonella infections may develop in patients with otherwise
uncomplicated malaria
- if the condition of a patient with severe malaria suddenly deteriorates
without an evident cause hypoglycaemia should be ruled out, blood cultures
performed and empirical therapy with broad-spectrum antimicrobials started
Investigations
- microscopy
of thick and thin blood films at a magnification of 1000. If
species is uncertain it should be considered to be P. falciparum.
Parasites should be counted. In severe malaria the developmental stage of the
parasites and the percentage of neutrophils containing malarial pigment should
be noted. Negative blood smear makes diagnosis of malaria very unlikely but if
there is still uncertainty the test should be repeated every 12h for 48h
- simple test strip for finger-prick blood samples, which uses a monoclonal
antibody to P. falciparum histidine-rich protein 2, has a diagnostic
sensitivity similar to that of microscopy
- hyperbilirubinaemia. Not usually associated with raised transaminases
Prognosis
- can kill within 72 h if not treated
- mortality 25-50% with treatment
- delay in treatment is major factor contributing to poor outcome
Features indicating poor prognosis in severe malaria
Mortality in excess of 90% in patients with four or more organ failures.
Clinical features
- impaired consciousness. The deeper the coma the worse the prognosis
- 3 or more convulsions in 24h
- respiratory distress
- substantial bleeding
- shock
Biochemical features
- creatinine 265 m
mol/l or more
- bilirubin >43 m mol/l. Combination of deep
jaundice and renal failure associated with a particularly grave prognosis
- metabolic acidosis (bicarbonate <15 mmol/l)
- hyperlactataemia (venous lacate >5 mmol/l)
- hypoglycaemia
- aminotransferase >3 times normal
Haematological
- parasitaemia (>500 000 parasites/ml or >10 000 mature trophozoites and
schizonts/ml) Trophozoites are mature parasites in which pigment is visible
under light microscopy
- ³ 5% of neutrophils contain malaria parasite
Treatment
- control convulsions with diazepam
- airway control
- IV mannitol or ventilation to PaCO2 < 4 kPa if signs of
deepening coma or tentorial herniation ± CT to
confirm cerebral oedema
- steroids prolong coma, increase GI bleeding, increase incidence of infection
and do not improve mortality
- no evidence to support the routine use of LMW dextrans, heparin, epinephrine,
cyclosporin A, prostacyclin or oxpentifylline
- prophylactic IM phenobarbitone decreases incidence of seizures but optimal
dose not known
- paracetamol for pyrexia
- consider if the patient is seriously ill and parasitaemia exceeds
15%. Should be considered even if parasitaemia only 5-15% if there are other
signs of poor prognosis
- but meta-analysis suggests that exchange transfusion does not alter
outcome
Anti-malarials
- chloroquine-resistant P. falciparum or origin unknown: quinine 20 mg of
salt/kg in 10 ml/kg isotonic fluid over 4h then 10 mg/kg over 4h 8-12 hrly
until patient can swallow
OR (ICU only): 7mg of salt/kg over 30 min then 10 mg/kg in 10 ml/kg isotonic
fluid over 4h 8-12 hrly until patient can swallow
OR (ICU only): quinidine 6.2 mg of base/kg IV over 1-2 h then 0.012mg/kg/min
by infusion pump for 72 h or until patient can swallow then quinine tablets to
complete 7 days treatment
- daily ECG. Decrease dose of quinine if QTc>0.6 secs or >25%
widening of QRS
- chloroquine sensitive: chloroquine 10 mg base/kg (max 600 mg) in isotonic
fluid by infusion over 8h followed by 15 mg/kg (max 900 mg) over 24 h
OR quinine as above
Quinine is preferable to quinidine because the latter has a fourfold greater
effect on the heart. IF quinidine is used the corrected QT interval should be
monitored and the infusion rate slowed if the QTc is prolonged by
>25% of baseline
- Principal adverse effect of both quinine and quinidine in severe malaria is
hyperinsulinaemic hypoglycaemia. Usually develops after at least 24h of
treatment and is a particular problem in pregnant women.
- Pharmacokinetics of quinidine and quinine are altered in malaria with a
contraction in the volume of distribution and a reduction in clearance that is
proportional to the severity of the disease. Doses should be reduced by 30-50%
after the third day to avoid accumulation of the drugs in patients who remain
seriously ill
Artemisinin and its derivatives are an alternative to cinchoma alkaloids.
Their exact place in the management of severe malaria is not yet clear.
Further reading
http://www.dpd.cdc.gov/dpdx/HTML/Malaria.htm
http://www.rph.wa.gov.au/labs/haem/malaria/treatment.html
Krishnan A et al Crit Care Med 2003; 31:2278-84
http://www.mmv.org
© Charles Gomersall November 1999, February 2004
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