>50kg: Paracetamol 1gm PO/NG q6hourly for 72 hours and febrile for 24 hours (maximum total dose 4g/24 hours) plus intravenous Artesunate
<50kg: Paracetamol 12.5-15mg/kg/dose q6hourly for 72 hours and febrile for 24 hours (maximum total dose 5 doses/24hours;75mg/kg) plus intravenous Artesunate

No paracetamol + Intravenous Artesunate
If temperature > 40°C, ibuprofen PO/PR will be administered in the absence of renal impairment and dehydration; 500mg paracetamol PO/PR will be administered in the presence of renal impairment or dehydration. Dengue testing will be done prior to the administration of ibuprofen.

Malaria

>50kg: Paracetamol 1gm PO/NG q6hourly for 72hours and afebrile for 24h (maximum total dose 4g/24 hours) plus intravenous Artesunate <50kg: Paracetamol 12.5-15mg/kg/dose q6hourly for 72hours and afebrile for 24h (maximum total dose 5 doses/24hours;75mg/kg) plus intravenous Artesunate

Paracetamol

No Paracetamol

Chittagong Medical College Hospital

Ramu Upazilla Health Complex

Paracetamol Effect on Oxidative Stress and Renal Function in Severe Malaria

Paracetamol Effect on Oxidative Stress and Renal Function in Severe Falciparum Malaria With Intravascular Haemolysis: A Randomised Controlled Clinical Trial

Compare the effect of therapeutic paracetamol concentrations compared with absent or low paracetamol concentration on renal function, peak creatinine levels or trough creatinine clearance, defined as the change at 72 hours compared to baseline, in patients with severe and moderately severe falciparum malaria stratified by the level of intravascular haemolysis (cell-free haemoglobin).

Duration of AKI will be defined as the length of time elapsed until serum creatinine returns to normal (<1mg/dL) in the absence of renal replacement therapy. Development of AKI will be assessed using the Acute Kidney Injury Network (AKIN) criteria, and by a creatinine increase of >= 0.5mg/dl or 25%. Plasma paracetamol concentration will be measured daily by liquid chromatography-mass spectrometer (LC-MS/MS).

Urine and plasma F2-isoprostanes and isofurans will be measured by gas chromatography-mass spectrometry. Cell-free haemoglobin measured as plasma concentration by enzyme linked immunosorbent assay (ELISA) on admission then daily for 72hours. Cell free haem measured in plasma using a chromogenic assay on admission then daily for 72hours. Haem-to-protein cross-links measured by high performance liquid chromatography (HPLC) on admission and daily for 72hours.

Blackwater fever assessed using a standardized urine colour chart and urine haemoglobin every 6 hours until clinical recovery between groups.

To compare mortality and hemodialysis trends between groups and evaluate if they correlate with level of oxidative stress, cell free haemoglobin and renal function.

Intravascular haemolysis according to G6PD status.

Compared fever clearance time defined as the time taken for the tympanic temperature to fall below 37.5°C and remain there for at least 24hours); Fever time defined as the duration in hours of an individuals temperature above 37.5°C; Area above the 37.5°C temperature versus time curve (AUC-T°) within first 24hours of treatment. Aural temperature will be measured every 6 hours until fever clearance.

Parasite clearance time assessed by microscopy of peripheral blood films will be assessed every 6hours for the presence of asexual parasitaemia until negative on 2 consecutive blood films. Parasite half lives and clearance time will be compared between groups. Parasites will also be staged to assess if sequestration is inhibited due to temperature reduction.

Parasite sequestration assessed by capillary flow in the rectal microcirculation using Orthogonal Polarization Spectral (OPS) imaging will be compared between groups.

Evaluation of pre-renal and acute tubular necrosis assessed by blood and urine biomarkers of pre-renal and renal injury including neutrophil gelatinase-associated lipocalcin (NGAL) and kidney injury molecule (KIM).

Urine colour will be assessed by standardized urine colour charts. Urine colour will be correlated with urine specific gravity, urine osmolality, urine haemoglobin and creatinine clearance.

Safety assessed by the number of patients with serious adverse events (SAEs) and by changes from baseline in vital signs and laboratory measurements.

Preliminary in vitro studies suggest that paracetamol potentiates the anti-parasitic effect of artesunate as lower 50% inhibitory concentration of artesunate is observed when paracetamol is added to parasites in culture. We will investigate whether this effect is dependent on the infecting P. falciparum parasite strain

Pharmacokinetic modelling of oral paracetamol in severe and moderately severe malaria

Pharmacodynamics on variables including temperature and parasitemia.

blackwater fever/peroxidase

Paracetamol Effect on Oxidative Stress and Renal Function in Severe Malaria

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