The effect of regularly dosed acetaminophen versus no acetaminophen on renal function in Plasmodium knowlesi malaria (PACKNOW): a randomised controlled trial.
Cooper DJ., Grigg MJ., Plewes K., Rajahram GS., Piera KA., William T., Menon J., Koleth G., Edstein MD., Birrell GW., Wattanakul T., Tarning J., Patel A., Yeo TW., Dondorp AM., Anstey NM., Barber BE.
BackgroundAcetaminophen inhibits cell-free hemoglobin-induced lipid peroxidation and improves renal function in severe falciparum malaria, but has not been evaluated in other infections with prominent hemolysis including Plasmodium knowlesi malaria.MethodsPACKNOW was an open-label randomised controlled trial of acetaminophen (500mg or 1000mg 6-hourly for 72 hours) versus no acetaminophen in Malaysian patients aged ≥5 years with knowlesi malaria of any severity. The primary endpoint was change in creatinine at 72 hours. Secondary endpoints included longitudinal changes in creatinine in patients with severe malaria or AKI (acute kidney injury), stratified by hemolysis.ResultsDuring 2016-2018, 396 patients (age 12-96 years) were randomised to acetaminophen (n=199) or no acetaminophen (n=197). Overall, creatinine fell by a mean (SD) 14.9% (18.1) in the acetaminophen arm versus 14.6% (16.0) in the control arm (p=0.81). In severe disease, creatinine fell by 31.0% (26.5) in the acetaminophen arm versus 20.4% (21.5) in the control arm (p=0.12), and in those with hemolysis by 35.8% (26.7) and 19% (16.6) respectively (p=0.07). No difference was seen overall in patients with AKI; however, in those with AKI and hemolysis, creatinine fell by 34.5% (20.7) in the acetaminophen arm versus 25.9% (15.8) in the control arm (p=0.041). Mixed-effects modelling demonstrated a benefit of acetaminophen at 72 hours (p=0.041) and 1 week (p=0.002) in patients with severe malaria and with AKI and hemolysis (p=0.027 and p=0.002 respectively).ConclusionsAcetaminophen did not improve creatinine among the entire cohort, but may improve renal function in patients with severe knowlesi malaria, and in those with AKI and hemolysis.