The Effect of Regularly Dosed Acetaminophen vs No Acetaminophen on Renal Function in Plasmodium knowlesi Malaria (PACKNOW): A Randomized, Controlled Trial

Daniel J Cooper, Matthew J Grigg, Katherine Plewes, Giri S Rajahram, Kim A Piera, Timothy William, Jayaram Menon, Glenn Koleth, Michael D Edstein, Geoffrey W Birrell, Thanaporn Wattanakul, Joel Tarning, Aatish Patel, Tsin Wen Yeo, Arjen M Dondorp, Nicholas M Anstey, Bridget E Barber

Research output: Contribution to journalArticlepeer-review

Abstract

Background
Acetaminophen 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.

Methods
PACKNOW was an open-label, randomized, controlled trial of acetaminophen (500 mg or 1000 mg every 6 hours for 72 hours) vs no acetaminophen in Malaysian patients aged ≥5 years with knowlesi malaria of any severity. The primary end point was change in creatinine at 72 hours. Secondary end points included longitudinal changes in creatinine in patients with severe malaria or acute kidney injury (AKI), stratified by hemolysis.

Results
During 2016–2018, 396 patients (aged 12–96 years) were randomized to acetaminophen (n = 199) or no acetaminophen (n = 197). Overall, creatinine fell by a mean (standard deviation) 14.9% (18.1) in the acetaminophen arm vs 14.6% (16.0) in the control arm (P = .81). In severe disease, creatinine fell by 31.0% (26.5) in the acetaminophen arm vs 20.4% (21.5) in the control arm (P = .12), and in those with hemolysis by 35.8% (26.7) and 19% (16.6), respectively (P = .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 vs 25.9% (15.8) in the control arm (P = .041). Mixed-effects modeling demonstrated a benefit of acetaminophen at 72 hours (P = .041) and 1 week (P = .002) in patients with severe malaria and with AKI and hemolysis (P = .027 and P = .002, respectively).

Conclusions
Acetaminophen 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.

Clinical Trials Registration
NCT03056391.
Original languageEnglish
Article numberciac152
Pages (from-to)1-10
Number of pages10
JournalClinical Infectious Diseases
DOIs
Publication statusE-pub ahead of print - Feb 2022

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