Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial

Plewes, Katherine; Kingston, Hugh; Ghose, Aniruddha; Wattanakul, Thanaporn; Hassan, M. Kabir; Haider, Shafiul; Dutta, Prodip Kumar; Islam, Akhterul; Alam, Shamsul; Jahangir, Selim Md; Zahed, Abu Shahed Md; Sattar, Abdus; Chowdhury, M A Hassan; Herdman, Michael; Leopold, Stije J.; Ishioka, Haruhiko; Piera, Kim A.; Charunwatthana, Prakaykaew; Silamut, Kamolrat; Yeo, Tsin Wen; Lee, Sue J.; Mukaka, Mavuto; Maude, Richard J.; Turner, Gareth D. H.; Faiz, Abul; Tärning, Joel; Oates, John A.; Anstey, Nicholas M.; White, Nicholas J.; Day, Nicholas P. J.; Hossain, Amir; Roberts, L. Jackson; Dondorp, Arjen M.

doi:10.1093/cid/ciy213

Cited by 50 publications

(39 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, a randomized control study in Bangladesh patients demonstrated that IV prostacyclin reduced the development of AKI [13,23]. Another randomized control trial found that acetaminophen greatly reduced serum creatine and lowered risk of AKI in patients with moderate to severe malaria [45]. As acetaminophen can be hepatotoxic, it must be used with caution as patients with malaria can experience liver dysfunction [46].…”

Section: Specific Therapiesmentioning

confidence: 99%

Malaria and acute kidney injury

et al. 2019

View full text Add to dashboard Cite

Malaria is a parasitic infection transmitted by mosquitos, resulting in significant morbidity and mortality. It affects 212 million worldwide, causing death in up to 303,000 children annually. In the USA, up to 1700 people are affected yearly. Although the prevalence in developed countries is less than in developing countries, travelers from low transmission areas, and those from endemic areas who later return, are very susceptible to malaria and its complications. Severe malaria can cause significant multiorgan dysfunction including acute kidney injury (AKI). The pathogenesis is not clearly understood but proposed mechanisms include acute tubular necrosis (ATN) due to impediments in renal microcirculation, infection-triggered proinflammatory reactions within the kidney, and metabolic disturbances. Providers must consider malarial infection in cases of AKI in someone with a travel history, as early recognition and treatment are crucial to improving outcomes. This article will review malariainduced AKI in order to provide a better understanding of this infection's effect on the kidneys.

show abstract

Section: Specific Therapiesmentioning

confidence: 99%

Malaria and acute kidney injury

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Furosemide and mannitol are ineffective in preventing and treating AKI and BWF, respectively, and may be harmful [ 92 , 93 ]. On the basis of the ability of paracetamol to inhibit hemoprotein-mediated AKI [ 94 ], a recent RCT of paracetamol in Bangladeshi adults with severe malaria found that acetaminophen improved kidney function and reduced the development of AKI, particularly in patients with high cell-free hemoglobin levels at enrollment [ 95 ▪ , 96 ]. Larger studies of paracetamol in adults and children with malaria are currently ongoing to further assess this renoprotective effect.…”

Section: Treatmentmentioning

confidence: 99%

Pathophysiology, clinical presentation, and treatment of coma and acute kidney injury complicating falciparum malaria

Plewes

Turner

Dondorp

2018

Current Opinion in Infectious Diseases

Self Cite

View full text Add to dashboard Cite

Purpose of reviewCerebral impairment and acute kidney injury (AKI) are independent predictors of mortality in both adults and children with severe falciparum malaria. In this review, we present recent advances in understanding the pathophysiology, clinical features, and management of these complications of severe malaria, and discuss future areas of research.Recent findingsCerebral malaria and AKI are serious and well recognized complications of severe malaria. Common pathophysiological pathways include impaired microcirculation, due to sequestration of parasitized erythrocytes, systemic inflammatory responses, and endothelial activation. Recent MRI studies show significant brain swelling in both adults and children with evidence of posterior reversible encephalopathy syndrome-like syndrome although targeted interventions including mannitol and dexamethasone are not beneficial. Recent work shows association of cell-free hemoglobin oxidation stress involved in the pathophysiology of AKI in both adults and children. Paracetamol protected renal function likely by inhibiting cell-free-mediated oxidative stress. It is unclear if heme-mediated endothelial activation or oxidative stress is involved in cerebral malaria.SummaryThe direct causes of cerebral and kidney dysfunction remain incompletely understood. Optimal treatment involves prompt diagnosis and effective antimalarial treatment with artesunate. Renal replacement therapy reduces mortality in AKI but delayed diagnosis is an issue.

show abstract

“…The following illustrates our suggested approach to assessing HTEs from RCT data and showing how this heterogeneity should be graphically visualised with the help of a multivariable risk model. We first constructed a multivariable risk model of death from severe malaria using data from more than 4000 patients from multiple randomised and observational studies (mostly Asian adults) [17,[21][22][23][24][25][26][27]. For all patients in this training dataset, risk of in-hospital mortality was then estimated using a mixed-effects logistic regression model, with the Fig.…”

Section: Case Study: the Hte Of Parenteral Artesunate For The Treatmementioning

confidence: 99%

Graphing and reporting heterogeneous treatment effects through reference classes

Watson

Holmes

2020

Trials

View full text Add to dashboard Cite

Background Exploration and modelling of heterogeneous treatment effects as a function of baseline covariates is an important aspect of precision medicine in randomised controlled trials (RCTs). Randomisation generally guarantees the internal validity of an RCT, but heterogeneity in treatment effect can reduce external validity. Estimation of heterogeneous treatment effects is usually done via a predictive model for individual outcomes, where one searches for interactions between treatment allocation and important patient baseline covariates. However, such models are prone to overfitting and multiple testing and typically demand a transformation of the outcome measurement, for example, from the absolute risk in the original RCT to log-odds of risk in the predictive model. Methods We show how reference classes derived from baseline covariates can be used to explore heterogeneous treatment effects via a two-stage approach. We first estimate a risk score which captures on a single dimension some of the heterogeneity in outcomes of the trial population. Heterogeneity in the treatment effect can then be explored via reweighting schemes along this axis of variation. This two-stage approach bypasses the search for interactions with multiple covariates, thus protecting against multiple testing. It also allows for exploration of heterogeneous treatment effects on the original outcome scale of the RCT. This approach would typically be applied to multivariable models of baseline risk to assess the stability of average treatment effects with respect to the distribution of risk in the population studied. Case study We illustrate this approach using the single largest randomised treatment trial in severe falciparum malaria and demonstrate how the estimated treatment effect in terms of absolute mortality risk reduction increases considerably in higher risk strata. Conclusions ‘Local’ and ‘tilting’ reweighting schemes based on ranking patients by baseline risk can be used as a general approach for exploring, graphing and reporting heterogeneity of treatment effect in RCTs. Trial registration ISRCTN clinical trials registry: ISRCTN50258054. Prospectively registered on 22 July 2005.

show abstract

Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial

Cited by 50 publications

References 29 publications

Malaria and acute kidney injury

Malaria and acute kidney injury

Pathophysiology, clinical presentation, and treatment of coma and acute kidney injury complicating falciparum malaria

Graphing and reporting heterogeneous treatment effects through reference classes

Contact Info

Product

Resources

About