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Monday, 21 March 2022

Is Acetaminophen (Paracetamol) use making the Covid-19 pandemic worse?

I've written in an earlier post about what's wrong with recommending paracetamol to people with Covid. There are no RCTs to show it's safe, and there are undisputed findings from toxicology and Covid-10 pathology which, taken together, suggest a potential for danger,[1]

Paracetamol overdoses used to kill around 200 people a year in New Zealand according to data which was regularly published in the 1970's and 1980's. Today the policy is to censor any information related to suicide. Does this work? On the one hand copy-cat effects are easy to confirm in real life, on the other hand the problem seems to have gotten worse overall under this "hear no evil" policy.
At any rate, deaths due to paracetamol fell sharply when Parvolex (NAC) was introduced as an antidote (which happened much later than it should have, and today the standard treatment seems to be reduced glutathione.[2]
Paracetamol (acetaminophen) metabolises to a free radical, which peroxidises lipids within the liver, causing liver failure. Glutathione, a reduced antioxidant peptide renewed by selenium enzymes, is the primary defense against lipid peroxidation. Lipid peroxidation is how SARS-CoV-2 destroys the lungs. The toxic metabolite is formed by CYP450 E21 enzyme degradation. In animal models, a diet high in polyunsaturated fat (the most peroxidizable fatty acids) and low in protein (the source of glutathione) accelerates liver damage caused by paracetamol toxicity - diets high in saturated fats and protein are protective.[3]

It's been suggested, based on a rational understanding of processes which as I've said are nowhere being disputed, that paracetamol, by increasing glutathione consumption, will have adverse effects on the people most vulnerable to Covid.[1]

To be honest I thought these effects were likely to be swallowed up in the noise of covid interactions, and appear as quite small risks in epidemiology until things were better understood.
I was wrong.[4]

METHODS: We conducted a retrospective analysis of patients admitted at Washington Hospital Center between February 2020 and- June 2020. Patients older than 18 years of age, diagnosed with COVID-19 were included in the study. Those who were directly admitted to the ICU were excluded. Acetaminophen exposure was calculated using a formula for average adjusted daily acetaminophen: total acetaminophen divided by number of day’s medication was administered. Groups were stratified to non-exposed and exposed. Within the exposed groups, we further divided them into moderate (100-1000 mg/day) or high exposure(>1000 mg/day). Comparison between groups for continuous variables was conducted using Kruskal Wallis test. Association between two categorical variables was tested using Fisher's exact test.

RESULTS: The cohort included 524 patients with non-exposed (n=136), moderate exposure (n=256), and high exposure (n=132) categories. Multivariable logistic regression showed that patients who were exposed to acetaminophen had a significantly higher odds of being triaged to a higher level of care [3.01 (CI 1.4-7.07 p <0.007) in moderate exposure group and 3.44 (CI 1.49-8.54 p<0.005) in high exposure groups]. Secondary outcomes included longer length of stay (5 vs 10 days, p < 0.001), higher mortality (5.1% vs 16.5% p = 0.001) and higher risk of requiring the ventilator support (2.9% vs 15.5% p<0.001) in the exposed group.

CONCLUSIONS: Previous studies have demonstrated that up to 85% of patients with COVID-19 develop fever and acetaminophen is commonly used as a treatment. Our study showed that acetaminophen exposure was associated with worse outcomes. Further studies are required to investigate this association, in particular to see if having a greater number of febrile episodes is independently associated with these same outcomes.[4]

Those are huge ORs. It's possible that fever itself, for which the paracetamol is being given, instead predicts the outcome.

In this paper, fever is associated with a 4x higher rate of adverse outcomes.[5]  This is concentrated in the symptomatic febrile cases, of whom only 4.8% received NSAIDs. Of course some studies say paracetamol is not an NSAID, others say it is, so it's possibly not even recorded correctly. However, as stated, this is a low correlation between fever and NSAID use, one which would not strongly support confounding-by-indication if it applied to the first paper..

So we have an unsatisfactory situation - a drug that WAS NEVER TESTED is being widely used by people with COVID-19. It's now associated with them getting worse. This could be due to confounding-by-indication, but no-one knows yet.

It's been three fucking years. I'm trying to follow the science, but it's always nodding off.

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 Sestili P., Fimognari C. Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? (2020)  Frontiers in Pharmacology,  11, art. no. 579944  


3] Hwang J. Diets with corn oil and/or low protein increase acute acetaminophen hepatotoxicity compared to diets with beef tallow in a rat model. Nutr Res Pract. 2009;3(2):95-101. doi:10.4162/nrp.2009.3.2.95

4] Manjani L, Desai N, Kohli A, Arya R, Woods C, Desale S. Effects of acetaminophen on outcomes in patients hospitalized with COVID-10. Presented at: CHEST 2021; October 17-20, 2021; Orlando, FL/Virtual. Abstract  A1072.

5] Chew, N W et al. “Fever as a predictor of adverse outcomes in COVID-19.” QJM : monthly journal of the Association of Physicians vol. 114,10 (2021): 706-714. doi:10.1093/qjmed/hcab023