The association of prior paracetamol intake with outcome of very old intensive care patients with COVID-19: results from an international prospective multicentre trial
Authors: Baldia Philipp Heinrich , Wernly Bernhard , Flaatten Hans , Fjølner Jesper , Artigas Antonio , Pinto Bernardo Bollen , Schefold Joerg C. , Kelm Malte , Beil Michael , Bruno Raphael Romano , Binnebößel Stephan , Wolff Georg , Erkens Ralf , Sigal Sviri , van Heerden Peter Vernon , Szczeklik Wojciech , Elhadi Muhammed , Joannidis Michael , Oeyen Sandra , Marsh Brian , Andersen Finn H. , Moreno Rui , Leaver Susannah , De Lange Dylan W. , Guidet Bertrand , Jung Christian ,   COVIP study group, Eller Philipp , Joannidis Michael , Mesotten Dieter , Reper Pascal , Swinnen Walter , Serck Nicolas , DEWAELE ELISABETH , Brix Helene , Brushoej Jens , Kumar Pritpal , Nedergaard Helene Korvenius , Balleby Ida Riise , Bundesen Camilla , Hansen Maria Aagaard , Uhrenholt Stine , Bundgaard Helle , Innes Richard , Gooch James , Cagova Lenka , Potter Elizabeth , Reay Michael , Davey Miriam , Abusayed Mohammed Abdelshafy , Humphreys Sally , Galbois Arnaud , Charron Cyril , Berlemont Caroline Hauw , Besch Guillaume , Rigaud Jean-Philippe , Maizel Julien , Djibré Michel , Burtin Philippe , Garcon Pierre , Nseir Saad , Valette Xavier , Alexandru Nica , Marin Nathalie , Vaissiere Marie , PLANTEFEVE Gaëtan , Vanderlinden Thierry , Jurcisin Igor , Megarbane Buno , Chousterman Benjamin Glenn , Dépret François , Garnier Marc , Besset Sebastien , Oziel Johanna , Ferre Alexis , Dauger Stéphane , Dumas Guillaume , Goncalves Bruno , Vettoretti Lucie , Thevenin Didier , Schaller Stefan , Schaller Stefan , Kurt Muhammed , Faltlhauser Andreas , Schaller Stefan , Milovanovic Milena , Lutz Matthias , Shala Gonxhe , Haake Hendrik , Randerath Winfried , Kunstein Anselm , Meybohm Patrick , Schaller Stefan , Steiner Stephan , Barth Eberhard , Poerner Tudor , Simon Philipp , Lorenz Marco , Dindane Zouhir , Kuhn Karl Friedrich , Welte Martin , Voigt Ingo , Kabitz Hans-Joachim , Wollborn Jakob , Goebel Ulrich , Stoll Sandra Emily , Kindgen-Milles Detlef , Dubler Simon , Jung Christian , Fuest Kristina , Schuster Michael , Papadogoulas Antonios , Mulita Francesk , Rovina Nikoletta , Aidoni Zoi , CHRISANTHOPOULOU EVANGELIA , KONDILI EUMORFIA , Andrianopoulos Ioannis , Groenendijk Martijn , Evers Mirjam , Evers Mirjam , van Lelyveld-Haas Lenneke , Meynaar Iwan , Cornet Alexander Daniel , Zegers Marieke , Dieperink Willem , de Lange Dylan , Dormans Tom , Hahn Michael , Sjøbøe Britt , Strietzel Hans Frank , Olasveengen Theresa , Romundstad Luis , Kluzik Anna , Zatorski Paweł , Drygalski Tomasz , Klimkiewicz Jakub , Solek-pastuszka Joanna , Onichimowski Dariusz , Czuczwar Miroslaw , Gawda Ryszard , Stefaniak Jan , Stefanska-Wronka Karina , Zabul Ewa , Oliveira Ana Isabel Pinho , Assis Rui , de Lurdes Campos Santos Maria , Santos Henrique , Cardoso Filipe Sousa , Gordinho André , Banzo MJosé Arche , Zalba-Etayo Begoña , CUBERO PATRICIA JIMENO , Priego Jesús , Gomà Gemma , Tomasa-Irriguible Teresa Maria , Sancho Susana , Ferreira Aida Fernández , Vázquez Eric Mayor , Mira Ángela Prado , Ibarz Mercedes , Iglesias David , Arias-Rivera Susana , Frutos-Vivar Fernando , Lopez-Cuenca Sonia , Aldecoa Cesar , Perez-Torres David , Canas-Perez Isabel , Tamayo-Lomas Luis , Diaz-Rodriguez Cristina , de Gopegui Pablo Ruiz , Ben-Hamouda Nawfel , Roberti Andrea , Fleury Yvan , Abidi Nour , Dullenkopf Alexander , Pugh Richard , Smuts Sara 
Published: December 2022

Abstract
Background
In the early COVID-19 pandemic concerns about the correct choice of analgesics in patients with COVID-19 were raised. Little data was available on potential usefulness or harmfulness of prescription free analgesics, such as paracetamol. This international multicentre study addresses that lack of evidence regarding the usefulness or potential harm of paracetamol intake prior to ICU admission in a setting of COVID-19 disease within a large, prospectively enrolled cohort of critically ill and frail intensive care unit (ICU) patients.

Methods
This prospective international observation study (The COVIP study) recruited ICU patients ≥ 70 years admitted with COVID-19. Data on Sequential Organ Failure Assessment (SOFA) score, prior paracetamol intake within 10 days before admission, ICU therapy, limitations of care and survival during the ICU stay, at 30 days, and 3 months. Paracetamol intake was analysed for associations with ICU-, 30-day- and 3-month-mortality using Kaplan Meier analysis. Furthermore, sensitivity analyses were used to stratify 30-day-mortality in subgroups for patient-specific characteristics using logistic regression.

Results
44% of the 2,646 patients with data recorded regarding paracetamol intake within 10 days prior to ICU admission took paracetamol. There was no difference in age between patients with and without paracetamol intake. Patients taking paracetamol suffered from more co-morbidities, namely diabetes mellitus (43% versus 34%, p < 0.001), arterial hypertension (70% versus 65%, p = 0.006) and had a higher score on Clinical Frailty Scale (CFS; IQR 2–5 versus IQR 2–4, p < 0.001). Patients under prior paracetamol treatment were less often subjected to intubation and vasopressor use, compared to patients without paracetamol intake (65 versus 71%, p < 0.001; 63 versus 69%, p = 0.007). Paracetamol intake was not associated with ICU-, 30-day- and 3-month-mortality, remaining true after multivariate adjusted analysis.

Conclusion
Paracetamol intake prior to ICU admission was not associated with short-term and 3-month mortality in old, critically ill intensive care patients suffering from COVID-19.
Trial registration.
This prospective international multicentre study was registered on ClinicalTrials.gov with the identifier “NCT04321265” on March 25, 2020.