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The association of prior paracetamol intake with outcome of very old intensive care patients with COVID-19: results from an international prospective multicentre trial

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.

Peer Review reports

Background

Older patients are more likely to die from COVID-19, the disease caused by Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) [1]. Early studies of COVID-19 have shown that especially old and frail patients are at particular risk for a worse outcome compared to younger people, with case fatality rates increasing up to 14.8% in patients aged 80 years and more. The majority of COVID-19 related deaths are in patients aged 80 years or greater [1,2,3,4,5]. These observations are in line with past studies of outcome of frail intensive care unit (ICU) patients showing that frailty – and not old age alone—is an important predictor of outcome in critically ill patients [6, 7]. In response to the eminently high vulnerability of old and frail patients, many countries chose to prioritize this vulnerable group in their vaccination programs to protect them from a likely fatal outcome [8]. This patient cohort is also of particular interest since they frequently take inter-current medications and have comorbid conditions.

In the early phase of the COVID-19 pandemic there were warnings not to use prescription-free analgesics such as ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs), since they were suspected to cause higher morbidity and mortality. Those statements were taken up by the media and led to widespread confusion and fear of – up to then – commonly used drugs for everyday ailments, like headaches and fever [9, 10].

Several studies suggested a potential influence of NSAIDs on the clinical course of respiratory viral diseases, namely worsening the overall outcome due to a suppression of the initial inflammatory cascade [11, 12]. Despite an early focus on a potential detrimental effect of NSAIDs on clinical outcomes, studies have shown no association of NSAID use with mortality [12, 13]. However, the role and influence of paracetamol, often used as an alternative to NSAIDs, remains unclear. To date, no data are available on the effects of paracetamol intake on COVID-19 disease in the vulnerable cohort of very old and critically ill patients admitted to ICUs.

This international multicentre study addresses this 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 ICU patients.

Methods

Design and settings

This international multicentre study is part of the Very old Intensive care Patients (VIP) project and has been endorsed by the European Society of Intensive Care Medicine (ESICM, http://www.vipstudy.org). Furthermore, it was registered on ClinicalTrials.gov (ID: NCT04321265) and planned in adherence to the European Union General Data Privacy Regulation (GDPR) directive, which is implemented in most participating countries. The COVIP (COVID-19 in very old intensive care patients) investigation aims to improve and enhance the knowledge about relevant factors for predicting mortality in older COVID-19 patients to help detect these patients early on and prevent a worse outcome. National coordinators were responsible for ICU recruitment, coordination of national and local ethical permissions and supervision of patient recruitment, as in the previous VIP studies [14, 15]. Ethical approval was mandatory for study participation. In most of the countries informed consent was obligatory for inclusion. However, due to a waiver of informed consent by some local Ethics committees, in a few countries, recruitment was possible without informed consent as previously described [16]. Overall, 138 intensive care units from 28 countries participated in the COVIP study [5, 17]. A list of all collaborating centers is given in the acknowledgement section.

Study population

COVIP recruited patients with proven COVID-19, defined as a positive polymerase chain reaction (PCR) test result, aged 70 years or older who were admitted to an ICU. Data collection started at ICU admission. Thus, data about pre-ICU triage were not available. The admission day was defined as day one, and all consecutive days were numbered sequentially from the admission date. The dataset contained patients enlisted to the COVIP study from 19th March 2020 until the 4th of February 2021.

Data collection

All study sites used a uniform online electronic case report form (eCRF). For this subgroup analysis, only patients with documented information regarding intake of paracetamol up to ten days prior to ICU admission were included.

Paracetamol intake

Paracetamol intake was defined as any oral or intravenous intake regardless of dosage and duration within the ten days prior to ICU admission, including during prior hospitalization, as reported by patient interviews; in case the patient was not able to respond, the relatives were asked to provide information. No differentiation was made between regular or irregular, i.e., single use, in reporting paracetamol intake.

The Sequential Organ Failure Score (SOFA) on admission was recorded [14, 15]. For calculation of the Horowitz Index (paO2/FiO2-ratio), the first arterial blood gas analysis after ICU admission was used ideally within one hour of ICU admission. Additionally, the need for non-invasive (NIV) or invasive ventilation, prone positioning, tracheostomy, vasopressor use, renal replacement therapy (RRT) and limitation or withdrawal of life-sustaining therapy during the ICU stay were recorded.

Data storage

The eCRF was constructed with the REDCap software [18]. Data storage and hosting of the eCRF took place on a secure server of Aarhus University in Denmark. The servers were operated in collaboration between the Information Technology Department and the Department of Clinical Medicine of the Aarhus University.

Frailty assessment

The frailty level prior to the acute illness and hospital admission was assessed using the Clinical Frailty Scale (CFS) as described previously [14, 15]. Patients were grouped into three categories: fit (CFS 0–3) vulnerable (CFS 4) and frail (CFS ≥ 5).

Statistical analysis

Continuous data were described as median ± interquartile range (IQR). Differences between independent groups were calculated using the Mann Whitney U-test. Categorical data were expressed as percentages. Kaplan–Meier analysis was used for assessment of mortality. For calculating differences between groups, the chi-square test was applied. Univariate and multivariate logistic regression analyses were performed to assess associations of paracetamol use with ICU-, 30-days and 3-months-mortality. We report (adjusted) odds ratios (OR) with respective 95% confidence intervals (CI). We performed sensitivity analyses plotting univariate OR and 95%CI. All tests were two-sided. A p-value of < 0.05 was considered statistically significant. Stata 16 was used for all statistical analyses (StataCorp LLC, 4905 Lakeway Drive, College Station, Brownsville, Texas, USA).

Results

Demographic data (age, sex, frailty, co-morbidities)

The study included 2,646 patients in total, of which 1,480 patients (56%) did not take paracetamol up to ten days prior to admission to an intensive care unit, whereas 1,166 patients (44%) confirmed paracetamol intake prior to ICU admission. The median age was 75 years in both groups (IQR 72–79 years, p > 0.98); significantly more women reported an intake of paracetamol 10 days prior to ICU admission. Patients on paracetamol intake were slightly more frail in comparison to patients without paracetamol intake (IQR 2–5 versus 2–4, p < 0.001). In addition, patients using paracetamol had more co-morbidities, such as arterial hypertension and diabetes mellitus in comparison to non-users (43% versus 34%, p < 0.001 for diabetes mellitus and 70% vs 65%, p = 0.006 for arterial hypertension). Concerning the occurrence of COVID-19 symptoms, patients under treatment with paracetamol had a shorter duration from symptom onset until ICU admission in comparison with patients without paracetamol medication (6 versus 7 days, p = 0.01). Additional data regarding patient demographics and co-morbidities are displayed in Table 1.

Table 1 Patient characteristics

Treatment in intensive care units

We observed a significant difference in SOFA scores on ICU admission between the two groups: those who received paracetamol treatment were admitted with a slightly higher SOFA score compared to those without paracetamol intake (5 versus 5, IQR 3–8 versus 3–8; cf. Table 1; p = 0.004). Furthermore, we observed several differences in intensive care treatment: Patients on paracetamol treatment prior to ICU admission were significantly less often subjected to endotracheal intubation and vasopressor treatment (65% versus 71%, p < 0.001 and 63% versus 68%, p = 0.007, respectively). No difference in tracheostomy rates were observed (16% versus 19%, p = 0.073). Additionally, the need for renal replacement therapy and NIV did not differ between both groups (14% versus 15%, p = 0.3; 26% vs 27%, p = 0.58, respectively). Concerning treatment withholding and withdrawal, patients with a reported paracetamol intake were less likely to be subjected to either treatment withholding or withdrawal, such as discontinuing respiratory or circulatory support, when compared to those without paracetamol intake (25% versus 29%, p = 0.021; 16% versus 19%, p = 0.011, respectively).

Mortality

No difference in mortality was observed between patients with and without paracetamol intake up to ten days prior to ICU admission (Fig. 1): ICU mortality was 46% vs 48% (p = 0.3) in patients with and without paracetamol intake respectively; 30-day mortality was 48% versus 51% (p = 0.12) in patients with and without paracetamol intake; 3-month mortality rates were 60% versus 64% (p = 0.059), respectively.

Fig. 1
figure 1

Kaplan–Meier curve for patients with (red) and without (blue) paracetamol intake prior to up to ten days before admission to intensive care units for COVID-19 (with 95% confidence interval)

Sensitivity analyses stratifying 30-day-mortality into subgroups for patient-specific characteristics using logistic regression producing univariate odds ratios are shown in Fig. 2. The 30-day-mortality was similar between patients with and without paracetamol intake regardless of treatment limitations, the use of NIV, age strata and the time from symptom onset until admission. There was a trend towards higher mortality in patients with paracetamol intake without intubation and in vulnerable patients as assessed by CFS.

Fig. 2
figure 2

Sensitivity analyses stratifying 30-day-mortality in subgroups for patient-specific characteristics using logistic regression producing univariate odds ratios. The 30-day-mortality was similar between patients with and without paracetamol intake regardless of treatment limitations, the use of NIV, age strata and the time from symptom onset until admission. Patients categorized as vulnerable according to CFS (OR 0.36) and without endotracheal intubation and vasopressor use (OR 0.62, respectively) were more likely to take paracetamol

After adjustment for age, sex, SOFA score and CFS at admission, paracetamol use was not associated with ICU (aOR 0.93 95%CI 0.78–1.11; p = 0.42), 30-day (aOR 0.86 95%CI 0.72–1.03; p = 0.10) and 3-month (aOR 0.88 95%CI 0.72–1.07; p = 0.20) mortality.

Discussion

In this subgroup analysis of critically ill patients ≥ 70 years of age, we investigated the influence of prior paracetamol intake on short-term and long-term mortality in patients with COVID-19. At the beginning of the pandemic, on the 14th of March 2020, the French Ministry of Health published data on 400 patients suffering from a severe clinical course of COVID-19 after taking ibuprofen; it therefore advised against the use of ibuprofen and other NSAIDs as the analgesics and antipyretics of choice. Instead, several health experts advised the use of paracetamol in case of fever or pain [9, 19, 20]. Previous studies investigated possible pathophysiological mechanisms by which NSAIDs and paracetamol could influence the clinical course of an infection with SARS-CoV-2 and other respiratory viruses [12, 21,22,23].

Paracetamol on the other hand is not included in the group of NSAIDs and has a more pronounced effect on cyclooxygenase (COX) 3 iso-enzyme, which is located in the central nervous system in contrast to the COX variants 1 and 2; thus, paracetamol has more central antipyretic and analgesic effects without compromising the systemic inflammatory cascade [24, 25]. Our findings are in line with current literature, confirming the safety of paracetamol as a potent analgesic and antipyretic drug in viral infections and especially in the case of COVID-19 disease [26, 27]. This is even true in a setting of critically ill and vulnerable, very old and frail people admitted to an ICU. We found no association of paracetamol intake prior to ICU admission with either ICU-, 30-day- and 3-months-mortality in patients with COVID-19 aged 70 years or more.

Since the study at hand did not report on analgesic use other than paracetamol, e.g., aspirin or NSAIDs, it remains unclear, whether paracetamol has any specific impact on the clinical course concerning the extent of intensive care treatment. Additionally, no differences in renal replacement therapy were observed. This may be explained by the mainly hepatic metabolism of paracetamol and a central activation of the COX 1 splice variant COX 3 as stated above [11, 24, 25, 28].

Patients on paracetamol treatment prior to hospitalization were also less prone to treatment withholding or withdrawal in comparison with those without paracetamol intake. In the light of the increased frailty of the paracetamol group, it remains unclear, why, despite this difference in co-morbidities, such as arterial hypertension and diabetes, they were less likely to have treatment withheld and withdrawn. This may be the result of the heterogeneity due to the international and multicentric setup of the COVIP study; hence individual differences, ethical, socio-medical patient backgrounds and the current epidemiological local burden of COVID-19 disease in the study sites must be considered, when discussing the observed differences in therapy and therapeutic limitations.

Our results are in line with findings by Park and colleagues, who showed safety of paracetamol in comparison to ibuprofen regarding the outcome of COVID-19 disease by analysing a propensity matched cohort of Korean patients in the first wave of the SARS-CoV-2 pandemic [29]. Similar results were published by Rinott et al. in a retrospective study on Israeli patients with a median age of 45 years, who reported ibuprofen or paracetamol intake up to 14 days prior to study inclusion; no difference in mortality or respiratory support rates were observed [30]. Further data on safety of paracetamol and NSAIDs were provided by Chandan and colleagues in a retrospective propensity matched study of 17,190 patients with osteoarthritis in the United Kingdom, who were prescribed either paracetamol and codeine, paracetamol and dihydrocodeine or NSAID: the study showed no increased risk of COVID-19 disease or mortality in both groups [31].

Importantly, we do neither observe paracetamols efficacy nor its safety in use. In summary, our multi-centre study suggests safety of paracetamol intake prior to hospitalization in intensive care units in a vulnerable and frail collective of more than 70 years old patients suffering from COVID-19 disease. This hypothesis is based on the evidence provided within this international, prospective multicentre study.

Limitations

Our study has some methodological limitations. Firstly, the study lacks a control group of younger patients admitted to ICU wards for severe COVID-19. Secondly, no control group of non-ICU patients age ≥ 70 was analyzed. Furthermore, data recording was only limited to time after ICU admission, thus leaving out information on pre-ICU care and possible triage. In addition, no detailed information on ICU equipment, quality of care, nurse-patient ratios and measure of staff stress was obtained; neither was paracetamol use during ICU treatment addressed. These local circumstances may affect the care of older ICU patients [32]. Also, participating countries varied widely in their care structure, thus resulting in a large heterogeneity in the level of care and the regional burden of care regarding local COVID-19 cases. Regarding paracetamol intake, we did not assess and document the doses of paracetamol ingested. Limitations of care in the pandemic surges did not allow to measure plasma metabolites and estimate true drug exposure, thus limiting data reliability. Lastly, our study did not analyze the intake of non-steroidal anti-inflammatory drugs, such as ibuprofen or aspirin and their corresponding impact on mortality and clinical course. Therefore, no recommendation towards a specific subgroup of analgesics can be made.

Conclusion

In the international multicentre COVIP study of old, critically ill patients with COVID-19, we found no association of paracetamol intake prior to ICU admission with short-term and 3-month mortality. Paracetamol is therefore likely safe for analgesic and antipyretic use in this group.

Availability of data and materials

Individual participant data that underlie the results reported in this article are available to investigators whose proposed use of the data has been approved by the COVIP steering committee. The anonymized data used and analyzed in this study can be requested from the corresponding author on reasonable request if required.

Abbreviations

BMI:

Body mass index (kg/m2)

CAD:

Coronary artery disease

CFS:

Clinical Frailty Scale

CI:

Confidence interval

CKD:

Chronic kidney disease

COVID-19:

Coronavirus disease 2019

COX:

Cyclooxygenase

eCRF:

Electronic case report form

FiO2 :

Fraction of inspired oxygen

ICU:

Intensive care unit

IQR:

Interquartile range

NIV:

Non-invasive ventilation

NSAID:

Non-steroidal anti-inflammatory drug

(a)OR:

(Adjusted) odds ratio

paO2 :

Arterial partial oxygen pressure

RRT:

Renal replacement therapy

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus type 2

SD:

Standard deviation

SOFA:

Sequential Organ Failure Score

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Acknowledgements

List of collaborators of the COVIP-study group.

Hospital City ICU Name
Austria
Medical University Graz Graz Allgemeine Medizin Intensivstation Philipp Eller
Medical University Innsbruck Innsbruck Division of Intensive Care and Emergency Medicine, Department of Internal Medicine Michael Joannidis
Belgium
Ziekenhuis Oost-Limburg Genk Department of Intensive Care Dieter Mesotten
CHR Haute Senne Soignies Department of Intensive Care Pascal Reper
Ghent University Hospital Ghent Department of Intensive Care Sandra Oeyen
AZ Sint-Blasius Dendermonde Department of Intensive Care Walter Swinnen
Clinique Saint Pierre Ottignies Ottignies Department of Intensive Care Nicolas Serck
Universitair Ziekenhuis Brussel Brussel ICU UZB ELISABETH DEWAELE
Denmark
Herlev og Gentofte Hospital Herlev Intensiv Behandling Helene Brix
Slagelse Slagelse Intensiv Jens Brushoej
Regionshospitalet Horsens Horsens Intensiv Pritpal Kumar
Odense University Hospital Odense Intensive Care Unit Helene Korvenius Nedergaard
Sygehus Lillebælt Kolding Intensiv Helene Korvenius Nedergaard
Regionshospitalet Viborg Viborg Intensiv Ida Riise Balleby
Sygehus Sønderjylland Aabenraa Department of Anaesthesia and Intensive Care Camilla Bundesen
Regionshospitalet Herning Herning Intensiv Afdeling Maria Aagaard Hansen
Nordsjællands Hospital Hillerød Department of Anaesthesia and Intensive Care Stine Uhrenholt
Regionshospitalet Randers Randers Intensiv Helle Bundgaard
Aarhus University Hospital Aarhus Department of Intensive Care Jesper Fjølner
England
Musgrove Park Adult ICU Taunton Richard Innes
Princess Alexandra Hospital Harlow Princess Alexandra Hospital ICU Essex James Gooch
Royal Papworth Hospital Cardiothoracic Critical Care Cambridge Lenka Cagova
Royal Surrey Hospital NHS Foundation Trust Intensive Care Unit Guildford Elizabeth Potter
Russells Hall Russells Hall Anaes Dept Dudley Michael Reay
Tunbridge Wells Hospital Tunbridge Wells Intensive Care/High Dependency Unit Tunbridge Wells Miriam Davey
Walsall Manor Hospital Walsall ICU Walsall Mohammed Abdelshafy Abusayed
West Suffolk NHS Foundation Trust Critical Care Bury St Edmunds Sally Humphreys
France
Hôpital Privé Claude Galien Quincy sous Sénart Medico-surgical ICU Arnaud Galbois
Saint Antoine Paris Medical ICU Bertrand Guidet
Hôpital Ambroise Paré Boulogne Billancourt Medico-urgical ICU Cyril Charron
Hopital Européen Georges Pompidou Paris Medical ICU Caroline Hauw Berlemont
CHU de Besançon Besançon Medico-surgical ICU Guillaume Besch
Dieppe General Hospital Dieppe Medical ICU Jean-Philippe Rigaud
CHU Amiens Amiens Medical ICU Julien Maizel
Tenon Paris Medico-surgical ICU Michel Djibré
Clinique Du Millenaire Montpellier Surgical ICU Philippe Burtin
Marne La Vallee Jossigny Medico-surgical ICU Pierre Garcon
CHU Lille Lille Medical ICU Saad Nseir
CHU de Caen Caen Medical ICU Xavier Valette
Compiegne Noyon Hospital Compiegne Medico-surgical ICU Nica Alexandru
Cochin Paris Medical ICU Nathalie Marin
CH Pau Pau Medico-surgical ICU Marie Vaissiere
Victor Dupouy Argenteuil Medico-surgical ICU Gaëtan PLANTEFEVE
CH Saint Philibert Lomme lez Lille Medical ICU Thierry Vanderlinden
Beaujon Clichy Medico-surgical ICU Igor Jurcisin
Lariboisière Paris Medical ICU Buno Megarbane
Lariboisière Paris Surgical ICU Benjamin Glenn Chousterman
Saint-Louis Paris Surgical ICU François Dépret
Saint Antoine Paris Surgical ICU Marc Garnier
Louis Mourier Colombes Medico-surgical ICU Sebastien Besset
Avicenne Bobigny Medico-surgical ICU Johanna Oziel
Centre hospitalier de Versailles Le Chesnay Medico-surgical ICU Alexis Ferre
Robert Debré Paris Pediatric ICU Stéphane Dauger
Saint-Louis Paris Medical ICU Guillaume Dumas
Sainte-Anne Paris Medico-surgical ICU Bruno Goncalves
CHU de Besancon Besançon Medical ICU Lucie Vettoretti
CH Dr SCHAFFNER, Reanimation polyvalente Lens Medico-surgical ICU Didier Thevenin
Germany
Charité - Universitätsmedizin Berlin Berlin 44i Stefan Schaller
Charité - Universitätsmedizin Berlin Berlin W1 Stefan Schaller
Florence-Nightingale Krankenhaus Duesseldorf 32 Muhammed Kurt
Kliniken Nordoberpfalz AG Klinikum Weiden Weiden Interdisziplinäre Intensivmedizin Andreas Faltlhauser
Charité - Universitätsmedizin Berlin Berlin 8i Stefan Schaller
Evangelisches Krankenhaus Düsseldorf Düsseldorf Intensivstation Christian Meyer
Malteser Krankenhaus St. Franziskus Hospital Flensburg Intensivstation 1 Milena Milovanovic
Uniklinik Schleswig Holstein Campus Kiel Kiel Internistische Intensivstation Matthias Lutz
Johanna Etienne Krankenhaus Neuss Station 2 Gonxhe Shala
Kliniken Maria Hilf Mönchengladbach Internistische Intensivstation I und II Hendrik Haake
Krankenhaus Bethanien GmbH Solingen Solingen Intensivpflege Bethanien Winfried Randerath
Uniklinik Düsseldorf Düsseldorf MX01 Anselm Kunstein
University Hospital Würzburg Würzburg   Patrick Meybohm
Charité - Universitätsmedizin Berlin Berlin 43i Stefan Schaller
St Vincenz Limburg ICU Stephan Steiner
University Hospital Ulm Ulm IOI-Interdisziplinäre Operative Intensivmedizin Eberhard Barth
Marienhospital Aachen Aachen ITS Tudor Poerner
University Hospital Leipzig / Klinik und Poliklinik für Anästhesiologie und Intensivtherapie Leipzig IOI (Interdisciplinary Operational/Surgical ICU) Philipp Simon
Charité - Universitätsmedizin Berlin Berlin 203i Marco Lorenz
Städtische Kliniken Mönchengladbach Mönchengladbach Interdisziplinäre Intensivstation Zouhir Dindane
Charité - Universitätsmedizin Berlin Berlin 144i Karl Friedrich Kuhn
Klinikum Darmstadt GmbH Darmstadt Interdiszipinaere Operative Intensivstation Klinik fuer Anaesthesiologie und operative Intensivmedizin Martin Welte
Elisabeth-Krankenhaus Essen Essen Kardiologisch-internistische Intensivstation Ingo Voigt
Klinikum Konstanz Konstanz I01 Hans-Joachim Kabitz
Medical Center - University of Freiburg Freiburg Anaesthesiologiesche Intensivtherapiestation Jakob Wollborn
St. Franziskus-Hospital Münster Münster Klinik für Anästhesie und operative Intensivmedizin Ulrich Goebel
University Hospital Cologne Cologne Surgical ICU of the Department of Anesthesiology Sandra Emily Stoll
University Hospital Duesseldorf Duesseldorf CIA1 Detlef Kindgen-Milles
Essen University Hospital Essen Ana Int Simon Dubler
University Hospital Duesseldorf Düsseldorf MI1/2 Christian Jung
Rechts der Isar Technical University Munich ICU 1 Kristina Fuest
Universitätsmedizin der Johannes Gutenberg-Universität Mainz Mainz Anästhesie-Intensivstation Michael Schuster
Greece
GENERAL HOSPITAL OF LARISSA LARISSA ICU Antonios Papadogoulas
General University Hospital of Patras Patras ΜΕΘ Francesk Mulita
Sotiria Hospital National and Kapodistrian University of Athens Athens ICU 1st Pulmonary and Critical Care Medicine Dpt Nikoletta Rovina
Ught Ahepa Thessaloniki Metha Zoi Aidoni
UNIVERSITY HOSPITAL (ATTIKON) HAIDARI 2nd DEPARTMENT OF CRITICAL CARE EVANGELIA CHRISANTHOPOULOU
UNIVERSITY HOSPITAL OF HERAKLION HERAKLION ICU UNIVERSITY HOSPITAL OF HERAKLION EUMORFIA KONDILI
UNIVERSITY HOSPITAL OF IOANNINA IOANNINA INTENSIVE CARE UNIT Ioannis Andrianopoulos
Netherland
Alrijne Zorggroep Leiderdorp ICU Department Martijn Groenendijk
Canisius Wilhelmina Hospital Nijmegen C38 Mirjam Evers
Canisius Wilhelmlina Ziekenhuis Nijmegen ICU Department Mirjam Evers
Diakonessenhuis Utrecht Utrecht Diakonessenhuis Lenneke van Lelyveld-Haas
Haga Ziekenhuis The Hague ICU Haga Iwan Meynaar
Medisch Spectrum Twente Enschede Intensive Care Center Alexander Daniel Cornet
Radboudumc Nijmegen Intensive Care department Radboudumc Marieke Zegers
University Medical Center Groningen Groningen Department of Critical Care Willem Dieperink
University Medical Center Utrecht Utrecht Intensive Care Dylan de Lange
Zuyderland mc Heerlen Intensive Care Tom Dormans
Norway
Haugesund Hospital Haugesund ICU Michael Hahn
Haukeland University Hospital Bergen KSK-ICU Britt Sjøbøe
Kristiansund Hospital Helse Møre og Romsdal HF Kristiansund ICU Hans Frank Strietzel
Oslo University Hospital Oslo Surgical ICU Theresa Olasveengen
Oslo University Hospital Rikshospitalet Medical Oslo Department of Critical Care and Emergencies Luis Romundstad
Ålesund Hospital Ålesund Dept. Anesthesia and Intensive Care Surgical ICU Finn H. Andersen
Poland
Clinical Hospital Heliodor Święcicki Medical University of Karol Marcinkowski in Poznan Poznan Anesthesiology Intensive Therapy and Pain Treatment Anna Kluzik
Infant Jesus Clinical Hospital Medical University of Warsaw Warsaw I Department of Anaesthesiology and Intensive Care Paweł Zatorski
Jagiellonia University Hospital Cracow Cracow   Tomasz Drygalski
Military Hospital Krakow ICU Wojciech Szczeklik
Military Institute of Medicine Warsaw COVID-19 ICU Jakub Klimkiewicz
Pomeranian Medical University szczecin ICU Joanna Solek-pastuszka
Provincial Specialist Hospital Olsztyn Department of Intensive Care Dariusz Onichimowski
SPSK-1 Lublin II Klinika Anestezjologii i Intensywnej Terapii Miroslaw Czuczwar
University Hospital in Opole Opole Department of Anesthesiology and Intensvie Care Ryszard Gawda
Uniwersyteckie Centrum Kliniczne w Gdańsku Gdańsk Klinika Anestezjologii i Intensywnej Terapii Jan Stefaniak
Voivodship Hospital in Poznan Poznan Intensive Care Unit Karina Stefanska-Wronka
ZDROWIE Sp. z o.o. Kwidzyn Oddział Anestezjologii i Intensywnej Terapii Ewa Zabul
Portugal
Centro Hospitalar de Tondela-Viseu EPE Viseu Unidade de Cuidados Intensivos Polivalente Ana Isabel Pinho Oliveira
Centro Hospitalar do Médio Tejo Abrantes Serviço de Medicina Intensiva Rui Assis
Centro Hospitalar e Universitário São João Porto Infectious Diseases ICU Maria de Lurdes Campos Santos
Centro Hospitalar Tráz os Montes e Alto Dour Vila Real D Henrique Santos
Curry Cabral Hospital Lisbon UCIP Filipe Sousa Cardoso
Hospital de Beatriz Ângelo Loures Serviço de Medicina Intensiva André Gordinho
Spain
Clínico Universitario Lozano-Blesa Zaragoza Unidad de Cuidados Intensivos M José Arche Banzo
Clínico Universitario Lozano-Blesa Zaragoza Unidad de Cuidados Intensivos Begoña Zalba-Etayo
COMPLEJO ASISTENCIAL DE SEGOVIA SEGOVIA UCI SEGOVIA PATRICIA JIMENO CUBERO
Complexo Hospitalario Universitario Ourense Ourense UCI CHUO Jesús Priego
Corporació Sanitària Parc Taulí Sabadell Parc Taulí Gemma Gomà
Germans Trias i Pujol Badalona General ICU Teresa Maria Tomasa-Irriguible
H. Universitari i Politècnic La Fe Valencia General ICU Susana Sancho
Hospital Alvaro Cunqueiro Vigo Servicio de Medicina Intensiva CHUVI Aida Fernández Ferreira
Hospital de Tortosa Verge de la Cinta Tortosa Unidad de Cuidados Intensivos Eric Mayor Vázquez
Hospital General Universitario de Albacete Albacete aapm111 Ángela Prado Mira
Hospital Universitari Sagrat Cor Barcelona ICU Mercedes Ibarz
Hospital Universitario de Burgos Burgos UCI Burgos David Iglesias
Hospital Universitario de Getafe Getafe Getafe Susana Arias-Rivera
Hospital Universitario de Getafe Getafe Medical-Surgical ICU Fernando Frutos-Vivar
Hospital universitario Rey Juan Carlos Mostoles Cuidados intensivos Sonia Lopez-Cuenca
Hospital Universitario Rio Hortega Valladolid Reanimación Quirurgica Cesar Aldecoa
Hospital Universitario Río Hortega Valladolid Servicio de Medicina Intensiva - Unidad 1 David Perez-Torres
Hospital Universitario Río Hortega Valladolid Servicio de Medicina Intensiva - Unidad 2 Isabel Canas-Perez
Hospital Universitario Río Hortega Valladolid Servicio de Medicina Intensiva - Unidad 3 Luis Tamayo-Lomas
Hospital Universitario Río Hortega Valladolid Servicio de Medicina Intensiva - Unidad 4 Cristina Diaz-Rodriguez
Miguel Servet University Hospital Zaragoza Servicio de Medicina Intensiva Pablo Ruiz de Gopegui
Switzerland
Centre Hospitalier Universitaire Vaudois Lausanne Service de Médecine Intensive Adulte (SMIA) Nawfel Ben-Hamouda
Clinica Luganese Moncucco Lugano Servizio di anestesia e rianimazione Andrea Roberti
Fribourg Hospital Fribourg Intensive Care Unit Yvan Fleury
Geneva University Hospitals Geneva Department of Acute Medicine Nour Abidi
Inselspital Bern Bern Universitätsklinik für Intensivmedizin Joerg C. Schefold
Kantonspital Thurgau Frauenfeld Frauenfeld Institut für Anästhesiologie und Intensivmedizin Ivan Chau
Kantonspital Thurgau Frauenfeld Frauenfeld Institut für Anästhesiologie und Intensivmedizin Alexander Dullenkopf
Wales
Glan Clwyd Hospital Bodelwyddan Critical Care Unit Richard Pugh
Wrexham Maelor Hospital Wrexham Critical Care Sara Smuts

Funding

Open Access funding enabled and organized by Projekt DEAL. This study was endorsed by the European Society of Intensive Care Medicine (ESICM). Free support for running the electronic database and was granted from the Department of Epidemiology, University of Aarhus, Denmark. The support of the study in France by a grant from Fondation Assistance Publique-Hôpitaux de Paris pour la recherche is greatly appreciated. In Norway, the study was supported by a grant from the Health Region West. In addition, the study was supported by a grant from the European Open Science Cloud (EOSC). EOSCsecretariat.eu has received funding from the European Union's Horizon Programme call H2020-INFRAEOSC-05–2018-2019, grant agreement number [831644]. This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich-Heine-University Düsseldorf, No. [2018-32] to GW and No. [2020-21] to RRB for a Clinician Scientist Track. No (industry) sponsorship has been received for this investigator-initiated study.

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Contributions

PHB, BW and CJ analyzed the data and wrote the first draft of the manuscript. HF and BG and DL contributed to statistical analysis and improved the paper. MK and MB and RRB and SB and GW and RE and SS and PVvH and ME and MJ and AA and BG and FHA and SL and JF and BM and RM and SO and BP and WS and JCS gave guidance and improved the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Christian Jung.

Ethics declarations

Ethics approval and consent to participate

The primary competent ethics committee was the Ethics Committee of the University of Duesseldorf, Germany (application number 2020–892). Each participating center received a copy of the study protocol. Institutional research ethic board approval was obtained from each study site and was mandatory for study participation.

Due to the observational nature of the study, participation in this study did not impact medical procedures, which were all executed in accordance with the relevant medical guidelines and regulations. No additional examinations, e.g., sampling and storage of biomaterials, such as blood or CT-scans and X-rays, were performed.

The study was planned in adherence to the European Union General Data Privacy Regulation (GDPR) directive, which is implemented in most participating countries. Deceased patients were included within strict consideration of local requirements set up by the local ethics committees. However, in a few countries, recruitment was possible without informed consent in accordance with the respective local ethics committee (see above).

Consent for publication

The manuscript does not contain any individual person’s data in any form.

Competing interests

The authors declare that they have no competing interests. JCS reports grants (full departmental disclosure) from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dräger AG, Teleflex Medical GmbH, Glaxo Smith Kline, Merck Sharp and Dohme AG, Eli Lilly and Company, Baxter, Astellas, Astra Zeneca, CSL Behring, Novartis, Covidien, Philips Medical, Phagenesis Ltd, Prolong Pharmaceuticals and Nycomed outside the submitted work. The money went into departmental funds. No personal financial gain applied.

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Baldia, P.H., Wernly, B., Flaatten, H. et al. The association of prior paracetamol intake with outcome of very old intensive care patients with COVID-19: results from an international prospective multicentre trial. BMC Geriatr 22, 1000 (2022). https://doi.org/10.1186/s12877-022-03709-w

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Keywords

  • COVID-19
  • Frailty
  • ICU
  • Paracetamol
  • Analgesics