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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

BMC Geriatrics volume 22, Article number: 1000 (2022) Cite this article

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
Full size table

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)

Full size image

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

Full size image

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.

Author information

Authors and Affiliations

  1. Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany

    Philipp Heinrich Baldia, Malte Kelm, Raphael Romano Bruno, Stephan Binnebößel, Georg Wolff, Ralf Erkens & Christian Jung

  2. Department of Anaesthesiology, Perioperative Medicine and Intensive Care Medicine, Paracelsus Medical University, Salzburg, Austria

    Bernhard Wernly

  3. Department of Clinical Medicine, Department of Anaestesia and Intensive Care, University of Bergen, Haukeland University Hospital, Bergen, Norway

    Hans Flaatten

  4. Department of Intensive Care, Aarhus University Hospital, Aarhus, Denmark

    Jesper Fjølner

  5. Critical Care Centre, Sabadell Hospital University Institute Parc Tauli, Sabadell Barcelona, Spain

    Antonio Artigas

  6. Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland

    Bernardo Bollen Pinto

  7. Department of Intensive Care Medicine, Inselspital, Universitätsspital, University of Bern, Bern, Switzerland

    Joerg C. Schefold

  8. General & Medical Intensive Care Units, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Michael Beil, Sviri Sigal & Peter Vernon van Heerden

  9. Department of Intensive Care and Perioperative Medicine, Jagiellonian University Medical College, Krakow, Poland

    Wojciech Szczeklik

  10. Faculty of Medicine, University of Tripoli, Tripoli, Libya

    Muhammed Elhadi

  11. Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria

    Michael Joannidis

  12. Department of Intensive Care 1K12IC, Ghent University Hospital, Ghent, Belgium

    Sandra Oeyen

  13. Mater Misericordiae University Hospital, Dublin, Ireland

    Brian Marsh

  14. Department Of Anaesthesia and Intensive Care, Ålesund Hospital, Ålesund, Norway. Dep. of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway

    Finn H. Andersen

  15. Multipurpose and Neurocritical Intensive Care Unit, Hospital of São José, Central Lisbon University Hospital Centre, Lisbon, Portugal

    Rui Moreno

  16. General Intensive Care, St George´S University Hospitals NHS Foundation Trust, London, UK

    Susannah Leaver

  17. Department of Intensive Care Medicine, University Medical Center, University Utrecht, Utrecht, Netherlands

    Dylan W. De Lange

  18. Institute Pierre Louis Epidemiology and Public Health, Medical Intensive Care Unit, Sorbonne University, UPMC, INSERM, Hôpital Saint-Antoine, Paris, France

    Bertrand Guidet

Authors
  1. Philipp Heinrich Baldia
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  2. Bernhard Wernly
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  3. Hans Flaatten
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  4. Jesper Fjølner
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  5. Antonio Artigas
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  6. Bernardo Bollen Pinto
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  7. Joerg C. Schefold
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  8. Malte Kelm
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  9. Michael Beil
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  10. Raphael Romano Bruno
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  11. Stephan Binnebößel
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  12. Georg Wolff
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  13. Ralf Erkens
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  14. Sviri Sigal
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  15. Peter Vernon van Heerden
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  16. Wojciech Szczeklik
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  17. Muhammed Elhadi
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  18. Michael Joannidis
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  19. Sandra Oeyen
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  20. Brian Marsh
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  21. Finn H. Andersen
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  22. Rui Moreno
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  23. Susannah Leaver
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  24. Dylan W. De Lange
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  25. Bertrand Guidet
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  26. Christian Jung
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Consortia

COVIP study group

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

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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  • DOI: https://doi.org/10.1186/s12877-022-03709-w

Keywords

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

BMC Geriatrics

ISSN: 1471-2318

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