Randomized Controlled Trial

. 2025 Jun 17;29(1):247.

doi: 10.1186/s13054-025-05461-0.

Sedation and analgesia in post-cardiac arrest care: a post hoc analysis of the TTM2 trial

Ameldina Ceric¹, Josef Dankiewicz², Tobias Cronberg³, Joachim Düring⁴, Marion Moseby-Knappe⁵, Martin Annborn⁶, Teresa L May⁷, Matthew Thomas⁸, Anders Morten Grejs^{9

10}, Christian Rylander¹¹, Jan Belohlavek^{12

13}, Pedro Wendel-Garcia¹⁴, Matthias Haenggi^{14

15}, Claudia Schrag¹⁶, Matthias P Hilty¹⁴, Thomas R Keeble¹⁷, Matt P Wise¹⁸, Paul Young¹⁹, Fabio Silvio Taccone²⁰, Chiara Robba²¹, Alain Cariou²², Glenn Eastwood²³, Manoj Saxena²⁴, Susann Ullén²⁵, Gisela Lilja²⁶, Janus C Jakobsen^{27

28}, Anna Lybeck²⁹, Niklas Nielsen⁶

Affiliations

¹ Anesthesia & Intensive Care, Department of Clinical Sciences, Lund University, Skane University Hospital, Carl Bertil Laurels Gata 9, 214 28, Malmö, Sweden. ameldina.ceric@med.lu.se.
² Cardiology Department, Lund University, Skåne University Hospital Lund, Lund, Sweden.
³ Neurology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
⁴ Department of Clinical Sciences, Anaesthesia and Intensive Care, Lund University, Skåne University Hospital, Malmö, Sweden.
⁵ Department of Clinical Sciences Lund, Neurology and Rehabilitation, Lund University, Lund, Sweden.
⁶ Department of Clinical Sciences, Anaesthesia and Intensive Care, Lund University, Helsingborg Hospital, Helsingborg, Sweden.
⁷ Department of Critical Care, Maine Medical Center, Portland, ME, USA.
⁸ Department of Intensive Care, University Hospitals Bristol and Weston, Bristol, UK.
⁹ Department of Intensive Care Medicine, Aarhus University Hospital, Aarhus N, Denmark.
¹⁰ Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
¹¹ Anaesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University and Uppsala University Hospital, Uppsala, Sweden.
¹² 2Nd Department of Internal Mediciny, Cardiovascular Medicine, General University Hospital, and 1St Medical School in Prague, Prague, Czech Republic.
¹³ Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland.
¹⁴ Institute of Intensive Care Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.
¹⁵ Department of Intensive Care Medicine, University Hospital Bern, University of Bern, Bern, Switzerland.
¹⁶ Intensive Care Department, Kantonsspital St. Gallen, St. Gallen, Switzerland.
¹⁷ Anglia Ruskin School of Medicine, Essex Cardiothoracic Centre, MSE NHS Trust, Essex, UK. MTRC, Chelmsford, Essex, UK.
¹⁸ Adult Critical Care, University Hospital of Wales, Cardiff, UK.
¹⁹ Intensive Care Unit, Wellington Hospital, Wellington, New Zealand and Medical Research Institute of New Zealand, Wellington, New Zealand.
²⁰ Department of Intensive Care, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
²¹ IRCCS Policlinico San Martino; Genoa, Italy and Dipartimento Di Scienze Chirurgiche Diagnostiche E Integrate, University of Genoa, Genoa, Italy.
²² Medical ICU Cochin University Hospital, AP-HP Centre Université Paris Cité, Paris, France.
²³ The Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia.
²⁴ Division of Critical Care and Trauma, George Institute for Global Health, and Bankstown-Lidcombe Hospital, South Western Sydney Local Health District, Sydney, Australia.
²⁵ Skåne University Hospital Lund, Lund University and Clinical Studies Sweden - Forum South, Skåne University Hospital, Lund, Sweden.
²⁶ Neurology Department of Clinical Sciences, Lund University, Lund, Sweden.
²⁷ Copenhagen Trial Unit - Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²⁸ The Faculty of Health Sciences, Department of Regional Health Research, University of Southern Denmark, Odense M, Denmark.
²⁹ Department of Clinical Sciences, Anaesthesia and Intensive Care, Skåne University Hospital, Lund University, Lund, Sweden.

PMID: 40528173
PMCID: PMC12175406
DOI: 10.1186/s13054-025-05461-0

Randomized Controlled Trial

Sedation and analgesia in post-cardiac arrest care: a post hoc analysis of the TTM2 trial

Ameldina Ceric et al. Crit Care. 2025.

. 2025 Jun 17;29(1):247.

doi: 10.1186/s13054-025-05461-0.

Authors

Affiliations

¹ Anesthesia & Intensive Care, Department of Clinical Sciences, Lund University, Skane University Hospital, Carl Bertil Laurels Gata 9, 214 28, Malmö, Sweden. ameldina.ceric@med.lu.se.
² Cardiology Department, Lund University, Skåne University Hospital Lund, Lund, Sweden.
³ Neurology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
⁴ Department of Clinical Sciences, Anaesthesia and Intensive Care, Lund University, Skåne University Hospital, Malmö, Sweden.
⁵ Department of Clinical Sciences Lund, Neurology and Rehabilitation, Lund University, Lund, Sweden.
⁶ Department of Clinical Sciences, Anaesthesia and Intensive Care, Lund University, Helsingborg Hospital, Helsingborg, Sweden.
⁷ Department of Critical Care, Maine Medical Center, Portland, ME, USA.
⁸ Department of Intensive Care, University Hospitals Bristol and Weston, Bristol, UK.
⁹ Department of Intensive Care Medicine, Aarhus University Hospital, Aarhus N, Denmark.
¹⁰ Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
¹¹ Anaesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University and Uppsala University Hospital, Uppsala, Sweden.
¹² 2Nd Department of Internal Mediciny, Cardiovascular Medicine, General University Hospital, and 1St Medical School in Prague, Prague, Czech Republic.
¹³ Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland.
¹⁴ Institute of Intensive Care Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.
¹⁵ Department of Intensive Care Medicine, University Hospital Bern, University of Bern, Bern, Switzerland.
¹⁶ Intensive Care Department, Kantonsspital St. Gallen, St. Gallen, Switzerland.
¹⁷ Anglia Ruskin School of Medicine, Essex Cardiothoracic Centre, MSE NHS Trust, Essex, UK. MTRC, Chelmsford, Essex, UK.
¹⁸ Adult Critical Care, University Hospital of Wales, Cardiff, UK.
¹⁹ Intensive Care Unit, Wellington Hospital, Wellington, New Zealand and Medical Research Institute of New Zealand, Wellington, New Zealand.
²⁰ Department of Intensive Care, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
²¹ IRCCS Policlinico San Martino; Genoa, Italy and Dipartimento Di Scienze Chirurgiche Diagnostiche E Integrate, University of Genoa, Genoa, Italy.
²² Medical ICU Cochin University Hospital, AP-HP Centre Université Paris Cité, Paris, France.
²³ The Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia.
²⁴ Division of Critical Care and Trauma, George Institute for Global Health, and Bankstown-Lidcombe Hospital, South Western Sydney Local Health District, Sydney, Australia.
²⁵ Skåne University Hospital Lund, Lund University and Clinical Studies Sweden - Forum South, Skåne University Hospital, Lund, Sweden.
²⁶ Neurology Department of Clinical Sciences, Lund University, Lund, Sweden.
²⁷ Copenhagen Trial Unit - Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²⁸ The Faculty of Health Sciences, Department of Regional Health Research, University of Southern Denmark, Odense M, Denmark.
²⁹ Department of Clinical Sciences, Anaesthesia and Intensive Care, Skåne University Hospital, Lund University, Lund, Sweden.

PMID: 40528173
PMCID: PMC12175406
DOI: 10.1186/s13054-025-05461-0

Abstract

Background: The routine use of sedation and analgesia during post-cardiac arrest care and its association with clinical outcomes remain unclear. This study aimed to describe the use of sedatives and analgesics in post-cardiac arrest care, and evaluate associations with good functional outcome, survival, clinical seizures, and late awakening.

Methods: This was a post hoc analysis of the TTM2-trial, which randomized 1900 out-of-hospital cardiac arrest patients to either normothermia or hypothermia. In both groups, deep sedation (Richmond Agitation and Sedation Scale ≤ -4) was mandatory during the 40-h intervention. Cumulative doses of sedatives and analgesic drugs were recorded within the first 72 h from randomization. Outcomes were functional outcome (modified Rankin Scale) and survival status at 6 months, occurrence of clinical seizures during the intensive care stay, and late awakening (Full outline of unresponsiveness motor score of four 96 h after randomization). Cumulative propofol doses were divided into quartiles (Q1-Q4). Logistic regression models were used to assess associations between sedative doses and functional outcome and survival, clinical seizures, and late awakening, adjusting for the severity of illness and other clinical factors influencing sedation.

Results: A total of 1861 patients were analyzed. In a multivariable logistic regression model, higher propofol doses (Q3, 100.7-153.6 mg/kg) were associated with good functional outcome (OR 1.62, 95%CI 1.12-2.34) and (Q2 and Q3, 43.9-153.6 mg/kg) with survival (OR 1.49, 95%CI 1.05-2.12 and OR 1.84, 95%CI 1.27-2.65, respectively). Receiving fentanyl and remifentanil were associated with good functional outcome (OR 1.69, 95%CI 1.27-2.26 and OR 1.50, 95%CI 1.11-2.02) and survival (OR 1.80, 95%CI 1.35-2.40 and OR 1.56, 95%CI 1.16-2.10). Receiving fentanyl (OR 0.64, 95%CI 0.48-0.86) and higher propofol doses (Q2-4 (43.9-669.4 mg/kg) were associated with the occurrence of clinical seizures. The highest quartile of propofol dose (153.7-669.4 mg/kg, OR 3.19, 95%CI 1.91-5.42) was associated with late awakening.

Conclusions: In this study, higher doses of propofol and the use of remifentanil and fentanyl were associated with good functional outcome and survival, occurrence of clinical seizures, and late awakening.

Keywords: Cardiac arrest; Midazolam; Propofol; Sedation; Seizures; Targeted temperature management.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The TTM2-trial was approved by Regional Ethical Review Board in Lund, Sweden (Nr 2015/228 and 2017/36) and in all participating countries and was carried out in accordance with the World Medical Association’s Declaration of Helsinki. Written informed consent was waived, deferred, or obtained from a legal surrogate, depending on the circumstances, and was obtained from each patient who regained mental capacity. For this sub analysis, no further ethical approval was required. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

**Fig. 1**
Flow chart of included and excluded patients in this post-hoc study of the TTM2-trial [18]

**Fig. 2**
The relationship between cumulative propofol dose and good functional outcome, survival, clinical seizures, and late awakening. A logistic regression was applied to visualize the relationship between cumulative propofol dose (mg/kg) and the probability of good functional outcome, survival, clinical seizures, and late awakening. Each point represents an individual patient (jittered for visibility), with the blue line indicating the predicted probability and the shaded area representing the 95% confidence interval. The increasing curve suggests a non-linear association, with higher cumulative doses associated with a greater probability of the outcome across the observed range

See this image and copyright information in PMC

References

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Sedation and analgesia in post-cardiac arrest care: a post hoc analysis of the TTM2 trial

Affiliations

Sedation and analgesia in post-cardiac arrest care: a post hoc analysis of the TTM2 trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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LinkOut - more resources

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