Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial

doi:10.1186/s13054-022-04107-9

Randomized Controlled Trial

. 2022 Jul 31;26(1):231.

doi: 10.1186/s13054-022-04107-9.

Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial

Joachim Düring¹, Martin Annborn², Alain Cariou³, Michelle S Chew⁴, Josef Dankiewicz⁵, Hans Friberg⁶, Matthias Haenggi⁷, Zana Haxhija⁶, Janus C Jakobsen^{8

9}, Halvor Langeland^{10

11}, Fabio Silvio Taccone¹², Matthew Thomas¹³, Susann Ullén¹⁴, Matt P Wise¹⁵, Niklas Nielsen²

Affiliations

¹ Department of Clinical Sciences, Anesthesia and Intensive Care, Lund University, Skåne University Hospital, Malmö, Sweden. Joachim.during@gmail.com.
² Department of Clinical Sciences, Anesthesia and Intensive Care, Lund University, Helsingborg Hospital, Helsingborg, Sweden.
³ Cochin University Hospital (APHP) and University of Paris (Medical School), Paris, France.
⁴ Department of Anesthesia and Intensive Care, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁵ Department of Clinical Sciences, Cardiology, Lund University, Skåne University Hospital, Lund, Sweden.
⁶ Department of Clinical Sciences, Anesthesia and Intensive Care, Lund University, Skåne University Hospital, Malmö, Sweden.
⁷ Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁸ Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region of Denmark, Denmark.
⁹ Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
¹⁰ Department of Anesthesiology and Intensive Care Medicine, St. Olav's University Hospital, Trondheim, Norway.
¹¹ Institute of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU, Trondheim, Norway.
¹² Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
¹³ Department of Intensive Care, University Hospitals Bristol and Weston, Bristol, UK.
¹⁴ Clinical Studies Sweden- Forum South, Skåne University Hospital, Lund, Sweden.
¹⁵ Adult Critical Care, University Hospital of Wales, Cardiff, UK.

PMID: 35909163
PMCID: PMC9339193
DOI: 10.1186/s13054-022-04107-9

Randomized Controlled Trial

Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial

Joachim Düring et al. Crit Care. 2022.

. 2022 Jul 31;26(1):231.

doi: 10.1186/s13054-022-04107-9.

Authors

Affiliations

¹ Department of Clinical Sciences, Anesthesia and Intensive Care, Lund University, Skåne University Hospital, Malmö, Sweden. Joachim.during@gmail.com.
² Department of Clinical Sciences, Anesthesia and Intensive Care, Lund University, Helsingborg Hospital, Helsingborg, Sweden.
³ Cochin University Hospital (APHP) and University of Paris (Medical School), Paris, France.
⁴ Department of Anesthesia and Intensive Care, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁵ Department of Clinical Sciences, Cardiology, Lund University, Skåne University Hospital, Lund, Sweden.
⁶ Department of Clinical Sciences, Anesthesia and Intensive Care, Lund University, Skåne University Hospital, Malmö, Sweden.
⁷ Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁸ Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region of Denmark, Denmark.
⁹ Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
¹⁰ Department of Anesthesiology and Intensive Care Medicine, St. Olav's University Hospital, Trondheim, Norway.
¹¹ Institute of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU, Trondheim, Norway.
¹² Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
¹³ Department of Intensive Care, University Hospitals Bristol and Weston, Bristol, UK.
¹⁴ Clinical Studies Sweden- Forum South, Skåne University Hospital, Lund, Sweden.
¹⁵ Adult Critical Care, University Hospital of Wales, Cardiff, UK.

PMID: 35909163
PMCID: PMC9339193
DOI: 10.1186/s13054-022-04107-9

Abstract

Background: Targeted temperature management at 33 °C (TTM33) has been employed in effort to mitigate brain injury in unconscious survivors of out-of-hospital cardiac arrest (OHCA). Current guidelines recommend prevention of fever, not excluding TTM33. The main objective of this study was to investigate if TTM33 is associated with mortality in patients with vasopressor support on admission after OHCA.

Methods: We performed a post hoc analysis of patients included in the TTM-2 trial, an international, multicenter trial, investigating outcomes in unconscious adult OHCA patients randomized to TTM33 versus normothermia. Patients were grouped according to level of circulatory support on admission: (1) no-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 mmHg; (2) moderate-vasopressor support MAP < 70 mmHg or any dose of dopamine/dobutamine or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and (3) high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Hazard ratios with TTM33 were calculated for all-cause 180-day mortality in these groups.

Results: The TTM-2 trial enrolled 1900 patients. Data on primary outcome were available for 1850 patients, with 662, 896, and 292 patients in the, no-, moderate-, or high-vasopressor support groups, respectively. Hazard ratio for 180-day mortality was 1.04 [98.3% CI 0.78-1.39] in the no-, 1.22 [98.3% CI 0.97-1.53] in the moderate-, and 0.97 [98.3% CI 0.68-1.38] in the high-vasopressor support groups with regard to TTM33. Results were consistent in an imputed, adjusted sensitivity analysis.

Conclusions: In this exploratory analysis, temperature control at 33 °C after OHCA, compared to normothermia, was not associated with higher incidence of death in patients stratified according to vasopressor support on admission. Trial registration Clinical trials identifier NCT02908308 , registered September 20, 2016.

Keywords: Cardiac arrest; Heart arrest; Hypothermia induced; Mortality; Shock; Sudden.

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Conflict of interest statement

JD: No financial or non-financial competing interests. MA: No financial or non-financial competing interests. AC: Received fees for lectures from Bard. MC: No financial or non-financial competing interests. JD: No financial or non-financial competing interests. HF: TEQCool (Lund, Sweden) Academic advisor. MH: No financial or non-financial competing interests. ZH: No financial or non-financial competing interests. JCJ: No financial or non-financial competing interests. HL: No financial or non-financial competing interests. FT: No financial or non-financial competing interests. MT: No financial competing interests, co-applicant on several NIHR cardiac arrest trials but not in the field of temperature management. SU: No financial or non-financial competing interests. MPW: No financial or non-financial competing interests. NN: No financial or non-financial competing interests.

Figures

**Fig. 1**
Probability of survival. Kaplan–Meier graph censored at 180 days indicating probability of survival in subgroups of vasopressor support on admission, stratified according to temperature intervention. No-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 with no inotropic or vasopressor support; moderate-vasopressor support, MAP < 70 or any dose dopamine, or dobutamine, or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Colored numbers at bottom of plot illustrate number of patients at risk in respective strata at specified timepoint. The vertical tick-marks correspond to censored data. Hazard ratios (HR) are presented with 95% confidence intervals; TTM33, targeted temperature management at 33 °C

**Fig. 2**
Cause of death. Kaplan–Meier graph censored at 30 days indicating cumulative risk of non-neurological versus neurological mortality in subgroups of vasopressor support on admission, stratified according to temperature intervention. No-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 with no inotropic or vasopressor support; moderate-vasopressor support, MAP < 70 or any dose dopamine, or dobutamine, or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Colored numbers at bottom of plot illustrate number of patients at risk in respective strata at specified timepoint. The vertical tick-marks correspond to censored data. Hazard ratios (HR) are presented with 95% confidence intervals; TTM33, targeted temperature management at 33 °C

**Fig. 3**
Circulatory status day 1–4. Graph illustrating the distribution of highest recorded circulatory support for each day. Patients are categorized according to vasopressor support on admission and stratified according to temperature intervention. No-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 with no inotropic or vasopressor support; moderate-vasopressor support, MAP < 70 or any dose dopamine, or dobutamine, or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. D/C, Discharge; ICU, Intensive care unit; Normo; normothermia; and TTM33, targeted temperature management at 33 °C

**Fig. 4**
Hemodynamics 0–72 h. Heart rate, mean arterial pressure, and lactate during the 0–72 h after randomization in groups of different levels of circulatory support on admission and stratified by temperature intervention at 33 °C versus normothermia. No-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 with no inotropic or vasopressor support; moderate-vasopressor support, MAP < 70 or any dose dopamine, or dobutamine, or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Boxes represent the interquartile range (IQR), with medians marked as vertical bands. Whiskers symbolize 1.5 × IQR, and dots outside this range represent outliers. TTM33; Targeted temperature management at 33 °C. *p < 0.003; **p < 0.0001; ***p < 0.00001

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References

1. Olai H, Thorneus G, Watson H, Macleod M, Rhodes J, Friberg H, Nielsen N, Cronberg T, Deierborg T. Meta-analysis of targeted temperature management in animal models of cardiac arrest. Intensive Care Med Exp. 2020;8(1):3. doi: 10.1186/s40635-019-0291-9. - DOI - PMC - PubMed
1. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–563. doi: 10.1056/NEJMoa003289. - DOI - PubMed
1. Hypothermia after Cardiac Arrest Study G Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–556. doi: 10.1056/NEJMoa012689. - DOI - PubMed
1. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, et al. Targeted temperature management at 33 degrees C versus 36 °C after cardiac arrest. N Engl J Med. 2013;369(23):2197–2206. doi: 10.1056/NEJMoa1310519. - DOI - PubMed
1. Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullén S, Rylander C, Wise MP, Oddo M, Cariou A, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384(24):2283–2294. doi: 10.1056/NEJMoa2100591. - DOI - PubMed

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[1] Olai H, Thorneus G, Watson H, Macleod M, Rhodes J, Friberg H, Nielsen N, Cronberg T, Deierborg T. Meta-analysis of targeted temperature management in animal models of cardiac arrest. Intensive Care Med Exp. 2020;8(1):3. doi: 10.1186/s40635-019-0291-9. - DOI - PMC - PubMed

[2] Olai H, Thorneus G, Watson H, Macleod M, Rhodes J, Friberg H, Nielsen N, Cronberg T, Deierborg T. Meta-analysis of targeted temperature management in animal models of cardiac arrest. Intensive Care Med Exp. 2020;8(1):3. doi: 10.1186/s40635-019-0291-9. - DOI - PMC - PubMed

[3] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–563. doi: 10.1056/NEJMoa003289. - DOI - PubMed

[4] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–563. doi: 10.1056/NEJMoa003289. - DOI - PubMed

[5] Hypothermia after Cardiac Arrest Study G Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–556. doi: 10.1056/NEJMoa012689. - DOI - PubMed

[6] Hypothermia after Cardiac Arrest Study G Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–556. doi: 10.1056/NEJMoa012689. - DOI - PubMed

[7] Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, et al. Targeted temperature management at 33 degrees C versus 36 °C after cardiac arrest. N Engl J Med. 2013;369(23):2197–2206. doi: 10.1056/NEJMoa1310519. - DOI - PubMed

[8] Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, et al. Targeted temperature management at 33 degrees C versus 36 °C after cardiac arrest. N Engl J Med. 2013;369(23):2197–2206. doi: 10.1056/NEJMoa1310519. - DOI - PubMed

[9] Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullén S, Rylander C, Wise MP, Oddo M, Cariou A, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384(24):2283–2294. doi: 10.1056/NEJMoa2100591. - DOI - PubMed

[10] Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullén S, Rylander C, Wise MP, Oddo M, Cariou A, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384(24):2283–2294. doi: 10.1056/NEJMoa2100591. - DOI - PubMed

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Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial

Affiliations

Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial

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