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Respective impact of lowering body temperature and heart rate on mortality in septic shock: mediation analysis of a randomized trial

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Abstract

Purpose

We previously showed that external cooling decreases day 14 mortality in febrile septic shock. Because cooling may participate in heart rate control, we studied the respective impact of heart rate and temperature lowering on mortality.

Methods

Post hoc analysis of the Sepsiscool randomized controlled trial database (NCT00527007). Cooling was applied to maintain normothermia (36.5–37 °C) during 48 h. We assessed the time spent below different thresholds of temperature and heart rate on day 14 mortality. The best threshold was selected by AUC-ROC and tested as a potential mediator of mortality reduction. Mediation analysis was adjusted for severity and treatments influencing temperature and heart rate evolution. Sensitivity analysis was done using only patients with appropriate antimicrobial therapy.

Results

A total of 197/200 patients with adequate heart rate and temperature monitoring were analyzed. The best threshold differentiating survivors and nonsurvivors was 38.4 °C for temperature and 95 b/min for heart rate. During the 48 h of intervention, cooling significantly increased the time spent with a temperature below 38.4 °C, p = 0.001, and with a heart rate below 95 b/min, p < 0.01. The longer was the time spent with a temperature below 38.4 °C, the lower was the mortality [adjOR 0.17 (0.06–0.49), p = 0.001]. The time spent with a heart rate below 95 b/min was similar in survivors and nonsurvivors [adjOR 0.68 (0.27–1.72), p = 0.42]. Mediation analysis showed that the time spent with a temperature below 38.4 °C was a significant mediator of mortality.

Conclusion

The time spent with a temperature below 38.4 °C was independently associated with patient’s outcome and explained 73 % of the effect of the randomization on the day 14 mortality. Heart rate lowering was not a mediator of mortality.

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Acknowledgment

This study was funded by The Assistance Publique-Hôpitaux de Paris, France. The sponsor participated in the study organization and monitoring but had no access to the data.

Sepsis Cool Investigators

Karine Clabault: Réanimation médicale CHU de Rouen, France.

Fabrice Cook: AP-HP, Groupe Hospitalier Henri Mondor, réanimation chirurgicale, Créteil, France.

Jean Dellamonica: Réanimation médicale CHU de Nice, France.

Jerome Devaquet: Réanimation polyvalente Hôpital Foch, Suresnes, France.

Nicolas Deye: APHP, Hôpital Lariboisière, réanimation médicale et toxicologique, Paris, France.

Alain Mercat: Réanimation médicale CHU Angers, France.

Author information

Authors and Affiliations

  1. Réanimation médicale, Hôpital Henri Mondor-APHP, Créteil, France

    Frédérique Schortgen

  2. Unité de recherche clinique, Hôpital Européen Georges Pompidou-APHP, Paris, France

    Anaïs Charles-Nelson & Sandrine Katsahian

  3. Réanimation médicale et infectieuse, Hôpital Bichat-Claude Bernard-APHP, Paris, France

    Lila Bouadma

  4. Unité de recherche clinique, Hôpital Henri Mondor-APHP, Créteil, France

    Geoffray Bizouard

  5. Keenan Research Centre, St Michael’s Hospital, Toronto, Canada

    Laurent Brochard

  6. Interdepartmental Division of Critical care, University of Toronto, Toronto, Canada

    Laurent Brochard

  7. INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France

    Anaïs Charles-Nelson & Sandrine Katsahian

Authors
  1. Frédérique Schortgen
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  2. Anaïs Charles-Nelson
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  3. Lila Bouadma
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  4. Geoffray Bizouard
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  5. Laurent Brochard
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  6. Sandrine Katsahian
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Corresponding author

Correspondence to Frédérique Schortgen.

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Conflicts of interest

Dr. Brochard’s laboratory has received research grant from Dräger (SmartCare), Covidien (PAV), General Electric (lung volume), Fisher Paykel (high flow oxygen), and Vygon (CPAP), educational grant from General Electric, and personal fees from Covidien (PAV). St Michael’s Hospital in Toronto is receiving royalties from Maquet (NAVA). Dr. Katsahian consulted for La générale de santé. The remaining authors have no conflict of interest.

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For the Sepsis Cool Investigators. The remaining members of the Sepsis Cool Investigators are listed at the end of the article.

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Schortgen, F., Charles-Nelson, A., Bouadma, L. et al. Respective impact of lowering body temperature and heart rate on mortality in septic shock: mediation analysis of a randomized trial. Intensive Care Med 41, 1800–1808 (2015). https://doi.org/10.1007/s00134-015-3987-7

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  • DOI: https://doi.org/10.1007/s00134-015-3987-7

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