Endothelial activation/injury and associations with severity of post-cardiac arrest syndrome and mortality after out-of-hospital cardiac arrest

John Bro-Jeppesen; Pär I Johansson; Christian Hassager; Michael Wanscher; Sisse R Ostrowski; Mette Bjerre; Jesper Kjaergaard

doi:10.1016/j.resuscitation.2016.08.006

Endothelial activation/injury and associations with severity of post-cardiac arrest syndrome and mortality after out-of-hospital cardiac arrest

John Bro-Jeppesen, Pär I Johansson, Christian Hassager, Michael Wanscher, Sisse R Ostrowski, Mette Bjerre, Jesper Kjaergaard

43 Citations (Scopus)

Abstract

Background Post-cardiac arrest syndrome (PCAS) is characterized by whole-body ischemia triggering systemic inflammation and damage of the endothelium. This study investigated the relationship between systemic inflammation, endothelial damage and severity of PCAS and the association between endothelial damage and outcome after out-of-hospital cardiac arrest (OHCA). Methods In this post hoc study, we analyzed 163 comatose patients included at a single center in the target temperature management (TTM) trial, randomly assigned to TTM at 33 °C or 36 °C for 24 h. Endothelial biomarkers (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin) and the inflammatory biomarker interleukin-6 (IL-6) were measured at admission (baseline) and 24, 48 and 72 h after OHCA. Severity of PCAS was assessed by Sequential Organ Failure Assessment score. Mortality at 30-days was evaluated by Cox regression analysis. Results By linear regression, baseline IL-6 levels (two-fold) was independently associated with glycocalyx damage (syndecan-1 (10.3 ng/ml (p = 0.01))), endothelial activation (sE-selectin (2.0 ng/ml (p = 0.03))) and endothelial damage (thrombomodulin 0.7 ng/ml (p = 0.0005)) at 24 h after OHCA. Adjusted for baseline IL-6, a two-fold increase in thrombomodulin from baseline to 48 h (1.7 (0.9–2.4), p < 0.0001) and 72 h (1.5 (0.6–2.3), p < 0.0007) was more closely associated with severity of PCAS than IL-6. Levels of syndecan-1, thrombomodulin and sVE-cadherin was not influenced by level of target temperature but levels of sE-selectin was significantly lower in the 36 °C group (−55 ng/ml (95%CI: −53 to −58 ng/ml), p = 0.005) compared to the 33 °C group. High levels of thrombomodulin at 24 h (HR = 2.1 (1.3–3.3), p = 0.001) and 48 h (HR = 1.75 (1.0–2.8), p = 0.02) were associated with increased 30-day mortality in univariate analysis, but not in multivariable analyses. Conclusion In comatose survivors after OHCA treated with TTM, systemic inflammation was associated with endothelial activation and endothelial damage. Sustained endothelial damage was independently associated with severity of PCAS, adjusted for level of systemic inflammation. TTM at 36 °C compared to 33 °C after OHCA was associated with lower endothelial activation, but not endothelial damage. Clinical Trial Registration: URL: clinicaltrials.gov/ct2/show/NCT01020916. Unique identifier: NCT01020916

Original language	English
Journal	Resuscitation
Volume	107
Pages (from-to)	71-9
Number of pages	9
ISSN	0300-9572
DOIs	https://doi.org/10.1016/j.resuscitation.2016.08.006
Publication status	Published - 1 Oct 2016

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Journal Article

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10.1016/j.resuscitation.2016.08.006

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@article{f3ed13910a874ac28476eabba0ef4e0a,

title = "Endothelial activation/injury and associations with severity of post-cardiac arrest syndrome and mortality after out-of-hospital cardiac arrest",

abstract = "Background Post-cardiac arrest syndrome (PCAS) is characterized by whole-body ischemia triggering systemic inflammation and damage of the endothelium. This study investigated the relationship between systemic inflammation, endothelial damage and severity of PCAS and the association between endothelial damage and outcome after out-of-hospital cardiac arrest (OHCA). Methods In this post hoc study, we analyzed 163 comatose patients included at a single center in the target temperature management (TTM) trial, randomly assigned to TTM at 33 °C or 36 °C for 24 h. Endothelial biomarkers (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin) and the inflammatory biomarker interleukin-6 (IL-6) were measured at admission (baseline) and 24, 48 and 72 h after OHCA. Severity of PCAS was assessed by Sequential Organ Failure Assessment score. Mortality at 30-days was evaluated by Cox regression analysis. Results By linear regression, baseline IL-6 levels (two-fold) was independently associated with glycocalyx damage (syndecan-1 (10.3 ng/ml (p = 0.01))), endothelial activation (sE-selectin (2.0 ng/ml (p = 0.03))) and endothelial damage (thrombomodulin 0.7 ng/ml (p = 0.0005)) at 24 h after OHCA. Adjusted for baseline IL-6, a two-fold increase in thrombomodulin from baseline to 48 h (1.7 (0.9–2.4), p < 0.0001) and 72 h (1.5 (0.6–2.3), p < 0.0007) was more closely associated with severity of PCAS than IL-6. Levels of syndecan-1, thrombomodulin and sVE-cadherin was not influenced by level of target temperature but levels of sE-selectin was significantly lower in the 36 °C group (−55 ng/ml (95%CI: −53 to −58 ng/ml), p = 0.005) compared to the 33 °C group. High levels of thrombomodulin at 24 h (HR = 2.1 (1.3–3.3), p = 0.001) and 48 h (HR = 1.75 (1.0–2.8), p = 0.02) were associated with increased 30-day mortality in univariate analysis, but not in multivariable analyses. Conclusion In comatose survivors after OHCA treated with TTM, systemic inflammation was associated with endothelial activation and endothelial damage. Sustained endothelial damage was independently associated with severity of PCAS, adjusted for level of systemic inflammation. TTM at 36 °C compared to 33 °C after OHCA was associated with lower endothelial activation, but not endothelial damage. Clinical Trial Registration: URL: clinicaltrials.gov/ct2/show/NCT01020916. Unique identifier: NCT01020916",

keywords = "Journal Article",

author = "John Bro-Jeppesen and Johansson, {P{\"a}r I} and Christian Hassager and Michael Wanscher and Ostrowski, {Sisse R} and Mette Bjerre and Jesper Kjaergaard",

year = "2016",

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doi = "10.1016/j.resuscitation.2016.08.006",

language = "English",

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TY - JOUR

T1 - Endothelial activation/injury and associations with severity of post-cardiac arrest syndrome and mortality after out-of-hospital cardiac arrest

AU - Bro-Jeppesen, John

AU - Johansson, Pär I

AU - Hassager, Christian

AU - Wanscher, Michael

AU - Ostrowski, Sisse R

AU - Bjerre, Mette

AU - Kjaergaard, Jesper

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Background Post-cardiac arrest syndrome (PCAS) is characterized by whole-body ischemia triggering systemic inflammation and damage of the endothelium. This study investigated the relationship between systemic inflammation, endothelial damage and severity of PCAS and the association between endothelial damage and outcome after out-of-hospital cardiac arrest (OHCA). Methods In this post hoc study, we analyzed 163 comatose patients included at a single center in the target temperature management (TTM) trial, randomly assigned to TTM at 33 °C or 36 °C for 24 h. Endothelial biomarkers (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin) and the inflammatory biomarker interleukin-6 (IL-6) were measured at admission (baseline) and 24, 48 and 72 h after OHCA. Severity of PCAS was assessed by Sequential Organ Failure Assessment score. Mortality at 30-days was evaluated by Cox regression analysis. Results By linear regression, baseline IL-6 levels (two-fold) was independently associated with glycocalyx damage (syndecan-1 (10.3 ng/ml (p = 0.01))), endothelial activation (sE-selectin (2.0 ng/ml (p = 0.03))) and endothelial damage (thrombomodulin 0.7 ng/ml (p = 0.0005)) at 24 h after OHCA. Adjusted for baseline IL-6, a two-fold increase in thrombomodulin from baseline to 48 h (1.7 (0.9–2.4), p < 0.0001) and 72 h (1.5 (0.6–2.3), p < 0.0007) was more closely associated with severity of PCAS than IL-6. Levels of syndecan-1, thrombomodulin and sVE-cadherin was not influenced by level of target temperature but levels of sE-selectin was significantly lower in the 36 °C group (−55 ng/ml (95%CI: −53 to −58 ng/ml), p = 0.005) compared to the 33 °C group. High levels of thrombomodulin at 24 h (HR = 2.1 (1.3–3.3), p = 0.001) and 48 h (HR = 1.75 (1.0–2.8), p = 0.02) were associated with increased 30-day mortality in univariate analysis, but not in multivariable analyses. Conclusion In comatose survivors after OHCA treated with TTM, systemic inflammation was associated with endothelial activation and endothelial damage. Sustained endothelial damage was independently associated with severity of PCAS, adjusted for level of systemic inflammation. TTM at 36 °C compared to 33 °C after OHCA was associated with lower endothelial activation, but not endothelial damage. Clinical Trial Registration: URL: clinicaltrials.gov/ct2/show/NCT01020916. Unique identifier: NCT01020916

AB - Background Post-cardiac arrest syndrome (PCAS) is characterized by whole-body ischemia triggering systemic inflammation and damage of the endothelium. This study investigated the relationship between systemic inflammation, endothelial damage and severity of PCAS and the association between endothelial damage and outcome after out-of-hospital cardiac arrest (OHCA). Methods In this post hoc study, we analyzed 163 comatose patients included at a single center in the target temperature management (TTM) trial, randomly assigned to TTM at 33 °C or 36 °C for 24 h. Endothelial biomarkers (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin) and the inflammatory biomarker interleukin-6 (IL-6) were measured at admission (baseline) and 24, 48 and 72 h after OHCA. Severity of PCAS was assessed by Sequential Organ Failure Assessment score. Mortality at 30-days was evaluated by Cox regression analysis. Results By linear regression, baseline IL-6 levels (two-fold) was independently associated with glycocalyx damage (syndecan-1 (10.3 ng/ml (p = 0.01))), endothelial activation (sE-selectin (2.0 ng/ml (p = 0.03))) and endothelial damage (thrombomodulin 0.7 ng/ml (p = 0.0005)) at 24 h after OHCA. Adjusted for baseline IL-6, a two-fold increase in thrombomodulin from baseline to 48 h (1.7 (0.9–2.4), p < 0.0001) and 72 h (1.5 (0.6–2.3), p < 0.0007) was more closely associated with severity of PCAS than IL-6. Levels of syndecan-1, thrombomodulin and sVE-cadherin was not influenced by level of target temperature but levels of sE-selectin was significantly lower in the 36 °C group (−55 ng/ml (95%CI: −53 to −58 ng/ml), p = 0.005) compared to the 33 °C group. High levels of thrombomodulin at 24 h (HR = 2.1 (1.3–3.3), p = 0.001) and 48 h (HR = 1.75 (1.0–2.8), p = 0.02) were associated with increased 30-day mortality in univariate analysis, but not in multivariable analyses. Conclusion In comatose survivors after OHCA treated with TTM, systemic inflammation was associated with endothelial activation and endothelial damage. Sustained endothelial damage was independently associated with severity of PCAS, adjusted for level of systemic inflammation. TTM at 36 °C compared to 33 °C after OHCA was associated with lower endothelial activation, but not endothelial damage. Clinical Trial Registration: URL: clinicaltrials.gov/ct2/show/NCT01020916. Unique identifier: NCT01020916

KW - Journal Article

U2 - 10.1016/j.resuscitation.2016.08.006

DO - 10.1016/j.resuscitation.2016.08.006

M3 - Journal article

C2 - 27523954

SN - 0300-9572

VL - 107

SP - 71

EP - 79

JO - Resuscitation

JF - Resuscitation

ER -

Endothelial activation/injury and associations with severity of post-cardiac arrest syndrome and mortality after out-of-hospital cardiac arrest

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