Copeptin as a marker of outcome after cardiac arrest: a sub-study of the TTM trial

Abstract

Background: Arginine vasopressin has complex actions in critically ill patients, involving vasoregulatory status, plasma volume, and cortisol levels. Copeptin, a surrogate marker for arginine vasopressin, has shown promising prognostic features in small observational studies and is used clinically for early rule out of acute coronary syndrome. The objective of this study was to explore the association between early measurements of copeptin, circulatory status, and short-term survival after out-of-hospital cardiac arrest.

Methods: Serial blood samples were collected at 24, 48, and 72 h as part of the target temperature management at 33 °C versus 36 °C after cardiac arrest trial, an international multicenter randomized trial where unconscious survivors after out-of-hospital cardiac arrest were allocated to an intervention of 33 or 36 °C for 24 h. Primary outcome was 30-day survival with secondary endpoints circulatory cause of death and cardiovascular deterioration composite; in addition, we examined the correlation with extended the cardiovascular sequential organ failure assessment (eCvSOFA) score.

Results: Six hundred ninety patients were included in the analyses, of whom 203 (30.3%) developed cardiovascular deterioration within 24 h, and 273 (39.6%) died within 30 days. Copeptin measured at 24 h was found to be independently associated with 30-day survival, hazard ratio 1.17 [1.06-1.28], p = 0.001; circulatory cause of death, odds ratio 1.03 [1.01-1.04], p = 0.001; and cardiovascular deterioration composite, odds ratio of 1.05 [1.02-1.08], p < 0.001. Copeptin at 24 h was correlated with eCvSOFA score with rho 0.19 [0.12-0.27], p < 0.001.

Conclusion: Copeptin is an independent marker of severity of the post cardiac arrest syndrome, partially related to circulatory failure.

Trial registration: Clinical Trials, NCT01020916. Registered November 26, 2009.

Keywords: AVP protein human; Arginine vasopressin; Biomarkers; Copeptin; Critical illness; Humans; Out-of hospital cardiac arrest; Prognosis; Survivors.

Conflict of interest statement

HF: Bard Medical (lecture fees), QuickCool (scientific advisor).

HRN: Medical Director at Thermo Fisher Scientific.

YD: Funds from; National Research Fund of Luxembourg (grants # C14/BM/8225223 and C17/BM/11613033), The Ministry of Higher Education and Research of Luxembourg and The Heart Foundation - Daniel Wagner.

MW: BARD Medical (2009: Advisory board). BARD Medical (2018: Lecture, accommodation and travel fees).

JK: Research on management of post cardiac arrest care supported by the NovoNordisk Foundation (NNF17OC0028706).

Figures

Fig. 1

Copeptin levels stratified according to 30-day mortality. Box plot illustrating difference in copeptin levels measured at 24, 48, and 72 h after cardiac arrest in survivors vs non-survivors at day 30. Copeptin on Y-axis is on a log scale

Fig. 2

Probability of 30-day survival. Kaplan-Meier graph illustrating the probability of survival after cardiac arrest according to copeptin levels stratified as above or below median at 24 h. Outcome was censored after 30 days. Shaded areas indicate 95% confidence interval. Survival was significantly higher in the group with copeptin levels below median at 24 h, p < 0.001

Fig. 3

Multivariate explanatory model for short time survival. Forest plot displaying hazard ratio for death within 30 days in a multivariate Cox proportional hazards model adjusted for log2-transformed copeptin at 24 h, age (years), adrenaline used (yes/no), admission pH, shockable rhythm (yes/no), cardiac arrest at home (yes/no), Glasgow Coma Scale motor component (GCSm) more than 1 or sedated at admission (yes/no), corneal or pupillary reflexes present at admission (yes/no), no flow time = time from cardiac arrest until start of chest compression or return of spontaneous circulation, whichever comes first (min), low flow time = from start of chest compressions until return of spontaneous circulation (min), admission arterial pCO2 below 4.5 kPa on admission (yes/no), and temperature management at 33 C after cardiac arrest (yes/no). p values below 0.05 were considered significant

Fig. 4

Multivariate explanatory model for cardiovascular deterioration composite, CvDC, at 24 h. Forest plot displaying odds ratios for a positive cardiovascular deterioration composite (CvDC) in a multivariate logistic regression model. CvDC was considered positive if the patient had an extended cardiovascular SOFA score (eCvSOFA) ≥ 5 or died from circulatory cause at within ± 12 h of time point or if eCvSOFA score increased more than two points within the previous 24 h. The model was adjusted for adjusted for log2-transformed copeptin at 24 h, age (years), adrenaline used (yes/no), admission pH, shockable rhythm (yes/no), cardiac arrest at home (yes/no), Glasgow Coma Scale motor component (GCSm) more than 1 or sedated at admission (yes/no), corneal or pupillary reflexes present at admission (yes/no), no flow time = time from cardiac arrest until start of chest compression or return of spontaneous circulation, whichever comes first (min), low flow time = from start of chest compressions until return of spontaneous circulation (min), admission arterial pCO2 below 4.5 kPa on admission (yes/no), and temperature management at 33 °C after cardiac arrest (yes/no). p values below 0.05 were considered significant