Intensive Care Med (2014) 40:1832–1842 DOI 10.1007/s00134-014-3519-x
Guillaume Debaty Maxime Maignan Dominique Savary Franc¸ois-xavier Koch Ste´phane Ruckly Michel Durand Julien Picard Christophe Escallier Renaud Chouquer Charles Santre Clemence Minet Dorra Guergour Laure Hammer He´le`ne Bouvaist Loic Belle Christophe Adrie Jean-Franc¸ois Payen Franc¸oise Carpentier Pierre-Yves Gueugniaud Vincent Danel Jean-Franc¸ois Timsit Received: 8 September 2014 Accepted: 9 October 2014 Published online: 28 October 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014 Electronic supplementary material The online version of this article (doi: 10.1007/s00134-014-3519-x) contains supplementary material, which is available to authorized users.
SEVEN-DAY PROFILE PUBLICATION
Impact of intra-arrest therapeutic hypothermia in outcomes of prehospital cardiac arrest: a randomized controlled trial
M. Durand J. Picard J.-F. Payen Department of Anesthesiology and Critical Care, Grenoble University Hospital, Grenoble, France R. Chouquer C. Santre Department of Anesthesiology and Critical Care, Annecy Hospital, Annecy, France C. Minet L. Hammer Department of Intensive Care Medicine, Grenoble University Hospital, Grenoble, France
G. Debaty M. Maignan UJF-Grenoble 1/CNRS/TIMC-IMAG UMR 5525/Team PRETA, 38041 Grenoble, France
D. Guergour Department of Biochemistry Toxicology Pharmacology, Grenoble University Hospital, Grenoble, France
G. Debaty ()) M. Maignan F. Koch C. Escallier F. Carpentier V. Danel SAMU 38, Poˆle Urgences-Me´decine Aigue¨, CHU Grenoble, 10217, 38043 Grenoble Cedex 09, France e-mail: [email protected] Tel.: (?33) 4 76 63 42 00
H. Bouvaist Department of Cardiology, Grenoble University Hospital, Grenoble, France L. Belle Department of Cardiology, Annecy Hospital, Annecy, France
D. Savary Department of Emergency Medicine, SAMU 74, Annecy Hospital, Annecy, France
C. Adrie Physiology Department, Cochin Hospital, ICU, Paris, France
S. Ruckly J.-F. Timsit University Joseph Fourrier, Albert Bonniot Institute, La Tronche Cedex, France
S. Ruckly P.-Y. Gueugniaud SAMU 69, Hospices Civils de Lyon, University of Lyon 1, Lyon, France
J.-F. Timsit UMR 1137-IAME Team 5-(DeSCID) Decision Sciences in Infectious Diseases, Control and Care, Inserm/Univ Paris Diderot, Sorbonne Paris Cite´, 75018 Paris, France
Abstract Purpose: Mild therapeutic hypothermia (TH) is recommended as soon as possible after the return of spontaneous circulation to improve outcomes after outof-hospital cardiac arrest (OHCA). Preclinical data suggest that the benefit of TH could be increased if treatment is started during cardiac arrest. We aimed to study the impact of intra-arrest therapeutic hypothermia (IATH) on neurological injury and inflammation following OHCA. Methods: We conducted a 1:1 randomized, multicenter study in three prehospital emergency medical services and four critical care units in France. OHCA patients, irrespective of the initial rhythm, received either an infusion of cold saline and external cooling during cardiac arrest (IATH group) or TH started after hospital admission (hospital-cooling group). The primary endpoint was neuron-
1833
specific enolase (NSE) serum concentrations at 24 h. Secondary endpoints included IL-6, IL-8, and IL-10 concentrations, and clinical outcome. Results: Of the 245 patients included, 123 were analyzed in the IATH group and 122 in the hospital-cooling group. IATH decreased time to reach temperature B34 °C by 75 min (95 % CI: 4; 269). The rate of patients admitted alive to hospital was not different between
groups [IATH n = 41 (33 %) vs. hospital cooling n = 36 (30 %); p = 0.51]. Levels of NSE and inflammatory biomarkers were not different between groups [median NSE at 24 h: IATH 96.7 lg/l (IQR: 49.9–142.8) vs. hospital cooling 97.6 lg/l (IQR: 74.3–142.4), p = 0.64]. No difference in survival and cerebral performance were found at 1 month. Conclusions: IATH did not affect biological markers of
Introduction Approximately 300,000 patients suffer from out-of-hospital cardiac arrest (OHCA) annually in Europe, and survival rate with favorable neurological function remains dismal [1]. Mild therapeutic hypothermia (TH) has been shown to improve survival and reduce neurological damage by limiting reperfusion injury after OHCA [2]. TH (32–34 °C) is recommended for 12–24 h as soon as possible after return of spontaneous circulation (ROSC) [3]. Therefore, the optimal timing for induction of TH and the optimal temperature remain uncertain [4]. In most studies, TH is induced after hospital admission, and time to reach the targeted temperature can be up to 8 h [2, 5]. Some clinical studies have shown that inducing TH in the prehospital setting is feasible. While the prehospital use of external ice packs is limited by a low cooling rate, the infusion of a large volume (30 ml/kg) of 4 °C has been shown to decrease temperature between 1.2 and 2.3 °C before hospital admission in OHCA patients [6–9]. However, prehospital cooling when performed after ROSC seems to be ineffective to improve survival or neurological outcomes [7–9]. This lack of benefit could be linked to the delay in the initiation of cooling. Several animal studies and some clinical data have suggested that the benefit to neurological outcome could be greatly increased if TH is started during cardiopulmonary resuscitation (CPR) [10–14]. Experimental investigations have also shown that intra-arrest therapeutic hypothermia (IATH) increases the success rate of defibrillation attempts in ventricular fibrillation (VF), improved left ventricular function, and reduced myocardial infarct size [15, 16]. Serum biochemical markers and inflammatory response markers, such as neuron-specific enolase (NSE), S100 calcium binding protein B (S-100B), and interleukin (IL)-6, -8, and -10, have been proposed as early prognostic markers after successful resuscitation of cardiac arrest [17–19]. Specifically, NSE has been reported to be the most promising and extensively studied marker to predict bad outcome after cardiac arrest [3]. Elevated
inflammation or brain damage or clinical outcome. Keywords Therapeutic hypothermia Cardiopulmonary resuscitation Resuscitation Cardiac arrest Post-cardiac arrest syndrome
level of NSE between 24 and 72 h were associated with initial illness severity [20]. The aim of the present study was to investigate the effects of IATH on neurological outcome and biological markers after OHCA. We hypothesized that IATH would be associated with lower neurological damage and reduced serum levels of NSE.
Methods Study design The study was approved by the institutional review board (CPP Sud Est V, 01/2009, Lyon, France). In accordance with French law, the board waived the requirement for obtaining informed consent from patients because of the emergency setting of the research; however, the subject’s legal representative was informed of the subject’s study participation, and patients who regained normal neurological function were asked to provide their consent for use of the data. The study was designed as a 1:1 randomized, multicenter trial. Three prehospital emergency medical services (EMS) and four intensive care units in two hospitals in France participated in the study from September 2009 to July 2012. In France, prehospital EMS consist of mobile intensive care units staffed by a paramedic driver, a nurse, and a senior emergency physician. Mobile intensive care units are dispatched in case of OHCA to provide advanced life support in addition to first rescuers response. As a consequence, patients are admitted to hospital only if they had a ROSC. In this study, OHCA patients over 18 years of age were recruited during resuscitation by the EMS physician. Patients eligible for advanced life support were included irrespective of rhythm. Patients with trauma, hemorrhage, asphyxia, already hypothermic (temperature \34 °C), women who were obviously pregnant, patients who had achieved ROSC before randomization, and patients with a do-not-attempt resuscitation order were not included. The
1834
randomization assignments were generated under a randomized permuted-block design, with block sizes of 4, in a 1:1 allocation. Each mobile intensive care unit was given sequentially numbered sealed envelopes containing single randomization assignments. The randomization list was stratified by centers. The envelope was opened if the patient fulfilled the inclusion criteria, and the patient was assigned to either IATH or to cooling treatment once admitted to the hospital (hospital cooling group). Treatment protocol
Secondary endpoints included IL-6, IL-8 and IL-10 concentrations during the first 72 h, cooling rates, ROSC rate, length of stay in the intensive care, survival (discharge, 30 days and 1 years), and neurological outcome (hospital discharge and 30 days). Secondary endpoints were also analyzed according to initial rhythm. NSE, IL6, IL-8 and IL-10 have been proposed as early prognostic markers after successful resuscitation of CA and have been evaluated in patients treated with hypothermia, in particular NSE has been the only marker recommended in American Guidelines in 2006 to predict outcome after cardiac arrest [17–19, 21, 22]. A safety end point was defined as the rate of complications during 72 h after OHCA. Complications included the rate of pulmonary edema, bleeding (bleeding causing fatality, intracranial bleeding, and other bleeding that required transfusion), infection (sepsis, pneumonia, urinary tract infection) with positive culture, arrhythmia (VF, ventricular tachycardia, atrial flutter, atrial fibrillation, need for pacing, new cardiac arrest), seizures, and hyperthermia ([38 °C within 72 h).
In all patients, the resuscitation attempt followed the European Resuscitation Council guidelines [1]. The 2010 changes in the guidelines have been implemented in all centers. At mobile intensive care unit arrival, intravenous access was established. Concomitantly, airways were secured by endotracheal intubation and core temperature was measured using an esophageal probe. In addition to usual care, IATH patients received an infusion of up to 2,000 mL of ice-cold 0.9 % saline solution at 100 mL/min during cardiac arrest by use of a standard infusion set and a pressure bag inflated to 300 mm Hg. Surface cooling was also induced using gel pads (Colpac; Chattanooga Medical Supply). Four cooling units were applied on the neck, abdomen and thighs. Fluid and surface cooling supplies were stored in an insulated container to ensure that temperature was\8 °C. In the IATH group, core temperature was maintained between 32 and 34 °C. Following ROSC, intravenous midazolam (0.1 mg/kg), sufentanil (0.2 lg/ kg) and cisatracurium (10 mg) were administered through continuous intravenous infusion to suppress shivering. Following hospital admission, TH was either maintained (IATH group) or induced (hospital cooling group) using cold saline infusion, cooling mattress, cold air circulation and/or extra corporeal life support if needed for hemodynamic support. Cooling was induced at a maximum rate with a target temperature of 32–34 °C. In both groups, the target temperature was maintained for 24 h, and a controlled rewarming phase was started at a set rate of 0.3–0.5 °C per hour to reach 37 °C. ROSC was defined as an organized rhythm and palpable pulse that was sustained for at least 2 min. All subjects received standard post-resuscitation treatment on hospital arrival per the institution’s standards. Intravenous sedation, analgesia, and neuromuscular blockade were initiated or continued. Ventilation was set to maintain normoxemia as well as normocapnia.
Data on cardiac arrest for individual patients were recorded in the Utstein style [23]. NSE, IL-6, IL-8, and IL-10 were collected and analyzed at baseline (just after randomization in the prehospital setting), and 3, 6, 12, 24, 48 and 72 h after baseline. Blood samples were stored on ice and centrifuged as soon as possible for 15 min at 2,000g at 4 °C, and plasma was stored at -80 °C until batch-wise analysis. Measurement of serum NSE was performed using an enzyme immunoassay by an automated Elecsys (Roche Diagnostics, Germany). Interleukins were determined using Biochip Array Technology (Randox Laboratories, Antrim, UK). Haemolyzed samples were excluded. Other clinical and biological data were collected at baseline, every 15 min in the prehospital setting, at hospital admission, at ICU admission, and 3, 6, 12, 24, 48 and 72 h after ICU admission. A chest x-ray was performed at admission and at 24 h. A cardiac ultrasound evaluation was performed 24 h after admission. Neurological outcome at hospital discharge and 30 days was assessed by a physician blinded to randomization using the five-grade Glasgow-Pittsburgh cerebral performance categories (CPC) [23].
Outcome
Statistical analysis
The aim of this study was to compare neurological damage and inflammation following OHCA between IATH and standard groups. We chose as primary endpoint the concentration of NSE at 24 h.
The sample size was difference of NSE of mean value of 10 lg/l the hospital cooling
Data collection
estimated a priori to measure a 5 lg/l at 24 h with an estimated in the IATH group and 15 lg/l in group (standard deviation was
1835
1559 Paents with out-of-hospital cardiac arrest assessed for eligibility 967 excluded 393 Dead 108 CPR stopped at ALS team arrival 24 Aged
Guillaume Debaty Maxime Maignan Dominique Savary Franc¸ois-xavier Koch Ste´phane Ruckly Michel Durand Julien Picard Christophe Escallier Renaud Chouquer Charles Santre Clemence Minet Dorra Guergour Laure Hammer He´le`ne Bouvaist Loic Belle Christophe Adrie Jean-Franc¸ois Payen Franc¸oise Carpentier Pierre-Yves Gueugniaud Vincent Danel Jean-Franc¸ois Timsit Received: 8 September 2014 Accepted: 9 October 2014 Published online: 28 October 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014 Electronic supplementary material The online version of this article (doi: 10.1007/s00134-014-3519-x) contains supplementary material, which is available to authorized users.
SEVEN-DAY PROFILE PUBLICATION
Impact of intra-arrest therapeutic hypothermia in outcomes of prehospital cardiac arrest: a randomized controlled trial
M. Durand J. Picard J.-F. Payen Department of Anesthesiology and Critical Care, Grenoble University Hospital, Grenoble, France R. Chouquer C. Santre Department of Anesthesiology and Critical Care, Annecy Hospital, Annecy, France C. Minet L. Hammer Department of Intensive Care Medicine, Grenoble University Hospital, Grenoble, France
G. Debaty M. Maignan UJF-Grenoble 1/CNRS/TIMC-IMAG UMR 5525/Team PRETA, 38041 Grenoble, France
D. Guergour Department of Biochemistry Toxicology Pharmacology, Grenoble University Hospital, Grenoble, France
G. Debaty ()) M. Maignan F. Koch C. Escallier F. Carpentier V. Danel SAMU 38, Poˆle Urgences-Me´decine Aigue¨, CHU Grenoble, 10217, 38043 Grenoble Cedex 09, France e-mail: [email protected] Tel.: (?33) 4 76 63 42 00
H. Bouvaist Department of Cardiology, Grenoble University Hospital, Grenoble, France L. Belle Department of Cardiology, Annecy Hospital, Annecy, France
D. Savary Department of Emergency Medicine, SAMU 74, Annecy Hospital, Annecy, France
C. Adrie Physiology Department, Cochin Hospital, ICU, Paris, France
S. Ruckly J.-F. Timsit University Joseph Fourrier, Albert Bonniot Institute, La Tronche Cedex, France
S. Ruckly P.-Y. Gueugniaud SAMU 69, Hospices Civils de Lyon, University of Lyon 1, Lyon, France
J.-F. Timsit UMR 1137-IAME Team 5-(DeSCID) Decision Sciences in Infectious Diseases, Control and Care, Inserm/Univ Paris Diderot, Sorbonne Paris Cite´, 75018 Paris, France
Abstract Purpose: Mild therapeutic hypothermia (TH) is recommended as soon as possible after the return of spontaneous circulation to improve outcomes after outof-hospital cardiac arrest (OHCA). Preclinical data suggest that the benefit of TH could be increased if treatment is started during cardiac arrest. We aimed to study the impact of intra-arrest therapeutic hypothermia (IATH) on neurological injury and inflammation following OHCA. Methods: We conducted a 1:1 randomized, multicenter study in three prehospital emergency medical services and four critical care units in France. OHCA patients, irrespective of the initial rhythm, received either an infusion of cold saline and external cooling during cardiac arrest (IATH group) or TH started after hospital admission (hospital-cooling group). The primary endpoint was neuron-
1833
specific enolase (NSE) serum concentrations at 24 h. Secondary endpoints included IL-6, IL-8, and IL-10 concentrations, and clinical outcome. Results: Of the 245 patients included, 123 were analyzed in the IATH group and 122 in the hospital-cooling group. IATH decreased time to reach temperature B34 °C by 75 min (95 % CI: 4; 269). The rate of patients admitted alive to hospital was not different between
groups [IATH n = 41 (33 %) vs. hospital cooling n = 36 (30 %); p = 0.51]. Levels of NSE and inflammatory biomarkers were not different between groups [median NSE at 24 h: IATH 96.7 lg/l (IQR: 49.9–142.8) vs. hospital cooling 97.6 lg/l (IQR: 74.3–142.4), p = 0.64]. No difference in survival and cerebral performance were found at 1 month. Conclusions: IATH did not affect biological markers of
Introduction Approximately 300,000 patients suffer from out-of-hospital cardiac arrest (OHCA) annually in Europe, and survival rate with favorable neurological function remains dismal [1]. Mild therapeutic hypothermia (TH) has been shown to improve survival and reduce neurological damage by limiting reperfusion injury after OHCA [2]. TH (32–34 °C) is recommended for 12–24 h as soon as possible after return of spontaneous circulation (ROSC) [3]. Therefore, the optimal timing for induction of TH and the optimal temperature remain uncertain [4]. In most studies, TH is induced after hospital admission, and time to reach the targeted temperature can be up to 8 h [2, 5]. Some clinical studies have shown that inducing TH in the prehospital setting is feasible. While the prehospital use of external ice packs is limited by a low cooling rate, the infusion of a large volume (30 ml/kg) of 4 °C has been shown to decrease temperature between 1.2 and 2.3 °C before hospital admission in OHCA patients [6–9]. However, prehospital cooling when performed after ROSC seems to be ineffective to improve survival or neurological outcomes [7–9]. This lack of benefit could be linked to the delay in the initiation of cooling. Several animal studies and some clinical data have suggested that the benefit to neurological outcome could be greatly increased if TH is started during cardiopulmonary resuscitation (CPR) [10–14]. Experimental investigations have also shown that intra-arrest therapeutic hypothermia (IATH) increases the success rate of defibrillation attempts in ventricular fibrillation (VF), improved left ventricular function, and reduced myocardial infarct size [15, 16]. Serum biochemical markers and inflammatory response markers, such as neuron-specific enolase (NSE), S100 calcium binding protein B (S-100B), and interleukin (IL)-6, -8, and -10, have been proposed as early prognostic markers after successful resuscitation of cardiac arrest [17–19]. Specifically, NSE has been reported to be the most promising and extensively studied marker to predict bad outcome after cardiac arrest [3]. Elevated
inflammation or brain damage or clinical outcome. Keywords Therapeutic hypothermia Cardiopulmonary resuscitation Resuscitation Cardiac arrest Post-cardiac arrest syndrome
level of NSE between 24 and 72 h were associated with initial illness severity [20]. The aim of the present study was to investigate the effects of IATH on neurological outcome and biological markers after OHCA. We hypothesized that IATH would be associated with lower neurological damage and reduced serum levels of NSE.
Methods Study design The study was approved by the institutional review board (CPP Sud Est V, 01/2009, Lyon, France). In accordance with French law, the board waived the requirement for obtaining informed consent from patients because of the emergency setting of the research; however, the subject’s legal representative was informed of the subject’s study participation, and patients who regained normal neurological function were asked to provide their consent for use of the data. The study was designed as a 1:1 randomized, multicenter trial. Three prehospital emergency medical services (EMS) and four intensive care units in two hospitals in France participated in the study from September 2009 to July 2012. In France, prehospital EMS consist of mobile intensive care units staffed by a paramedic driver, a nurse, and a senior emergency physician. Mobile intensive care units are dispatched in case of OHCA to provide advanced life support in addition to first rescuers response. As a consequence, patients are admitted to hospital only if they had a ROSC. In this study, OHCA patients over 18 years of age were recruited during resuscitation by the EMS physician. Patients eligible for advanced life support were included irrespective of rhythm. Patients with trauma, hemorrhage, asphyxia, already hypothermic (temperature \34 °C), women who were obviously pregnant, patients who had achieved ROSC before randomization, and patients with a do-not-attempt resuscitation order were not included. The
1834
randomization assignments were generated under a randomized permuted-block design, with block sizes of 4, in a 1:1 allocation. Each mobile intensive care unit was given sequentially numbered sealed envelopes containing single randomization assignments. The randomization list was stratified by centers. The envelope was opened if the patient fulfilled the inclusion criteria, and the patient was assigned to either IATH or to cooling treatment once admitted to the hospital (hospital cooling group). Treatment protocol
Secondary endpoints included IL-6, IL-8 and IL-10 concentrations during the first 72 h, cooling rates, ROSC rate, length of stay in the intensive care, survival (discharge, 30 days and 1 years), and neurological outcome (hospital discharge and 30 days). Secondary endpoints were also analyzed according to initial rhythm. NSE, IL6, IL-8 and IL-10 have been proposed as early prognostic markers after successful resuscitation of CA and have been evaluated in patients treated with hypothermia, in particular NSE has been the only marker recommended in American Guidelines in 2006 to predict outcome after cardiac arrest [17–19, 21, 22]. A safety end point was defined as the rate of complications during 72 h after OHCA. Complications included the rate of pulmonary edema, bleeding (bleeding causing fatality, intracranial bleeding, and other bleeding that required transfusion), infection (sepsis, pneumonia, urinary tract infection) with positive culture, arrhythmia (VF, ventricular tachycardia, atrial flutter, atrial fibrillation, need for pacing, new cardiac arrest), seizures, and hyperthermia ([38 °C within 72 h).
In all patients, the resuscitation attempt followed the European Resuscitation Council guidelines [1]. The 2010 changes in the guidelines have been implemented in all centers. At mobile intensive care unit arrival, intravenous access was established. Concomitantly, airways were secured by endotracheal intubation and core temperature was measured using an esophageal probe. In addition to usual care, IATH patients received an infusion of up to 2,000 mL of ice-cold 0.9 % saline solution at 100 mL/min during cardiac arrest by use of a standard infusion set and a pressure bag inflated to 300 mm Hg. Surface cooling was also induced using gel pads (Colpac; Chattanooga Medical Supply). Four cooling units were applied on the neck, abdomen and thighs. Fluid and surface cooling supplies were stored in an insulated container to ensure that temperature was\8 °C. In the IATH group, core temperature was maintained between 32 and 34 °C. Following ROSC, intravenous midazolam (0.1 mg/kg), sufentanil (0.2 lg/ kg) and cisatracurium (10 mg) were administered through continuous intravenous infusion to suppress shivering. Following hospital admission, TH was either maintained (IATH group) or induced (hospital cooling group) using cold saline infusion, cooling mattress, cold air circulation and/or extra corporeal life support if needed for hemodynamic support. Cooling was induced at a maximum rate with a target temperature of 32–34 °C. In both groups, the target temperature was maintained for 24 h, and a controlled rewarming phase was started at a set rate of 0.3–0.5 °C per hour to reach 37 °C. ROSC was defined as an organized rhythm and palpable pulse that was sustained for at least 2 min. All subjects received standard post-resuscitation treatment on hospital arrival per the institution’s standards. Intravenous sedation, analgesia, and neuromuscular blockade were initiated or continued. Ventilation was set to maintain normoxemia as well as normocapnia.
Data on cardiac arrest for individual patients were recorded in the Utstein style [23]. NSE, IL-6, IL-8, and IL-10 were collected and analyzed at baseline (just after randomization in the prehospital setting), and 3, 6, 12, 24, 48 and 72 h after baseline. Blood samples were stored on ice and centrifuged as soon as possible for 15 min at 2,000g at 4 °C, and plasma was stored at -80 °C until batch-wise analysis. Measurement of serum NSE was performed using an enzyme immunoassay by an automated Elecsys (Roche Diagnostics, Germany). Interleukins were determined using Biochip Array Technology (Randox Laboratories, Antrim, UK). Haemolyzed samples were excluded. Other clinical and biological data were collected at baseline, every 15 min in the prehospital setting, at hospital admission, at ICU admission, and 3, 6, 12, 24, 48 and 72 h after ICU admission. A chest x-ray was performed at admission and at 24 h. A cardiac ultrasound evaluation was performed 24 h after admission. Neurological outcome at hospital discharge and 30 days was assessed by a physician blinded to randomization using the five-grade Glasgow-Pittsburgh cerebral performance categories (CPC) [23].
Outcome
Statistical analysis
The aim of this study was to compare neurological damage and inflammation following OHCA between IATH and standard groups. We chose as primary endpoint the concentration of NSE at 24 h.
The sample size was difference of NSE of mean value of 10 lg/l the hospital cooling
Data collection
estimated a priori to measure a 5 lg/l at 24 h with an estimated in the IATH group and 15 lg/l in group (standard deviation was
1835
1559 Paents with out-of-hospital cardiac arrest assessed for eligibility 967 excluded 393 Dead 108 CPR stopped at ALS team arrival 24 Aged
