Resuscitation 89 (2015) 142–148
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical Paper
Target temperature management of 33 ◦ C and 36 ◦ C in patients with out-of-hospital cardiac arrest with initial non-shockable rhythm – A TTM sub-study夽 Martin Frydland a,∗ , Jesper Kjaergaard a , David Erlinge b , Michael Wanscher a , Niklas Nielsen c , Tommaso Pellis d , Anders Åneman e , Hans Friberg f , Jan Hovdenes g , Janneke Horn h , Jørn Wetterslev i , Matilde Winther-Jensen a , Matthew P. Wise j , Michael Kuiper k , Pascal Stammet l , Tobias Cronberg m , Yvan Gasche n , Christian Hassager a a
The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark Department of Cardiology, Skåne University Hospital, Lund, Sweden Department of Anaesthesia and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden d Department of Intensive Care, Santa Maria degli Angeli, Pordenone, Italy e Department of Intensive Care, Liverpool hospital, Sydney, New South Wales, Australia f Department of Anaesthesia and Intensive Care, Skåne University Hospital, Lund University, Lund, Sweden g Department of Anaesthesia and Intensive Care, Oslo University Hospital, Rikshospitalet, Oslo, Norway h Department of Intensive Care, Academic Medical Centrum, Amsterdam, The Netherlands i Copenhagen Trial Unit, Centre of Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark j Department of Intensive Care, University Hospital of Wales, Cardiff, United Kingdom k Department of Intensive Care, Leeuwarden Medical Centrum, Leeuwarden, The Netherlands l Department of Anaesthesia and Intensive Care, Centre Hospitalier de Luxembourg, Luxembourg m Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden n Department of Intensive Care, Geneva University Hospital, Geneva, Switzerland b c
a r t i c l e
i n f o
Article history: Received 4 November 2014 Received in revised form 19 December 2014 Accepted 22 December 2014 Keywords: Out-of-hospital cardiac arrest Non-shockable rhythm Targeted temperature management Mortality Neurologic function SOFA score
a b s t r a c t Purpose: Despite a lack of randomized trials in comatose survivors of out-of-hospital cardiac arrest (OHCA) with an initial non-shockable rhythm (NSR), guidelines recommend induced hypothermia to be considered in these patients. We assessed the effect on outcome of two levels of induced hypothermia in comatose patient resuscitated from NSR. Methods: Hundred and seventy-eight patients out of 950 in the TTM trial with an initial NSR were randomly assigned to targeted temperature management at either 33 ◦ C (TTM33, n = 96) or 36 ◦ C (TTM36, n = 82). We assessed mortality, neurologic function (Cerebral Performance Score (CPC) and modified Rankin Scale (mRS)), and organ dysfunction (Sequential Organ Failure Assessment (SOFA) score). Results: Patients with NSR were older, had longer time to ROSC, less frequently had bystander CPR and had higher lactate levels at admission compared to patients with shockable rhythm, p < 0.001 for all. Mortality in patients with NSR was 84% in both temperature groups (unadjusted HR 0.92, adjusted HR 0.75; 95% CI 0.53–1.08, p = 0.12). In the TTM33 group 3% survived with poor neurological outcome (CPC 3–4, mRS 4–5), compared to 2% in the TTM36 group (adjusted OR 0.67; 95% CI 0.08–4.73, p = 0.69 for both). Thirteen percent in the TTM33 group and 15% in the TTM36 group had good neurologic outcome (CPC 1–2, mRS 0–3, OR 1.5, CI 0.21–12.5, p = 0.69). The SOFA-score did not differ between temperature groups. Conclusion: Comatose patients after OHCA with initial NSR continue to have a poor prognosis. We found no effect of targeted temperature management at 33 ◦ C compared to 36 ◦ C in these patients. © 2015 Elsevier Ireland Ltd. All rights reserved.
夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2014.12.033. ∗ Corresponding author at: The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 København Ø, Denmark. E-mail address: [email protected] (M. Frydland). http://dx.doi.org/10.1016/j.resuscitation.2014.12.033 0300-9572/© 2015 Elsevier Ireland Ltd. All rights reserved.
M. Frydland et al. / Resuscitation 89 (2015) 142–148
1. Introduction Out-of-hospital cardiac arrest (OHCA) is associated with a high risk of dying and of neurologic impairment in survivors.1 Even though recent data suggest an increase in survival after OHCA,2 overall mortality remains approximately 90%. Annual incidence of OHCA is estimated to be 28–55 per 100,000 person-years with considerable variance amongst different populations.3 Non-shockable primary rhythm as first recorded rhythm on scene is known to have major prognostic importance,2 not only by reducing chances of obtaining return of spontaneous circulation (ROSC)4 but also with regards to chances of surviving to hospital discharge.2,4 Neurological injury from anoxic brain damage remains the leading cause of death, independent of initial rhythm.5,6 Targeted temperature management (TTM) at 32–34 ◦ C for 12–24 h was adopted in international guidelines as being part of postresuscitation care in patients not regaining consciousness after resuscitation from an initial shockable rhythm7–9 and was later extrapolated to be considered in patients with cardiac arrest with initial non-shockable rhythms (NSR). Previous studies examining hypothermia in patients with NRS were mainly observational.10–21 Patients resuscitated from NSR are often older, have more pre-existing comorbidities, and at increased risk of developing multiple organ dysfunction, all of which may increase mortality.2,23–25 Whether this group would benefit from or would be at greater risk of adverse events during TTM has not been thoroughly tested in clinical trials. The recent Target Temperature Management at 33 ◦ C vs. 36 ◦ C after Cardiac Arrest (TTM)-trial included patients resuscitated from OHCA of presumed cardiac cause regardless of primary arrhythmia.26 The interaction analysis between NSR and mortality has previously been published in the TTM-trial manuscript,26 and the present analysis represents an in-depth analysis of the sub-group presenting with NSR. We aimed to assess the effect of targeted temperature management at 33 ◦ C (TTM33) vs. 36 ◦ C (TTM36) on mortality, neurologic outcome, and the development of multiple organ dysfunction evaluated by the SOFA score27 in unconscious patients after OHCA with initial NSR.
2. Materials and methods The TTM-trial was a multi-center, randomized, parallel-group, assessor-blinded, monitored, and investigator-initiated clinical trial investigating targeted temperature management of 33 ◦ C and 36 ◦ C, respectively in unconscious patients resuscitated from outof-hospital cardiac arrest. Patients were centrally randomized, stratified for site, with adequate allocation sequence generation and concealment between November 2010 and January 2013.28 Patients at the age ≥18, comatose (Glasgow Coma Scale < 8) at hospital admission after OHCA with presumed cardiac cause were included. Eligible patients had sustained return of spontaneous circulation (ROSC) of more than 20 min. Patients were excluded if (a) randomization was not performed within 240 min after ROSC, (b) cardiac arrest with an initial rhythm of asystole was unwitnessed, and (c) the patient suffered from refractory shock. A full list of exclusion criteria has been published elsewhere.28 Written informed consent was obtained or waived as previously described.26 Patients were randomized in a 1:1 ratio to either TTM33 or TTM36 for 24 h after ROSC. All patients were sedated, intubated and mechanically ventilated until the end of the intervention period. Active treatment was maintained for a predefined period of minimum 108 h after ROSC, and strict criteria for discontinuation of life support were predefined.28 Pre-hospital data regarding cardiac arrest including initial arrhythmia and factors traditionally associated with mortality
143
were systematically collected at admission in accordance with the Utstein guidelines.29 2.1. Outcome The primary outcome was mortality in the NSR group at the end of the trial with all patients followed-up for at least 180 days after cardiac arrest. We assessed mortality in a multivariate model of induced temperature, age, gender, pulseless electrical activity (PEA), lactate at admission, time to ROSC, bystander cardio pulmonary resuscitation (CPR), SOFA score on day one, largest 2 sites, and witnessed cardiac arrest. In 9 patients initial lactate measurements was missing and therefore excluded from the multivariate analysis. Finally we examined causes of death in the total cohort of patients with NSR. Cause of death was determined by the local physician as the most probable cause of death. The protocol had no requirement for autopsy in fatal cases. Secondary outcome was poor neurologic function at 180 days post-CA. Neurologic function was assessed by cerebral performance category (CPC)30 and the modified Rankin Scale (mRS).31 Poor neurological function was defined as CPC 3–4/mRS 4–5 and good as CPC 1–2/mRS 0–3. Thirdly we assessed the possible association between initial rhythm and the allocated target temperature on the development of multiple organ dysfunction. The Sequential Organ Failure Assessment (SOFA) score was used to assess the severity of organ dysfunction.27 The SOFA score assesses the respiratory (PaO2 /FiO2 ), coagulation (platelet count), liver (bilirubin concentration), renal (creatinine concentration), cerebral (Glasgow Coma Scale), and cardiovascular (hypotension–mean arterial pressure – need for adrenergic agent administration) functions. Each item scores from 0 to 4, with 0 being the best value. The individual organ scores are summarized. SOFA score was registered as the maximum score on day 1, 2, and 3. A possible association between initial rhythm and targeted temperature level on the cardiovascular part of the SOFA-score were also examined separately. 2.2. Ethical approval The TTM-trial is registered at ClinicalTrials.gov (Identifier: NCT01020916) and ethical committees in each participating country approved the protocol. Informed consent was waived or obtained from all participants or relatives according to national legislations. 2.3. Statistics Data are presented as mean ± standard deviation (SD) for normally distributed data, and median and 25th and 75th percentile for skewed data (IQR). Categorical data are presented as numbers and percentages. Differences between groups were tested by t-test, Kruskall-Wallis, Wilcoxon’s, Cochran-Armitage’s and 2 tests as appropriate. Differences in mortality at 30 days and at end of trial as well as neurological outcome at 180 days between strata were assessed by log-rank test, and univariable and multivariable proportional hazard ratio, the latter adjusted for potential confounding factors. Due to the limited sample size we adjusted for age, gender, PEA, lactate on admission, time to ROSC, bystander CPR, total SOFAscore on day 1, and witnessed arrest as these have previously been found to be strong predictors of outcome in OHCA patients.24,32,33 Proportional hazard models were tested for underlying assumption of proportionality, linearity and for interactions. A comparison of the effect of targeting 36 degrees over 33 was performed by adding this variable to the model. Difference in SOFA-score and cardiovascular subscore were tested by binary linear regression with unstructured covariance and repeated measurements.
144
M. Frydland et al. / Resuscitation 89 (2015) 142–148
All statistical analyses were performed using the R. 3.01 software (R Foundation for Statistical Computing, R Core Team; 2013). 3. Results 3.1. Patients A total of 950 patients were originally enrolled in the TTM trial. Overall, no significant differences with regards to the primary outcome were found between TTM33 and TTM36 degrees.26 Fortythree patients were excluded and 907 patients therefore comprised the study cohort of whom 178 patients had initial NSR and comprised the group primarily studied (Fig. 1). Patients in the NSR group were older, had more co-morbidities, more unfavorable intra-arrest circumstances (place of cardiac arrest, bystander CPR, time to advanced life support (ALS) and to ROSC), and poorer initial neurologic status than patients with initial shockable rhythm (Table 1). We found no statistical significant demographic differences between the TTM33 and TTM36 groups in patients with NSR (Table 1).
Fig. 1. Flowchart. Assessment and randomization. Shockable rhythm = VT/VF, nonshockable rhythm = PEA/asystole.
3.2. Mortality At the end of the trial, 81 of 96 patients in the TTM33 group (84%) and 69 of 82 patients in the TTM36 group (84%) died (adjusted Hazard ratio (HR), 0.75; 95%, Confidence Interval (CI) 0.53–1.08, p = 0.12) (Fig. 2; Table 2). Overall, patients with PEA had the same rate of mortality as patients with asystole (HR 0.93; 95%, CI 0.63–1.37, p = 0.63) (Table 3). After 30 days 78 of 96 patients with an initial NSR in the TTM33 group (81%) and 62 of 82 patients in the TTM36 group (76%) had died (Fig. 2), corresponding to an adjusted HR of 0.71; CI
0.49–1.02, p-value 0.06. Factors significantly associated with death were age (adjusted HR 1.03; CI 1.01–1.05, p = 0.01), initial lactate level (adjusted HR 1.10; CI 1.04–1.11, p < 0.001) and time to ROSC (adjusted HR 1.01; CI 1.01–1.02, p < 0.001) (Table 3). Initial GCS, pupil-, and corneal reflex were in 1/4 of the patients affected by sedation and did not affect the HR in the multivariate analysis (data not shown). Ninety-nine patients (66%) died from anoxic brain damage, 28 patients (19%) from cardiovascular conditions, 20 (13%) from multi organ failure and 3 (2%) from other causes. We found no difference
Table 1 Baseline characteristics. Comparing patients with initial non-shockable rhythm (NSR) to patients with shockable rhythm as well as patients with NSR randomized to TTM33 to TTM36. Shockable (n = 729) VT, n (% of total) VF, n (% of total) PEA, n (% of total) Aystole, n (% of total) Sex, male, n (%) Age, mean (SD) Number of comorbidities, median (IQR) Heart failure (%) Previous AMI (%) Ischemic heart disease (%) Atrial fibrillation/flutter (%) Hypertension (%) Previous TIA or stroke (%) Diabetes mellitus (%) Asthma or COPD (%) Previous PCI (%) Previous CABG (%) Place of CA, public, n (%) Witnessed CA, n (%) Bystander CPR, n (%) Bystander defibrillation, n (%) Time to ALS, minutes, median (25%; 75%) Time to ROSC, minutes, median (25%; 75%) Shock at admission Arterial lactate concentration, mean (SD) Glasgow Coma Scale score, median (IQR) Corneal reflex present – no/total no. (%) Pupillary reflex present – no/total no. (%) Target temperature management, 36 ◦ C, n (%) a b c d e
Data not available in one patient. Data not available in 15 patients. Data not available in 50 patients. Data not available in nine patients. Data not available in three patients.
Non-shockable (n = 178)
p
TTM33 (n = 96)
TTM36 (n = 82)
37 (39) 59 (62) 75 (78) 68 (16.25) 2 (2) 7 (7) 23 (24) 31 (32) 9 (9) 48 (50) 10 (10) 17 (18) 13 (14) 15 (16) 12 (13) 29 (30) 82 (85) 53 (55) 6 (6) 11 (8) 30 (25.5) 18 (19) 7.7 (6.9) 3 (0) 36/86 (44) 53/95 (56)
28 (34) 54 (66) 60 (73) 68 (16) 2 (3.75) 6 (7) 16 (20) 22 (27) 5 (6) 38 (46) 8 (10) 17 (21) 14 (17) 8 (10) 8 (10) 24 (29) 75 (92) 43 (52) 3 (4) 10 (9) 31 (35.75) 17 (21) 7.5 (6.4) 3 (0) 27/65 (42) 46/80 (58)
24 (2.6) 705 (75.1)
600 (82.3) 63.2 (12.2) 1 (3) 6.4 19.8 27.0 17.0 38.1 6.9 14.1 8.8 11.0 8.9e 313 (42.9) 656 (89.9) 567 (77.8)a 71 (9.7)a 9.0 (6.0; 12.0)b 25.0 (16.5; 37.0) 101 (14%) 6.3 (4.3)c 3 (2) 450/631 (71) 596/724 (82) 368 (50.5)
65 (6.9) 113 (12.0) 135 (75.8) 67.4 (11.3) 2 (3) 7.3 21.9 29.8 18.0 48.3 10.1 19.1 15.2 12.9 11.2 53 (29.8) 157 (88.2) 96 (53.9) 9 (5.1) 10.0 (6.0; 15.0) 30.5 (19.75; 54.0) 35 (20%) 8.3 (4.8)d 3 (0) 63/151 (42) 99/175 (57) 82 (46.1)
0.07
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical Paper
Target temperature management of 33 ◦ C and 36 ◦ C in patients with out-of-hospital cardiac arrest with initial non-shockable rhythm – A TTM sub-study夽 Martin Frydland a,∗ , Jesper Kjaergaard a , David Erlinge b , Michael Wanscher a , Niklas Nielsen c , Tommaso Pellis d , Anders Åneman e , Hans Friberg f , Jan Hovdenes g , Janneke Horn h , Jørn Wetterslev i , Matilde Winther-Jensen a , Matthew P. Wise j , Michael Kuiper k , Pascal Stammet l , Tobias Cronberg m , Yvan Gasche n , Christian Hassager a a
The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark Department of Cardiology, Skåne University Hospital, Lund, Sweden Department of Anaesthesia and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden d Department of Intensive Care, Santa Maria degli Angeli, Pordenone, Italy e Department of Intensive Care, Liverpool hospital, Sydney, New South Wales, Australia f Department of Anaesthesia and Intensive Care, Skåne University Hospital, Lund University, Lund, Sweden g Department of Anaesthesia and Intensive Care, Oslo University Hospital, Rikshospitalet, Oslo, Norway h Department of Intensive Care, Academic Medical Centrum, Amsterdam, The Netherlands i Copenhagen Trial Unit, Centre of Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark j Department of Intensive Care, University Hospital of Wales, Cardiff, United Kingdom k Department of Intensive Care, Leeuwarden Medical Centrum, Leeuwarden, The Netherlands l Department of Anaesthesia and Intensive Care, Centre Hospitalier de Luxembourg, Luxembourg m Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden n Department of Intensive Care, Geneva University Hospital, Geneva, Switzerland b c
a r t i c l e
i n f o
Article history: Received 4 November 2014 Received in revised form 19 December 2014 Accepted 22 December 2014 Keywords: Out-of-hospital cardiac arrest Non-shockable rhythm Targeted temperature management Mortality Neurologic function SOFA score
a b s t r a c t Purpose: Despite a lack of randomized trials in comatose survivors of out-of-hospital cardiac arrest (OHCA) with an initial non-shockable rhythm (NSR), guidelines recommend induced hypothermia to be considered in these patients. We assessed the effect on outcome of two levels of induced hypothermia in comatose patient resuscitated from NSR. Methods: Hundred and seventy-eight patients out of 950 in the TTM trial with an initial NSR were randomly assigned to targeted temperature management at either 33 ◦ C (TTM33, n = 96) or 36 ◦ C (TTM36, n = 82). We assessed mortality, neurologic function (Cerebral Performance Score (CPC) and modified Rankin Scale (mRS)), and organ dysfunction (Sequential Organ Failure Assessment (SOFA) score). Results: Patients with NSR were older, had longer time to ROSC, less frequently had bystander CPR and had higher lactate levels at admission compared to patients with shockable rhythm, p < 0.001 for all. Mortality in patients with NSR was 84% in both temperature groups (unadjusted HR 0.92, adjusted HR 0.75; 95% CI 0.53–1.08, p = 0.12). In the TTM33 group 3% survived with poor neurological outcome (CPC 3–4, mRS 4–5), compared to 2% in the TTM36 group (adjusted OR 0.67; 95% CI 0.08–4.73, p = 0.69 for both). Thirteen percent in the TTM33 group and 15% in the TTM36 group had good neurologic outcome (CPC 1–2, mRS 0–3, OR 1.5, CI 0.21–12.5, p = 0.69). The SOFA-score did not differ between temperature groups. Conclusion: Comatose patients after OHCA with initial NSR continue to have a poor prognosis. We found no effect of targeted temperature management at 33 ◦ C compared to 36 ◦ C in these patients. © 2015 Elsevier Ireland Ltd. All rights reserved.
夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2014.12.033. ∗ Corresponding author at: The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 København Ø, Denmark. E-mail address: [email protected] (M. Frydland). http://dx.doi.org/10.1016/j.resuscitation.2014.12.033 0300-9572/© 2015 Elsevier Ireland Ltd. All rights reserved.
M. Frydland et al. / Resuscitation 89 (2015) 142–148
1. Introduction Out-of-hospital cardiac arrest (OHCA) is associated with a high risk of dying and of neurologic impairment in survivors.1 Even though recent data suggest an increase in survival after OHCA,2 overall mortality remains approximately 90%. Annual incidence of OHCA is estimated to be 28–55 per 100,000 person-years with considerable variance amongst different populations.3 Non-shockable primary rhythm as first recorded rhythm on scene is known to have major prognostic importance,2 not only by reducing chances of obtaining return of spontaneous circulation (ROSC)4 but also with regards to chances of surviving to hospital discharge.2,4 Neurological injury from anoxic brain damage remains the leading cause of death, independent of initial rhythm.5,6 Targeted temperature management (TTM) at 32–34 ◦ C for 12–24 h was adopted in international guidelines as being part of postresuscitation care in patients not regaining consciousness after resuscitation from an initial shockable rhythm7–9 and was later extrapolated to be considered in patients with cardiac arrest with initial non-shockable rhythms (NSR). Previous studies examining hypothermia in patients with NRS were mainly observational.10–21 Patients resuscitated from NSR are often older, have more pre-existing comorbidities, and at increased risk of developing multiple organ dysfunction, all of which may increase mortality.2,23–25 Whether this group would benefit from or would be at greater risk of adverse events during TTM has not been thoroughly tested in clinical trials. The recent Target Temperature Management at 33 ◦ C vs. 36 ◦ C after Cardiac Arrest (TTM)-trial included patients resuscitated from OHCA of presumed cardiac cause regardless of primary arrhythmia.26 The interaction analysis between NSR and mortality has previously been published in the TTM-trial manuscript,26 and the present analysis represents an in-depth analysis of the sub-group presenting with NSR. We aimed to assess the effect of targeted temperature management at 33 ◦ C (TTM33) vs. 36 ◦ C (TTM36) on mortality, neurologic outcome, and the development of multiple organ dysfunction evaluated by the SOFA score27 in unconscious patients after OHCA with initial NSR.
2. Materials and methods The TTM-trial was a multi-center, randomized, parallel-group, assessor-blinded, monitored, and investigator-initiated clinical trial investigating targeted temperature management of 33 ◦ C and 36 ◦ C, respectively in unconscious patients resuscitated from outof-hospital cardiac arrest. Patients were centrally randomized, stratified for site, with adequate allocation sequence generation and concealment between November 2010 and January 2013.28 Patients at the age ≥18, comatose (Glasgow Coma Scale < 8) at hospital admission after OHCA with presumed cardiac cause were included. Eligible patients had sustained return of spontaneous circulation (ROSC) of more than 20 min. Patients were excluded if (a) randomization was not performed within 240 min after ROSC, (b) cardiac arrest with an initial rhythm of asystole was unwitnessed, and (c) the patient suffered from refractory shock. A full list of exclusion criteria has been published elsewhere.28 Written informed consent was obtained or waived as previously described.26 Patients were randomized in a 1:1 ratio to either TTM33 or TTM36 for 24 h after ROSC. All patients were sedated, intubated and mechanically ventilated until the end of the intervention period. Active treatment was maintained for a predefined period of minimum 108 h after ROSC, and strict criteria for discontinuation of life support were predefined.28 Pre-hospital data regarding cardiac arrest including initial arrhythmia and factors traditionally associated with mortality
143
were systematically collected at admission in accordance with the Utstein guidelines.29 2.1. Outcome The primary outcome was mortality in the NSR group at the end of the trial with all patients followed-up for at least 180 days after cardiac arrest. We assessed mortality in a multivariate model of induced temperature, age, gender, pulseless electrical activity (PEA), lactate at admission, time to ROSC, bystander cardio pulmonary resuscitation (CPR), SOFA score on day one, largest 2 sites, and witnessed cardiac arrest. In 9 patients initial lactate measurements was missing and therefore excluded from the multivariate analysis. Finally we examined causes of death in the total cohort of patients with NSR. Cause of death was determined by the local physician as the most probable cause of death. The protocol had no requirement for autopsy in fatal cases. Secondary outcome was poor neurologic function at 180 days post-CA. Neurologic function was assessed by cerebral performance category (CPC)30 and the modified Rankin Scale (mRS).31 Poor neurological function was defined as CPC 3–4/mRS 4–5 and good as CPC 1–2/mRS 0–3. Thirdly we assessed the possible association between initial rhythm and the allocated target temperature on the development of multiple organ dysfunction. The Sequential Organ Failure Assessment (SOFA) score was used to assess the severity of organ dysfunction.27 The SOFA score assesses the respiratory (PaO2 /FiO2 ), coagulation (platelet count), liver (bilirubin concentration), renal (creatinine concentration), cerebral (Glasgow Coma Scale), and cardiovascular (hypotension–mean arterial pressure – need for adrenergic agent administration) functions. Each item scores from 0 to 4, with 0 being the best value. The individual organ scores are summarized. SOFA score was registered as the maximum score on day 1, 2, and 3. A possible association between initial rhythm and targeted temperature level on the cardiovascular part of the SOFA-score were also examined separately. 2.2. Ethical approval The TTM-trial is registered at ClinicalTrials.gov (Identifier: NCT01020916) and ethical committees in each participating country approved the protocol. Informed consent was waived or obtained from all participants or relatives according to national legislations. 2.3. Statistics Data are presented as mean ± standard deviation (SD) for normally distributed data, and median and 25th and 75th percentile for skewed data (IQR). Categorical data are presented as numbers and percentages. Differences between groups were tested by t-test, Kruskall-Wallis, Wilcoxon’s, Cochran-Armitage’s and 2 tests as appropriate. Differences in mortality at 30 days and at end of trial as well as neurological outcome at 180 days between strata were assessed by log-rank test, and univariable and multivariable proportional hazard ratio, the latter adjusted for potential confounding factors. Due to the limited sample size we adjusted for age, gender, PEA, lactate on admission, time to ROSC, bystander CPR, total SOFAscore on day 1, and witnessed arrest as these have previously been found to be strong predictors of outcome in OHCA patients.24,32,33 Proportional hazard models were tested for underlying assumption of proportionality, linearity and for interactions. A comparison of the effect of targeting 36 degrees over 33 was performed by adding this variable to the model. Difference in SOFA-score and cardiovascular subscore were tested by binary linear regression with unstructured covariance and repeated measurements.
144
M. Frydland et al. / Resuscitation 89 (2015) 142–148
All statistical analyses were performed using the R. 3.01 software (R Foundation for Statistical Computing, R Core Team; 2013). 3. Results 3.1. Patients A total of 950 patients were originally enrolled in the TTM trial. Overall, no significant differences with regards to the primary outcome were found between TTM33 and TTM36 degrees.26 Fortythree patients were excluded and 907 patients therefore comprised the study cohort of whom 178 patients had initial NSR and comprised the group primarily studied (Fig. 1). Patients in the NSR group were older, had more co-morbidities, more unfavorable intra-arrest circumstances (place of cardiac arrest, bystander CPR, time to advanced life support (ALS) and to ROSC), and poorer initial neurologic status than patients with initial shockable rhythm (Table 1). We found no statistical significant demographic differences between the TTM33 and TTM36 groups in patients with NSR (Table 1).
Fig. 1. Flowchart. Assessment and randomization. Shockable rhythm = VT/VF, nonshockable rhythm = PEA/asystole.
3.2. Mortality At the end of the trial, 81 of 96 patients in the TTM33 group (84%) and 69 of 82 patients in the TTM36 group (84%) died (adjusted Hazard ratio (HR), 0.75; 95%, Confidence Interval (CI) 0.53–1.08, p = 0.12) (Fig. 2; Table 2). Overall, patients with PEA had the same rate of mortality as patients with asystole (HR 0.93; 95%, CI 0.63–1.37, p = 0.63) (Table 3). After 30 days 78 of 96 patients with an initial NSR in the TTM33 group (81%) and 62 of 82 patients in the TTM36 group (76%) had died (Fig. 2), corresponding to an adjusted HR of 0.71; CI
0.49–1.02, p-value 0.06. Factors significantly associated with death were age (adjusted HR 1.03; CI 1.01–1.05, p = 0.01), initial lactate level (adjusted HR 1.10; CI 1.04–1.11, p < 0.001) and time to ROSC (adjusted HR 1.01; CI 1.01–1.02, p < 0.001) (Table 3). Initial GCS, pupil-, and corneal reflex were in 1/4 of the patients affected by sedation and did not affect the HR in the multivariate analysis (data not shown). Ninety-nine patients (66%) died from anoxic brain damage, 28 patients (19%) from cardiovascular conditions, 20 (13%) from multi organ failure and 3 (2%) from other causes. We found no difference
Table 1 Baseline characteristics. Comparing patients with initial non-shockable rhythm (NSR) to patients with shockable rhythm as well as patients with NSR randomized to TTM33 to TTM36. Shockable (n = 729) VT, n (% of total) VF, n (% of total) PEA, n (% of total) Aystole, n (% of total) Sex, male, n (%) Age, mean (SD) Number of comorbidities, median (IQR) Heart failure (%) Previous AMI (%) Ischemic heart disease (%) Atrial fibrillation/flutter (%) Hypertension (%) Previous TIA or stroke (%) Diabetes mellitus (%) Asthma or COPD (%) Previous PCI (%) Previous CABG (%) Place of CA, public, n (%) Witnessed CA, n (%) Bystander CPR, n (%) Bystander defibrillation, n (%) Time to ALS, minutes, median (25%; 75%) Time to ROSC, minutes, median (25%; 75%) Shock at admission Arterial lactate concentration, mean (SD) Glasgow Coma Scale score, median (IQR) Corneal reflex present – no/total no. (%) Pupillary reflex present – no/total no. (%) Target temperature management, 36 ◦ C, n (%) a b c d e
Data not available in one patient. Data not available in 15 patients. Data not available in 50 patients. Data not available in nine patients. Data not available in three patients.
Non-shockable (n = 178)
p
TTM33 (n = 96)
TTM36 (n = 82)
37 (39) 59 (62) 75 (78) 68 (16.25) 2 (2) 7 (7) 23 (24) 31 (32) 9 (9) 48 (50) 10 (10) 17 (18) 13 (14) 15 (16) 12 (13) 29 (30) 82 (85) 53 (55) 6 (6) 11 (8) 30 (25.5) 18 (19) 7.7 (6.9) 3 (0) 36/86 (44) 53/95 (56)
28 (34) 54 (66) 60 (73) 68 (16) 2 (3.75) 6 (7) 16 (20) 22 (27) 5 (6) 38 (46) 8 (10) 17 (21) 14 (17) 8 (10) 8 (10) 24 (29) 75 (92) 43 (52) 3 (4) 10 (9) 31 (35.75) 17 (21) 7.5 (6.4) 3 (0) 27/65 (42) 46/80 (58)
24 (2.6) 705 (75.1)
600 (82.3) 63.2 (12.2) 1 (3) 6.4 19.8 27.0 17.0 38.1 6.9 14.1 8.8 11.0 8.9e 313 (42.9) 656 (89.9) 567 (77.8)a 71 (9.7)a 9.0 (6.0; 12.0)b 25.0 (16.5; 37.0) 101 (14%) 6.3 (4.3)c 3 (2) 450/631 (71) 596/724 (82) 368 (50.5)
65 (6.9) 113 (12.0) 135 (75.8) 67.4 (11.3) 2 (3) 7.3 21.9 29.8 18.0 48.3 10.1 19.1 15.2 12.9 11.2 53 (29.8) 157 (88.2) 96 (53.9) 9 (5.1) 10.0 (6.0; 15.0) 30.5 (19.75; 54.0) 35 (20%) 8.3 (4.8)d 3 (0) 63/151 (42) 99/175 (57) 82 (46.1)
0.07
