Resuscitation 91 (2015) 92–98
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical Paper
Mortality and neurological outcome in the elderly after target temperature management for out-of-hospital cardiac arrest夽 Matilde Winther-Jensen a,∗ , Tommaso Pellis b , Michael Kuiper c , Matty Koopmans c , Christian Hassager a , Niklas Nielsen d , Jørn Wetterslev e , Tobias Cronberg f , David Erlinge g , Hans Friberg h , Yvan Gasche i , Janneke Horn j , Jan Hovdenes k , Pascal Stammet l , Michael Wanscher a , Matthew P. Wise m , Anders Åneman n , Jesper Kjaergaard a a
The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark Department of Intensive Care, Santa Maria degli Angeli, Pordenone, Italy c Department of Intensive Care, Leeuwarden Medical Centrum, Leeuwarden, The Netherlands d Department of Anesthesia and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden e Copenhagen Trial Unit, Centre of Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark f Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden g Department of Cardiology, Skåne University Hospital, Lund, Sweden h Department of Anesthesia and Intensive Care, Skåne University Hospital, Lund University, Lund, Sweden i Department of Intensive Care, Geneva University Hospital, Geneva, Switzerland j Department of Intensive Care, Academic Medical Centrum, Amsterdam, The Netherlands k Department of Anesthesia and Intensive Care, Oslo University Hospital, Rikshospitalet, Oslo, Norway l Department of Anesthesia and Intensive Care, Centre Hospitalier de Luxembourg, Luxembourg m Department of Intensive Care, University Hospital of Wales, Cardiff, United Kingdom n Department of Intensive Care, Liverpool hospital, Sydney, New South Wales, Australia b
a r t i c l e
i n f o
Article history: Received 9 October 2014 Received in revised form 12 December 2014 Accepted 22 December 2014 Keywords: Out-of hospital cardiac arrest Therapeutic hypothermia Age
a b s t r a c t Aim: To assess older age as a prognostic factor in patients resuscitated from out-of-hospital-cardiac arrest (OHCA) and the interaction between age and level of target temperature management. Methods and results: 950 patients included in the target temperature management (TTM) trial were randomly allocated to TTM at 33 or 36 ◦ C for 24 h. We assessed survival and cerebral outcome (cerebral performance category, CPC and modified Rankin scale, mRS) using age as predictor, dividing patients into 5 age groups: ≤65 (median), 66–70, 71–75, 76–80 and >80 years of age. Shockable rhythm decreased with higher age groups, p = 0.001, the same was true for ST segment elevation on ECG at admission, p < 0.01. Increasing age was associated with a higher mortality rate (HR = 1.04 per year, 95% CI = 1.03–1.06, p < 0.001) after adjusting for confounders. Octogenarians had an increased mortality (HR = 3.5, CI: 2.5–5.0, p < 0.001) compared to patients ≤65 years of age. Favorable vs. unfavorable outcome measured by CPC and mRS in survivors was different between age groups with adverse outcomes more prevalent in higher age groups (CPC: p = 0.04, mRS: p = 0.001). The interaction between age and target temperature allocation was not statistically significant for either mortality or neurological outcome. Conclusion: Increasing age is associated with significantly increased mortality after OHCA, but mortality rate is not influenced by level of target temperature. Risk of poor neurological outcome also increases with age, but is not modified by level of target temperature. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
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.2014.12.030. ∗ Corresponding author. E-mail address: [email protected] (M. Winther-Jensen). http://dx.doi.org/10.1016/j.resuscitation.2014.12.030 0300-9572/© 2015 Elsevier Ireland Ltd. All rights reserved.
Age remains an important determinant of mortality in the majority of acute and chronic diseases, and healthcare-related costs in the elderly are substantial and increasing. Management guidelines in elderly patients are rarely based on robust evidence in contrast to younger patients, since this population is either excluded from randomized clinical trials by age alone or by a higher
M. Winther-Jensen et al. / Resuscitation 91 (2015) 92–98
likelihood of comorbidities limiting eligibility for inclusion. Guidelines for post resuscitation care following out-of-hospital cardiac arrest (OHCA) are no exception,1 and in particular temperature management in the elderly cohort has not been studied. Previous randomized trials2,3 suggested a beneficial effect of target temperature management at 32–34 ◦ C. However elderly patients were underrepresented since patients >75 years were excluded from the largest trial.2 A recent registry study found a 25% short-term survival and 91% with good neurological outcome in elderly >75.4 The demographics of Western populations are changing with growing numbers of elderly individuals.5 Consequently the number of potential elderly OHCA patients needing specialized postresuscitation care is increasing.6 However, elderly have been found to receive less invasive procedures, which to some extent confound investigations of prognosis.7,8 The target temperature management after cardiac arrest trial (TTM-trial) showed no benefit of targeting a temperature of 33 ◦ C versus 36 ◦ C after OHCA.9 A further analysis of the effect of age on treatment benefits may identify additional subgroups, apart from 65 as analyzed in the TTM-trial, in which TTM at 33 ◦ C is beneficial or harmful. This sub-study of the TTM-trial investigates the impact of age as prognostic factor on mortality and neurological outcome after cardiac arrest and the effect of TTM in different age groups. 2. Methods 2.1. Study design and population This study is a post-hoc sub-study of the TTM-trial including 950 OHCA patients admitted to 36 intensive care units (ICU’s) in Europe and Australia from November 2010 to January 2013.9 The study was pre-defined internally before approval from the TTM steering group. The primary outcome was all-cause mortality at the end of the trial in July 2013. Neither the primary nor secondary outcomes of neurological function differed between the TTM33 and TTM36 groups.9 As a predefined design variable the effect of TTM33 and TTM36 stratified by median age has been published.9 Patients included were ≥18 years and scored 80: n = 76. 65 years was chosen as first cut-off, because this was the median age in the total sample. 2.2. Ethical approval The TTM-trial is registered at ClinicalTrials.gov (Identifier: NCT01020916) and the protocol has been approved by ethical committees in each participating country. Informed consent has been waived or obtained from all participants or relatives according to national legislation.
93
2.3. Outcome Mortality was assessed using the survival status in the TTMdataset, obtained from hospital registry, public registry or contact with patient, relatives or physician 6 months after randomization. Patients alive 6 months after were checked for survival status at end of trial. A blinded assessor scored the patients neurological function by the cerebral performance category (CPC) and the modified Rankin scale (mRS) 180 days after OHCA. The CPC scale ranks neurological outcome in 5 categories 1–5, where lower numbers (1–2) signify good cerebral outcome, while 5 signifies death. The mRS starts at 0 signifying no symptoms and increases until 6, which is death. CPC scores 1–2 and mRS 0–3 are considered good outcome 2.4. Statistical analyses Data are presented as total number of patients and proportion (%) of patient in each age group. Continuous data are reported as mean ± standard deviation or as median (quartiles) in case of a non-normal distribution of data. Differences were assessed by Cochran–Armitage trend test (linear weights) for variables with two outcome categories or Kruskal–Wallis rank sum test for distribution of variables among >2 categories. Comorbidities were pooled into two categories, ≤2 (2: mean) and >2 comorbidities. P-values were corrected for multiple testing using the Bonferroni–Holm method. Mortality at 30 days and end of trial was assessed by Kaplan–Meier plots and Cox regression and compared using log-rank tests. Multivariate proportional hazard Cox regression was applied to check the influence on other variables. Hazard ratio (HR) and 95% confidence interval (CI) are reported. A proportional hazard model with cubic spline was plotted for both temperature groups to illustrate the association of 1-year mortality and age. Factors influencing neurological outcome (favorable versus unfavorable), performance of coronary angiography (CAG) and percutaneous intervention (PCI) were analyzed in binary linear models and Firth’s penalized-likelihood logistic regression was implemented upon perfect separation of predictors. Analyses on CAG/PCI were also performed in STEMI and No-STEMI patients separately. STEMI patients are defined as those with ST-elevation on admission ECG, while No-STEMI contains all other admission ECGs, including NSTEMI. All analyses were performed in R.3.01.12 3. Results 3.1. Population and in-hospital differences between age groups There were no differences in the age strata regarding witnessed arrest, place of OHCA, bystander defibrillation, time to ROSC, basic and advanced life support, or bystander CPR (Table 1). The randomization to TTM group was balanced in all age groups, p = 0.99. Frequency of having >2 comorbidities differed amongst age groups (p < 0.001), with no significant trend. First monitored rhythm (shockable/non-shockable) differed with decreasing fractions of shockable rhythm with higher age group, p = 0.001 (Table 1). ST segment elevation myocardial infarction (STEMI) and CAG and PCI (75 years (34%) than in patients between 71 and 75 years (30%) and 80 years. Multiorgan failure was more common with increasing age, being the cause of death in 22% of patients >80 years and only in 8% in the youngest age group (≤65 years) (Table 2).
94
M. Winther-Jensen et al. / Resuscitation 91 (2015) 92–98
Table 1 Population and OHCA characteristics in the 5 age groups. OHCA: out-of-hospital cardiac arrest, CPR: cardiopulmonary resuscitation, BLS: basic life support, ALS: advanced life support, ROSC: return of spontaneous circulation, VF: ventricular fibrillation, VT: ventricular tachycardia, PEA: pulseless electrical activity, CA: cardiac arrest, ECG: electrocardiogram, LBBB: Left bundle branch block. P-values were corrected for multiple testing using the Bonferroni–Holm method. 2 comorbidities Temperature 33 ◦ C 36 ◦ C Cooling by surface device OHCA in public place Bystander witnessed OHCA Bystander CPR Bystander defibrillation Time CA to BLS Time CA to ALS Time CA to ROSC First monitored rhythm VF/VT PEA Asystole ROSC-bystander CPR Lactate at admission ECG findings at admission Acute ST-elevation Acute LBBB Normal/unchanged f. prior ECG Other abnormality
54.10 (8.33)
66–70 (n = 194)
71–75 (n = 132)
67.43 (1.71)
72.96 (1.45)
76–80 (n = 83)
>80 (n = 76)
p value
77.96 (1.49)
84.59 (3.25)
73 years.16,17 Often analysis on survival in elderly after OHCA is limited to hospital discharge or 30-day survival,18,19 but some observational studies investigate long-term outcome and do not recommend that age should influence treatment decision20,21 or find that most elderly >65 VF OHCA survivors return to work post-arrest.22 The increased mortality in the elderly also impacts the assessment of neurological outcome by the CPC and mRS scales, but when focusing on survivors, the elderly had increased risk of poor neurological outcome. The susceptibility of the elderly to ischemic brain injury is increased23 and it may be expected that this population would have a higher mortality, but also worse functional
96
M. Winther-Jensen et al. / Resuscitation 91 (2015) 92–98
Table 3 Hazard ratios for death per year of increase in age and age groups in univariate and multivariate models for 30 days follow up as well as end of trial. 30-Day follow up
Full study period
Univariate
Age, per year Age groups ≤65 (median) 66–70 71–75 76–80 >80
Multivariate
Univariate
Multivariate
HR (95% CI)
p-value
HR (95% CI)
p-value
HR (95% CI)
p-value
HR (95% CI)
p-value
1.04 (1.03–1.05)
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical Paper
Mortality and neurological outcome in the elderly after target temperature management for out-of-hospital cardiac arrest夽 Matilde Winther-Jensen a,∗ , Tommaso Pellis b , Michael Kuiper c , Matty Koopmans c , Christian Hassager a , Niklas Nielsen d , Jørn Wetterslev e , Tobias Cronberg f , David Erlinge g , Hans Friberg h , Yvan Gasche i , Janneke Horn j , Jan Hovdenes k , Pascal Stammet l , Michael Wanscher a , Matthew P. Wise m , Anders Åneman n , Jesper Kjaergaard a a
The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark Department of Intensive Care, Santa Maria degli Angeli, Pordenone, Italy c Department of Intensive Care, Leeuwarden Medical Centrum, Leeuwarden, The Netherlands d Department of Anesthesia and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden e Copenhagen Trial Unit, Centre of Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark f Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden g Department of Cardiology, Skåne University Hospital, Lund, Sweden h Department of Anesthesia and Intensive Care, Skåne University Hospital, Lund University, Lund, Sweden i Department of Intensive Care, Geneva University Hospital, Geneva, Switzerland j Department of Intensive Care, Academic Medical Centrum, Amsterdam, The Netherlands k Department of Anesthesia and Intensive Care, Oslo University Hospital, Rikshospitalet, Oslo, Norway l Department of Anesthesia and Intensive Care, Centre Hospitalier de Luxembourg, Luxembourg m Department of Intensive Care, University Hospital of Wales, Cardiff, United Kingdom n Department of Intensive Care, Liverpool hospital, Sydney, New South Wales, Australia b
a r t i c l e
i n f o
Article history: Received 9 October 2014 Received in revised form 12 December 2014 Accepted 22 December 2014 Keywords: Out-of hospital cardiac arrest Therapeutic hypothermia Age
a b s t r a c t Aim: To assess older age as a prognostic factor in patients resuscitated from out-of-hospital-cardiac arrest (OHCA) and the interaction between age and level of target temperature management. Methods and results: 950 patients included in the target temperature management (TTM) trial were randomly allocated to TTM at 33 or 36 ◦ C for 24 h. We assessed survival and cerebral outcome (cerebral performance category, CPC and modified Rankin scale, mRS) using age as predictor, dividing patients into 5 age groups: ≤65 (median), 66–70, 71–75, 76–80 and >80 years of age. Shockable rhythm decreased with higher age groups, p = 0.001, the same was true for ST segment elevation on ECG at admission, p < 0.01. Increasing age was associated with a higher mortality rate (HR = 1.04 per year, 95% CI = 1.03–1.06, p < 0.001) after adjusting for confounders. Octogenarians had an increased mortality (HR = 3.5, CI: 2.5–5.0, p < 0.001) compared to patients ≤65 years of age. Favorable vs. unfavorable outcome measured by CPC and mRS in survivors was different between age groups with adverse outcomes more prevalent in higher age groups (CPC: p = 0.04, mRS: p = 0.001). The interaction between age and target temperature allocation was not statistically significant for either mortality or neurological outcome. Conclusion: Increasing age is associated with significantly increased mortality after OHCA, but mortality rate is not influenced by level of target temperature. Risk of poor neurological outcome also increases with age, but is not modified by level of target temperature. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
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.2014.12.030. ∗ Corresponding author. E-mail address: [email protected] (M. Winther-Jensen). http://dx.doi.org/10.1016/j.resuscitation.2014.12.030 0300-9572/© 2015 Elsevier Ireland Ltd. All rights reserved.
Age remains an important determinant of mortality in the majority of acute and chronic diseases, and healthcare-related costs in the elderly are substantial and increasing. Management guidelines in elderly patients are rarely based on robust evidence in contrast to younger patients, since this population is either excluded from randomized clinical trials by age alone or by a higher
M. Winther-Jensen et al. / Resuscitation 91 (2015) 92–98
likelihood of comorbidities limiting eligibility for inclusion. Guidelines for post resuscitation care following out-of-hospital cardiac arrest (OHCA) are no exception,1 and in particular temperature management in the elderly cohort has not been studied. Previous randomized trials2,3 suggested a beneficial effect of target temperature management at 32–34 ◦ C. However elderly patients were underrepresented since patients >75 years were excluded from the largest trial.2 A recent registry study found a 25% short-term survival and 91% with good neurological outcome in elderly >75.4 The demographics of Western populations are changing with growing numbers of elderly individuals.5 Consequently the number of potential elderly OHCA patients needing specialized postresuscitation care is increasing.6 However, elderly have been found to receive less invasive procedures, which to some extent confound investigations of prognosis.7,8 The target temperature management after cardiac arrest trial (TTM-trial) showed no benefit of targeting a temperature of 33 ◦ C versus 36 ◦ C after OHCA.9 A further analysis of the effect of age on treatment benefits may identify additional subgroups, apart from 65 as analyzed in the TTM-trial, in which TTM at 33 ◦ C is beneficial or harmful. This sub-study of the TTM-trial investigates the impact of age as prognostic factor on mortality and neurological outcome after cardiac arrest and the effect of TTM in different age groups. 2. Methods 2.1. Study design and population This study is a post-hoc sub-study of the TTM-trial including 950 OHCA patients admitted to 36 intensive care units (ICU’s) in Europe and Australia from November 2010 to January 2013.9 The study was pre-defined internally before approval from the TTM steering group. The primary outcome was all-cause mortality at the end of the trial in July 2013. Neither the primary nor secondary outcomes of neurological function differed between the TTM33 and TTM36 groups.9 As a predefined design variable the effect of TTM33 and TTM36 stratified by median age has been published.9 Patients included were ≥18 years and scored 80: n = 76. 65 years was chosen as first cut-off, because this was the median age in the total sample. 2.2. Ethical approval The TTM-trial is registered at ClinicalTrials.gov (Identifier: NCT01020916) and the protocol has been approved by ethical committees in each participating country. Informed consent has been waived or obtained from all participants or relatives according to national legislation.
93
2.3. Outcome Mortality was assessed using the survival status in the TTMdataset, obtained from hospital registry, public registry or contact with patient, relatives or physician 6 months after randomization. Patients alive 6 months after were checked for survival status at end of trial. A blinded assessor scored the patients neurological function by the cerebral performance category (CPC) and the modified Rankin scale (mRS) 180 days after OHCA. The CPC scale ranks neurological outcome in 5 categories 1–5, where lower numbers (1–2) signify good cerebral outcome, while 5 signifies death. The mRS starts at 0 signifying no symptoms and increases until 6, which is death. CPC scores 1–2 and mRS 0–3 are considered good outcome 2.4. Statistical analyses Data are presented as total number of patients and proportion (%) of patient in each age group. Continuous data are reported as mean ± standard deviation or as median (quartiles) in case of a non-normal distribution of data. Differences were assessed by Cochran–Armitage trend test (linear weights) for variables with two outcome categories or Kruskal–Wallis rank sum test for distribution of variables among >2 categories. Comorbidities were pooled into two categories, ≤2 (2: mean) and >2 comorbidities. P-values were corrected for multiple testing using the Bonferroni–Holm method. Mortality at 30 days and end of trial was assessed by Kaplan–Meier plots and Cox regression and compared using log-rank tests. Multivariate proportional hazard Cox regression was applied to check the influence on other variables. Hazard ratio (HR) and 95% confidence interval (CI) are reported. A proportional hazard model with cubic spline was plotted for both temperature groups to illustrate the association of 1-year mortality and age. Factors influencing neurological outcome (favorable versus unfavorable), performance of coronary angiography (CAG) and percutaneous intervention (PCI) were analyzed in binary linear models and Firth’s penalized-likelihood logistic regression was implemented upon perfect separation of predictors. Analyses on CAG/PCI were also performed in STEMI and No-STEMI patients separately. STEMI patients are defined as those with ST-elevation on admission ECG, while No-STEMI contains all other admission ECGs, including NSTEMI. All analyses were performed in R.3.01.12 3. Results 3.1. Population and in-hospital differences between age groups There were no differences in the age strata regarding witnessed arrest, place of OHCA, bystander defibrillation, time to ROSC, basic and advanced life support, or bystander CPR (Table 1). The randomization to TTM group was balanced in all age groups, p = 0.99. Frequency of having >2 comorbidities differed amongst age groups (p < 0.001), with no significant trend. First monitored rhythm (shockable/non-shockable) differed with decreasing fractions of shockable rhythm with higher age group, p = 0.001 (Table 1). ST segment elevation myocardial infarction (STEMI) and CAG and PCI (75 years (34%) than in patients between 71 and 75 years (30%) and 80 years. Multiorgan failure was more common with increasing age, being the cause of death in 22% of patients >80 years and only in 8% in the youngest age group (≤65 years) (Table 2).
94
M. Winther-Jensen et al. / Resuscitation 91 (2015) 92–98
Table 1 Population and OHCA characteristics in the 5 age groups. OHCA: out-of-hospital cardiac arrest, CPR: cardiopulmonary resuscitation, BLS: basic life support, ALS: advanced life support, ROSC: return of spontaneous circulation, VF: ventricular fibrillation, VT: ventricular tachycardia, PEA: pulseless electrical activity, CA: cardiac arrest, ECG: electrocardiogram, LBBB: Left bundle branch block. P-values were corrected for multiple testing using the Bonferroni–Holm method. 2 comorbidities Temperature 33 ◦ C 36 ◦ C Cooling by surface device OHCA in public place Bystander witnessed OHCA Bystander CPR Bystander defibrillation Time CA to BLS Time CA to ALS Time CA to ROSC First monitored rhythm VF/VT PEA Asystole ROSC-bystander CPR Lactate at admission ECG findings at admission Acute ST-elevation Acute LBBB Normal/unchanged f. prior ECG Other abnormality
54.10 (8.33)
66–70 (n = 194)
71–75 (n = 132)
67.43 (1.71)
72.96 (1.45)
76–80 (n = 83)
>80 (n = 76)
p value
77.96 (1.49)
84.59 (3.25)
73 years.16,17 Often analysis on survival in elderly after OHCA is limited to hospital discharge or 30-day survival,18,19 but some observational studies investigate long-term outcome and do not recommend that age should influence treatment decision20,21 or find that most elderly >65 VF OHCA survivors return to work post-arrest.22 The increased mortality in the elderly also impacts the assessment of neurological outcome by the CPC and mRS scales, but when focusing on survivors, the elderly had increased risk of poor neurological outcome. The susceptibility of the elderly to ischemic brain injury is increased23 and it may be expected that this population would have a higher mortality, but also worse functional
96
M. Winther-Jensen et al. / Resuscitation 91 (2015) 92–98
Table 3 Hazard ratios for death per year of increase in age and age groups in univariate and multivariate models for 30 days follow up as well as end of trial. 30-Day follow up
Full study period
Univariate
Age, per year Age groups ≤65 (median) 66–70 71–75 76–80 >80
Multivariate
Univariate
Multivariate
HR (95% CI)
p-value
HR (95% CI)
p-value
HR (95% CI)
p-value
HR (95% CI)
p-value
1.04 (1.03–1.05)
