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Temperature variability during targeted temperature management is not associated with neurological outcomes following cardiac arrest
American Journal of Emergency Medicine 35 (2017) 889–892
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Temperature variability during targeted temperature management is not associated with neurological outcomes following cardiac arrest☆,☆☆ Arash Nayeri a,⁎, Nirmanmoh Bhatia b, Benjamin Holmes b, Nyal Borges c, William Armstrong c, Meng Xu d, Eric Farber-Eger b, Quinn S. Wells b, John A. McPherson b a
University of California, Los Angeles, Department of Medicine, 757 Westwood Plaza, St. 7501, Los Angeles, CA 90095-7417, United States Vanderbilt University Medical Center, Division of Cardiovascular Medicine, 2220 Pierce Avenue, 383 Preston Research Building, Nashville, TN 37232-6300, United States Vanderbilt University Medical Center, Department of Medicine, 1161 21st Avenue South, D-3100e Medical Center North, Nashville, TN 37232, United States d Vanderbilt University Medical Center, Department of Biostatistics, 2525 West End Ave, St 1100, Nashville, TN 37203, United States b c
a r t i c l e
i n f o
Article history: Received 6 December 2016 Received in revised form 19 January 2017 Accepted 26 January 2017 Keywords: Targeted temperature management (TTM) Therapeutic hypothermia (TH) Cardiac arrest Temperature variability Cerebral performance category (CPC)
a b s t r a c t Introduction: Recent studies on comatose survivors of cardiac arrest undergoing targeted temperature management (TTM) have shown similar outcomes at multiple target temperatures. However, details regarding core temperature variability during TTM and its prognostic implications remain largely unknown. We sought to assess the association between core temperature variability and neurological outcomes in patients undergoing TTM following cardiac arrest. Methods: We analyzed a prospectively collected cohort of 242 patients treated with TTM following cardiac arrest at a tertiary care hospital between 2007 and 2014. Core temperature variability was defined as the statistical variance (i.e. standard deviation squared) amongst all core temperature recordings during the maintenance phase of TTM. Poor neurological outcome at hospital discharge, defined as a Cerebral Performance Category (CPC) score N 2, was the primary outcome. Death prior to hospital discharge was assessed as the secondary outcome. Multivariable logistic regression was used to examine the association between temperature variability and neurological outcome or death at hospital discharge. Results: A poor neurological outcome was observed in 147 (61%) patients and 136 (56%) patients died prior to hospital discharge. In multivariable logistic regression, increased core temperature variability was not associated with increased odds of poor neurological outcomes (OR 0.38, 95% CI 0.11–1.38, p = 0.142) or death (OR 0.43, 95% CI 0.12–1.53, p = 0.193) at hospital discharge. Conclusion: In this study, individual core temperature variability during TTM was not associated with poor neurological outcomes or death at hospital discharge. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Cardiac arrest is a major cause of morbidity and mortality in the United States, affecting approximately 400 000 patients annually and accounting for 15% of all-cause mortality [1,2]. The rate of survival to hospital discharge remains exceedingly low and b10% of cardiac arrest ☆ Authorship disclosure: All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ☆☆ Conflicts of interest: No potential conflicts of interest are disclosed. No grant support was used in the preparation of this work. ⁎ Corresponding author. E-mail addresses: [email protected] (A. Nayeri), [email protected] (N. Bhatia), [email protected] (B. Holmes), [email protected] (N. Borges), [email protected] (W. Armstrong), Meng.xu@ vanderbilt.edu (M. Xu), [email protected] (E. Farber-Eger), [email protected] (Q.S. Wells), [email protected] (J.A. McPherson).
http://dx.doi.org/10.1016/j.ajem.2017.01.058 0735-6757/© 2017 Elsevier Inc. All rights reserved.
victims are discharged with a favorable neurological outcome [3]. Neurological injury remains the leading cause of death in this patient population and accounts for approximately two-thirds of all-cause mortality [4]. In an effort to minimize ongoing neurological injury, the use of targeted temperature management (TTM) in comatose survivors of cardiac arrest has become the standard of care [5,6]. Modifiable factors with regard to TTM include duration of treatment, mechanism of cooling, rate of rewarming, and target temperatures. There is a paucity of observational data that evaluate most of these variables as prognostic indicators. However, with regard to target temperatures, the argument for more aggressive TTM with lower temperatures was refuted by the findings of a large international randomized trial, which showed no differences in neurological outcome or survival based on a target temperature of 33 °C or 36 °C [7,8]. The effects of temperature variation outside the range of 33–36 °C have only been evaluated in observational studies. There is some
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evidence that hyperthermia in the first 48 h following cardiac arrest is associated with worse neurological outcomes and lower odds of survival [9]. The effects of significant hyperthermia or hypothermia exclusively in patients undergoing TTM following cardiac arrest are not as clear [10]. Moreover, to our knowledge there has been no previous study that evaluates the prognostic significance of continuous variations in core temperatures during TTM. We sought to better characterize core temperature variability during the maintenance phase of TTM and to assess for any relationship between increased temperature variability and neurological outcomes. 2. Methods 2.1. Patient population & study design The study population included 242 consecutive patients treated at a tertiary care hospital between 2007 and 2014 who met the following criteria: cardiac arrest from non-traumatic etiology, comatose following successful return of spontaneous circulation (ROSC), and treatment with the institution's TTM protocol for at least 24 h. All patients were cooled externally using an active surface-cooling device, the Arctic Sun System, to maintain a core body temperature of 33 °C during the maintenance phase of TTM [11]. This was followed by active rewarming with a goal rate of 0.25 °C per hour. Following approval from the institutional review board, demographic and clinical data were collected for each patient in a prospective manner and stored in a REDCap database [12]. These variables included age, sex, location of arrest, initial rhythm at time of arrest, receipt of bystander cardiopulmonary resuscitation (CPR), time to ROSC, and Cerebral Performance Category (CPC) scores at hospital discharge. Initial rhythm was assessed as either a shockable [ventricular tachycardia (VT) or ventricular fibrillation (VF)] or non-shockable rhythm. Presence of shock at admission was defined as systolic blood pressures (SBP) b 90 or by the use of vasopressors. Mechanical circulatory support was defined as the use of either (1) an intra-aortic balloon pump (IABP), (2) extracorporeal membrane oxygenation (ECMO), or (3) ventricular assist device (VAD). Time to the initiation of TTM and time to reach target temperature were calculated from the time to ROSC. Time at target temperature was calculated via a review of the vital signs in the electronic health record (EHR) to estimate the duration of time each patient's core temperature was maintained at a goal of 33 °C. Troponin I concentrations were recorded where available and are reported as μg/l (normal b 0.05 μg/l). Each patient's course of TTM was conceptualized in four parts: induction, maintenance, rewarming, and normothermia. The maintenance phase was defined as starting with first core temperature at or below the target and ending with the first attempt at active rewarming. Core temperature variability was defined as the statistical variance (i.e. standard deviation squared) amongst all core temperature recordings during the maintenance phase. The primary outcome of this study was poor neurological outcome at hospital discharge, defined as a CPC score N 2 [13]. A favorable neurological outcome (neurologically intact survival) was defined as a CPC score of 1 or 2. Death prior to hospital discharge was assessed as the secondary outcome. 2.2. Statistical analysis All information was de-identified prior to statistical analysis in Stata Statistical Software: Release 14 (College Station, TX, USA) [14]. Descriptive statistics were calculated as the median with interquartile ranges (IQR) for continuous variables. Frequencies (percentages) are depicted for categorical variables. Multivariable logistic regression was used to assess for an association between core temperature variability and neurological outcomes while adjusting for age, location of arrest, receipt of bystander CPR, initial rhythm, initial temperature, time to ROSC, time to TTM, time at target temperature, in addition to maximum and
minimum temperatures within 48 h of cardiac arrest. A similar analysis was done to assess the association between core temperature variability and survival to hospital discharge. Odds ratios (OR) with 95% confidence intervals (CI) are presented. All tests were two-tailed and a pvalue of less than or equal to 0.05 was considered statistically significant. 3. Results Baseline demographic and clinical characteristics of the cohort are presented in Table 1. The median core temperature during the maintenance was 32.9 °C (IQR 32.4 °C–33.3 °C). Core temperature variability was calculated as the statistical variance amongst core temperature recordings during the maintenance phase of TTM. Amongst all patients, the median variability during the maintenance phase was 0.22 °C2 (IQR 0.08–0.42 °C2). A comparison of core temperature variability with CPC scores at hospital discharge is provided in Fig. 1. A poor neurological outcome was observed in 147 (61%) patients and 136 (56%) patients died prior to hospital discharge. Multivariable logistic regression was used to test for an association of core temperature variability with poor neurological outcomes and death at hospital discharge. The covariates in the models were age, receipt of bystander CPR, initial rhythm, initial temperature, location of arrest, time spent at target temperature, time to ROSC, time to TTM, and the highest and lowest recorded temperatures within 48 h of arrest. Higher levels of core temperature variability were not associated with poor neurological outcomes at hospital discharge (p = 0.142). Advanced age (p = 0.046) and increasing time to ROSC (p b 0.001) were associated with higher odds of poor neurological outcomes. Shockable rhythms (p b 0.001) and in-hospital arrest (p = 0.036) predicted lower odds of poor neurological outcomes, Fig. 2. Increased core temperature variability during TTM was not significantly associated with death prior to hospital discharge (p = 0.193). Lengthier times to ROSC were associated with higher odds of death (p b 0.001). Shockable rhythms (p b 0.001) and in-hospital arrest (p = 0.039) were associated with lower odds of death, Table 2. 4. Discussion The primary findings of this observational study are as follows: (1) individual variation in core temperatures amongst patients treated Table 1 Baseline characteristics. Data are presented as median (IQR) for continuous variables and number (percentage) of patients for categorical variables. N represents the number of non-missing values. CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation; T-max, maximum temperature; T-min, minimum temperature; TTM, targeted temperature management. Characteristic
Overall
N
Age (years) Male (%) In-hospital arrest (%) Shockable rhythm (%) Witnessed arrest (%) Received bystander CPR (%) Time to ROSC (min) Time to initiation of TTM (min) Time to reach target temperature (min) Initial body temperature (°C) Time at target temperature (h) Core temperature variability (°C2) T-max within 48 h of arrest (°C) T-min within 48 h of arrest (°C) ST-segment elevation myocardial infarction (%) Peak Troponin I (μg/l) Coronary angiography (%) Percutaneous coronary intervention (%) Shock on admission (%) Mechanical circulatory support device (%)
61 (51–69) 145 (60%) 44 (18%) 131 (56%) 190 (79%) 121 (50%) 20 (15–34) 122 (65–240) 165 (75–270) 36 (34.7–36.7) 21 (18–24) 0.22 (0.08–0.42) 37.6 (37.2–38.2) 31.9 (31.5–32.4) 56 (23%) 2.74 (0.42–16.94) 142 (59%) 65 (27%) 95 (39%) 37 (15%)
242 242 242 235 241 242 229 232 242 242 242 242 242 242 239 232 242 242 242 242
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Table 2 Odds ratios of poor neurological outcomes and death. CI, confidence interval; CPR, cardiopulmonary resuscitation; OR, odds ratio; ROSC, return of spontaneous circulation; T-max, maximum temperature; T-min, minimum temperature; TTM, targeted temperature management. Characteristic
Fig. 1. CPC scores at hospital discharge versus core temperature variability. An arrow indicates two additional patients with a CPC score of 1 at hospital discharge and core temperature variability of 1.58 °C2 and 2.83 °C2, respectively.
with TTM is common, and (2) this variation does not predict poor neurological outcomes. The prognostic implications of temperature variability following cardiac arrest have been previously reported with somewhat conflicting results. In 2009 Suffoletto et al. examined the association of body temperature changes with short-term outcomes [15]. This observational study included roughly 3400 patients, only 58 of which underwent induced TTM. The principal finding of the study was that hyperthermia following cardiac arrest was associated with death and unfavorable neurological outcomes. Temperature lability and hypothermia were both associated with lower odds of survival, although no statistically significant association with neurological outcomes was seen. There are a number of key differences in study design and variable definitions between our study and the one mentioned above that are important to address. Suffoletto et al. studied a patient population where TTM was used
Fig. 2. Forest plot representation of predictors of poor neurological outcomes. For each variable, the odds ratio is represented by a black box and the 95% confidence interval is represented by a horizontal line. CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation; T-max, maximum.
OR
95% CI
p value
Poor neurological outcome at hospital discharge Age (years) 1.02 Bystander CPR 0.84 Core temperature variability 0.38 Shockable rhythm 0.15 Initial temperature 1.11 In-hospital arrest 0.37 Time at target temperature (h) 1.02 Time to ROSC (min) 1.06 Time to TTM (min) 1.00 T-max within 48 h of arrest 0.79 T-min within 48 h of arrest 0.74
1.01–1.05 0.40–1.78 0.11–1.38 0.07–0.33 0.88–1.40 0.14–0.94 0.93–1.11 1.03–1.09 0.99–1.00 0.54–1.16 0.41–1.36
0.046 0.654 0.142 b0.001 0.373 0.036 0.730 b0.001 0.397 0.227 0.335
Death prior to hospital discharge Age (years) Bystander CPR Core temperature variability Shockable rhythm Initial temperature In-hospital arrest Time at target temperature (h) Time to ROSC (min) Time to TTM (min) T-max within 48 h of arrest T-min within 48 h of arrest
0.99–1.04 0.39–1.64 0.12–1.53 0.09–0.37 0.83–1.30 0.16–0.95 0.93–1.11 1.02–1.07 0.99–1.00 0.53–1.10 0.44–1.44
0.155 0.534 0.193 b0.001 0.712 0.039 0.745 b0.001 0.341 0.150 0.454
1.02 0.80 0.43 0.18 1.04 0.39 1.01 1.05 1.00 0.76 0.80
in a small minority of patients and most of the observed cases of hypothermia were passive in nature. Moreover, hypothermia was defined as a core temperature below 36 °C, temperature lability was defined as a categorical variable, and only patients with in-hospital cardiac arrest were evaluated. In 2015, Nobile et al. reported the first study on temperature variability exclusively in comatose survivors of cardiac arrest undergoing TTM [16]. Amongst a cohort of 229 patients in Belgium, increased temperature variability during TTM was not associated with poor neurological outcomes at 3 months post-arrest. Of note, similar to this study, there was a non-significant directional association between increased temperature variability and favorable neurological outcomes. Despite the similar results, there is a key difference in study design and variable definition between the two studies. Nobile et al. assessed temperature variability during TTM as the standard deviation of core temperature recordings and arbitrarily chose a deviation N 1 °C as the definition of “high variability”. This categorical measure of temperature variability was used in the primary analyses. In contrast, we assessed core temperature variability as a continuous measure and were able to demonstrate a lack of prognostic significance across all levels of observed variation. Regardless of being defined as a categorical or continuous variable, temperature variation during TTM is common [16]. The underlying causes of these variations and opportunities for intervention remain poorly understood. Temperature variation during TTM may in some cases represent a physiological response to an underlying stressor. Increased risk of bacteremia from translocation in ischemic gut or pulmonary aspiration may in fact contribute to temperature fluctuations during the maintenance phase of TTM [17,18]. There may also likely exist a number of other host-related factors that lead to increased temperature fluctuations following ROSC and during TTM. Iatrogenic variables, particularly variability in TTM protocols and delivery methodology amongst institutions, also likely contribute to temperature variability in these patients. It remains unknown to what extent endogenous and exogenous factors contribute to temperature fluctuations during TTM and concordantly whether or not there is any difference in prognostic implication between them. Moreover, due to the observational nature of this study, the utility or danger of therapeutic control over temperature variation remains to be examined.
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Regardless of the underlying cause of variation, there are a number of viable concerns in patients with marked core temperature variability. Electrolyte disturbances, particularly those of potassium, during the induction and rewarming phases of TTM are well-known [19,20]. Increased core temperature variability during the maintenance phase could lead to increased electrolyte shifts in these patients. Particularly in patients with lower target temperatures (33 °C) where episodes of hypokalemia are more common, increased temperature variability might precipitate such electrolyte disturbances [7]. For patients with a target temperature of 36 °C, significant degrees of core temperature variability might lead to periods of normothermia or even hyperthermia. Although core temperature variability was not associated with poor outcomes in our cohort, the target core temperature for all patients included in the study was 33 °C. There is a need for further assessment of temperature fluctuations during the TTM as a potential prognostic indicator in cohorts with higher target temperatures. Overall, despite rigorous research efforts, little remains known regarding the optimal delivery of TTM following cardiac arrest with the exceptions of active avoidance of hyperthermia for the first 48 h and the lack of outcome difference based on a target temperature of 33 °C to 36 °C. Even after the recent advances in CPR and post-resuscitation care, the overall prognosis following cardiac arrest remains dismal. In our select cohort of patients who achieved ROSC and subsequently underwent TTM, only 39% experienced a favorable neurological outcome. For a number of these patients, particularly those with lengthier times to ROSC and those without shockable rhythms, a poor outcome might be pre-determined prior to any in-hospital intervention [21,22]. For the remaining subset with better odds of a favorable neurological outcome, it remains unknown whether a number of technique modifications can increase the clinical utility of TTM. That is, with regard to the length of treatment, mechanism of temperature control, and therapeutic control over temperature variation, randomized trials are necessary to better evaluate any association with outcomes. 4.1. Study limitations This study has a number of limitations. The design as a retrospective cohort study only allows for inference of association instead of causation. While we attempted to account for a number of potential confounders in the multivariable analyses, it is plausible that other unidentified variables may have influenced the results. Given the relatively small cohort of patients, insufficient statistical power is a concern. As a single institution study, the findings presented here may not be applicable to patients in other institutions with different TTM protocols. The patients in this study were externally cooled with the Arctic Sun System and our descriptions of core temperature variability may likely not apply to other mechanisms of achieving therapeutic hypothermia. Additionally, all patients in this cohort had a target temperature of 33 °C and the effects of temperature variation in cohorts with a target temperature of 36 °C remain unknown. We were also unable to assess temperature variation in each patient as a product of physiological thermoregulation or iatrogenic processes. However, this will be very difficult to do even in a prospective study or randomized trial. Finally, due to the observational nature of the study, we are unable to comment on the potential benefit or harm of therapeutic control over temperature variation.
5. Conclusions In this study of comatose survivors of cardiac arrest undergoing TTM, there was no association between individual core temperature variability during TTM and poor neurological outcomes or death at hospital discharge. There is a great need for prospective studies and randomized trials to better evaluate the association between particular details of TTM delivery and patient outcomes. References [1] Roger VL, Go AS, Lloyd-jones DM, et al. Executive summary: heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 2012;125(1):188–97. [2] Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001;104(18):2158–63. [3] Mozaffarian D, Benjamin EJ, Go AS, et al. Executive summary: heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133(4):447–54. [4] Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 2004;30(11):2126–8. [5] Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia. J Med]–>N Engl J Med 2002; 346(8):557–63. [6] The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. J Med]–>N Engl J Med 2002; 346(8):549–56. [7] Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. J Med]–>N Engl J Med 2013;369(23):2197–206. [8] Cronberg T, Lilja G, Horn J, et al. Neurologic function and health-related quality of life in patients following targeted temperature management at 33 °C vs 36 °C after outof-hospital cardiac arrest: a randomized clinical trial. JAMA Neurol 2015;72(6): 634–41. [9] Zeiner A, Holzer M, Sterz F, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med 2001;161(16):2007–12. [10] Gebhardt K, Guyette FX, Doshi AA, Callaway CW, Rittenberger JC. Prevalence and effect of fever on outcome following resuscitation from cardiac arrest. Resuscitation 2013;84(8):1062–7. [11] Haugk M, Sterz F, Grassberger M, et al. Feasibility and efficacy of a new non-invasive surface cooling device in post-resuscitation intensive care medicine. Resuscitation 2007;75(1):76–81. [12] Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap) - a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42(2):377–81. [13] Becker LB, Aufderheide TP, Geocadin RG, et al. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation 2011;124(19):2158–77. [14] StataCorp. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP; 2015. [15] Suffoletto B, Peberdy MA, Van Der Hoek T, Callaway C. Body temperature changes are associated with outcomes following in-hospital cardiac arrest and return of spontaneous circulation. Resuscitation 2009;80(12):1365–70. [16] Nobile L, Lamanna I, Fontana V, et al. Greater temperature variability is not associated with a worse neurological outcome after cardiac arrest. Resuscitation 2015;96: 268–74. [17] Gaussorgues P, Gueugniaud PY, Vedrinne JM, Salord F, Mercatello A, Robert D. Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med 1988;14(5):575–7. [18] Hickey RW, Kochanek PM, Ferimer H, Graham SH, Safar P. Hypothermia and hyperthermia in children after resuscitation from cardiac arrest. Pediatrics 2000;106(1 Pt 1):118–22. [19] Polderman KH, Peerdeman SM, Girbes AR. Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury. J Neurosurg 2001; 94(5):697–705. [20] Aibiki M, Kawaguchi S, Maekawa N. Reversible hypophosphatemia during moderate hypothermia therapy for brain-injured patients. Crit Care Med 2001;29(9):1726–30. [21] Hosmane VR, Mustafa NG, Reddy VK, et al. Survival and neurologic recovery in patients with ST-segment elevation myocardial infarction resuscitated from cardiac arrest. J Am Coll Cardiol 2009;53(5):409–15. [22] Young MN, Hollenbeck RD, Pollock JS, et al. Higher achieved mean arterial pressure during therapeutic hypothermia is not associated with neurologically intact survival following cardiac arrest. Resuscitation 2015;88:158–64.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Temperature variability during targeted temperature management is not associated with neurological outcomes following cardiac arrest☆,☆☆ Arash Nayeri a,⁎, Nirmanmoh Bhatia b, Benjamin Holmes b, Nyal Borges c, William Armstrong c, Meng Xu d, Eric Farber-Eger b, Quinn S. Wells b, John A. McPherson b a
University of California, Los Angeles, Department of Medicine, 757 Westwood Plaza, St. 7501, Los Angeles, CA 90095-7417, United States Vanderbilt University Medical Center, Division of Cardiovascular Medicine, 2220 Pierce Avenue, 383 Preston Research Building, Nashville, TN 37232-6300, United States Vanderbilt University Medical Center, Department of Medicine, 1161 21st Avenue South, D-3100e Medical Center North, Nashville, TN 37232, United States d Vanderbilt University Medical Center, Department of Biostatistics, 2525 West End Ave, St 1100, Nashville, TN 37203, United States b c
a r t i c l e
i n f o
Article history: Received 6 December 2016 Received in revised form 19 January 2017 Accepted 26 January 2017 Keywords: Targeted temperature management (TTM) Therapeutic hypothermia (TH) Cardiac arrest Temperature variability Cerebral performance category (CPC)
a b s t r a c t Introduction: Recent studies on comatose survivors of cardiac arrest undergoing targeted temperature management (TTM) have shown similar outcomes at multiple target temperatures. However, details regarding core temperature variability during TTM and its prognostic implications remain largely unknown. We sought to assess the association between core temperature variability and neurological outcomes in patients undergoing TTM following cardiac arrest. Methods: We analyzed a prospectively collected cohort of 242 patients treated with TTM following cardiac arrest at a tertiary care hospital between 2007 and 2014. Core temperature variability was defined as the statistical variance (i.e. standard deviation squared) amongst all core temperature recordings during the maintenance phase of TTM. Poor neurological outcome at hospital discharge, defined as a Cerebral Performance Category (CPC) score N 2, was the primary outcome. Death prior to hospital discharge was assessed as the secondary outcome. Multivariable logistic regression was used to examine the association between temperature variability and neurological outcome or death at hospital discharge. Results: A poor neurological outcome was observed in 147 (61%) patients and 136 (56%) patients died prior to hospital discharge. In multivariable logistic regression, increased core temperature variability was not associated with increased odds of poor neurological outcomes (OR 0.38, 95% CI 0.11–1.38, p = 0.142) or death (OR 0.43, 95% CI 0.12–1.53, p = 0.193) at hospital discharge. Conclusion: In this study, individual core temperature variability during TTM was not associated with poor neurological outcomes or death at hospital discharge. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Cardiac arrest is a major cause of morbidity and mortality in the United States, affecting approximately 400 000 patients annually and accounting for 15% of all-cause mortality [1,2]. The rate of survival to hospital discharge remains exceedingly low and b10% of cardiac arrest ☆ Authorship disclosure: All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ☆☆ Conflicts of interest: No potential conflicts of interest are disclosed. No grant support was used in the preparation of this work. ⁎ Corresponding author. E-mail addresses: [email protected] (A. Nayeri), [email protected] (N. Bhatia), [email protected] (B. Holmes), [email protected] (N. Borges), [email protected] (W. Armstrong), Meng.xu@ vanderbilt.edu (M. Xu), [email protected] (E. Farber-Eger), [email protected] (Q.S. Wells), [email protected] (J.A. McPherson).
http://dx.doi.org/10.1016/j.ajem.2017.01.058 0735-6757/© 2017 Elsevier Inc. All rights reserved.
victims are discharged with a favorable neurological outcome [3]. Neurological injury remains the leading cause of death in this patient population and accounts for approximately two-thirds of all-cause mortality [4]. In an effort to minimize ongoing neurological injury, the use of targeted temperature management (TTM) in comatose survivors of cardiac arrest has become the standard of care [5,6]. Modifiable factors with regard to TTM include duration of treatment, mechanism of cooling, rate of rewarming, and target temperatures. There is a paucity of observational data that evaluate most of these variables as prognostic indicators. However, with regard to target temperatures, the argument for more aggressive TTM with lower temperatures was refuted by the findings of a large international randomized trial, which showed no differences in neurological outcome or survival based on a target temperature of 33 °C or 36 °C [7,8]. The effects of temperature variation outside the range of 33–36 °C have only been evaluated in observational studies. There is some
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evidence that hyperthermia in the first 48 h following cardiac arrest is associated with worse neurological outcomes and lower odds of survival [9]. The effects of significant hyperthermia or hypothermia exclusively in patients undergoing TTM following cardiac arrest are not as clear [10]. Moreover, to our knowledge there has been no previous study that evaluates the prognostic significance of continuous variations in core temperatures during TTM. We sought to better characterize core temperature variability during the maintenance phase of TTM and to assess for any relationship between increased temperature variability and neurological outcomes. 2. Methods 2.1. Patient population & study design The study population included 242 consecutive patients treated at a tertiary care hospital between 2007 and 2014 who met the following criteria: cardiac arrest from non-traumatic etiology, comatose following successful return of spontaneous circulation (ROSC), and treatment with the institution's TTM protocol for at least 24 h. All patients were cooled externally using an active surface-cooling device, the Arctic Sun System, to maintain a core body temperature of 33 °C during the maintenance phase of TTM [11]. This was followed by active rewarming with a goal rate of 0.25 °C per hour. Following approval from the institutional review board, demographic and clinical data were collected for each patient in a prospective manner and stored in a REDCap database [12]. These variables included age, sex, location of arrest, initial rhythm at time of arrest, receipt of bystander cardiopulmonary resuscitation (CPR), time to ROSC, and Cerebral Performance Category (CPC) scores at hospital discharge. Initial rhythm was assessed as either a shockable [ventricular tachycardia (VT) or ventricular fibrillation (VF)] or non-shockable rhythm. Presence of shock at admission was defined as systolic blood pressures (SBP) b 90 or by the use of vasopressors. Mechanical circulatory support was defined as the use of either (1) an intra-aortic balloon pump (IABP), (2) extracorporeal membrane oxygenation (ECMO), or (3) ventricular assist device (VAD). Time to the initiation of TTM and time to reach target temperature were calculated from the time to ROSC. Time at target temperature was calculated via a review of the vital signs in the electronic health record (EHR) to estimate the duration of time each patient's core temperature was maintained at a goal of 33 °C. Troponin I concentrations were recorded where available and are reported as μg/l (normal b 0.05 μg/l). Each patient's course of TTM was conceptualized in four parts: induction, maintenance, rewarming, and normothermia. The maintenance phase was defined as starting with first core temperature at or below the target and ending with the first attempt at active rewarming. Core temperature variability was defined as the statistical variance (i.e. standard deviation squared) amongst all core temperature recordings during the maintenance phase. The primary outcome of this study was poor neurological outcome at hospital discharge, defined as a CPC score N 2 [13]. A favorable neurological outcome (neurologically intact survival) was defined as a CPC score of 1 or 2. Death prior to hospital discharge was assessed as the secondary outcome. 2.2. Statistical analysis All information was de-identified prior to statistical analysis in Stata Statistical Software: Release 14 (College Station, TX, USA) [14]. Descriptive statistics were calculated as the median with interquartile ranges (IQR) for continuous variables. Frequencies (percentages) are depicted for categorical variables. Multivariable logistic regression was used to assess for an association between core temperature variability and neurological outcomes while adjusting for age, location of arrest, receipt of bystander CPR, initial rhythm, initial temperature, time to ROSC, time to TTM, time at target temperature, in addition to maximum and
minimum temperatures within 48 h of cardiac arrest. A similar analysis was done to assess the association between core temperature variability and survival to hospital discharge. Odds ratios (OR) with 95% confidence intervals (CI) are presented. All tests were two-tailed and a pvalue of less than or equal to 0.05 was considered statistically significant. 3. Results Baseline demographic and clinical characteristics of the cohort are presented in Table 1. The median core temperature during the maintenance was 32.9 °C (IQR 32.4 °C–33.3 °C). Core temperature variability was calculated as the statistical variance amongst core temperature recordings during the maintenance phase of TTM. Amongst all patients, the median variability during the maintenance phase was 0.22 °C2 (IQR 0.08–0.42 °C2). A comparison of core temperature variability with CPC scores at hospital discharge is provided in Fig. 1. A poor neurological outcome was observed in 147 (61%) patients and 136 (56%) patients died prior to hospital discharge. Multivariable logistic regression was used to test for an association of core temperature variability with poor neurological outcomes and death at hospital discharge. The covariates in the models were age, receipt of bystander CPR, initial rhythm, initial temperature, location of arrest, time spent at target temperature, time to ROSC, time to TTM, and the highest and lowest recorded temperatures within 48 h of arrest. Higher levels of core temperature variability were not associated with poor neurological outcomes at hospital discharge (p = 0.142). Advanced age (p = 0.046) and increasing time to ROSC (p b 0.001) were associated with higher odds of poor neurological outcomes. Shockable rhythms (p b 0.001) and in-hospital arrest (p = 0.036) predicted lower odds of poor neurological outcomes, Fig. 2. Increased core temperature variability during TTM was not significantly associated with death prior to hospital discharge (p = 0.193). Lengthier times to ROSC were associated with higher odds of death (p b 0.001). Shockable rhythms (p b 0.001) and in-hospital arrest (p = 0.039) were associated with lower odds of death, Table 2. 4. Discussion The primary findings of this observational study are as follows: (1) individual variation in core temperatures amongst patients treated Table 1 Baseline characteristics. Data are presented as median (IQR) for continuous variables and number (percentage) of patients for categorical variables. N represents the number of non-missing values. CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation; T-max, maximum temperature; T-min, minimum temperature; TTM, targeted temperature management. Characteristic
Overall
N
Age (years) Male (%) In-hospital arrest (%) Shockable rhythm (%) Witnessed arrest (%) Received bystander CPR (%) Time to ROSC (min) Time to initiation of TTM (min) Time to reach target temperature (min) Initial body temperature (°C) Time at target temperature (h) Core temperature variability (°C2) T-max within 48 h of arrest (°C) T-min within 48 h of arrest (°C) ST-segment elevation myocardial infarction (%) Peak Troponin I (μg/l) Coronary angiography (%) Percutaneous coronary intervention (%) Shock on admission (%) Mechanical circulatory support device (%)
61 (51–69) 145 (60%) 44 (18%) 131 (56%) 190 (79%) 121 (50%) 20 (15–34) 122 (65–240) 165 (75–270) 36 (34.7–36.7) 21 (18–24) 0.22 (0.08–0.42) 37.6 (37.2–38.2) 31.9 (31.5–32.4) 56 (23%) 2.74 (0.42–16.94) 142 (59%) 65 (27%) 95 (39%) 37 (15%)
242 242 242 235 241 242 229 232 242 242 242 242 242 242 239 232 242 242 242 242
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Table 2 Odds ratios of poor neurological outcomes and death. CI, confidence interval; CPR, cardiopulmonary resuscitation; OR, odds ratio; ROSC, return of spontaneous circulation; T-max, maximum temperature; T-min, minimum temperature; TTM, targeted temperature management. Characteristic
Fig. 1. CPC scores at hospital discharge versus core temperature variability. An arrow indicates two additional patients with a CPC score of 1 at hospital discharge and core temperature variability of 1.58 °C2 and 2.83 °C2, respectively.
with TTM is common, and (2) this variation does not predict poor neurological outcomes. The prognostic implications of temperature variability following cardiac arrest have been previously reported with somewhat conflicting results. In 2009 Suffoletto et al. examined the association of body temperature changes with short-term outcomes [15]. This observational study included roughly 3400 patients, only 58 of which underwent induced TTM. The principal finding of the study was that hyperthermia following cardiac arrest was associated with death and unfavorable neurological outcomes. Temperature lability and hypothermia were both associated with lower odds of survival, although no statistically significant association with neurological outcomes was seen. There are a number of key differences in study design and variable definitions between our study and the one mentioned above that are important to address. Suffoletto et al. studied a patient population where TTM was used
Fig. 2. Forest plot representation of predictors of poor neurological outcomes. For each variable, the odds ratio is represented by a black box and the 95% confidence interval is represented by a horizontal line. CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation; T-max, maximum.
OR
95% CI
p value
Poor neurological outcome at hospital discharge Age (years) 1.02 Bystander CPR 0.84 Core temperature variability 0.38 Shockable rhythm 0.15 Initial temperature 1.11 In-hospital arrest 0.37 Time at target temperature (h) 1.02 Time to ROSC (min) 1.06 Time to TTM (min) 1.00 T-max within 48 h of arrest 0.79 T-min within 48 h of arrest 0.74
1.01–1.05 0.40–1.78 0.11–1.38 0.07–0.33 0.88–1.40 0.14–0.94 0.93–1.11 1.03–1.09 0.99–1.00 0.54–1.16 0.41–1.36
0.046 0.654 0.142 b0.001 0.373 0.036 0.730 b0.001 0.397 0.227 0.335
Death prior to hospital discharge Age (years) Bystander CPR Core temperature variability Shockable rhythm Initial temperature In-hospital arrest Time at target temperature (h) Time to ROSC (min) Time to TTM (min) T-max within 48 h of arrest T-min within 48 h of arrest
0.99–1.04 0.39–1.64 0.12–1.53 0.09–0.37 0.83–1.30 0.16–0.95 0.93–1.11 1.02–1.07 0.99–1.00 0.53–1.10 0.44–1.44
0.155 0.534 0.193 b0.001 0.712 0.039 0.745 b0.001 0.341 0.150 0.454
1.02 0.80 0.43 0.18 1.04 0.39 1.01 1.05 1.00 0.76 0.80
in a small minority of patients and most of the observed cases of hypothermia were passive in nature. Moreover, hypothermia was defined as a core temperature below 36 °C, temperature lability was defined as a categorical variable, and only patients with in-hospital cardiac arrest were evaluated. In 2015, Nobile et al. reported the first study on temperature variability exclusively in comatose survivors of cardiac arrest undergoing TTM [16]. Amongst a cohort of 229 patients in Belgium, increased temperature variability during TTM was not associated with poor neurological outcomes at 3 months post-arrest. Of note, similar to this study, there was a non-significant directional association between increased temperature variability and favorable neurological outcomes. Despite the similar results, there is a key difference in study design and variable definition between the two studies. Nobile et al. assessed temperature variability during TTM as the standard deviation of core temperature recordings and arbitrarily chose a deviation N 1 °C as the definition of “high variability”. This categorical measure of temperature variability was used in the primary analyses. In contrast, we assessed core temperature variability as a continuous measure and were able to demonstrate a lack of prognostic significance across all levels of observed variation. Regardless of being defined as a categorical or continuous variable, temperature variation during TTM is common [16]. The underlying causes of these variations and opportunities for intervention remain poorly understood. Temperature variation during TTM may in some cases represent a physiological response to an underlying stressor. Increased risk of bacteremia from translocation in ischemic gut or pulmonary aspiration may in fact contribute to temperature fluctuations during the maintenance phase of TTM [17,18]. There may also likely exist a number of other host-related factors that lead to increased temperature fluctuations following ROSC and during TTM. Iatrogenic variables, particularly variability in TTM protocols and delivery methodology amongst institutions, also likely contribute to temperature variability in these patients. It remains unknown to what extent endogenous and exogenous factors contribute to temperature fluctuations during TTM and concordantly whether or not there is any difference in prognostic implication between them. Moreover, due to the observational nature of this study, the utility or danger of therapeutic control over temperature variation remains to be examined.
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Regardless of the underlying cause of variation, there are a number of viable concerns in patients with marked core temperature variability. Electrolyte disturbances, particularly those of potassium, during the induction and rewarming phases of TTM are well-known [19,20]. Increased core temperature variability during the maintenance phase could lead to increased electrolyte shifts in these patients. Particularly in patients with lower target temperatures (33 °C) where episodes of hypokalemia are more common, increased temperature variability might precipitate such electrolyte disturbances [7]. For patients with a target temperature of 36 °C, significant degrees of core temperature variability might lead to periods of normothermia or even hyperthermia. Although core temperature variability was not associated with poor outcomes in our cohort, the target core temperature for all patients included in the study was 33 °C. There is a need for further assessment of temperature fluctuations during the TTM as a potential prognostic indicator in cohorts with higher target temperatures. Overall, despite rigorous research efforts, little remains known regarding the optimal delivery of TTM following cardiac arrest with the exceptions of active avoidance of hyperthermia for the first 48 h and the lack of outcome difference based on a target temperature of 33 °C to 36 °C. Even after the recent advances in CPR and post-resuscitation care, the overall prognosis following cardiac arrest remains dismal. In our select cohort of patients who achieved ROSC and subsequently underwent TTM, only 39% experienced a favorable neurological outcome. For a number of these patients, particularly those with lengthier times to ROSC and those without shockable rhythms, a poor outcome might be pre-determined prior to any in-hospital intervention [21,22]. For the remaining subset with better odds of a favorable neurological outcome, it remains unknown whether a number of technique modifications can increase the clinical utility of TTM. That is, with regard to the length of treatment, mechanism of temperature control, and therapeutic control over temperature variation, randomized trials are necessary to better evaluate any association with outcomes. 4.1. Study limitations This study has a number of limitations. The design as a retrospective cohort study only allows for inference of association instead of causation. While we attempted to account for a number of potential confounders in the multivariable analyses, it is plausible that other unidentified variables may have influenced the results. Given the relatively small cohort of patients, insufficient statistical power is a concern. As a single institution study, the findings presented here may not be applicable to patients in other institutions with different TTM protocols. The patients in this study were externally cooled with the Arctic Sun System and our descriptions of core temperature variability may likely not apply to other mechanisms of achieving therapeutic hypothermia. Additionally, all patients in this cohort had a target temperature of 33 °C and the effects of temperature variation in cohorts with a target temperature of 36 °C remain unknown. We were also unable to assess temperature variation in each patient as a product of physiological thermoregulation or iatrogenic processes. However, this will be very difficult to do even in a prospective study or randomized trial. Finally, due to the observational nature of the study, we are unable to comment on the potential benefit or harm of therapeutic control over temperature variation.
5. Conclusions In this study of comatose survivors of cardiac arrest undergoing TTM, there was no association between individual core temperature variability during TTM and poor neurological outcomes or death at hospital discharge. There is a great need for prospective studies and randomized trials to better evaluate the association between particular details of TTM delivery and patient outcomes. References [1] Roger VL, Go AS, Lloyd-jones DM, et al. Executive summary: heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 2012;125(1):188–97. [2] Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001;104(18):2158–63. [3] Mozaffarian D, Benjamin EJ, Go AS, et al. Executive summary: heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133(4):447–54. [4] Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 2004;30(11):2126–8. [5] Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia. J Med]–>N Engl J Med 2002; 346(8):557–63. [6] The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. J Med]–>N Engl J Med 2002; 346(8):549–56. [7] Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. J Med]–>N Engl J Med 2013;369(23):2197–206. [8] Cronberg T, Lilja G, Horn J, et al. Neurologic function and health-related quality of life in patients following targeted temperature management at 33 °C vs 36 °C after outof-hospital cardiac arrest: a randomized clinical trial. JAMA Neurol 2015;72(6): 634–41. [9] Zeiner A, Holzer M, Sterz F, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med 2001;161(16):2007–12. [10] Gebhardt K, Guyette FX, Doshi AA, Callaway CW, Rittenberger JC. Prevalence and effect of fever on outcome following resuscitation from cardiac arrest. Resuscitation 2013;84(8):1062–7. [11] Haugk M, Sterz F, Grassberger M, et al. Feasibility and efficacy of a new non-invasive surface cooling device in post-resuscitation intensive care medicine. Resuscitation 2007;75(1):76–81. [12] Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap) - a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42(2):377–81. [13] Becker LB, Aufderheide TP, Geocadin RG, et al. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation 2011;124(19):2158–77. [14] StataCorp. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP; 2015. [15] Suffoletto B, Peberdy MA, Van Der Hoek T, Callaway C. Body temperature changes are associated with outcomes following in-hospital cardiac arrest and return of spontaneous circulation. Resuscitation 2009;80(12):1365–70. [16] Nobile L, Lamanna I, Fontana V, et al. Greater temperature variability is not associated with a worse neurological outcome after cardiac arrest. Resuscitation 2015;96: 268–74. [17] Gaussorgues P, Gueugniaud PY, Vedrinne JM, Salord F, Mercatello A, Robert D. Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med 1988;14(5):575–7. [18] Hickey RW, Kochanek PM, Ferimer H, Graham SH, Safar P. Hypothermia and hyperthermia in children after resuscitation from cardiac arrest. Pediatrics 2000;106(1 Pt 1):118–22. [19] Polderman KH, Peerdeman SM, Girbes AR. Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury. J Neurosurg 2001; 94(5):697–705. [20] Aibiki M, Kawaguchi S, Maekawa N. Reversible hypophosphatemia during moderate hypothermia therapy for brain-injured patients. Crit Care Med 2001;29(9):1726–30. [21] Hosmane VR, Mustafa NG, Reddy VK, et al. Survival and neurologic recovery in patients with ST-segment elevation myocardial infarction resuscitated from cardiac arrest. J Am Coll Cardiol 2009;53(5):409–15. [22] Young MN, Hollenbeck RD, Pollock JS, et al. Higher achieved mean arterial pressure during therapeutic hypothermia is not associated with neurologically intact survival following cardiac arrest. Resuscitation 2015;88:158–64.