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The association of body mass index with time to target temperature and outcomes following post-arrest targeted temperature management
Resuscitation 85 (2014) 244–247
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical paper
The association of body mass index with time to target temperature and outcomes following post-arrest targeted temperature management夽 Marion Leary a,∗ , Marisa J. Cinousis a , Mark E. Mikkelsen b , David F. Gaieski a , Benjamin S. Abella a,b , Barry D. Fuchs b a Center for Resuscitation Science, Department of Emergency Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States b Section of Pulmonary Allergy and Critical Care, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
a r t i c l e
i n f o
Article history: Received 19 July 2013 Received in revised form 11 September 2013 Accepted 24 October 2013
Keywords: Cardiac arrest Targeted temperature management Therapeutic hypothermia Sudden death Body mass index Adverse events
a b s t r a c t Background: Evidence suggests that more rapid attainment of target temperature (32–34 ◦ C) improves neurologic outcome following cardiac arrest and targeted temperature management (TTM). It is unclear to what extent body mass index (BMI) is associated with the time to reach target temperature and subsequent clinical outcomes. Objective: We sought to determine whether the time to target temperature was affected by BMI. In addition, we wished to determine whether the incidence of skin breakdown, survival to discharge and neurologic outcomes were associated with BMI. Methods: Multicenter retrospective cohort study of cardiac arrest patients who underwent TTM between July 2007 and December 2012. We examined the association between BMI and the time from initiation of cooling to attainment of target temperature (32–34 ◦ C). Results: Of 236 patients treated with TTM, 184 were included in the study. Mean age was 57.8 ± 17.0 years; 78/184 (42%) were female and 48/184 (26%) had VF/VT as the initial rhythm. Median time to reach target temperature from ROSC was 6.4 (4.1, 9.8) h and median time from initiation of TTM to target temperature was 3.4 (2.1, 5.8) h. Cooling duration was a median of 24.0 (23.0, 24.0) h and median rewarming time was 12.0 (9.5, 18.0) h. Overall, 104/184 (56.5%) achieved target temperature within 4 h and 128/184 (69.6%) within 6 h. Increased BMI was associated with a longer time to achieve target temperature from initiation of TTM (p = 0.01). There was no significant difference across BMI groups in time to achieve target temperature from ROSC (0.07), skin breakdown (p = 0.35), survival (p = 0.21), nor rate of good neurologic outcome (p = 0.32). Conclusions: Target temperature was frequently achieved within 4–6 h; as BMI increased, the time to reach target temperature from initiation of TTM was prolonged. There was no significant difference across BMI groups for survival or good neurologic outcome. © 2013 Published by Elsevier Ireland Ltd.
1. Introduction The induction of Therapeutic Hypothermia or Targeted Temperature Management (TTM) after cardiac arrest has been shown to increase survival to discharge and neurologic recovery.1,2 Several
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.2013.10.027. ∗ Corresponding author at: Center for Resuscitation Science, Department of Emergency Medicine, University of Pennsylvania, 3400 Spruce Street, Ground Ravdin, Philadelphia, PA 19104, United States. E-mail address: [email protected] (M. Leary). 0300-9572/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.resuscitation.2013.10.027
investigations suggest that establishing the desired target temperature (32–34 ◦ C) rapidly may enhance survival.3,4 Current protocols in clinical use suggest reaching target temperature as quickly as possible but within 4–6 h.5–7 Reaching target temperature within this acceptable window in the obese patient population can be difficult. Obesity is also a major public health concern in the United States with an estimated 119 million overweight or obese adults.8 Obesity has been shown to worsen the outcomes associated with a number of other health conditions including diabetes, musculoskeletal disorders, and cardiovascular disease.8,9 Whether obesity has an effect on outcomes in the post-arrest patient population treated with TTM is currently unknown.
M. Leary et al. / Resuscitation 85 (2014) 244–247
In a post-arrest patient cohort treated with TTM, we sought to determine how frequently the target temperature was achieved within 4–6 h and whether the time to target temperature was affected by body mass index (BMI). In addition, we wished to determine whether survival to discharge and neurologic outcomes, as well as adverse events such as skin breakdown from external cooling systems, were associated with BMI. 2. Methods We performed a retrospective cohort study of post-arrest patients who were treated with TTM at two hospitals within the University of Pennsylvania Health System. This study was approved by the University of Pennsylvania Institutional Review Board. Post-arrest patients were included in our investigation if they had TTM administered at the Hospital of the University of Pennsylvania (HUP) or the Penn Presbyterian Medical Center (PPMC) between July 2007 and December 2012. Only those patients who achieved Return of Spontaneous Circulation (ROSC) and received a full course of TTM, including the attainment of normothermia after rewarming, were included. Patients were excluded from data analysis if cooling was begun at an outside hospital with no documented date and time of ROSC or TTM initiation, they did not complete TTM, did not reach target temperature, or did not have BMI clearly documented. The post-arrest TTM protocol employed for patients in this cohort was similar at both institutions. All adult patients who achieved ROSC, regardless of arrest location (in-hospital or outof-hospital) and regardless of presenting rhythm (ventricular fibrillation, pulseless ventricular tachycardia, pulseless electrical activity, asystole) were eligible to receive TTM. Initiation of TTM was begun as soon as possible following ROSC using an infusion of cold saline and external cooling wraps. Both TTM protocols required all patients to be treated with sedation and paralysis prior to initiation of cooling. The goal to achieve target temperature was within 4–6 h of initiation of ROSC. TTM was maintained for 24 h from the time target temperature was reached, at which point rewarming was initiated at a rate of 0.33 ◦ C h−1 until normothermia (37 ◦ C) was attained. 2.1. Body mass index (BMI) BMI was calculated as weight in kilograms (kg) divided by height in meters squared. Patients were categorized according to the World Health Organization classification as either: underweight (≤18.4 kg m−2 ), normal (18.5–25 kg m−2 ), overweight (25.1–29.9 kg m−2 ) or obese (≥30 kg m−2 ) based on their documented weight and height. Time from ROSC to attainment of target temperature and time from initiation of cooling to attainment of target temperature were then analyzed in each of the BMI categories, as well as the time from initiation of rewarming to normothermia in each group. Skin breakdown, survival to hospital discharge and survival with good neurologic outcomes were assessed in all groups. Skin breakdown was defined as any documentation in the integumentary section in the medical chart not within normal limits (reddened area through exposure of muscle or bone) from initiation through one day post rewarming. Good neurologic outcome was defined as a Cerebral Performance Category (CPC) of 1 or 2 at hospital discharge. 2.2. Statistical analysis Data were analyzed using a standard statistical software package (STATA 12, Statacorp, College Station, TX). The Kruskal–Wallis rank test and the Chi-squared test were used
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to compare continuous variables and BMI. We used the nonparametric test for trends across ordered groups to examine whether the time to target temperature increased as BMI increased or if outcomes differed as BMI increased. 3. Results Of the 236 patients treated with TTM following cardiac arrest resuscitation, 184 were included in the study (Table 1). Thirty-six patients were excluded due to missing time data precluding the calculation of time to target temperature, 7 patients were excluded in whom BMI could not be calculated due to a missing height or weight documentation, and 9 patients were excluded because they were already at target temperature at ROSC. In this TTM-treated cohort, mean age was 57.8 ± 17.0 years; 78/184 (42%) were female and 48/184 (26%) had VF/VT as the initial rhythm. Patient temperatures prior to TTM initiation were 36.2 ± 1.5 ◦ C. TTM initiation began a median of 2.0 (0.6, 4.4) h after ROSC. Median time to reach target temperature from ROSC was 6.4 (4.1, 9.8) h and median time from initiation of TTM to target temperature was 3.4 (2.1, 5.8) h. Cooling duration was a median of 24.0 (23.0, 24.0) h and median rewarming time was 12.0 (9.5, 18.0) h. Overall, 104/184 (56.5%) achieved target temperature within 4 h and 128/184 (69.6%) achieved target temperature within 6 h. Overall survival to discharge was 81/184 (44%). Rates of survival to hospital discharge were indistinguishable when time to target temperature was dichomotized to either 4 or 6 h. Increasing BMI was not associated with a longer time from ROSC to initiation (p = 0.97) nor from ROSC to reaching target temperature (0.07). However there was an association with increasing BMI and time from initiation of TTM to achieving target temperature (p = 0.01). As BMI increased the time to reach target temperature between 4 h (p = 0.07) and 6 h (p = 0.04) decreased. However, there was no significant difference in the time required to rewarm across BMI groups (p = 0.84). There were no statistically significant differences in clinical or demographic data between the BMI subgroups Table 1 Demographics and clinical data in the TTM cohort (n = 184). Mean age, y ± SD Gender, n (%) Female Male Location, n (%) Out-of-hospital In-hospital a OSH Tx Other Initial rhythm, n (%) VF/VT PEA Asystole Other/unknown Time intervals ROSC to TTM initiation, h (IQR) ROSC to target temp, h (IQR) Initiation to target temp, h (IQR) Cooling duration, h (IQR) Rewarming duration, h (IQR) Outcomes Survival to discharge, n (%) Target temp. reached within 4 h, n (%) Target temp. reached within 6 h, n (%) CPC 1 or 2 (among survivors), n (%)
57.8 ± 17.0 78 (42%) 106 (58%) 91 (49.5%) 54 (29%) 38 (21%) 1 (0.5%) 48 (25%) 87 (47%) 31 (17%) 18 (11%) 2.0 (0.6, 4.4) 6.4 (4.1, 9.8) 3.4 (2.1, 5.8) 24.0 (23.0, 24.0) 12.0 (9.5, 18.0) 81 (44%) 104 (56.5%) 128 (69.6%) 58 (72%)
TTM, targeted temperature management; y, years; h, hours; IQR, Interquartile range; SD, standard deviation; OSH Tx, Outside hospital transfer, VF/VT, ventricular fibrillation/ventricular tachycardia; PEA, pulseless electrical activity; CPC, cerebral performance category. a Of those whose arrest location was coded as ‘OSH Tx’, all patients were out-ofhospital arrests.
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Table 2 Demographics and clinical data across BMI subgroups.
n (%) Age Male, n (%) Location-in-hospital, n (%) Initial rhythm-VF/VT, n (%) Initial temp., ◦ C Time from ROSC to initiation, min (IQR) Time from ROSC to target temp., min (IQR) Time from initiation* to target temp., min Time to target temp within 4 h, n (%) Time to target temp within 6 h, n (%) Rewarming time, h (IQR) Skin breakdown Survival to discharge Good neurological outcome
Underweight (<18.5)
Normal (18.5–24.9)
Overweight (25–29.9)
Obese (≥30)
8 (4) 58 (38–64) 3 (38) 2 (25) 2 (25) 36.1 ± 0.8 99 (49, 240) 373 (256, 474) 174 (108, 277) 5 (62) 6 (75) 15 (7, 25) 2 (25) 3 (38) 1 (33)
49 (27) 58 (37–71) 34 (69) 16 (33) 9 (18) 36.2 ± 1.0 110 (46, 293) 337 (241, 470) 169 (120, 254) 33 (67) 39 (80) 13 (10, 16) 8 (16) 18 (37) 13 (72)
59 (32) 65 (54–71) 35 (59) 17 (29) 19 (32) 36.3 ± 1.2 136 (37, 273) 397 (239, 584) 194 (120, 333) 34 (58) 40 (68) 13 (9, 19) 14 (24) 27 (46) 19 (70)
68 (37) 60 (46–70) 32 (47) 19 (28) 20 (29) 36.1 ± 1.6 119 (29, 259) 439 (429, 719) 255 (158, 450) 32 (47) 43 (63) 12 (10, 16) 21 (31) 33 (48) 25 (76)
n, number; VF/VT, ventricular fibrillation/ventricular tachycardia; ◦ C, degree Celsius; temp, temperature; ROSC, return of spontaneous circulation; min, minutes; IQR, Interquartile range; h, hours. There was no association between BMI group and age (p = 0.16), gender (p = 0.11), location of arrest (p = 0.23), or initial rhythm (p = 0.26). As BMI increased the time to reach target temperature between 4 h (p = 0.07) and 6 hours (p = 0.04) decreased. * p = 0.01.
(Table 2). Rates of skin breakdown were indistinguishable between these subgroups as well. There were no significant differences in survival to hospital discharge or the frequency of good neurologic outcome in survivors. 4. Discussion In this multicenter retrospective cohort study of resuscitated cardiac arrest patients treated with TTM, we found that target temperature was frequently achieved within 4–6 h and that increasing BMI was associated with a longer duration to reach target temperature from initiation. In the overall cohort, variations in BMI were not associated with skin breakdown, survival to hospital discharge or survival with good neurological outcome. Obesity has been shown to worsen the outcomes associated with a number of other health conditions including diabetes, musculoskeletal disorders, and heart disease.8,9 Additionally, obesity adversely affects the cutaneous micro- and macrocirculation, which may impair wound healing.8,9 Since cooling causes vasoconstriction of the cutaneous circulation, we were concerned for an increased risk of skin problems in obese patients undergoing TTM. However, our data suggests there was no difference in the rate of skin breakdown between cohorts. Our finding that increasing BMI was associated with a longer time to reach target temperature may be explained by the poor thermal conductivity of fatty tissue, which reduces heat loss, and because of the kinetics of cooling larger mass. Other studies have examined the impact of BMI on the rate of heat loss, for example, one study examining BMI during abdominal surgery found that obese patients resist cooling more than their nonobese counterparts.10 Additionally, another study examining the effectiveness and safety of cooling found that post-cardiac arrest patients who had undergone TTM had BMI values that were not associated with mean cooling rates.11 Additionally, Lyden et al. also found that time to target temperature was uninfluenced by BMI, however, endovascular cooling was employed in their investigation, which has very different thermal kinetics than external cooling as was employed in our study.12 As some investigations suggest that outcomes are improved when target temperature is achieved more quickly, we hypothesized that increasing BMI may be associated with worse outcomes owing to a slower rate of cooling. Our findings failed to support this hypothesis. The rate at which subjects reach target temperature may be associated with those patients whose neurologic status
is more severely compromised and therefore unable to adequately regulate body temperature. Benz-Woerner et al. examined the relationship between body temperature and outcomes after cardiac arrest and also found that time to target temperature was shorter among non-survivors versus survivors (200 [25–363] min vs. 270 [158–375] min, p = 0.03).13 Other studies have examined an “obesity paradox” with regards to mortality and have found that obese patients had improved outcomes. Stamou et al. evaluated patients following cardiac surgery and found that overweight and obese patients had better neurologic outcomes than normal weight patients.14 In addition, in four clinical trials of close to 50,000 patients with cardiovascular disease, Uretsky et al. reported that overweight and obese patients consistently had a lower cardiovascular event rate.15 In a study that looked specifically at BMI and outcomes in cardiac arrest survivors, there was no direct influence on survival 6 months post-cardiac arrest but patients with moderately elevated BMI had a better neurologic prognosis.16 Additionally, a recent study examining cardiac arrest patients separated out by shockable versus non-shockable rhythms found that for those patients whose arrest was caused by shockable rhythms, underweight, normal weight, and very obese patients had lower rates of survival to discharge compared to overweight. Survival to discharge was similar across BMI for nonshockable rhythms with the exception of the underweight group.17 The current work has a number of limitations. The primary limitation is that this study was a nonrandomized, retrospective observational design. Thus, we could not rule out the possibility of potential confounding variables that we did not control for and we did not account for center-level effects. These challenges, inherent in retrospective investigations, can only be overcome in future prospective data collection strategies. Additionally there were a number of missing data (43/236) due to BMI variables and/or cooling times not being documented in the patient’s chart. Given the relatively small number of subjects, we were underpowered to detect an association between BMI and outcomes, however these findings suggest an important hypothesis for future prospective studies evaluating the relationship between BMI and cooling dynamics. Further investigation, including studies of longer-term outcome, is required to determine whether the relationship between time to target temperature and BMI impacts survival. Additionally, time from ROSC to achieving target temperature has a number of confounders that should be taken into consideration in future studies, including total ischemic time, neurologic injury, other co-morbidities, location of arrest and time of
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year.13,18,19 In addition, given our protocolized approach to TTM, our findings may not be generalizeable to other institutions. 5. Conclusions In post-cardiac arrest patients treated with TTM, the time to reaching target temperature was frequently achieved within 4–6 h and was prolonged as BMI increased. Whether the differences observed in time to target temperature result in different outcomes (survival, neurologic recovery) remains unclear and warrants further investigation. Conflict of interest statement Dr. Abella has received honoraria from Medivance Corporation, Stryker Medical and Philips Healthcare and research support from the NIH, Stryker Medical, and Philips Healthcare. Dr. Abella has ownership in Resuscor, LLC. Dr. Gaieski has received research support from Stryker Medical. Marion Leary has received honoraria from Philips Healthcare and Stryker Medical. Ms. Leary has ownership in Resuscor, LLC. References 1. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56. 2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63. 3. Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB. Intraarrest cooling improves outcomes in a murine cardiac arrest model. Circulation 2004;109:2786–91. 4. Gessner P, Dugan G, Janusek L. Target temperature within 3 hours: community hospital’s experience with therapeutic hypothermia. AACN Adv Crit Care 2012;23:246–57.
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5. Gaieski DF, Band RA, Abella BS, et al. Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest. Resuscitation 2009;80:418–24. 6. Soga T, Nagao K, Sawano H, et al. Neurological benefit of therapeutic hypothermia following return of spontaneous circulation for out-of-hospital non-shockable cardiac arrest. Circ J 2012;76:2579–85. 7. Leary M, Grossestreuer AV, Iannacone S, et al. Pyrexia and neurologic outcomes after therapeutic hypothermia for cardiac arrest. Resuscitation 2013;84:1056–61. 8. Yosipovitch G, DeVore A, Dawn A. Obesity and the skin: skin physiology and skin manifestations of obesity. J Am Acad Dermatol 2007;56:901–16 [quiz 917–20]. 9. Shipman AR, Millington GWM. Obesity and the skin. Br J Dermatol 2011;165:743–50. 10. Fernandes LA, Braz LG, Koga FA, et al. Comparison of peri-operative core temperature in obese and non-obese patients. Anaesthesia 2012;67: 1364–9. 11. Jarrah S, Dziodzio J, Lord C, et al. Surface cooling after cardiac arrest: effectiveness, skin safety, and adverse events in routine clinical practice. Neurocrit Care 2011;14:382–8. 12. Lyden P, Ernstrom K, Cruz-Flores S, et al. Determinants of effective cooling during endovascular hypothermia. Neurocrit Care 2012;16:413–20. 13. Benz-Woerner J, Delodder F, Benz R, et al. Body temperature regulation and outcome after cardiac arrest and therapeutic hypothermia. Resuscitation 2012;83:338–42. 14. Stamou SC, Nussbaum M, Stiegel RM, et al. Effect of body mass index on outcomes after cardiac surgery: is there an obesity paradox? Ann Thorac Surg 2011;91:42–7. 15. Uretsky S, Bangalore S, Messerli FH. Obesity and mortality: a poorly understood relationship. Am J Cardiol 2007;99:876–7. 16. Testori C, Sterz F, Losert H, et al. Cardiac arrest survivors with moderate elevated body mass index may have a better neurological outcome: a cohort study. Resuscitation 2011;82:869–73. 17. Jain R, Nallamothu BK, Chan PS. American Heart Association National Registry of Cardiopulmonary Resuscitation (NRCPR) investigators. Body mass index and survival after in-hospital cardiac arrest. Circ Cardiovasc Qual Outcomes 2010;3:490–7. 18. Nielsen N, Hovdenes J, Nilsson F, et al. Hypothermia Network. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 2009;53:926–34. 19. Stratil P, Wallmueller C, Schober A, et al. Seasonal variability and influence of outdoor temperature on body temperature of cardiac arrest victims. Resuscitation 2013;84:630–4.
Contents lists available at ScienceDirect
Resuscitation journal homepage: www.elsevier.com/locate/resuscitation
Clinical paper
The association of body mass index with time to target temperature and outcomes following post-arrest targeted temperature management夽 Marion Leary a,∗ , Marisa J. Cinousis a , Mark E. Mikkelsen b , David F. Gaieski a , Benjamin S. Abella a,b , Barry D. Fuchs b a Center for Resuscitation Science, Department of Emergency Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States b Section of Pulmonary Allergy and Critical Care, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
a r t i c l e
i n f o
Article history: Received 19 July 2013 Received in revised form 11 September 2013 Accepted 24 October 2013
Keywords: Cardiac arrest Targeted temperature management Therapeutic hypothermia Sudden death Body mass index Adverse events
a b s t r a c t Background: Evidence suggests that more rapid attainment of target temperature (32–34 ◦ C) improves neurologic outcome following cardiac arrest and targeted temperature management (TTM). It is unclear to what extent body mass index (BMI) is associated with the time to reach target temperature and subsequent clinical outcomes. Objective: We sought to determine whether the time to target temperature was affected by BMI. In addition, we wished to determine whether the incidence of skin breakdown, survival to discharge and neurologic outcomes were associated with BMI. Methods: Multicenter retrospective cohort study of cardiac arrest patients who underwent TTM between July 2007 and December 2012. We examined the association between BMI and the time from initiation of cooling to attainment of target temperature (32–34 ◦ C). Results: Of 236 patients treated with TTM, 184 were included in the study. Mean age was 57.8 ± 17.0 years; 78/184 (42%) were female and 48/184 (26%) had VF/VT as the initial rhythm. Median time to reach target temperature from ROSC was 6.4 (4.1, 9.8) h and median time from initiation of TTM to target temperature was 3.4 (2.1, 5.8) h. Cooling duration was a median of 24.0 (23.0, 24.0) h and median rewarming time was 12.0 (9.5, 18.0) h. Overall, 104/184 (56.5%) achieved target temperature within 4 h and 128/184 (69.6%) within 6 h. Increased BMI was associated with a longer time to achieve target temperature from initiation of TTM (p = 0.01). There was no significant difference across BMI groups in time to achieve target temperature from ROSC (0.07), skin breakdown (p = 0.35), survival (p = 0.21), nor rate of good neurologic outcome (p = 0.32). Conclusions: Target temperature was frequently achieved within 4–6 h; as BMI increased, the time to reach target temperature from initiation of TTM was prolonged. There was no significant difference across BMI groups for survival or good neurologic outcome. © 2013 Published by Elsevier Ireland Ltd.
1. Introduction The induction of Therapeutic Hypothermia or Targeted Temperature Management (TTM) after cardiac arrest has been shown to increase survival to discharge and neurologic recovery.1,2 Several
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.2013.10.027. ∗ Corresponding author at: Center for Resuscitation Science, Department of Emergency Medicine, University of Pennsylvania, 3400 Spruce Street, Ground Ravdin, Philadelphia, PA 19104, United States. E-mail address: [email protected] (M. Leary). 0300-9572/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.resuscitation.2013.10.027
investigations suggest that establishing the desired target temperature (32–34 ◦ C) rapidly may enhance survival.3,4 Current protocols in clinical use suggest reaching target temperature as quickly as possible but within 4–6 h.5–7 Reaching target temperature within this acceptable window in the obese patient population can be difficult. Obesity is also a major public health concern in the United States with an estimated 119 million overweight or obese adults.8 Obesity has been shown to worsen the outcomes associated with a number of other health conditions including diabetes, musculoskeletal disorders, and cardiovascular disease.8,9 Whether obesity has an effect on outcomes in the post-arrest patient population treated with TTM is currently unknown.
M. Leary et al. / Resuscitation 85 (2014) 244–247
In a post-arrest patient cohort treated with TTM, we sought to determine how frequently the target temperature was achieved within 4–6 h and whether the time to target temperature was affected by body mass index (BMI). In addition, we wished to determine whether survival to discharge and neurologic outcomes, as well as adverse events such as skin breakdown from external cooling systems, were associated with BMI. 2. Methods We performed a retrospective cohort study of post-arrest patients who were treated with TTM at two hospitals within the University of Pennsylvania Health System. This study was approved by the University of Pennsylvania Institutional Review Board. Post-arrest patients were included in our investigation if they had TTM administered at the Hospital of the University of Pennsylvania (HUP) or the Penn Presbyterian Medical Center (PPMC) between July 2007 and December 2012. Only those patients who achieved Return of Spontaneous Circulation (ROSC) and received a full course of TTM, including the attainment of normothermia after rewarming, were included. Patients were excluded from data analysis if cooling was begun at an outside hospital with no documented date and time of ROSC or TTM initiation, they did not complete TTM, did not reach target temperature, or did not have BMI clearly documented. The post-arrest TTM protocol employed for patients in this cohort was similar at both institutions. All adult patients who achieved ROSC, regardless of arrest location (in-hospital or outof-hospital) and regardless of presenting rhythm (ventricular fibrillation, pulseless ventricular tachycardia, pulseless electrical activity, asystole) were eligible to receive TTM. Initiation of TTM was begun as soon as possible following ROSC using an infusion of cold saline and external cooling wraps. Both TTM protocols required all patients to be treated with sedation and paralysis prior to initiation of cooling. The goal to achieve target temperature was within 4–6 h of initiation of ROSC. TTM was maintained for 24 h from the time target temperature was reached, at which point rewarming was initiated at a rate of 0.33 ◦ C h−1 until normothermia (37 ◦ C) was attained. 2.1. Body mass index (BMI) BMI was calculated as weight in kilograms (kg) divided by height in meters squared. Patients were categorized according to the World Health Organization classification as either: underweight (≤18.4 kg m−2 ), normal (18.5–25 kg m−2 ), overweight (25.1–29.9 kg m−2 ) or obese (≥30 kg m−2 ) based on their documented weight and height. Time from ROSC to attainment of target temperature and time from initiation of cooling to attainment of target temperature were then analyzed in each of the BMI categories, as well as the time from initiation of rewarming to normothermia in each group. Skin breakdown, survival to hospital discharge and survival with good neurologic outcomes were assessed in all groups. Skin breakdown was defined as any documentation in the integumentary section in the medical chart not within normal limits (reddened area through exposure of muscle or bone) from initiation through one day post rewarming. Good neurologic outcome was defined as a Cerebral Performance Category (CPC) of 1 or 2 at hospital discharge. 2.2. Statistical analysis Data were analyzed using a standard statistical software package (STATA 12, Statacorp, College Station, TX). The Kruskal–Wallis rank test and the Chi-squared test were used
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to compare continuous variables and BMI. We used the nonparametric test for trends across ordered groups to examine whether the time to target temperature increased as BMI increased or if outcomes differed as BMI increased. 3. Results Of the 236 patients treated with TTM following cardiac arrest resuscitation, 184 were included in the study (Table 1). Thirty-six patients were excluded due to missing time data precluding the calculation of time to target temperature, 7 patients were excluded in whom BMI could not be calculated due to a missing height or weight documentation, and 9 patients were excluded because they were already at target temperature at ROSC. In this TTM-treated cohort, mean age was 57.8 ± 17.0 years; 78/184 (42%) were female and 48/184 (26%) had VF/VT as the initial rhythm. Patient temperatures prior to TTM initiation were 36.2 ± 1.5 ◦ C. TTM initiation began a median of 2.0 (0.6, 4.4) h after ROSC. Median time to reach target temperature from ROSC was 6.4 (4.1, 9.8) h and median time from initiation of TTM to target temperature was 3.4 (2.1, 5.8) h. Cooling duration was a median of 24.0 (23.0, 24.0) h and median rewarming time was 12.0 (9.5, 18.0) h. Overall, 104/184 (56.5%) achieved target temperature within 4 h and 128/184 (69.6%) achieved target temperature within 6 h. Overall survival to discharge was 81/184 (44%). Rates of survival to hospital discharge were indistinguishable when time to target temperature was dichomotized to either 4 or 6 h. Increasing BMI was not associated with a longer time from ROSC to initiation (p = 0.97) nor from ROSC to reaching target temperature (0.07). However there was an association with increasing BMI and time from initiation of TTM to achieving target temperature (p = 0.01). As BMI increased the time to reach target temperature between 4 h (p = 0.07) and 6 h (p = 0.04) decreased. However, there was no significant difference in the time required to rewarm across BMI groups (p = 0.84). There were no statistically significant differences in clinical or demographic data between the BMI subgroups Table 1 Demographics and clinical data in the TTM cohort (n = 184). Mean age, y ± SD Gender, n (%) Female Male Location, n (%) Out-of-hospital In-hospital a OSH Tx Other Initial rhythm, n (%) VF/VT PEA Asystole Other/unknown Time intervals ROSC to TTM initiation, h (IQR) ROSC to target temp, h (IQR) Initiation to target temp, h (IQR) Cooling duration, h (IQR) Rewarming duration, h (IQR) Outcomes Survival to discharge, n (%) Target temp. reached within 4 h, n (%) Target temp. reached within 6 h, n (%) CPC 1 or 2 (among survivors), n (%)
57.8 ± 17.0 78 (42%) 106 (58%) 91 (49.5%) 54 (29%) 38 (21%) 1 (0.5%) 48 (25%) 87 (47%) 31 (17%) 18 (11%) 2.0 (0.6, 4.4) 6.4 (4.1, 9.8) 3.4 (2.1, 5.8) 24.0 (23.0, 24.0) 12.0 (9.5, 18.0) 81 (44%) 104 (56.5%) 128 (69.6%) 58 (72%)
TTM, targeted temperature management; y, years; h, hours; IQR, Interquartile range; SD, standard deviation; OSH Tx, Outside hospital transfer, VF/VT, ventricular fibrillation/ventricular tachycardia; PEA, pulseless electrical activity; CPC, cerebral performance category. a Of those whose arrest location was coded as ‘OSH Tx’, all patients were out-ofhospital arrests.
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Table 2 Demographics and clinical data across BMI subgroups.
n (%) Age Male, n (%) Location-in-hospital, n (%) Initial rhythm-VF/VT, n (%) Initial temp., ◦ C Time from ROSC to initiation, min (IQR) Time from ROSC to target temp., min (IQR) Time from initiation* to target temp., min Time to target temp within 4 h, n (%) Time to target temp within 6 h, n (%) Rewarming time, h (IQR) Skin breakdown Survival to discharge Good neurological outcome
Underweight (<18.5)
Normal (18.5–24.9)
Overweight (25–29.9)
Obese (≥30)
8 (4) 58 (38–64) 3 (38) 2 (25) 2 (25) 36.1 ± 0.8 99 (49, 240) 373 (256, 474) 174 (108, 277) 5 (62) 6 (75) 15 (7, 25) 2 (25) 3 (38) 1 (33)
49 (27) 58 (37–71) 34 (69) 16 (33) 9 (18) 36.2 ± 1.0 110 (46, 293) 337 (241, 470) 169 (120, 254) 33 (67) 39 (80) 13 (10, 16) 8 (16) 18 (37) 13 (72)
59 (32) 65 (54–71) 35 (59) 17 (29) 19 (32) 36.3 ± 1.2 136 (37, 273) 397 (239, 584) 194 (120, 333) 34 (58) 40 (68) 13 (9, 19) 14 (24) 27 (46) 19 (70)
68 (37) 60 (46–70) 32 (47) 19 (28) 20 (29) 36.1 ± 1.6 119 (29, 259) 439 (429, 719) 255 (158, 450) 32 (47) 43 (63) 12 (10, 16) 21 (31) 33 (48) 25 (76)
n, number; VF/VT, ventricular fibrillation/ventricular tachycardia; ◦ C, degree Celsius; temp, temperature; ROSC, return of spontaneous circulation; min, minutes; IQR, Interquartile range; h, hours. There was no association between BMI group and age (p = 0.16), gender (p = 0.11), location of arrest (p = 0.23), or initial rhythm (p = 0.26). As BMI increased the time to reach target temperature between 4 h (p = 0.07) and 6 hours (p = 0.04) decreased. * p = 0.01.
(Table 2). Rates of skin breakdown were indistinguishable between these subgroups as well. There were no significant differences in survival to hospital discharge or the frequency of good neurologic outcome in survivors. 4. Discussion In this multicenter retrospective cohort study of resuscitated cardiac arrest patients treated with TTM, we found that target temperature was frequently achieved within 4–6 h and that increasing BMI was associated with a longer duration to reach target temperature from initiation. In the overall cohort, variations in BMI were not associated with skin breakdown, survival to hospital discharge or survival with good neurological outcome. Obesity has been shown to worsen the outcomes associated with a number of other health conditions including diabetes, musculoskeletal disorders, and heart disease.8,9 Additionally, obesity adversely affects the cutaneous micro- and macrocirculation, which may impair wound healing.8,9 Since cooling causes vasoconstriction of the cutaneous circulation, we were concerned for an increased risk of skin problems in obese patients undergoing TTM. However, our data suggests there was no difference in the rate of skin breakdown between cohorts. Our finding that increasing BMI was associated with a longer time to reach target temperature may be explained by the poor thermal conductivity of fatty tissue, which reduces heat loss, and because of the kinetics of cooling larger mass. Other studies have examined the impact of BMI on the rate of heat loss, for example, one study examining BMI during abdominal surgery found that obese patients resist cooling more than their nonobese counterparts.10 Additionally, another study examining the effectiveness and safety of cooling found that post-cardiac arrest patients who had undergone TTM had BMI values that were not associated with mean cooling rates.11 Additionally, Lyden et al. also found that time to target temperature was uninfluenced by BMI, however, endovascular cooling was employed in their investigation, which has very different thermal kinetics than external cooling as was employed in our study.12 As some investigations suggest that outcomes are improved when target temperature is achieved more quickly, we hypothesized that increasing BMI may be associated with worse outcomes owing to a slower rate of cooling. Our findings failed to support this hypothesis. The rate at which subjects reach target temperature may be associated with those patients whose neurologic status
is more severely compromised and therefore unable to adequately regulate body temperature. Benz-Woerner et al. examined the relationship between body temperature and outcomes after cardiac arrest and also found that time to target temperature was shorter among non-survivors versus survivors (200 [25–363] min vs. 270 [158–375] min, p = 0.03).13 Other studies have examined an “obesity paradox” with regards to mortality and have found that obese patients had improved outcomes. Stamou et al. evaluated patients following cardiac surgery and found that overweight and obese patients had better neurologic outcomes than normal weight patients.14 In addition, in four clinical trials of close to 50,000 patients with cardiovascular disease, Uretsky et al. reported that overweight and obese patients consistently had a lower cardiovascular event rate.15 In a study that looked specifically at BMI and outcomes in cardiac arrest survivors, there was no direct influence on survival 6 months post-cardiac arrest but patients with moderately elevated BMI had a better neurologic prognosis.16 Additionally, a recent study examining cardiac arrest patients separated out by shockable versus non-shockable rhythms found that for those patients whose arrest was caused by shockable rhythms, underweight, normal weight, and very obese patients had lower rates of survival to discharge compared to overweight. Survival to discharge was similar across BMI for nonshockable rhythms with the exception of the underweight group.17 The current work has a number of limitations. The primary limitation is that this study was a nonrandomized, retrospective observational design. Thus, we could not rule out the possibility of potential confounding variables that we did not control for and we did not account for center-level effects. These challenges, inherent in retrospective investigations, can only be overcome in future prospective data collection strategies. Additionally there were a number of missing data (43/236) due to BMI variables and/or cooling times not being documented in the patient’s chart. Given the relatively small number of subjects, we were underpowered to detect an association between BMI and outcomes, however these findings suggest an important hypothesis for future prospective studies evaluating the relationship between BMI and cooling dynamics. Further investigation, including studies of longer-term outcome, is required to determine whether the relationship between time to target temperature and BMI impacts survival. Additionally, time from ROSC to achieving target temperature has a number of confounders that should be taken into consideration in future studies, including total ischemic time, neurologic injury, other co-morbidities, location of arrest and time of
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year.13,18,19 In addition, given our protocolized approach to TTM, our findings may not be generalizeable to other institutions. 5. Conclusions In post-cardiac arrest patients treated with TTM, the time to reaching target temperature was frequently achieved within 4–6 h and was prolonged as BMI increased. Whether the differences observed in time to target temperature result in different outcomes (survival, neurologic recovery) remains unclear and warrants further investigation. Conflict of interest statement Dr. Abella has received honoraria from Medivance Corporation, Stryker Medical and Philips Healthcare and research support from the NIH, Stryker Medical, and Philips Healthcare. Dr. Abella has ownership in Resuscor, LLC. Dr. Gaieski has received research support from Stryker Medical. Marion Leary has received honoraria from Philips Healthcare and Stryker Medical. Ms. Leary has ownership in Resuscor, LLC. References 1. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56. 2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63. 3. Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB. Intraarrest cooling improves outcomes in a murine cardiac arrest model. Circulation 2004;109:2786–91. 4. Gessner P, Dugan G, Janusek L. Target temperature within 3 hours: community hospital’s experience with therapeutic hypothermia. AACN Adv Crit Care 2012;23:246–57.
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