The Extent of Myocardial Injury During Prolonged Targeted Temperature Management After Out-of-Hospital Cardiac Arrest

CLINICAL RESEARCH STUDY

The Extent of Myocardial Injury During Prolonged Targeted Temperature Management After Out-ofHospital Cardiac Arrest Anders Morten Grejs, MD,a,b,c Jakob Gjedsted, MD, PhD,b,c Kristian Thygesen, MD, DMSc,d Jens Flensted Lassen, MD, PhD,e Bodil Steen Rasmussen, MD, PhD,f,g Anni Nørgaard Jeppesen, MD,a,b,c Christophe Henri Valdemar Duez, MD,a,c Eldar Søreide, MD, PhD,h,i Hans Kirkegaard, MD, DMSc, PhDa,c a

Research Center for Emergency Medicine and bDepartment of Anesthesiology and Intensive Care Medicine, Aarhus University Hospital, Denmark; cDepartment of Clinical Medicine, Aarhus University, Denmark; dDepartment of Cardiology, Aarhus University Hospital, Denmark; eDepartment of Cardiology, Rigshospitalet, University Hospital of Copenhagen, Denmark; fDepartment of Anesthesiology and Intensive Care Medicine and gDepartment of Clinical Medicine, Aalborg University, Denmark; hDepartment of Anesthesiology and Intensive Care, Stavanger University Hospital, Norway; iDepartment of Clinical Medicine, University of Bergen, Norway.

ABSTRACT AIM: The aim of this study is to evaluate the extent of myocardial injury by cardiac biomarkers during prolonged targeted temperature management of 24 hours vs 48 hours after out-of-hospital cardiac arrest. METHODS: This randomized Scandinavian multicenter study compares the extent of myocardial injury quantified by area under the curve (AUC) of cardiac biomarkers during prolonged targeted temperature management at 33
C  1
C of 24 hours and 48 hours, respectively. Through a period of 2.5 years, 161 comatose out-of-hospital cardiac arrest patients were randomized to targeted temperature management for 24 hours (n ¼ 77) or 48 hours (n ¼ 84). The AUC was calculated using both high-sensitivity cardiac troponin T (hs-cTnTAUC) and creatine kinase-myocardial band (CK-MBAUC) that were based upon measurements of these biomarkers every 6 hours upon admission until 96 hours after reaching target temperature. RESULTS: The median hs-cTnTAUC of 33,827 ng/L/h (interquartile range [IQR] 11,366-117,690) of targeted temperature management at 24 hours did not differ significantly from that of 28,973 ng/L/h (IQR 10,656-163,655) at 48 hours. In contrast, the median CK-MBAUC of 1829 mg/L/h (IQR 800-6799) during targeted temperature management at 24 hours was significantly lower than that of 2428 mg/L/h (IQR 1163-10,906) within targeted temperature management at 48 hours, P <.05. CONCLUSION: This study of comatose out-of-hospital cardiac arrest survivors showed no difference between the extents of myocardial injury estimated by hs-cTnTAUC of prolonged targeted temperature management of 48 hours vs 24 hours, although the CK-MBAUC was significantly higher during 48 hours vs 24 hours. Hence, it seems unlikely that the duration of targeted temperature management has a beneficial effect on the extent of myocardial injury after out-of-hospital cardiac arrest, and may even have a worsening effect. Ó 2016 Elsevier Inc. All rights reserved.  The American Journal of Medicine (2016) -, --KEYWORDS: Body temperature regulation; CK-MB; Heart arrest; Induced mild hypothermia; Out-of-hospital cardiac arrest; Troponin T; Targeted temperature management

Targeted temperature management is recommended as an integrated part of postresuscitation care after out-of-hospital cardiac arrest.1-3 Although the main goal with targeted ClinicalTrials.gov Identifier: NCT02066753. Funding: See last page of article. Conflict of Interest: See last page of article. Authorship: See last page of article.

0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2016.06.047

temperature management is to reduce the cerebral injury and to improve survival,4-6 the practical value of the treatment to moderate the myocardial injury occurring in out-of-hospital Requests for reprints should be addressed to Anders Morten Grejs, MD, Department of Anesthesiology and Intensive Care Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark. E-mail address: [email protected]

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cardiac arrest survivors has also been discussed for This study was approved by the Ethics Committee (file years.7-12 The extent of myocardial injury, whether ischemic number 20110022) and carried out according to the Declaor nonischemic, is reflected by the released amount of carration of Helsinki. Computer-based random block randomdiac biomarkers into the blood, enabling the assessment of ization was conducted after obtaining written informed area under the curve (AUC) and the determination of peak consent from a legal representative and the patient’s general values. In this way, the AUC and the peak values of practitioner. The treating physicians and the project different cardiac biomarkers have personnel accomplished the inbeen applied to evaluate the carclusion of the patients. The incluCLINICAL SIGNIFICANCE dioprotective effect of targeted sion and exclusion criteria are temperature management in newshown in Table 1.  The myocardial injury extent assessed by borns with perinatal asphyxia by Some patients were cooled with areas under the curve of troponin T means of cardiac troponin I (hscold saline or external ice packs prior measurements did not differ between cTnI) measurements13 and in to arrival at the hospital, according to targeted temperature management of 48 adults by measuring creatine kiprevious guidelines,20 but the ma
C in out-ofhours vs 24 hours at 33 nase and creatine kinasejority started their cooling at admishospital cardiac arrest survivors. myocardial band (CK-MB).7 sion. The patients were cooled as fast as possible to a target temperature of The high-sensitivity cardiac  By analogous creatine kinase-MB mea33
C  1
C. Targeted temperature troponin T (hs-cTnT) has been surements, the myocardial injury extent proven to be a more specific and management was maintained for was significantly higher when cooling sensitive indicator for myocardial either 24 hours or 48 hours, and was performed for 48 hours. injury than CK-MB,14 and its rewarming was conducted at a  Prolonged cooling seems inefficient or maximum rate of 0.5
C/h. levels reflect myocardial injury well, following resuscitation after may have a worsening effect on cardiac arrest.15 Additionally, it myocardial injury extent in out-ofData has been applied as a prognostic hospital cardiac arrest survivors. marker following targeted temFrom February 2013 to October perature management in data from 2015, we included a total of 161 the FINNRESUSCI study.16 Detection of an acute unconscious out-of-hospital cardiac arrest patients, 63 of whom had a myocardial infarction myocardial infarction in cardiac arrest patients is expedited diagnosed21 (Figure 1). by hs-cTnT measurements, even with confounding condi17 tions due to the resuscitation per se and critical illness. We collected study population characteristics such as sex, age, body mass index, previous medical history, and However, factors like timing, cooling rate, depth, and Simplified Acute Physiology Score (SAPS II), along with length of targeted temperature management are still undeterprehospital data following the Utstein template19 mined regarding the impact on the myocardial injury. Therefore, a potential demonstration of an alteration of the AUC of (Table 2). Furthermore, we collected in-hospital data cardiac biomarkers through targeted temperature management, from the cardiac catheterization laboratories and from the as an estimation of a cardioprotective effect, would be ICUs. Data were managed using REDCap electronic data important. To the best of our knowledge, such an assessment capture tools.22 of prolonged targeted temperature management in adult outof-hospital cardiac arrest survivors has never been performed. Blood Sampling Thus, the aim of this study was to investigate whether there is a difference in the extent of myocardial injury as We collected blood samples for analyses upon admission, assessed by AUC of hs-cTnT and CK-MB of targeted temevery 6 hours after reaching the target temperature up to 48 perature management at 33
C  1
C for 48 hours compared hours, and thereafter at 72 and 96 hours (Figure 2) for the calculation of AUCs, as well as for determination of peak with 24 hours in out-of-hospital cardiac arrest survivors. values of the cardiac biomarkers. The Elecsys 2010 hsTroponin T immunoassay (Roche Diagnostics, Penzberg, Germany) was used for measuring the hs-cTnT concentraMATERIALS AND METHODS tions, while the ARCHITECT STAT CK-MB immunoassay Study Design (Abbott Laboratories, Lake Bluff, Ill.) was applied for the measurement of the CK-MB values. Routinely, the hs-cTnT This study is a cardioprotective focused, randomized, clinwas applied for detecting myocardial injury and for diagical multicenter study based on 161 out-of-hospital cardiac nosing myocardial infarction23 (cut point: 14 ng/L [99th arrest survivors enrolled at 3 Scandinavian intensive care 18 units (ICUs) in the TTH48 trial, which evaluates propercentile of the upper reference limit (URL)]). Additionlonged targeted temperature management for 48 hours ally, the measurements of CK-MB were carried out as a against 24 hours in consecutively admitted out-of-hospital supplemental option for detecting myocardial injury and cardiac arrest patients with a presumed cardiac origin. diagnosing myocardial infarction (cut points: 4.0 mg/L URL

Grejs et al Table 1

Prolonged Targeted Temperature Management and Myocardial Injury

3

Inclusion and Exclusion Criteria

Inclusion Criteria

Exclusion Criteria

   

 Estimated return of spontaneous circulation time >60 min  Terminal illness (eg, cancer or advanced heart disease with estimated life expectancy within 6 mo)  Coagulopathy (medical anticoagulant therapy, including thrombolysis, is not a contraindication)  Unwitnessed asystole  Time from cardiac arrest to start of targeted temperature management >240 min  Pregnancy  Persistent cardiogenic shock, systolic blood pressure <80 mm Hg despite vasoactive treatment and aortic balloon pump intervention.  Cerebral performance category19 >2 prior to cardiac arrest  Suspected acute intracerebral hemorrhage or stroke  Acute coronary artery bypass grafting  Lack of consent (patient, general practitioner, or patient if consciousness is regained)

Out-of-hospital cardiac arrest with a presumed cardiac origin Return of spontaneous circulation sustained for at least 20 min Glasgow Coma Scale score <8 Age 18 and <80 y old

Both patients with shockable and nonshockable initial rhythms were included.

for women and 7.0 mg/L URL for men). We measured and analyzed serum creatinine at admission, after 24 hours, 48 hours, 72 hours, and 96 hours. Creatinine clearance was calculated using the Cockcroft-Gault formula.24

were analyzed by a chi-squared test. A 2-tailed P-value <.05 was considered statistically significant. We used the Stata 13.1 (StataCorp LP, College Station, Texas) for all analyses.

Intensive Care Treatment

RESULTS

A screening temperature at hospital arrival was taken by a tympanic Braun thermometer (Welch Allyn, Skaneateles, NY) or a urinary catheter with a thermosensor (Coviden, Dublin, Ireland). The ICUs used both endovascular and surface cooling systems providing core temperature feedback. The bladder temperature, as representative for the core temperature, guided all interventions. Patients were sedated by propofol/midazolam and remifentanil/ fentanyl, and cisatracurium was used to prevent shivering. During cooling, norepinephrine was the vasopressor of choice.

Of the 161 included patients, 77 patients were allocated to 24 hours of cooling and 84 patients to 48 hours of cooling (Figure 1). The study population characteristics of the 2 groups were comparable, except that the 48-hour group reached their target temperature significantly faster and was treated with an endovascular cooling system more often than the patients in the 24-hour group (Table 2). The release-elimination profiles of hs-cTnT and CK-MB values are illustrated as time curves for all 161 included patients (Figure 3). The time to return of spontaneous circulation (ROSC) was approximately 20 minutes in each group, and the time from ROSC to admission was approximately 80 minutes in each group. All patients but one had admission hs-cTnT values above the URL, whereas the CK-MB arrival values were close to the URL (Table 2). Analyses showed a peak value of hs-cTnT within 6 hours, followed by a gradual fall beyond 96 hours, whereas the peak value of CK-MB appeared later, at 18 hours, with a steeper decrease reaching the base line prior to 96 hours (Figure 3). The median values (IQR) being divided in the 24-hour and 48-hour groups are entered in Table 3. The rather large IQRs reflect a great variability of the measurements. However, no significant differences of the hs-cTnT values were detected between the 24-hour and the 48-hour groups, whether assessed by AUC or

Statistics The power calculation of the study was based on hs-cTnT values from out-of-hospital cardiac arrest patients derived from the Western Denmark Heart Registry.25 In order to detect a relative reduction of the AUC of 25%, a prerequisite of 73 patients in each group was calculated, when aiming for a power of 90%, a significance level of .05, and a variability of 50%. We decided to enroll a total of 160 patients, considering an expected dropout rate of 10%. Baseline characteristics and demographic data are presented as medians  interquartile range (IQR), and numbers (%) for categorical variables. All continuous data were analyzed by AUC (trapezoid method) and compared by a Mann-Whitney U test. Binary baseline characteristics

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Figure 1 Consort diagram showing the 375 patients screened for eligibility of whom 161 patients were included for analyses and of whom 63 patients had an acute myocardial infarction.

measurements at 72 hours or 96 hours after reaching the target temperature (Figure 4). Similarly, no significant differences were observed in the groups with myocardial infarction, showing 76,116 ng/L/h (33,060-213,315) of hs-cTnTAUC in the 24-hour group vs 141,860 ng/L/h (30,148-255,335) in the 48-hour group. Conversely, the results from the CK-MB analyses revealed a significantly lower CK-MBAUC of 1829 mg/L/h (800-6799) in the 24-hour group, compared with 2428 mg/L/h (1163-10,906) in the 48-hour group; P <.05 (Table 3, Figure 4). However, in the myocardial infarction group, the median CK-MBAUC of 6821 mg/L/h (1659-13,741) in the 24-hour group was not significantly different from 9777 mg/L/h (2411-21,084) in the 48-hour group. The analysis of renal function showed no difference in the values between the 2 intervention groups (Table 2).

DISCUSSION This prospective multicenter trial of consecutively admitted comatose out-of-hospital cardiac arrest survivors showed no difference in the extent of myocardial injury assessed by AUCs of serial hs-cTnT measurements, when targeted temperature management of 33
C  1
C for 24 hours was compared with 48 hours. However, the AUC of CK-MB measurements showed a significantly greater extent of myocardial injury of targeted temperature management during 48 hours when compared with targeted temperature management through 24 hours. This discrepancy may be related to different release patterns, including different sensitivities and specificities of the cardiac biomarkers. Whatever the mechanisms may be, it seems likely that the duration of targeted temperature management does not have any beneficial influence, or perhaps an even worsening

Grejs et al Table 2

Prolonged Targeted Temperature Management and Myocardial Injury

5

Study Population Characteristics

Characteristic

24 h (n ¼ 77)

48 h (n ¼ 84)

P-Value

Age e y Male sex e n (%) Body mass index e kg/m2 Diabetes mellitus e n (%) Smoker e n (%) Previous Never No answer Hyperlipidemia e n (%) Hypertension e n (%) Previous myocardial infarction e n (%) Alcohol abuse e n (%) Resuscitation CPR prior to EMS e n (%) First rhythm VF/VT e n (%) No-Flow time e (min) Low-Flow time e (min) ROSC time e (min) Use of LUCAS e n (%) Catheterization laboratory ROSC to primary CAG e (min)* Acute myocardial infarction e n (%) ROSC to PCI if myocardial infarctione (min) Tympanic temperature at PCI e (
C)† Intensive care unit Admission hs-cTnT e (ng/L)‡ Admission CK-MB e (mg/L)§ ROSC to target temperature e (min) Time inside target temperature e (min) TTM method e endovascular (%) First lactate e (mmol/L) SAPS II e (value) Creatinine clearanceAUC e (mL/min/h)

61 67 27.4 12 23 24 16 14 27 34 20 8

63 67 27.5 17 32 25 14 13 29 47 18 5

(54-69) (80) (24.4-30.0) (20) (38) (30) (17) (15) (35) (56) (21) (6)

.92 .22 .69 .44 .72

(89) (87) (0-1) (15-26) (15-26) (37)

.73 .82 .86 .46 .82 .21

70 66 1 18 20 21

(54-69) (87) (24.3-29.3) (16) (30) (31) (21) (18) (36) (44) (26) (11) (91) (86) (0-1) (12-31) (14-32) (28)

75 73 1 20 21 31

.98 .14 .50 .29

85 29 83 35.5

(67-123) (38) (67-123) (34.9-36.1)

79 34 80 35.4

(56-109) (40) (57-106) (34.4-35.9)

.11 .58 .49 .17

125 7.4 352 26.1 35 2.7 53 7934

(56-329) (4.5-14.0) (264-428) (22.8-26.9) (45) (1.7-5.9) (44-64) (5433-10,565)

127 6.2 293 49.0 54 2.9 52 8595

(59-278) (3.7-15.3) (233-383) (43.0-50.3) (64) (1.4-4.6) (47-60) (5951-11,500)

.90 .35 .02 .02 .43 .62 .35

Data are presented as medians (interquartile range) for continuous data and number (%) for binary data. AUC ¼ area under the curve; CAG ¼ coronary angiography; CPR ¼ cardiopulmonary resuscitation; EMS ¼ emergency medical service; LUCAS ¼ Lund University Cardiopulmonary Assist System e mechanical compression device; PCI ¼ percutaneous cardiac intervention; ROSC ¼ return of spontaneous circulation; SAPSII ¼ simplified acute physiology score II; TTM ¼ targeted temperature management; VF ¼ ventricular fibrillation; VT ¼ pulseless ventricular tachycardia. *Primary CAG definition: if ROSC to CAG time <240 min. †n ¼ 91. ‡hs-cTnT ¼ high-sensitivity cardiac troponin T (cut point: 14 ng/L). §CK-MB ¼ creatine kinase-myocardial band (cut point: woman 4.0 mg/L/men 7.0 mg/L).

effect, on the extent of myocardial injury when applied for a longer time in postresuscitation care.

Targeted Temperature Management for Comatose Out-of-Hospital Cardiac Arrest Survivors Cerebral and myocardial injuries following out-of-hospital cardiac arrest account for over 90% of the mortality.26 The presenting neurological symptoms of survivors are mainly impairment of arousal in the early phase, and later, affected short-term memory and dysfunction of movement and coordination.27 In this respect, cooling is considered

important for neuroprotection and for lowering the mortality of comatose out-of-hospital cardiac arrest survivors.3,28 It protects the brain in a multifactorial way against many destructive processes following ischemia/reperfusion, such as production of free radicals, excitotoxicity, apoptosis, neuroinflammation, destruction of adenosine triphosphate stores, and destruction of vessels/bloodebrain barrier, among others, although it may give rise to adverse events such as pneumonia and hypokalemia.4-6,28,29 The cooling dosage, that is, the temperature level and duration, is widely discussed for neuroprotection.30 Nielsen et al6 investigated the impact of the different temperature levels, 33
C vs 36
C, and found no difference in survival and neurological

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Figure 2 Flowchart. The flowchart shows times on the x-axis and temperature on the y-axis with the intervals for biomarker sampling plotted. After 24 hours the 24-hour group is rewarmed at a rate of 0.5
C/h until 37
C (dotted line). After 48 hours the 48-hour group is rewarmed at a rate of 0.5
C/h until 37
C (dashed line). Dotted gray horizontal lines mark the target temperature zone between 32
C and 34
C.

outcome, or in serious adverse events. On the other hand, both Eicher et al31 and the Cool Cap trial32 found a benefit of prolonged targeted temperature management for 48 hours and 72 hours, respectively, in neonates suffering hypoxicischemic encephalopathy.

Assessment of Myocardial Injury by Cardiac Biomarkers Cardiac biomarkers have commonly been used to reflect the extent of myocardial injury as assessed by both AUC and peak values. That has been shown to correlate well with the

Figure 3 Cardiac biomarker profiles after out-of-hospital cardiac arrest. The curves of the total numbers of median values of high-sensitivity cardiac troponin T (hs-cTnT) and creatine kinase-myocardial band (CK-MB) in relation to the timing after out-of-hospital cardiac arrest. All hs-cTnT arrival values were elevated above the 99th percentile and the peak values of hs-cTnT occurred within the first 6 hours. The CKMB arrival values were close to the upper reference limit and the peak values occurred at around 18 hours.

extent of myocardial dysfunction,7,15,33,34 which has also been corroborated by imaging techniques.34 These tools are thus considered reliable to evaluate the degree of cardioprotection as suggested in previous cardiac arrest studies.7,16,35,36 In order to accurately assess the extent of myocardial injury by AUC during the prolonged cooling period, we sampled blood for the analyses every 6 hours during the first 48 hours and thereafter at 72 hours and 96 hours. The applied cardiac biomarkers consisted of hs-cTnT and CKMB, of which hs-cTnT has a higher sensitivity and specificity for the detection of myocardial injury when compared with CK-MB.23 Furthermore, the study showed that the hscTnT had a faster appearance, seeing that the values were elevated upon arrival and besides, displayed an earlier peak value in contrast to CK-MB. The rise and fall profiles of both the hs-cTnT and CKMB concentrations seen in our study resemble those of an evolving acute myocardial infarction and the development of acute nonischemic myocardial injury.37,38 A number of causes for nonischemic myocardial injury include cardiac contusion, cardiac pulmonary resuscitation, repetitive defibrillation shocks, coronary angiography, heart failure, critical illness, and postcardiac arrest syndrome.12,39 This diversity of potential causes, reflecting the multifactorial conditions after out-of-hospital cardiac arrest, may explain the large variability of the biomarker measurements in our study which has also been demonstrated by others.35 Beyond myocardial injury, cardiac biomarkers can be elevated in relation to cerebral injury, as demonstrated by Kerr et al,40 who showed that elevation of hs-cTnT values may be present after stroke and other cerebral catastrophes.40-42 It is worth considering that hypoxic injured neurons after out-of-hospital cardiac arrest might have contributed to the release of biomarkers in our study.

Grejs et al

Cardiac Biomarkers from Admission Until 96 Hours After Reaching a Target Temperature of 33
C Arrival

6h

12 h

Serial median hs-cTnT (ng/L) values including IQR in the 24 h 124 688 530 (56-254) (193-1862) (143-1665) 48 h 116 659 625 (57-266) (226-2201) (225-2695) Myocardial infarction patients, n ¼ 63 24 h 137 1317 1083 (70-340) (563-3387) (729-2596) 48 h 181 1483 954 (92-330) (531-3463) (485-3692)

18 h

24 h

30 h

36 h

42 h

48 h

72 h

96 h

458 (116-1668) 267 (99-1571)

356 (104-1320) 247 (92-1385)

320 (72-1119) 272 (96-1272)

231 (42-884) 259 (68-1149)

1314 (561-2189) 1473 (226-2685)

988 (159-2406) 1285 (212-2925)

839 (327-2059) 1170 (215-2782)

889 (279-2845) 1272 (258-3533)

866 (279-2447) 1206 (297-3366)

25.5 (9.9-80.6) 45.2 (17.4-194.0)

20.2 (9.5-69.0) 40.1 (15.4-130.8)

12.4 (5.7-42.8) 24.9 (13.5-122.1)

5.2 (2.6-16.3) 11.8 (6.1-35.8)

3.8 (1.7-6.9) 6.1 (3.0-13.7)

68.0 (15.6-150.1) 131.8 (34.7-300.0)

45.9 (17.9-96.7) 102.5 (40.1-268.3)

31.8 (7.4-59.0) 79.8 (20.4-225.0)

7.8 (3.7-16.9) 27.6 (8.4-69.3)

4.3 (1.9-7.6) 8.3 (5.3-33.6)

24-h and in the 48-h group, All patients, n ¼ 161 487 379 411 437 (195-1482) (114-1417) (144-1286) (149-1584) 539 463 340 260 (173-2647) (171-2009) (130-2106) (109-1816) 1141 (440-2981) 1602 (447-3369)

1107 (417-2704) 1809 (382-2922)

1972 (668-2603) 1621 (241-3125)

Serial median CK-MB (mg/L) values including IQR in the 24-h and in the 48-h group, All patients, n ¼ 161 24 h 7.4 35.0 38.6 45.3 41.8 35.5 (4.5-14.0) (16.7-170.8) (19.9-194.1) (20.4-185.3) (19.3-154.3) (14.3-105.4) 48 h 6.2 47.6 73.2 60.4 51.3 56.5 (3.7-15.3) (15.6-190.8) (19.4-269.0) (20.8-253.6) (20.5-237.4) (19.3-208.9) Myocardial infarction patients, n ¼ 63 24 h 7.9 172.6 154.3 185.3 110.3 105.4 (5.3-22.7) (35.1-338.4) (28.9-365.6) (45.3-360.2) (34.6-306.0) (35.1-281.2) 48 h 7.8 182.5 228.5 229.4 168.2 161 (4.4-32.2) (60.0-356.6) (66.5-508.0) (75.5-473.5) (49.3-447.6) (54.5-360.4)

Prolonged Targeted Temperature Management and Myocardial Injury

Table 3

The upper part of the table presents median hs-cTnT (IQR) values at the serial sampling times from the 161 patients, whereas the analogous values of the subgroup of 63 patients having a myocardial infarction are shown below. The lower part of the table presents median CK-MB (IQR) values at the serial sampling times from the 161 patients while the analogous values of the 63 patients with a myocardial infarction are shown below. CK-MB ¼ creatine kinase-myocardial band; hs-cTnT ¼ high-sensitivity cardiac troponin T; IQR ¼ interquartile range.

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Myocardial Infarct Size Related to Targeted Temperature Management

Figure 4 Areas under the curve (AUC) of cardiac biomarkers, arranged according to the duration of targeted temperature management of 24 hours vs 48 hours after out-ofhospital cardiac arrest. The left part of the figure shows the high-sensitivity cardiac troponin T (hs-cTnT)AUC of all 161 out-of-hospital cardiac arrest patients, showing no significant difference between 24 hours vs 48 hours of targeted temperature management. Conversely, in the right part of the figure, creatine kinase-myocardial band (CK-MB)AUC of all the 161 out-of-hospital cardiac arrest patients shows that 48 hours is significantly higher than 24 hours of targeted temperature management.

The Extent of Myocardial Injury Related to Targeted Temperature Management It has been shown experimentally that cooling is able to reduce the extent of myocardial injury as evaluated histologically, and is also able to preserve more adenosine triphosphate and to decrease the amount of apoptosis, although not reflected by measurement of hs-cTnI.11 Furthermore, Liu et al13 have demonstrated that prolonged targeted temperature management could be cardioprotective based on their findings of cardiac arrest in newborns showing a reduction of both AUC and peak values of hscTnI, when targeted temperature management at 33.5
C was performed through 72 hours. On the other hand, Koreny et al7 were unable to confirm a benefit from targeted temperature management when estimating myocardial injury by CK, CK-MB, and electrocardiogram. Our results did not indicate a difference in the extent of myocardial injury assessed by the AUCs of hs-cTnT measurements, but even so, the AUC of the CK-MB measurements was larger during targeted temperature management of 48 hours, despite the latter being the most rapidly cooled group. That could be explained by the fact that prolonged cooling may provoke more shivering, with an increased release of the striated muscle components of CK-MB.43 The magnitude of AUC is influenced by the release and removal of the cardiac biomarkers. Elimination of hs-cTnT and CK-MB is primarily renal, and because the kidney is exposed to both cooling and ischemia/reperfusion, the evaluation of the renal function is essential.38,44,45 We were attentive to this potential renal effect on the measurements. However, we found that the renal function did not differ in the 2 groups.

It appeared, from the analyses of the out-of-hospital cardiac arrest patients suffering a myocardial infarction, that there was no difference in the infarct sizes as estimated by the AUCs of hs-cTnT and CK-MB values, when comparing targeted temperature management for 24 hours vs 48 hours. As expected, the levels of both the hs-cTnT and the CK-MB values were higher, and those of the myocardial infarction patients decreased more slowly when compared with the levels of the rest of the cardiac arrest patients (Table 3). These findings are consistent with the results of Oh et al,35 who compared peak measurements of CK-MB and hs-cTnI in order to differentiate myocardial infarction from nonmyocardial infarction in out-of-hospital cardiac arrest patients. In a noncardiac arrest myocardial infarction setting, the impact of cooling on the size of infarction has been investigated in both animal and human studies.10,46-48 The conclusion of these studies is that the timing of the targeted temperature management intervention is of great importance. Achievement of the right target temperature prior to revascularization should be prioritized even though this may result in an extension of the ischemic period.49,50 However, this is problematic in the setting of out-of-hospital cardiac arrest, seeing that prolongation of the ischemic phase during resuscitation may lead to more brain injury. In our study, reperfusion was started at ROSC prior to the start of targeted temperature management. The median temperatures at admission were 35.5
C (24 hours) and 35.4
C (48 hours), respectively, which may be above the optimal therapeutic temperature for myocardial protection, even though Nielsen et al6 have demonstrated that a target temperature of 36
C, compared with 33
C, may be equally good for cerebral outcome and mortality.

Limitations Some selection bias of the inclusion of these comatose patients may have occurred because of the wait for retrieving the required written informed consent. This could delay the randomization, with the potential result that the most critically ill patients could expire prior to the inclusion. Actually, despite computer random block stratification, there was a small imbalance in the distribution of patients in the 24hour vs 48-hour groups (Figure 1), but this seems to be without any importance, considering that there were no significant differences between the demographics.

CONCLUSION It appeared that the duration of targeted temperature management at a temperature of 33
C  1
C in out-of-hospital cardiac arrest survivors did not affect the extent of myocardial injury assessed by AUC of serial hs-cTnT measurements when comparing 24 hours vs 48 hours. Conversely, the AUC of the CK-MB measurements showed

Grejs et al

Prolonged Targeted Temperature Management and Myocardial Injury

a significantly higher extent of myocardial injury of targeted temperature management during 48 hours when compared with 24 hours. In terms of specific myocardial protection, we interpret these results with caution, seeing that CK-MB is less specific than hs-cTnT. However, it seems unlikely that the duration of targeted temperature management has a beneficial effect and may even lead to worse outcomes on the extent of myocardial injury when applied in postresuscitation care.

ACKNOWLEDGMENT The authors thank Anne Larsen, Wenche Mathiesen, Aase Reinertsen, and Simon Granum for their help on collecting data.

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ClinicalTrials.gov Identifier: NCT02066753. Funding: Aarhus University Hospital, Aalborg University Hospital, Stavanger University Hospital, The Danish Society of Anesthesiology and Intensive Care Medicine, The Scandinavian Society of Anesthesiology and Intensive Care Medicine, Foundation of 1870 and the Aase and Ejnar Danielsen Foundation financially supported this study. The sponsors had no influence on the analysis, the manuscript, or the choice of publishing journal. None of the contributors are from the pharmaceutical industry. Conflict of Interest: All authors declare no conflict of interest. Authorship: All authors had access to the data and participated in writing the manuscript according to the Vancouver protocol.