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Target temperature management of 33°C and 36°C in patients with out-of-hospital cardiac arrest with initial non-shockable rhythm – A TTM sub-study

      Abstract

      Purpose

      Despite a lack of randomized trials in comatose survivors of out-of-hospital cardiac arrest (OHCA) with an initial non-shockable rhythm (NSR), guidelines recommend induced hypothermia to be considered in these patients. We assessed the effect on outcome of two levels of induced hypothermia in comatose patient resuscitated from NSR.

      Methods

      Hundred and seventy-eight patients out of 950 in the TTM trial with an initial NSR were randomly assigned to targeted temperature management at either 33 °C (TTM33, n = 96) or 36 °C (TTM36, n = 82). We assessed mortality, neurologic function (Cerebral Performance Score (CPC) and modified Rankin Scale (mRS)), and organ dysfunction (Sequential Organ Failure Assessment (SOFA) score).

      Results

      Patients with NSR were older, had longer time to ROSC, less frequently had bystander CPR and had higher lactate levels at admission compared to patients with shockable rhythm, p < 0.001 for all. Mortality in patients with NSR was 84% in both temperature groups (unadjusted HR 0.92, adjusted HR 0.75; 95% CI 0.53–1.08, p = 0.12). In the TTM33 group 3% survived with poor neurological outcome (CPC 3–4, mRS 4–5), compared to 2% in the TTM36 group (adjusted OR 0.67; 95% CI 0.08–4.73, p = 0.69 for both). Thirteen percent in the TTM33 group and 15% in the TTM36 group had good neurologic outcome (CPC 1–2, mRS 0–3, OR 1.5, CI 0.21–12.5, p = 0.69). The SOFA-score did not differ between temperature groups.

      Conclusion

      Comatose patients after OHCA with initial NSR continue to have a poor prognosis. We found no effect of targeted temperature management at 33 °C compared to 36 °C in these patients.

      Keywords

      1. Introduction

      Out-of-hospital cardiac arrest (OHCA) is associated with a high risk of dying and of neurologic impairment in survivors.
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      Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review.
      Even though recent data suggest an increase in survival after OHCA,
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      Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest.
      overall mortality remains approximately 90%. Annual incidence of OHCA is estimated to be 28–55 per 100,000 person-years with considerable variance amongst different populations.
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      Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of 67 prospective studies.
      Non-shockable primary rhythm as first recorded rhythm on scene is known to have major prognostic importance,
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      • et al.
      Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest.
      not only by reducing chances of obtaining return of spontaneous circulation (ROSC)
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      but also with regards to chances of surviving to hospital discharge.
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      Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest.
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      Neurological injury from anoxic brain damage remains the leading cause of death, independent of initial rhythm.
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      Mode of death after admission to an intensive care unit following cardiac arrest.
      Targeted temperature management (TTM) at 32–34 °C for 12–24 h was adopted in international guidelines as being part of post-resuscitation care in patients not regaining consciousness after resuscitation from an initial shockable rhythm
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      and was later extrapolated to be considered in patients with cardiac arrest with initial non-shockable rhythms (NSR). Previous studies examining hypothermia in patients with NRS were mainly observational.
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      • et al.
      Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms.
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      • Ramu B.
      • et al.
      Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms.
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      European Resuscitation Council Hypothermia After Cardiac Arrest Registry Study G. Clinical application of mild therapeutic hypothermia after cardiac arrest.
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      • et al.
      Therapeutic hypothermia after out-of-hospital cardiac arrest in Finnish intensive care units: the FINNRESUSCI study.
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      Mild hypothermia induced by a helmet device: a clinical feasibility study.
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      • et al.
      High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study.
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      • et al.
      The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest.
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      • Maynard C.
      • et al.
      Active surface cooling protocol to induce mild therapeutic hypothermia after out-of-hospital cardiac arrest: a retrospective before-and-after comparison in a single hospital.
      • Pfeifer R.
      • Jung C.
      • Purle S.
      • et al.
      Survival does not improve when therapeutic hypothermia is added to post-cardiac arrest care.
      • Dumas F.
      • Grimaldi D.
      • Zuber B.
      • et al.
      Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients? Insights from a large registry.
      • Storm C.
      • Nee J.
      • Roser M.
      • Jorres A.
      • Hasper D.
      Mild hypothermia treatment in patients resuscitated from non-shockable cardiac arrest.
      • Oddo M.
      • Schaller M.D.
      • Feihl F.
      • Ribordy V.
      • Liaudet L.
      From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest.
      Patients resuscitated from NSR are often older, have more pre-existing comorbidities, and at increased risk of developing multiple organ dysfunction, all of which may increase mortality.
      • Wissenberg M.
      • Lippert F.K.
      • Folke F.
      • et al.
      Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest.
      • Kim F.
      • Nichol G.
      • Maynard C.
      • et al.
      Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial.
      • Rittenberger J.C.
      • Tisherman S.A.
      • Holm M.B.
      • Guyette F.X.
      • Callaway C.W.
      An early, novel illness severity score to predict outcome after cardiac arrest.
      • Donnino M.W.
      • Andersen L.W.
      • Giberson T.
      • et al.
      Initial lactate and lactate change in post-cardiac arrest: a multicenter validation study.
      Whether this group would benefit from or would be at greater risk of adverse events during TTM has not been thoroughly tested in clinical trials. The recent Target Temperature Management at 33 °C vs. 36 °C after Cardiac Arrest (TTM)-trial included patients resuscitated from OHCA of presumed cardiac cause regardless of primary arrhythmia.
      • Nielsen N.
      • Wetterslev J.
      • Cronberg T.
      • et al.
      Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
      The interaction analysis between NSR and mortality has previously been published in the TTM-trial manuscript,
      • Nielsen N.
      • Wetterslev J.
      • Cronberg T.
      • et al.
      Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
      and the present analysis represents an in-depth analysis of the sub-group presenting with NSR. We aimed to assess the effect of targeted temperature management at 33 °C (TTM33) vs. 36 °C (TTM36) on mortality, neurologic outcome, and the development of multiple organ dysfunction evaluated by the SOFA score
      • Vincent J.L.
      • de Mendonca A.
      • Cantraine F.
      • et al.
      Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine.
      in unconscious patients after OHCA with initial NSR.

      2. Materials and methods

      The TTM-trial was a multi-center, randomized, parallel-group, assessor-blinded, monitored, and investigator-initiated clinical trial investigating targeted temperature management of 33 °C and 36 °C, respectively in unconscious patients resuscitated from out-of-hospital cardiac arrest. Patients were centrally randomized, stratified for site, with adequate allocation sequence generation and concealment between November 2010 and January 2013.
      • Nielsen N.
      • Wetterslev J.
      • al-Subaie N.
      • et al.
      Target Temperature Management after out-of-hospital cardiac arrest – a randomized, parallel-group, assessor-blinded clinical trial – rationale and design.
      Patients at the age ≥18, comatose (Glasgow Coma Scale < 8) at hospital admission after OHCA with presumed cardiac cause were included. Eligible patients had sustained return of spontaneous circulation (ROSC) of more than 20 min. Patients were excluded if (a) randomization was not performed within 240 min after ROSC, (b) cardiac arrest with an initial rhythm of asystole was unwitnessed, and (c) the patient suffered from refractory shock. A full list of exclusion criteria has been published elsewhere.
      • Nielsen N.
      • Wetterslev J.
      • al-Subaie N.
      • et al.
      Target Temperature Management after out-of-hospital cardiac arrest – a randomized, parallel-group, assessor-blinded clinical trial – rationale and design.
      Written informed consent was obtained or waived as previously described.
      • Nielsen N.
      • Wetterslev J.
      • Cronberg T.
      • et al.
      Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
      Patients were randomized in a 1:1 ratio to either TTM33 or TTM36 for 24 h after ROSC. All patients were sedated, intubated and mechanically ventilated until the end of the intervention period. Active treatment was maintained for a predefined period of minimum 108 h after ROSC, and strict criteria for discontinuation of life support were predefined.
      • Nielsen N.
      • Wetterslev J.
      • al-Subaie N.
      • et al.
      Target Temperature Management after out-of-hospital cardiac arrest – a randomized, parallel-group, assessor-blinded clinical trial – rationale and design.
      Pre-hospital data regarding cardiac arrest including initial arrhythmia and factors traditionally associated with mortality were systematically collected at admission in accordance with the Utstein guidelines.
      • Langhelle A.
      • Nolan J.
      • Herlitz J.
      • et al.
      Recommended guidelines for reviewing, reporting, and conducting research on post-resuscitation care: the Utstein style.

      2.1 Outcome

      The primary outcome was mortality in the NSR group at the end of the trial with all patients followed-up for at least 180 days after cardiac arrest. We assessed mortality in a multivariate model of induced temperature, age, gender, pulseless electrical activity (PEA), lactate at admission, time to ROSC, bystander cardio pulmonary resuscitation (CPR), SOFA score on day one, largest 2 sites, and witnessed cardiac arrest. In 9 patients initial lactate measurements was missing and therefore excluded from the multivariate analysis. Finally we examined causes of death in the total cohort of patients with NSR. Cause of death was determined by the local physician as the most probable cause of death. The protocol had no requirement for autopsy in fatal cases.
      Secondary outcome was poor neurologic function at 180 days post-CA. Neurologic function was assessed by cerebral performance category (CPC)
      • Jennett B.
      • Bond M.
      Assessment of outcome after severe brain damage.
      and the modified Rankin Scale (mRS).
      • Rankin J.
      Cerebral vascular accidents in patients over the age of 60. II. Prognosi.
      Poor neurological function was defined as CPC 3–4/mRS 4–5 and good as CPC 1–2/mRS 0–3.
      Thirdly we assessed the possible association between initial rhythm and the allocated target temperature on the development of multiple organ dysfunction. The Sequential Organ Failure Assessment (SOFA) score was used to assess the severity of organ dysfunction.
      • Vincent J.L.
      • de Mendonca A.
      • Cantraine F.
      • et al.
      Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine.
      The SOFA score assesses the respiratory (PaO2/FiO2), coagulation (platelet count), liver (bilirubin concentration), renal (creatinine concentration), cerebral (Glasgow Coma Scale), and cardiovascular (hypotension–mean arterial pressure – need for adrenergic agent administration) functions. Each item scores from 0 to 4, with 0 being the best value. The individual organ scores are summarized. SOFA score was registered as the maximum score on day 1, 2, and 3. A possible association between initial rhythm and targeted temperature level on the cardiovascular part of the SOFA-score were also examined separately.

      2.2 Ethical approval

      The TTM-trial is registered at ClinicalTrials.gov (Identifier: NCT01020916) and ethical committees in each participating country approved the protocol. Informed consent was waived or obtained from all participants or relatives according to national legislations.

      2.3 Statistics

      Data are presented as mean ± standard deviation (SD) for normally distributed data, and median and 25th and 75th percentile for skewed data (IQR). Categorical data are presented as numbers and percentages. Differences between groups were tested by t-test, Kruskall-Wallis, Wilcoxon's, Cochran-Armitage's and χ2 tests as appropriate. Differences in mortality at 30 days and at end of trial as well as neurological outcome at 180 days between strata were assessed by log-rank test, and univariable and multivariable proportional hazard ratio, the latter adjusted for potential confounding factors. Due to the limited sample size we adjusted for age, gender, PEA, lactate on admission, time to ROSC, bystander CPR, total SOFA-score on day 1, and witnessed arrest as these have previously been found to be strong predictors of outcome in OHCA patients.
      • Rittenberger J.C.
      • Tisherman S.A.
      • Holm M.B.
      • Guyette F.X.
      • Callaway C.W.
      An early, novel illness severity score to predict outcome after cardiac arrest.
      • Herlitz J.
      • Svensson L.
      • Engdahl J.
      • Silfverstolpe J.
      Characteristics and outcome in out-of-hospital cardiac arrest when patients are found in a non-shockable rhythm.
      • Bro-Jeppesen J.
      • Kjaergaard J.
      • Soholm H.
      • et al.
      Hemodynamics and vasopressor support in therapeutic hypothermia after cardiac arrest: prognostic implications.
      Proportional hazard models were tested for underlying assumption of proportionality, linearity and for interactions. A comparison of the effect of targeting 36 degrees over 33 was performed by adding this variable to the model. Difference in SOFA-score and cardiovascular subscore were tested by binary linear regression with unstructured covariance and repeated measurements.
      All statistical analyses were performed using the R. 3.01 software (R Foundation for Statistical Computing, R Core Team; 2013).

      3. Results

      3.1 Patients

      A total of 950 patients were originally enrolled in the TTM trial. Overall, no significant differences with regards to the primary outcome were found between TTM33 and TTM36 degrees.
      • Nielsen N.
      • Wetterslev J.
      • Cronberg T.
      • et al.
      Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
      Forty-three patients were excluded and 907 patients therefore comprised the study cohort of whom 178 patients had initial NSR and comprised the group primarily studied (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Flowchart. Assessment and randomization. Shockable rhythm = VT/VF, non-shockable rhythm = PEA/asystole.
      Patients in the NSR group were older, had more co-morbidities, more unfavorable intra-arrest circumstances (place of cardiac arrest, bystander CPR, time to advanced life support (ALS) and to ROSC), and poorer initial neurologic status than patients with initial shockable rhythm (Table 1). We found no statistical significant demographic differences between the TTM33 and TTM36 groups in patients with NSR (Table 1).
      Table 1Baseline characteristics. Comparing patients with initial non-shockable rhythm (NSR) to patients with shockable rhythm as well as patients with NSR randomized to TTM33 to TTM36.
      Shockable (n = 729)Non-shockable (n = 178)pTTM33 (n = 96)TTM36 (n = 82)
      VT, n (% of total)24 (2.6)
      VF, n (% of total)705 (75.1)
      PEA, n (% of total)65 (6.9)37 (39)28 (34)
      Aystole, n (% of total)113 (12.0)59 (62)54 (66)
      Sex, male, n (%)600 (82.3)135 (75.8)0.0775 (78)60 (73)
      Age, mean (SD)63.2 (12.2)67.4 (11.3)<0.00168 (16.25)68 (16)
      Number of comorbidities, median (IQR)1 (3)2 (3)0.0042 (2)2 (3.75)
       Heart failure (%)6.47.30.77 (7)6 (7)
       Previous AMI (%)19.821.90.523 (24)16 (20)
       Ischemic heart disease (%)27.029.80.531 (32)22 (27)
       Atrial fibrillation/flutter (%)17.018.00.89 (9)5 (6)
       Hypertension (%)38.148.30.0248 (50)38 (46)
       Previous TIA or stroke (%)6.910.10.210 (10)8 (10)
       Diabetes mellitus (%)14.119.10.117 (18)17 (21)
       Asthma or COPD (%)8.815.20.0313 (14)14 (17)
       Previous PCI (%)11.012.90.515 (16)8 (10)
       Previous CABG (%)8.9
      Data not available in three patients.
      11.20.3412 (13)8 (10)
      Place of CA, public, n (%)313 (42.9)53 (29.8)0.00229 (30)24 (29)
      Witnessed CA, n (%)656 (89.9)157 (88.2)0.582 (85)75 (92)
      Bystander CPR, n (%)567 (77.8)
      Data not available in one patient.
      96 (53.9)<0.00153 (55)43 (52)
      Bystander defibrillation, n (%)71 (9.7)
      Data not available in one patient.
      9 (5.1)0.026 (6)3 (4)
      Time to ALS, minutes, median (25%; 75%)9.0 (6.0; 12.0)
      Data not available in 15 patients.
      10.0 (6.0; 15.0)0.0511 (8)10 (9)
      Time to ROSC, minutes, median (25%; 75%)25.0 (16.5; 37.0)30.5 (19.75; 54.0)<0.00130 (25.5)31 (35.75)
      Shock at admission101 (14%)35 (20%)0.0618 (19)17 (21)
      Arterial lactate concentration, mean (SD)6.3 (4.3)
      Data not available in 50 patients.
      8.3 (4.8)
      Data not available in nine patients.
      <0.0017.7 (6.9)7.5 (6.4)
      Glasgow Coma Scale score, median (IQR)3 (2)3 (0)<0.0013 (0)3 (0)
      Corneal reflex present – no/total no. (%)450/631 (71)63/151 (42)<0.00136/86 (44)27/65 (42)
      Pupillary reflex present – no/total no. (%)596/724 (82)99/175 (57)<0.00153/95 (56)46/80 (58)
      Target temperature management, 36 °C, n (%)368 (50.5)82 (46.1)0.3
      a Data not available in one patient.
      b Data not available in 15 patients.
      c Data not available in 50 patients.
      d Data not available in nine patients.
      e Data not available in three patients.

      3.2 Mortality

      At the end of the trial, 81 of 96 patients in the TTM33 group (84%) and 69 of 82 patients in the TTM36 group (84%) died (adjusted Hazard ratio (HR), 0.75; 95%, Confidence Interval (CI) 0.53–1.08, p = 0.12) (Fig. 2; Table 2).
      Figure thumbnail gr2
      Fig. 2Primary outcome (mortality) in patients resuscitated form out of hospital cardiac arrest with initial shockable and non-shockable rhythm. (A) Mortality after 30 days. (B) Mortality at the end of trial. Differences tested by the log-rank test.
      Table 2Primary and secondary outcome and CPC/mRS distribution.
      TTM33TTM36Hazard ratio or risk ratio (95% CI)p value
      Primary outcome: mortality at the end of trial, n/total (%)81/96 (84)69/82 (84)0.75 (0.53–1.08)0.12
      Secondary outcome: neurologic outcome
       CPC 3–4, n/total (%)84/96 (87)70/82 (85)0.67 (0.08–4.73)0.69
       Modified Rankin Scale 4–5, n/total (%)84/96 (87)70/82 (85)0.67 (0.08–4.73)0.69
      CPC at follow up, n total (%)96 (54)82 (46)
      Category, n (%)19 (9)11 (13)
      23 (3)1 (1)
      32 (2)1 (1)
      41 (1)1 (1)
      581 (84)68 (83)
      p value for trend0.66
      Chi-square test0.001
      mRS at follow up, n total (%)96 (54)82 (46)
      Category, n (%)04 (4)4 (5)
      14 (4)6 (7)
      22 (2)2 (2)
      32 (2)0 (0)
      41 (1)0 (0)
      52 (2)2 (2)
      681 (84)68 (83)
      p value for trend0.61
      Chi-square test0.001
      TTM = targeted temperature management, CPC = cerebral performance category, mRS = modified Rankin Scale.
      Overall, patients with PEA had the same rate of mortality as patients with asystole (HR 0.93; 95%, CI 0.63–1.37, p = 0.63) (Table 3). After 30 days 78 of 96 patients with an initial NSR in the TTM33 group (81%) and 62 of 82 patients in the TTM36 group (76%) had died (Fig. 2), corresponding to an adjusted HR of 0.71; CI 0.49–1.02, p-value 0.06. Factors significantly associated with death were age (adjusted HR 1.03; CI 1.01–1.05, p = 0.01), initial lactate level (adjusted HR 1.10; CI 1.04–1.11, p < 0.001) and time to ROSC (adjusted HR 1.01; CI 1.01–1.02, p < 0.001) (Table 3).
      Table 3Uni- and multi-variate analysis of early risk factors in patients resuscitated from OHCA with initial NSR.
      Univariate analysisMultivariate analysis
      HR(CI)pHR(CI)p
      Temperature (36 °C)0.920.67–1.260.600.750.53–1.080.12
      Age1.021.01–1.040.011.031.01–1.050.01
      Gender (male)0.930.64–1.340.690.760.49–1.160.69
      PEA0.940.67–1.310.690.930.63–1.370.63
      Lactate at admission1.071.04–1.11<0.0011.111.04–1.11<0.001
      Time to ROSC1.011.01–1.02<0.0011.011.01–1.02<0.001
      Bystander CPR0.800.58–1.100.170.950.58–1.100.17
      SOFA score, day 11.041.02–1.170.011.030.95–1.110.50
      Largest 2 sites0.990.60–1.610.950.730.41–1-310.30
      Witnessed arrest0.770.47–1.240.280.700.40–1.210.20
      ROSC = return of spontaneous circulation, CPR = cardiopulmonary resuscitation.
      Initial GCS, pupil-, and corneal reflex were in 1/4 of the patients affected by sedation and did not affect the HR in the multivariate analysis (data not shown).
      Ninety-nine patients (66%) died from anoxic brain damage, 28 patients (19%) from cardiovascular conditions, 20 (13%) from multi organ failure and 3 (2%) from other causes. We found no difference in distribution of cause of death between the TTM33 and TTM36 groups.

      3.3 Neurologic outcome

      After 180 days, 3 of 96 patients in the TTM33 group (3%) and 2 of 82 patients in the TTM36 group (2%) were alive with poor neurologic function estimated by CPC 3–4 and mRS 4–5 (risk ratio 0.67; CI 0.08–4.73, p = 0.69 for both) (Table 2). Twelve patients (13%) in the TTM33 group and 12 patients (15%) in the TTM36 group had a good neurologic function (CPC 1–2, mRS 0–3). We found no difference in the distribution of patients throughout each CPC and mRS subgroup (CPC: p = 0.66 and mRS: p = 0.61 for trend) (Table 2).

      3.4 Multiorgan dysfunction

      Patients with NSR had a significantly higher total SOFA score compared to patients with shockable rhythm (SR) at day 1 (mean ± SD, NSR vs. SR; 10.9 ± 2.4 vs. 10.0 ± 2.2, p < 0.0001), which remained statistically significant at day 2 and day 3: 10.9 ± 2.4 vs. 10.3 ± 2.2, p = 0.002 and 10.9 ± 2.7 vs. 10.1 ± 2.6, p = 0.002, respectively.
      We found no difference in SOFA score and the cardiovascular subscore of the SOFA score between the TTM33 group and TTM36 group at day 1, 2 and 3 (SOFA score on day 1, 2, 3: TTM33 11, 11, 11 vs. TTM36 11, 11, 10, respectively, p = 0.35, cardiovascular subscore on day 1, 2, 3: TTM33 3, 4, 3 vs. TTM36 3, 3, 3, respectively, p = 0.91). In a multivariate model, total- and isolated cardiovascular SOFA-score was an independent predictor of death on day three (total SOFA-score: HR 1.10, CI 1.02–1.18, p = 0.01; isolated cardiovascular SOFA-score HR: 1.18, CI 1.04–1.35, p = 0.01). In an interaction analysis, TTM did not potentiate the association of SOFA-score and death (data not shown).

      4. Discussion

      Initial NSR in comatose survivors of OHCA remains a harbinger of poor outcome with the leading cause of death being anoxic brain damage. Despite guidelines recommending 33 °C for TTM, very little evidence exists to support this. The present study did not find any benefit of TTM at 33 °C over 36 °C with regards to mortality, neurological outcome and SOFA-score within the three initial days.
      In accordance with previous studies, cardiac arrest with initial non-shockable rhythms (NSR) was associated with considerably worse outcome than cardiac arrest with initial shockable rhythm (SR).
      • Wissenberg M.
      • Lippert F.K.
      • Folke F.
      • et al.
      Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest.
      • Kim F.
      • Nichol G.
      • Maynard C.
      • et al.
      Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial.
      In addition, risk of dying in patients hospitalized with NSR was not associated with bystander CPR and witnessed arrest, traditionally associated with outcome, however time to ROSC, initial lactate and age remained significant risk factors after multivariate adjustment. Several pre- and intra-arrest factors may have influenced this. Patients with NSR were older, had more co-morbidities and more unfavorable conditions during cardiac arrest, e.g. longer time to ROSC compared to patients with SR, which is in accordance with previous findings.
      • Kim F.
      • Nichol G.
      • Maynard C.
      • et al.
      Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial.
      The high lactate on admission likely reflects a longer no-flow/low-flow period. Initial high lactate has previously been found to correlate with poor outcome.
      • Donnino M.W.
      • Andersen L.W.
      • Giberson T.
      • et al.
      Initial lactate and lactate change in post-cardiac arrest: a multicenter validation study.
      Since patients with NSR had more co-morbidities and longer low-flow/no-flow times the potential benefit of TTM could be expected to be higher than in patients with SR. This was, however, not the case.
      As the confidence interval of the main analysis is wide and the adjusted HR in the multivariate model indicates a potential inferior effect of TTM of 33 °C when compared to 36 °C a randomized study with sufficient power may detect a clinically relevant difference. The required sample size is, when the HR of 0.75 from the multivariable model is used, 254 in each group to detect a beneficial effect of TTM36 compared to TTM33, with a power of 90%.
      Hemodynamic instability is frequent in patients resuscitated from cardiac arrest.
      • Nolan J.P.
      • Neumar R.W.
      • Adrie C.
      • et al.
      Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.
      This may lead to insufficient end-organ blood supply with critical oxygen depletion and subsequent organ dysfunction as a part of the post-cardiac arrest syndrome (PCAS).
      • Nolan J.P.
      • Neumar R.W.
      • Adrie C.
      • et al.
      Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.
      The four key components of PCAS comprise (1) brain injury, (2) myocardial dysfunction, (3) systemic ischemia/reperfusion response, and (4) persistent precipitating pathology. A tool for evaluating organ dysfunction is the SOFA score.
      • Vincent J.L.
      • de Mendonca A.
      • Cantraine F.
      • et al.
      Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine.
      Previous studies have found a correlation between high SOFA score, PCAS severity and mortality.
      • Rittenberger J.C.
      • Tisherman S.A.
      • Holm M.B.
      • Guyette F.X.
      • Callaway C.W.
      An early, novel illness severity score to predict outcome after cardiac arrest.
      We confirmed an increased SOFA score in patients with cardiac arrest with initial NSR compared to SR.
      • Rittenberger J.C.
      • Tisherman S.A.
      • Holm M.B.
      • Guyette F.X.
      • Callaway C.W.
      An early, novel illness severity score to predict outcome after cardiac arrest.
      This may be due to more severe pre-cardiac arrest comorbidity (Table 1) and more severe organ ischemia as suggested by the increased lactate levels. We did not detect any demographic differences between the two NSR intervention groups when examining the post-arrest organ (dys-)function.
      SOFA-score and cardiovascular subscore at day 3 were however independently associated with mortality, suggesting that patients with persistent post-arrest organ dysfunction were in poorer condition than patients without. Our study therefore supports the use of SOFA score as a tool for monitoring post-arrest organ function in patients with NSR. The SOFA score may provide additional prognostic information to lactate clearance
      • Donnino M.W.
      • Andersen L.W.
      • Giberson T.
      • et al.
      Initial lactate and lactate change in post-cardiac arrest: a multicenter validation study.
      as PCAS is caused by both compromised macro- and microcirculation.
      • Nolan J.P.
      • Neumar R.W.
      • Adrie C.
      • et al.
      Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.
      However, studies examining this hypothesis are required.
      In 2002, an Australian
      • Bernard S.A.
      • Gray T.W.
      • Buist M.D.
      • et al.
      Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
      and a European (HACA)
      • Hypothermia after Cardiac Arrest Study Group
      Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
      trial suggested that induced hypothermia improved outcome in patients with ROSC, comatose after cardiac arrest with initial SR. Since then, TTM of 32–34 °C for 12–24 h has been recommended as a part of post resuscitation care by international guidelines.
      • Deakin C.D.
      • Nolan J.P.
      • Soar J.
      • et al.
      European Resuscitation Council guidelines for resuscitation 2010 Section 4. Adult advanced life support.
      • Peberdy M.A.
      • Callaway C.W.
      • Neumar R.W.
      • et al.
      Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
      • Nolan J.P.
      • Hazinski M.F.
      • Billi J.E.
      • et al.
      Part 1: executive summary: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations.
      In a literature search (using the following terms in various combinations searching at Pubmed: “Cardiac arrest”, “Therapeutic hypothermia”, “Target temperature management”, “Non-shockable rhythm”, “Pulseless electrical activity” and “Asystole”), we found a total of 12 studies assessing TTM in patients with OHCA and NSR as initial rhythm. Two randomized trials
      • Hachimi-Idrissi S.
      • Corne L.
      • Ebinger G.
      • Michotte Y.
      • Huyghens L.
      Mild hypothermia induced by a helmet device: a clinical feasibility study.
      • Laurent I.
      • Adrie C.
      • Vinsonneau C.
      • et al.
      High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study.
      and ten observational studies (four retrospective
      • Testori C.
      • Sterz F.
      • Behringer W.
      • et al.
      Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms.
      • Lundbye J.B.
      • Rai M.
      • Ramu B.
      • et al.
      Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms.
      • Pfeifer R.
      • Jung C.
      • Purle S.
      • et al.
      Survival does not improve when therapeutic hypothermia is added to post-cardiac arrest care.
      • Oddo M.
      • Schaller M.D.
      • Feihl F.
      • Ribordy V.
      • Liaudet L.
      From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest.
      and six prospective, observational
      • Arrich J.
      European Resuscitation Council Hypothermia After Cardiac Arrest Registry Study G. Clinical application of mild therapeutic hypothermia after cardiac arrest.
      • Vaahersalo J.
      • Hiltunen P.
      • Tiainen M.
      • et al.
      Therapeutic hypothermia after out-of-hospital cardiac arrest in Finnish intensive care units: the FINNRESUSCI study.
      • Bro-Jeppesen J.
      • Kjaergaard J.
      • Horsted T.I.
      • et al.
      The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest.
      • Don C.W.
      • Longstreth Jr., W.T.
      • Maynard C.
      • et al.
      Active surface cooling protocol to induce mild therapeutic hypothermia after out-of-hospital cardiac arrest: a retrospective before-and-after comparison in a single hospital.
      • Dumas F.
      • Grimaldi D.
      • Zuber B.
      • et al.
      Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients? Insights from a large registry.
      • Storm C.
      • Nee J.
      • Roser M.
      • Jorres A.
      • Hasper D.
      Mild hypothermia treatment in patients resuscitated from non-shockable cardiac arrest.
      ) assessed mild hypothermia in patients suffering from OHCA with NSR. Although no randomized clinical trials support this, TTM has been recommended for NSR.
      • Deakin C.D.
      • Nolan J.P.
      • Soar J.
      • et al.
      European Resuscitation Council guidelines for resuscitation 2010 Section 4. Adult advanced life support.
      • Peberdy M.A.
      • Callaway C.W.
      • Neumar R.W.
      • et al.
      Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
      • Nolan J.P.
      • Hazinski M.F.
      • Billi J.E.
      • et al.
      Part 1: executive summary: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations.
      Only three observational studies supported the use of TTM in patients with OHCA and initial NSR.
      • Testori C.
      • Sterz F.
      • Behringer W.
      • et al.
      Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms.
      • Lundbye J.B.
      • Rai M.
      • Ramu B.
      • et al.
      Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms.
      • Arrich J.
      European Resuscitation Council Hypothermia After Cardiac Arrest Registry Study G. Clinical application of mild therapeutic hypothermia after cardiac arrest.
      The only randomized trial specifically designed to examine TTM and NSR was conducted by Hachimi-Idrissi et al. in 2001.
      • Hachimi-Idrissi S.
      • Corne L.
      • Ebinger G.
      • Michotte Y.
      • Huyghens L.
      Mild hypothermia induced by a helmet device: a clinical feasibility study.
      They found no beneficial effect of TTM, which is in line with the majority of the studies conducted
      • Vaahersalo J.
      • Hiltunen P.
      • Tiainen M.
      • et al.
      Therapeutic hypothermia after out-of-hospital cardiac arrest in Finnish intensive care units: the FINNRESUSCI study.
      • Laurent I.
      • Adrie C.
      • Vinsonneau C.
      • et al.
      High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study.
      • Bro-Jeppesen J.
      • Kjaergaard J.
      • Horsted T.I.
      • et al.
      The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest.
      • Don C.W.
      • Longstreth Jr., W.T.
      • Maynard C.
      • et al.
      Active surface cooling protocol to induce mild therapeutic hypothermia after out-of-hospital cardiac arrest: a retrospective before-and-after comparison in a single hospital.
      • Pfeifer R.
      • Jung C.
      • Purle S.
      • et al.
      Survival does not improve when therapeutic hypothermia is added to post-cardiac arrest care.
      • Dumas F.
      • Grimaldi D.
      • Zuber B.
      • et al.
      Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients? Insights from a large registry.
      • Storm C.
      • Nee J.
      • Roser M.
      • Jorres A.
      • Hasper D.
      Mild hypothermia treatment in patients resuscitated from non-shockable cardiac arrest.
      • Oddo M.
      • Schaller M.D.
      • Feihl F.
      • Ribordy V.
      • Liaudet L.
      From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest.
      – however their feasibility trial was underpowered for this conclusion. In addition, the study period of hypothermia of 4 h may limit the potential efficacy of the intervention. The 2010 ILCOR guidelines refer to three additional studies, however these studies do not specifically address the effect of TTM in NSR.
      • Holzer M.
      • Mullner M.
      • Sterz F.
      • et al.
      Efficacy and safety of endovascular cooling after cardiac arrest: cohort study and Bayesian approach.
      • Busch M.
      • Soreide E.
      • Lossius H.M.
      • Lexow K.
      • Dickstein K.
      Rapid implementation of therapeutic hypothermia in comatose out-of-hospital cardiac arrest survivors.
      • Sunde K.
      • Pytte M.
      • Jacobsen D.
      • et al.
      Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest.
      Only a single randomized trial examining in-hospital TTM in 11 patients with OHCA and initial NSR has been published, underlining the need for additional trials supporting or refuting the current guidelines.
      • Laurent I.
      • Adrie C.
      • Vinsonneau C.
      • et al.
      High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study.
      The present study is by far the largest randomized study that included patients with NSR treated with in-hospital TTM, but its power to draw firm conclusions on this study population remains limited.
      The planned French multicenter, randomized trial “HYPERION”, examining induced hypothermia of 32.5–33.5 vs. 36.5–37.5 in patients with cardiac arrest with initial NSR, may provide us with greater insight on potential benefits of TTM in this subgroup of patients with cardiac arrest (clinicalTrials.gov Identifier: NCT01994772).

      5. Study limitations

      The size of our study population does not allow for definite answers regarding the effect of induced hypothermia in NSR, as our substudy included 178 patients and was not randomized nor powered to detect differences in mortality in this subgroup.

      6. Conclusion

      Despite initial NSR being a marker of severe organ ischemia and risk of death, we found no difference in mortality or neurological outcome in comatose patients resuscitated from out-of-hospital cardiac arrest managed with Targeted Temperature Management at 33 °C compared with 36 °C.

      Conflict of interest statement

      Drs. Frydland, Erlinge, Wanscher, Åneman,Hovdenes, Horn,Wetterslev, Winther-Jensen, Kuiper, Stammet, Cronberg, Gasche, and Hassager report no conflicts of interest. Dr. Kjaergaard reports grants from the EU Interreg IV A programme funding for establishing ‘Centre for Resuscitation Science in the Oresund Region’ 2013–2014, grants from Danish Heart Association. Dr. Nielsen reports Speakers Honorarium from BARD Medical. Dr. Pellis reports lecture fees from BARD Medical, outside the submitted work. Dr. Friberg reports lecture fees from BARD Medical and Natus Inc., outside the submitted work. Dr. Wise reports personal fees from BARD medical, outside the submitted work.

      Acknowledgements

      The TTM main study was supported by independent research grants from the Swedish Heart–Lung Foundation, Arbetsmarknadens Försäkringsaktiebolag Insurance Foundation, Swedish Research Council, Region Skåne (Sweden), National Health Service (Sweden), Thelma Zoega Foundation, Krapperup Foundation, Thure Carlsson Foundation, Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research, Skåne University Hospital, TrygFonden (Denmark), and European Clinical Research Infrastructures Network.
      This work was supported by the European Regional Development Fund through the Interreg IV A OKS Programme [NYPS ID: 167157].

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