John Bro-Jeppesen

Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest

BACKGROUND Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. METHODS In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. RESULTS In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. CONCLUSIONS In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).

The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest

AIMS To assess the impact of therapeutic hypothermia on cognitive function and quality of life in comatose survivors of out of Hospital Cardiac arrest (OHCA). METHODS We prospectively studied comatose survivors of OHCA consecutively admitted in a 4-year period. Therapeutic hypothermia was implemented in the last 2-year period, intervention period (n=79), and this group was compared to patients admitted the 2 previous years, control period (n=77). We assessed Cerebral Performance Category (CPC), survival, Mini Mental State Examination (MMSE) and self-rated quality of life (SF-36) 6 months after OHCA in the subgroup with VF/VT as initial rhythm. RESULTS CPC in patients alive at hospital discharge was significantly better in the intervention period with a CPC of 1-2 in 97% vs. 71% in the control period, p=0.003, corresponding to an adjusted odds ratio of a favourable cerebral outcome of 17, p=0.01. No significant differences were found in long-term survival (57% vs. 56% alive at 30 months), MMSE, or SF-36. Therapeutic hypothermia (hazard ratio: 0.15, p=0.007) and bystander CPR (hazard ratio 0.19, p=0.002) were significantly related to survival in the intervention period. CONCLUSION CPC at discharge from hospital was significantly improved following implementation of therapeutic hypothermia in comatose patients resuscitated from OCHA with VF/VT. However, significant improvement in survival, cognitive status or quality of life could not be detected at long-term follow-up.

Target temperature management after out-of-hospital cardiac arrest-a randomized, parallel-group, assessor-blinded clinical trial-rationale and design

BACKGROUND Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32°C to 34°C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known. METHODS The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33°C or 36°C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm. DISCUSSION The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.

Post-hypothermia fever is associated with increased mortality after out-of-hospital cardiac arrest

OBJECTIVE Post-cardiac arrest fever has been associated with adverse outcome before implementation of therapeutic hypothermia (TH), however the prognostic implications of post-hypothermia fever (PHF) in the era of modern post-resuscitation care including TH has not been thoroughly investigated. The aim of the study was to assess the prognostic implication of PHF in a large consecutive cohort of comatose survivors after out-of-hospital cardiac arrest (OHCA) treated with TH. METHODS In the period 2004-2010, a total of 270 patients resuscitated after OHCA and surviving a 24-h protocol of TH with a target temperature of 32-34°C were included. The population was stratified in two groups by median peak temperature (≥38.5°C) within 36h after rewarming: PHF and no-PHF. Primary endpoint was 30-days mortality and secondary endpoint was neurological outcome assessed by Cerebral Performance Category (CPC) at hospital discharge. RESULTS PHF (≥38.5°C) was associated with a 36% 30-days mortality rate compared to 22% in patients without PHF, plog-rank=0.02, corresponding to an adjusted hazard rate (HR) of 1.8 (95% CI: 1.1-2.7), p=0.02). The maximum temperature (HR=2.0 per °C above 36.5°C (95% CI: 1.4-3.0), p=0.0005) and the duration of PHF (HR=1.6 per 8h (95% CI: 1.3-2.0), p<0.0001) were also independent predictors of 30-days mortality in multivariable models. Good neurological outcome (CPC1-2) versus unfavourable outcome (CPC3-5) at hospital discharge was found in 61% vs. 39% in the PHF group compared to 75% vs. 25% in the No PHF group, p=0.02. CONCLUSIONS Post-hypothermia fever ≥38.5°C is associated with increased 30-days mortality, even after controlling for potential confounding factors. Avoidance of PHF as a therapeutic target should be evaluated in prospective randomized trials.

Emergency coronary angiography in comatose cardiac arrest patients: do real-life experiences support the guidelines?

Aims: To describe the use of emergency coronary angiography (CAG) and primary percutaneous coronary intervention (PCI) and the association with short- and long-term survival in consecutive comatose survivors after out-of-hospital cardiac arrest (OHCA). Methods: In the period 2004–10, a total of 479 consecutive patients with OHCA of suspected cardiac cause were referred to a tertiary cardiac centre, 360 patients were comatose and admitted to the ICU for post-resuscitative care. The population was stratified in two groups according to the pattern of the first ECG obtained after re-established circulation; ST-segment elevation (STEMI, n=116) and ECG without STEMI pattern (No-STEMI, n=244). Emergency CAG (≤12 hours after OHCA) was performed at the discretion of the attending cardiologist. Primary outcome was 30-day and 1-year survival. Results: Emergency CAG was performed in all patients in the STEMI group compared to 82 (34%) in the group without STEMI pattern (p<0.0001) with significant coronary lesions found in 108 (93%) compared to 43 (52%) patients, respectively (p<0.0001). Survival at 30 day according to emergency CAG vs. no emergency CAG was 65% in the STEMI group compared to 66% and 54% in the group without STEMI pattern (plog-rank=0.11). The use of emergency CAG in the group without STEMI pattern was not associated with reduced mortality (HRadjusted=0.69, 95% CI 0.4–1.2, p=0.18). Conclusions: In comatose survivors of OHCA presenting with STEMI, a high prevalence of coronary disease and culprit lesions suitable for emergency PCI was found, whereas in patients without STEMI pattern, significant coronary stenosis was less frequent. Clinical benefits of emergency CAG/PCI in comatose survivors of OHCA presenting without STEMI could not be identified.

Tertiary centres have improved survival compared to other hospitals in the Copenhagen area after out-of-hospital cardiac arrest ☆

AIMS Out-of-hospital cardiac arrest (OHCA) has been reported to carry very varying morbidity and mortality. However, it remains unclear whether this is caused by intrinsic factors of the OHCA or due to the level of in-hospital care. The aim of this study is to compare 30-day and long-term mortality after OHCA at tertiary heart centres and non-tertiary university hospitals. METHODS AND RESULTS Data from the Copenhagen OHCA registry from June 2002 through December 2010 included a total of 1218 consecutive patients treated by the same mobile emergency care unit (MECU) with either return of spontaneous circulation (ROSC) or on-going resuscitation (n=53) at hospital arrival. The MECU transported patients to the nearest hospital unless an ECG on scene suggested ST-segment elevation myocardial infarction, in which case patients were transported to the nearest tertiary centre for acute coronary angiography. Therefore, patients with ST-elevation myocardial infarction (n=198) were excluded from the analysis. 30-day mortality was 56% vs. 76% and long term (up to 8years) mortality was 78% vs. 94% for tertiary and non-tertiary hospitals, respectively, both p<0.001. Multivariate analysis showed that admission to a non-tertiary hospital was independently associated with increased risk of death (HR=1.32, 95% CI: 1.09-1.59, p=0.004). Exclusion of patients with on-going resuscitation at admission resulted in HR=1.34 (1.11-1.62), p=0.003. A matched pair propensity score analysis of 255 patients confirmed the results of the proportional hazard analysis (HR=1.35, 95% CI: 1.11-1.65 p=0.003). CONCLUSION Admission to tertiary centres is associated with lower mortality rates after OHCA compared with non-tertiary hospitals.

Cognitive Function in Survivors of Out-of-Hospital Cardiac Arrest After Target Temperature Management at 33°C Versus 36°C

Background— Target temperature management is recommended as a neuroprotective strategy after out-of-hospital cardiac arrest. Potential effects of different target temperatures on cognitive impairment commonly described in survivors have not been investigated sufficiently. The primary aim of this study was to evaluate whether a target temperature of 33°C compared with 36°C was favorable for cognitive function; the secondary aim was to describe cognitive impairment in cardiac arrest survivors in general. Methods and Results— Study sites included 652 cardiac arrest survivors originally randomized and stratified for site to temperature control at 33°C or 36°C within the Target Temperature Management trial. Survival until 180 days after the arrest was 52% (33°C, n=178/328; 36°C, n=164/324). Survivors were invited to a face-to-face follow-up, and 287 cardiac arrest survivors (33°C, n=148/36°C, n=139) were assessed with tests for memory (Rivermead Behavioural Memory Test), executive functions (Frontal Assessment Battery), and attention/mental speed (Symbol Digit Modalities Test). A control group of 119 matched patients hospitalized for acute ST-segment–elevation myocardial infarction without cardiac arrest performed the same assessments. Half of the cardiac arrest survivors had cognitive impairment, which was mostly mild. Cognitive outcome did not differ (P>0.30) between the 2 temperature groups (33°C/36°C). Compared with control subjects with ST-segment–elevation myocardial infarction, attention/mental speed was more affected among cardiac arrest patients, but results for memory and executive functioning were similar. Conclusions— Cognitive function was comparable in survivors of out-of-hospital cardiac arrest when a temperature of 33°C and 36°C was targeted. Cognitive impairment detected in cardiac arrest survivors was also common in matched control subjects with ST-segment–elevation myocardial infarction not having had a cardiac arrest. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01946932.

The inflammatory response after out-of-hospital cardiac arrest is not modified by targeted temperature management at 33 °C or 36 °C

AIM Survivors after cardiac arrest (CA) exhibits a systemic inflammatory response as part of post-cardiac arrest syndrome (PCAS). We investigated the association between systemic inflammation and severity of PCAS and whether level of targeted temperature management (TTM) modifies level of the inflammatory response. METHODS We studied 169 patients included at a single center in the TTM-trial, randomly assigned to TTM at 33 °C or 36 °C for 24 h. Plasma samples were analyzed for inflammatory markers including interleukin (IL) IL-1β,IL-4,IL-6,IL-10, tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and procalcitonin (PCT) at randomization and 24, 48 and 72 h after CA. Severity of PCAS was assessed by Sequential Organ Failure Assessment (SOFA) score. RESULTS Plasma levels of both IL-6 and IL-10 determined at randomization correlated with severity of PCAS at day 2 (r=0.36 and r=0.27, p<0.001) and day 3 (r=0.32 and r=0.22, p<0.001). IL-6 at randomization was an independent predictor of severity of PCAS at day 2 (p=0.003) and day 3 (p<0.0001) and was a significantly stronger predictor of severity of PCAS at day 3 compared to CRP (p=0.04) and PCT (p=0.03). Level of TTM did not modify level of the inflammatory markers IL-1β, IL-6, TNF-α, IL-4, IL-10, CRP and PCT, (p=NS for each inflammatory marker). CONCLUSIONS Level of inflammatory response was associated with severity of PCAS with IL-6 being consistently and more strongly associated with severity of PCAS than the inflammatory markers CRP and PCT. The systemic inflammatory response after CA was not modified by TTM at 33 °C or 36 °C.

Hemodynamics and vasopressor support during targeted temperature management at 33°C Versus 36°C after out-of-hospital cardiac arrest: a post hoc study of the target temperature management trial*.

Objective:To investigate the hemodynamic profile associated with different target temperatures and to assess the prognostic implication of inotropic/vasopressor support and mean arterial pressure after out-of-hospital cardiac arrest. There is a lack of information how different target temperatures may affect hemodynamics. Design:Post hoc analysis of a prospective randomized study. Setting:Thirthy-six ICUs in 10 countries. Patients:Nine hundred twenty patients (97%) with available vasopressor data out of 950 patients from the Target Temperature Management trial randomly assigned patients to a targeted temperature management at 33°C or 36°C. Interventions:None. Measurements and Main Results:Mean arterial pressure, heart rate, and lactate were registered at prespecified time points. The population was stratified according to cardiovascular Sequential Organ Failure Assessment = 4 defining the high vasopressor group and cardiovascular Sequential Organ Failure Assessment less than or equal to 3 defining the low vasopressor group. The targeted temperature management 33 (TTM33) group had a hemodynamic profile with lower heart rate (–7.0 min–1 [95% confidence limit, –8.7, –5.1]; pgroup < 0.0001), similar mean arterial pressure (–1.1 mm Hg [95% confidence limit, –2.3, 0.2]; pgroup = 0.10), and increased lactate (0.6 mmol/L [95% confidence limit, 0.3, 0.8]; pgroup < 0.0001) compared with the targeted temperature management 36 (TTM36) group. A cardiovascular Sequential Organ Failure Assessment score = 4 was recorded in 54% versus 45%, p = 0.03 in the TTM33 and the TTM36 group, respectively. The high vasopressor group carried a 53% mortality rate when compared with a 34% in the low vasopressor group, plog-rank less than 0.0001, with an adjusted hazard ratio of 1.38 (95% CI, 1.11–1.71; p = 0.004). There was no interaction between vasopressor group and allocated target temperature group (p = 0.40). An inverse relationship between mean arterial pressure and mortality was identified (p = 0.0008). Conclusions:Targeted temperature management at 33°C was associated with hemodynamic alterations with decreased heart rate, elevated levels of lactate, and need for increased vasopressor support compared with targeted temperature management at 36°C. Low mean arterial pressure and need for high doses of vasopressors were associated with increased mortality independent of allocated targeted temperature management.

Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest: A Substudy of the Target Temperature Management Trial.

Objectives:Whole-body ischemia during out-of-hospital cardiac arrest triggers immediate activation of inflammatory systems leading to a sepsis-like syndrome. The aim was to investigate the association between level of systemic inflammation and mortality in survivors after out-of-hospital cardiac arrest treated with targeted temperature management. Design:Post hoc analysis. Setting:Single-center study of a prospective multicenter randomized study. Patients:One hundred sixty-nine patients (99%) with available blood samples out of 171 patients included in the Target Temperature Management trial, randomly assigning patients to targeted temperature management at 33°C or 36°C. Intervention:None. Measurements and Main Results:At baseline and 24, 48, and 72 hours after out-of-hospital cardiac arrest, blood samples were obtained and screened for a battery of inflammatory markers. Level of interleukin-1&bgr;, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-9, interleukin-10, interleukin-12, interleukin-13, tumor necrosis factor-&agr;, interferon-&ggr;, C-reactive protein, and procalcitonin were measured. Mortality at 30 days was evaluated by Cox analysis, and the predictive capability of inflammatory markers was evaluated by area under the curve. Level of all inflammatory markers changed significantly within 72 hours after out-of-hospital cardiac arrest (all p values < 0.001), but only procalcitonin levels showed overall differences between nonsurvivors and survivors (p = 0.0002). At baseline, interleukin-6 was independently associated with mortality, whereas both interleukin-6 levels (hazard ratio = 1.23 [1.01–1.49]; p = 0.04) and procalcitonin levels (hazard ratio = 1.20 [1.03–1.39]; p = 0.02) 24 hours after out-of-hospital cardiac arrest were associated with 30-day mortality with no interactions between targeted temperature management group and levels of interleukin-6 (p = 0.25) or procalcitonin (p = 0.85). None of the other inflammatory markers were independently associated with mortality. Area under the curve for procalcitonin and interleukin-6, 24 hours after out-of-hospital cardiac arrest, were 0.74 and 0.63, respectively. Conclusions:Level of inflammation, assessed by interleukin-6 and procalcitonin, was independently associated with increased mortality with the highest discriminative value obtained 24 hours after out-of-hospital cardiac arrest. Interventions aiming at decreasing level of inflammation as a way to improve outcome may be investigated in future studies.