Tobias Cronberg

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.).

Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis

Fibronectin performs essential roles in embryonic development and is prominently expressed during tissue repair. Two forms of fibronectin have been identified: plasma fibronectin (pFn), which is expressed by hepatocytes and secreted in soluble form into plasma; and cellular fibronectin (cFn), an insoluble form expressed locally by fibroblasts and other cell types and deposited and assembled into the extracellular matrix. To investigate the role of pFn in vivo, we generated pFn-deficient adult mice using Cre-loxP conditional gene-knockout technology. Here we show that pFn-deficient mice show increased neuronal apoptosis and larger infarction areas following transient focal cerebral ischemia. However, pFn is dispensable for skin-wound healing and hemostasis.

European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015: Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015

Department of Anaesthesia and Intensive Care Medicine, Royal United Hospital, Bath, UK School of Clinical Sciences, University of Bristol, UK Anaesthesia and Intensive Care Medicine, Southmead Hospital, Bristol, UK Cochin University Hospital (APHP) and Paris Descartes University, Paris, France Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden Adelante, Centre of Expertise in Rehabilitation and Audiology, Hoensbroek, The Netherlands Cardiac Anaesthesia and Cardiac Intensive Care and NIHR Southampton Respiratory Biomedical Research Unit, University Hospital, Southampton, UK Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany Department of Clinical Sciences, Division of Anesthesia and Intensive Care Medicine, Lund University, Lund, Sweden Department of Anaesthesiology, Division of Emergencies and Critical Care, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, slo, Norway Department of Anaesthesiology and Intensive Care, Catholic University School of Medicine, Rome, Italy

Prognostication in comatose survivors of cardiac arrest: An advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine ☆

OBJECTIVES To review and update the evidence on predictors of poor outcome (death, persistent vegetative state or severe neurological disability) in adult comatose survivors of cardiac arrest, either treated or not treated with controlled temperature, to identify knowledge gaps and to suggest a reliable prognostication strategy. METHODS GRADE-based systematic review followed by expert consensus achieved using Web-based Delphi methodology, conference calls and face-to-face meetings. Predictors based on clinical examination, electrophysiology, biomarkers and imaging were included. RESULTS AND CONCLUSIONS Evidence from a total of 73 studies was reviewed. The quality of evidence was low or very low for almost all studies. In patients who are comatose with absent or extensor motor response at ≥72 h from arrest, either treated or not treated with controlled temperature, bilateral absence of either pupillary and corneal reflexes or N20 wave of short-latency somatosensory evoked potentials were identified as the most robust predictors. Early status myoclonus, elevated values of neuron specific enolase at 48 72 h from arrest, unreactive malignant EEG patterns after rewarming, and presence of diffuse signs of postanoxic injury on either computed tomography or magnetic resonance imaging were identified as useful but less robust predictors. Prolonged observation and repeated assessments should be considered when results of initial assessment are inconclusive. Although no specific combination of predictors is sufficiently supported by available evidence, a multimodal prognostication approach is recommended in all patients.

Continuous amplitude-integrated electroencephalogram predicts outcome in hypothermia-treated cardiac arrest patients

Objective:To assess the prognostic value of continuous amplitude-integrated electroencephalogram in comatose survivors after cardiac arrest and treated with hypothermia. Design:Prospective observational study. Setting:General intensive care unit at a university hospital. Patients:Comatose patients after cardiac arrest and treated with hypothermia. Interventions:Patients were sedated and continuously monitored using an amplitude-integrated electroencephalogram. Monitoring was commenced on arrival in the intensive care unit and continued until recovery of consciousness, death, or 120 hrs after cardiac arrest. The amplitude-integrated electroencephalogram was interpreted together with the original electroencephalogram and analyzed without knowledge of the patients clinical status. The amplitude-integrated electroencephalogram patterns at start of registration and at normothermia and the transitions of the amplitude-integrated electroencephalogram patterns over time were correlated to outcome. Measurements and Main Results:A total of 111 consecutive patients were assessed; 11 patients were not included because of technical reasons and five were excluded because of death before normothermia. Ninety-five patients remained; 57 (60%) eventually regained consciousness, of whom 49 (52%) lived an independent life at 6 months. Thirty-one patients (33%) at start of registration and 62 patients (65%) at normothermia had a continuous electroencephalogram pattern, and this was strongly associated with recovery of consciousness (29/31 [90%] and 54/62 [87%]). A suppression-burst pattern was always transient and patients with suppression-burst at any time remained in coma until death. An initial flat pattern was registered in 47 patients, but this had no prognostic value. Electrographic status epilepticus was a common finding (26/95 patients [27%]) and two types of electrographic status epilepticus were identified: one developed from suppression-burst and one developed from a continuous background. Two patients from the latter group regained consciousness. Conclusions:Continuous amplitude-integrated electroencephalogram adds valuable early positive and negative prognostic information in comatose survivors after cardiac arrest. We identified two types of postanoxic electrographic status epilepticus, which is a novel finding with possible therapeutic implications.

The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest

BACKGROUND Brain injury is considered the main cause of death in patients who are hospitalized after cardiac arrest (CA). Induced hypothermia is recommended as neuroprotective treatment after (CA) but may affect prognostic parameters. We evaluated the effect of delayed neurological prognostication on the mode of death in hypothermia-treated CA-survivors. STUDY DESIGN Retrospective study at a Swedish university hospital, analyzing all in-hospital and out-of-hospital CA-patients treated with hypothermia during a 5-year period. Cause of death was categorized as brain injury, cardiac disorder or other. Multimodal neurological prognostication and decision on level of care was performed in comatose patients 72 h after rewarming. Neurological function was evaluated by Cerebral Performance Categories scale (CPC). RESULTS Among 162 patients, 76 survived to hospital discharge, 65 of whom had a good neurological outcome (CPC 1-2), and 11 were severely disabled (CPC 3). No patient was in vegetative state. The cause of death was classified as brain injury in 61 patients, cardiac disorder in 14 and other in 11. Four patients were declared brain dead and became organ donors. They were significantly younger (median 40 years) and with long time to ROSC. Active intensive care was withdrawn in 50 patients based on a statement of poor neurological prognosis at least 72 h after rewarming. These patients died, mainly from respiratory complications, at a median 7 days after CA. CONCLUSION Following induced hypothermia and delayed neurological prognostication, brain injury remains the main cause of death after CA. Most patients with a poor prognosis statement died within 2 weeks.

Neuron specific enolase and S-100B as predictors of outcome after cardiac arrest and induced hypothermia.

AIM To assess the prognostic value of repetitive serum samples of neuron specific enolase (NSE) and S-100B in cardiac arrest patients treated with hypothermia. METHODS In a three-centre study, comatose patients after cardiac arrest were treated with hypothermia at 33 degrees C for 24h, regardless of cause or the initial rhythm. Serum samples were collected at 2, 24, 48 and 72h after the arrest and analysed for NSE and S-100B in a non-blinded way. The cerebral performance categories scale (CPC) was used as the outcome measure; a best CPC of 1-2 during 6 months was regarded as a good outcome, a best CPC of 3-5 a poor outcome. RESULTS One centre was omitted in the NSE analysis due to missing 24 and 48h samples. Two partially overlapping groups were studied, the NSE group (n=102) and the S-100B group (n=107). NSE at 48h >28microg/l (specificity 100%, sensitivity 67%) and S-100B >0.51microg/l at 24h (specificity 96%, sensitivity 62%) correlated with a poor outcome, and so did a rise in NSE of >2microg/l between 24 and 48h (odds ratio 9.8, CI 3.5-27.7). A majority of missing samples (n=123) were from the 2h sampling time (n=56) due to referral from other hospitals or inter-hospital transfer. CONCLUSION NSE was a better marker than S-100B for predicting outcome after cardiac arrest and induced hypothermia. NSE above 28microg/l at 48h and a rise in NSE of more than 2microg/l between 24 and 48h were markers for a poor outcome.

Neuron-specific enolase correlates with other prognostic markers after cardiac arrest

Objective: Therapeutic hypothermia (TH) is a recommended treatment for survivors of cardiac arrest. Prognostication is complicated since sedation and muscle relaxation are used and established indicators of a poor prognosis are lacking. This prospective, observational study describes the pattern of commonly used prognostic markers in a hypothermia-treated cohort of cardiac arrest patients with prolonged coma. Methods: Among 111 consecutive patients, 19 died, 58 recovered, and 34 were in coma 3 days after normothermia (4.5 days after cardiac arrest), defined as prolonged coma. All patients were monitored with continuous amplitude-integrated EEG and repeated samples of neuron-specific enolase (NSE) were collected. In patients with prolonged coma, somatosensory evoked potentials (SSEP) and brain MRI were performed. A postmortem brain investigation was undertaken in patients who died. Results: Six of the 17 patients (35%) with NSE levels <33 μg/L at 48 hours regained the capacity to obey verbal commands. By contrast, all 17 patients with NSE levels >33 failed to recover consciousness. In the >33 NSE group, all 10 studied with MRI had extensive brain injury on diffusion-weighted images, 12/16 lacked cortical responses on SSEP, and all 6 who underwent autopsy had extensive severe histologic damage. NSE levels also correlated with EEG pattern, but less uniformly, since 11/17 with NSE <33 had an electrographic status epilepticus (ESE), only one of whom recovered. A continuous EEG pattern correlated to NSE <33 and awakening. Conclusions: NSE correlates well with other markers of ischemic brain injury. In patients with no other signs of brain injury, postanoxic ESE may explain a poor outcome.

Long-term neurological outcome after cardiac arrest and therapeutic hypothermia

AIM OF THE STUDY To analyse the neurological status of survivors after cardiac arrest (CA) treated with hypothermia. METHODS We prospectively included all patients with CA treated with hypothermia at intensive care units (ICU) in two university hospitals and one regional hospital. All adult survivors at 6 months after CA, n=48, were invited for neurological follow-up and 43 accepted. History, clinical status, ability testing and questionnaires were administered to screen for difficulties, including Assessment of Motor and Process Skills, Neurobehavioral Cognitive Status Examination, Frontal Lobe Assessment Battery, EQ-VAS quality of life scale, Skåne Sleep Index, Hospital Anxiety and Depression Rating Scale, Self-reported Montgomery and Astrand Depression Rating Scale, Global Deterioration Scale, Rivermead Behavioural Memory Test, and the Cerebral Performance Categories (CPC). RESULTS No patient was found to be in a chronic vegetative state and all patients were living at home, one with extensive help. Thirty-six patients were in CPC1 at follow-up, and some degree of neurological sequelae was found in 40 patients, but was mild in all but 3. Three patients had no subjective complaints, nor could any deficits be detected. Initial defects improved over-time. Short-term memory loss, executive frontal lobe dysfunction along with mild depression and sleep rhythm disturbances were the most common findings. CONCLUSIONS Mild cognitive impairment is common following hypothermia-treated cardiac arrest but has little effect on activities of daily living or quality of life.

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.