Sten Rubertsson

Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest

Background: Therapeutic hypothermia (TH) after cardiac arrest protects from neurological sequels and death and is recommended in guidelines. The Hypothermia Registry was founded to the monitor outcome, performance and complications of TH.

Mechanical Chest Compressions and Simultaneous Defibrillation vs Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest: The LINC Randomized Trial

IMPORTANCE A strategy using mechanical chest compressions might improve the poor outcome in out-of-hospital cardiac arrest, but such a strategy has not been tested in large clinical trials. OBJECTIVE To determine whether administering mechanical chest compressions with defibrillation during ongoing compressions (mechanical CPR), compared with manual cardiopulmonary resuscitation (manual CPR), according to guidelines, would improve 4-hour survival. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial of 2589 patients with out-of-hospital cardiac arrest conducted between January 2008 and February 2013 in 4 Swedish, 1 British, and 1 Dutch ambulance services and their referring hospitals. Duration of follow-up was 6 months. INTERVENTIONS Patients were randomized to receive either mechanical chest compressions (LUCAS Chest Compression System, Physio-Control/Jolife AB) combined with defibrillation during ongoing compressions (n = 1300) or to manual CPR according to guidelines (n = 1289). MAIN OUTCOMES AND MEASURES Four-hour survival, with secondary end points of survival up to 6 months with good neurological outcome using the Cerebral Performance Category (CPC) score. A CPC score of 1 or 2 was classified as a good outcome. RESULTS Four-hour survival was achieved in 307 patients (23.6%) with mechanical CPR and 305 (23.7%) with manual CPR (risk difference, -0.05%; 95% CI, -3.3% to 3.2%; P > .99). Survival with a CPC score of 1 or 2 occurred in 98 (7.5%) vs 82 (6.4%) (risk difference, 1.18%; 95% CI, -0.78% to 3.1%) at intensive care unit discharge, in 108 (8.3%) vs 100 (7.8%) (risk difference, 0.55%; 95% CI, -1.5% to 2.6%) at hospital discharge, in 105 (8.1%) vs 94 (7.3%) (risk difference, 0.78%; 95% CI, -1.3% to 2.8%) at 1 month, and in 110 (8.5%) vs 98 (7.6%) (risk difference, 0.86%; 95% CI, -1.2% to 3.0%) at 6 months with mechanical CPR and manual CPR, respectively. Among patients surviving at 6 months, 99% in the mechanical CPR group and 94% in the manual CPR group had CPC scores of 1 or 2. CONCLUSIONS AND RELEVANCE Among adults with out-of-hospital cardiac arrest, there was no significant difference in 4-hour survival between patients treated with the mechanical CPR algorithm or those treated with guideline-adherent manual CPR. The vast majority of survivors in both groups had good neurological outcomes by 6 months. In clinical practice, mechanical CPR using the presented algorithm did not result in improved effectiveness compared with manual CPR. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00609778.

Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia.

Objectives:To investigate the association between adverse events recorded during critical care and mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. Design:Prospective, observational, registry-based study. Setting:Twenty-two hospitals in Europe and the United States. Patients:Between October 2004 and October 2008, 765 patients were included. Interventions:None. Measurements and Main Results:Arrhythmias (7%–14%), pneumonia (48%), metabolic and electrolyte disorders (5%–37%), and seizures (24%) were common adverse events in the critical care period in cardiac arrest patients treated with therapeutic hypothermia, whereas sepsis (4%) and bleeding (6%) were less frequent. Sustained hyperglycemia (blood glucose >8 mmol/L for >4 hrs; odds ratio 2.3, 95% confidence interval 1.6–3.6, p < .001) and seizures treated with anticonvulsants (odds ratio 4.8, 95% confidence interval 2.9–8.1, p < .001) were associated with increased mortality in a multivariate model. An increased frequency of bleeding and sepsis occurred after invasive procedures (coronary angiography, intravascular devices for cooling, intra-aortic balloon pump), but bleeding and sepsis were not associated with increased mortality (odds ratio 1.0, 95% confidence interval 0.46–2.2, p = .91, and odds ratio 0.30, 95% confidence interval 0.12–0.79, p = .01, respectively). Conclusions:Adverse events were common after out-of-hospital cardiac arrest. Sustained hyperglycemia and seizures treated with anticonvulsants were associated with increased mortality. Bleeding and infection were more common after invasive procedures, but these adverse events were not associated with increased mortality in our study.

Identification of tissue-specific cell death using methylation patterns of circulating DNA

Significance We describe a blood test for detection of cell death in specific tissues based on two principles: (i) dying cells release fragmented DNA to the circulation, and (ii) each cell type has a unique DNA methylation pattern. We have identified tissue-specific DNA methylation markers and developed a method for sensitive detection of these markers in plasma or serum. We demonstrate the utility of the method for identification of pancreatic β-cell death in type 1 diabetes, oligodendrocyte death in relapsing multiple sclerosis, brain cell death in patients after traumatic or ischemic brain damage, and exocrine pancreas cell death in pancreatic cancer or pancreatitis. The approach allows minimally invasive monitoring of tissue dynamics in humans in multiple physiological and pathological conditions. Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.

Targeted temperature management in critical care: A report and recommendations from five professional societies*

Objective:Representatives of five international critical care societies convened topic specialists and a nonexpert jury to review, assess, and report on studies of targeted temperature management and to provide clinical recommendations. Data Sources:Questions were allocated to experts who reviewed their areas, made formal presentations, and responded to questions. Jurors also performed independent searches. Sources used for consensus derived exclusively from peer-reviewed reports of human and animal studies. Study Selection:Question-specific studies were selected from literature searches; jurors independently determined the relevance of each study included in the synthesis. Conclusions and Recommendations:1) The jury opines that the term “targeted temperature management” replace “therapeutic hypothermia.” 2) The jury opines that descriptors (e.g., “mild”) be replaced with explicit targeted temperature management profiles. 3) The jury opines that each report of a targeted temperature management trial enumerate the physiologic effects anticipated by the investigators and actually observed and/or measured in subjects in each arm of the trial as a strategy for increasing knowledge of the dose/duration/response characteristics of temperature management. This enumeration should be kept separate from the body of the report, be organized by body systems, and be made without assertions about the impact of any specific effect on the clinical outcome. 4) The jury STRONGLY RECOMMENDS targeted temperature management to a target of 32°C–34°C as the preferred treatment (vs. unstructured temperature management) of out-of-hospital adult cardiac arrest victims with a first registered electrocardiography rhythm of ventricular fibrillation or pulseless ventricular tachycardia and still unconscious after restoration of spontaneous circulation (strong recommendation, moderate quality of evidence). 5) The jury WEAKLY RECOMMENDS the use of targeted temperature management to 33°C–35.5°C (vs. less structured management) in the treatment of term newborns who sustained asphyxia and exhibit acidosis and/or encephalopathy (weak recommendation, moderate quality of evidence).

No difference in autopsy detected injuries in cardiac arrest patients treated with manual chest compressions compared with mechanical compressions with the LUCAS™ device―A pilot study

AIM To compare the variety and incidence of internal injuries after manual and mechanical chest compressions during CPR. METHODS In a prospective pilot study conducted in two Swedish cities, 85 patients underwent autopsy after unsuccessful resuscitation attempts with manual or mechanical chest compressions, the latter with the LUCAS device. Autopsy was performed and the results were evaluated according to a specified protocol. RESULTS No injuries were found in 26/47 patients in the manual group and in 16/38 patients in the LUCAS group (p=0.28). Sternal fracture was present in 10/47 in the manual group and 11/38 in the LUCAS group (p=0.46), and there were multiple rib fractures (> or =3 fractures) in 13/47 in the manual group and in 17/38 in the LUCAS group (p=0.12). Bleeding in the ventral mediastinum was noted in 2/47 and 3/38 in the manual and LUCAS groups respectively (p=0.65), retrosternal bleeding in 1/47 and 3/38 (p=0.32), epicardial bleeding in 1/47 and 4/38 (p=0.17), and haemopericardium in 4/47 and 3/38 (p=1.0) respectively. One patient in the LUCAS group had a small rift in the liver and one patient in the manual group had a rift in the spleen. These injuries were not considered to have contributed to the patients death. CONCLUSION Mechanical chest compressions with the LUCAS device appear to be associated with the same variety and incidence of injuries as manual chest compressions.

Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: Results of a pilot study

OBJECTIVE To conduct a pilot study to evaluate the prognostic potential of serum tau protein measurements to predict neurological outcome 6 months following resuscitation from cardiac arrest. METHODS In this retrospective observational study, we employed a new ultra sensitive digital immunoassay technology to examine serial serum samples from 25 cardiac arrest patients to examine tau release into serum as a result of brain hypoxia, and probe for its significance predicting six-month neurological outcome. Serial blood samples were obtained from resuscitated cardiac arrest survivors during their first five days in an intensive care unit, and serum total tau was measured. Cerebral function assessments were made using Cerebral Performance Categorization (CPC) at discharge from the ICU and six months later. Tau data were analyzed in the context of 6-month CPC scores. RESULTS Tau elevations ranged from modest (<10 pg/mL) to very high (hundreds of pg/mL), and exhibited unexpected bi-modal kinetics in some patients. Early tau elevations appeared within 24h of cardiac arrest, and delayed elevations appeared after 24-48 h. In patients with delayed elevations, areas under the curves of tau concentration vs. hours since cardiac arrest were highly predictive of 6-month outcome (P<0.0005). CONCLUSION High-sensitivity serum tau measurements combined with an understanding of tau release kinetics could have utility for hypoxic brain injury assessment and prediction of cerebral function outcome.

Neurological prognostication after cardiac arrest—Recommendations from the Swedish Resuscitation Council

Cardiopulmonary resuscitation is started in 5000 victims of out-of-hospital cardiac arrest in Sweden each year and the survival rate is approximately 10%. The subsequent development of a global ischaemic brain injury is the major determinant of the neurological prognosis for those patients who reach the hospital alive. Induced hypothermia is a recommended treatment after cardiac arrest and has been implemented in most Swedish hospitals. Recent studies indicate that induced hypothermia may affect neurological prognostication and previous international recommendations are therefore no longer valid when hypothermia is applied. An expert group from the Swedish Resuscitation Council has reviewed the literature and made recommendations taking into account the effects of induced hypothermia and concomitant sedation. A delayed neurological evaluation at 72 h after rewarming is recommended for hypothermia treated patients. This evaluation should be based on several independent methods and the possibility of lingering pharmacological effects should be considered.

Development of a novel biomarker of free radical damage in reperfusion injury after cardiac arrest

In a porcine model of cardiopulmonary resuscitation (CPR), we investigated changes in the plasma levels of 8‐iso‐PGF2α, a marker for oxidative injury, and 15‐keto‐dihydro‐PGF2α, an inflammatory response indicator during the post‐resuscitation period after cardiac arrest. Twelve piglets were subjected to either 2 or 5 min (VF2 and VF5 group) of ventricular fibrillation (VF) followed by 5 min of closed‐chest CPR. Six piglets without cardiac arrest were used as controls. In VF5 group, 8‐iso‐PGF2α in the jugular bulb plasma (draining the brain) increased four‐fold. Jugular bulb 8‐iso‐PGF2α in the control group remained unchanged. The 15‐keto‐dihydro‐PGF2α also increased four‐fold in the VF5 group. Thus, 8‐iso‐PGF2α and 15‐keto‐dihydro‐PGF2α measurements in jugular bulb plasma may be used as biomarkers for quantification of free radical catalyzed oxidative brain injury and inflammatory response in reperfusion injury.

Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans.

Amyloid β (Aβ) peptides are proteolytic products from amyloid precursor protein (APP) and are thought to play a role in Alzheimer disease (AD) pathogenesis. While much is known about molecular mechanisms underlying cerebral Aβ accumulation in familial AD, less is known about the cause(s) of brain amyloidosis in sporadic disease. Animal and postmortem studies suggest that Aβ secretion can be up-regulated in response to hypoxia. We employed a new technology (Single Molecule Arrays, SiMoA) capable of ultrasensitive protein measurements and developed a novel assay to look for changes in serum Aβ42 concentration in 25 resuscitated patients with severe hypoxia due to cardiac arrest. After a lag period of 10 or more hours, very clear serum Aβ42 elevations were observed in all patients. Elevations ranged from approximately 80% to over 70-fold, with most elevations in the range of 3–10-fold (average approximately 7-fold). The magnitude of the increase correlated with clinical outcome. These data provide the first direct evidence in living humans that ischemia acutely increases Aβ levels in blood. The results point to the possibility that hypoxia may play a role in the amyloidogenic process of AD.