Lactate, lactate clearance and outcome after cardiac arrest: A post-hoc analysis of the TTM-Trial.

BACKGROUND: Admission lactate and lactate clearance are implemented for risk stratification in sepsis and trauma. In out-of-hospital cardiac arrest, results regarding outcome and lactate are conflicting. METHODS: This is a post-hoc analysis of the Target Temperature Management trial in which 950 unconscious patents after out-of-hospital cardiac arrest were randomized to a temperature intervention of 33°C or 36°C. Serial lactate samples during the first 36 hours were collected. Admission lactate, 12-hour lactate, and the clearance of lactate within 12 hours after admission were analyzed and the association with 30-day mortality assessed. RESULTS: Samples from 877 patients were analyzed. In univariate logistic regression analysis, the odds ratio for death by day 30 for each mmol/L was 1.12 (1.08-1.16) for admission lactate, P < .01, 1.21 (1.12-1.31) for 12-hour lactate, P < .01, and 1.003 (1.00-1.01) for each percentage point increase in 12-hour lactate clearance, P = .03. Only admission lactate and 12-hour lactate levels remained significant after adjusting for known predictors of outcome. The area under the receiver operating characteristic curve was 0.65 (0.61-0.69), P < .001, 0.61 (0.57-0.65), P < .001, and 0.53 (0.49-0.57), P = .15 for admission lactate, 12-hour lactate, and 12-hour lactate clearance, respectively. CONCLUSIONS: Admission lactate and 12-hour lactate values were independently associated with 30-day mortality after out-of-hospital cardiac arrest while 12-hour lactate clearance was not. The clinical value of lactate as the sole predictor of outcome after out-of-hospital cardiac arrest is, however, limited.

CT-proAVP (copeptin), MR-proANP and Peroxiredoxin 4 after cardiac arrest: release profiles and correlation to outcome.

BACKGROUND: Further characterization of the post-cardiac arrest syndrome (PCAS) is essential to better understand the mechanisms resulting in injury and death. We investigated serial serum concentrations of the stress hormone c-terminal provasopressin (CT-proAVP or copeptin), the cardiac biomarker MR-proANP and a biomarker of oxidation injury, Peroxiredoxin 4 (Prx4) in patients treated with mild hypothermia (MHT) after cardiac arrest, and studied their association to the PCAS and long-term outcome. METHODS: Serum samples from cardiac arrest patients were collected serially: at admission, 2, 6, 12, 24, 36, 48 and 72 h after cardiac arrest. CT-proAVP, MR-proANP and Prx4 concentrations were determined and tested for association with two surrogate markers of PCAS (time to return of spontaneous circulation and circulation-SOFA score) and with cerebral performance category (CPC) at 6 months. Good outcome was defined as CPC 1 to 2. RESULTS: Eighty-four patients were included. CT-proAVP, MR-proANP and Prx4 were early biomarkers with maximum concentrations soon after cardiac arrest and with a significant discriminatory ability between good and poor long-term outcome at most time points. CT-proAVP predicted a poor outcome with the highest accuracy, followed by MR-proANP and Prx4 (area under the receiving operating characteristics curve at 12 h of 0.85, 0.77 and 0.76 respectively). CT-proAVP and MR-proANP showed best correlation to the PCAS. CONCLUSION: In 84 resuscitated patients receiving MHT after cardiac arrest, there is a significant difference in concentrations of CT-proAVP, MR-proANP and Prx4 between patients with good and poor outcome. CT-proAVP and MR-proANP have a significant correlation to surrogate markers of the PCAS.

Continuous evaluation of neurological prognosis after cardiac arrest.

Post-resuscitation care has changed in the last decade, and outcome after cardiac arrest has improved, thanks to several combined measures. Induced hypothermia has shown a treatment benefit in two randomized trials, but some doubts remain. General care has improved, including the use of emergency coronary intervention. Assessment of neurological function and prognosis in comatose cardiac arrest patient is challenging, especially when treated with hypothermia. In this review, we evaluate the recent literature and discuss the available evidence for prognostication after cardiac arrest in the era of temperature management. Relevant literature was identified searching PubMed and reading published papers in the field, but no standardized search strategy was used. The complexity of predicting outcome after cardiac arrest and induced hypothermia is recognized in the literature, and no single test can predict a poor prognosis with absolute certainty. A clinical neurological examination is still the gold standard, but the results need careful interpretation because many patients are affected by sedatives and by hypothermia. Common adjuncts include neurophysiology, brain imaging and biomarkers, and a multimodal strategy is generally recommended. Current guidelines for prediction of outcome after cardiac arrest and induced hypothermia are not sufficient. Based on our expert opinion, we suggest a multimodal approach with a continuous evaluation of prognosis based on repeated neurological examinations and electroencephalography. Somatosensory-evoked potential is an established method to help determine a poor outcome and is recommended, whereas biomarkers and magnetic resonance imaging are promising adjuncts. We recommend that a decisive evaluation of prognosis is performed at 72 h after normothermia or later in a patient free of sedative and analgetic drugs.

Phosphate-containing dialysis solution prevents hypophosphatemia during continuous renal replacement therapy.

BACKGROUND: hypophosphatemia occurs in up to 80% of the patients during continuous renal replacement therapy (CRRT). Phosphate supplementation is time-consuming and the phosphate level might be dangerously low before normophosphatemia is re-established. This study evaluated the possibility to prevent hypophosphatemia during CRRT treatment by using a new commercially available phosphate-containing dialysis fluid. METHODS: forty-two heterogeneous intensive care unit patients, admitted between January 2007 and July 2008, undergoing hemodiafiltration, were treated with a new Gambro dialysis solution with 1.2 mM phosphate (Phoxilium) or with standard medical treatment (Hemosol B0). The patients were divided into three groups: group 1 (n=14) receiving standard medical treatment and intravenous phosphate supplementation as required, group 2 (n=14) receiving the phosphate solution as dialysate solution and Hemosol B0 as replacement solution and group 3 (n=14) receiving the phosphate-containing solution as both dialysate and replacement solutions. RESULTS: standard medical treatment resulted in hypophosphatemia in 11 of 14 of the patients (group 1) compared with five of 14 in the patients receiving phosphate solution as the dialysate solution and Hemosol B0 as the replacement solution (group 2). Patients treated with the phosphate-containing dialysis solution (group 3) experienced stable serum phosphate levels throughout the study. Potassium, ionized calcium, magnesium, pH, pCO(2) and bicarbonate remained unchanged throughout the study. CONCLUSION: the new phosphate-containing replacement and dialysis solution reduces the variability of serum phosphate levels during CRRT and eliminates the incidence of hypophosphatemia.

Scandinavian glutamine trial: a pragmatic multi-centre randomised clinical trial of intensive care unit patients.

BACKGROUND: Low plasma glutamine concentration is an independent prognostic factor for an unfavourable outcome in the intensive care unit (ICU). Intravenous (i.v.) supplementation with glutamine is reported to improve outcome. In a multi-centric, double-blinded, controlled, randomised, pragmatic clinical trial of i.v. glutamine supplementation for ICU patients, we investigated outcomes regarding sequential organ failure assessment (SOFA) scores and mortality. The hypothesis was that the change in the SOFA score would be improved by glutamine supplementation. METHODS: Patients (n=413) given nutrition by an enteral and/or a parenteral route with the aim of providing full nutrition were included within 72 h after ICU admission. Glutamine was supplemented as i.v. l-alanyl-l-glutamine, 0.283 g glutamine/kg body weight/24 h for the entire ICU stay. Placebo was saline in identical bottles. All included patients were considered as intention-to-treat patients. Patients given supplementation for >3 days were considered as predetermined per protocol (PP) patients. RESULTS: There was a lower ICU mortality in the treatment arm as compared with the controls in the PP group, but not at 6 months. For change in the SOFA scores, no differences were seen, 1 (0,3) vs. 2 (0.4), P=0.792, for the glutamine group and the controls, respectively. CONCLUSION: In summary, a reduced ICU mortality was observed during i.v. glutamine supplementation in the PP group. The pragmatic design of the study makes the results representative for a broad range of ICU patients.

Outcomes and interventions in patients transported to hospital with ongoing CPR after out-of-hospital cardiac arrest - An observational study.

INTRODUCTION: The main objective was to present characteristics and outcome of patients without sustained field return of spontaneous circulation (ROSC) transported to hospital with ongoing cardiopulmonary resuscitation (CPR). Our secondary objectives were to investigate hospital-based interventions and the performance of the universal Termination of Resuscitation-rule (uTOR). METHODS: In this retrospective observational cohort study, out-of-hospital cardiac arrest (OHCA) patients arriving to the emergency department of a university hospital in Sweden during a six-year period (2010-2015) were identified using a prospectively recorded hospital-based registry. Additional data were retrieved from medical records and from the Swedish cardiopulmonary resuscitation registry. RESULTS: Among 409 patients transported with ongoing CPR, 7 survived to hospital discharge (1.7%). Hospital-based interventions against a suspected cause of arrest were attempted during ongoing resuscitation in 34 patients (8.3%), of whom 3 survived to hospital discharge. The remaining 4 survivors had spontaneous in-hospital ROSC. Survivors presented with either a shockable rhythm (n = 4) or pulseless electrical activity (n = 3). The uTOR identified non-survivors with a positive predictive value (PPV) of 98.4% and a specificity of 71.4% for termination. CONCLUSION: Survival after OHCA where sustained prehospital ROSC is not achieved is rare and available in-hospital interventions are rarely utilised. No patient with asystole as the first recorded rhythm survived. The uTOR identified non-survivors with a PPV of 98.4% but showed poor specificity.

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. METHODS: Data on out-of-hospital cardiac arrest (OHCA) patients admitted to intensive care for TH were registered. Hospital survival and long-term outcome (6-12 months) were documented using the Cerebral Performance Category (CPC) scale, CPC 1-2 representing a good outcome and 3-5 a bad outcome. RESULTS: From October 2004 to October 2008, 986 TH-treated OHCA patients of all causes were included in the registry. Long-term outcome was reported in 975 patients. The median time from arrest to initiation of TH was 90 min (interquartile range, 60-165 min) and time to achieving the target temperature (< or =34 degrees C) was 260 min (178-400 min). Half of the patients underwent coronary angiography and one-third underwent percutaneous coronary intervention (PCI). Higher age, longer time to return of spontaneous circulation, lower Glasgow Coma Scale at admission, unwitnessed arrest and initial rhythm asystole were all predictors of bad outcome, whereas time to initiation of TH and time to reach the goal temperature had no significant association. Bleeding requiring transfusion occurred in 4% of patients, with a significantly higher risk if angiography/PCI was performed (2.8% vs. 6.2%P=0.02). CONCLUSIONS: Half of the patients survived, with >90% having a good neurological function at long-term follow-up. Factors related to the timing of TH had no apparent association to outcome. The incidence of adverse events was acceptable but the risk of bleeding was increased if angiography/PCI was performed.

Improved glycaemic control of thrice-daily biphasic insulin aspart compared with twice-daily biphasic human insulin; a randomized, open-label trial in patients with type 1 or type 2 diabetes.

AIM: This trial evaluated the potential for improving glycaemic control by intensifying a conventional twice-daily therapy with premixed human insulin (HI) to a thrice-daily regimen using premixed formulations of biphasic insulin aspart (BIAsp) in patients with type 1 or type 2 diabetes. METHODS: This was a multicentre, open-label, parallel group trial. After a 4-week run-in period, patients were randomized 1 : 1 to 16 weeks of treatment. A total of 748 patients were screened, 664 were exposed to trial drug and 604 completed the trial. RESULTS: Haemoglobin A(1c), the primary efficacy endpoint, was shown to be significantly lower for the BIAsp treatment group compared with the biphasic HI (BHI) 30 group [estimated mean difference: -0.32, 95% confidence interval (CI) (-0.48; -0.16), p = 0.0001]. The average blood glucose level was significantly lower in the BIAsp group [estimated mean difference: -0.79, 95% CI (-1.17; -0.40), p = 0.0001]. There were few major hypoglycaemic episodes, 11 in the BIAsp group and 7 in the BHI 30 group. Although intensification of insulin therapy with BIAsp three times a day was associated with a higher risk of minor hypoglycaemia (relative risk = 1.58, p = 0.0038), the overall rate of minor hypoglycaemia remained low with both the BIAsp and the BHI treatments (13.1 vs. 8.3 episodes/patient year respectively). Overall safety and patient satisfaction were similar with the two insulin therapies. CONCLUSIONS: This trial confirmed that a thrice-daily BIAsp regimen can safely be used to intensify treatment for patients inadequately controlled on twice-daily BHI. A treat-to-target trial is required to explore the full potential of the BIAsp regimens and evaluate their use as a viable alternative to intensification with a basal-bolus regimen.

Highly malignant routine EEG predicts poor prognosis after cardiac arrest in the Target Temperature Management trial.

INTRODUCTION: Routine EEG is widely used and accessible for post arrest neuroprognostication. Recent studies, using standardised EEG terminology, have proposed highly malignant EEG patterns with promising predictive ability. OBJECTIVES: To validate the performance of standardised routine EEG patterns to predict neurological outcome after cardiac arrest. METHODS: In the prospective multicenter Target Temperature Management trial, comatose cardiac arrest patients were randomised to different temperature levels (950 patients, 36 sites). According to the prospective protocol a routine EEG was performed in patients who remained comatose after the 36 h temperature control intervention. EEGs were retrospectively reviewed blinded to outcome using the standardised American Clinical Neurophysiology Society terminology. Highly malignant, malignant and benign EEG patterns were correlated to poor and good outcome, defined by best achieved Cerebral Performance Category up to 180 days. RESULTS: At 20 sites 207 patients had a routine EEG performed at median 76 h after cardiac arrest. Highly malignant patterns (suppression or burst-suppression with or without discharges) had a high specificity for poor outcome (98%, CI 92-100), but with limited sensitivity (31%, CI 24-39). Our false positive patient had a burst-suppression pattern during ongoing sedation. A benign EEG, i.e. continuous normal-voltage background without malignant features, identified patients with good outcome with 77% (CI 66-86) sensitivity and 80% (CI 73-86) specificity. CONCLUSION: Highly malignant routine EEG after targeted temperature management is a strong predictor of poor outcome. A benign EEG is an important indicator of a good outcome for patients remaining in coma.

Out-of-hospital cardiac arrest termination of resuscitation with ongoing CPR: An observational study.

INTRODUCTION: Termination of resuscitation guidelines for out-of-hospital cardiac arrest can identify patients in whom continuing resuscitation has little chance of success. This study examined the outcomes of patients transferred to hospital with ongoing CPR. It assessed outcomes for those who would have met the universal prehospital termination of resuscitation criteria (no shocks administered, unwitnessed by emergency medical services, no return of spontaneous circulation). METHODS: A retrospective cohort study of consecutive adult patients who were transported to hospital with ongoing CPR was conducted at three hospitals in the West Midlands, UK between September 2016 and November 2017. Patient characteristics, interventions and response to treatment (ROSC, survival to discharge) were identified. RESULTS: 227 (median age 69 years, 67.8% male) patients were identified. 89 (39.2%) met the universal prehospital termination of resuscitation criteria. Seven (3.1%) were identified with a potentially reversible cause of cardiac arrest. After hospital arrival, patients received few specialist interventions that were not available in the prehospital setting. Most (n = 210, 92.5%) died in the emergency department. 17 were admitted (14 to intensive care), of which 3 (1.3%) survived to hospital discharge. There were no survivors (0%) in those who met the criteria for universal prehospital termination of resuscitation. CONCLUSION: Overall survival amongst patients transported to hospital with ongoing CPR was very poor. Application of the universal prehospital termination of resuscitation rule, in patients without obvious reversible causes of cardiac arrest, would have allowed resuscitation to have been discontinued at the scene for 39.2% of patients who did not survive.

Time to epileptiform activity and EEG background recovery are independent predictors after cardiac arrest.

OBJECTIVE: Investigate the temporal development of EEG and prognosis. METHODS: Prospective observational substudy of the Target Temperature Management trial. Six sites performed simplified continuous EEG-monitoring (cEEG) on comatose patients after cardiac arrest, blinded to treating physicians. We determined time-points of recovery of a normal-voltage continuous background activity and the appearance of an epileptiform EEG, defined as abundant epileptiform discharges, periodic/rhythmic discharges or electrographic seizure activity. RESULTS: 134 patients were included, 65 had a good outcome. Early recovery of continuous background activity (within 24 h) occurred in 72 patients and predicted good outcome since 55 (76%) had good outcome, increasing the odds for a good outcome seven times compared to a late background recovery. Early appearance of an epileptiform EEG occurred in 38 patients and 34 (89%) had a poor outcome, increasing the odds for a poor outcome six times compared to a late debut. The time to background recovery and the time to epileptiform activity were highly associated with outcome and levels of neuron-specific enolase. Multiple regression analysis showed that both variables were independent predictors. CONCLUSIONS: Time to epileptiform activity and background recovery are independent prognostic indicators. SIGNIFICANCE: Patients with early background recovery combined with late appearance of epileptiform activity may have a good outcome.

Pre-meal insulin aspart compared with pre-meal soluble human insulin in type 1 diabetes.

Insulin aspart has been shown, in medium-term studies, to achieve reductions in HbA(1c) without increasing the risk of major hypoglycaemia compared with pre-meal human insulin. The aim of the present 3-year study was to evaluate the long-term safety and efficacy of insulin aspart in people with type 1 diabetes. This was a 30-month extension of a multinational, multicentre, open-label, parallel-group study of 753 people with type 1 diabetes, originally randomly allocated to treatment with insulin aspart or unmodified human insulin before meals, with NPH insulin as basal insulin. Main outcomes measures were hypoglycaemia (major or minor), adverse events and HbA(1c). As insulin aspart became commercially available in some countries before the end of the trial, analyses of HbA(1c) used 30-month data to maintain statistical power. The relative risk estimate of major hypoglycaemia was similar between treatment groups (relative risk [RR] 1.00 [95% CI 0.72, 1.39]). The risk of having a minor hypoglycaemic episode was higher with insulin aspart than with human soluble insulin (RR 1.24 [1.09, 1.39] p=0.024). Insulin aspart was significantly superior to human insulin with respect to overall glycaemic control, with a baseline-adjusted HbA(1c) difference of -0.16 (-0.32, -0.01)% (p=0.035). Insulin aspart was well tolerated and effective during long-term treatment. The HbA(1c) advantage was maintained with insulin aspart without any adverse impact on the rate of major hypoglycaemia.

Post resuscitation care: what are the therapeutic alternatives and what do we know?

A large proportion of deaths in the Western World are caused by ischaemic heart disease. Among these patients a majority die outside hospital due to sudden cardiac death. The prognosis among these patients is in general, poor. However, a significant proportion are admitted to a hospital ward alive. The proportion of patients who survive the hospital phase of an out of hospital cardiac arrest varies considerably. Several treatment strategies are applicable during the post resuscitation care phase, but the level of evidence is weak for most of them. Four treatments are recommended for selected patients based on relatively good clinical evidence: therapeutic hypothermia, beta-blockers, coronary artery bypass grafting, and an implantable cardioverter defibrillator. The patient's cerebral function might influence implementation of the latter two alternatives. There is some evidence for revascularisation treatment in patients with suspected myocardial infarction. On pathophysiological grounds, an early coronary angiogram is a reasonable alternative. Further randomised clinical trials of other post resuscitation therapies are essential.

Protocol for meta-analysis of temperature reduction in animal models of cardiac arrest.

Targeted temperature management (TTM) of 32-34 °C has been the standard treatment for out-of-hospital cardiac arrest since clinical trials in 2002 showed benefits to survival and neurological outcome. Recently, this treatment has been challenged by another clinical trial showing no difference in outcome between TTM of 33 °C and 36 °C. This protocol describes the methodology for a meta-analysis detailing temperature-reducing interventions to treat global ischaemia in animal models. By combining relevant data sets in the literature, we will explore the experimental evidence for TTM. Our aims are to explain possible translational gaps and provide methodological considerations for future experimental research and clinical trials.

The pharmacokinetic and pharmacodynamic properties of biphasic insulin Aspart 70 (BIAsp 70) are significantly different from those of biphasic insulin Aspart 30 (BIAsp 30).

AIMS: To evaluate the pharmacokinetic and pharmacodynamic properties of two different formulations of premixed analogue (mixed biphasic insulin aspart [BIAsp]), BIAsp 30 (30 % soluble insulin aspart [IAsp] and 70 % protaminated IAsp) and BIAsp 70 (70 % soluble IAsp and 30 % protaminated IAsp), in patients with type 1 diabetes using a 12-hour euglycaemic clamp technique. METHODS: In this randomised, double-blind, two-period crossover trial, 27 patients with type 1 diabetes received 7 days of treatment with BIAsp 30 three times daily (TID) and 7 days of treatment with BIAsp 70 TID, with a 2 - 6 week washout period between treatment periods. At the start (day 1) and end (day 8) of each treatment period, 12-hour serum IAsp profiles and glucose infusion rate (GIR) profiles were determined during an overnight euglycaemic clamp following subcutaneous (sc) administration of a single 0.3 U/kg dose of trial insulin. All pharmacokinetic and pharmacodynamic endpoints were derived from individual serum IAsp and GIR profiles. RESULTS: The larger fraction of soluble IAsp in BIAsp 70 compared with BIAsp 30 resulted in greater metabolic effect during the initial post-dosing phase (0 - 6 hours) and decreased activity during the late phase (6 - 12 hours). On day 8, AUC (GIR 0 - 6 hours) was 16 % greater for BIAsp 70 than for BIAsp 30 (p = 0.016) and AUC (GIR 6 - 12 hours) was 90 % (p < 0.001) greater for BIAsp 30 relative to BIAsp 70, reflecting the increased proportion of intermediate-acting (protamine co-crystallised) IAsp in BIAsp 30. Overall metabolic effect (AUC (GIR 0 - 12 hours)) was similar for both insulin formulations on day 8 (Ratio, BIAsp 30:BIAsp 70 = 1.04, p = 0.538). Likewise, the larger fraction of soluble IAsp in BIAsp 70 compared with BIAsp 30 resulted in greater exposure to IAsp during the initial post-dosing phase (0 - 6 hours) and a smaller exposure to IAsp during the late phase (6 - 12 hours). On day 8, AUC (IAsp 0 - 6 hours) was 59 % (p < 0.001) greater for BIAsp 70 than for BIAsp 30, and AUC (IAsp 6 - 12 hours) was 61 % (p < 0.001) greater for BIAsp 30 than for BIAsp 70, reflecting the increased proportion of intermediate-acting (protamine co-crystallised) IAsp in BIAsp 30. However, the overall IAsp exposure (AUC 0 - 12 hours) on day 8 was significantly greater for BIAsp 70 than for BIAsp 30 (Ratio, BIAsp 30:BIAsp 70 = 0.73, p < 0.001). The GIR profiles on day 8 were similar to those on day 1. Serum IAsp profiles on day 8 showed a slight increase compared with day 1. CONCLUSIONS: The different proportions of soluble and protaminated IAsp result in differences in the pharmacokinetic and pharmacodynamic properties of BIAsp 30 and BIAsp 70. The pharmacokinetic and pharmacodynamic differences observed may allow for flexibility and individualised treatment regimens in patients with diabetes, while maintaining a limited number of daily injections.

Survival in patients without acute ST elevation after cardiac arrest and association with early coronary angiography: a post hoc analysis from the TTM trial.

PURPOSE: To investigate whether early coronary angiography (CAG) after out-of-hospital cardiac arrest of a presumed cardiac cause is associated with improved outcomes in patients without acute ST elevation. METHODS: The target temperature management after out-of-hospital cardiac arrest (TTM) trial showed no difference in all-cause mortality or neurological outcome between an intervention of 33 and 36 °C. In this post hoc analysis, 544 patients where the admission electrocardiogram did not show acute ST elevation were included. Early CAG was defined as being performed on admission or within the first 6 h after arrest. Primary outcome was mortality at the end of trial. A Cox proportional hazard model was created to estimate hazard of death, adjusting for covariates. In addition, a propensity score matched analysis was performed. RESULTS: A total of 252 patients (46 %) received early CAG, whereas 292 (54 %) did not. At the end of the trial, 122 of 252 patients who received an early CAG (48 %) and 159 of 292 patients who did not (54 %) had died. The adjusted hazard ratio for death was 1.03 in the group that received an early CAG; 95 % CI 0.80-1.32, p = 0.82. In the propensity score analysis early CAG was not significantly associated with survival. CONCLUSIONS: In this post hoc observational study of a large randomized trial, early coronary angiography for patients without acute ST elevation after out-of-hospital cardiac arrest of a presumed cardiac cause was not associated with improved survival. A randomized trial is warranted to guide clinical practice.

Anxiety and depression among out-of-hospital cardiac arrest survivors.

AIM: Survivors of out-of-hospital cardiac arrest (OHCA) may experience psychological distress but the actual prevalence is unknown. The aim of this study was to investigate anxiety and depression within a large cohort of OHCA-survivors. METHODS: OHCA-survivors randomized to targeted temperature of 33 °C or 36 °C within the Target Temperature Management trial (TTM-trial) attended a follow-up after 6 months that included the questionnaire Hospital Anxiety and Depression Scale (HADS). A control group with ST-elevation myocardial infarction (STEMI) completed the same follow-up. Correlations to variables assumed to be associated with anxiety and depression in OHCA-survivors were tested. RESULTS: At follow-up 278 OHCA-survivors and 119 STEMI-controls completed the HADS where 24% of OHCA-survivors (28% in 33 °C group/22% in 36 °C group, p=0.83) and 19% of the STEMI-controls reported symptoms of anxiety (OR 1.32; 95% CI (0.78-2.25), p=0.30). Depressive symptoms were reported by 13% of OHCA-survivors (equal in both intervention groups, p=0.96) and 8% of STEMI-controls (OR 1.76; 95% CI (0.82-3.79), p=0.15). Anxiety and depression among OHCA-survivors correlated to Health-Related Quality-of-Life, and subjectively reported cognitive deterioration by patient or observer. In addition, depression was associated with a poor neurological outcome. CONCLUSION: One fourth of OHCA-survivors reported symptoms of anxiety and/or depression at 6 months which was similar to STEMI-controls and previous normative data. Subjective cognitive problems were associated with an increased risk for psychological distress. Since psychological distress affects long-term prognosis of cardiac patients in general it should be addressed during follow-up of survivors with OHCA due to a cardiac cause. ClinicalTrials.gov NCT01020916/NCT01946932.

Blockade of the mitochondrial permeability transition pore diminishes infarct size in the rat after transient middle cerebral artery occlusion.

The mitochondrial permeability transition pore is an inducer of cell death. During the reperfusion phase after cerebral ischemia, calcium accumulates in mitochondria, and a burst of free radical formation occurs, conditions that favor the activation of the mitochondrial permeability transition pore. Here the authors demonstrate that a blocker of the mitochondrial permeability transition pore, the nonimmunosuppressive cyclosporin A analogue N-methyl-Val-4-cyclosporin A (10 mg/kg intraperitoneally), administered during reperfusion and at 24 hours of reperfusion, diminishes infarct size in a rat model of transient focal ischemia of 2 hours' duration. The mitochondrial permeability transition pore may be an important target for drugs against stroke.

Quantitative measurements of cerebral blood flow using SPECT and [99mTc]-d,l-HM-PAO compared to xenon-133.

The uptake and retention in a 2 cm thick brain section was recorded serially by SPECT after i.v. injection of [99mTc]-d,l-HM-PAO (HM-PAO). In 16 patients, the fraction of the administered dose retained by the brain was 5.2 +/- 1%, showing a peak after 40-50s, then decreasing by 10% within the first 10 min and then by only 0.4% per hour. The image contrast was measured in each patient as the regional hemispheric asymmetry difference in percent of the highest value of the two regions. It decreased from 31% at 30-40 s to 25% at 10 min. At 24 h, a value of 19% was reached. Using the images obtained at 10 min after injection, a region to region comparison of the original and corrected HM-PAO images to the xenon-133 regional cerebral blood flow (rCBF) images was performed. Forty-four patients with stroke, epilepsy, dementia, basal ganglia disease, and tumors and control subjects were included in this comparison. The algorithm proposed by Lassen et al. was used to correct the original images for back diffusion of tracer (brain to blood); a good correlation very close to the line of identity between the corrected HM-PAO and xenon-133 data was obtained when using a conversion/clearance ratio of 1.5 and when the noninvolved hemisphere was used as a reference region (r = 0.86, p less than 0.0001). Serial arterial and cerebral venous blood sampling was performed over 10 min following i.v. injection of HM-PAO in six patients. An overall brain retention fraction of 0.37 +/- 0.03 (mean +/- SEM) was calculated from the data. An average CBF of 0.62 +/- 0.12 ml/g/min was determined on the basis of the Fick principle; this compared to a value of 0.59 +/- 0.09 ml/g/min (mean +/- SEM) measured by the xenon-133 inhalation method. The two sets of CBF values correlated linearly with a correlation coefficient of 0.97 (p less than 0.01). Inserting the average CBF value for the hemisphere as measured by the Fick principle into the algorithm described by Lassen et al. yields absolute rCBF values (ml/g/min) directly from the corrected HM-PAO images.(ABSTRACT TRUNCATED AT 400 WORDS)

Assessment of the arterial input curve for [99mTc]-d,l-HM-PAO by rapid octanol extraction.

The in vitro conversion of the lipophilic molecule [99mTc]-d,l-hexamethylpropyleneamine oxime [( 99mTc]-d,l-HM-PAO) to a hydrophilic form was studied in saline, plasma, and blood at 37 degrees C by paper chromatography and by octanol extraction. The octanol:saline ratio was 79.9. From this value and the corresponding octanol: plasma and octanol:blood partitioning values, an estimate of the transport of the lipophilic compound by various components of blood was made: 20% is carried in hemoglobin, 53% by the plasma proteins and 27% by the water phases of the red blood cell and plasma. Octanol extraction provided a rapid method for measuring the radiochemical purity (RCP) of lipophilic [99mTc]-d,l-HM-PAO. In saline, the RCP declined with a half-life of more than 1 h. In human plasma and whole blood, the conversion of [99mTc]-d,l-HM-PAO was biexponential due to the differences in the conversion rates of the d and l isomeric forms. The initial half-life representing the conversion rate of the l form was 1.7 min in blood and 1.4 min in plasma, while the conversion half-life of the d form was 7.4 and 24.4 min, respectively. In vivo, the RCP of arterial blood sampled after an i.v. bolus injection showed an initial peak value of 75% (68-79%) during the initial, first passage of the bolus. It declined to approximately 35% (29-40%) after 1.5 min and reached very low levels (about 1%) at 6 to 10 min. Quantitative measurements of cerebral blood flow using [99mTc]-d,l-HM-PAO necessitates a rapid method for RCP determination in arterial blood such as the one described here.