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In a randomized trial involving 8014 patients with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than placebo but not a higher rate of survival with a favorable neurologic outcome.

Background The impact of the permissive hypotension approach in clinically well infants on regional cerebral oxygen saturation (rScO 2 ) and autoregulatory capacity (CAR) remains unknown. Methods Prospective cohort study of blinded rScO 2 measurements within a randomized controlled trial of management of hypotension (HIP trial) in extremely preterm infants. rScO 2 , mean arterial blood pressure, duration of cerebral hypoxia, and transfer function (TF) gain inversely proportional to CAR, were compared between hypotensive infants randomized to receive dopamine or placebo and between hypotensive and non-hypotensive infants, and related to early intraventricular hemorrhage or death. Results In 89 potentially eligible HIP trial patients with rScO 2 measurements, the duration of cerebral hypoxia was significantly higher in 36 hypotensive compared to 53 non-hypotensive infants. In 29/36 hypotensive infants (mean GA 25 weeks, 69% males) receiving the study drug, no significant difference in rScO 2 was observed after dopamine ( n  = 13) compared to placebo ( n  = 16). Duration of cerebral hypoxia was associated with early intraventricular hemorrhage or death.  Calculated TF gain ( n  = 49/89) was significantly higher reflecting decreased CAR in 16 hypotensive compared to 33 non-hypotensive infants. Conclusions Dopamine had no effect on rScO 2 compared to placebo in hypotensive infants. Hypotension and cerebral hypoxia are associated with early intraventricular hemorrhage or death. Impact Treatment of hypotension with dopamine in extremely preterm infants increases mean arterial blood pressure, but does not improve cerebral oxygenation. Hypotensive extremely preterm infants have increased duration of cerebral hypoxia and reduced cerebral autoregulatory capacity compared to non-hypotensive infants. Duration of cerebral hypoxia and hypotension are associated with early intraventricular hemorrhage or death in extremely preterm infants. Since systematic treatment of hypotension may not be associated with better outcomes, the diagnosis of cerebral hypoxia in hypotensive extremely preterm infants might guide treatment.

We compared epinephrine and dopamine as a first-line vasoactive drug in 40 neonates (enrolled in two gestational age strata ≤ 306/7 and ≥ 310/7 weeks) with fluid-refractory septic shock. Epinephrine or dopamine was initiated at 0.2 or 10 μg/kg/min, respectively. If shock persisted after 15 min, epinephrine or dopamine was increased to 0.3 or 15 μg/kg/min, respectively (16–30 min), and thereafter to 0.4 or 20 μg/kg/min (31–45 min). Proportion of neonates achieving ‘reversal of shock’ (defined as systolic and diastolic BP > fifth centile and capillary filling time < 3 s and left ventricular output ≥ 150 mL/kg/min) by 45 min [5 (25%) vs 6 (30%), RR 0.83 (95% CI 0.30, 2.29)]; haemodynamic stability (shock reversal for ≥ 120 min without escalation of vasoactive drugs) anytime during therapy [10 (50%) vs 6 (30%), RR 1.67 (95% CI 0.75, 3.71)]; and all-cause mortality by 28 days [14 (70%) vs 16 (80%), RR 0.87 (95% CI 0.61, 1.26)] were comparable in the epinephrine and dopamine groups, respectively. On stratified analysis, we observed an interaction of gestational age strata with the group of allocation favouring epinephrine in neonates ≤ 306/7 weeks.Conclusion: Epinephrine (0.2–0.4 μg/kg/min) and dopamine (10–20 μg/kg/min) had comparable efficacy and safety in neonatal septic shock.Clinical Trial registry name and registration number: The study was registered with Clinical Trial Registry of India CTRI/2015/10/006285.What is Known:• The choice of vasoactive drugs in neonatal septic shock is empirical and dopamine is the conventional first-line vasoactive drug.• There are no randomized controlled trials comparing dopamine and epinephrine in neonatal septic shock.What is New:• In this study, epinephrine and dopamine had comparable efficacy and safety as a first-line vasoactive drug in management of neonatal septic shock.• On stratified analysis in a limited sample, epinephrine was associated with better outcomes in neonates ≤ 306/7 weeks.

Aims/hypothesis Brown adipose tissue (BAT) activation increases energy expenditure and may have therapeutic potential to combat obesity. The primary activating and adaptive signal for BAT is via β-adrenergic signalling. We previously demonstrated that human BAT is acutely responsive to oral administration of the sympathomimetic, ephedrine. Here we aimed to determine whether adaptive thermogenesis can be induced via chronic treatment with ephedrine. Methods Twenty-three healthy young men, recruited from the general public in Melbourne, Australia, who were non-smokers, physically inactive and non-medicated with no prior history of cardiovascular disease or diabetes were recruited for this study. They were assigned to receive either 1.5 mg kg −1  day −1 ephedrine (‘active’ group; n  = 12, age 23 ± 1 years, BMI 24 ± 1 kg/m 2 ) or placebo ( n  = 11; 22 ± 2 years, 23 ± 2 kg/m 2 ) for 28 days in a randomised (computer-generated random order sequence), placebo-controlled, parallel-group trial. Participants and all investigators were blinded to treatments. Body composition was measured before and after the intervention by dual energy X-ray absorptiometry. BAT activity, measured via 18 F-fluorodeoxyglucose positron emission tomography-computed tomography, in response to a single dose of 2.5 mg/kg ephedrine, was the primary outcome measure to be determined before and after the 28 day treatment period. Results Twenty-eight individuals were randomised and consented to the study. Twenty-three completed the trial and only these participants were included in the final analyses. After 28 days of treatment, the active group lost a significant amount of total body fat (placebo 1.1 ± 0.3 kg, ephedrine −0.9 ± 0.5 kg; p  < 0.01) and visceral fat (placebo 6.4 ± 19.1 g, ephedrine −134 ± 43 g; p  < 0.01), with no change in lean mass or bone mineral content compared with the placebo group. In response to acute ephedrine, BAT activity (change in mean standardised uptake value: placebo −3 ± 7%, ephedrine −22 ± 6%) and the increase in systolic blood pressure were significantly reduced ( p  < 0.05) in the active group compared with placebo. Conclusions/interpretation Chronic ephedrine treatment reduced body fat content, but this was not associated with an increase in BAT activity. Rather, chronic ephedrine suppressed BAT glucose disposal, suggesting that chronic ephedrine treatment decreased, rather than increased, BAT activity. Trial registration : ClinicalTrials.gov NCT02236962 Funding : This study was funded by the National Health and Medical Research Council of Australia Program Grant (1036352) and the OIS scheme from the Victorian State Government.

Epinephrine is recommended for use in the resuscitation of patients with cardiac arrest. In this clinical trial, vasopressin, as compared with epinephrine, improved the rates of survival to hospital admission and discharge, but only among patients with asystolic cardiac arrest. There was no advantage to vasopressin therapy in patients with ventricular fibrillation or pulseless electrical activity. As compared with epinephrine, improved the rates of survival to hospital admission. There are more than 600,000 sudden deaths in North America and Europe each year. More than half of these deaths occur before 65 years of age, which underscores the need for optimal cardiopulmonary resuscitation (CPR) strategies in order to improve patients' chances of survival. Epinephrine has been used during CPR for more than 100 years 1 but has become controversial because it is associated with increased myocardial oxygen consumption, ventricular arrhythmias, and myocardial dysfunction during the period after resuscitation. 2 Since it was found that endogenous vasopressin levels in successfully resuscitated patients were significantly higher than levels in patients who died, it . . .

Background Phase III trials often require large sample sizes, leading to high costs and delays in clinical decision-making. Group sequential designs can improve trial efficiency by allowing for early stopping for efficacy and/or futility and thus may decrease the sample size, trial duration and associated costs. Bayesian approaches may offer additional benefits by incorporating previous information into the analyses and using decision criteria that are more practically relevant than those used in frequentist approaches. Frequentist group sequential designs have often been used for phase III studies, but the use of Bayesian group sequential designs is less common. The aim of this work was to explore how Bayesian group sequential designs could be constructed for phase III trials conducted in emergency medicine. Methods The PARAMEDIC2 trial was a phase III randomised controlled trial that compared the use of adrenaline to placebo in out-of-hospital cardiac arrest patients on 30-day survival rates. It used a frequentist group sequential design to allow early stopping for efficacy or harm. We constructed several alternative Bayesian group sequential designs and studied their operating characteristics via simulation. We then virtually re-executed the trial by applying the Bayesian designs to the PARAMEDIC2 data to demonstrate what might have happened if these designs had been used in practice. Results We produced three alternative Bayesian group sequential designs, each of which had greater than 90% power to detect the target treatment effect. A Bayesian design which performed interim analyses every 500 patients recruited produced the lowest average sample size. Using the alternative designs, the PARAMEDIC2 trial could have declared adrenaline superior for 30-day survival with approximately 1500 fewer patients. Conclusions Using the PARAMEDIC2 trial as a case study, we demonstrated how Bayesian group sequential designs can be constructed for phase III emergency medicine trials. The Bayesian framework enabled us to obtain efficient designs using decision criteria based on the probability of benefit or harm. It also enabled us to incorporate information from previous studies on the treatment effect via the prior distributions. We recommend the wider use of Bayesian approaches in phase III clinical trials. Trial registration PARAMEDIC2 Trial registration ISRCTN, ISRCTN73485024. Registered 13 March 2014, http://www.isrctn.com/ISRCTN73485024

This study aimed to investigate the clinical effects of early goal-directed therapy according to the global end-diastolic volume index (GEDI) on chronic obstructive pulmonary disease (COPD) patients with septic shock. A total of 71 COPD patients with septic shock were randomly assigned to 2 groups. In the control group (n = 37), fluid resuscitation was performed based on the central venous pressure. In the study group (n = 34), fluid resuscitation was performed until GEDI reached 800 mL/m2. The following indices were observed for the 2 groups: 6- and 24-hour fluid volumes, norepinephrine dosage, 24-hour blood lactate clearance rate, duration of mechanical ventilation, intensive care unit (ICU) length of stay, ICU mortality, and 90-day survival rate. At both 6- and 24-hour measurements, the fluid volume was lower and norepinephrine dosage was higher in the control group than in the study group (P < .05). The blood lactate clearance rate was lower, the duration of mechanical ventilation was longer, and the length of stay in the ICU was longer in the control group than in the study group (P < .05). No significant difference in mortality or 90-day survival rate was found between the 2 groups. The GEDI goal-directed fluid resuscitation shows better clinical effects than that shown by central venous pressure for COPD patients with septic shock; however, it cannot reduce the mortality rate.

To compare the effects of a cerebral perfusion pressure (CPP) intervention achieved with dopamine and norepinephrine after severe head injury. Prospective, controlled, trial. Neurosciences critical care unit. Eleven patients with a head injury, requiring dopamine or norepinephrine infusions to support CPP. Cerebral tissue gas measurements were recorded using a multimodal sensor, and regional chemistry was assessed using microdialysis. Patients received in, randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 65 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 85 mmHg. Data were then acquired using the second agent. Haemodynamic measurements and measurements of cerebral physiology were made during each period. The CPP augmentation with norepinephrine, but not with dopamine, resulted in a significant reduction in arterial-venous oxygen difference (37+/-11 vs 33+/-12 ml/l) and a significant increase in brain tissue oxygen (2.6+/-1.1 vs 3.0+/-1.1 kPa). The CPP intervention did not significantly affect intracranial pressure. There were no significant differences between norepinephrine and dopamine on cerebral oxygenation or metabolism either at baseline or following a CPP intervention; however, the response to a CPP intervention with dopamine seemed to be more variable than the response achieved with norepinephrine. If CPP is to be raised to a level higher than 65-70 mmHg, then it is important to recognise that the response to the intervention may be unpredictable and that the vasoactive agent used may be of importance.

Background: Midodrine is an α-agonist prodrug of desglymidodrine (DGM) that has been reported to be of clinical benefit in patients with neurocardiogenic syncope. Its effects may be mediated not only by its hypertensive properties but also by its neurohumoral influences independent of blood pressure (BP). Objective: The present study aimed to simultaneously characterize the effects of midodrine on BP, plasma catecholamines, plasma atrial natriuretic peptide (ANP), and power spectral analysis of heart rate (HR) in healthy volunteers. Methods: This was a prospective, randomized, single-blind, 2-period, crossover study in which a single, oral, 5-mg dose of midodrine was compared with placebo. The washout period between midodrine and placebo was 1 week. The study parameters included plasma DGM (as measured by high-performance liquid chromatography [HPLC]); systolic and diastolic BP (as measured with an oscillometric monitor); HR; plasma catecholamines (measured by HPLC); plasma ANP, also known as venous return (measured by a radio-immunoassay); and low- and high-frequency HR variation (calculated from computerized 5-minute electrocardiographic recordings). All study parameters were measured simultaneously 12 times just before and over a period of 8 hours after drug administration. Results: Fifteen healthy nonsmoking male subjects (14 white, 1 black; mean [SD] age, 28.6 [4.7] years; weight, 74.5 [16.4] kg; seated BP, 109.9 [9.0]/73.6 [9.5] mm Hg; seated HR, 63.8 [8.4] bpm) were randomized. No significant effects of midodrine on BP were observed. At C max, midodrine decreased norepinephrine from 188.4 (30.6) to 162.5 (29.8) pg/mL ( P = 0.011) and HR from 57.2 (7.3) to 54.9 (6.6) bpm ( P = 0.022). A significant correlation was found between DGM concentration and HR ( ϕ -0.61; P = 0.014). A DGM-related increase in plasma ANP (+29.6 [90.0] fmoL/mL) was observed. Conclusion: This study in healthy male volunteers found that midodrine has sympatholytic influences that are independent of BP but related to augmented venous return.

Vasoplegic syndrome is a common occurrence following cardiothoracic surgery and is characterized as a high-output shock state with poor systemic vascular resistance. The pathophysiology is complex and includes dysregulation of vasodilatory and vasoconstrictive properties of smooth vascular muscle cells. Specific bypass machine and patient factors play key roles in occurrence. Research into treatment of this syndrome is limited and extrapolated primarily from that pertaining to septic shock, but is evolving with the expanded use of catecholamine-sparing agents. Recent reports demonstrate potential benefit in novel treatment options, but large clinical trials are needed to confirm.