Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial.

Importance: Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. ß-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. Objectives: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. Design, Setting, and Participants: An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 µg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. Intervention: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. Main Outcomes and Measures: The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. Results: The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, -0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, -4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, -1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event. Conclusion and Relevance: Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. Trial Registration: EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919.

biomArker-guided Duration of Antibiotic treatment in hospitalised Patients with suspecTed Sepsis (ADAPT-Sepsis): A protocol for a multicentre randomised controlled trial.

Aim: To describe the protocol for a multi-centre randomised controlled trial to determine whether treatment protocols monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with sepsis. Design: Multicentre three-arm randomised controlled trial. Setting: UK NHS hospitals. Target population: Hospitalised critically ill adults who have been commenced on intravenous antibiotics for sepsis. Health technology: Three protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily CRP monitoring; (c) standard care + daily PCT monitoring. Standard care will be based on routine sepsis management and antibiotic stewardship. Measurement of outcomes and costs. Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; antibiotic dose; length and level of critical care stay and length of hospital stay. Ninety-day all-cause mortality rates will also be collected. An assessment of cost effectiveness will be performed. Conclusion: In the setting of routine NHS care, if this trial finds that a treatment protocol based on monitoring CRP or PCT safely allows a reduction in duration of antibiotic therapy, and is cost effective, then this has the potential to change clinical practice for critically ill patients with sepsis. Moreover, if a biomarker-guided protocol is not found to be effective, then it will be important to avoid its use in sepsis and prevent ineffective technology becoming widely adopted in clinical practice.

Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial.

Importance: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. Objective: To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. Design, Setting, and Participants: A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. Interventions: Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). Main Outcomes and Measures: The primary outcome was a composite of tracheal intubation or mortality within 30 days. Results: The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings. Trial Registration: isrctn.org Identifier: ISRCTN16912075.

The impact of the Queensland Government's Tackling Alcohol-Fuelled Violence Policy on live music performances in Fortitude Valley, Brisbane, Australia.

INTRODUCTION: The Queensland Government's Tackling Alcohol-Fuelled Violence (TAFV) Policy was met with concern from live music venue owners who feared decreased patronage and associated revenue. This study investigates the impact of the TAFV Policy on live music venues and performances in Fortitude Valley, an inner-city suburb of Brisbane, Australia recognised as a hub of live music performances. METHODS: Data relating to live music venues and performances in Fortitude Valley for the 2000-2018 financial years were obtained from the Australasian Performing Right Association (APRA AMCOS), who maintains an online data portal allowing artists to enter performance details to collect royalty payments. These data were supplemented with six precinct mapping audits of live music venues operating in the Fortitude Valley Safe Night Precinct between July 2016 and September 2019. RESULTS: APRA AMCOS data show increases in the number of reported live music performances and venues in Fortitude Valley between 2000 and 2019. Precinct mapping audits show minimal changes in the operation of live music venues in Fortitude Valley between 2016 and 2019. DISCUSSION AND CONCLUSIONS: As the first study to independently document the impact of licenced venue trading hour changes on live music, this study shows the number of live performances reported to APRA AMCOS and original live music venues trading in the Fortitude Valley Safe Night Precinct were unchanged by the introduction of the TAFV. The study highlights the value of using performance returns and venue audits to track live music in a contested policy space.

Adrenaline to improve survival in out-of-hospital cardiac arrest: the PARAMEDIC2 RCT.

BACKGROUND: Adrenaline has been used as a treatment for cardiac arrest for many years, despite uncertainty about its effects on long-term outcomes and concerns that it may cause worse neurological outcomes. OBJECTIVES: The objectives were to evaluate the effects of adrenaline on survival and neurological outcomes, and to assess the cost-effectiveness of adrenaline use. DESIGN: This was a pragmatic, randomised, allocation-concealed, placebo-controlled, parallel-group superiority trial and economic evaluation. Costs are expressed in Great British pounds and reported in 2016/17 prices. SETTING: This trial was set in five NHS ambulance services in England and Wales. PARTICIPANTS: Adults treated for an out-of-hospital cardiac arrest were included. Patients were ineligible if they were pregnant, if they were aged < 16 years, if the cardiac arrest had been caused by anaphylaxis or life-threatening asthma, or if adrenaline had already been given. INTERVENTIONS: Participants were randomised to either adrenaline (1 mg) or placebo in a 1 : 1 allocation ratio by the opening of allocation-concealed treatment packs. MAIN OUTCOME MEASURES: The primary outcome was survival to 30 days. The secondary outcomes were survival to hospital admission, survival to hospital discharge, survival at 3, 6 and 12 months, neurological outcomes and health-related quality of life through to 6 months. The economic evaluation assessed the incremental cost per quality-adjusted life-year gained from the perspective of the NHS and Personal Social Services. Participants, clinical teams and those assessing patient outcomes were masked to the treatment allocation. RESULTS: From December 2014 to October 2017, 8014 participants were assigned to the adrenaline (n = 4015) or to the placebo (n = 3999) arm. At 30 days, 130 out of 4012 participants (3.2%) in the adrenaline arm and 94 out of 3995 (2.4%) in the placebo arm were alive (adjusted odds ratio for survival 1.47, 95% confidence interval 1.09 to 1.97). For secondary outcomes, survival to hospital admission was higher for those receiving adrenaline than for those receiving placebo (23.6% vs. 8.0%; adjusted odds ratio 3.83, 95% confidence interval 3.30 to 4.43). The rate of favourable neurological outcome at hospital discharge was not significantly different between the arms (2.2% vs. 1.9%; adjusted odds ratio 1.19, 95% confidence interval 0.85 to 1.68). The pattern of improved survival but no significant improvement in neurological outcomes continued through to 6 months. By 12 months, survival in the adrenaline arm was 2.7%, compared with 2.0% in the placebo arm (adjusted odds ratio 1.38, 95% confidence interval 1.00 to 1.92). An adjusted subgroup analysis did not identify significant interactions. The incremental cost-effectiveness ratio for adrenaline was estimated at £1,693,003 per quality-adjusted life-year gained over the first 6 months after the cardiac arrest event and £81,070 per quality-adjusted life-year gained over the lifetime of survivors. Additional economic analyses estimated incremental cost-effectiveness ratios for adrenaline at £982,880 per percentage point increase in overall survival and £377,232 per percentage point increase in neurological outcomes over the first 6 months after the cardiac arrest. LIMITATIONS: The estimate for survival with a favourable neurological outcome is imprecise because of the small numbers of patients surviving with a good outcome. CONCLUSIONS: Adrenaline improved long-term survival, but there was no evidence that it significantly improved neurological outcomes. The incremental cost-effectiveness ratio per quality-adjusted life-year exceeds the threshold of £20,000-30,000 per quality-adjusted life-year usually supported by the NHS. FUTURE WORK: Further research is required to better understand patients' preferences in relation to survival and neurological outcomes after out-of-hospital cardiac arrest and to aid interpretation of the trial findings from a patient and public perspective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN73485024 and EudraCT 2014-000792-11. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 25. See the NIHR Journals Library website for further project information.

Cardiac arrest is a medical emergency that happens when the heart suddenly stops pumping effectively. When cardiac arrest happens, awareness is lost within seconds. If emergency treatment is not started quickly, the person will die. The first treatments of cardiac arrest involve pressing on the chest, giving rescue breaths and defibrillation (electric shocks applied to the heart). If these treatments do not work, ambulance paramedics use a drug called adrenaline to try to restart the heart. Although this treatment has been used for many years, some recent research suggests that it may cause more harm than good. In this research study, we compared the effects of giving adrenaline with the effects of not giving adrenaline to people who had a cardiac arrest in the community. The research showed that adrenaline was effective at restarting the heart, so more people survived long enough to be admitted to hospital. Thirty days later, 130 out of 4012 patients (3.2%) who received adrenaline and 94 out of 3995 (2.4%) who did not receive adrenaline were alive. However, adrenaline did not improve the number of patients who went home from hospital having made a good recovery and were able to care for themselves. The evidence suggests that adrenaline represents a poor use of NHS funds on cost-effectiveness grounds. In a community survey, 95% of people who responded thought that long-term survival with good brain function was more important than just being alive. Further research exploring the opinions of patients and the public will help to understand the results of this research for the NHS.

Long term outcomes of participants in the PARAMEDIC2 randomised trial of adrenaline in out-of-hospital cardiac arrest.

AIMS: We recently reported early outcomes in patients enrolled in a randomised trial of adrenaline in out-of-hospital cardiac arrest: the PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) trial. The purpose of the present paper is to report long-term survival, quality of life, functional and cognitive outcomes at 3, 6 and 12-months. METHODS: PARAMEDIC2 was a pragmatic, individually randomised, double blind, controlled trial with an economic evaluation. Patients were randomised to either adrenaline or placebo. This paper reports results on the modified Rankin Scale scores at 6-months, survival at 6 and 12-months, as well as other cognitive, functional and quality of life outcomes collected at 3 and 6 months (Two Simple Questions, the Mini Mental State Examination, the Informant Questionnaire on Cognitive Decline Evaluation for Cardiac Arrest, Hospital Anxiety and Depression Scale, the Post Traumatic Stress Disorder Checklist - Civilian Version, Short-Form 12-item Health Survey and the EuroQoL EQ-5D-5L). RESULTS: 8014 patients were randomised with confirmed trial drug administration. At 6-months, 78 (2.0%) of the patients in the adrenaline group and 58 (1.5%) of patients in the placebo group had a favourable neurological outcome (adjusted odds ratio 1.35 [95% confidence interval: 0.93, 1.97]). 117 (2.9%) patients were alive at 6-months in the adrenaline group compared with 86 (2.2%) in the placebo group (1.43 [1.05, 1.96], reducing to 107 (2.7%) and 80 (2.0%) respectively at 12-months (1.38 [1.00, 1.92]). Measures of 3 and 6-month cognitive, functional and quality of life outcomes were reduced, but there was no strong evidence of differences between groups. CONCLUSION: Adrenaline improved survival through to 12-months follow-up. The study did not find evidence of improvements in favourable neurological outcomes. (ISCRTN 73485024).

Study into the reversal of septic shock with landiolol (beta blockade): STRESS-L Study protocol for a randomised trial.

INTRODUCTION: In 2013, a single-centre study reported the safe use of esmolol in patients with septic shock and tachycardia who required vasopressor therapy for more than 24 hours. Although not powered to detect a change in mortality, marked improvements were seen in survival (adjusted HR, 0.39; 95% CI, 0.26 to 0.59; p<0.001). Beta blockers are one of the most studied groups of drugs but their effect in septic shock is poorly understood; proposed mechanisms include not only the modulation of cardiac function but also immunomodulation. METHODS AND ANALYSIS: STRESS-L is a randomised, open-label, non-blinded clinical trial which is enrolling a total of 340 patients with septic shock as defined by Sepsis-3 consensus definition and a tachycardia (heart rate ≥95 beats per minute (bpm)) after vasopressor treatment of at least 24 hours. Standard randomisation (1:1 ratio) allocates patients to receive usual care (according to international standards) versus usual care and a continuous landiolol infusion to reduce the heart rate between 80 and 94 bpm. The primary endpoint is the mean Sequential Organ Failure Assessment score over 14 days from entry into the trial and while in intensive care unit. Results will inform current clinical practice guidelines. ETHICS AND DISSEMINATION: This trial has clinical trial authorisation from the UK competent authority, the Medicines and Healthcare products Regulatory Agency, and has been approved by the East of England-Essex Research Ethics Committee (reference: 17/EE/0368).The results of the trial will be reported first to trial collaborators. The main report will be drafted by the trial coordinating team, and the final version will be agreed by the Trial Steering Committee before submission for publication, on behalf of the collaboration. REGISTRATION: The trial is funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) (Project Number: EME-14/150/85) and registered ISRCTN12600919 and EudraCT: 2017-001785-14.

Mechanical versus manual chest compressions in the treatment of in-hospital cardiac arrest patients in a non-shockable rhythm: A multi-centre feasibility randomised controlled trial (COMPRESS-RCT).

BACKGROUND: Mechanical chest compression devices deliver high-quality chest compressions. Early data suggests that mechanical devices may be superior to manual chest compressions in adults following an in-hospital cardiac arrest patients. To determine the feasibility of undertaking an effectiveness trial in this population, we undertook a feasibility randomised controlled trial. METHODS: We undertook a multi-centre parallel group feasibility randomised controlled trial (COMPRESS-RCT). Adult in-hospital cardiac arrest patients that were in a non-shockable rhythm were randomised in a 3:1 ratio to receive mechanical CPR (Jolfe AB/Stryker, Lund, Sweden) or ongoing manual CPR. Recruitment was led by the clinical cardiac arrest team. The primary study outcome was the proportion of eligible participants randomised in the study during site operational recruitment hours. Patients were enrolled under a model of deferred consent. We report data using descriptive statistics, point estimates and 95% confidence intervals. RESULTS: Over a two-year period, we recruited 127 patients across five UK hospitals. We recruited 55.2% (95% CI 48.5%-61.8%) of eligible study participants in site operational recruitment hours. Most participants were male (n = 76, 59.8%) with a mean age of 72 (95% CI: 69.9-74.9) years. Median arrest duration was 18 (IQR 13-29) minutes. In patients randomised to mech-CPR, median time from CPR start to device deployment was 11 (IQR 7-15) minutes. ROSC was achieved in 27.6% (n = 35) participants and 4.7% (n = 6) were alive at 30-days. CONCLUSION: COMPRESS-RCT identified important factors that preclude progression to an effectiveness trial of mechanical CPR in the hospital setting in the UK. Findings will inform the design of future in-hospital intra-arrest intervention trials. ISRCTN38139840, date of registration 9th January 2017.

RECOVERY- Respiratory Support: Respiratory Strategies for patients with suspected or proven COVID-19 respiratory failure; Continuous Positive Airway Pressure, High-flow Nasal Oxygen, and standard care: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVE: The trial objective is to determine if Continuous Positive Airway Pressure (CPAP) or High-Flow Nasal Oxygen (HFNO) is clinically effective compared to standard oxygen therapy in patients with confirmed or suspected COVID-19. TRIAL DESIGN: Adaptive (group-sequential), parallel group, pragmatic, superiority randomised controlled, open-label, multi-centre, effectiveness trial. PARTICIPANTS: The trial is being conducted across approximately 60 hospitals across England, Wales, Scotland, and Northern Ireland. Inpatients at participating hospitals are eligible to participate if they have respiratory failure with suspected or proven COVID-19, and meet all of the inclusion criteria and none of the exclusion criteria. INCLUSION CRITERIA: 1) Adults ≥ 18 years; 2) Admitted to hospital with suspected or proven COVID-19; 3) Receiving oxygen with fraction of inspired oxygen (FiO2) ≥0.4 and peripheral oxygen saturation (SpO2) ≤94%; and 4) Plan for escalation to tracheal intubation if needed. EXCLUSION CRITERIA: 1) Planned tracheal intubation and mechanical ventilation imminent within 1 hour; 2) Known or clinically apparent pregnancy; 3) Any absolute contraindication to CPAP or HFNO; 4) Decision not to intubate due to ceiling of treatment or withdrawal of treatment anticipated; and 5) Equipment for both CPAP and HFNO not available. INTERVENTION AND COMPARATOR: Intervention one: Continuous positive airway pressure delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention two: High-flow nasal oxygen delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Comparator group: Standard care- oxygen delivered by face mask or nasal cannula (excluding the use of continuous positive airway pressure or high-flow nasal oxygen). Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention delivery continues up to the point of death, tracheal intubation, or clinical determination that there is no ongoing need (palliation or improvement). MAIN OUTCOMES: The primary outcome is a composite outcome comprising tracheal intubation or mortality within 30 days following randomisation. Secondary outcomes include tracheal intubation rate, time to tracheal intubation, duration of invasive ventilation, mortality rate, time to mortality, length of hospital stay, and length of critical care stay. RANDOMISATION: Participants are randomised in a 1:1:1 ratio to receive either continuous positive airway pressure, high-flow nasal oxygen or standard care. Due to the challenging environment of study delivery, a specific intervention may not always be available at the hospital site. The study uses two integrated randomisation systems to allow, where required, the site to randomise between all three interventions, between CPAP and standard care, and between HFNO and standard care. System integration ensures maintenance of balance between interventions. Randomisation is performed using a telephone-based interactive voice response system to maintain allocation concealment. The randomisation sequence was computer-generated using the minimisation method. Participant randomisation is stratified by site, gender (M/F), and age (<50, >=50 years). BLINDING (MASKING): The nature of the trial interventions precludes blinding of the researcher, patient and clinical team. Primary and secondary outcomes are all objective outcomes, thereby minimising the risk of detection bias. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 4002 participants (1334 to be randomized to each of the three study arms) TRIAL STATUS: Current protocol: Version 4.0, 29th May 2020. Recruitment began on April 6, 2020 and is anticipated to be complete by April 5, 2021. The trial has been awarded Urgent Public Health status by the National Institute of Health Research on 13th April 2020. TRIAL REGISTRATION: ISRCTN, ISRCTN16912075. Registered 6th April 2020, http://www.isrctn.com/ISRCTN16912075 FULL PROTOCOL: The full protocol (version 4.0, 29th May 2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.

BACKGROUND: Concern about the use of epinephrine as a treatment for out-of-hospital cardiac arrest led the International Liaison Committee on Resuscitation to call for a placebo-controlled trial to determine whether the use of epinephrine is safe and effective in such patients. METHODS: In a randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest in the United Kingdom, paramedics at five National Health Service ambulance services administered either parenteral epinephrine (4015 patients) or saline placebo (3999 patients), along with standard care. The primary outcome was the rate of survival at 30 days. Secondary outcomes included the rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale (which ranges from 0 [no symptoms] to 6 [death]). RESULTS: At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02). There was no evidence of a significant difference in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (87 of 4007 patients [2.2%] vs. 74 of 3994 patients [1.9%]; unadjusted odds ratio, 1.18; 95% CI, 0.86 to 1.61). At the time of hospital discharge, severe neurologic impairment (a score of 4 or 5 on the modified Rankin scale) had occurred in more of the survivors in the epinephrine group than in the placebo group (39 of 126 patients [31.0%] vs. 16 of 90 patients [17.8%]). CONCLUSIONS: In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group. (Funded by the U.K. National Institute for Health Research and others; Current Controlled Trials number, ISRCTN73485024 .).

Correlation between light levels and the development of deprivation myopia.

PURPOSE: In chicks, daily exposure to bright light (15,000 lux) retards the development of form-deprivation myopia (FDM) by roughly 60%. This study investigated whether higher light intensities increase the amount of protection against FDM, and whether protection and light intensity are correlated. Furthermore, we examined if exposure to bright light can prevent the progression of FDM or whether it affects only the onset of experimental myopia. METHODS: Experiment 1: Chicks wore translucent diffusers monocularly for a period of 7 days, with exposure to one of five light intensities (500, 10,000, 20,000, 30,000, and 40,000 lux, n = 12 per group). Experiment 2: Chickens wore translucent diffusers monocularly for 11 days and were split into three groups: (1) chicks reared under 500 lux, (2) chicks reared under 40,000 lux, and (3) chicks reared under 500 lux for the first 4 days and 40,000 lux for the remaining 7 days. RESULTS: A significant correlation was observed between log light intensity and the development of FDM, with a lesser myopic refraction (F (28, 330) = 60.86, P < 0.0001) and shorter axial length (F (4, 20) = 8.87, P < 0.0001) seen with increasing light intensities. The progression of FDM was halted in chicks that were switched from 500 to 40,000 lux. CONCLUSIONS: The level of protection from the development of FDM increases with increasing light intensity. Daily exposure to 40,000 lux almost completely prevents the onset of FDM and, once myopia is established, halts further progression.

Gene expression within the amacrine cell layer of chicks after myopic and hyperopic defocus.

PURPOSE. Ocular growth is regulated locally by signals produced in the retina. The highly heterogeneous nature of the retina may mask important changes in gene expression during global analysis. This study was conducted to investigate changes in gene expression specifically within the amacrine cell layer (ACL), the most likely generator of growth signals, during optical manipulation of ocular growth. METHOD. Chicks were monocularly treated with either -7-D (n = 6) or +7-D (n = 6) lenses for 24 hours. Untreated age-matched chicks served as control subjects (n = 6). Total RNA from the ACL was isolated from 10-mum-thick sections, obtained using laser capture microdissection. Labeled cRNA was prepared from three samples per condition and hybridized to chicken genome microarrays. Changes in gene expression were validated by using semiquantitative real-time RT-PCR. RESULTS. One hundred twenty-eight genes were differentially expressed in the ACL of the minus lens-treated eyes, whereas the plus lens-treated eyes displayed 58 changes 24 hours after treatment. Only 11 genes were differentially expressed under both experimental conditions, whereas the expression of only one gene (clone ChEST927g14) was modulated by the sign of defocus. Compared with previous studies in the field, the magnitude of changes observed in the present work were larger, with more than 30% of differentially expressed genes showing a twofold or greater modulation in expression. The results, obtained from independent validation by real-time RT-PCR technology, correlated highly with the original microarray data. The differential expression of four of eight genes was validated in plus lens-treated eyes, and eight of nine genes were independently validated in minus lens-treated eyes. CONCLUSIONS. The targeted investigation of the ACL enabled the identification of several novel genes that may form part of the growth regulatory pathways of the eye. Different retinal pathways may underlie the response of the eyes to plus and minus lens compensation, as there was limited overlap in the regulated genes observed within the ACL under both conditions.