Goal directed therapy: how long can we wait?

Intensive monitoring and aggressive management of perioperative haemodynamics (goal directed therapy) have repeatedly been reported to reduce the significant morbidity and mortality associated with high risk surgery. It may not matter what particular monitor is used to assess cardiac output but it is essential to ensure adequate oxygen delivery. If this management cannot begin preoperatively, it is still worth beginning goal directed therapy in the immediate postoperative period

Protocol for a randomised control trial of methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients (MOTION)

Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood-brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid-induced constipation and gastrointestinal dysmotility.This is a single-centre, multisite, double-blind, randomised, placebo-controlled trial. 84 patients will be recruited from 4 intensive care units (ICUs) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects.The trial protocol, the patient/legal representative information sheets and consent forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. On completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.2014-004687-37; Pre-results

Thoracic Epidural analgesia versus Rectus Sheath Catheters for open midline incisions in major abdominal surgery within an enhanced recovery programme (TERSC):study protocol for a randomised controlled trial

BACKGROUND: Thoracic epidural analgesia (TEA) is recommended for post-operative pain relief in patients undergoing major abdominal surgery via a midline incision. However, the effectiveness of TEA is variable with high failure rates reported post-operatively. Common side effects such as low blood pressure and motor block can reduce mobility and hinder recovery, and a number of rare but serious complications can also occur following their use.Rectus sheath catheters (RSC) may provide a novel alternative approach to somatic analgesia without the associated adverse effects of TEA. The aim of this study is to compare the efficacy of both techniques in terms of pain relief, patient experience, post-operative functional recovery, safety and cost-effectiveness. METHODS/DESIGN: This is a single-centre randomised controlled non-blinded trial, which also includes a nested qualitative study. Over a two-year period, 132 patients undergoing major abdominal surgery via a midline incision will be randomised to receive either TEA or RSC for post-operative analgesia. The primary outcome measures pain scores on moving from a supine to a sitting position at 24 hours post wound closure, and the patient experience between groups evaluated through in-depth interviews. Secondary outcomes include pain scores at rest and on movement at other time points, opiate consumption, functional recovery, morbidity and cost-effectiveness. DISCUSSION: This will be the first randomised controlled trial comparing thoracic epidurals to ultrasound-guided rectus sheath catheters in adults undergoing elective midline laparotomy. The standardised care provided by an Enhanced Recovery Programme makes this a comparison between two complex pain packages and not simply two analgesic techniques, in order to ascertain if RSC is a viable alternative to TEA. TRIAL REGISTRATION: Current Controlled Trials ISRCTN81223298 (16 January 2014)

Are large randomised controlled trials in severe sepsis and septic shock statistically disadvantaged by repeated inadvertent underestimates of required sample size?

OBJECTIVES: We sought to understand why randomised controlled trials in septic shock have failed to demonstrate effectiveness in the face of improving overall outcomes for patients and seemingly promising results of early phase trials of interventions. DESIGN: We performed a retrospective analysis of large critical care trials of severe sepsis and septic shock. Data were collected from the primary trial manuscripts, prepublished statistical plans or by direct communication with corresponding authors. SETTING: Critical care randomised control trials in severe sepsis and septic shock. PARTICIPANTS: 14 619 patients randomised in 13 trials published between 2005 and 2015, enrolling greater than 500 patients and powered to a primary outcome of mortality. INTERVENTION: Multiple interventions including the evaluation of treatment strategies and novel therapeutics. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary outcome measure was the difference between the anticipated and actual control arm mortality. Secondary analysis examined the actual effect size and the anticipated effect size employed in sample size calculation. RESULTS: In this post hoc analysis of 13 trials with 14 619 patients randomised, we highlight a global tendency to overestimate control arm mortality in estimating sample size (absolute difference 9.8%, 95% CI -14.7% to -5.0%, p<0.001). When we compared anticipated and actual effect size of a treatment, there was also a substantial overestimation in proposed values (absolute difference 7.4%, 95% CI -9.0% to -5.8%, p<0.0001). CONCLUSIONS: An interpretation of our results is that trials are consistently underpowered in the planning phase by employing erroneous variables to calculate a satisfactory sample size. Our analysis cannot establish if, given a larger sample size, a trial would have had a positive result. It is disappointing so many promising phase II results have not translated into durable phase III outcomes. It is possible that our current framework has biased us towards discounting potentially life-saving treatments

Ultrafast electronic energy transfer beyond the weak coupling limit in a proximal but orthogonal molecular dyad

Electronic energy transfer (EET) from a donor to an acceptor is an important mechanism that controls the light harvesting efficiency in a wide variety of systems, including artificial and natural photosynthesis and contemporary photovoltaic technologies. The detailed mechanism of BET at short distances or large angles between the donor and acceptor is poorly understood. Here the influence of the orientation between the donor and acceptor on EET is explored using a molecule with two nearly perpendicular chromophores. Very fast EET with a time constant of 120 fs is observed, which is at least 40 times faster than the time predicted by Coulombic coupling calculations. Depolarization of the emission signal indicates that the transition dipole rotates through ca. 64 degrees, indicating the near orthogonal nature of the EET event. The rate of EET is found to be similar to structural relaxation rates in the photoexcited oligothiophene donor alone, which suggests that this initial relaxation brings the dyad to a conical intersection where the excitation jumps to the acceptor.PostprintPeer reviewe

Mapping genes with longitudinal phenotypes via Bayesian posterior probabilities

Most association studies focus on disease risk, with less attention paid to disease progression or severity. These phenotypes require longitudinal data. This paper presents a new method for analyzing longitudinal data to map genes in both population-based and family-based studies. Using simulated systolic blood pressure measurements obtained from Genetic Analysis Workshop 18, we cluster the phenotype data into trajectory subgroups. We then use the Bayesian posterior probability of being in the high subgroup as a quantitative trait in an association analysis with genotype data. This method maintains high power (\u3e80%) in locating genes known to affect the simulated phenotype for most specified significance levels (a). We believe that this method can be useful to aid in the discovery of genes that affect severity or progression of disease

Svećenik Rudolf Mikec, mučenik za vjeru otaca : (jedno novigradsko sjećanje)

Background New-onset atrial fibrillation (AF) is the most common arrhythmia in critically ill patients. Although evidence base and expert consensus opinion for management have been summarised in several international guidelines, no specific considerations for critically ill patients have been included. We aimed to establish current practice of management of critically ill patients with new-onset AF. Methods We designed a short user-friendly online questionnaire. All members of the Intensive Care Society were invited via email containing a link to the questionnaire, which comprised 21 questions. The online survey was conducted between November 2016 and December 2016. Results The response rate was 397/3152 (12.6%). The majority of respondents (81.1%) worked in mixed Intensive Care Units and were consultants (71.8%). Most respondents (39.5%) would start intervention on patients with fast new-onset AF and stable blood pressure at a heart rate between 120 and 139 beats/min. However, 34.8% of participants would treat all patients who developed new-onset fast AF. Amiodarone and beta-blockers (80.9% and 11.6% of answers) were the most commonly used anti-arrhythmics. A total of 63.8% of respondents do not regularly anti-coagulate critically ill patients with new-onset fast AF, while 30.8% anti-coagulate within 72 hours. A total of 68.0% of survey respondents do not routinely use stroke risk scores in critically ill patients with new-onset AF. A total of 85.4% of participants would consider taking part in a clinical trial investigating treatment of new-onset fast AF in the critically ill. Discussion Our results suggest a considerable disparity between contemporary practice of management of new-onset AF in critical illness and treatment recommendations for the general patient population suffering from AF, particularly with regard to anti-arrhythmics and anti-coagulation used. Amongst intensivists, there is a substantial interest in research for management of new-onset AF in critically ill patients

(1+3) Covariant Dynamics of Scalar Perturbations in Braneworlds

We discuss the dynamics of linear, scalar perturbations in an almost Friedmann-Robertson-Walker braneworld cosmology of Randall-Sundrum type II using the 1+3 covariant approach. We derive a complete set of frame-independent equations for the total matter variables, and a partial set of equations for the non-local variables which arise from the projection of the Weyl tensor in the bulk. The latter equations are incomplete since there is no propagation equation for the non-local anisotropic stress. We supplement the equations for the total matter variables with equations for the independent constituents in a cold dark matter cosmology, and provide solutions in the high and low-energy radiation-dominated phase under the assumption that the non-local anisotropic stress vanishes. These solutions reveal the existence of new modes arising from the two additional non-local degrees of freedom. Our solutions should prove useful in setting up initial conditions for numerical codes aimed at exploring the effect of braneworld corrections on the cosmic microwave background (CMB) power spectrum. As a first step in this direction, we derive the covariant form of the line of sight solution for the CMB temperature anisotropies in braneworld cosmologies, and discuss possible mechanisms by which braneworld effects may remain in the low-energy universe.Comment: 22 pages replaced with additional references and minor corrections in Revtex4, and accepted for publication in Phys. Rev.