Protocol for a systematic review and network meta-analysis of the management of new onset atrial fibrillation in critically unwell adult patients.

BACKGROUND: New onset atrial fibrillation is the most commonly encountered arrhythmia in critically unwell patients with a reported incidence of 4% to 29%. The occurrence of new onset atrial fibrillation may precipitate acute heart failure and lead to thromboembolic complications as well as being associated with increased in-hospital and in intensive care unit (ICU) mortality. Despite being common, much of our current knowledge regarding the treatment of new onset atrial fibrillation comes from patients with chronic atrial fibrillation or post cardiac surgery. It is unclear if management strategies in these patient cohorts can be applied to new onset atrial fibrillation in the general ICU. This protocol for a systematic review and network meta-analysis aims to address this uncertainty and define what is the most effective management strategy for the treatment of new onset atrial fibrillation (NOAF) in acutely unwell adult patients. METHODS: In this systematic review and network meta-analysis, we plan to search electronic databases (Cochrane Central Register of Controlled Trials [CENTRAL], MEDLINE, EMBASE, Science Citation Index Expanded on Web of Science and relevant trial registries) for relevant randomised and non-randomised trials. Citations will be reviewed by title, abstract and full text by two independent reviewers and disagreement resolved by discussion and a third independent reviewer, if necessary. The Cochrane Risk of Bias tool will be used to assess risk of bias in randomised trials and the Risk of Bias in Nonrandomised Studies of Interventions (ROBINS-I) tool will be used for non-randomised studies. Statistical analysis will be carried out using R package meta and netmeta. We will first conduct a pairwise meta-analysis. If conditions for indirect comparison are satisfied and suitable data are available, we will conduct network meta-analysis using frequentist methodology. Treatments will be ranked according to efficacy with associated P-scores. We will assess the quality of the evidence in the pairwise using GRADE methodology and network meta-analysis comparisons in the CINeMA module in R package meta. DISCUSSION: Our review will be the first to assess direct and indirect evidence to assess the efficacy and rank the treatments available for new onset atrial fibrillation in critically unwell patients. Our review findings will be applicable to the care of people in a range of acute settings including, ICU, the emergency department and acute medical units. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number: CRD42019121739.

Major sources of critical incidents in intensive care.

INTRODUCTION: In recent years, critical incident (CI) reporting has increasingly been regarded as part of ongoing quality management. CI databanks also aim to improve health and safety issues for patients as well as staff. The aim of this study was to identify frequent causes of adverse events in critical care with the potential to harm patients, staff or visitors by analysing data from a voluntary and optionally anonymous critical incident reporting system. METHODS: The study includes all critical incidents reported during a 90-month period in a 13-bed adult general intensive care unit (ICU). Reporting of incidents was performed via an electronic reporting system or by a manual critical incident report. All CIs were classified in the following main categories: equipment, administration, pharmaceuticals, clinical practice, and health & safety hazards. The overall distribution of incidents within the different categories was compared with the regional database of ICUs in the Cheshire and Mersey region of northwest England for 2008. RESULTS: A total of 1127 CIs were reported during the study period. The frequencies within the main categories were: equipment 338 (30%), clinical practice 257 (22.8%), pharmaceuticals 238 (21.1%), administration 213 (18.9%), health and safety hazards 81 (7.2%). The regional database had a similar frequency of critical incidents within the different categories, suggesting that our results may reflect a general distribution pattern of CIs in intensive care. CONCLUSIONS: Critical incident reporting helps to identify frequent causes of adverse events in critical care. Improvements in quality of care following implementation of preventative strategies such as introduction of regular equipment training sessions will have to be assessed further in future studies.

Hemodynamic effects of dobutamine and dopexamine after cardiopulmonary bypass in pediatric cardiac surgery.

BACKGROUND: After surgical repair of congenital heart disease, inotropic support is sometimes necessary to wean from cardiopulmonary bypass. In pediatric cardiac surgery, dobutamine and dopamine are often used as inotropic support. Dopexamine is a synthetic catecholamine, which has positive inotropic and vasodilating properties. Because the hemodynamic effects of catecholamines are modified after cardiopulmonary bypass, the aim of this study was to investigate the effects of dobutamine and dopexamine on cardiac index and systemic vascular resistance index after cardiopulmonary bypass in pediatric cardiac surgery. METHODS: The study was performed in a prospective, randomized, and double-blinded cross-over design. The investigation included 11 children for elective, noncomplex congenital heart surgery. After weaning from cardiopulmonary bypass and a 20-min period of steady state, children received either 2.5 microg x kg(-1) x min(-1) dobutamine or 1 microg x kg(-1) x min(-1) dopexamine for 20 min. Cardiac index (transpulmonary thermodilution), mean arterial pressure, central venous pressure, stroke volume, systemic vascular resistance, and central venous oxygen saturation were determined. The primary outcome variable was cardiac index. RESULTS: No difference in cardiac index was observed between the two groups (P = 0.594). Both drugs increased cardiac index, dopexamine from 3.9 +/- 0.6 to 4.7 +/- 0.8 l x min(-1) x m(-2) (P = 0.003) and dobutamine from 4.1 +/- 0.7 to 4.8 +/- 0.7 l x min(-1) x m(-2) (P = 0.004). During treatment with dobutamine, children presented with significantly higher mean arterial pressure (P = 0.003) and systemic vascular resistance index (P = 0.026). CONCLUSIONS: This trial demonstrates that low-dose dobutamine and dopexamine both increase cardiac index during pediatric cardiac surgery but with different hemodynamic effects.

Performance and customization of 4 prognostic models for postoperative onset of nausea and vomiting in ear, nose, and throat surgery.

OBJECTIVE: To evaluate the performance of 4 published prognostic models for postoperative onset of nausea and vomiting (PONV) by means of discrimination and calibration and the possible impact of customization on these models. DESIGN: Prospective, observational study. SETTING: Tertiary care university hospital. PATIENTS: 748 adult patients (>18 years old) enrolled in this study. Severe obesity (weight > 150 kg or body mass index > 40 kg/m) was an exclusion criterion. INTERVENTIONS: All perioperative data were recorded with an anesthesia information management system. A standardized patient interview was performed on the postoperative morning and afternoon. MEASUREMENTS: Individual PONV risk was calculated using 4 original regression equations by Koivuranta et al, Apfel et al, Sinclair et al, and Junger et al Discrimination was assessed using receiver operating characteristic (ROC) curves. Calibration was tested using Hosmer-Lemeshow goodness-of-fit statistics. New predictive equations for the 4 models were derived by means of logistic regression (customization). The prognostic performance of the customized models was validated using the "leaving-one-out" technique. MAIN RESULTS: Postoperative onset of nausea and vomiting was observed in 11.2% of the specialized patient population. Discrimination could be demonstrated as shown by areas under the receiver operating characteristic curve of 0.62 for the Koivuranta et al model, 0.63 for the Apfel et al model, 0.70 for the Sinclair et al model, and 0.70 for the Junger et al model. Calibration was poor for all 4 original models, indicated by a P value lower than 0.01 in the C and H statistics. Customization improved the accuracy of the prediction for all 4 models. However, the simplified risk scores of the Koivuranta et al model and the Apfel et al model did not show the same efficiency as those of the Sinclair et al model and the Junger et al model. This is possibly a result of having relatively few patients at high risk for PONV in combination with an information loss caused by too few dichotomous variables in the simplified scores. CONCLUSIONS: The original models were not well validated in our study. An antiemetic therapy based on the results of these scores seems therefore unsatisfactory. Customization improved the accuracy of the prediction in our specialized patient population, more so for the Sinclair et al model and the Junger et al model than for the Koivuranta et al model and the Apfel et al model.

Identification of morphine-6-glucuronide in chromaffin cell secretory granules.

We report for the first time that morphine-6-glucuronide, a highly analgesic morphine-derived molecule, is present in adrenal chromaffin granules and secreted from chromaffin cells upon stimulation. We also demonstrate that phosphatidylethanolamine-binding protein (alternatively named Raf-1 kinase inhibitor protein or RKIP) acts as an endogenous morphine-6-glucuronide-binding protein. An UDP-glucuronosyltransferase 2B-like enzyme, described to transform morphine into morphine-6-glucuronide, has been immunodetected in the chromaffin granule matrix, and morphine-6-glucuronide de novo synthesis has been characterized, demonstrating the possible involvement of intragranular UDP-glucuronosyltransferase 2B-like enzyme in morphine-6-glucuronide metabolism. Once secreted into the circulation, morphine-6-glucuronide may mediate several systemic actions (e.g. on immune cells) based on its affinity for mu-opioid receptors. These activities could be facilitated by phosphatidylethanolamine-binding protein (PEBP), acting as a molecular shield and preventing morphine-6-glucuronide from rapid clearance. Taken together, our data represent an important observation on the role of morphine-6-glucuronide as a new endocrine factor.

The hippocampal cholinergic neurostimulating peptide, the N-terminal fragment of the secreted phosphatidylethanolamine-binding protein, possesses a new biological activity on cardiac physiology.

Phosphatidylethanolamine-binding protein (PEBP), alternatively named Raf-1 kinase inhibitor protein, is the precursor of the hippocampal cholinergic neurostimulating peptide (HCNP) corresponding to its natural N-terminal fragment, previously described to be released by hippocampal neurons. PEBP is a soluble cytoplasmic protein, also associated with plasma and reticulum membranes of numerous cell types. In the present report, using biochemistry and cell biology techniques, we report for the first time the presence of PEBP in bovine chromaffin cell, a well described secretion model. We have examined its presence at the subcellular level and characterized this protein on both secretory granule membranes and intragranular matrix. In addition, its presence in bovine chromaffin cell and platelet exocytotic medium, as well as in serum, was reported showing that it is secreted. Like many other proteins that lack signal sequence, PEBP may be secreted through non-classic signal secretory mechanisms, which could be due to interactions with granule membrane lipids and lipid rafts. By two-dimensional liquid chromatography-tandem mass spectrometry, HCNP was detected among the intragranular matrix components. The observation that PEBP and HCNP were secreted with catecholamines into the circulation prompted us to investigate endocrine effects of this peptide on cardiovascular system. By using as bioassay an isolated and perfused frog (Rana esculenta) heart preparation, we show here that HCNP acts on the cardiac mechanical performance exerting a negative inotropism and counteracting the adrenergic stimulation of isoproterenol. All together, these data suggest that PEBP and HCNP might be considered as new endocrine factors involved in cardiac physiology.