Successful use of extracorporeal life support and hemadsorption in the context of venlafaxine intoxication requiring cardiopulmonary resuscitation: a case report.

Venlafaxine is a serotonin and noradrenalin reuptake inhibitor prescribed as an antidepressant. Overdose clinically manifests with neurological, cardiovascular and gastrointestinal abnormalities based on, amongst others, serotonin syndrome and can be life-threatening due to cardiovascular collapse. Besides immediate decontamination via gastric lavage and inhibition of enteral absorption through active charcoal, successful hemadsorption with CytoSorb® has been reported. We present the case of a 17-year-old female who required extracorporeal life support (ECLS) for cardiovascular collapse as a result of life-threatening venlafaxine intoxication. Serial serum blood concentrations of venlafaxine/desmethylvenlafaxine on admission at a tertiary hospital (approx. 24 h after ingestion) and subsequently 6 h and 18 h thereafter, as well as on days 2 and 4, were measured. CytoSorb® was initiated 6 h after admission and changed three times over 72 h. The initial blood concentration of venlafaxine/desmethylvenlafaxine was 53.52 µmol/l. After 6 h, it declined to 30.7 µmol/l and CytoSorb® was initiated at this point. After 12 h of hemadsorption, the blood level decreased to 9.6 µmol/l. On day 2, it was down to 7.17 µmol/l and decreased further to 3.74 µmol/l. Additional continuous renal replacement therapy using CVVHD was implemented on day 5. The combination of hemadsorption, besides traditional decontamination strategies along maximal organ supportive therapy with ECLS, resulted in the intact neurological survival of the highest venlafaxine intoxication reported in the literature to date. Hemadsorption with CytoSorb® might help to reduce blood serum levels of venlafaxine. Swift clearance of toxic blood levels may support cardiovascular recovery after life-threatening intoxications.

Anomalous Origin of Left Circumflex Coronary Artery From Right Pulmonary Artery: An Unusual Cause of Sudden Cardiac Arrest.

Anomalous origin of the left circumflex coronary artery from the right pulmonary artery is an extremely rare coronary anomaly out of the group of anomalous coronary arteries arising from the pulmonary artery. We present the case of a 27-year-old male, in whom the diagnosis of an anomalous left circumflex coronary artery from the pulmonary artery was made after sudden cardiac arrest. The diagnosis was confirmed by multimodal imaging and the patient underwent successful surgical correction. Abnormal origins of a coronary artery may become symptomatic later in life and may occur as an isolated cardiac malformation. Due to a potentially unfavorable clinical course, surgical correction should be considered as soon as a diagnosis is made.

Independent External Validation of a Preoperative Prediction Model for Delirium After Cardiac Surgery: A Prospective Observational Cohort Study.

OBJECTIVE: This investigation provided independent external validation of an existing preoperative risk prediction model. DESIGN: A prospective observational cohort study of patients undergoing cardiac surgery covering the period between April 16, 2018 and January 18, 2022. SETTING: Two academic hospitals in Switzerland. PARTICIPANTS: Adult patients (≥60 years of age) who underwent elective cardiac surgery, including coronary artery bypass graft, mitral or aortic valve replacement or repair, and combined procedures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was the incidence of postoperative delirium (POD) in the intensive or intermediate care unit, diagnosed using the Intensive Care Delirium Screening Checklist. The prediction model contained 4 preoperative risk factors to which the following points were assigned: Mini-Mental State Examination (MMSE) score ≤23 received 2 points; MMSE 24-27, Geriatric Depression Scale (GDS) >4, prior stroke and/or transient ischemic attack (TIA), and abnormal serum albumin (≤3.5 or ≥4.5 g/dL) received 1 point each. The missing data were handled using multiple imputation. In total, 348 patients were included in the study. Sixty patients (17.4%) developed POD. For point levels in the prediction model of 0, 1, 2, and ≥3, the cumulative incidence of POD was 12.6%, 22.8%, 25.8%, and 35%, respectively. The validation resulted in a pooled area under the receiver operating characteristics curve of 0.60 (median CI, 0.525-0.679). CONCLUSIONS: The evaluated predictive model for delirium after cardiac surgery in this patient cohort showed only poor discriminative capacity but fair calibration.

MitraClip® procedure as bridge to left ventricular assist device: Enable extracorporeal membrane oxygenation weaning and reduce perioperative risk.

Secondary mitral valve regurgitation is a frequent consequence of left ventricular dysfunction in patients with severe heart failure. The management of this disease can be challenging since it often culminates in refractory pulmonary edema and multi-organ failure. We present the case of a 50-year-old male who was admitted in cardiogenic shock following myocardial infarction. After successful revascularization, percutaneous mitral valve repair using the MitraClip® device enabled weaning from extracorporeal membrane oxygenation followed by the implantation of a left ventricular assist device as bridge to transplant.

Wingless-related integration site (WNT) signaling is activated during the inflammatory response upon cardiac surgery: A translational study.

Objective: Cardiac surgery and the use of cardiopulmonary bypass initiate a systemic inflammatory response. Wingless-related integration site (WNT) signaling is part of the innate immunity and has been attributed a major role in the regulation of inflammation. In preclinical research, WNT-5a may sustain an inflammatory response and cause endothelial dysfunction. Our aim was to investigate WNT signaling after cardiac surgery and its association with postoperative inflammation (Clinicaltrials.gov, NCT04058496). Methods: In this prospective, single-center, observational study, 64 consecutive patients for coronary artery bypass grafting (CABG) ± valve surgery were assigned into three groups: off-pump CABG (n = 28), on-pump CABG (n = 16) and combined valve-CABG surgery (n = 20). Blood samples were acquired before surgery, at intensive care unit (ICU) admission and 4, 8, and 48 h thereafter. Plasma concentrations of WNT-5a and its antagonists Secreted frizzled-related protein 1 (sFRP-1), Secreted frizzled-related protein 5 (sFRP-5), and WNT inhibitory factor 1 (WIF-1) were determined by enzyme-linked immunosorbent assay. In addition, plasma concentrations of six inflammatory cytokines were measured by multiplex immunoassay. Parameters were analyzed for evolution of plasma concentration over time, interactions, intergroup differences, and association with clinical outcome parameters. Results: At baseline, WNT-5a, sFRP-1, and WIF-1 were present in a minimal concentration, while sFRP-5 was elevated. A higher baseline value of WNT-5a, sFRP-5, and WIF-1 resulted in higher subsequent values of the respective parameter. At ICU admission, WNT-5a and sFRP-5 reached their maximum and minimum value, respectively. WIF-1 decreased over time and was lowest 8 h after surgery. sFRP-1 changed minimally over time. While WNT-5a returned to the baseline within 48 h, sFRP-5 and WIF-1 did not reach their baseline value at 48 h. Of the investigated WNT system components, only WIF-1 partially reflected the severity of surgery. WNT-5a and WIF-1 had an impact on postoperative fluid balance and noradrenaline requirement. Conclusion: WNT-5a, sFRP-5, and WIF-1 are part of the systemic inflammatory response after cardiac surgery. WNT-5a peaks immediately after cardiac surgery and returns to baseline within 48 h, presumably modulated by its antagonist sFRP-5. Based on this translational study, WNT-5a antagonism may be further investigated to assess potentially beneficial effects in patients with a dysregulated inflammation after cardiac surgery.

Acute on Chronic Thromboembolic Pulmonary Hypertension: Case Series and Review of Management.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct form of precapillary pulmonary hypertension classified as group 4 by the World Symposium on Pulmonary Hypertension (WSPH) and should be excluded during an episode of acute pulmonary embolism (PE). Patients presenting to emergency departments with sudden onset of signs and symptoms of acute PE may already have a pre-existing CTEPH condition decompensated by the new PE episode. Identifying an underlying and undiagnosed CTEPH during acute PE, while challenging, is an important consideration as it will alter the patients' acute and long-term management. Differential diagnosis and evaluation require an interdisciplinary expert team. Analysis of the clinical condition, the CT angiogram, and the hemodynamic situation are important considerations; patients with CTEPH usually have significantly higher sPAP at the time of index PE, which is unusual and unattainable in the context of acute PE and a naïve right ventricle. The imaging may reveal signs of chronic disease such as right ventricle hypertrophy bronchial collaterals and atypical morphology of the thrombus. There is no standard for the management of acute on chronic CTEPH. Herein, we provide a diagnostic and management algorithm informed by several case descriptions and a review of the literature.

European association of cardiothoracic anesthesiology and intensive care (EACTAIC) fellowship curriculum: second edition

Abstract Pediatric cardiac anesthesia is a subspecialty of cardiac and pediatric anesthesiology dedicated to the perioperative care of patients with congenital heart disease. Members of the Congenital and Education Subcommittees of the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) agreed on the necessity to develop an EACTAIC pediatric cardiac anesthesia fellowship curriculum. This manuscript represents a consensus on the composition and the design of the EACTAIC Pediatric Cardiac Anesthesia Fellowship program. This curriculum provides a basis for the training of future pediatric cardiac anesthesiologists by clearly defining the theoretical and practical requirements for fellows and host centers.

Prior intake of new oral anticoagulants adversely affects outcome following surgery for acute type A aortic dissection.

OBJECTIVES: Oral anticoagulation prior to emergency surgery is associated with an increased risk of perioperative bleeding, especially when this therapy cannot be discontinued or reversed in time. The goal of this study was to analyse the impact of different oral anticoagulants on the outcome of patients who underwent emergency surgery for acute type A aortic dissection (ATAAD). METHODS: This was a single-centre retrospective study of patients treated with oral anticoagulation at the time of surgery for ATAAD. Outcomes of patients on new oral anticoagulant (NOAC) therapy were compared to respective outcomes of patients on Coumadin. Additionally, a survival analysis was performed comparing these 2 groups with patients who were operated on with no prior anticoagulation. RESULTS: Between January 2013 and April 2020, a total of 437 patients (63.8 ± 11.8 years, 68.4% male) received emergency surgery for ATAAD; 35 (8%) were taking oral anticoagulation at the time of hospital admission: 20 received phenprocoumon; 14, rivaroxaban; and 1, dabigatran. Compared to Coumadin, NOAC was associated with a greater need for blood-product transfusions and haemodynamic compromise. Operative mortality was 53% in the NOAC group and 30% in the Coumadin group. A 5-year survival analysis showed no significant difference between the NOAC and the Coumadin group (P = 0.059). Compared to 402 patients treated during the study period without anticoagulation, patients taking NOAC had significantly worse survival (P = 0.001), whereas that effect was not observed in patients undergoing surgery who were taking Coumadin (P = 0.99). CONCLUSIONS: Emergency surgery for ATAAD in patients taking NOAC is associated with high morbidity and mortality. NOAC are a major risk factor for uncontrollable bleeding and haemodynamic compromise. New treatment strategies must be defined to improve surgical outcomes in these high-risk patients.

European association of cardiothoracic anesthesiology and intensive care pediatric cardiac anesthesia fellowship curriculum: first edition

ABSTRACT: Pediatric cardiac anesthesia is a subspecialty of cardiac and pediatric anesthesiology dedicated to the perioperative care of patients with congenital heart disease. Members of the Congenital and Education Subcommittees of the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) agreed on the necessity to develop an EACTAIC pediatric cardiac anesthesia fellowship curriculum. This manuscript represents a consensus on the composition and the design of the EACTAIC Pediatric Cardiac Anesthesia Fellowship program. This curriculum provides a basis for the training of future pediatric cardiac anesthesiologists by clearly defining the theoretical and practical requirements for fellows and host centers.

European Association of Cardiothoracic Anesthesiology and Intensive Care Pediatric Cardiac Anesthesia Fellowship Curriculum: First Edition.

Pediatric cardiac anesthesia is a subspecialty of cardiac and pediatric anesthesiology dedicated to the perioperative care of patients with congenital heart disease. Members of the Congenital and Education Subcommittees of the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) agreed on the necessity to develop an EACTAIC pediatric cardiac anesthesia fellowship curriculum. This manuscript represents a consensus on the composition and the design of the EACTAIC Pediatric Cardiac Anesthesia Fellowship program. This curriculum provides a basis for the training of future pediatric cardiac anesthesiologists by clearly defining the theoretical and practical requirements for fellows and host centers.

Complex Multi-Stage Total Aortic and Subclavian Artery Replacement in a 9-year old boy with Loeys-Dietz-Syndrome.

BACKGROUND: Loeys-Dietz Syndrome is a rare connective tissue disorder that is associated with arterial pathologies such as aortic dissections, tortuosity and aneurysms.We present a child with Loeys-Dietz Syndrome type 2 that received total aortic and bilateral subclavian artery replacement. CASE REPORT: A 9-year old boy with Loeys-Dietz Syndrome type 2 and acute type B aortic dissection received an urgent complete thoracic and thoraco-abdominal aortic repair within three days. First, the ascending aorta and aortic root were replaced in a Tirone David and Frozen Elephant Trunk procedure. Then, the descending and supramesenteric aorta was replaced by a Dacron interposition graft with direct implantation of the celiac trunk. During the 15 months follow-up, the patient required three more surgical interventions for rapid expanding aneurysms of both subclavian arteries and the infrarenal aorta. No major adverse event nor secondary interventions occurred. Ultrasonographic and magnetic resonance imaging follow-up is continued at 6-months intervals. CONCLUSION: Children with Loeys-Dietz Syndrome may require extensive aortic repair for aortic dissection and show rapidly expanding aneurysms. Referral to a center with pediatric vascular expertise and long-term follow-up examinations are crucial.

Outcome, demography and resource utilization in ICU Patients with delirium and malignancy.

Delirium in the general intensive care unit (ICU) population is common, associated with adverse outcomes and well studied. However, knowledge on delirium in the increasing number of ICU patients with malignancy is scarce. The aim was to assess the frequency of delirium and its impact on resource utilizations and outcomes in ICU patients with malignancy. This retrospective, single-center longitudinal cohort study included all patients with malignancy admitted to ICUs of a University Hospital during one year. Delirium was diagnosed by an Intensive Care Delirium Screening Checklist (ICDSC) score ≥ 4. Of 488 ICU patients with malignancy, 176/488 (36%) developed delirium. Delirious patients were older (66 [55-72] vs. 61 [51-69] years, p = 0.001), had higher SAPS II (41 [27-68] vs. 24 [17-32], p < 0.001) and more frequently sepsis (26/176 [15%] vs. 6/312 [1.9%], p < 0.001) and/or shock (30/176 [6.1%] vs. 6/312 [1.9%], p < 0.001). In multivariate analysis, delirium was independently associated with lower discharge home (OR [95% CI] 0.37 [0.24-0.57], p < 0.001), longer ICU (HR [95% CI] 0.30 [0.23-0.37], p < 0.001) and hospital length of stay (HR [95% CI] 0.62 [0.50-0.77], p < 0.001), longer mechanical ventilation (HR [95% CI] 0.40 [0.28-0.57], p < 0.001), higher ICU nursing workload (B [95% CI] 1.92 [1.67-2.21], p < 0.001) and ICU (B [95% CI] 2.08 [1.81-2.38], p < 0.001) and total costs (B [95% CI] 1.44 [1.30-1.60], p < 0.001). However, delirium was not independently associated with in-hospital mortality (OR [95% CI] 2.26 [0.93-5.54], p = 0.074). In conclusion, delirium was a frequent complication in ICU patients with malignancy independently associated with high resource utilizations, however, it was not independently associated with in-hospital mortality.

An update on levosimendan in acute cardiac care: applications and recommendations for optimal efficacy and safety.

Introduction: In the 20 years since its introduction to the palette of intravenous hemodynamic therapies, the inodilator levosimendan has established itself as a valuable asset for the management of acute decompensated heart failure. Its pharmacology is notable for delivering inotropy via calcium sensitization without an increase in myocardial oxygen consumption.Areas covered: Experience with levosimendan has led to its applications expanding into perioperative hemodynamic support and various critical care settings, as well as an array of situations associated with acutely decompensated heart failure, such as right ventricular failure, cardiogenic shock with multi-organ dysfunction, and cardio-renal syndrome. Evidence suggests that levosimendan may be preferable to milrinone for patients in cardiogenic shock after cardiac surgery or for weaning from extracorporeal life support and may be superior to dobutamine in terms of short-term survival, especially in patients on beta-blockers. Positive effects on kidney function have been noted, further differentiating levosimendan from catecholamines and phosphodiesterase inhibitors.Expert opinion:Levosimendan can be a valuable resource in the treatment of acute cardiac dysfunction, especially in the presence of beta-blockers or ischemic cardiomyopathy. When attention is given to avoiding or correcting hypovolemia and hypokalemia, an early use of the drug in the treatment algorithm is preferred.

Extracorporeal life support as bridge to recovery in yew poisoning: case reports and literature review.

AIMS: This short communication aims to review the treatment of cardiogenic shock in patients with yew poisoning based on two case reports from our institution, focusing on the use of extracorporeal life support (ECLS). METHODS AND RESULTS: We report two cases of Taxus baccata poisoning treated with ECLS at our institution and review the literature based on a search in PubMed and Google Scholar on the topic of yew poisoning and ECLS. All cases were combined for analysis of demographics, ECLS therapy, and outcome. Case 1: A 35-year-old woman developed polymorphic ventricular tachycardia followed by cardiovascular arrest 5 h after orally ingesting a handful of yew needles. Successful resuscitation required ECLS for 72 h due to ongoing cardiac arrhythmias and cardiogenic shock. The patient left the hospital without neurological sequelae after 10 days. Case 2: A 30-year-old woman developed refractory cardiac arrhythmias and circulatory arrest. Resuscitation included ECLS for 71 h. T. baccata needles found by gastroscopy confirmed the diagnosis. The patient had no neurologic deficits and was transferred to psychiatry after 11 days. REVIEW OF THE LITERATURE: Nine case reports were found and analysed along with our two cases. Five out of the 11 (45%) patients were female. Median (range) age was 28 (19-46) years. T. baccata needles were ingested with a suicidal intention in all patients. Median (range) duration of ECLS was 70 h (24-120 h). Eight (73%) patients had full neurological recovery. CONCLUSIONS: Yew poisoning is a differential diagnosis in young psychiatric patients presenting with polymorphic ventricular tachycardia and cardiogenic shock. A characteristic cardiac contraction pattern in echocardiography may present a diagnostic clue. The early use of ECLS is a valuable bridge to recovery in most of these patients.

Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

Cardiovascular Safety of Clonidine and Dexmedetomidine in Critically Ill Patients after Cardiac Surgery.

PURPOSE: The aim of this retrospective study was to assess the haemodynamic adverse effects of clonidine and dexmedetomidine in critically ill patients after cardiac surgery. METHODS: 2769 patients were screened during the 30-month study period. Heart rate (HR), mean arterial pressure (MAP), and norepinephrine requirements were assessed 3-hourly during the first 12 hours of the continuous drug infusion. Results are given as median (interquartile range) or numbers (percentages). RESULTS: Patients receiving clonidine (n = 193) were younger (66 (57-73) vs 70 (63-77) years, p=0.003) and had a lower SAPS II (35 (27-48) vs 41 (31-54), p=0.008) compared with patients receiving dexmedetomidine (n = 141). At the start of the drug infusion, HR (90 (75-100) vs 90 (80-105) bpm, p=0.028), MAP (70 (65-80) vs 70 (65-75) mmHg, p=0.093), and norepinephrine (0.05 (0.00-0.11) vs 0.12 (0.03-0.19) mcg/kg/min, p < 0.001) were recorded in patients with clonidine and dexmedetomidine. Bradycardia (HR < 60 bpm) developed in 7.8% with clonidine and 5.7% with dexmedetomidine (p=0.51). Between baseline and 12 hours, norepinephrine remained stable in the clonidine group (0.00 (-0.04-0.02) mcg/kg/min) and decreased in the dexmedetomidine group (-0.03 (-0.10-0.02) mcg/kg/min, p=0.007). CONCLUSIONS: Dexmedetomidine and the low-cost drug clonidine can both be used safely in selected patients after cardiac surgery.

QTc prolongation after haloperidol administration in critically ill patients post cardiovascular surgery: A cohort study and review of the literature.

OBJECTIVE: From case reports, haloperidol administration has been associated with QTc prolongation, torsades de pointes, and sudden cardiac death. In a vulnerable population of critically ill patients after cardiac surgery, however, it is unclear whether haloperidol administration affects the QTc interval. Thus, the aim of this study is to explore the effect of haloperidol in low doses on this interval. METHOD: This retrospective cohort study was performed on a cardio-surgical intensive care unit (ICU), screened 2,216 patients and eventually included 68 patients with delirium managed with oral and intravenous haloperidol. In this retrospective analysis, electrocardiograms were taken prior and within 24 h after haloperidol administration. The effect of haloperidol on QTc was determined with a Person correlation, and inter-group differences were measured with new long QT comparisons. RESULTS: In total, 68 patients were included, the median age was 71 (64-79) years and predominantly male (77%). Haloperidol administration followed ICU admission by three days and the cumulative dose was 4 (2-9) mg. As a result, haloperidol administration did not affect the QTc (r = 0.144, p = 0.23). In total, 31% (21/68 patients) had a long QT before and 27.9% (19/68 patients) after haloperidol administration. Only 12% (8/68 patients) developed a newly onset long QT. These patients were not different in the route of administration, cumulative haloperidol doses, comorbidities, laboratory findings, or medications. SIGNIFICANCE OF RESULTS: These results indicated that low-dose intravenous haloperidol was safe and not clinically relevant for the development of a newly onset long QT syndrome or adverse outcomes and support recent findings inside and outside the ICU setting.