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.

Gastrointestinal dysfunction in the critically ill: a systematic scoping review and research agenda proposed by the Section of Metabolism, Endocrinology and Nutrition of the European Society of Intensive Care Medicine.

BACKGROUND: Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies. METHODS: This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds. RESULTS: Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness. CONCLUSIONS: Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.

Diarrhoea in the critically ill.

PURPOSE OF REVIEW: To summarize existing evidence on definition, epidemiology, mechanisms, risk factors, consequences, outcome and management of diarrhoea in the critically ill. RECENT FINDINGS: In health, diarrhoea is defined as the passage of three or more loose or liquid stools per day. In the critically ill, the diagnosis is yet to be formalized and reported prevalence of diarrhoea varies according to the definition used. Recent studies estimate the prevalence between 14 and 21% and describe risk factors for diarrhoea in critically ill patients. The precipitant of diarrhoea always needs to be identified, as targeted therapies are important for several causes. Although the majority of patients with diarrhoea require only supportive care, it is always essential to exclude, or confirm and treat infectious diarrhoea. There is little evidence to support delaying or withdrawing provision of enteral nutrition in patients with diarrhoea, and we recommend continuing enteral nutrition whenever possible. However, the consequences of diarrhoea - hypovolaemia, electrolyte disturbances, malnutrition, skin lesions and contamination of wounds - should be avoided or at least recognized promptly. SUMMARY: A definition of diarrhoea and a practical approach to identify the precipitant and to manage diarrhoea in critically ill patients are proposed.

Vitamin D status and its association with season, hospital and sepsis mortality in critical illness.

INTRODUCTION: Vitamin D plays a key role in immune function. Deficiency may aggravate the incidence and outcome of infectious complications in critically ill patients. We aimed to evaluate the prevalence of vitamin D deficiency and the correlation between serum 25-hydroxyvitamin D (25(OH) D) and hospital mortality, sepsis mortality and blood culture positivity. METHODS: In a single-center retrospective observational study at a tertiary care center in Graz, Austria, 655 surgical and nonsurgical critically ill patients with available 25(OH) D levels hospitalized between September 2008 and May 2010 were included. Cox regression analysis adjusted for age, gender, severity of illness, renal function and inflammatory status was performed. Vitamin D levels were categorized by month-specific tertiles (high, intermediate, low) to reflect seasonal variation of serum 25(OH) D levels. RESULTS: Overall, the majority of patients were vitamin D deficient (<20 ng/ml; 60.2%) or insufficient (≥20 and <30 ng/dl; 26.3%), with normal 25(OH) D levels (>30 ng/ml) present in only 13.6%. The prevalence of vitamin D deficiency and mean 25(OH) D levels was significantly different in winter compared to summer months (P <0.001). Hospital mortality was 20.6% (135 of 655 patients). Adjusted hospital mortality was significantly higher in patients in the low (hazard ratio (HR) 2.05, 95% confidence interval (CI) 1.31 to 3.22) and intermediate (HR 1.92, 95% CI 1.21 to 3.06) compared to the high tertile. Sepsis was identified as cause of death in 20 of 135 deceased patients (14.8%). There was no significant association between 25(OH) D and C-reactive protein (CRP), leukocyte count or procalcitonin levels. In a subgroup analysis (n = 244), blood culture positivity rates did not differ between tertiles (23.1% versus 28.2% versus 17.1%, P = 0.361). CONCLUSIONS: Low 25(OH) D status is significantly associated with mortality in the critically ill. Intervention studies are needed to investigate the effect of vitamin D substitution on mortality and sepsis rates in this population.

Serum 1,3-beta-d-glucan for antifungal treatment stratification at the intensive care unit and the influence of surgery.

The purpose of this study was to evaluate a preemptive approach with serum 1,3-beta-d-glucan (BDG) as a marker for treatment stratification of systemic antifungal (AF) therapy in patients with clinical suspected invasive fungal infections (IFI) at intensive care units (ICU), and the impact of surgical procedures. A total of 66 ICU patients with clinical suspected IFI were included in this retrospective analysis. Serum BDG testing was performed prior to initiation of AF treatment and in addition to routine diagnostic measures. Based on the BDG results the initial clinical decision whether or not to start systemic AF therapy was re-evaluated. Impact of surgical procedures on clinical utility of serum BDG was evaluated in a sub-group of 25 patients who had undergone surgical procedures prior to BDG evaluation. BDG test results led to discontinuation of AF therapy in 13 patients, and initiation of AF therapy in seven patients. In 46 patients the clinical decision was confirmed by BDG. The majority of suspected, probable and proven IFI cases (10/13, 77%) was predicted by the test. BDG testing turned out positive in 9/25 (36%) of patients that had undergone recent surgery and levels correlated with clinical findings. Serum BDG evaluation seems to be a promising tool to guide AF therapy in ICU patients even after recent surgical procedures.

[Comfort Terminal Care in the intensive care unit: recommendations for practice]. / Comfort Terminal Care auf der Intensivstation: Empfehlungen für die Praxis.

BACKGROUND AND OBJECTIVE: The Working Group on Ethics in Anesthesia and Intensive Care Medicine of the Austrian Society for Anesthesiology Resuscitation and Intensive Care Medicine (ÖGARI) already developed documentation tools for the adaption of therapeutic goals 10 years ago. Since then the practical implementation of Comfort Terminal Care in the daily routine in particular has raised numerous questions, which are discussed in this follow-up paper and answered in an evidence-based manner whenever possible. RESULTS: The practical implementation of pain therapy and reduction of anxiety, stress and respiratory distress that are indicated in the context of Comfort Terminal Care are described in more detail. The measures that are not (or no longer) indicated, such as oxygen administration and ventilation as well as the administration of fluids and nutrition, are also commented on. Furthermore, recommendations are given regarding monitoring, (laboratory) findings and drug treatment and the importance of nursing actions in the context of Comfort Terminal Care is mentioned. Finally, the support for the next of kin and the procedure in the time after death are presented. DISCUSSION: A change in treatment goals with a timely switch to Comfort Terminal Care enables good and humane care for seriously ill patients and their relatives at the end of life and the appreciation of their previous life with the possibility of positive experiences until the end.

Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies.

Voriconazole plasma concentrations (VPCs) vary widely, and concentrations outside the therapeutic range are associated with either worse outcome in invasive aspergillosis (IA) or increased toxicity. The primary goal of this cohort study conducted in a real-life setting was to identify potential factors associated with inadequate VPCs in ICU patients and patients with hematological malignancies. Within a period of 12 months, trough VPCs were obtained and analyzed with high-performance liquid chromatography, and the adequate range was defined as 1.5 to 5.5 mg/liter. VPCs of <1.5 mg/liter were defined as low, whereas VPCs of >5.5 mg/liter were defined as potentially toxic. A total of 221 trough VPCs were obtained in 61 patients receiving voriconazole, and 124/221 VPCs (56%) were found to be low. Multivariate analysis revealed that low VPCs were significantly associated with clinical failure of voriconazole, prophylactic use, younger age, underlying hematological malignancy, concomitant proton pump inhibitor (PPI) (pantoprazole was used in 88% of the patients), and absence of side effects. Low VPCs remained an independent predictor of clinical failure of voriconazole. The defined adequate range was reached in 79/221 (36%) VPCs. In 18 samples (8%), potentially toxic levels were measured. Multivariate analysis revealed higher body mass index (BMI), absence of hematological malignancy, therapeutic application, and diarrhea as factors associated with potentially toxic VPCs. Neurotoxic adverse events occurred in six patients and were mostly associated with VPCs in the upper quartile of our defined adequate range. In conclusion, potential factors like younger age, prophylaxis, underlying hematological malignancy, BMI, and concomitant PPI should be considered within the algorithm of voriconazole treatment.

Ventilator-associated pneumonia caused by OXA-48-producing Escherichia coli complicated by ciprofloxacin-associated rhabdomyolysis.

We report the emergence of OXA-48 carbapenemase-producing Escherichia coli in Austria causing ventilator-associated pneumonia in a traveler returning from Egypt. Depending on resistance testing, quinolones may remain a therapeutic option for infections caused by these multiple resistant pathogens, as this class of drugs has a favorable safety and tolerability profile when compared to the alternatives. In this patient, however, the clinical course was dramatically complicated by the development of ciprofloxacin-associated rhabdomyolysis.

[Definitions, decision-making and documentation in end of life situations in the intensive care unit]. / Therapiezieländerungen auf der Intensivstation - Definitionen, Entscheidungsfindung und Dokumentation.

The present work provides assistance for physicians concerning decision making in clinical borderline situations in the ICU. Based on a structured checklist the two fundamental aspects of any medical decision, the medical indication and the patient's preference are queried in a systematic way. Four possible steps of withholding and/or withdrawing therapy are discussed. Finally, recommendations regarding appropriate documentation of end of life decisions are provided.

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.

Hypophosphatemia in critically ill adults and children - A systematic review.

BACKGROUND & AIMS: Phosphate is the main intracellular anion essential for numerous biological processes. Symptoms of hypophosphatemia are non-specific, yet potentially life-threatening. This systematic review process was initiated to gain a global insight into hypophosphatemia, associated morbidity and treatments. METHODS: A systematic review was conducted (PROSPERO CRD42020163191). Nine clinically relevant questions were generated, seven for adult and two for pediatric critically ill patients, and prevalence of hypophosphatemia was assessed in both groups. We identified trials through systematic searches of Medline, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, and Web of Science. Quality assessment was performed using the Cochrane risk of bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. RESULTS: For all research questions, we identified 2727 titles in total, assessed 399 full texts, and retained 82 full texts for evidence synthesis, with 20 of them identified for several research questions. Only 3 randomized controlled trials were identified with two of them published only in abstract form, as well as 28 prospective and 31 retrospective studies, and 20 case reports. Relevant risk of bias regarding selection and comparability was identified for most of the studies. No meta-analysis could be performed. The prevalence of hypophosphatemia varied substantially in critically ill adults and children, but no study assessed consecutive admissions to intensive care. In both critically ill adults and children, several studies report that hypophosphatemia is associated with worse outcome (prolonged length of stay and the need for respiratory support, and higher mortality). However, there was insufficient evidence regarding the optimal threshold upon which hypophosphatemia becomes critical and requires treatment. We found no studies regarding the optimal frequency of phosphate measurements, and regarding the time window to correct hypophosphatemia. In adults, nutrient restriction on top of phosphate repletion in patients with refeeding syndrome may improve survival, although evidence is weak. CONCLUSIONS: Evidence on the definition, outcome and treatment of clinically relevant hypophosphatemia in critically ill adults and children is scarce and does not allow answering clinically relevant questions. High quality clinical research is crucial for the development of respective guidelines.

Effect of ICU interventions on gastrointestinal motility.

PURPOSE OF REVIEW: Early detection of gastrointestinal motility disturbances is a major goal to reduce the incidence of this potentially disastrous event by prophylactic managements and early goal-directed therapy in patients at risk. RECENT FINDINGS: Gastroparesis frequently results in the inability to feed critically ill patients, aggravating problems such as bacterial translocation and stress-induced intestinal damage. Recently published data have advanced our understanding of the pathophysiologic background of gastroparesis, intestinal stress damage and the effect of early enteral nutrition on gastrointestinal function. New techniques, such as ultrasound and the capsule techniques, might help to assess intestinal function beyond the aspiration of gastric residual volumes and the passage of stool. Therapeutic options such as opioid antagonists and the 5-hydroxytryptamine receptor 4 agonist prucalopride might help to restore intestinal function. SUMMARY: Gastrointestinal motility disturbances are caused by a myriad of pathological processes. Moreover, bowel integrity is governed by comorbidity, impaired metabolic function and pharmacological interventions in critically ill patients. Restoring gastrointestinal function, therefore, requires a multimodal approach including prophylactic management strategies and the sensible use of substances with inhibitory effects on intestinal motility.

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.

Gastrointestinal complications following on-pump cardiac surgery-A propensity matched analysis.

BACKGROUND: Gastrointestinal complications following on-pump cardiac surgery are orphan but serious risk factors for postoperative morbidity and mortality. We aimed to assess incidence, perioperative risk factors, treatment modalities and outcomes. MATERIAL AND METHODS: A university medical center audit comprised 4883 consecutive patients (median age 69 [interquartile range IQR 60-76] years, 33% female, median logistic EuroScore 5 [IQR 3-11]) undergoing all types of cardiac surgery including surgery on the thoracic aorta; patients undergoing repair of congenital heart disease, implantation of assist devices or cardiac transplantation were excluded. Coronary artery disease was the leading indication for on-pump cardiac surgery (60%), patients undergoing cardiac surgery under urgency or emergency setting were included in analysis. We identified a total of 142 patients with gastrointestinal complications. To identify intra- and postoperative predictors for gastrointestinal complications, we applied a 1:1 propensity score matching procedure based on a logistic regression model. RESULTS: Overall, 30-day mortality for the entire cohort was 5.4%; the incidence of gastrointestinal complications was 2.9% and median time to complication 8 days (IQR 4-12). Acute pancreatitis (n = 41), paralytic ileus (n = 14) and acute cholecystitis (n = 18) were the leading pathologies. Mesenteric ischemia and gastrointestinal bleeding accounted for 16 vs. 18 cases, respectively. While 72 patients (51%) could be managed conservatively, 27 patients required endoscopic/radiological (19%) or surgical intervention (43/142 patients, 30%); overall 30-day mortality was 12.1% (p<0.001). Propensity score matching identified prolonged skin-to-skin times (p = 0.026; Odds Ratio OR 1.003, 95% Confidence Interval CI 1.000-1.007) and extended on-pump periods (p = 0.010; OR 1.006, 95%CI 1.001-1.011) as significant perioperative risk factors. COMMENT: Prolonged skin-to-skin times and extended on-pump periods are important perioperative risk factors regardless of preoperative risk factors.

Gastrointestinal motility in acute illness.

Critical illness affects gastrointestinal motility - not only as a primary problem, which brings the patient to the intensive care unit (ICU), but also as a complication consecutive to the ICU stay. Motility disturbances may result from impaired function of gastrointestinal muscle, pacemaker cell function and nerve activity. The most important neural control system is the enteric nervous system that contains the largest collection of neurons (10(8) cells) outside the central nervous system. Through its organization it can operate independently of the brain and generate motility patterns according to need: a postprandial motility pattern starting after food intake, and an interdigestive motility pattern starting several hours after a meal. Undisturbed intestinal motility depends critically on a balanced interaction between inhibition and excitation, and a disturbance in this balance leads to severe derangements of intestinal motility. These motility disturbances differ in clinical appearance and location but can affect all parts of the gastrointestinal tract. This review focuses on select motility disturbances such as gastroparesis, postoperative ileus, and Ogilvie's syndrome. Generally effective methods to treat these conditions are given. Finally, we focus on special management options to prevent such motility disturbances or to reduce their severity.

Effects of enteral nutrition on gastrointestinal function in patients who are critically ill.

Nutritional management is a cornerstone of therapy for patients who are critically ill. Data show that enteral nutrition is better than parenteral nutrition with regard to the morbidity of critcally ill patients, especially for infectious complications. These findings suggest that feeding patients enterally has other beneficial effects besides delivering nutrients. In the absence of enteral nutrition, the mucosal architecture changes distinctly, leading to an impairment in function of the gastrointestinal barrier. This impairment facilitates the migration of bacteria from the intestinal lumen into the submucosal tissue and triggers epithelial inflammation. Consequently, proinflammatory and anti-inflammatory factors are imbalanced, leading to further degradation of gastrointestinal mucosal resistance. The enteral stimulus is also important to maintain physiological interaction of commensal bacteria with enteric immune cells. The absence of enteral nutrition induces deregulation of receptors that modulate the immunological response to commensal bacteria and pathogens-an important factor that initiates intestinal inflammation. Additionally, without enteral nutrients, the gastrointestinal mucosa atrophies because epithelial cells absorb nutrients directly from the gastrointestinal tract to meet their nutritional requirements. All these negative effects of absent enteral nutrition can be explained by a distinct change in cellular signalling pathways. Studies show that the physiological stimulus of enteral nutrition is crucial to maintain gastrointestinal functions such as barrier, immunological, and resorptive function. Enteral nutrients are important to maintain intact gastrointestinal motility since the nutrients stimulate the secretion of motility-regulating gastrointestinal hormones.

Intestinal motility disturbances in intensive care patients pathogenesis and clinical impact.

BACKGROUND: Gastrointestinal motility disturbances in critically ill patients are frequent in the ICU setting, causing considerable discomfort and are associated with increased rates of morbidity and mortality. This review focuses on the pathophysiological basis of intestinal motility, the major patterns of pathological motility alterations, the impact on patient outcome, and current therapeutic options. DISCUSSION: Intestinal motility is controlled by the enteric nervous system, modulated by hormones and extrinsic afferent and efferent neurons. Pathological motility disturbances can affect the stomach, small bowel, and colon separately or in combination. Changes in esophageal motor activity contribute to the aspiration of gastric juice, whereas early enteral feeding most frequently fails due to gastric intolerance. Disturbances in digestive and interdigestive motility patterns and the inability to switch motor activity from the interdigestive to the digestive pattern also contribute to feeding disability and thus to increased morbidity and mortality as well. CONCLUSIONS: The therapeutic options for motility disturbances in critically ill patients include the adjustment of electrolyte imbalances, tailored fluid management, early enteral feeding, appropriate management of catecholamines and drugs used for analgosedation, and prokinetic drugs. Unfortunately, the therapeutic options for treating motility disturbances in ICU patients are still limited. This situation requires careful assessment of ICU patients with respect to gut motility disturbances and their pathophysiological mechanisms and an individually tailored treatment to prevent further aggravation of existing motility disturbances.

Immunosuppressive treatment in fulminant myocarditis and gene expression pattern associated with, but no histological confirmation of giant cell myocarditis.

A healthy woman with acute onset of pulmonary oedema and severely depressed left ventricular function underwent endomyocardial biopsy under the clinical suspicion of fulminant myocarditis. While awaiting the results of biopsy, the situation deteriorated to Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) and extracorporeal membrane oxygenation was implanted. Finally, immunohistochemistry in biopsy specimen corresponded to fulminant lymphocytic myocarditis, although active myocarditis was excluded. Furthermore, gene expression profiling identified giant cell myocarditis although multinuclear cells were absent. This prompted the start of immunosuppression with cortisone and cyclosporine. The patient fully recovered.

Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines.

PURPOSE: To provide evidence-based guidelines for early enteral nutrition (EEN) during critical illness. METHODS: We aimed to compare EEN vs. early parenteral nutrition (PN) and vs. delayed EN. We defined "early" EN as EN started within 48 h independent of type or amount. We listed, a priori, conditions in which EN is often delayed, and performed systematic reviews in 24 such subtopics. If sufficient evidence was available, we performed meta-analyses; if not, we qualitatively summarized the evidence and based our recommendations on expert opinion. We used the GRADE approach for guideline development. The final recommendations were compiled via Delphi rounds. RESULTS: We formulated 17 recommendations favouring initiation of EEN and seven recommendations favouring delaying EN. We performed five meta-analyses: in unselected critically ill patients, and specifically in traumatic brain injury, severe acute pancreatitis, gastrointestinal (GI) surgery and abdominal trauma. EEN reduced infectious complications in unselected critically ill patients, in patients with severe acute pancreatitis, and after GI surgery. We did not detect any evidence of superiority for early PN or delayed EN over EEN. All recommendations are weak because of the low quality of evidence, with several based only on expert opinion. CONCLUSIONS: We suggest using EEN in the majority of critically ill under certain precautions. In the absence of evidence, we suggest delaying EN in critically ill patients with uncontrolled shock, uncontrolled hypoxaemia and acidosis, uncontrolled upper GI bleeding, gastric aspirate >500 ml/6 h, bowel ischaemia, bowel obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding access.

Advanced heart failure: an appraisal of the potential of levosimendan in this end-stage scenario and some related ethical considerations.

INTRODUCTION: The later stages of heart failure are characterized by a steady decline in quality of life. Clinical priorities should be to maintain functional capacity and quality of life. In the absence of sufficient organs for transplantation, options include left ventricular assist devices and inotropic support. Areas covered: We examined data published in the last two decades on the use of inotropes and inodilators in advanced heart failure. Expert commentary: In the literature, use of conventional inotropes, including adrenergic agonists and phosphodiesterase inhibitors, appears to be suboptimal for achieving the clinical priorities of late-stage heart failure. Evidence suggests instead that the calcium-sensitizing inodilator levosimendan, administered intermittently, delivers improvements in functional capacity and quality of life and does so with no adverse impact on life expectancy. At a terminal or near-terminal stage of heart failure, the therapeutic philosophy should shift towards meeting patients' existential priorities rather than traditional heart failure-centric targets.