Tight Blood-Glucose Control without Early Parenteral Nutrition in the ICU.

BACKGROUND: Randomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of early parenteral nutrition and in insulin-induced severe hypoglycemia might explain this inconsistency. METHODS: We randomly assigned patients, on ICU admission, to liberal glucose control (insulin initiated only when the blood-glucose level was >215 mg per deciliter [>11.9 mmol per liter]) or to tight glucose control (blood-glucose level targeted with the use of the LOGIC-Insulin algorithm at 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]); parenteral nutrition was withheld in both groups for 1 week. Protocol adherence was determined according to glucose metrics. The primary outcome was the length of time that ICU care was needed, calculated on the basis of time to discharge alive from the ICU, with death accounted for as a competing risk; 90-day mortality was the safety outcome. RESULTS: Of 9230 patients who underwent randomization, 4622 were assigned to liberal glucose control and 4608 to tight glucose control. The median morning blood-glucose level was 140 mg per deciliter (interquartile range, 122 to 161) with liberal glucose control and 107 mg per deciliter (interquartile range, 98 to 117) with tight glucose control. Severe hypoglycemia occurred in 31 patients (0.7%) in the liberal-control group and 47 patients (1.0%) in the tight-control group. The length of time that ICU care was needed was similar in the two groups (hazard ratio for earlier discharge alive with tight glucose control, 1.00; 95% confidence interval, 0.96 to 1.04; P = 0.94). Mortality at 90 days was also similar (10.1% with liberal glucose control and 10.5% with tight glucose control, P = 0.51). Analyses of eight prespecified secondary outcomes suggested that the incidence of new infections, the duration of respiratory and hemodynamic support, the time to discharge alive from the hospital, and mortality in the ICU and hospital were similar in the two groups, whereas severe acute kidney injury and cholestatic liver dysfunction appeared less prevalent with tight glucose control. CONCLUSIONS: In critically ill patients who were not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality. (Funded by the Research Foundation-Flanders and others; TGC-Fast ClinicalTrials.gov number, NCT03665207.).

Distinct immunometabolic signatures in circulating immune cells define disease outcome in acute-on-chronic liver failure.

BACKGROUND AIMS: Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and non-recovery in ACLF. APPROACH RESULTS: Here we mapped the single-cell transcriptome of circulating immune cells from ACLF-, acute decompensated (AD) cirrhosis patients and healthy individuals. We further interrogate how these findings as well as immunometabolic- and functional profiles associate with ACLF recovery (ACLF-R) or non-recovery (ACLF-NR). Our analysis unveiled two distinct states of classical monocytes (cMon). Hereto, ACLF-R cMons were characterized by transcripts associated with immune- and stress tolerance, including anti-inflammatory genes such as RETN and LGALS1 . Additional metabolomic- and functional validation experiments implicated an elevated oxidative phosphorylation metabolic program as well as an impaired ACLF-R cMon functionality. Interestingly, we observed a common stress-induced tolerant state, oxidative phosphorylation program and blunted activation among lymphoid populations in ACLF-R patients. Conversely, ACLF-NR cMon featured elevated expression of inflammatory- and stress response genes such as VIM , LGALS2 , and TREM1 along with blunted metabolic activity and increased functionality. CONCLUSIONS: This study identifies distinct immuno-metabolic cellular states that contribute to disease outcome in ACLF patients. Our findings provide valuable insights into the pathogenesis of ACLF, shedding light on factors driving either recovery or non-recovery phenotypes which may be harnessed as potential therapeutic targets in the future.

Profiling Bacteria in the Lungs of Patients with Severe Influenza Versus COVID-19 with or without Aspergillosis.

RATIONALE: The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza- or COVID-19-associated pulmonary aspergillosis (IAPA or CAPA) is yet to be explored. OBJECTIVES: To explore the composition of the lung bacterial microbiome and its association with viral and fungal infection, immunity and outcome in severe influenza versus COVID-19 with or without aspergillosis. METHODS: We performed a retrospective study in mechanically ventilated influenza and COVID-19 patients with or without invasive aspergillosis in whom bronchoalveolar lavage (BAL) for bacterial culture (with or without PCR) was obtained within two weeks after ICU admission. Additionally, 16S rRNA gene sequencing data and viral and bacterial load of BAL samples from a subset of these patients, and of patients requiring non-invasive ventilation, were analyzed. We integrated 16S rRNA gene sequencing data with existing immune parameter datasets. MEASUREMENTS AND MAIN RESULTS: Potential bacterial pathogens were detected in 20% (28/142) of influenza and 37% (104/281) of COVID-19 patients, while aspergillosis was detected in 38% (54/142) of influenza and 31% (86/281) of COVID-19 patients. A significant association between bacterial pathogens in BAL and 90-day mortality was found only in influenza patients, particularly IAPA patients. COVID-19 but not influenza patients showed increased pro-inflammatory pulmonary cytokine responses to bacterial pathogens. CONCLUSIONS: Aspergillosis is more frequently detected in lungs of severe influenza patients than bacterial pathogens. Detection of bacterial pathogens associates with worse outcome in influenza patients, particularly in those with IAPA, but not in COVID-19 patients. The immunological dynamics of tripartite viral-fungal-bacterial interactions deserve further investigation. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

High Burden of COVID-19-Associated Pulmonary Aspergillosis in Severely Immunocompromised Patients Requiring Mechanical Ventilation.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a frequent superinfection in critically ill patients with COVID-19 and is associated with increased mortality rates. The increasing proportion of severely immunocompromised patients with COVID-19 who require mechanical ventilation warrants research into the incidence and impact of CAPA during the vaccination era. METHODS: We performed a retrospective, monocentric, observational study. We collected data from adult patients with severe COVID-19 requiring mechanical ventilation who were admitted to the intensive care unit (ICU) of University Hospitals Leuven, a tertiary referral center, between 1 March 2020 and 14 November 2022. Probable or proven CAPA was diagnosed according to the 2020 European Confederation for Medical Mycology/International Society for Human and Animal Mycology (ECMM/ISHAM) criteria. RESULTS: We included 335 patients. Bronchoalveolar lavage sampling was performed in 300 (90%), and CAPA was diagnosed in 112 (33%). The incidence of CAPA was 62% (50 of 81 patients) in European Organisation for Research and Treatment of Cancer (EORTC)/Mycosis Study Group Education and Research Consortium (MSGERC) host factor-positive patients, compared with 24% (62 of 254) in host factor-negative patients. The incidence of CAPA was significantly higher in the vaccination era, increasing from 24% (57 of 241) in patients admitted to the ICU before October 2021 to 59% (55 of 94) in those admitted since then. Both EORTC/MSGERC host factors and ICU admission in the vaccination era were independently associated with CAPA development. CAPA remained an independent risk factor associated with mortality risk during the vaccination era. CONCLUSIONS: The presence of EORTC/MSGERC host factors for invasive mold disease is associated with increased CAPA incidence and worse outcome parameters, and it is the main driver for the significantly higher incidence of CAPA in the vaccination era. Our findings warrant investigation of antifungal prophylaxis in critically ill patients with COVID-19.

A Pathology-based Case Series of Influenza- and COVID-19-associated Pulmonary Aspergillosis: The Proof Is in the Tissue.

Rationale: Invasive pulmonary aspergillosis has emerged as a frequent coinfection in severe coronavirus disease (COVID-19), similarly to influenza, yet the clinical invasiveness is more debated. Objectives: We investigated the invasive nature of pulmonary aspergillosis in histology specimens of influenza and COVID-19 ICU fatalities in a tertiary care center. Methods: In this monocentric, descriptive, retrospective case series, we included adult ICU patients with PCR-proven influenza/COVID-19 respiratory failure who underwent postmortem examination and/or tracheobronchial biopsy during ICU admission from September 2009 until June 2021. Diagnosis of probable/proven viral-associated pulmonary aspergillosis (VAPA) was made based on the Intensive Care Medicine influenza-associated pulmonary aspergillosis and the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) COVID-19-associated pulmonary aspergillosis consensus criteria. All respiratory tissues were independently reviewed by two experienced pathologists. Measurements and Main Results: In the 44 patients of the autopsy-verified cohort, 6 proven influenza-associated and 6 proven COVID-19-associated pulmonary aspergillosis diagnoses were identified. Fungal disease was identified as a missed diagnosis upon autopsy in 8% of proven cases (n = 1/12), yet it was most frequently found as confirmation of a probable antemortem diagnosis (n = 11/21, 52%) despite receiving antifungal treatment. Bronchoalveolar lavage galactomannan testing showed the highest sensitivity for VAPA diagnosis. Among both viral entities, an impeded fungal growth was the predominant histologic pattern of pulmonary aspergillosis. Fungal tracheobronchitis was histologically indistinguishable in influenza (n = 3) and COVID-19 (n = 3) cases, yet macroscopically more extensive at bronchoscopy in influenza setting. Conclusions: A proven invasive pulmonary aspergillosis diagnosis was found regularly and with a similar histological pattern in influenza and in COVID-19 ICU case fatalities. Our findings highlight an important need for VAPA awareness, with an emphasis on mycological bronchoscopic work-up.

Atypical Hemolytic Uremic Syndrome Occurring After Receipt of mRNA-1273 COVID-19 Vaccine Booster: A Case Report.

Atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a dysregulation of the alternative complement pathway. Here, we report a previously healthy 38-year-old woman in whom aHUS developed after a COVID-19 vaccine booster. One day after receipt of a booster dose of mRNA-1273 vaccine, she felt ill. Because of persistent headache, nausea, and general malaise, she went to her general practitioner, who referred her to the hospital after detecting hypertension and acute kidney injury. A diagnosis of TMA was made. Her treatment consisted of blood pressure control, hemodialysis, plasma exchange, and respiratory support. Kidney biopsy confirmed the diagnosis of acute TMA. The patient was referred for treatment with eculizumab, and kidney function improved after initiation of this therapy. Genetic analysis revealed a pathogenic C3 variant. SARS-CoV-2 infection as a trigger for complement activation and development of aHUS has been described previously. In addition, there is one reported case of aHUS occurring after receipt of the adenovirus-based COVID-19 vaccine ChAdOx1 nCoV-19, but, to our knowledge, this is the first case of aHUS occurring after a booster dose of an mRNA COVID-19 vaccine in a patient with an underlying pathogenic variant in complement C3. Given the time frame, we hypothesize that the vaccine probably was the trigger for development of aHUS in this patient.

Do Cerebral Cortex Perfusion, Oxygen Delivery, and Oxygen Saturation Responses Measured by Near-Infrared Spectroscopy Differ Between Patients Who Fail or Succeed in a Spontaneous Breathing Trial? A Prospective Observational Study.

BACKGROUND: Alterations in perfusion to the brain during the transition from mechanical ventilation (MV) to a spontaneous breathing trial (SBT) remain poorly understood. The aim of the study was to determine whether changes in cerebral cortex perfusion, oxygen delivery (DO2), and oxygen saturation (%StiO2) during the transition from MV to an SBT differ between patients who succeed or fail an SBT. METHODS: This was a single-center prospective observational study conducted in a 16-bed medical intensive care unit of the University Hospital Leuven, Belgium. Measurements were performed in 24 patients receiving MV immediately before and at the end of a 30-min SBT. Blood flow index (BFI), DO2, and %StiO2 in the prefrontal cortex, scalene, rectus abdominis, and thenar muscle were simultaneously assessed by near-infrared spectroscopy using the tracer indocyanine green dye. Cardiac output, arterial blood gases, and systemic oxygenation were also recorded. RESULTS: During the SBT, prefrontal cortex BFI and DO2 responses did not differ between SBT-failure and SBT-success groups (p > 0.05). However, prefrontal cortex %StiO2 decreased in six of eight patients (75%) in the SBT-failure group (median [interquartile range 25-75%]: MV = 57.2% [49.1-61.7] vs. SBT = 51.0% [41.5-62.5]) compared to 3 of 16 patients (19%) in the SBT-success group (median [interquartile range 25-75%]: MV = 65.0% [58.6-68.5] vs. SBT = 65.1% [59.5-71.1]), resulting in a significant differential %StiO2 response between groups (p = 0.031). Similarly, a significant differential response in thenar muscle %StiO2 (p = 0.018) was observed between groups. A receiver operating characteristic analysis identified a decrease in prefrontal cortex %StiO2 > 1.6% during the SBT as an optimal cutoff, with a sensitivity of 94% and a specificity of 75% to predict SBT failure and an area under the curve of 0.79 (95% CI: 0.55-1.00). Cardiac output, systemic oxygenation, scalene, and rectus abdominis BFI, DO2, and %StiO2 responses did not differ between groups (p > 0.05); however, during the SBT, a significant positive association in prefrontal cortex BFI and partial pressure of arterial carbon dioxide was observed only in the SBT-success group (SBT success: Spearman's ρ = 0.728, p = 0.002 vs. SBT failure: ρ = 0.048, p = 0.934). CONCLUSIONS: This study demonstrated a reduced differential response in prefrontal cortex %StiO2 in the SBT-failure group compared with the SBT-success group possibly due to the insufficient increase in prefrontal cortex perfusion in SBT-failure patients. A > 1.6% drop in prefrontal cortex %StiO2 during SBT was sensitive in predicting SBT failure. Further research is needed to validate these findings in a larger population and to evaluate whether cerebral cortex %StiO2 measurements by near-infrared spectroscopy can assist in the decision-making process on liberation from MV.

Five-year outcome of respiratory muscle weakness at intensive care unit discharge: secondary analysis of a prospective cohort study.

PURPOSE: To assess the association between respiratory muscle weakness (RMW) at intensive care unit (ICU) discharge and 5-year mortality and morbidity, independent from confounders including peripheral muscle strength. METHODS: Secondary analysis of the prospective 5-year follow-up of the EPaNIC cohort (ClinicalTrials.gov: NCT00512122), limited to 366 patients screened for respiratory and peripheral muscle strength in the ICU with maximal inspiratory pressure (MIP) after removal of the artificial airway, and the Medical Research Council sum score. RMW was defined as an absolute value of MIP <30 cmH2O. Associations between RMW at (or closest to) ICU discharge and all-cause 5-year mortality, and key measures of 5-year physical function, comprising respiratory muscle strength (MIP), hand-grip strength (HGF), 6 min walk distance (6MWD) and physical function of the SF-36 quality-of-life questionnaire (PF-SF-36), were assessed with Cox proportional hazards and linear regression models, adjusted for confounders including peripheral muscle strength. RESULTS: RMW was present in 136/366 (37.2%) patients at ICU discharge. RMW was not independently associated with 5-year mortality (HR with 95% CI 1.273 (0.751 to 1.943), p=0.352). Among 156five-year survivors, those with, as compared with those without RMW demonstrated worse physical function (MIP (absolute value, cmH2O): 62(42-77) vs 94(78-109), p<0.001; HGF (%pred): 67(44-87) vs 96(68-110), p<0.001; 6MWD (%pred): 87(74-102) vs 99 (80-111), p=0.009; PF-SF-36 (score): 55 (30-80) vs 80 (55-95), p<0.001). Associations between RMW and morbidity endpoints remained significant after adjustment for confounders (effect size with 95% CI: MIP: -23.858 (-32.097 to -15.027), p=0.001; HGF: -18.591 (-30.941 to -5.744), p=0.001; 6MWD (transformed): -1587.007 (-3073.763 to -179.253), p=0.034; PF-SF-36 (transformed): 1.176 (0.144-2.270), p=0.036). CONCLUSIONS: RMW at ICU discharge is independently associated with 5-year morbidity but not 5-year mortality.

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization.

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis. METHODS: Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation-perfusion (V/Q) scan to screen for incidental pulmonary embolism. RESULTS: Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported. CONCLUSION: In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.

Advances in acute pancreatitis.

PURPOSE OF REVIEW: With a potentially life-threatening course, acute pancreatitis (AP) is one of the most common gastrointestinal diseases requiring hospitalization and often necessitating intensive care. Based on recent insights and recommendations, this review provides an overview on clinical management of AP patients with a focus on intensive care unit care. RECENT FINDINGS: Possible benefits of percutaneous paracentesis and/or drainage on outcome or inflammation have been further explored. Combined opioid and epidural analgesia for pain management might be a valuable alternative for pain management. Very recent international guidelines now agree on a step-up approach for the management of acute necrotizing pancreatitis favoring a minimally invasive approach with either endoscopic or percutaneous drainage first. Studies for the best timing of these interventions are ongoing. In spite of a better understanding of pathophysiological mechanisms mediating AP, specific treatments are still awaited. SUMMARY: New evidence and recent international consensus direct the current management of AP toward a tailored, multidisciplinary and less invasive therapy with complementary roles for hepatologists, intensivists, radiologists, and surgeons.

Recanalization of portal axis after cavoportal hemitransposition in a liver transplant recipient with complete splanchnic thrombosis.

BACKGROUND: Diffuse splanchnic thrombosis may render standard LTx difficult or even technically impossible. A 19-year-old woman with acute-on-chronic Budd-Chiari syndrome and complete splanchnic thrombosis underwent conventional LTx. Only limited anatomical portal inflow could be restored, and urgent re-transplantation for recurrent splanchnic vein thrombosis became necessary. METHODS: At re-transplant, and in addition to the reestablishment of some portal inflow through the preserved original porto (native)-portal (graft) connection, a cavoportal shunt was created (first partial via 30% tapering of the vena cava, but eventually complete by total occlusion of the vena cava). RESULTS: The postoperative course was then uneventful, and interestingly, the native portomesenteric axis gradually reopened. Two years post-transplant, the liver graft is perfused via both physiological and non-physiological sources. Liver function is normal. There is no IVC syndrome and no residual PHT. She is leading a normal life. CONCLUSION: Creation of CPHT, in addition to the preservation of portal inflow from the native splanchnic system, should be considered in patients with diffuse splanchnic thrombosis, when sufficient physiological portal inflow cannot be restored at the time of LTx, but in whom the splanchnic circulation may reopen up later.

Lactate Improves Prediction of Short-Term Mortality in Critically Ill Patients With Cirrhosis: A Multinational Study.

Lactate levels and lactate clearance are known predictors of outcome in critically ill patients in the intensive care unit (ICU). The prognostic value of lactate is not well established in liver cirrhosis and acute-on-chronic liver failure (ACLF). The aim of this study was to assess the prognostic value of lactate levels and clearance in critically ill patients with cirrhosis. Patients with cirrhosis admitted to the ICU were studied at the University Medical Center Hamburg-Eppendorf (n = 566, derivation cohort) and the Medical University of Vienna and the University Hospitals Leuven (n = 250, validation cohort). Arterial lactate was measured on admission and during the first 24 hours. Patients were followed for 1 year and outcome was assessed. Admission lactate was directly related to the number of organs failing and to 28-day mortality (area under receiver operating characteristic [AUROC] 0.72; P < 0.001). This also applied to lactate follow-up measurements after 6, 12, and 24 hours (P < 0.001 for all, AUROC > 0.70 for all). Lactate clearance had significant predictive ability for 28-day mortality in patients with elevated serum lactate ≥5 mmol/L. Admission lactate and 12-hour lactate clearance (in patients with admission lactate ≥5 mmol/L), respectively, were identified as significant predictors of 1-year mortality, independent of Chronic Liver Failure Consortium acute-on-chronic liver failure score (CLIF-C ACLFs). A lactate-adjusted CLIF-C ACLFs was developed (CLIF-C ACLFsLact ), which performed significantly better than the original CLIF-C ACLFs in prediction of 28-day mortality in the derivation and validation cohort. Conclusion: Lactate levels appropriately reflect severity of disease and organ failure and were independently associated with short-term mortality in critically ill patients with liver cirrhosis. Lactate is a simple but accurate prognostic marker, and its incorporation improved performance of CLIF-C ACLFs significantly.

Towards a fasting-mimicking diet for critically ill patients: the pilot randomized crossover ICU-FM-1 study.

BACKGROUND: In two recent randomized controlled trials, withholding parenteral nutrition early in critical illness improved outcome as compared to early up-to-calculated-target nutrition, which may be explained by beneficial effects of fasting. Outside critical care, fasting-mimicking diets were found to maintain fasting-induced benefits while avoiding prolonged starvation. It is unclear whether critically ill patients can develop a fasting response after a short-term nutrient interruption. In this randomized crossover pilot study, we investigated whether 12-h nutrient interruption initiates a metabolic fasting response in prolonged critically ill patients. As a secondary objective, we studied the feasibility of monitoring autophagy in blood samples. METHODS: In a single-center study in 70 prolonged critically ill patients, 12-h up-to-calculated-target feeding was alternated with 12-h fasting on day 8 ± 1 in ICU, in random order. Blood samples were obtained at the start of the study, at the crossover point, and at the end of the 24-h study period. Primary endpoints were a fasting-induced increase in serum bilirubin and decrease in insulin requirements to maintain normoglycemia. Secondary outcomes included serum insulin-like growth factor I (IGF-I), serum urea, plasma beta-hydroxybutyrate (BOH), and mRNA and protein markers of autophagy in whole blood and isolated white blood cells. To obtain a healthy reference, mRNA and protein markers of autophagy were assessed in whole blood and isolated white blood cells of 23 matched healthy subjects in fed and fasted conditions. Data were analyzed using repeated-measures ANOVA, Fisher's exact test, or Mann-Whitney U test, as appropriate. RESULTS: A 12-h nutrient interruption significantly increased serum bilirubin and BOH and decreased insulin requirements and serum IGF-I (all p ≤ 0.001). Urea was not affected. BOH was already increased from 4 h fasting onwards. Autophagic markers in blood samples were largely unaffected by fasting in patients and healthy subjects. CONCLUSIONS: A 12-h nutrient interruption initiated a metabolic fasting response in prolonged critically ill patients, which opens perspectives for the development of a fasting-mimicking diet. Blood samples may not be a good readout of autophagy at the tissue level. TRIAL REGISTRATION: ISRCTN, ISRCTN98404761. Registered 3 May 2017.

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.

COVID-19 and gastrointestinal endoscopy: What should be taken into account?

On March 11, 2020 the World Health Organization declared COVID-19 pandemic, leading to a subsequent impact on the entire world and health care system. Since the causing Severe Acute Respiratory Syndrome Coronavirus 2 houses in the aerodigestive tract, activities in the gastrointestinal outpatient clinic and endoscopy unit should be limited to emergencies only. Health care professionals are faced with the need to perform endoscopic or endoluminal emergency procedures in patients with a confirmed positive or unknown COVID-19 status. With this report, we aim to provide recommendations and practical relevant information for gastroenterologists based on the limited amount of available data and local experience, to guarantee a high-quality patient care and adequate infection prevention in the gastroenterology clinic.

Five-year mortality and morbidity impact of prolonged versus brief ICU stay: a propensity score matched cohort study.

PURPOSE: Long-term outcomes of critical illness may be affected by duration of critical illness and intensive care. We aimed to investigate differences in mortality and morbidity after short (<8 days) and prolonged (≥8 days) intensive care unit (ICU) stay. METHODS: Former EPaNIC-trial patients were included in this preplanned prospective cohort, 5-year follow-up study. Mortality was assessed in all. For morbidity analyses, all long-stay and-for feasibility-a random sample (30%) of short-stay survivors were contacted. Primary outcomes were total and post-28-day 5-year mortality. Secondary outcomes comprised handgrip strength (HGF, %pred), 6-minute-walking distance (6MWD, %pred) and SF-36 Physical Function score (PF SF-36). One-to-one propensity-score matching of short-stay and long-stay patients was performed for nutritional strategy, demographics, comorbidities, illness severity and admission diagnosis. Multivariable regression analyses were performed to explore ICU factors possibly explaining any post-ICU observed outcome differences. RESULTS: After matching, total and post-28-day 5-year mortality were higher for long-stayers (48.2% (95%CI: 43.9% to 52.6%) and 40.8% (95%CI: 36.4% to 45.1%)) versus short-stayers (36.2% (95%CI: 32.4% to 40.0%) and 29.7% (95%CI: 26.0% to 33.5%), p<0.001). ICU risk factors comprised hypoglycaemia, use of corticosteroids, neuromuscular blocking agents, benzodiazepines, mechanical ventilation, new dialysis and the occurrence of new infection, whereas clonidine could be protective. Among 276 long-stay and 398 short-stay 5-year survivors, HGF, 6MWD and PF SF-36 were significantly lower in long-stayers (matched subset HGF: 83% (95%CI: 60% to 100%) versus 87% (95%CI: 73% to 103%), p=0.020; 6MWD: 85% (95%CI: 69% to 101%) versus 94% (95%CI: 76% to 105%), p=0.005; PF SF-36: 65 (95%CI: 35 to 90) versus 75 (95%CI: 55 to 90), p=0.002). CONCLUSION: Longer duration of intensive care is associated with excess 5-year mortality and morbidity, partially explained by potentially modifiable ICU factors. TRAIL REGISTRATION NUMBER: NCT00512122.

The intensive care unit course and outcome in acute-on-chronic liver failure are comparable to other populations.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis, development of organ failure and high short-term mortality. Whether the outcome in patients admitted to the intensive care unit (ICU) with ACLF differs from other ICU populations is unknown. We compared the clinical course and host response in ICU patients with or without ACLF, matched for baseline severity of illness scores and characteristics. METHODS: From the large prospective EPaNIC randomized control trial database (n = 4,640), 133 patients were identified with cirrhosis of whom 71 fulfilled the Chronic Liver Failure Consortium criteria for ACLF. These patients were matched for type and severity of illness and demographics to 71 septic and 71 medical ICU patients from the same database without chronic liver disease. Clinical, biochemical and outcome parameters were compared in this cohort study of 213 patients. In a subset of 100 patients, day 1 serum cytokines were quantified. RESULTS: The outcome of ACLF, when compared to septic or medical ICU patients, matched for baseline parameters of illness severity, was similar regarding length of ICU stay, development of new infections, organ failure and septic shock. ICU, hospital and 90-day mortality were similar between the groups. C-reactive protein and platelet levels were lower in patients with ACLF throughout the first week. Cytokines, including IL-10, IL-1ß, IL-6, and IL-8, were similarly elevated in ACLF and septic ICU patients on day 1. However, TNF-α levels were higher in patients with ACLF. CONCLUSION: Patients with ACLF admitted to the ICU showed comparable clinical and ICU outcomes as ICU patients without chronic liver disease, but with similar baseline severity of illness characteristics. This suggests that ICU admission criteria should not be different in ACLF populations. LAY SUMMARY: Liver function may abruptly deteriorate in patients with chronic liver disease with cirrhosis, often resulting in these patients being admitted to an intensive care unit (ICU) with organ failure. Previous studies have indicated that this sudden deterioration, called acute-on-chronic liver failure is associated with very high mortality rates, which often resulted in deferred ICU care because of a perception of futility. Our study now shows that the ICU course and outcome are not different when patients with acute-on-chronic liver failure are compared to other ICU patients matched for severity of illness. This demonstrates that patients with acute-on-chronic liver failure deserve the same ICU care given to other ICU populations.

Appropriateness of Acid Suppression Therapy.

BACKGROUND: The inappropriate startup of long-term acid suppressive therapy (AST) can have clinical and pharmacoeconomic impacts on ambulatory care. OBJECTIVE: To assess the proportion of patients with appropriate initiation of long-term AST in non-critically ill patients. To describe possible risk factors for nonappropriate AST. To calculate the potential savings when eliminating the nonappropriate startup of AST. METHOD: This observational, retrospective study evaluated the appropriateness of startup of long-term AST in medical records using a broad variety of international criteria and guidelines and using a validated screening instrument. RESULTS: A sample of 597 patients was included in the analysis. In 57% of them, AST was appropriately initiated. No specific risk profile could be defined. There was some indication that the availability of a clinical pharmacist and the use of standing orders were correlated to the outcome. Extrapolation to the total population (ie, 2836 patients) led to a total cost of €8880 during hospital stay plus an extra €40 391 per month after discharge. Avoiding inappropriate initiation of AST could lead to a saving of €3805 plus €17 441 per month. CONCLUSION: In all, 43% of initiation of long-term AST in the hospital was inappropriate. The potential savings from avoiding this could be substantial from a health care payer perspective. No patient characteristics that could predict for inappropriate initiation of AST were identified. A correlation between inappropriate initiation and medical disciplines using standing orders that include AST was seen.

Software-guided versus nurse-directed blood glucose control in critically ill patients: the LOGIC-2 multicenter randomized controlled clinical trial.

BACKGROUND: Blood glucose control in the intensive care unit (ICU) has the potential to save lives. However, maintaining blood glucose concentrations within a chosen target range is difficult in clinical practice and holds risk of potentially harmful hypoglycemia. Clinically validated computer algorithms to guide insulin dosing by nurses have been advocated for better and safer blood glucose control. METHODS: We conducted an international, multicenter, randomized controlled trial involving 1550 adult, medical and surgical critically ill patients, requiring blood glucose control. Patients were randomly assigned to algorithm-guided blood glucose control (LOGIC-C, n = 777) or blood glucose control by trained nurses (Nurse-C, n = 773) during ICU stay, according to the local target range (80-110 mg/dL or 90-145 mg/dL). The primary outcome measure was the quality of blood glucose control, assessed by the glycemic penalty index (GPI), a measure that penalizes hypoglycemic and hyperglycemic deviations from the chosen target range. Incidence of severe hypoglycemia (<40 mg/dL) was the main safety outcome measure. New infections in ICU, duration of hospital stay, landmark 90-day mortality and quality of life were clinical safety outcome measures. RESULTS: The median GPI was lower in the LOGIC-C (10.8 IQR 6.2-16.1) than in the Nurse-C group (17.1 IQR 10.6-26.2) (P < 0.001). Mean blood glucose was 111 mg/dL (SD 15) in LOCIC-C versus 119 mg/dL (SD 21) in Nurse-C, whereas the median time-in-target range was 67.0% (IQR 52.1-80.1) in LOGIC-C versus 47.1% (IQR 28.1-65.0) in the Nurse-C group (both P < 0.001). The fraction of patients with severe hypoglycemia did not differ between LOGIC-C (0.9%) and Nurse-C (1.2%) (P = 0.6). The clinical safety outcomes did not differ between groups. The sampling interval was 2.3 h (SD 0.5) in the LOGIC-C group versus 3.0 h (SD 0.8) in the Nurse-C group (P < 0.001). CONCLUSIONS: In a randomized controlled trial of a mixed critically ill patient population, the use of the LOGIC-Insulin blood glucose control algorithm, compared with blood glucose control by expert nurses, improved the quality of blood glucose control without increasing hypoglycemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02056353 . Registered on 4 February 2014.