Role of Point-of-Care ultrasound (POCUS) in clinical hepatology.

Hospitalized patients with cirrhosis frequently require critical care management for sepsis, hepatic encephalopathy, respiratory failure, acute variceal bleeding, acute kidney injury (AKI), shock and optimization for liver transplantation (LT), while outpatients have unique care considerations. Point-of-care ultrasonography (POCUS) enhances bedside examination of the hepatobiliary system and relevant extrahepatic sites. POCUS includes cardiac ultrasound and is used to assess volume status and hemodynamic parameters like cardiac output, systemic vascular resistance, cardiac contractility, and pulmonary artery pressure, which aid in the early and accurate diagnosis of heart failure, cirrhotic cardiomyopathy, porto-pulmonary hypertension, hepatopulmonary syndrome, arrhythmia, and pulmonary embolism. This also helps in fluid management and vasopressor use in resuscitation of patients with cirrhosis. Lung ultrasound can help in differentiating pneumonia, effusion, and edema. Further, ultrasonography guides interventions such as line placement, drainage of abdominal collections/abscesses, relief of tension pneumothorax, drainage of pleural and pericardial effusions, and biliary drainage in cholangitis. Additionally, its role is essential to assess liver masses, foci of sepsis, for appropriate sites for paracentesis, and to assess for vascular disorders such as portal vein or hepatic vein thrombosis. Renal ultrasound can identify renal and post-renal causes of AKI and aid in diagnosis of pre-renal AKI through volume assessment. In this review, we address the principles and methods of POCUS in hospitalized patients and in outpatients with cirrhosis and discuss the application of this diverse modality in clinical hepatology.

Society of Critical Care Medicine and American Society of Health-System Pharmacists Guideline for the Prevention of Stress-Related Gastrointestinal Bleeding in Critically Ill Adults.

RATIONALE: Critically ill adults can develop stress-related mucosal damage from gastrointestinal hypoperfusion and reperfusion injury, predisposing them to clinically important stress-related upper gastrointestinal bleeding (UGIB). OBJECTIVES: The objective of this guideline was to develop evidence-based recommendations for the prevention of UGIB in adults in the ICU. DESIGN: A multiprofessional panel of 18 international experts from dietetics, critical care medicine, nursing, and pharmacy, and two methodologists developed evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guideline development including task force selection and voting. METHODS: The panel members identified and formulated 13 Population, Intervention, Comparison, and Outcome questions. We conducted a systematic review for each question to identify the best available evidence, statistically analyzed the evidence, and then assessed the certainty of the evidence using the GRADE approach. We used the evidence-to-decision framework to formulate the recommendations. Good practice statements were included to provide additional guidance. RESULTS: The panel generated nine conditional recommendations and made four good practice statements. Factors that likely increase the risk for clinically important stress-related UGIB in critically ill adults include coagulopathy, shock, and chronic liver disease. There is no firm evidence for mechanical ventilation alone being a risk factor. Enteral nutrition probably reduces UGIB risk. All critically ill adults with factors that likely increase the risk for stress-related UGIB should receive either proton pump inhibitors or histamine-2 receptor antagonists, at low dosage regimens, to prevent UGIB. Prophylaxis should be discontinued when critical illness is no longer evident or the risk factor(s) is no longer present despite ongoing critical illness. Discontinuation of stress ulcer prophylaxis before transfer out of the ICU is necessary to prevent inappropriate prescribing. CONCLUSIONS: The guideline panel achieved consensus regarding the recommendations for the prevention of stress-related UGIB. These recommendations are intended for consideration along with the patient's existing clinical status.

Ammonia and urea metabolism in acute liver failure: A multicentre cohort study.

BACKGROUND & AIMS: Ammonia is metabolized into urea in the liver. In acute liver failure (ALF), ammonia has been associated with survival. However, urea variation has been poorly studied. METHODS: Observational cohort including ALF patients from Curry Cabral Hospital (Lisbon, Portugal) and Clinic Hospital (Barcelona, Spain) between 10/2010 and 01/2023. The United States ALF Study Group cohort was used for external validation. Primary exposures were serum ammonia and urea on ICU admission. Primary endpoint was 30-day transplant-free survival (TFS). Secondary endpoint was explanted liver weight. RESULTS: Among 191 ALF patients, median (IQR) age was 46 (32; 57) years and 85 (44.5%) were males. Overall, 86 (45.0%) patients were transplanted and 75 (39.3%) died. Among all ALF patients, following adjustment for age, sex, body weight, and aetiology, higher ammonia or lower urea was independently associated with higher INR on ICU admission (p < .009). Among all ALF patients, following adjustment for sex, aetiology, and lactate, higher ammonia was independently associated with lower TFS (adjusted odds ratio (95% confidence interval [CI]) = 0.991 (0.985; 0.997); p = .004). This model predicted TFS with good discrimination (area under receiver operating curve [95% CI] = 0.78 [0.75; 0.82]) and reasonable calibration (R2 of 0.43 and Brier score of 0.20) after external validation. Among transplanted patients, following adjustment for age, sex, actual body weight, and aetiology, higher ammonia (p = .024) or lower (p < .001) urea was independently associated with lower explanted liver weight. CONCLUSIONS: Among ALF patients, serum ammonia and urea were associated with ALF severity. A score incorporating serum ammonia predicted TFS reasonably well.

Improvement in survival after transplantation for critically ill patients with cirrhosis in the United States.

BACKGROUND: There is considerable debate over the indication of liver transplantation (LT) for critically ill patients with cirrhosis, in part due to their potentially poor post-LT prognosis. AIM: We analyzed the epidemiology and outcome of liver transplantation (LT) for critically ill patients with cirrhosis over 4 time periods of 4 years. METHODS: We included adult patients who underwent liver transplant alone between 2005 and 2020 using the United Network for Organ Sharing registry database. We defined critically ill patients with cirrhosis as being in the intensive care unit with one or more of the following characteristics at the time of LT: (i) grade III/IV hepatic encephalopathy, (ii) mechanical ventilation, (iii) dialysis, (iv) vasopressors. RESULTS: A total of 85,594 LT recipients were included, 5,827 (6.8%) of whom were classified as being critically ill with cirrhosis at the time of LT. The number and percentage of critically ill LT recipients with cirrhosis increased over the study period: 819 (4.3%) in 2005-2008 vs. 2,067 (7.9%) in 2017-2020 p<0.001. There was a 17% absolute increase in 1-year survival after LT: 72.5% in 2005-2008 vs. 89.5% in 2017-2020, p<0.001. The one-year post-LT survival gap between critically ill and non-critically ill patients with cirrhosis narrowed over the study period: 16.7 percentage points in 2005-2008 vs. 4.6 percentage points in 2017-2020. The year of LT was independently associated with lower one-year post-LT mortality (HR (95%CI): 0.92 (0.91-0.93) p<0.001). CONCLUSION: The absolute number and relative percentage of LT recipients who were critically ill increased over time, as did one-year post-LT survival. Meanwhile, the gap in survival between this group of patients and non-critically ill patients with cirrhosis decreased, but persisted. Cautious access to selected LT candidates that are critically ill may be warranted, provided the gap in survival with non-critically ill patients remains as small as possible.

Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape.

BACKGROUND: Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or ß-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups. MAIN BODY: Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with 111In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [111In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with ß-particle emitting 177Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [90Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [177Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (111In, 99mTc, 125I, 103Pd, 193mPt, 195mPt), ß-particles (177Lu, 186Re, 188Re, 90Y, 198Au, 131I) or α-particles (225Ac, 213Bi, 212Pb, 211At, 223Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity. CONCLUSIONS: Radiation nanomedicines have shown great promise for treating cancer in preclinical studies. Local intratumoural administration avoids sequestration by the liver and spleen and is most effective for treating tumours, while minimizing normal tissue toxicity.

Macrophage activation markers are associated with infection and mortality in patients with acute liver failure.

BACKGROUND AND AIMS: Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. METHODS: Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1-3) and late (>Day 3) time points were analysed for MAMs by enzyme-linked immunosorbent assay correlated to markers of illness severity and 21-day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. RESULTS: All MAMs serum concentrations were significantly higher in ALF compared to controls (p < .0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p = .002) and infection in general (p = .006). In MELD-adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p < .001) was higher in patients with ALF compared with controls and correlated with SOFA score (p = .018). sCD206 was independently validated as a predictor of infection in an external cohort. CONCLUSIONS: sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF.

Perturbations in human bile acid profiles following drug-induced liver injury investigated using semitargeted high-resolution mass spectrometry.

RATIONALE: Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF) in North America. To investigate the effect of drug-induced liver injury (DILI) on circulating bile acid (BA) profiles, serum from ALF patients and healthy controls were analyzed using a semitargeted high-resolution mass spectrometry approach to measure BAs in their unconjugated and amidated forms and their glucuronide and sulfate conjugates. METHODS: Human serum samples from 20 healthy volunteers and 34 ALF patients were combined with deuterated BAs and extracted, prior to liquid chromatography high-resolution tandem mass spectrometry analysis. A mix of 46 standards helped assign 26 BAs in human serum by accurate mass and retention time matching. Moreover, other isomers of unconjugated and amidated BAs, as well as glucuronide and sulfate conjugates, were assigned by accurate mass filtering. In vitro incubations of standard BAs provided increased information for certain peaks of interest. RESULTS: A total of 275 BA metabolites, with confirmed or putative assignments, were measured in human serum samples. APAP overdose significantly influenced the levels of most BAs, promoting glycine conjugation, and, to a lesser extent, taurine conjugation. When patient outcome was considered, 11 BAs were altered significantly, including multiple sulfated species. Although many of the BAs measured did not have exact structures assigned, several putatively identified BAs of interest were further characterized using in vitro incubations. CONCLUSION: An optimized chromatographic separation tailored to BAs of ranging polarities was combined with accurate mass measurements to investigate the effect that DILI has on their complex profiles and metabolism to a much wider extent than previously possible. The analysis of complex BA profiles enabled in-depth analysis of the BA metabolism perturbations in ALF, including certain metabolites related to patient outcomes.

Bridging the critically ill patient with acute to chronic liver failure to liver transplantation.

Liver transplantation (LT) has emerged as an effective therapy for severe forms of acute-on-chronic liver failure (ACLF), an entity characterized by the development of multiorgan failure and high short-term mortality. The aim of critical care management of ACLF patients is to rapidly treat precipitating events and aggressively support failing organs to ensure that patients may successfully undergo LT or, less frequently, recover. Malnutrition and sarcopenia are frequently present, adversely impacting the prognosis of these patients. Management of critical care patients with ACLF is complex and requires the participation of different specialties. Once the patient is stabilized, a rapid evaluation for salvage LT should be performed because the time window for LT is often narrow. The development of sepsis and prolonged organ support may preclude LT or diminish its chances of success. The current review describes strategies to bridge severe ACLF patients to LT, highlights the minimal evaluation required for listing and the currently suggested contraindications to proceed with LT, and addresses different aspects of management during the perioperative and early posttransplant period.

Trait impulsivity moderates rate of alcohol consumption in daily life.

INTRODUCTION: Rate of alcohol consumption, the speed with which people drink, has been linked to a range of outcomes, including alcohol use disorder symptoms and increased positive affect. However, minimal work has identified who is most likely to drink at elevated rates. Impulsivity is associated with increased attention to positive reinforcers specifically (e.g., positive affect). We therefore examined whether people higher in trait impulsivity engage in faster consumption during drinking episodes. METHODS: Participants were current drinkers (N = 113; 54 people with borderline personality disorder [BPD], a disorder that involves elevated impulsivity, and 59 community people) who completed a 21-day ecological momentary assessment (EMA) protocol. Multilevel models of drinking episodes (Nobservations = 3,444) examined whether self-reported trait impulsivity, measured at baseline, was associated with faster rise in estimated blood alcohol concentration (eBAC) at each follow-up period. RESULTS: All UPPS sub-scales were associated with faster rise in eBAC across a drinking episode. In a multivariate model including all sub-scales as simultaneous predictors, sensation seeking and (lack of) perseverance were independently positively associated with rate of consumption. Additional analyses indicated that greater negative urgency and sensation seeking were associated with faster rises in eBAC in participants with BPD, relative to community comparisons. CONCLUSION: In a sample that captured a wide spectrum of impulsivity, greater impulsivity was associated with drinking alcohol at a faster rate. People higher in sensation seeking and (lack of) perseverance may be prone to drink at faster rates out of a desire to maximize the hedonic effects of alcohol. PUBLIC SIGNIFICANCE STATEMENT: This study finds that people who are more impulsive tend to drink alcohol faster, putting them at greater risk for negative consequences. This may explain, in part, why impulsivity is linked to experiencing alcohol-related problems.

Continuous renal replacement therapy and survival in acute liver failure: A systematic review and meta-analysis.

OBJECTIVE: Acute liver failure (ALF) is a rare syndrome leading to significant morbidity and mortality. An important cause of mortality is cerebral edema due to hyperammonemia. Different therapies for hyperammonemia have been assessed including continuous renal replacement therapy (CRRT). We conducted a systematic review and meta-analysis to determine the efficacy of CRRT in ALF patients. MATERIALS AND METHODS: We searched MEDLINE, EMBASE, Cochrane Library, and Web of Science. Inclusion criteria included adult patients admitted to an ICU with ALF. Intervention was the use of CRRT for one or more indications with the comparator being standard care without the use of CRRT. Outcomes of interest were overall survival, transplant-free survival (TFS), mortality and changes in serum ammonia levels. RESULTS: In total, 305 patients underwent CRRT while 1137 patients did not receive CRRT. CRRT was associated with improved overall survival [risk ratio (RR) 0.83, 95% confidence interval (CI) 0.70-0.99, p-value 0.04, I2 = 50%] and improved TFS (RR 0.65, 95% CI 0.49-0.85, p-value 0.002, I2 = 25%). There was a trend towards higher mortality with no CRRT (RR 1.24, 95% CI 0.84-1.81, p-value 0.28, I2 = 37%). Ammonia clearance data was unable to be pooled and was not analyzable. CONCLUSION: Use of CRRT in ALF patients is associated with improved overall and transplant-free survival compared to no CRRT.

Cyclosporine A Does Not Mitigate Liver Ischemia/Reperfusion Injury in an Ex Vivo Porcine Model of Donation After Circulatory Death.

BACKGROUND Ischemia/reperfusion injury (IRI) is an inherent problem in organ transplantation, owing to the obligate period of ischemia that organs must endure. Cyclosporine A (CsA), though better know as an immunosuppressant, has been shown to mitigate warm IRI in a variety of organ types, including the liver. However, there is little evidence for CsA in preventing hepatic IRI in the transplant setting. MATERIAL AND METHODS In the present study, we tested the effect of CsA on hepatic IRI in a large-animal ex vivo model of donation after circulatory death (DCD). Porcine donors were pre-treated with either normal saline control or 20 mg/kg of CsA. Animals were subject to either 45 or 60 minutes of warm ischemia before hepatectomy, followed by 2 or 4 hours of cold storage prior to reperfusion on an ex vivo circuit. Over the course of a 12-hour perfusion, perfusion parameters were recorded and perfusate samples and biopsies were taken at regular intervals. RESULTS Peak perfusate lactate dehydrogenase was significantly decreased in the lower-ischemia group treated with CsA compared to the untreated group (4220 U/L [3515-5815] vs 11 305 [10 100-11 674]; P=0.023). However, no difference was seen between controls and CsA-treated groups on other parameters in perfusate alanine or asparagine aminotransferase (P=0.912, 0.455, respectively). Correspondingly, we found no difference on midpoint histological injury score (P=0.271). CONCLUSIONS We found minimal evidence that CsA is protective against hepatic IRI in our DCD model.

What every Intensivist should know about ... Ammonia in liver failure.

PURPOSE: Acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) patients have high short-term mortality and morbidity. In the context of liver failure, increased serum ammonia is associated with worse neurological outcomes, including high-grade hepatic encephalopathy (HE), cerebral edema, and intracranial hypertension. Besides its neurotoxicity, hyperammonemia may contribute to immune dysfunction and the risk of infection, a frequent trigger for multi-organ failure in these patients. MATERIAL AND METHODS: We performed a literature-based narrative review. Publications available in PubMed® up to June 2023 were considered. RESULTS: In the ICU management of liver failure patients, serum ammonia may play an important role. Accordingly, in this review, we focus on recent insights about ammonia metabolism, serum ammonia measurement strategies, hyperammonemia prognostic value, and ammonia-targeted therapeutic strategies. CONCLUSIONS: Serum ammonia may have prognostic value in liver failure. Effective ammonia targeted therapeutic strategies are available, such as laxatives, rifaximin, L-ornithine-l-aspartate, and continuous renal replacement therapy.

Adjuvant Auger Electron-Emitting Radioimmunotherapy with [111In]In-DOTA-Panitumumab in a Mouse Model of Local Recurrence and Metastatic Progression of Human Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has a high risk for recurrence and metastasis. We studied the effectiveness of Auger electron (AE) radioimmunotherapy (RIT) with antiepidermal growth factor receptor (EGFR) panitumumab conjugated with DOTA complexed to 111In ([111In]In-DOTA-panitumumab) for preventing metastatic progression after local treatment of 231/LM2-4 Luc+ human TNBC tumors in the mammary fat pad of NRG mice. Prior to RIT, the primary tumor was resected, and tumor margins were treated with X-irradiation (XRT; 5 days × 6 Gy/d). RIT was administered 1 day post-XRT by intravenous injection of 26 MBq (15 µg) or 2 × 10 MBq (15 µg each) separated by 7 d. These treatments were compared to tumor resection with or without XRT combined with DOTA-panitumumab (15 µg) or irrelevant [111In]In-DOTA-IgG2 (24 MBq; 15 µg), and efficacy was evaluated by Kaplan-Meier survival curves. The effect of [111In]In-DOTA-panitumumab (23 MBq; 15 µg) after tumor resection without local XRT was also studied. Tumor resection followed by XRT and RIT with 26 MBq [111In]In-DOTA-panitumumab significantly increased the median survival to 35 d compared to tumor resection with or without XRT (23-24 d; P < 0.0001). Local treatment with tumor resection and XRT followed by 2 × 10 MBq of [111In]In-DOTA-panitumumab, DOTA-panitumumab, or [111In]In-DOTA-IgG2 did not significantly improve median survival (26 days for all treatments). RIT alone with [111In]In-DOTA-panitumumab postresection of the tumor without XRT increased median survival to 29 days, though this was not significant. Despite significantly improved survival in mice treated with tumor resection, XRT, and RIT with [111In]In-DOTA-panitumumab, all mice eventually succumbed to advanced metastatic disease by 45 d post-tumor resection. SPECT/CT with [111In]In-DOTA-panitumumab, PET/MRI with [64Cu]Cu-DOTA-panitumumab F(ab')2, and PET/CT with [18F]FDG were used to detect recurrent and metastatic disease. Uptake of [111In]In-DOTA-panitumumab at 4 d p.i. in the MFP tumor was 26.8 ± 9.7% ID/g and in metastatic lymph nodes (LN), lungs, and liver was 34.2 ± 26.9% ID/g, 17.5 ± 6.0% ID/g, and 9.4 ± 2.4%ID/g, respectively, while uptake in the lungs (6.0 ± 0.9% ID/g) and liver (5.2 ± 2.9% ID/g) of non-tumor-bearing NRG was significantly lower (P < 0.05). Radiation-absorbed doses in metastatic LN, lungs, and liver were 9.7 ± 6.1, 6.4 ± 2.1, and 10.9 ± 2.7 Gy, respectively. In conclusion, we demonstrated that RIT with [111In]In-DOTA-panitumumab combined with tumor resection and XRT significantly improved the survival of mice with recurrent TNBC. However, the aggressive nature of 231/LM2-4 Luc+ tumors in NRG mice may have contributed to the tumor recurrence and progression observed.

Systemic Nonsteroidal Anti-Inflammatories for Analgesia in Postoperative Critical Care Patients: A Systematic Review and Meta-Analysis of Randomized Control Trials.

While opioids are part of usual care for analgesia in the ICU, there are concerns regarding excess use. This is a systematic review of nonsteroidal anti-inflammatory drugs (NSAIDs) use in postoperative critical care adult patients. DATA SOURCES: We searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, trial registries, Google Scholar, and relevant systematic reviews through March 2023. STUDY SELECTION: Titles, abstracts, and full texts were reviewed independently and induplicate by two investigators to identify eligible studies. We included randomized control trials (RCTs) that compared NSAIDs alone or as an adjunct to opioids for systemic analgesia. The primary outcome was opioid utilization. DATA EXTRACTION: In duplicate, investigators independently extracted study characteristics, patient demographics, intervention details, and outcomes of interest using predefined abstraction forms. Statistical analyses were conducted using Review Manager software Version 5.4. (The Cochrane Collaboration, Copenhagen, Denmark). DATA SYNTHESIS: We included 15 RCTs (n = 1,621 patients) for admission to the ICU for postoperative management after elective procedures. Adjunctive NSAID therapy to opioids reduced 24-hour oral morphine equivalent consumption by 21.4 mg (95% CI, 11.8-31.0 mg reduction; high certainty) and probably reduced pain scores (measured by Visual Analog Scale) by 6.1 mm (95% CI, 12.2 decrease to 0.1 increase; moderate certainty). Adjunctive NSAID therapy probably had no impact on the duration of mechanical ventilation (1.6 hr reduction; 95% CI, 0.4 hr to 2.7 reduction; moderate certainty) and may have no impact on ICU length of stay (2.1 hr reduction; 95% CI, 6.1 hr reduction to 2.0 hr increase; low certainty). Variability in reporting adverse outcomes (e.g., gastrointestinal bleeding, acute kidney injury) precluded their meta-analysis. CONCLUSIONS: In postoperative critical care adult patients, systemic NSAIDs reduced opioid use and probably reduced pain scores. However, the evidence is uncertain for the duration of mechanical ventilation or ICU length of stay. Further research is required to characterize the prevalence of NSAID-related adverse outcomes.

Early serum ammonia variation in critically ill patients with cirrhosis: A multicentre cohort study.

BACKGROUND: Serum ammonia variation in critically ill patients with cirrhosis has been poorly studied. AIM: To describe and assess the impact of serum ammonia variation in these patients' outcomes. METHODS: We studied patients ≥18 years old admitted to the intensive care units (ICUs) at University of Alberta Hospital (Edmonton, Canada) and Curry Cabral Hospital (Lisbon, Portugal; derivation cohort, n = 492) and Northwestern University Hospital (Chicago, USA; validation cohort, n = 600) between January 2010 and December 2021. Primary exposure was ICU days 1-3 serum ammonia. Primary endpoint was all-cause hospital mortality. RESULTS: In the derivation cohort, 330 (67.1%) patients were male and median (IQR) age was 57 (50-63) years. On ICU day 1, median ammonia was higher in patients with grade 3/4 hepatic encephalopathy (HE) than those with grade 2 HE or grade 0/1 HE (112 vs. 88 vs. 77 µmoL/L, respectively; p < 0.001). Furthermore, medium ammonia was higher in hospital non-survivors than survivors (99 vs. 86 µmol/L; p < 0.030). Following adjustment for significant confounders (age, HE, vasopressor use and renal replacement therapy delivery), higher ICU day 2 ammonia was independently associated with higher hospital mortality (adjusted OR per each 10 µmoL/L increment [95% CI] = 1.11 [1.01-1.21]; p = 0.024). In the validation cohort, this model with serial ammonia (ICU days 1 and 3) predicted hospital mortality with reasonably good discrimination (c-statistic = 0.73) and calibration (R2 = 0.19 and Brier score = 0.17). CONCLUSIONS: Among patients with cirrhosis in the ICU, early serum ammonia variation was independently associated with hospital mortality. In this context, serial serum ammonia may have prognostic value.

Post liver transplantation delirium assessment using the CAM-ICU-7 scale: A cohort analysis.

Background: We applied the Confusion Assessment Method (CAM)-Intensive Care Unit (ICU)-7 delirium scale to patients who underwent liver transplant (LT). Methods: Retrospective cohort including patients who underwent LT for cirrhosis admitted to the ICU from June 2013 to June 2016 at the University of Alberta Hospital, Canada. Delirium was assessed using the CAM-ICU-7 scale (0-7 points) twice daily on days one and 3 post LT, with the highest score being considered. Primary endpoint was hospital mortality. Results: Among all patients, 101/150 (67.3%) were men and mean age was 52.4 (SD 11.8) years. On days 1 and 3 post LT, mean CAM-ICU-7 scores were 1.8 (SD 1.3) and 1.6 (SD 1.8), respectively. Therefore, on days 1 and 3 post LT, 38/150 (25.3%) and 26/95 (27.4%) patients had delirium. While delirium on day 3 post LT was associated with higher hospital mortality (11.5% versus 0%; p = 0.019), it was not associated with length-of-hospital stay (29.2 versus 34.4 days; p = 0.36). Following adjustment for APACHEII score, delirium on day 3 post LT was associated with higher odds of hospital mortality (adjusted odds ratio [aOR] 1.89 [95% CI 1.02-3.50]). Following adjustment for Glasgow Coma Scale and mechanical ventilation, serum creatinine was associated with higher odds of delirium on day 3 post LT (aOR 2.02 [95% CI 1.08-3.77]). Conclusions: Using the CAM-ICU-7 scale, delirium was diagnosed in a fourth of patients who underwent LT. Delirium on day 3 post LT was associated with higher odds of hospital mortality.

The novel SALT-M score predicts 1-year post-transplant mortality in patients with severe acute-on-chronic liver failure.

BACKGROUND & AIMS: Twenty-eight-day mortality ranges from 30-90% in patients with acute-on-chronic liver failure grades 2/3 (severe ACLF). Though liver transplantation (LT) has demonstrated a survival benefit, the scarcity of donor organs and uncertainty regarding post-LT mortality among patients with severe ACLF may cause hesitancy. We developed and externally validated a model to predict 1-year post-LT mortality in severe ACLF, called the Sundaram ACLF-LT-Mortality (SALT-M) score, and estimated the median length of stay (LoS) after LT (ACLF-LT-LoS). METHODS: In 15 LT centers in the US, we retrospectively identified a cohort of patients with severe ACLF transplanted between 2014-2019, followed up to Jan'2022. Candidate predictors included demographics, clinical and laboratory values, and organ failures. We selected predictors in the final model using clinical criteria and externally validated them in two French cohorts. We provided measures of overall performance, discrimination, and calibration. We used multivariable median regression to estimate LoS after adjusting for clinically relevant factors. RESULTS: We included 735 patients, of whom 521 (70.8%) had severe ACLF (120 ACLF-3, external cohort). The median age was 55 years, and 104 with severe ACLF (19.9%) died within 1-year post-LT. Our final model included age >50 years, use of 1/≥2 inotropes, presence of respiratory failure, diabetes mellitus, and BMI (continuous). The c-statistic was 0.72 (derivation) and 0.80 (validation), indicating adequate discrimination and calibration based on the observed/expected probability plots. Age, respiratory failure, BMI, and presence of infection independently predicted median LoS. CONCLUSIONS: The SALT-M score predicts mortality within 1-year after LT in patients with ACLF. The ACLF-LT-LoS score predicted median post-LT stay. Future studies using these scores could assist in determining transplant benefits. IMPACT AND IMPLICATIONS: Liver transplantation (LT) may be the only life-saving procedure available to patients with acute-on-chronic liver failure (ACLF), but clinically instability can augment the perceived risk of post-transplant mortality at 1 year. We developed a parsimonious score with clinically and readily available parameters to objectively assess 1-year post-LT survival and predict median length of stay after LT. We developed and externally validated a clinical model called the Sundaram ACLF-LT-Mortality score in 521 US patients with ACLF with 2 or ≥3 organ failure(s) and 120 French patients with ACLF grade 3. The c-statistic was 0.72 in the development cohort and 0.80 in the validation cohort. We also provided an estimation of the median length of stay after LT in these patients. Our models can be used in discussions on the risks/benefits of LT in patients listed with severe ACLF. Nevertheless, the score is far from perfect and other factors, such as patient's preference and center-specific factors, need to be considered when using these tools.