Serum lactate and mean arterial pressure thresholds in patients with cirrhosis and septic shock.

BACKGROUND: The Sepsis-3 guidelines have incorporated serum lactate levels of >2 mmol/L in septic shock definition to account for higher observed mortality. Further evidence is needed to support this threshold in cirrhosis, as well as target mean arterial pressure (MAP) during resuscitation. METHODS: This observational cohort study investigated the association between initial serum lactate and resuscitation MAP levels on in-hospital mortality in patients with and without cirrhosis. Patients admitted to the intensive care unit for the treatment of septic shock between 2006 and 2021 in a quaternary academic center were included. Patients with cirrhosis documented on imaging and International Classification of Disease codes (n=595) were compared to patients without cirrhosis (n=575). The association of intensive care unit admission lactate levels and median 2-hour MAP with in-hospital mortality and the need for continuous renal replacement therapy was assessed. The association between median 24-hour MAP and in-hospital mortality was analyzed post hoc. RESULTS: Within the cirrhosis group, admission lactate levels of 2-4 and >4 mmol/L were associated with increased in-hospital mortality compared to lactate <2 mmol/L [adjusted odds ratio (aOR): 1.69, CI: 1.03-2.81, aOR: 4.02, CI: 2.53-6.52]. Median 24-hour MAP 60-65 and <60 mm Hg were also associated with increased in-hospital mortality compared with MAP >65 mm Hg (aOR: 2.84, CI: 1.64-4.92 and aOR: 7.34, CI: 3.17-18.76). In the noncirrhosis group, associations with in-hospital mortality were weaker for lactate 2-4 and >4 mmol/L (aOR: 1.32, CI: 0.77-2.27 and aOR: 2.25, CI: 1.40-3.67) and median 24-hour MAP 60-65 and <60 mm Hg (aOR: 1.70, CI: 0.65-4.14 and aOR: 4.41, CI: 0.79-29.38). CONCLUSIONS: These findings support utilizing lactate >2 mmol/L in the definition of septic shock, as well as a target MAP of >65 mm Hg during resuscitation in patients with cirrhosis.

Incidence and outcomes of acute kidney injury including hepatorenal syndrome in hospitalized patients with cirrhosis in the US.

BACKGROUND & AIMS: Acute kidney injury (AKI) in cirrhosis is common and associated with high morbidity, but the incidence rates of different etiologies of AKI are not well described in the US. We compared incidence rates, practice patterns, and outcomes across etiologies of AKI in cirrhosis. METHODS: We performed a retrospective cohort study of 11 hospital networks, including consecutive adult patients admitted with AKI and cirrhosis in 2019. The etiology of AKI was adjudicated based on pre-specified clinical definitions (prerenal/hypovolemic AKI, hepatorenal syndrome [HRS-AKI], acute tubular necrosis [ATN], other). RESULTS: A total of 2,063 patients were included (median age 62 [IQR 54-69] years, 38.3% female, median MELD-Na score 26 [19-31]). The most common etiology was prerenal AKI (44.3%), followed by ATN (30.4%) and HRS-AKI (12.1%); 6.0% had other AKI, and 7.2% could not be classified. In our cohort, 8.1% of patients received a liver transplant and 36.5% died by 90 days. The lowest rate of death was observed in patients with prerenal AKI (22.2%; p <0.001), while death rates were higher but not significantly different from each other in those with HRS-AKI and ATN (49.0% vs. 52.7%; p = 0.42). Using prerenal AKI as a reference, the adjusted subdistribution hazard ratio (sHR) for 90-day mortality was higher for HRS-AKI (sHR 2.78; 95% CI 2.18-3.54; p <0.001) and ATN (sHR 2.83; 95% CI 2.36-3.41; p <0.001). In adjusted analysis, higher AKI stage and lack of complete response to treatment were associated with an increased risk of 90-day mortality (p <0.001 for all). CONCLUSION: AKI is a severe complication of cirrhosis. HRS-AKI is uncommon and is associated with similar outcomes to ATN. The etiology of AKI, AKI stage/severity, and non-response to treatment were associated with mortality. Further optimization of vasoconstrictors for HRS-AKI and supportive therapies for ATN are needed. IMPACT AND IMPLICATIONS: Acute kidney injury (AKI) in cirrhosis carries high morbidity, and management is determined by the etiology of injury. However, a large and well-adjudicated multicenter database from US centers that uses updated AKI definitions is lacking. Our findings demonstrate that acute tubular necrosis and hepatorenal syndrome have similar outcomes (∼50% mortality at 90 days), though hepatorenal syndrome is uncommon (12% of all AKI cases). These findings represent practice patterns at US transplant/tertiary centers and can be used as a baseline, presenting the situation prior to the adoption of terlipressin in the US.

Cirrhosis Management in the Intensive Care Unit.

Patients with cirrhosis frequently require admission to the intensive care unit as complications arise in the course of their disease. These admissions are associated with high short- and long-term morbidity and mortality. Thus, understanding and characterizing complications and unique needs of patients with cirrhosis and acute-on-chronic liver failure helps providers identify appropriate level of care and evidence-based treatments. While there is no widely accepted critical care admission criteria for patients with cirrhosis, the presence of organ failure and primary or nosocomial infections are associated with particularly high in-hospital mortality. Optimal management of patients with cirrhosis in the critical care setting requires a system-based approach that acknowledges deviations from canonical pathophysiology. In this review, we discuss appropriate considerations and evidence-based practices for the general care of patients with cirrhosis and critical illness.

Overproduction of endothelin-1 impairs glucose tolerance but does not promote visceral adipose tissue inflammation or limit metabolic adaptations to exercise.

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity. We found that 1) diet-induced obesity, AT inflammation, and glycemic dysregulation were not accompanied by significantly increased levels of ET-1 in AT or circulation in wild-type mice and that endothelial overexpression of ET-1 and consequently increased ET-1 levels did not cause AT inflammation yet impaired glucose tolerance; 2) reduced AT inflammation and improved glucose tolerance with voluntary wheel running was not associated with decreased levels of ET-1 in AT or circulation in obese mice nor did endothelial overexpression of ET-1 impede such exercise-induced metabolic adaptations; 3) chronic pharmacological blockade of ET-1 receptors did not suppress AT inflammation in obese mice but improved glucose tolerance; and 4) in a cohort of human subjects with a wide range of body mass indexes, ET-1 levels in AT, or circulation were not correlated with markers of inflammation in AT. In aggregate, we conclude that ET-1 signaling is not implicated in the development of visceral AT inflammation but promotes glucose intolerance, thus representing an important therapeutic target for glycemic dysregulation in conditions characterized by hyperendothelinemia. Furthermore, we show that the salutary effects of exercise on AT and systemic metabolic function are not contingent on the suppression of ET-1 signaling.

Disconnect between adipose tissue inflammation and cardiometabolic dysfunction in Ossabaw pigs.

OBJECTIVE: The Ossabaw pig is emerging as an attractive model of human cardiometabolic disease because of its size and susceptibility to atherosclerosis, among other characteristics. The relationship between adipose tissue inflammation and metabolic dysfunction in this model was investigated here. METHODS: Young female Ossabaw pigs were fed a Western-style high-fat diet (HFD) (n = 4) or control low-fat diet (LFD) (n = 4) for a period of 9 months and compared for cardiometabolic outcomes and adipose tissue inflammation. RESULTS: The HFD-fed "OBESE" pigs were 2.5 times heavier (P < 0.001) than LFD-fed "LEAN" pigs and developed severe obesity. HFD feeding caused pronounced dyslipidemia, hypertension, and insulin resistance (systemic and adipose), as well as induction of inflammatory genes, impairments in vasomotor reactivity to insulin, and atherosclerosis in the coronary arteries. Remarkably, visceral, subcutaneous, and perivascular adipose tissue inflammation (via FACS analysis and RT-PCR) was not increased in OBESE pigs, nor were circulating inflammatory cytokines. CONCLUSIONS: These findings reveal a disconnect between adipose tissue inflammation and cardiometabolic dysfunction induced by Western diet feeding in the Ossabaw pig model.

Cerebral and lower limb near-infrared spectroscopy in adults on extracorporeal membrane oxygenation.

Percutaneous femoral venoarterial (VA) or jugular venovenous (VV) extracorporeal membrane oxygenation (ECMO) can result in delivery of hypoxic blood to the brain, coronaries, and upper extremities. Additionally, VA-ECMO by percutaneous femoral artery cannulation may compromise perfusion to the lower limbs. Use of near-infrared spectroscopy (NIRS) detects regional ischemia and warns of impending hypoxic damage. We report the first known series with standardized monitoring of this parameter in adults on ECMO. This is an institutional review board-approved single institution retrospective review of patients with NIRS monitoring on ECMO from July 2010 until June 2011. Patients were analyzed for drops in NIRS tracings below 40 or >25% from baseline. VA-ECMO and VV-ECMO were initiated by percutaneous cannulation of the femoral vessels and the internal jugular vein, respectively. Sensors were placed on the patients' foreheads and on the lower limbs. NIRS tracings were recorded, analyzed, and correlated with clinical events. Twenty patients were analyzed (median age: 47.5 years): 17 patients were placed on VA-ECMO, and three patients on VV-ECMO. The median duration on ECMO was 7 days (range 2-26). One hundred percent of patients had a significant drop in bilateral cerebral oximetry tracings resulting in hemodynamic interventions, which involved increasing pressure, oxygenation, and/or ECMO flow. In 16 patients (80%), these interventions corrected the underlying ischemia. Four patients (20%) required further diagnostic intervention for persistent decreased bilateral and/or unilateral cerebral oximetry tracings, and were found to have a cerebrovascular accident (CVA). Six (30%) patients had persistent unilateral lower limb oximetry events, which resolved upon placement or replacement of a distal perfusion cannula. No patient was found to have either lower limb ischemia or a CVA with normal NIRS tracings. Use of NIRS with ECMO is important in detecting ischemic cerebral and peripheral vascular events. This allows for potential correction of the underlying process, thus preventing permanent ischemic damage.