Ram M. Subramanian

Second infections independently increase mortality in hospitalized patients With cirrhosis: the north american consortium for the study of end‐stage liver disease (NACSELD) experience

Bacterial infections are an important cause of mortality in cirrhosis, but there is a paucity of multicenter studies. The aim was to define factors predisposing to infection‐related mortality in hospitalized patients with cirrhosis. A prospective, cohort study of patients with cirrhosis with infections was performed at eight North American tertiary‐care hepatology centers. Data were collected on admission vitals, disease severity (model for endstage liver disease [MELD] and sequential organ failure [SOFA] scores), first infection site, type (community‐acquired, healthcare‐associated [HCA] or nosocomial), and second infection occurrence during hospitalization. The outcome was mortality within 30 days. A multivariate logistic regression model predicting mortality was created. 207 patients (55 years, 60% men, MELD 20) were included. Most first infections were HCA (71%), then nosocomial (15%) and community‐acquired (14%). Urinary tract infections (52%), spontaneous bacterial peritonitis (SBP, 23%) and spontaneous bacteremia (21%) formed the majority of the first infections. Second infections were seen in 50 (24%) patients and were largely preventable: respiratory, including aspiration (28%), urinary, including catheter‐related (26%), fungal (14%), and Clostridium difficile (12%) infections. Forty‐nine patients (23.6%) who died within 30 days had higher admission MELD (25 versus 18, P < 0.0001), lower serum albumin (2.4 g/dL versus 2.8 g/dL, P = 0.002), and second infections (49% versus 16%, P < 0.0001) but equivalent SOFA scores (9.2 versus 9.9, P = 0.86). The case fatality rate was highest for C. difficile (40%), respiratory (37.5%), and spontaneous bacteremia (37%), and lowest for SBP (17%) and urinary infections (15%). The model for mortality included admission MELD (odds ratio [OR]: 1.12), heart rate (OR: 1.03) albumin (OR: 0.5), and second infection (OR: 4.42) as significant variables. Conclusion: Potentially preventable second infections are predictors of mortality independent of liver disease severity in this multicenter cirrhosis cohort. (HEPATOLOGY 2012;56:2328–2335)

Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures

Infections worsen survival in cirrhosis; however, simple predictors of survival in infection‐related acute‐on‐chronic liver failure (I‐ACLF) derived from multicenter studies are required in order to improve prognostication and resource allocation. Using the North American Consortium for Study of End‐stage Liver Disease (NACSELD) database, data from 18 centers were collected for survival analysis of prospectively enrolled cirrhosis patients hospitalized with an infection. We defined organ failures as 1) shock, 2) grade III/IV hepatic encephalopathy (HE), 3) need for dialysis and mechanical ventilation. Determinants of survival with these organ failures were analyzed. In all, 507 patients were included (55 years, 52% hepatitis C virus [HCV], 15.8% nosocomial infection, 96% Child score ≥7) and 30‐day evaluations were available in 453 patients. Urinary tract infection (UTI) (28.5%), and spontaneous bacterial peritonitis (SBP) (22.5%) were the most prevalent infections. During hospitalization, 55.7% developed HE, 17.6% shock, 15.1% required renal replacement, and 15.8% needed ventilation; 23% died within 30 days and 21.6% developed second infections. Admitted patients developed none (38.4%), one (37.3%), two (10.4%), three (10%), or four (4%) organ failures. The 30‐day survival worsened with a higher number of extrahepatic organ failures, none (92%), one (72.6%), two (51.3%), three (36%), and all four (23%). I‐ACLF was defined as ≥2 organ failures given the significant change in survival probability associated at this cutoff. Baseline independent predictors for development of ACLF were nosocomial infections, Model for Endstage Liver Disease (MELD) score, low mean arterial pressure (MAP), and non‐SBP infections. Independent predictors of poor 30‐day survival were I‐ACLF, second infections, and admission values of high MELD, low MAP, high white blood count, and low albumin. Conclusion: Using multicenter study data in hospitalized decompensated infected cirrhosis patients, I‐ACLF defined by the presence of two or more organ failures using simple definitions is predictive of poor survival. (Hepatology 2014;60:250–256)

New Consensus Definition of Acute Kidney Injury Accurately Predicts 30-Day Mortality in Patients With Cirrhosis and Infection

BACKGROUND & AIMS Participants at a consensus conference proposed defining cirrhosis-associated acute kidney injury (AKI) based on a >50% increase in serum creatinine level from the stable baseline value in <6 months or an increase of ≥ 0.3 mg/dL in <48 hours. We performed a prospective study to evaluate the ability of these criteria to predict mortality within 30 days of hospitalization among patients with cirrhosis and infection. METHODS We followed up 337 patients with cirrhosis who were admitted to the hospital with an infection or developed an infection during hospitalization (56% men; 56 ± 10 years of age; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) at 12 centers in North America. We compared data on 30-day mortality, length of stay in the hospital, and organ failure between patients with and without AKI. RESULTS In total, based on the consensus criteria, 166 patients (49%) developed AKI during hospitalization. Patients who developed AKI were admitted with higher Child-Pugh scores than those who did not develop AKI (11.0 ± 2.1 vs 9.6 ± 2.1; P < .0001) as well as higher MELD scores (23 ± 8 vs 17 ± 7; P < .0001) and lower mean arterial pressure (81 ± 16 vs 85 ± 15 mm Hg; P < .01). Higher percentages of patients with AKI died within 30 days of hospitalization (34% vs 7%), were transferred to the intensive care unit (46% vs 20%), required ventilation (27% vs 6%), or went into shock (31% vs 8%); patients with AKI also had longer stays in the hospital (17.8 ± 19.8 vs 13.3 ± 31.8 days) (all P < .001). Of the AKI episodes, 56% were transient, 28% were persistent, and 16% resulted in dialysis. Mortality was higher among those without renal recovery (80%) compared with partial (40%) or complete recovery (15%) or those who did not develop AKI (7%; P < .0001). CONCLUSIONS Among patients with cirrhosis, 30-day mortality is 10-fold higher among those with irreversible AKI than those without AKI. The consensus definition of AKI accurately predicts 30-day mortality, length of hospital stay, and organ failure.

Original ResearchFull Report: Clinical—LiverNew Consensus Definition of Acute Kidney Injury Accurately Predicts 30-Day Mortality in Patients With Cirrhosis and Infection

BACKGROUND & AIMS Participants at a consensus conference proposed defining cirrhosis-associated acute kidney injury (AKI) based on a >50% increase in serum creatinine level from the stable baseline value in <6 months or an increase of ≥ 0.3 mg/dL in <48 hours. We performed a prospective study to evaluate the ability of these criteria to predict mortality within 30 days of hospitalization among patients with cirrhosis and infection. METHODS We followed up 337 patients with cirrhosis who were admitted to the hospital with an infection or developed an infection during hospitalization (56% men; 56 ± 10 years of age; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) at 12 centers in North America. We compared data on 30-day mortality, length of stay in the hospital, and organ failure between patients with and without AKI. RESULTS In total, based on the consensus criteria, 166 patients (49%) developed AKI during hospitalization. Patients who developed AKI were admitted with higher Child-Pugh scores than those who did not develop AKI (11.0 ± 2.1 vs 9.6 ± 2.1; P < .0001) as well as higher MELD scores (23 ± 8 vs 17 ± 7; P < .0001) and lower mean arterial pressure (81 ± 16 vs 85 ± 15 mm Hg; P < .01). Higher percentages of patients with AKI died within 30 days of hospitalization (34% vs 7%), were transferred to the intensive care unit (46% vs 20%), required ventilation (27% vs 6%), or went into shock (31% vs 8%); patients with AKI also had longer stays in the hospital (17.8 ± 19.8 vs 13.3 ± 31.8 days) (all P < .001). Of the AKI episodes, 56% were transient, 28% were persistent, and 16% resulted in dialysis. Mortality was higher among those without renal recovery (80%) compared with partial (40%) or complete recovery (15%) or those who did not develop AKI (7%; P < .0001). CONCLUSIONS Among patients with cirrhosis, 30-day mortality is 10-fold higher among those with irreversible AKI than those without AKI. The consensus definition of AKI accurately predicts 30-day mortality, length of hospital stay, and organ failure.

Management of the critically ill patient with cirrhosis: A multidisciplinary perspective.

a r Management of the critically ill patient with cirrhosis: A multidisciplinary perspective Mitra K. Nadim1,⇑, Francois Durand, John A. Kellum, Josh Levitsky, Jacqueline G. O’Leary, Constantine J. Karvellas, Jasmohan S. Bajaj, Andrew Davenport, Rajiv Jalan, Paolo Angeli, Stephen H. Caldwell, Javier Fernández, Claire Francoz, Guadalupe Garcia-Tsao, Pere Ginès, Michael G. Ison, David J. Kramer, Ravindra L. Mehta, Richard Moreau, David Mulligan, Jody C. Olson, Elizabeth A. Pomfret, Marco Senzolo, Randolph H. Steadman, Ram M. Subramanian, Jean-Louis Vincent, Yuri S. Genyk

Transjugular Intrahepatic Portosystemic Shunt for Symptomatic Refractory Hepatic Hydrothorax in Patients With Cirrhosis

OBJECTIVES:We sought to study effectiveness, survival, and complications after transjugular intrahepatic portosystemic shunt (TIPS) in patients with cirrhosis and symptomatic refractory hepatic hydrothorax.METHODS:Consecutive patients who underwent TIPS between January 1992 and December 2008 for refractory hydrothorax were reviewed retrospectively. Clinical, laboratory, and procedural data were collected for all patients by retrospective chart review. Chi-square test was used to compare categorical variables and t-test to compare continuous variables. The Kaplan–Meier method was used for survival analysis. Survival curves were compared using the log-rank test.RESULTS:Seventy-three patients were included in the study, and their mean age at TIPS creation was 55.62 years (s.d. 11.65). The mean pre- and post-TIPS portosystemic gradients were 18.9 (s.d. 4.7) mm Hg and 5.7 (s.d. 2.4) mm Hg (P<0.001), respectively. The rates of favorable clinical response within 1 month and at 6 months after TIPS were 79% (58/73) and 75% (30/40), respectively. Median survival of the study group was 517 days (95% CI 11–626). The short-term survival rates at 30, 60, and 90 days were 81, 78, and 72%, respectively. The long-term survival rates at 1, 3, and 5 years were 48, 26, and 15%, respectively. Multivariate analysis by Cox proportional hazards method showed that pre-TIPS model for end-stage liver disease (MELD) score (P=0.039, HR 1.9 (95% CI 1.0–3.7)) and clinical response (P=0.003, HR 2.5 (95% CI 1.4–4.5)) were significantly and independently associated with overall survival. The 30-day mortality rate was 19%. Pre-TIPS creatinine levels (P=0.024, HR 3.42 (95% CI 1.2–9.9)) were significantly associated with 30-day mortality.CONCLUSIONS:TIPS can be successfully used to achieve symptomatic relief in patients with refractory hepatic hydrothorax. Better clinical response after TIPS and pre-TIPS MELD score less than 15 were associated with longer survival after TIPS.

The 3‐month readmission rate remains unacceptably high in a large North American cohort of patients with cirrhosis

In smaller single‐center studies, patients with cirrhosis are at a high readmission risk, but a multicenter perspective study is lacking. We evaluated the determinants of 3‐month readmissions among inpatients with cirrhosis using the prospective 14‐center North American Consortium for the Study of End‐Stage Liver Disease cohort. Patients with cirrhosis hospitalized for nonelective indications provided consent and were followed for 3 months postdischarge. The number of 3‐month readmissions and their determinants on index admission and discharge were calculated. We used multivariable logistic regression for all readmissions and for hepatic encephalopathy (HE), renal/metabolic, and infection‐related readmissions. A score was developed using admission/discharge variables for the total sample, which was validated on a random half of the total population. Of the 1353 patients enrolled, 1177 were eligible on discharge and 1013 had 3‐month outcomes. Readmissions occurred in 53% (n = 535; 316 with one, 219 with two or more), with consistent rates across sites. The leading causes were liver‐related (n = 333; HE, renal/metabolic, and infections). Patients with cirrhosis and with worse Model for End‐Stage Liver Disease score or diabetes, those taking prophylactic antibiotics, and those with prior HE were more likely to be readmitted. The admission model included Model for End‐Stage Liver Disease and diabetes (c‐statistic = 0.64, after split‐validation 0.65). The discharge model included Model for End‐Stage Liver Disease, proton pump inhibitor use, and lower length of stay (c‐statistic = 0.65, after split‐validation 0.70). Thirty percent of readmissions could not be predicted. Patients with liver‐related readmissions consistently had index‐stay nosocomial infections as a predictor for HE, renal/metabolic, and infection‐associated readmissions (odds ratio = 1.9‐3.0). Conclusions: Three‐month readmissions occurred in about half of discharged patients with cirrhosis, which were associated with cirrhosis severity, diabetes, and nosocomial infections; close monitoring of patients with advanced cirrhosis and prevention of nosocomial infections could reduce this burden. (Hepatology 2016;64:200–208)

Long-term Use of Antibiotics and Proton-Pump Inhibitors Predict Development of Infections in Patients with Cirrhosis

BACKGROUND & AIMS Bacterial infections, particularly repeated infections, are significant causes of morbidity and mortality among patients with cirrhosis. We investigated and characterized risk factors for repeat infections in these patients. METHODS In a prospective study, we collected data from 188 patients hospitalized with cirrhosis and infections and enrolled in the North American Consortium for the Study of End-Stage Liver Disease (12 centers). Patients were followed up for 6 months after hospital discharge and data were analyzed on type of infections and factors associated with subsequent infections. RESULTS Six months after hospital discharge, 14% of subjects had received liver transplants, 27% died, and 59% were alive without liver transplantation. After discharge, 45% had subsequent infections, but only 26% of the subsequent infections occurred at the same site. Compared with patients not re-infected, patients with repeat infections were older and a higher proportion used proton pump inhibitors (PPIs) (P = .006), rifaximin (P < .001), or prophylactic therapy for spontaneous bacterial peritonitis (SBP) (P < .001). Logistic regression showed that SBP prophylaxis (odds ratio [OR], 3.44; 95% confidence interval [CI], 1.56-7.63), PPI use (OR, 2.94; 95% CI, 1.39-6.20), SBP at hospital admission (OR, 0.37; 95% CI, 0.15-0.91), and age (OR, 1.06; 95% CI, 1.02-1.11) were independent predictors of subsequent infections. CONCLUSIONS Patients hospitalized with cirrhosis and infections are at high risk for subsequent infections, mostly at different sites, within 6 months of index infection resolution. Those at highest risk include previously infected older patients receiving PPIs and/or SBP prophylaxis, although these associations do not prove that these factors cause the infections. New strategies are needed to prevent infections in patients with cirrhosis.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

Context Whether changes have occurred in the causes of acute liver failure (ALF), its management, or the survival of patients with the condition (with or without liver transplantation) is not known. Contribution This large cohort study found that despite similar causes and severity of ALF among patients referred to specialty centers from 1998 to 2013, the proportion of patients listed for liver transplantation decreased and survival improved among those who did not receive a transplant as well as those who did. Implication More study is warranted to better understand the specific changes in care that may have led to improved survival of patients with ALF. Acute liver failure (ALF) is defined as severe liver injury with rapid onset that results in hepatic encephalopathy (HE) and coagulopathy in persons without preexisting liver disease. The principal causes of ALF include acetaminophen (N-acetyl-p-aminophenol [APAP]) overdose, ischemic and pregnancy-associated liver injury, acute infection with hepatitis A or B virus, drug-induced liver injury, autoimmune hepatitis, BuddChiari syndrome, and Wilson disease (1, 2). For some causes, such as APAP toxicity, outcomes are favorable and transplant-free survival (TFS) approaches 70%, whereas other causes have unfavorable outcomes, including a much lower likelihood (<30%) of recovery without liver transplantation (2). One-year survival after emergency liver transplantation in patients with ALF in the United States and Europe is reportedly good but is lower than among patients with cirrhosis who receive a transplant (3). Patients with ALF often deteriorate rapidly and therefore receive the most urgent ranking (status 1) in the United Network for Organ Sharing transplantation system. Treatment of ALF in the intensive care unit is largely supportive and includes ventilator and vasopressor support for respiratory and/or circulatory failure, renal replacement therapy, plasma and blood transfusions, antibiotics, and measures to decrease intracranial pressure (46). N-acetylcysteine is used to treat APAP overdose and has shown efficacy in patients with ALF not due to APAP toxicity, particularly those referred early and having only mild HE (7). However, few disease-specific or general treatments are available that yield improved outcomes. In this study, our aim was to update the U.S. experience with ALF at specialized liver disease and transplant centers since the last published overview by the Acute Liver Failure Study Group (ALFSG) in 2002 (2). This group initiated its registry in January 1998 to better characterize the causes, clinical features, and outcomes of this super-orphan condition and aimed to enroll cases prospectively from participating liver transplant centers across North America. Accordingly, we analyzed data on all patients with ALF enrolled between 1998 and 2013, focusing on whether clinical features or outcomes of the ALF syndrome have changed over time. In addition, we sought to determine the relationship between ALF causes and rates of TFS and whether utilization of liver transplantation changed in the 16-year observation period. Methods Study Population From 1 January 1998 through 31 December 2013, adult patients were consecutively enrolled in the ALFSG registry (2) from 31 U.S. academic liver centers (of which only 5 legacy sites participated continuously throughout the 16-year period). All enrolled patients had both coagulopathy (international normalized ratio [INR] 1.5) and any grade of HE (as clinically defined by the classic West Haven criteria [8]) within 26 weeks of the first symptoms and had no evidence of significant chronic liver disease, especially cirrhosis. Patients for whom prior liver transplantation failed (due to primary graft nonfunction or other causes) were excluded. During the 16-year period, the number of sites participating, their geographic locations, and the number of cases contributed per site varied depending on each sites ability to continually identify and enroll patients over time (Appendix Figure 1). Appendix Figure 1. Site enrollment over time. Patients were usually admitted to intensive care units; 82.4% were hospitalized before transfer to the referral tertiary care study site, and the remainder were admitted directly to the study site. All were screened for inclusion according to the ALF criteria defined earlier. Written informed consent was obtained from the legal next of kin. A log of screen failures and consent refusal was maintained. All centers complied with local institutional review board requirements. Data Management and Integrity At enrollment into the study, we prospectively collected patient demographic characteristics (age, sex, race, and ethnicity); a complete medical history, including the timing of the first symptom of ill health, onset of jaundice and HE, and the number of days between the first symptom, hospital admission, transfer to the study site (where relevant), and enrollment in the study; and clinical features, including blood pressure and need for vasopressor support, mechanical ventilation, and renal replacement therapy, which allowed calculation of the systemic inflammatory response syndrome (SIRS) score (9). We also collected standard liver and metabolic test results and clinical data daily for up to 7 days, as well as serologic and other tests to determine the cause. All data were managed and housed on a central server at the Medical University of South Carolina. A data query system and periodic monitoring are in place to manage data integrity. In addition, ALFSG leadership conducted annual visits to clinical sites to verify data and ensure compliance with study procedures. Statistical Analysis Statistical analyses were performed using SAS, version 9.4 (SAS Institute). Missing values were not replaced or estimated. Patients with missing data were excluded from the respective analyses for those variables, and patients who were lost to follow-up before 21 days were excluded from the study. Descriptive statistics were used to characterize the demographic and other clinical variables. Categorical variables were compared using the chi-square test or the Fisher exact test (the latter when expected cell counts were <5). Medians were reported with interquartile ranges (IQRs) and were compared with the Wilcoxon rank-sum test. Survival and transplant outcomes at 21 days after study enrollment were classified as TFS (survival without liver transplantation), liver transplantation, or death (2). Outcomes were also determined at 1 and 2 years after study enrollment, but these data were less complete than the 21-day outcome data. Survival rates over time were assessed descriptively at the individual-site level to verify that changes in TFS were not affected by varying accrual of patients from different sites. Treatment utilization and survival and transplant outcomes were analyzed over time annually for trends and were also stratified into two 8-year periods: early (1998 to 2005) and later (2006 to 2013). Trends over time were analyzed using the CochranArmitage test. A significance level of less than 0.05 was used for all comparisons. Role of the Funding Source This study was funded by the National Institutes of Health. The funding source had no direct role in the design, conduct, or reporting of the study. Results Demographic Characteristics and Comorbidities During the 16-year study, 2070 patients (median age, 39.0 years [IQR, 29.0 to 52.0 years]) were enrolled in the ALFSG registry. Over the same interval, there were 660 confirmed ALF screen failures (286 due to failure to meet inclusion criteria, 212 for whom consent could not be obtained, and 162 for other reasons). Among enrolled patients, 69.3% were women and 76.4% were white (Table 1). Patients did not differ in sex, race, or ethnicity between the two 8-year periods but were significantly older and heavier in the later period. Prevalence of hypertension, heart disease, diabetes, psychiatric illness, and substance dependency all increased significantly between the early and later periods, whereas prevalence of renal disease did not. Table 1. Demographic Characteristics, Comorbidities, Clinical Severity, and Causes at Admission Causes and Clinical Severity of ALF The percentage of enrollment as a reflection of the most common causes of ALF did not change during the two 8-year periods. Hepatotoxicity due to APAP accounted for almost half the cases of ALF for the entire 16-year period (Table 1), with the highest annual prevalence (53.0%) occurring in 2013. Unintentional APAP overdoses (those in which patients took excessive medication over several days for such ailments as pain, malaise, or fever [10, 11]) were more common than intentional (suicidal) overdoses. Hepatitis A virus infection was significantly less evident during the later period (9 cases [0.8%]) than the early period (28 cases [2.8%]) (P< 0.001). Hepatic ischemia and autoimmune hepatitis increased modestly, whereas hepatitis B virus infection, drug-induced liver injury, Wilson disease, and BuddChiari syndrome were less frequently noted. Patients entered either the primary or the referral (study) site more rapidly after initial symptom onset in the later period (2.0 days [IQR, 0.0 to 8.0 days]) than the early period (3.0 days [IQR, 1.0 to 14.0 days]) (P< 0.001) (Table 1). However, the corresponding interval between symptom onset and HE onset was 4.0 days in both the early (IQR, 1.0 to 15.0 days) and later (IQR, 1.0 to 12.0 days) periods, and time from onset of jaundice to enrollment also was unchanged (3.0 days in each period [IQRs, 1.0 to 12.0 and 1.0 to 10.0 days, respectively]). Most patients with ALF were severely ill at study enrollment, with nearly 50% having grade 3 or 4 (that is, deep) HE throughout. Biochemical liver test results varied widely but indicated severe illness in most patients (Appendix Table 1). Appendix Table 1. Laboratory Values at Study Enrollment Laboratory Tests fo

Hypoxic conformance of metabolism in primary rat hepatocytes: A model of hepatic hibernation

Following prolonged hypoxia, mammalian cells invoke adaptive mechanisms to enhance oxygen delivery and promote energy conservation. We previously reported that hepatocytes subjected to prolonged moderate hypoxia (PO2 = 20‐50 mmHg for >3 hours) demonstrated a reversible inhibition of cellular respiration with maintenance of cell viability, associated with a decrease in mitochondrial adenosine triphosphate (ATP) synthesis; acute hypoxia (similar PO2 for <30 minutes) did not induce a similar suppression of respiration and ATP synthesis. In the current study, using an in vitro model of primary rat hepatocytes, we measured the changes in metabolic demand for ATP during hypoxic conformance, and tested whether viability is maintained by preferentially suppressing nonessential processes while sustaining processes essential for maintaining cell homeostasis. In addition, the rate of recovery of oxygen consumption and ATP concentrations following reoxygenation after prolonged and acute hypoxia/anoxia was compared. Oxygen consumption and ATP concentrations decreased during prolonged hypoxia compared with acute hypoxia. However, ouabain‐inhibitable respiration did not decrease during prolonged hypoxia, indicating that membrane Na+/K+ ATPase activity, an essential process for cell viability, was maintained. In contrast, ATP‐dependent glucuronidation and sulfation of acetaminophen, deemed “non‐essential” processes, were decreased significantly compared with normoxic cells. After reoxygenation, cells exposed to prolonged moderate hypoxia demonstrated a more rapid recovery of respiration compared to acute hypoxia/anoxia. Conclusion: This “hepatic hibernation” during prolonged moderate hypoxia may represent an anticipatory adaptation that seeks to maintain cell viability while delaying or preventing the onset of lethal hypoxia, and facilitates rapid recovery after the resumption of normoxia. (HEPATOLOGY 2007.)