Elizabeth Sizer

Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure

High circulating ammonia concentrations are common in patients with acute liver failure (ALF) and are associated with hepatic encephalopathy (HE) and intracranial hypertension (ICH). Other risk factors are poorly characterized. We evaluated the relation of the admission arterial ammonia concentration and other clinical variables with the development of HE and ICH. Arterial ammonia was measured on admission to the intensive care unit in 257 patients; 165 had ALF and severe HE, and there were 3 control groups: acute hepatic dysfunction without severe HE (n = 50), chronic liver disease (n = 33), and elective surgery (n = 9). Variables associated with ICH and HE were investigated with regression analysis. Ammonia was higher in ALF patients than controls. An independent risk factor for the development of severe HE and ICH, a level greater than 100 μmol/L predicted the onset of severe HE with 70% accuracy. The model for end‐stage liver disease (MELD) score was also independently predictive of HE, and its combination with ammonia increased specificity and accuracy. ICH developed in 55% of ALF patients with a level greater than 200 μmol/L, although this threshold failed to identify most cases. After admission, ammonia levels remained high in those developing ICH and fell in those who did not. Youth, a requirement for vasopressors, and renal replacement therapy were additional independent risk factors. Conclusion: Ammonia is an independent risk factor for the development of both HE and ICH. Additional MELD scoring improved the prediction of HE. Factors other than ammonia also appear important in the pathogenesis of ICH. Ammonia measurements could form part of risk stratification for HE and ICH, identifying patients for ammonia‐lowering therapies and invasive monitoring. (HEPATOLOGY 2007.)

Outcome after wait-listing for emergency liver transplantation in acute liver failure: A single centre experience

BACKGROUND/AIMS Though emergency liver transplantation (ELT) is an established treatment for severe acute liver failure (ALF), outcomes are inferior to elective surgery. Despite prioritization, many patients deteriorate, becoming unsuitable for ELT. METHODS We examined a single-centre experience of 310 adult patients with ALF registered for ELT over a 10-year period to determine factors associated with failure to transplant, and in those patients undergoing ELT, those associated with 90-day mortality. RESULTS One hundred and thirty-two (43%) patients had ALF resulting from paracetamol and 178 (57%) from non-paracetamol causes. Seventy-four patients (24%) did not undergo surgery; 92% of these died. Failure to transplant was more likely in patients requiring vasopressors at listing (hazard ratio 1.9 (95% CI 1.1-3.6)) paracetamol aetiology (2.5 (1.4-4.6)) but less likely in blood group A (0.5 (0.3-0.9)). Post-ELT survival at 90-days and one-year increased from 66% and 63% in 1994-1999 to 81% and 79% in 2000-2004 (p<0.01). Four variables were associated with post-ELT mortality; age >45 years (3 (1.7-5.3)), vasopressor requirement (2.2 (1.3-3.8), transplantation before 2000 (1.9 (1.1-3.3)) and use of high-risk grafts (2.3 (1.3-4.2). CONCLUSIONS The data indicate improved outcomes in the later era, despite higher level patient dependency and greater use of high-risk grafts, through improved graft/recipient matching.

Increased model for end‐stage liver disease score at the time of liver transplant results in prolonged hospitalization and overall intensive care unit costs

Organ allocation based on Model for End‐Stage Liver Disease (MELD) resulted in decreased waiting list mortality in the United States. However, reports suggest an increase in resource utilization as a consequence of this. The aim of this study is to assess the correlation of MELD at transplant with post–liver transplant (LT) intensive care unit (ICU) costs. We assessed clinical and demographic variables of 402 adult patients who underwent LT at Kings College Hospital, London, UK, between January 2000 and December 2003. ICU cost calculations were based on the therapeutic intervention scoring system (TISS). Graft quality was assessed using the donor risk index (DRI). Patients with a MELD score > 24 had significantly longer post‐LT ICU stay (P < 0.0001) and total post‐LT hospital stay (P = 0.008). In addition, they had significantly increased TISS scores, ICU cost, and need for renal replacement therapy (RRT) (P < 0.001). MELD score (by point) and MELD > 24 was associated with prolonged ICU stay (P = 0.004 and P = 0.005, respectively). On univariate analysis, etiology of alcohol‐related liver disease (ALD), repeat LT, Budd‐Chiari syndrome, and refractory ascites were associated with prolonged ICU stay. Using multivariate analysis, MELD > 24, refractory ascites, ALD and Budd‐Chiari syndrome were associated with prolonged ICU stay. There was no association between using grafts with higher DRI and longer ICU stay, need for RRT, increased cost, or hospital survival on univariate analyses (P = not significant). Use of MELD as a method of organ allocation results in significant increase in ICU cost after LT. Using TISS as surrogate marker for ICU costs reveals that the cost implications are related to the need for RRT and prolonged ICU stay. Liver Transpl 16:668‐677, 2010.

Intensive Care Management of Acute Liver Failure

The care of patients with acute liver failure (ALF) presents unique clinical challenges to the practicing physician. It combines the management of rapidly progressive, severe multiple organ failure, unpredictable and often devastating complications, and a need for urgent decision-making in the application of emergency liver transplantation. However, outcomes for patients with this condition have shown progressive improvement over the last four decades. In this article, practical clinical approaches to the care of critically ill patients with ALF are discussed, taking an organ systems-based perspective and discussing the underlying pathophysiological processes and major areas of uncertainty as to what constitutes best practice.

Safety and efficacy of combined use of sildenafil, bosentan, and iloprost before and after liver transplantation in severe portopulmonary hypertension†

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild‐to‐moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second−1 cm−5. The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long‐term consequences. Liver Transpl 14:287–291, 2008.

Bacteremia, acute physiology and chronic health evaluation II and modified end stage liver disease are independent predictors of mortality in critically ill nontransplanted patients with acute on chronic liver failure

Objectives:To determine what physiological and biochemical factors predict development of bacteremia in nontransplanted patients with acute on chronic liver failure and, on diagnosis of bacteremia, what is the natural history of bacteremic patients versus control subjects (acute on chronic liver failure). Interventions:None. Design:Retrospective analysis of data collected prospectively and entered into a dedicated physiology database. Setting:Specialist liver intensive therapy unit. Patients:Critically ill non-transplanted patients with acute on chronic liver failure admitted between January 2003 and July 2005. Measurements and Main Results:One hundred eighty-four patients were defined with acute on chronic liver failure; 67 (36%) had bacteremia. One hundred seventeen (64%) patients did not (acute on chronic liver failure). Fifty-eight percent of isolates were Gram-negative organisms, 36% were Gram-positives, and 6% fungemia. Median time to first bacteremia was 8 days (range, 3–12 days). On admission (univariate), bacteremic patients had significantly higher Modified End Stage Liver Disease scores (27 vs. 24, p = .037), Acute Physiology and Chronic Health Evaluation II scores (23 vs. 21, p = .049), and greater degrees of encephalopathy (Glasgow Coma Scale score 10 vs. 12, p = .001). During their liver intensive therapy unit course, bacteremic patients had significantly greater requirements for renal replacement therapy (64% vs. 49%, p = .043), mechanical ventilation (88% vs. 68%, p = .002), and a longer median liver intensive therapy unit stay (16 vs. 5 days, p < .001). Survival to hospital discharge was worse in the bacteremic group (25% vs. 56%, p < .001). Multivariate analysis (logistic regression) was performed separately modeling with Acute Physiology and Chronic Health Evaluation II and Modified End Stage Liver Disease. In the first model, Acute Physiology and Chronic Health Evaluation II (odds ratio 1.24) and bacteremia (2.24) were independent predictors of mortality. In the later model, Modified End Stage Liver Disease (odds ratio, 1.06), requirement for renal replacement therapy (3.08), Glasgow Coma Scale (0.72), and bacteremia (2.30) were significant. Both models performed similarly (Modified End Stage Liver Disease area under the receiver operating characteristic curve, 0.864; Acute Physiology and Chronic Health Evaluation II, 0.862). Conclusions:In nontransplanted patients with acute on chronic liver failure, bacteremia was associated with increased severity of illness on admission, greater requirements for organ support, and independently adversely impacted on survival. Higher Acute Physiology and Chronic Health Evaluation II and Modified End Stage Liver Disease scores were also independently predictive of mortality.

Predictors of bacteraemia and mortality in patients with acute liver failure

PurposeTo determine what physiological and biochemical factors predict development of bacteraemia and mortality in patients with acute liver failure (ALF).MethodsRetrospective analysis of 206 ALF patients admitted to a specialist liver intensive therapy unit (LITU) from January 2003 to July 2005 (data collected prospectively).ResultsA total of 206 patients were defined with ALF: 72 (35%) suffered bacteraemia (BAClf) and 134 (65%) did not (NBAClf). Gram positive organisms were observed in 44% of isolates, gram negatives in 52% and fungaemia in 4%. Median time to first bacteraemia was 10 (7–16) days. On admission, BAClf patients had higher SIRS scores and degrees of hepatic encephalopathy (HE). During their LITU course, BAClf patients had significantly increased requirements for renal replacement therapy (RRT), mechanical ventilation, and longer median LITU stay. Multivariate analysis (logistical regression) demonstrated significant predictors of bacteraemia on admission were HE grade >2 (Odds Ratio 1.6) and SIRS score >1 (OR 2.7). In all patients, independent predictors of mortality (logistical) were age (OR 1.41), maximum HE grade pre-intubation (1.76), Lactate (1.14) and Acute Physiology and Chronic Health Evaluation II score (APACHEII) (1.09), but not bacteraemia. Transplantation was protective (OR 0.20).ConclusionIn this study, severity of hepatic encephalopathy and SIRS score >1 were predictive of bacteraemia. APACHEII was independently predictive of mortality in all ALF patients but not bacteraemia.

The impact of organ dysfunction in cirrhosis: survival at a cost?

BACKGROUND & AIMS The incidence of cirrhosis and subsequent development of organ dysfunction (OD) requiring intensive care unit (ICU) support is rising. Historically, critically ill cirrhotics are perceived as having poor prognosis and substantial cost of care. METHODS The aim was to prospectively analyse resource utilisation and cost of a large cohort of patients (n=660) admitted to a Liver ICU from 2000 to 2007 with cirrhosis and OD. Child Pugh, MELD, SOFA, APACHE II, and organ support requirements were collected. The Therapeutic Intervention Scoring System (TISS) score, a validated tool for estimating cost in ICU, was calculated daily. Logistic regression was used to determine independent predictors of increased cost. RESULTS Alcohol was the most common etiology (47%) and variceal bleeding (VB) the most common reason for admission (35%). Invasive ventilatory support was required in 74% of cases, vasopressors in 49%, and 50% required renal replacement therapy. Forty-nine per cent of non-transplanted patients survived to ICU discharge. Median TISS score and ICU cost per patient were 261 and €14,139, respectively. VB patients had the highest survival rates (53% vs. 24%; p<0.001) and lower associated cost. A combination of VB (OR 0.48), need for ventilation (OR 2.81), low PO(2)/FiO(2) on admission (OR 0.97), and lactate (OR 0.93) improved cost prediction on multivariate analysis (AUROC 0.7; p<0.001) but organ failure scores per se were poor predictors of cost. CONCLUSIONS Patients with cirrhosis and OD result in considerable resource expenditure but have acceptable hospital survival. Further health economic assessment and outcome prediction tools are required to appropriately target resource utilisation.

Aerobic capacity during cardiopulmonary exercise testing and survival with and without liver transplantation for patients with chronic liver disease

Chronic liver disease (CLD) is associated with muscle wasting, reduced exercise tolerance and aerobic capacity (AC). Measures of AC determined with cardiopulmonary exercise testing (CPET) may predict survival after liver transplantation (LT), but the relationship with nontransplant outcomes is uncertain. In patients assessed for LT, we examined the relationship of CPET AC parameters with the severity of liver disease, nutritional state, and survival with and without LT. Patients assessed for elective first LT who underwent CPET and an anthropometric assessment at a single center were studied. CPET‐derived measures of AC that were evaluated included the peak oxygen consumption (VO2 peak) and the anaerobic threshold (AT). Three hundred ninety‐nine patients underwent CPET, and 223 underwent LT; 45% of the patients had a VO2 peak < 50% of the predicted value, and 31% had an AT < 9 mL/kg/minute. The VO2 peak and AT values correlated with the Model for End‐Stage Liver Disease score, but they more closely correlated with serum sodium and albumin levels. The handgrip strength correlated strongly with the VO2 peak. Patients with impaired AC had prolonged hospitalization after LT, and nonsurvivors had lower AT values than survivors 1 year after transplantation (P < 0.05); this was significant in a multivariate analysis. One hundred seventy‐six patients did not undergo LT; the 1‐year mortality rate was 34.6%. The AT (P < 0.05) and VO2 peak values (P < 0.001) were lower for nonsurvivors. In a multivariate analysis, AT was independently associated with nonsurvival. In conclusion, AC was markedly impaired in many patients with CLD. In patients who did not undergo transplantation, impaired AT was predictive of mortality, and in patients undergoing LT, it was related to postoperative hospitalization and survival. AC should be evaluated as a modifiable factor for improving patient survival whether or not LT is anticipated. Liver Transpl 20:54–62, 2014.

Increased Survival for Patients With Cirrhosis and Organ Failure in Liver Intensive Care and Validation of the Chronic Liver Failure–Sequential Organ Failure Scoring System

BACKGROUND & AIMS During the past decade, survival has increased among patients admitted to general intensive care units, but it is not clear if it has increased for patients admitted with cirrhosis and organ failure. The chronic liver failure-sequential organ failure assessment (CLIF-SOFA) recently was developed as an adaptation to the SOFA to predict outcomes of patients, but requires validation. We investigated changes in outcomes of patients with cirrhosis and organ failure since 2000, compared the abilities of SOFA and CLIF-SOFA to predict patient survival, and validated the CLIF-SOFA system. METHODS In a retrospective study, we collected data from 971 patients (median age, 52 y; age range, 16-90 y; 62% male) with cirrhosis (54% alcohol associated, 12% viral, and 34% other causes). The patients were admitted under emergency conditions from January 1, 2000, to December 31, 2010, to a liver intensive therapy unit in the United Kingdom. Patient survival while in the hospital was compared with measures of illness severity, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, model for end-stage liver disease (MELD) scores, SOFA scores, and CLIF-SOFA scores. RESULTS Patients had a median APACHE II score of 21 (range, 5-50) and a median MELD score of 23 (range, 6-40). The median APACHE II score at admission decreased from 23 to 22 over the study period (P < .001), whereas the median MELD score at admission decreased from 23 to 18 (P < .001). Overall survival until hospital discharge was 51%; this value increased from 40% in 2000 to 63% in 2010 (P < .001). The unadjusted odds ratio for change in mortality/year was 0.87 (95% confidence interval, 0.83-0.91; P < .001). The APACHE II score adjusted odds ratio for mortality was 0.89 (95% confidence interval, 0.84-0.93; P < .001). The etiology of cirrhosis was not associated with a significant difference in survival. CLIF-SOFA and SOFA scores at the time of admission predicted patient survival with area under the receiver operating curve (AUROC) values of 0.813 and 0.799, respectively; the scores at 48 hours after admission predicted survival with AUROC values of 0.853 and 0.840, and scores after 1 week predicted survival with AUROC values of 0.842 and 0.844, respectively. These AUROC values were higher than those obtained from APACHE II or MELD scores. CONCLUSIONS The proportion of patients with cirrhosis who survived after admission to intensive care increased from 2000 to 2010. SOFA and CLIF-SOFA scores during the first week of critical care appear to have similar abilities to predict patient survival.