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.

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.

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.

Acute kidney injury in patients admitted to a liver intensive therapy unit with paracetamol-induced hepatotoxicity.

BACKGROUND: Paracetamol overdose can cause acute kidney injury (AKI) independent of its hepatotoxic effects. We aimed to determine the prevalence of AKI (AKI Network definition) in those with paracetamol-induced hepatotoxicity, identify factors associated with development, assess impact on the outcomes of patient survival and length of stay and determine the proportion of patients recovering renal function (estimated glomerular filtration rate > 60 mL/min) by the time of hospital discharge or transfer out. METHODS: Between 2000 and 2007, patients admitted to a tertiary referral liver intensive therapy unit (LITU) with paracetamol-induced hepatotoxicity were identified from a prospectively maintained database and evaluated. RESULTS: Those receiving a liver transplant were excluded (n = 54), leaving 302 patients. Renal function remained normal in 21%, the remainder developing AKI (Stages 1-8%, 2-6% and 3-65%). Vasopressor requirement, mechanical ventilation, higher admission phosphate and lower sodium levels along with a higher Day 3 lactate and lower haematocrit were associated with AKI. In survivors with AKI, 51% had recovery of renal function, while 7% remained dialysis dependant although none required it chronically. Overall, there was 25% mortality, all having Stage 3 AKI but AKI was only a univariate not multivariate predictor of reduced patient survival. AKI independently predicted longer length of stay. CONCLUSIONS: AKI is very common in critically ill patients with paracetamol-induced hepatotoxicity requiring LITU admission. Although outcomes are poorer with AKI than with normal renal function, they are better than those found in other intensive therapy unit populations. Gradual recovery of renal function is seen in all patients.

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.

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 King's 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.

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.

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

UNLABELLED: 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 mumol/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 mumol/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.

Percutaneous tracheostomy in patients with severe liver disease and a high incidence of refractory coagulopathy: a prospective trial.

BACKGROUND: To assess the safety of percutaneous dilational tracheostomy (PDT) performed by experienced operators in critically ill patients with liver disease and coagulopathy. METHODS: Prospective cohort study in a ten bed specialist liver intensive care unit of a tertiary university teaching hospital. Sixty consecutive patients in need of tracheostomy insertion. Patients were categorized as having refractory coagulopathy if their platelet count was < or = 50 x 10(9) cells/L or the INR > 1.5 on the day of and the subsequent 72 hours following PDT despite clotting support. RESULTS: Twenty five patients fulfilled the definition criteria of refractory coagulopathy. There was no significant difference in the number of adverse incidents between groups. Only 1 patient in the coagulopathy group had a severe bleeding complication, however this did not require open surgical intervention. The rate of clinically relevant early complications in all patients was not higher than expected (n = 7, 12%). Resource utilisation was higher for patients with coagulopathy, who received significantly more platelet transfusions over the 3 day period (80 vs 49 units, p = 0.009) and demonstrated a trend towards increased fresh frozen plasma requirements (p = 0.059). The number of patients requiring platelet transfusion was higher in the coagulopathy group (21/25 versus 20/35 p = 0.029). Hospital survival did not differ between groups. CONCLUSION: PDT is safe and not contraindicated in patients with severe liver disease and refractory coagulopathy.

Development and validation of a dynamic outcome prediction model for paracetamol-induced acute liver failure: a cohort study.

BACKGROUND: Early, accurate prediction of survival is central to management of patients with paracetamol-induced acute liver failure to identify those needing emergency liver transplantation. Current prognostic tools are confounded by recent improvements in outcome independent of emergency liver transplantation, and constrained by static binary outcome prediction. We aimed to develop a simple prognostic tool to reflect current outcomes and generate a dynamic updated estimation of risk of death. METHODS: Patients with paracetamol-induced acute liver failure managed at intensive care units in the UK (London, Birmingham, and Edinburgh) and Denmark (Copenhagen) were studied. We developed prognostic models, excluding patients who underwent transplantation, using Cox proportional hazards in a derivation dataset, and tested in initial and recent external validation datasets. Mortality was estimated in patients who had emergency liver transplantation. Model discrimination was assessed using area under receiver operating characteristic curve (AUROC) and calibration by root mean square error (RMSE). Admission (day 1) variables of age, Glasgow coma scale, arterial pH and lactate, creatinine, international normalised ratio (INR), and cardiovascular failure were used to derive an initial predictive model, with a second (day 2) model including additional changes in INR and lactate. FINDINGS: We developed and validated new high-performance statistical models to support decision making in patients with paracetamol-induced acute liver failure. Applied to the derivation dataset (n=350), the AUROC for 30-day survival was 0·92 (95% CI 0·88-0·96) using the day 1 model and 0·93 (0·88-0·97) using the day 2 model. In the initial validation dataset (n=150), the AUROC for 30-day survival was 0·89 (0·84-0·95) using the day 1 model and 0·90 (0·85-0·95) using the day 2 model. Assessment of calibration using RMSE in prediction of 30-day survival gave values of 0·1642 for the day 1 model and 0·0626 for the day 2 model. In the external validation dataset (n=412), the AUROC for 30-day survival was 0·91 (0·87-0·94) using the day 1 model and 0·91 (0·88-0·95) using the day 2 model, and assessment of calibration using RMSE gave values of 0·079 for the day 1 model and 0·107 for the day 2 model. Applied to patients who underwent emergency liver transplantation (n=116), median predicted 30-day survival was 51% (95% CI 33-85). INTERPRETATION: The models developed here show very good discrimination and calibration, confirmed in independent datasets, and suggest that many patients undergoing transplantation based on existing criteria might have survived with medical management alone. The role and indications for emergency liver transplantation in paracetamol-induced acute liver failure require re-evaluation. FUNDING: Foundation for Liver Research.

The effect of body position on compartmental intra-abdominal pressure following liver transplantation.

BACKGROUND: Current assumptions rely on intra-abdominal pressure (IAP) being uniform across the abdominal cavity. The abdominal contents are, however, a heterogeneous mix of solid, liquid and gas, and pressure transmission may not be uniform. The current study examines the upper and lower IAP following liver transplantation. METHODS: IAP was measured directly via intra-peritoneal catheters placed at the liver and outside the bladder. Compartmental pressure data were recorded at 10-min intervals for up to 72 h following surgery, and the effect of intermittent posture change on compartmental pressures was also studied. Pelvic intra-peritoneal pressure was compared to intra-bladder pressure measured via a FoleyManometer. RESULTS: A significant variation in upper and lower IAP of 18% was observed with a range of differences of 0 to 16 mmHg. A sustained difference in inter-compartmental pressure of 4 mmHg or more was present for 23% of the study time. Head-up positioning at 30° provided a protective effect on upper intra-abdominal pressure, resulting in a significant reduction in all patients. There was excellent agreement between intra-bladder and pelvic pressure. CONCLUSIONS: A clinically significant variation in inter-compartmental pressure exists following liver transplantation, which can be manipulated by changes to body position. The existence of regional pressure differences suggests that IAP monitoring at the bladder alone may under-diagnose intra-abdominal hypertension and abdominal compartment syndrome in these patients. The upper and lower abdomen may need to be considered as separate entities in certain conditions.

High values of intrathoracic blood volume in hepatopulmonary syndrome.

Advanced haemodynamic monitoring via transpulmonary thermodilution (TPTD) devices has gained popularity in recent years. The intrathoracic blood volume index (ITBVI) and the global end-diastolic blood volume index (GEDVI) calculated by single indicator TPTD devices have been shown to reliably estimate cardiac preload. The normal range of values for ITBVI is provided by the manufacturers. Evidence is now emerging that certain clinical scenarios can lead to increased ITBVI values. We report two cases of persistently high ITBVI in patients with hepatic cirrhosis complicated by hepatopulmonary syndrome.

Predictors of bacteraemia and mortality in patients with acute liver failure.

PURPOSE: To determine what physiological and biochemical factors predict development of bacteraemia and mortality in patients with acute liver failure (ALF). METHODS: Retrospective analysis of 206 ALF patients admitted to a specialist liver intensive therapy unit (LITU) from January 2003 to July 2005 (data collected prospectively). RESULTS: A 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). CONCLUSION: In 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.

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.

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.

Change in model for end-stage liver disease score on the transplant waiting list predicts survival in patients undergoing liver transplantation.

Allocation of donor livers through the model for end-stage liver disease (MELD) score has resulted in a fall in waiting list deaths in the United States. Change in MELD score (DeltaMELD) whilst awaiting transplant has been suggested as a method of refining organ allocation. Our aims were to analyse the effect of DeltaMELD between listing and transplant, and examine its impact on patient survival, intensive care stay and hospital stay in 402 patients transplanted for chronic liver disease at a single centre. Patients who had a DeltaMELD score of >+1 point were more likely to die in hospital following transplant (P < 0.05) and had a significantly worse 12- and 36-month survival post transplant (P < 0.0001) when compared with patients with DeltaMELD