Maria Torrens

Minimal Hepatic Encephalopathy Is Associated With Falls

OBJECTIVES:Minimal hepatic encephalopathy (MHE) reduces quality of life and impacts daily functioning. It is known to impair fitness to drive, but deficits in attention and reaction may also be associated with falls. Falls may have important consequences in patients with cirrhosis due to coagulopathy, osteoporosis, and operative risk. However, the relationship between MHE and falls has not yet been evaluated. The objective of this study is to retrospectively investigate whether MHE is associated with falls in patients with cirrhosis.METHODS:We included 130 cirrhotic outpatients and 43 controls. MHE was diagnosed according to the results of the psychometric hepatic encephalopathy score (PHES). We recorded the reported incidence and number of falls in the 12 months before the study, the severity of injuries, and the need for healthcare services.RESULTS:Forty-five (34.6%) patients with cirrhosis exhibited MHE. The proportion of patients with MHE that reported falls (40%) was higher than those without MHE (12.9%, P<0.001), which was similar to controls (11.6%). In patients with MHE, there was a higher need for primary healthcare services (8.8 vs. 0%, P=0.004) and hospitalization (6.6 vs. 2.3%, P=0.34) due to falls than in patients without MHE. Patients on psychoactive drugs (n=21) showed a stronger association between MHE and falls: 6/8 (75%) patients with MHE presented falls vs. 2/13 (15.3%) patients without MHE (P=0.01). In patients not receiving psychoactive drugs (n=109), the incidence of falls was 12/37 (32.4%) in patients with MHE vs. 9/72 (12.5%) in those without MHE (P=0.01). Multivariate analysis showed that MHE (odds ratio (OR): 2.91, 95% confidence interval (CI): 1.13–7.48, P=0.02), previous encephalopathy (OR: 2.87, 95% CI: 1.10–7.50, P=0.03), and antidepressant therapy (OR: 3.91, 95% CI: 0.96–15.9, P=0.05) were independent factors associated to previous falls.CONCLUSIONS:Falls are more frequent in cirrhotic patients with MHE, particularly in those on treatment with psychoactive drugs, and are a significant cause for healthcare and hospitalization requirements.

Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: A randomized double-blind study

BACKGROUND & AIMS Episodic hepatic encephalopathy is frequently precipitated by factors that induce circulatory dysfunction, cause oxidative stress-mediated damage or enhance astrocyte swelling. The administration of albumin could modify these factors and improve the outcome of hepatic encephalopathy. The aim of this study is to assess the efficacy of albumin in a multicenter, prospective, double-blind, controlled trial (ClinicalTrials.gov number, NCT00886925). METHODS Cirrhotic patients with an acute episode of hepatic encephalopathy (grade II-IV) were randomized to receive albumin (1.5g/kg on day 1 and 1.0g/kg on day 3) or isotonic saline, in addition to the usual treatment (laxatives, rifaximin 1200mg per day). The primary end point was the proportion of patients in which encephalopathy was resolved on day 4. The secondary end points included survival, length of hospital stay, and biochemical parameters. RESULTS Fifty-six patients were randomly assigned to albumin (n=26) or saline (n=30) stratified by the severity of HE. Both groups were comparable regarding to demographic data, liver function, and precipitating factors. The percentage of patients without hepatic encephalopathy at day 4 did not differ between both groups (albumin: 57.7% vs. saline: 53.3%; p>0.05). However, significant differences in survival were found at day 90 (albumin: 69.2% vs. saline: 40.0%; p=0.02). CONCLUSIONS Albumin does not improve the resolution of hepatic encephalopathy during hospitalization. However, differences in survival after hospitalization suggest that the development of encephalopathy may identify a subgroup of patients with advanced cirrhosis that may benefit from the administration of albumin.

Safety of ornithine phenylacetate in cirrhotic decompensated patients: an open-label, dose-escalating, single-cohort study.

Aims: Confirm in patients with cirrhosis and gastrointestinal bleeding the safety of ornithine phenylacetate (OP) and assess the pharmacokinetic profile of OP and its effects on plasma ammonia. Background: OP is a drug that has shown experimentally to decrease hyperammonemia and improve hepatic encephalopathy. OP is safe in healthy subjects and in stable patients with cirrhosis, but there are no data in decompensated cirrhosis. Methods: We performed a study to assess safety and tolerance of OP in cirrhotic patients after an episode of upper gastrointestinal bleeding.Ten patients were included within 24 hours of an upper gastrointestinal bleeding. OP was administered as a continuous infusion up to a maximum of 10 g/24 h (0.42 g/h) for 5 days. The infusion was started at 33% of the target dose and increased at 12-hour intervals achieving target dose at 24 hours. Ammonia was also assessed in control group of 10 patients. Results: No severe adverse events were observed. Mild adverse events were reported in 4 patients. Plasma ammonia (baseline: 80±43 &mgr;mol/L) showed a progressive drop between baseline and 36 hours (42±15 &mgr;mol/L), 72 hours (44±15 &mgr;mol/L), 96 hours (40±24 &mgr;mol/L), and 120 hours (33±14 &mgr;mol/L). Plasma ammonia at 24 hours was significantly higher in the control group. Plasma glutamine showed a significant decrease (−37% at day 5) and its excretion in urine as phenylacetylglutamine, a progressive rise (52±35 mmol at day 5). Conclusions: OP is a safe and well-tolerated drug in decompensated cirrhotics that may decrease plasma ammonia by inducing its appearance as phenylacetylglutamine in urine.

Cognitive dysfunction in cirrhosis is associated with falls: a prospective study.

Falls are frequent among patients with debilitating disorders and can have a serious effect on health status. Mild cognitive disturbances associated with cirrhosis may increase the risk for falls. Identifying subjects at risk may allow the implementation of preventive measures. Our aim was to assess the predictive value of the Psychometric Hepatic Encephalopathy Score (PHES) in identifying patients likely to sustain falls. One hundred and twenty‐two outpatients with cirrhosis were assessed using the PHES and were followed at specified intervals. One third of them exhibited cognitive dysfunction (CD) according to the PHES (<−4). Seventeen of the forty‐two patients (40.4%) with CD had at least one fall during follow‐up. In comparison, only 5 of 80 (6.2%) without CD had falls (P < 0.001). Fractures occurred in 4 patients (9.5%) with CD, but in no patients without CD (P = 0.01). Patients with CD needed more healthcare (23.8% versus 2.5%; P < 0.001), more emergency room care (14.2% versus 2.5%; P = 0.02), and more hospitalization (9.5% versus 0%; P = 0.01) as a result of falls than patients without CD. Patients taking psychoactive treatment (n = 21) had a higher frequency of falls, and this was related to an abnormal PHES. In patients without psychoactive treatment (n = 101), the incidence of falls was 32.4% in patients with CD versus 7.5% in those without CD (P = 0.003). In the multivariate analysis, CD was the only independent predictive factor of falls (odds ratio, 10.2; 95% confidence interval, 3.4‐30.4; P < 0.001). The 1‐year probability of falling was 52.3% in patients with CD and 6.5% in those without (P < 0.001). Conclusion: An abnormal PHES identifies patients with cirrhosis who are at risk for falls. This psychometric test may be useful to promote awareness of falls and identify patients who may benefit from preventive strategies. (HEPATOLOGY 2012;55:1922–1930)

Falls and cognitive dysfunction impair health-related quality of life in patients with cirrhosis.

Introduction Falls are frequent in patients with cirrhosis and cognitive dysfunction and can deteriorate health-related quality of life (HRQoL). Objective To evaluate the relationship between previous falls and HRQoL in patients with cirrhosis. Methods We measured HRQoL in 118 outpatients with cirrhosis using the Medical Outcomes Study Short Form (SF-36) questionnaire, grouping items into the Physical Component Score (PCS) and the Mental Component Score (MCS). The incidence of accidental falls in the 12 months before the study was assessed using a specific questionnaire. The Psychometric Hepatic Encephalopathy Score (PHES) was administered to assess cognitive dysfunction. We considered cognitive dysfunction if PHES was less than −4. HRQoL was compared between patients with falls and patients without falls. Results HRQoL was lower in patients with previous falls than in patients without falls (P<0.05 in all domains of SF-36). In the multivariate analysis, the only independent factors that affected the HRQoL in the PCS were (B coefficient, 95% confidence interval) cognitive dysfunction (6.5, 3.2–9.7, P<0.001), previous variceal bleeding (3.9, 0.4–7.3, P=0.02), anemia (3.2, 0.07–6.4, P=0.049), and hyponatremia (9.3, 1.07–17.5, P<0.02). Multivariate analysis for MCS showed the independent factors for worse HRQoL were female sex (12.2, 6.9–17.5, P<0.001) and previous falls (10.3, 4.0–16.5, P=0.001). Conclusion Falls and cognitive dysfunction are independent factors associated with impaired HRQoL in patients with cirrhosis. Strategies addressed to improve HRQoL in these patients should consider the treatment of cognitive dysfunction and prevention of falls.

Impact of ornithine phenylacetate (OCR-002) in lowering plasma ammonia after upper gastrointestinal bleeding in cirrhotic patients

Background: Ornithine phenylacetate (OP) has been proven effective in lowering ammonia plasma levels in animals, and to be well tolerated in cirrhotic patients. A trial to assess OP efficacy in lowering plasma ammonia levels versus placebo in cirrhotic patients after an upper gastrointestinal bleeding was performed. The primary outcome was a decrease in venous plasma ammonia at 24 hours. Methods: A total of 38 consecutive cirrhotic patients were enrolled within 24 hours of an upper gastrointestinal bleed. Patients were randomized (1:1) to receive OP (10 g/day) or glucosaline for 5 days. Results: The primary outcome was not achieved. A progressive decrease in ammonia was observed in both groups, being slightly greater in the OP group, with significant differences only at 120 hours. The subanalysis according to Child–Pugh score showed a statistically significant ammonia decrease in Child–Pugh C-treated patients at 36 hours, as well as in the time-normalized area under the curve (TN-AUC) 0–120 hours in the OP group [40.16 μmol/l (37.7–42.6); median (interquartile range) (IQR)] versus placebo group [65.5 μmol/l (54–126);p = 0.036]. A decrease in plasma glutamine levels was observed in the treated group compared with the placebo group, and was associated with the appearance of phenylacetylglutamine in urine. Adverse-event frequency was similar in both groups. No differences in hepatic encephalopathy incidence were observed. Conclusions: OP failed to significantly decrease plasma ammonia at the given doses (10 g/day). Higher doses of OP might be required in Child–Pugh A and B patients. OP appeared well tolerated.

Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial

BACKGROUND & AIMS Patients with decompensated cirrhosis on the waiting list for liver transplantation (LT) commonly develop complications that may preclude them from reaching LT. Circulatory dysfunction leading to effective arterial hypovolemia and activation of vasoconstrictor systems is a key factor in the pathophysiology of complications of cirrhosis. The aim of this study was to investigate whether treatment with midodrine, an alpha-adrenergic vasoconstrictor, together with intravenous albumin improves circulatory dysfunction and prevents complications of cirrhosis in patients awaiting LT. METHODS A multicenter, randomized, double-blind, placebo-controlled trial (NCT00839358) was conducted, including 196 consecutive patients with cirrhosis and ascites awaiting LT. Patients were randomly assigned to receive midodrine (15-30 mg/day) and albumin (40 g/15 days) or matching placebos for one year, until LT or drop-off from inclusion on the waiting list. The primary endpoint was incidence of any complication (renal failure, hyponatremia, infections, hepatic encephalopathy or gastrointestinal bleeding). Secondary endpoints were mortality, activity of endogenous vasoconstrictor systems and plasma cytokine levels. RESULTS There were no significant differences between both groups in the probability of developing complications of cirrhosis during follow-up (p = 0.402) or one-year mortality (p = 0.527). Treatment with midodrine and albumin was associated with a slight but significant decrease in plasma renin activity and aldosterone compared to placebo (renin -4.3 vs. 0.1 ng/ml.h, p < 0.001; aldosterone -38 vs. 6 ng/dl, p = 0.02, at week 48 vs. baseline). Plasma norepinephrine only decreased slightly at week 4. Neither arterial pressure nor plasma cytokine levels changed significantly. CONCLUSIONS In patients with cirrhosis awaiting LT, treatment with midodrine and albumin, at the doses used in this study, slightly suppressed the activity of vasoconstrictor systems, but did not prevent complications of cirrhosis or improve survival. LAY SUMMARY Patients with cirrhosis who are on the liver transplant waiting list often develop complications which prevent them from receiving a transplant. Circulatory dysfunction is a key factor behind a number of complications. This study was aimed at investigating whether treating patients with midodrine (a vasoconstrictor) and albumin would improve circulatory dysfunction and prevent complications. This combined treatment, at least at the doses administered in this study, did not prevent the complications of cirrhosis or improve the survival of these patients.

243 ALBUMIN FOR ACUTE EPISODIC HEPATIC ENCEPHALOPATHY (ALFAE STUDY)

242 HYPONATREMIA IN HOSPITALIZED PATIENTS WITH CIRRHOSIS: INTERIM DATA FROM AN OBSERVATIONAL, PROSPECTIVE, MULTI-CENTER, GLOBAL HYPONATREMIA REGISTRY S. Sigal, A. Amin, J. Chiong, J. Dasta, A. Greenberg, J. Verbalis, J. Chiodo, K. Friend. New York University School of Medicine, New York, NY, University of California, Irvine, Loma Linda University, Loma Linda, CA, University of Texas College of Pharmacy, Austin, TX, Duke University Medical Center, Durham, NC, Georgetown University Medical Center, Washington, DC, Otsuka America Pharmaceutical, Inc., Princeton, NJ, USA E-mail: samuel.sigal@nyumc.org