Early intervention key to improving patient outcomes.
The emergency medical service box crackled again during a busy Monday evening shift: “84-year-old obese male, found obtunded in bed.” When the paramedics arrived, they started normal saline intravenously and intubated the patient. Vitals included blood pressure, 113/62 mmHg; heart rate, 70 beats/min (bpm); respiratory rate, 12 breaths/min; and pulse oxygen, 100% on room air. The result of a dextrose stick was 187 mg/dL, and the patient was administered vecuronium, midazolam and dopamine.
At the hospital, vitals were recorded: blood pressure, 133/71 mmHg; heart rate, 60 bpm; respiratory rate, 19 breaths/min; and temperature, 94.5°F. Physical examination showed the patient had a Glasgow Coma Scale score of 3 (intubated), no signs of trauma and abdominal ascites (Figure). Medical records revealed a history of atrial fibrillation, cirrhosis, coronary artery disease, diabetes mellitus, and hypertension.
Surgical history included coronary artery bypass graft and pacemaker/defibrillator implantation. Current medications included amiodarone, carvedilol, furosemide, lactulose, levothyroxine, linagliptin, liraglutide, patiromer, sodium bicarbonate, spironolactone, tamsulosin and warfarin.
Evaluation: Differential & Treatment Concerns
The differential diagnosis of altered mental status involves extensive examination, particularly in this patient with multiple comorbidities: stroke (ischemic, hemorrhagic), cardiac (acute coronary event, dysrhythmia), trauma, metabolic derangements (hypoglycemia, diabetic ketoacidosis, hepatic encephalopathy, hyponatremia), acute gastrointestinal bleed with hypovolemia, sepsis, toxidrome (alcohol intoxication or withdrawal, overdose – intentional, accidental), neoplasm, adrenal crisis and medication noncompliance.
Laboratory test results included: white blood cell count, 5 x 10³/µL; hemoglobin, 9 g/dL; hematocrit, 28%; platelet level, 176 x 10³/µL; sodium, 140 mmol/L; potassium, 2.8 mmol/L; blood urea nitrogen, 43 mg/dL; creatinine, 3 mg/dL; glucose, 193 mg/dL; international normalized ratio, 2; total bilirubin, 1.2 mg/dL; aspartate aminotransferase, 23 IU/L; alkaline phosphatase, 156 IU/L; ammonia, 155 µg/dL; and brain natriuretic peptide, 866 pg/mL.
Creatine kinase, lactate and thyroid stimulating hormone levels were normal. Blood culture testing, toxicology screening and urinalysis results were negative. Electrocardiography (ECG) showed atrial fibrillation (75 bpm), occasional premature ventricular contractions, and non-specific T-wave abnormalities. Chest X-ray and computed tomography (CT) scans of the head and cervical spine revealed no acute abnormalities.
Serial troponins, ECGs, and extended focused assessment with sonography for trauma (eFAST) exam ruled out cardiac etiologies. Head and neck CT ruled out ischemic and hemorrhagic stroke or cervical spine injury, while head and neck CT angiography excluded a large vessel occlusion. Laboratory evaluation did not reveal metabolic derangements, signs of infection, or toxidrome; however, ammonia levels were three times the upper limit of normal. The patient remained hemodynamically stable with no signs of gastrointestinal bleed; therefore, dopamine was discontinued. The patient was diagnosed with hepatic encephalopathy (HE).
In the United States, 85,099 patients with cirrhosis (primary diagnosis) visited the ED in 2014.(1) The prevalence of cirrhosis is increasing because of increased survival rates and increased diagnoses of alcoholic liver disease, hepatitis C, and, particularly, nonalcoholic fatty liver disease.(2,3) The clinical course of cirrhosis includes an asymptomatic compensated phase followed by transition to a decompensated phase, during which cirrhosis-related complications (eg, ascites, HE) develop.(4)
Given the complexity of the disease and typical comorbidities patients with cirrhosis have, the incidence of complications and ED visits is increasing.(1) According to the Healthcare Cost and Utilization Project Nationwide ED Sample, ED visits for HE increased annually between 2006 (42,687) and 2014 (57,578).(1)
HE is a neurologic complication with a broad range of symptoms, ranging from mild cognitive impairment to disorientation and behavioral changes to confusion and, in the most severe cases, coma.(5) HE should be considered in patients with cirrhosis with cognitive impairment, an altered sleep–wake cycle, and disorientation or confusion, as well as in those who are unconscious.(6) Among 265 patients with cirrhosis with a prior HE episode (n=387 episodes), the most common features of HE were confusion (77.5%); changes in mental status (57.1%); disorientation to time, place or person (48.3%); lethargy (46.3%); and asterixis (45.2%).7 Of key importance, a high blood ammonia level alone in patients with HE does not provide value as a tool for diagnosis, severity staging or prognosis.(5,8)
Early intervention and treatment of sepsis, ischemic and hemorrhagic stroke, hyponatremia and shock improve patient outcomes.(9-13) Similarly, HE is a time-sensitive diagnosis and requires emergent treatment to optimize outcomes.(5) For example, studies have demonstrated that treatment of HE with rifaximin decreased the number and duration of hospital stays.(14-16)
Treatment of the current HE episode and precipitating factors, as well as prevention of future (ie, recurrent) episodes, are recommended.(5) Notably, certain medications including analgesics (eg, opiates) and sedatives (eg, benzodiazepines) should be avoided in patients with cirrhosis because these medications may precipitate HE episodes.(17,18)
Prevention of HE recurrence is important to minimize the risk of rehospitalization in patients with cirrhosis. In 2014, 25.3% of patients hospitalized for cirrhosis-related conditions were readmitted within 90 days (47.1% of these were related to HE).19 In one prospective study, 23.7% of patients with cirrhosis with a previous hospitalization experienced an HE-related rehospitalization within three months.20 Data from a large urban healthcare system showed that the 30-day readmission rate for patients with HE was significantly greater than that for patients with cirrhosis without HE (33.3% vs 10.2%, respectively; P=0.02); further, patients with HE had a more than four times greater risk of 30-day hospital readmission versus patients without HE (odds ratio [OR], 4.4; P=0.02).21
Lactulose syrup, a nonabsorbable disaccharide titrated to maintain two to three bowel movements per day, is used as first-line therapy for patients with HE(.5) However, nonadherence with lactulose monotherapy has been associated with three times greater odds of HE recurrence versus patients adherent to treatment (OR, 3.3); gastrointestinal-related adverse events, including diarrhea, abdominal pain and bloating, were associated with lactulose nonadherence.22 While the mean time to HE recurrence was shorter in 39 patients nonadherent to lactulose versus the overall study population of 137 patients (3 ± 2 vs 9 ± 1 months, respectively), the majority (75.2%) of the 137 patients experienced HE recurrence within 9 ± 1 months.(22) Of note, the excessively sweet taste of lactulose may also contribute to nonadherence.(23)
Practice guidelines recommend rifaximin, which, at a dose of 550 mg twice daily, reduces the risk of HE recurrence in combination with lactulose.(5,24) In a randomized, double-blind study of patients in remission from HE (≥two episodes during previous six months), rifaximin reduced the relative risk of HE recurrence by 58% versus placebo during a six-month period.(25) Further, rifaximin reduced the risk of HE-related hospitalization by 50% compared with placebo.(25) In that study, 91.2% of patients in each treatment group received concomitant lactulose. The incidence of diarrhea was comparable in the rifaximin and placebo groups (10.7% vs 13.2%, respectively).(25)
Data from that trial also indicated that rifaximin treatment may reduce the risk of other cirrhosis-related complications, including spontaneous bacterial peritonitis, variceal bleeding and acute kidney injury/hepatorenal syndrome.(26)
Recognition of HE as a neurologic complication of cirrhosis is critical, given that patients with cirrhosis and changes in mental status may present to the ED. Long-term prophylaxis with rifaximin with or without lactulose is recommended to reduce the risk of HE recurrence and reduce hospitalization and disease burden in patients with cirrhosis.
Clinical Course and Discharge
The patient with HE received treatment with rifaximin 550 mg twice daily and lactulose. As his mental status improved, he became less ventilator-dependent and was extubated. Upon discharge, the patient was instructed to increase lactulose dose until two to three bowel movements were maintained per day and take rifaximin 550 mg twice daily to reduce the risk of HE recurrence.
- Agency for Healthcare Research and Quality. HCPUnet, Healthcare Cost and Utilization Project. http://hcupnet.ahrq.gov/. 2020. Accessed January 2, 2020.
- Mellinger JL, Shedden K, Winder GS, et al. The high burden of alcoholic cirrhosis in privately insured persons in the United States. Hepatology. 2018;68(3):872-882.
- Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-133.
- D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217-231.
- Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735.
- Shawcross DL, Dunk AA, Jalan R, et al. How to diagnose and manage hepatic encephalopathy: a consensus statement on roles and responsibilities beyond the liver specialist. Eur J Gastroenterol Hepatol. 2016;28(2):146-152.
- Landis CS, Ghabril M, Rustgi V, et al. Prospective multicenter observational study of overt hepatic encephalopathy. Dig Dis Sci. 2016;61(6):1728-1734.
- Lockwood AH. Blood ammonia levels and hepatic encephalopathy. Metab Brain Dis. 2004;19(3-4):345-349.
- Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: the evolution in definition, pathophysiology, and management. SAGE Open Med. 2019;7:2050312119835043.
- Prabhakaran S, Ruff I, Bernstein RA. Acute stroke intervention: a systematic review. JAMA. 2015;313(14):1451-1462.
- Urdaneta AE, Bhalla P. Cutting edge acute ischemic stroke management. Emerg Med Clin North Am. 2019;37(3):365-379.
- Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1-42.
- Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369(18):1726-1734.
- Oey RC, Buck LEM, Erler NS, van Buuren HR, de Man RA. The efficacy and safety of rifaximin-alpha: a 2-year observational study of overt hepatic encephalopathy. Therap Adv Gastroenterol. 2019;12:1756284819858256.
- Orr JG, Currie CJ, Berni E, et al. The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-α. Liver Int. 2016;36(9):1295-1303.
- Neff GW, Kemmer N, Zacharias VC, et al. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Transplant Proc. 2006;38(10):3552-3555.
- Soleimanpour H, Safari S, Shahsavari Nia K, Sanaie S, Alavian SM. Opioid drugs in patients with liver disease: a systematic review. Hepat Mon. 2016;16(4):e32636.
- Gronbaek L, Watson H, Vilstrup H, Jepsen P. Benzodiazepines and risk for hepatic encephalopathy in patients with cirrhosis and ascites. United European Gastroenterol J. 2018;6(3):407-412.
- Shaheen AA, Nguyen HH, Congly SE, Kaplan GG, Swain MG. Nationwide estimates and risk factors of hospital readmission in patients with cirrhosis in the United States. Liver Int. 2019;39(5):878-884.
- Bajaj JS, Reddy KR, Tandon P, et al. The 3-month readmission rate remains unacceptably high in a large North American cohort of patients with cirrhosis. Hepatology. 2016;64(1):200-208.
- Sood KT, Wong RJ. Hepatic encephalopathy is a strong predictor of early hospital readmission among cirrhosis patients. J Clin Exp Hepatol. 2019;9(4):484-490.
- Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012-1017.
- Khungar V, Poordad F. Hepatic encephalopathy. Clin Liver Dis. 2012;16(2):301-320.
- Xifaxan® (rifaximin) tablets, for oral use [package insert]. Bridgewater, NJ: Salix Pharmaceuticals; 2018.
- Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071-1081.
- Flamm SL, Mullen KD, Heimanson Z, Sanyal AJ. Rifaximin has the potential to prevent complications of cirrhosis. Therap Adv Gastroenterol. 2018;11:1756284818800307.