HEPATIC ENCEPHALOPATHY

Justice O. Bempah

Pharm. D Candidate

Western New England University

Preceptor: Dr. Yoonsun Mo Pharm. D

OBJECTIVES Discuss the pathophysiology and

precipitants of hepatic encephalopathy. Briefly highlight the clinical presentation,

classification, and diagnostic criteria for hepatic encephalopathy.

Identify goals and common treatment regimens.

Discuss evidence based treatment study. Given patient case, devise plan for acute

management of hepatic encephalopathy.

CC: “Weakness and persistent diarrhea”HPI: GW, a 58-year-old female H/o cirrhosis s/p transjugular intrahepatic

portosystemic shunt (TIPS), Cellulitis, abscess, diabetes and alcohol abuse

Presents to the ER with complaints of weakness and diarrhea

Started 4 days ago with N/V. Developed excruciating pain in the right

side of her back and in the flank, felt nauseated.

HPI Continued: EMS - BP 70 systolic, IV hydration

initiated. ER- BP 93/52, T 36.8, O2 Sat 93% on

room air, very weak, acute renal failure and with 30% bands on her CBC.

Aggressive IV hydration with 3L of NS initiated.

Remains hypotensive (BP 89/54), Mg and Ca were replenished

EKG : Rate: 82, Rhythm: NSR , No ischemic changes.

CXR: Mild symmetric patchy markings over the medial lung base

HPI Continued: Suggest pulmonary edema or bronchitis.

Appeared septic, piperacillin/tazobactam

started for antibiotic coverage.

Admitted to ICU for further management

Reported that her dog licked and

scratched her wound.

PMH Cirrhosis, s/p TIPS 5 yrs ago Cellulitis and abscess on the left leg Diabetes + alcohol abuse Right-sided inguinal hernia s/p repair Surgical removal of infected inguinal

hernia repair

FH: Breast cancer

SH: Alcohol use and smoke half pack a day

MEDS Lantus 50 units at night on sliding

scale insulin Lasix 80 mg po daily Spironolactone 100 mg po daily Iron sulfate 325 mg po daily Folic acid 1 mg po daily Thiamine 100 mg po daily

ALLERGIES: NKDA

REVIEW OF SYSTEMS Poor appetite for the last 3 days Denied fevers, headaches, cough,

SOB, chest pain, has right-sided neck pain.

N/V resolved. (+) diarrhea and right flank pain.

(-) blood per rectum or abdominal pain.

Generalized weakness and lightheadedness.

PHYSICAL EXAM GEN: Obese female, tired appearing,

talking full sentences, in mild distress VS: T 36°C HR 101, RR 22 , BP

114/55 mmHg, P 92, Wt 115.44 kg, Ht 5ft 8 in, O2 Sat 95% on 2 L nasal cannula.

HEENT: Dry mucous membranes. CV: tachycardic, regular, distant heart

sounds. LUNG/THORAX: Mildly tachypneic,

Lungs CTA bilaterally

PHYSICAL EXAM Continued… ABD: Obese, soft, tender to

palpation in the RUQ, (+) Bowel sounds

SKIN: a small 1-2 cm wound on the left leg. Some redness in the lower extremities

MS/EXT: Bilateral lower edema present.

NEURO: Generally weak, A & O x3. CN II-XII grossly intact.

LABS:Na 128 mEq/L

K 4.2 mEq/L Cl 98 mEq/L CO2 17 mEq/L

Ca 9.0 Mg 2.0 BUN 62 mg/dL

Creat 2.23mg/dL

Plt 98 x 103/mm3

Hct 28.7 WBC 23.1 x 103/mm3

Hgb 10.4 g/dL

AST 16 ALT 22

Phos 3.4 Glu 205 mg/dL

INR 1.94 Album 2.0Amylase 15 and Lipase 28, Lactic acid of 7.4 Ammonia 42 GFR 30

ABG: pH 7.31; pCO2 31 mm Hg; pO2 35 mm Hg; HCO3 16 mEq/L; Oxygen sat 89%

Band 12%, Neut, 66% Lymph 2, Mono 4, Eosi 0, Baso 0

CRITICAL CARE COURSE Multisystem organ failure Respiratory failure

Sepsis/septic shock from group G streptococcus

Aspiration pneumonia

Cellulitis Renal failure

Cirrhosis due to alcohol abuse

Critical care myopathy

Hepatic encephalopathy

PAD & Lymph edema

Liver failure Peripheral neuropathy

Hypotension Pancreatitis

ARDS Bacteremia, fungemia (candida glabrata)

Diabetes

CRITICAL CARE COURSE Sepsis/septic shock from group G

streptococcal, Cellulitis◦ Ceftriaxone 2g IV Q24H Day 3-5◦ Clindamycin 900 mg IV Q8H Day 3-9◦ Doxycyline 100 mg Q12H IV Day 5-8◦ Meropenem 1g Q12H Day 5-9

Hypotension◦ Norepinephrine-NS 8 mg/250mL IV cont◦ Dobutamine 3mcg/kg/min Q10H IV cont.◦ Albumin human 5% 250-500 ml Day 8◦ Hydrocortisone 100 mg once IV Day 9 and

Hydrocortisone 50 mg Q8H IV Day 11-13◦ Midodrine 10 mg po BID for HD associated

hypotension Day 15

CRITICAL CARE COURSE ARDS/Respiratory failure

◦ Albuterol/ipratropium 2.5 mg/3mL via neb◦ Bumetanide 1- 2 mg Q12 IV x3 days – Day 3-5◦ Place on mechanical Vent. Day 7

Pain ◦ Hydromorphone 1mg IV Q3H PRN

Diabetes◦ Insulin human regular drip10-50 units (6ml/hr) PRN

per protocol Bacteriemia/fungemia - candida glabrata

◦ IV PCN G 4 million units every 12Q12H Day 10-17◦ Micafungin 100 mg Q24H Day 11- 16

Renal failure ◦ Place on HD Day15

HEPATIC ENCEPHALOPATHY(HE)

Hepatic encephalopathy refers to a reversible impairment of neuropsychiatric function associated with acute or chronic hepatic insufficiency or dysfunction after exclusion of other known brain disease2.

It ranges from mild to stupor to coma.4

PATHOPHYSIOLOGY OF HE A healthy liver clears almost all of the

portal vein ammonia, converting it into glutamine and preventing its entry into the systemic circulation.

In severe liver disease the ability to adequately filter blood from toxins and byproducts is reduced.

Gut derived nitrogenous toxic substance (eg, ammonia) in the blood accumulate.

Build up in brain results in encephalopathy.

PATHOPHYSIOLOGY OF HE

CLINICAL MANIFESTATION OF HE

Disturbances of consciousness

Disorientation

Intellectual changes Confusion

Altered mood Forgetfulness

Poor concentration Asterixis (hand tremor)

Altered sleep-wake cycle

Fetor hepaticus

Sluggish movements Drowsiness

CLINICAL MANIFESTATION OF HE

CLASSIFICATION OF HE Several systems used to classify

HE. Most frequently in the US is the

West Haven criteria (Conn score) for altered mental statusobased on a pt's level of consciousness,

intellectual function, and behavior.4 (Table 1.)

West Haven criteria (Conn score) for altered mental status.4

PRECIPITANTS OF HEDrugs Dehydration

Benzodiazepines Vomiting

Narcotics Diarrhea

Alcohol Hemorrhage

Increased ammonia in the brain

Diuretics

Excess dietary intake of protein

Large volume paracentesis

Gastrointestinal bleeding Portosystemic shunting (eg, TIPS)

Infection Vascular occlusion

Electrolyte disturbances (hypokalemia)

Portal vein thrombosis

Constipation Hepatic vein thrombosis

Metabolic alkalosis Primary hepatocellular carcinoma

DIAGNOSIS History and physical examination to

detect the cognitive and neuromuscular impairments that characterize HE.2

Exclusion of other causes of mental status changes

Serum laboratory testing to rule out metabolic abnormalities

Computed tomography (CT) scans of the braino If the clinical findings suggest another cause

for the patient's HE may be presentoEx: subdural hematoma from trauma, cerebral

edema.2

LABORATORY TESTS Ammonia is the best characterized

neurotoxin that precipitates hepatic encephalopathy. 2

oAn elevated serum ammonia concentration is not required to make the diagnosis

oNot specific for hepatic encephalopathy.

PHARMACOLOGIC TREATMENT OF HE

Goal:oIdentify and treat precipitating factors

oReduce ammonia level in the blood.2

Lactulose (Constulose®, Enulose®, Kristalose®) First line agent2

MOA: oLactulose is broken down by GI bacteria

to form lactic, acetic and formic acids in the colon which convert ammonia (NH3) to ammonium ion (NH4+) which is non polar and its absorption is decreased.

oDose (10 g/15mL): Give 30-45 mL (or 20-30 g powder) PO TID-QID• Titrate to bowel movements of 2-4 soft stools

per dayEnema: given Q4-6H PRN

Lactulose (Constulose®, Enulose®, Kristalose®)

Side Effects: oFlatulence, abdominal distention,

N/V/D, dehydration, hypokalemia and intestinal cramping.

Monitoring: oMental status, blood ammonia, bowel

movements, fluid and electrolytes status.

Rifaximin (Xifaxan®) Used in lactulose non-responders MOA: oSynthetic antibiotic that reduces GI

ammonia absorption by inhibiting urease-producing bacteria, which decreases ammonia production and facilitate its elimination.

oDose: 400 mg PO TID x 5-10 days for treatment or 550 mg PO BID for prevention.

Rifaximin (Xifaxan®) Side Effects: oPeripheral edema, dizziness, fatigue,

N/V, anemia, ascites and flatulence Monitoring:oMental status, blood ammonia and CBC

Sharma et al. Rifaximin + Lactulose Study5

Objective: Drugs used in the treatment of HE are

primarily used to reduce blood ammonia levels.

Rifaximin and lactulose have shown to be effective in HE.1,3,6

The study evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE.

Method:Patients with liver cirrhosis

172

Inclusion criteria Age: 18 – 80 y/oLiver cirrhosis and overt HE

Exclusion criteria Scr >1.5 mg/dlRecent alcohol intake <4 wksHepatocellular carcinomaSignificant systemic illness

Primary end point Complete reversal of HE

Secondary end point DeathHospital stay (Days)

Method: Group A: rifaximin 400mg po TID

and lactulose 30 to 60 ml TID titrated to 2 to 3 semisoft BM/day

Group B: Placebo capsule + lactulose 30 to 60 ml TID titrated to 2 to 3 semisoft BM/day

Results:Group A (n =63) B (n =57) P

value

Treatment Lactulose + Rifaximin

Lactulose + Placebo

Complete reversal of HE per West Haven Criteria

n =48 (76%) n =25 (44%) P =0.004

Death n =15 (23.8%)

n =28 (49.1%)

P<0.05

Sepsis deaths 1 17

Hospital stay (Days)

5.8 ± 3.4 8.2 ± 4.6 P =0.001

Limitations: No results on how many patients had

significant improvements in their HE vs. complete resolution HE.

Most pts were far sicker (grade 3-4 HE) than normal at baseline and the death rate in the placebo group was about 50%. Makes it difficult to know how these results can be extrapolated to pts that are less sick (grade 1-2 HE).

No long term follow up to see whether mortality benefit lasted.

Conclusion of study: Patients who received rifaximin and

lactulose were more likely than those who received lactulose alone to have complete resolution of their hepatic encephalopathy (76 vs. 44 %) and lower mortality (24 vs 49 %).5

ASSESSMENT HE OF GWRisk factors: Liver cirrhosis Infection Alcohol abuse TIPS Dehydration Diarrhea

ASSESSMENT HE OF GWDay

Symptoms Encephalopathy/West Haven criteria grade

Serum ammonia (Umol/L)

1 Generally weak, A & O x3

0 (minimal) 42

6 Mildly confused, forgetful, alert and oriented to person, but not time and place (A & O × 1).

1-2 93

7 confused, grossly disoriented, responded to her name by just opening her eyes (verbal stimuli). (A & O x 0)

3 142

13 Mildly alert and oriented to person, place, but not time (A & O x 2)

1 46

TREATMENT OPTIONS

Lactulose Rifaximin Lactulose + Rifaximin

TREATMENT OF GWDay

Medication and dosage

Encephalopathy/West Haven criteria grade

Serum ammonia (Umol/L)

1 Thiamine 100 mg po daily20-60 mg lactulose PO daily

0 (minimal) 42

6 Thiamine 100 mg po daily60 mg lactulose po daily

1-2 93

7 Thiamine 100 mg po daily20 mg lactulose po dailyRifaximin 550 mg po Q12H

3 142

13 Thiamine 100 mg po daily20 mg lactulose po dailyRifaximin 550 mg po Q12H

1 46

CONCLUSION Rifaximin plus lactulose appears to be

more effective than lactulose alone in the treatment of hepatic encephalopathy.

This evidence suggests that there may be a mortality benefit (decreased sepsis deaths) with rifaximin addition.

At this point it seems reasonable to add rifaximin in patients with lactulose failure by considering pt’s specific conditions and cost

REFERENCE

1. Bass, N., Mullen, K., Sanyal, A., Poordad, F., Neff, G., Leevy, C., & ... Forbes, W. (2010). Rifaximin treatment in hepatic encephalopathy. The New England Journal Of Medicine, 362(12), 1071-1081.

2. Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol (2014), http://dx.doi.org/10.1016/j.jhep.2014.05.042

3. 24. Jiang Q, Jiang XH, Zheng MH, et al. Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol 2008; 20:1064.

4. Mullen KD, Ferenci P, Bass NM, Leevy CB, Keeffe EB. An algorithm for the management of hepatic encephalopathy. Semin Liver Dis. 2007;27:32-48.

5. Sharma, B., Sharma, P., Lunia, M., Srivastava, S., Goyal, R., & Sarin, S. (2013). A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. The American Journal Of Gastroenterology, 108(9), 1458-1463. doi:10.1038/ajg.2013.219

6. Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose vs. placebo. Gastroenterology 2009;137:885–891, [891.e1].

QUESTIONS