Rifaximin + Lactulose is more effective than Lactulose alone in preventing recurrent hepatic encephalopathy.

1. Hepatic
Encephalopathy.
Daniel Vela-Duarte, MD
Int. Medicine / Neurology
Loyola University Medical Center

2. Case
 62 yo male with h/o ESLD 2/2 NASH and 1AT def,
hepatorenal syndrome type II, DM II, who has presented
multiple admissions for altered mental status, alternating
somnolence, agitation and belligerence, diagnosed
subsequently with hepatic encephalopathy and treated
several times with large volume paracentesis and weekly
albumin infusions.
 Pt was admitted for fluctuating changes in mental status,
anuria, noted worsening renal function, fluid overload,
hypotension and hemodialysis.

3. Question …
 What is the best treatment to
prevent recurrent hepatic
encephalopathy?
 A. Lactulose 15ml BID / daily
 B. Lactulose 15ml BID / daily + Rifaximin 550mg BID /daily
 C. Rifaximin 550mg BID / daily
 D. Lactulose 15ml BID during hospitalization
 E. Neomycin 5 g / daily + Lactulose 15ml BID /daily

4. Cordoba et Al, Curr Opin Crit Care. 2011 Apr;17(2):177-83.
Enterobacteriacea
e
Proteus
Clostridium
Urease Glutaminase
Urea NH3 + CO2 Glutamine NH3 + Glutamate

5. Back to the Case
Intravascularly depleteted
 62 yo male with h/o ESLD 2/2 (Peripheral /splanchnic pooling)
NASH and 1AT def,
hepatorenal syndrome type II, DM II, who has presented
 Renin-Angiotensin-Aldost.
multiple admissions for altered mental status, alternating
 Na / water retention
somnolence, agitation and belligerence, diagnosed
subsequently with hepatic encephalopathy and treated
 Intrarenal vasoconstriction
several times with large volumeATN ?
paracentesis and weekly
ESLD =  Alb
albumin infusions. of Ammonia
-Impaired detox
 Renal Perfusion
 GFR
 Pt was admitted for fluctuating changes in mental status,
anuria, noted worsening renal function, fluid overload,
hypotension and emergent hemodialysis.
Schepke M, Nephrol Dial Transplant (2007) 22 [Suppl 8]: viii2–viii4

6. Hepatic encephalopathy
 Type A: Acute liver failure
 Type B: Portosystemic Bypass
 Type C: Cirrhosis - Dehydration,  Na
- Gi Bleeding
- Infections
 Episodic - Constipation Impairs daily
- Protein intake functioning
 Precipitated
- Renal Failure, K
 Spontaneous - TIPS  Health-related
 Recurrent: >2 / y - HCC quality of life.
- Infections
 Persistent - Opioids Might predicts overt
 Mild - Benzodiazepines HE and poor
 Severe outcome
 Treatment-dependent
 Minimal: cognitive dysfunction (subtle motor deficits)
Sundaram V, Med Clin North Am. 2009 Jul;93(4):819-36, vi

7. Frederick RT., Gastroenterol Hepatol. 2011 Apr;7(4):222-33.
Diagnosis
 Asterixis: inability to maintain position.
 Tested by having the patient outstretch his or her arms and hold
them in dorsiflexion.
 Elicited with tongue protrusion, dorsiflexion of the foot, or having
the patient grasp the examiner’s fingers.

8. Diagnosis
Overt Hepatic encephalopathy
 Impaired mental status
 (Conn score / West Haven criteria) 0 - 4.
 Impaired neuromotor function
 hypereflexia, rigidity.
 myoclonus, and asterixis
 Minimal Hepatic encephalopathy
 Subtle personality changes
 Altered level of consciousness
 Neuromuscular dysfunction
 No “Gold standard” to Dx.

9. Lactulose
 It improves minimal HE, cognitive
functions and health-related quality of life
in cirrhotic patients.
Is lactulose effective decreasing
recurrence of overt HE after recovery of
a previous episode?

10.  Screening of
300 pts with
Cirrhosis and
HE.
 140 pts
enrolled
 Exclusion:
 Recent EtOH
 HCC
 Meds/performance
Gastroenterology, 2009 Sep;137(3):885-91, 891.e1. Epub 2009 Jun 6.

11.  Pts were
46.8% followed up
over a median
of 14 months
19.6%
 33.6%
developed an
No difference between median time of recurrence of episode of
HE between 2 groups.
overt HE.
Gastroenterology, 2009 Sep;137(3):885-91, 891.e1. Epub 2009 Jun 6.

12.  Patients with
Cirrhosis and
MHE.
 (No recurrent HE)
 Improvement of
quality of life by
measurement of
SIP score
(Sickness impact
profile)
Prasad S et Al, Hepatology. 2007 Mar;45(3):549-59.

13. Rifaximin
 Efficacy and safety of rifaximin, for the
maintenance of remission from episodes
of HE in outpatients with a recent hx of
recurrent, overt HE (Prevention for 6m)

14.  2 Episodes or more
of overt HE during
last 6 months
Primary efficacy Endpoint.  Conn score > 2
time to the first breakthrough
episode of hepatic  On Remission at
Encephalopathy. enrollment. Conn
score: 0-1
Secondary efficacy Endpoint.
 Exclusion: pts with
Time to the first hospitalization
precipitants.
involving hepatic encephalopathy  HipoK
 Renal Failure
 SBP
 Infection
 HypoNa
Bass NM et Al, N Engl J Med. 2010 Mar 25;362(12):1071-81.

15.  Results.
 Rate of compliance: over 80%
for both
 31 / 140 pts. Rifaximin group (22.1%)
 73 / 159 pts. placebo group (45.9%)
 RRR by 58% with rifaximin vs
placebo
 NNT: 4
 19 / 140 pts Rifaximin group (13.6%)
and
 36 / 159 pts placebo group (22.6%).
 RRR by 50% with rifaximin vs
placebo
 NNT: 9
Bass NM et Al, N Engl J Med. 2010 Mar 25;362(12):1071-81.

16. Conclusions
 Rifaximin reduces the risk of a breakthrough episode of
HE by 58% vs placebo (Lactulose only) during the at
least 6 months of treatment.
 Rifaximin reduces the risk of a hospitalization involving
HE by 50% vs placebo (Lactulose only) during the at
least 6 months of treatment.
 Lactulose: 30 -60 ml / 2-3 doses, improves cognitive
functions in patients with minimal HE after 3 months of
treatment.
 Lactulose: 30 -60 ml / 2-3 doses, decreases the
incidence of recurrent HE (RRR 58%)