162

FLUMAZENIL

Based on the theory of accumulation of endogenous benzodiazepine-like substances

in HE, flumazenil, a benzodiazepine antagonist, has been evaluated for its role in the

treatment of HE. Several trials have demonstrated both clinical and

electrophysiologic improvement in patients with HE.

170 However, an IV product with

modest benefits in the treatment of HE is not an ideal treatment option.

Lactulose versus Rifaximin

An extensive review of rifaximin for the treatment of HE conducted by Lawrence et

al.

171

found that rifaximin was equally effective, and in some studies superior to

lactulose in mild-to-moderate disease. Patients treated with rifaximin required fewer,

shorter and less costly hospitalization than lactulose-treated patients.

171

Bucci et al.

172 conducted a double-blind study comparing rifaximin (1,200 mg/day)

and lactulose (30 g/day) for 15 days in patients with moderate to severe HE. After 7

days, ammonia concentrations normalized and at the end of the treatment period,

cognitive function test scores improved in both groups. Rifaximin therapy was better

tolerated.

172 Although the data reported from these and other trials suggest a benefit

with rifaximin for the treatment of HE, larger trials must be conducted to determine

its superiority over lactulose. In addition, the current cost of rifaximin is

considerably higher than both lactulose and neomycin (estimated cash price:

lactulose [60–100 g daily] ~$170–280/month; neomycin [500 mg 4 times daily]

~$220/month; and rifaximin [550 mg twice daily] ~$2,000/month; data per

goodrx.com).

Rifaximin versus Neomycin

Miglio et al.

173 conducted a randomized, controlled, double-blind study to evaluate

the efficacy and tolerability of rifaximin (400 mg 3 times daily) in comparison to

neomycin (1 g 3 times daily) treatment for 14 days each month over 6 months. During

the study, blood ammonia concentrations in both the rifaximin and neomycin groups

decreased a similar amount.

173 Pedretti et al.

174 compared rifaximin 400 mg every 8

hours to neomycin 1 g every 8 hours in patients with cirrhosis and reported a higher

rate of adverse events (increases in BUN, creatinine, nausea, abdominal pain, and

vomiting) in the neomycin group after 21 days of therapy. Both drugs significantly

decreased blood-ammonia concentrations. However, rifaximin produced an earlier

reduction of blood ammonia.

174 Because of the lower adverse-effect profile and

considerable efficacy, rifaximin has taken over as second-line therapy for HE over

neomycin at many institutions.

Lactulose versus Neomycin

Orlandi et al.

175

found that lactulose and neomycin appear to have similar efficacy for

the acute treatment of HE. However, in the treatment of an acute exacerbation,

particularly in an acute GI bleed, lactulose may produce a faster response than

neomycin.

Interestingly, although lactose therapy is considered the standard of practice in

OHE treatment and prevention, a meta-analysis evaluating the efficacy of lactulose in

patients with HE questions its benefit.

176 Large randomized, controlled trials are

needed to

p. 553

p. 554

determine the optimal treatment for HE management.

147 The AASLD/EASL

guidelines consider neomycin as an alternative choice for treatment of OHE.

144

Lactulose would be the preferred option to treat R.C.’s HE because it would

shorten the time to clear the blood from his GI tract and hopefully lead to a rapid

resolution of his confusion. Although neomycin is not contraindicated for R.C., the

potential for worsening of his coagulopathy (by interfering with vitamin K

absorption) and risk of nephrotoxicity (SCr, 1.4 mg/dL) make this a less optimal

choice. If R.C.’s renal function continues to decline, neomycin may become

contraindicated. Lactulose can be initiated at 25 mL every 1 to 2 hours until at least

two soft or loose stools per day are produced. The dose can then be reduced to

maintain 2 to 3 soft stools per day and improved mental status. R.C. may receive

lactulose by NG tube if necessary in the early treatment period.

COMBINATION THERAPY WITH LACTULOSE

CASE 25-3, QUESTION 6: Would combination therapy provide any additive beneficial effect for R.C.?

A randomized, double-blind, placebo-controlled trial by Bass et al.

167 compared

rifaximin versus placebo in the prevention of HE and hospitalization in patients

recovering from recurrent HE (≥2 episodes within the previous 6 months). Patients

were assigned to either rifaximin at a dose of 550 mg twice daily or placebo for 6

months. The study allowed the use of lactulose (approximately 90% of patients

received concomitant therapy). The results of the study showed that a breakthrough

episode of HE occurred in 22.1% with rifaximin and 45.9% with placebo.

Hospitalization involving HE was lower with rifaximin (13.6%) than with placebo

(22.6%). Adverse events were similar amongst the two groups.

167 The

AASLD/EASL considers rifaximin as an effective add-on therapy to lactulose for

prevention of OHE recurrence.

144 Previous HE guidelines (American College of

Gastroenterology) stated that combination therapy of lactulose and neomycin may be

reasonable in patients who do not respond to monotherapy.

162 The current

AASLD/EASL guidelines do not address this combination.

144 R.C. would not benefit

from combination therapy at this time.

HEPATORENAL SYNDROME

CASE 25-3, QUESTION 7: Lactulose treatment was initiated at 25 mL every hour and titrated to effect with

some improvement in R.C.’s mental status. A few days after resolution of his GI bleeding, his serum creatinine

increased from 1.4 to 2.7 mg/dL and he became progressively oliguric. His BP was 85/65 mm Hg, pulse rate

was 70 beats/minute, and respiratory rate was 16 breaths/minute. Furosemide was discontinued, and R.C. was

treated with albumin infusions to allow volume expansion and improve urine output. A renal ultrasound did not

reveal any specific abnormalities. Minimal improvement occurred in his blood pressure and urine output.

Laboratory results included the following:

Na, 123 mEq/L

K, 3.6 mEq/L

Cl, 98 mEq/L

Bicarbonate, 25 mEq/L

BUN, 96 mg/dL

SCr, 2.7 mg/dL

Hgb, 8.4 g/dL

Hct, 27.1%

AST, 640 IU

Alkaline phosphatase, 304 IU

LDH, 315 IU

Total bilirubin, 4.1 mg/dL

PT, 22 seconds (INR, 1.8)

A 24-hour urinalysis showed the following:

Protein, 50 mg/day

Red blood cells, 1 to 2 per high power field

Negative for WBC, glucose, and ketones

After exclusion of other possible causes of kidney disease, R.C. is diagnosed with hepatorenal syndrome.

What are potential treatment options for R.C.’s hepatorenalsyndrome?

Pathogenesis

Hepatorenal syndrome (HRS) is a complication of advanced cirrhosis characterized

by an intense renal vasoconstriction, which leads to a very low renal perfusion and

glomerular filtration rate, as well as a severe reduction in the ability to excrete

sodium and free water.

177 Cárdenas et al.

178 summarized the pathogenesis and the

precipitating factors of HRS, which can be found on nature.com

(http://www.nature.com/nrgastro/journal/v3/n6/fig_tab/ncpgasthep0517_F1.html

HRS is diagnosed by exclusion of other known causes of kidney disease in the

absence of parenchymal disease. The revised criteria for the diagnosis of HRS as

defined by the International Ascites Club (IAC) can be found at icascites.org

(http://www.icascites.org/about/guidelines/).

179,180

Hepatorenal syndrome can be classified into two categories. Type 1 HRS is

characterized by an acute and progressive kidney failure defined by doubling of the

initial serum creatinine concentrations to a level greater than 2.5 mg/dL in less than 2

weeks. Type 1 HRS is precipitated by factors such as SBP or large-volume

paracentesis, but can occur without a precipitating event. This usually occurs within

the setting of an acute deterioration of circulatory function characterized by

hypotension and activation of endogenous vasoconstrictor systems. It may be

associated with impaired cardiac and liver functions as well as HE. The prognosis of

patients exhibiting type 1 HRS is very poor.

180,181

In contrast, type 2 HRS is a

progressive deterioration of kidney function with a serum creatinine from 1.5 to 2.5

mg/dL. It is often associated with refractory ascites, and has a better survival rate

than that of patients with type 1 HRS.

178,179,180

Treatment

Treatments for HRS are still investigational. HRS is associated with a high mortality

rate (within 2 weeks for type 1 HRS and 6 months for type 2 HRS). The definitive

treatment for type 1 and type 2 HRS is liver transplantation, which is the only

treatment that assures long-term survival.

68 The main goal of pharmacologic therapy

is to manage HRS sufficiently so that the patient can survive long enough to obtain a

suitable donor liver.

179,180 Diuretic therapy worsens HRS and should be

discontinued.

178

Solanki et al.

182

randomized patients with type 1 HRS to terlipressin 1 mg IV every

12 hours or placebo. Both groups also received albumin. Urine output, creatinine

clearance, mean arterial pressures, and survival (42% vs. 0%) were significantly

better with terlipressin than with placebo (p < 0.05). All survivors in the terlipressin

group had a reversal of HRS.

182

Sanyal et al.

183 conducted a prospective, double-blind, placebo-controlled clinical

study in which patients with type 1 HRS were randomly assigned to terlipressin (1

mg IV every 6 hours) or placebo. If, after 3 days of therapy, the SCr level had not

decreased by ≥30% from baseline, the dose was increased to 2 mg every 6 hours. All

patients in this study also received albumin. The primary end point at day 14 was

SCr ≤ 1.5 mg/dL on two occasions at least 48 hours apart, without dialysis, death, or

recurrence of type 1 HRS. The primary end point was achieved twice as often with

terlipressin than with placebo (25% vs. 12.5%,

p. 554

p. 555

respectively), although this did not reach statistical significance. In addition,

terlipressin did not improve survival. However, terlipressin was superior to placebo

for type 1 HRS reversal as defined by SCr ≤ 1.5 mg/dL (34% vs. 13%; p = 0.008).

Adverse events were similar between groups.

183

In 2009, the FDA accepted the final

section of the New Drug Application seeking marketing approval for terlipressin for

the treatment of type 1 HRS, and granted priority review and fast-track designation.

In 2013, terlipressin was granted Orphan Drug Status.

Other nonrandomized studies suggest that vasoconstrictor therapy with

norepinephrine (combined with albumin and furosemide) or midodrine (combined

with octreotide and albumin) improve renal function in patients with type 1

HRS.

184–186 Esrailian et al.

187 conducted a retrospective chart review of type 1 HRS

patients who received a combination of octreotide, midodrine, and albumin

compared to untreated controls who received albumin only. Octreotide

administration started at 100 mcg subcutaneously TID, with the goal to increase the

dose to 200 mcg subcutaneous TID. Midodrine administration started at 5, 7.5, or 10

mg TID orally, with the goal to increase the dose to 12.5 or 15 mg if necessary.

Adjustment in medication doses was based on a goal of increasing the mean arterial

pressure by at least 15 mm Hg from baseline. All patients received intravenous

expansion of plasma volume with 1.5 L of saline combined with an average of 120 g

of human albumin after diuretic withdrawal. The authors found that at 30 days, 40%

of treated patients had a sustained reduction in SCr, compared with 10% of the

concurrent untreated controls (p = 0.01). In that same time period, 43% of patients in

the treatment group had died, compared with 71% of controls (p = 0.03).

187

Duvoux et al.

186 conducted a pilot study describing the efficacy and safety of

norepinephrine in combination with IV albumin and furosemide in patients with type

1 HRS. Norepinephrine was given for 10 ± 3 days, at a mean dosage of 0.8 ± 0.3

mg/hour. Reversal of HRS was observed in 83% of patients after a median of 7 days,

with a reduction in SCr (358 ± 161 to 145 ± 78 μmol/L; p <0.001), a rise in

creatinine clearance (13 ± 9 to 40 ± 15 mL/minute; p = 0.003), an increase in mean

arterial pressure (65 ± 7 to 73 ± 9 mm Hg, p = 0.01), and a marked reduction in

active renin and aldosterone plasma concentrations (p <0.05).

186

Two small, open-labeled, randomized, pilot studies evaluated the efficacy and

safety of norepinephrine compared to terlipressin in the treatment of HRS.

188,189 All

subjects also received albumin. Both drugs significantly improved renal function and

had similar effects with respect to efficacy and safety. This preliminary data suggests

that norepinephrine may be a safe, effective, and less costly alternative to terlipressin

in the treatment of type 1 HRS. Further research is warranted.

The IAC guidelines recommend vasoconstrictors and albumin for first-line

treatment of type 1 HRS. They advocate for the use of terlipressin (2–12 mg/day) in

combination with albumin (20–40 g/day after 1 g/kg on the first day), and mention

that about 60% of renal failure cases recover with this therapy. The IAC recommends

midodrine (in addition to octreotide) and norepinephrine as two possible alternatives

to terlipressin.

180 The latest AASLD recommendation is to consider the use of

albumin plus octreotide and midodrine (largely because of the lack of availability of

terlipressin in the United States).

38 Studies mention that the combination of both

octreotide and midodrine are required to be effective.

190,191 The AASLD guidelines

also recommend that albumin plus norepinephrine as a treatment option of type 1

HRS; however, this approach requires an intensive care unit.

38 Vasoconstrictor

efficacy and safety requires further evaluation in large, randomized clinical

trials.

184–186

Type 2 HRS manifests itself as a progressive disease and, therefore, patients do

not present acutely with deterioration in kidney function. No particular treatment

exists for type 2 HRS. The main clinical problem in type 2 HRS is refractory ascites,

which can be controlled by large-volume paracentesis along with IV albumin or

TIPS.

178,184,192 Studies are needed to determine the place in therapy for

vasoconstrictors and other potential treatments in patients with type 2 HRS.

180

R.C. should continue to receive albumin 10 to 20 g IV per day, octreotide 100 mcg

SC 3 times daily with a target dose of 200 mcg SC 3 times daily and midodrine 5 to

10 mg orally 3 times daily, with the goal to titrate up to 12.5 mg orally 3 times per

day. The target increase in mean arterial pressure is 15 mm Hg.

38 Because of the poor

prognosis associated with hepatorenal syndrome, R.C. should be evaluated for liver

transplantation.

CASE 25-3, QUESTION 8: Why should liver transplantation be considered in patients with end-stage liver

disease such as R.C.?

Liver transplantation for appropriate candidates may be the best option for endstage liver disease and its complications leading to improved quality and duration of

life. Transplantation is generally considered in patients with refractory ascites,

severe hepatic encephalopathy, esophageal or gastric varices, and hepatorenal

syndrome.

193 Because of the shortage of organs available and significant

complications associated with transplantation, therapeutic alternatives should be

considered to avoid the necessity for transplantation. For patients such as R.C., who

are candidates for transplantation, therapeutic strategies to improve outcomes after

transplantation should be considered in therapeutic decision-making before

transplantation (see Chapter 34, Kidney and Liver Transplantation, for further

information on the indications for liver transplantation).

192

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