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HEPATORENAL SYNDROME: THE IMPORTANT ROLE OF PHARMACISTS IN IMPROVING
PATIENT OUTCOMES
Introduction
Hepatorenal syndrome (HRS) is a type of progressive renal failure that
occurs primarily in patients with cirrhosis without any accompanying
structural kidney damage.1 This condition is responsible for 11%
to 20% of all acute kidney injury (AKI) cases and is linked to high
mortality among hospitalized patients with cirrhosis.2 Results
of a prospective cohort study suggest that approximately 45.8% of
hospitalized patients with cirrhosis and renal failure may have HRS. 3 In this study, the 3-month mortality rates were 76% for
patients with type 1 HRS and 60% for patients with type 2 HRS.
The pathophysiology of HRS involves an interplay of the
renin-angiotensin-aldosterone (RAAS), sympathetic nervous, and cardiac
systems.4 Progressive liver cirrhosis increases vascular
resistance within the liver leading to portal hypertension.2,4
Increased portal hypertension and stress on portal blood vessels cause the
endothelium to produce vasodilators, such as prostanoids, nitric oxide, and
endogenous cannabinoids. These vasodilators interact with the splanchnic
vasculature leading to vasodilation. Cardiac output is unable to compensate
for the reduced systemic vascular resistance and signals a decreased
circulating volume. The decreased mean arterial blood pressure activates
the RAAS, visceral sympathetic nervous system, and the release of
vasopressin and local endothelin resulting in increased cardiac output and
heart rate, reduced intraglomerular blood flow, and retention of water and
sodium.
Several risk factors or triggering events may precipitate HRS, specifically
type 1 HRS, a more severe type of HRS, while type 2 HRS occurs
spontaneously in most cases.5,6 Spontaneous bacterial
peritonitis remains the most common trigger for type 1 HRS.5
Patients presenting with acute-on-chronic liver failure (ACLF), marked by
acute hepatic or extrahepatic organ failure, is another risk factor for
developing AKI and HRS. Other triggering events for HRS include a history
of progressive jaundice, gastrointestinal bleeding, and large volume
paracentesis. Providers should monitor for type 1 HRS in patients with a
recent spontaneous bacterial peritonitis and/or ACLF.
Diagnosis of HRS
The International Club of Ascites (ICA) provides guidelines on the
diagnosis of HRS.6 The diagnosis encompasses the presence of
cirrhosis, ascites, and an elevated serum creatinine (SCr) (>1.5 mg/dL
or 133 µmol/L) for at least 48 hours despite diuretic withdrawal and
treatment with albumin. Per the guideline, albumin should be administered
at 1 g/kg of body weight up to a maximum of 100 g of albumin per day.
Patients must be free from any parenchymal kidney disease (defined as
proteinuria >500 mg/day, microhematuria, and/or abnormal results from
renal ultrasound scanning), shock, and current or recent use of nephrotoxic
drugs. Hepatorenal syndrome is classified into 2 types: type 1 and type 2
(Table 1). Patients with type 1 HRS experience rapid worsening of renal
failure over less than 2 weeks, while patients with type 2 HRS have
moderate renal failure (defined as SCr >1.5 mg/dL or 133 µmol/L) over a
more extended time period.
Table 1. Comparison of definitions for type 1 and type 2 HRS.5,6 |
Criterium |
Type 1 HRS |
Type 2 HRS |
Elevations in SCr |
Doubling of SCr to >2.5 mg/dL or 220 µmol/L in less than 2 weeks |
Gradual increase in SCr to >1.5 mg/dL or 133 µmol/L |
Precipitating factors |
Spontaneous bacterial peritonitis (most common), ACLF, progressive jaundice, gastrointestinal bleeding, large volume paracentesis |
Spontaneous occurrence |
Concomitant effects |
Deterioration of circulatory function (eg, arterial hypotension), liver function impairment, encephalopathy |
Refractory ascites |
Prognosis |
Very poor |
Shorter survival compared to patients with ascites but no renal failure |
Abbreviations: ACLF= acute-on-chronic liver failure, HRS=hepatorenal syndrome, SCr=serum creatinine. |
Proposed changes to the current diagnostic criteria
Recently, practitioners recognized that the ICA diagnostic criteria for
types 1 and 2 HRS may delay administration of effective treatments. 7,8 For example, the ICA criteria encourage clinicians to wait
until a SCr >2.5 mg/dL to diagnose, and subsequently initiate
appropriate treatment, in patients with type 1 HRS. However, patients with
lower SCr levels respond faster and have better outcomes to some agents
used for HRS treatment.
In 2015, the ICA published revised consensus recommendations to the HRS
definition.8 This document advises removal of the current cutoff
for SCr values, especially for type 1 HRS, since SCr levels may not
reliably represent renal impairment in patients with cirrhosis, which may
change dynamically over time.2 Assay interference with
bilirubin, reduced hepatic creatine synthesis, decreased muscle mass, and
malnutrition may affect SCr levels in patients with cirrhosis as well. 2,9
In 2019, another document, authored by the same leading author as the 2015
revised consensus recommendations, proposed changes to the HRS
classification.7 The document advises to classify HRS by types
of renal dysfunction instead of by types 1 and 2 HRS. The proposed subtypes
of HRS consist of HRS-AKI (HRS due to AKI), HRS-AKD (HRS due to acute
kidney disease (AKD)), and HRS-CKD (HRS due to chronic kidney disease
(CKD)). Table 2 lists the accepted definitions for AKI, AKD, and CKD, while
Table 3 shows the proposed re-classification and corresponding definitions
of HRS subtypes. Due to these changes, the definition for HRS-AKI
incorporates urine output (obtained only via a urinary catheter) and
updated SCr thresholds.7 The definitions for HRS-AKD and HRS-CKD
change historic SCr thresholds to glomerular filtration rate (GFR)
thresholds as GFR thresholds are more commonly utilized in CKD or AKD
settings. To date, most of the literature still uses historic nomenclature
of types 1 and 2 HRS, and the ICA website links to the initial definitions
of types 1 and 2 HRS.6
Table 2. Definitions for different types of renal dysfunction.7,10 |
Terms |
Definitions |
Acute kidney injury (AKI) |
An absolute increase in SCr ≥0.3 mg/dL from baseline or a ≥50% increase in SCr from baseline |
Acute kidney disease (AKD) |
Renal dysfunction at a GFR <60 ml/min/1.73 m2 not meeting the criteria for AKI and lasting less than 90 days |
Chronic kidney disease (CKD) |
Renal dysfunction involving kidney structure or function at a GFR <60 ml/min/1.73m2 and lasting for >90 days |
Abbreviations: GFR=glomerular filtration rate, SCr=serum creatinine. |
Table 3. Proposed re-classification of HRS subtypes and corresponding definitions.7,8 |
Proposed classification |
Previous classification |
Definition |
HRS-AKI |
Type 1 HRS |
Absolute increase in SCr ≥0.3 mg/dL within 48 h and/or urinary output ≤0.5 mL/kg for ≥6 h (urinary output measured with a urinary catheter)
OR
Increase in SCr ≥50% from baseline |
HRS-AKD |
Type 2 HRS |
eGFR <60 ml/min/1.73 m2 for < 90 days in the absence of other causes
OR
Increase in SCr ≥50% from baseline |
HRS-CKD |
Type 2 HRS |
eGFR <60 ml/min/1.73 m2 for ≥90 days in the absence of other causes |
Abbreviations: AKD=acute kidney disease, AKI=acute kidney injury, CKD=chronic kidney disease, eGFR=estimated glomerular filtration rate, HRS =hepatorenal syndrome, SCr=serum creatinine. |
Predicting prognosis
Several factors assist in predicting prognosis in patients with HRS
including disease classification, cardiac function, biomarkers, and
infection.2
A diagnosis of type 1 HRS is linked to worse morbidity and mortality
compared with type 2 HRS.11 Using historic definitions of
HRS types, patients with type 1 HRS typically present with more severe
liver and renal failure and impaired circulatory function compared to
patients with type 2 HRS. The estimated median survival is 1 month for
type 1 HRS and 6.7 months for type 2 HRS.
Patients with a low cardiac output in the presence of systemic
vasodilation, as with cirrhosis and refractory ascites, are at risk for HRS
and have a worse prognosis.2 Close to 45% of patients with
cirrhosis, ascites, and reduced cardiac output may develop type 1 HRS. 12 Low cardiac output is the consequence of cirrhotic
cardiomyopathy, which is an abnormal cardiac response affecting patients
with cirrhosis. Administering beta-blockers such as propranolol to patients
with cirrhosis and spontaneous bacterial peritonitis may increase the
diagnostic rate of HRS, prolong hospitalization time, and decrease
survival.13-15
Serum creatinine and cystatin C may serve as biomarkers to predict
prognosis in patients with HRS.2 Increasing SCr correlates with
the severity of AKI. However, renal function is not the only factor
contributing to SCr levels. Dietary protein intake, muscle mass, and
nonrenal clearance can also affect SCr. Lately, serum cystatin C has been
used as an alternative to SCr to predict outcomes in patients with HRS. All
nucleated cells in the body secrete cystatin C, which only kidneys can
remove.
An observational study showed that increased serum cystatin C is an
independent predictor of mortality and development of type 1 HRS in
patients with cirrhosis and ascites.
16
The presence of infection in patients with type 1 HRS signals worse
outcomes. The survival of patients with type 1 HRS due to infection is
estimated to be around 75% after 3 months.17 Lack of infection
resolution is a key mortality predictor as it prevents HRS reversal.
Patients with persistent type 1 HRS and infection that develop septic shock
experience 100% mortality after 3 months. Therefore, immediate treatment of
infection in patients with type 1 HRS is crucial.
Treatment approach to HRS
The management of HRS involves pharmacologic and non-pharmacologic
interventions. Once providers establish an HRS diagnosis, the first step is
to discontinue diuretics, beta-blockers, vasodilators, and medications that
decrease blood volume.1,7 Providers should also halt nephrotoxic
medications such as nonsteroidal anti-inflammatory drugs,
angiotensin-converting enzyme inhibitors, and certain antibiotics. 2
Promptly initiating appropriate pharmacologic therapy may lead to improved
renal function and better survival, especially in patients with type 1 HRS. 7 To counteract splanchnic vasodilation, vasoconstrictors in
combination with albumin are the first-line pharmacologic treatments for
HRS.2 Albumin expands intravascular volume, and thus, increases
mean arterial pressure in patients with hemodynamic dysfunction, while
vasoconstrictors attenuate splanchnic arterial vasodilation. 1,2,18 As a result, the combination of a vasoconstrictor with
albumin leads to better kidney perfusion and improves renal function. 18 Vasoconstrictors used concomitantly with albumin are
terlipressin, norepinephrine, octreotide, and midodrine.2
Terlipressin is the first-line vasoconstrictor in Europe and has been
extensively studied for this indication
; however, it is unavailable in the United States and Canada.
9,19
Terlipressin remains non-Food and Drug Administration (FDA)-approved as
the results of a study performed in the United States and Canada showed
similar survival and HRS reversal outcomes with terlipressin and
albumin versus albumin alone.2,20 Moreover, patients
receiving terlipressin experienced more ischemic events.
Other vasoconstrictors – norepinephrine, octreotide, and midodrine – are
available in the United States.21
The combination of a vasoconstrictor and albumin is typically administered
for up to 14 days and then discontinued if patients do not respond to
treatment.7 Depending on the therapies used, up to 50% of
patients with type 1 HRS may respond to the combination therapy, but close
to 20% of patients may experience recurrence after therapy discontinuation. 7,22 Recurrence is especially high in patients with type 2 HRS
who received terlipressin with albumin. Patients experiencing recurrence
may benefit from retreatment with pharmacologic therapies, but may require
long-term treatment and prolonged hospitalization.22 Outpatient
pharmacologic treatment is an option for these patients, but further
studies are necessary to identify the appropriate agents for this setting.
Nonpharmacologic interventions for HRS consist of paracentesis,
transjugular intrahepatic portosystemic shunting (TIPS), and liver
transplantation.2 Paracentesis drains ascites, provides symptom
relief for increased intra-abdominal pressure, and may improve renal
function in patients with type 1 HRS. Patients with tense and symptomatic
ascites are candidates for paracentesis.
Patients who do not respond to pharmacologic therapy or have several
relapses may benefit from TIPS, which improves renal blood flow. 2
The main limitation of TIPS is an increased incidence of hepatic
encephalopathy and the potential worsening of arterial vasodilation for
up to 12 months
.2,18 Because TIPS may potentially worsen renal function in
patients with renal dysfunction, new research on outcomes with TIPS in HRS
had not been published for over a decade.18 The available
evidence suggests that TIPS improves renal function mainly in patients with
type 2 HRS.22 The procedure is also contraindicated in patients
with severe liver failure, which limits its use in patients with HRS. Renal
replacement therapy (RRT), such as intermittent hemodialysis or continuous
RRT, is an option for patients with HRS not responding to vasoconstrictor
therapy.18 Renal replacement therapy is not a definitive
treatment, but instead a bridge to liver transplantation. A study showed
that RRT in addition to combination therapy with vasoconstrictors and
albumin does not improve survival and actually prolongs hospital stay in
patients with type 1 HRS.23
Liver transplantation is the definitive treatment for HRS because
curing liver disease reverses HRS.2
Patients not responding to vasoconstrictors are candidates for liver
transplantation.18 Predicting renal recovery remains
challenging, and the following factors may influence renal outcomes:
pre-existing comorbidities, intrinsic renal disease, perioperative events,
and post-transplant immunosuppression.7 For example, patients
receiving dialysis for a shorter time period are more likely to experience
HRS reversal after liver transplantation.18 A simultaneous liver
and kidney transplant may benefit patients with HRS at high risk for renal
nonrecovery. Providers must assess the duration of AKI, dialysis needs, and
presence of underlying CKD to identify the best candidates for simultaneous
liver and kidney transplantation.7
Evidence behind pharmacologic options
Adding albumin to vasoconstrictor therapies (terlipressin,
norepinephrine, and the combination of midodrine and octreotide)
improves clinical outcomes because albumin maintains or increases
cardiac output even in the advanced stages of liver disease. 7 Results from a prospective nonrandomized study of 21
patients with HRS (16 with type 1 HRS and 5 with type 2 HRS) revealed
that adding albumin to terlipressin improved rates for completely
reversing HRS compared with terlipressin alone (77% versus 25%,
respectively; p=0.03).24 Moreover, combination therapy
decreased SCr levels, increased arterial pressure, and suppressed RAAS,
outcomes that terlipressin alone failed to achieve.
As noted prior, terlipressin, a vasopressin analog, has been
extensively studied and is the first-line therapy for HRS in Europe.
2
Terlipressin creates vasoconstrictor effects primarily in the splanchnic
bed due to greater affinity for vasopressin 1 receptors in this area
compared with vasopressin 2 receptors in the kidneys. Terlipressin is a
prodrug, which slowly releases lysine vasopressin.25 The
half-life of terlipressin is 6 hours, while the half-life of vasopressin is
24 minutes. Terlipressin’s half-life allows for administering it as an
intermittent bolus. Patients with ischemic heart disease, peripheral
vascular disease, or recent stroke should not receive terlipressin because
it may cause ischemia.2
In the United States, some institutions may use vasopressin instead of
terlipressin, but the literature supporting use of this agent is limited. 2 The recently published literature does not discuss vasopressin
as an option for HRS; the article supporting its use is an observational
study published in 2005.26 That study included 43 patients with
HRS and revealed that vasopressin alone or in combination with octreotide
improved the recovery rate for SCr compared with octreotide monotherapy
(42% versus 38% versus 0%, p=0.01 for each comparison to octreotide
monotherapy).
Norepinephrine is a catecholamine with a-adrenergic agonist properties,
which causes vasoconstriction in the vasculature and minimal effects on the
myocardium.27 In many countries, norepinephrine is cheaper than
terlipressin and is the preferred agent.7
But because norepinephrine is administered through a central venous
line and requires continuous monitoring, only intensive care units
provide an adequate environment for administering this agent.
For managing HRS, midodrine and octreotide are combined to improve outcomes
and are used only if terlipressin or norepinephrine is unavailable or
contraindicated.27 Midodrine possesses α-adrenergic agonist
properties, while octreotide is a somatostatin analog.
Vasoconstrictors alone may improve mortality in patients with HRS. A
meta-analysis of 10 randomized controlled trials involving 376 patients
with type 1 or type 2 HRS revealed that vasoconstrictor monotherapy or in
combination with albumin reduced mortality compared with albumin alone or
no intervention (relative risk [RR], 0.82; 95% confidence interval [CI],
0.70 to 0.96).28 A subgroup analysis showed improved mortality
mainly with the combination of terlipressin and albumin compared with
albumin alone (RR, 0.81; 95% CI, 0.68 to 0.97). In another meta-analysis of
8 studies that included 377 patients, terlipressin decreased all-cause
mortality by 15% (risk difference, -0.15%; 95% CI,-0.26 to -0.03) and
HRS-related mortality by 9% (risk difference,-0.09%; 95% CI, -0.18 to
0.00).29 However, not all meta-analyses reveal mortality
benefits with vasoconstrictor therapy. A meta-analysis of 12 randomized
controlled trials involving 700 patients with type 1 HRS had unclear
mortality benefits when comparing the combination of terlipressin and
albumin with albumin alone or placebo.30 The results showed that
the combination of terlipressin and albumin reversed HRS more frequently
(RR, 2.54; 95% CI, 1.51 to 4.26), but patients in the terlipressin group
experienced a trend towards higher rate of adverse events (RR, 4.32; 95%
CI, 0.75 to 24.86), especially ischemic events (RR, 3.56; 95% CI, 1.64 to
7.72).
The comparative evidence supports similar clinical outcomes between
terlipressin and norepinephrine.
A Cochrane review of 25 trials that included 1,263 patients with
decompensated cirrhosis and HRS showed similar mortality among the most
common interventions such as terlipressin with albumin versus
norepinephrine with albumin, and terlipressin with albumin versus albumin
alone.31 Another Cochrane review of 10 trials with 474 patients
showed that terlipressin had similar effects on mortality as other
vasoactive medications (RR, 0.96; 95% CI, 0.88 to 1.06).32 A
meta-analysis of 4 studies with 154 patients diagnosed with HRS showed
similar 30-day mortality outcomes between treatments with terlipressin
versus norepinephrine (RR, 1.04; 95% CI, 0.84 to 1.30).33 A
meta-analysis of 12 randomized controlled trials revealed that the
combination of terlipressin with albumin and norepinephrine with albumin
had similar effects on the reversal of type 1 HRS.30
However, a recent open-label randomized controlled trial of 120 patients
with ACLF and AKI-HRS indicated significantly better outcomes with
terlipressin and albumin compared with norepinephrine and albumin for the
following measures: reversal of HRS (40% versus 16.7%; p=0.004), reduction
in the need for RRT (56.6% versus 80%; p=0.006), and improvement in 28-day
survival (48.3% versus 20%; p=0.001).34
The comparative evidence suggests that treatment with midodrine and
octreotide yields inferior clinical outcomes compared with other
therapies such as terlipressin with albumin or norepinephrine with
albumin.
Two Cochrane reviews revealed that terlipressin with albumin reversed HRS
more effectively compared with midodrine plus octreotide plus albumin or
octreotide plus albumin.31,32 A network meta-analysis of 13
randomized studies that included 739 patients with type 1 HRS revealed that
terlipressin plus albumin (odds ratio (OR) 26.25; 95% CI 3.07 to 224.21)
and norepinephrine plus albumin (OR, 10.00; 95% CI, 1.49 to 50.00) are
superior to midodrine plus octreotide plus albumin for reversing HRS. 35 Another network meta-analysis of 16 randomized controlled
trials found higher rates for completely reversing HRS with terlipressin
plus albumin (OR, 6.7; 95% CI, 2.1 to 21.3) and norepinephrine plus albumin
(OR, 6.8; 95% CI, 1.9 to 24.8) compared with albumin alone, but complete
HRS reversal was similar between midodrine plus octreotide plus albumin
versus albumin alone (OR 0.3; 95% CI, 0.02 to 3.1).36
Although available pharmacologic therapies may reduce mortality and reverse
HRS, pharmacologic therapy developments for managing HRS have stagnated
over the past 2 decades. A meta-analysis of 14 randomized controlled trials
carried out between 2002 and 2018, enrolling a total of 778 patients with
type 1 HRS, revealed that more recent studies showed similar survival rates
(OR, 1.02; 95% CI, 0.94 to 1.11; p=0.66) and HRS reversal rates (OR, 1.03;
95% CI, 0.96 to 1.11; p=0.41) as studies performed in the early 2000s. 37 Thus, a need exists for continued research on optimizing
available pharmacologic treatments as well as developing new agents to
treat HRS.
Dosing and monitoring of pharmacologic options
The appropriate dosing and monitoring of pharmacologic therapies are
essential for positive outcomes in patients with HRS (Table 4).
The recommended dosing of intravenous (IV) albumin consists of 1 g/kg
(up to 100 g) on the first day, followed by 20 to 40 g per day on the
following days
.27 In the United States, albumin is available as a solution at
concentrations of 5% and 25%; albumin 25% is indicated in patients with
cirrhosis.21,38,39Providers should measure central venous
pressure or use other measures for assessing blood volume to titrate the
dose of albumin and avoid fluid overload.22 Other laboratory
monitoring includes blood pressure, pulse, urinary output, electrolytes,
and hemoglobin/hematocrit.38 Providers should monitor for signs
of allergic or anaphylactic reactions. Typically, the combination of a
vasoconstrictor and albumin is administered until SCr is within 0.3 mg/dL
of the patient’s baseline SCr.7 The treatment is discontinued
after 14 days in patients without an appropriate response.
Table 4. Recommended dosing for medications in HRS.2,7,22,27 |
Medication |
Recommended dose |
Albumin 25% |
20 g to 40 g IV per day |
Terlipressin |
Bolus: 0.5 mg to 1 mg IV every 4 to 6 h; maximum 2 mg every4 h
Continuous IV infusion: 2 mg/day; maximum 12 mg/day
|
Norepinephrine |
0.5 mg/h to 3 mg/h IV infusion |
Midodrine |
Oral: 7.5 mg three times a day; maximum 12.5 mg three times a day |
Octreotide |
Subcutaneous: 100 µg three times a day; maximum 0 µg three times a day |
Abbreviations: IV=intravenous |
A meta-analysis of 19 studies (N=574 patients) determined that a
dose-response relationship exists between a cumulative dose of albumin
and survival of patients with type 1 HRS.40 Survival
improved as the cumulative albumin dose increased in increments of 100
g. The survival rates at 30 days were 43.2% with 200 g of cumulative
albumin dose, 51.4% with 400 g, and 59.0% with 600 g. Thus, some
providers recommend administering albumin at 40 g per day, the higher
end of the recommended range, to patients with type 1 HRS if tolerated. 27
Terlipressin may be administered as a continuous IV infusion or
intermittent IV boluses.2 Providers should double the dose of
terlipressin in a stepwise manner up to a maximum of 12 mg/day if SCr does
not increase by >25% after 2 to 3 days of treatment.7,22,27
Treatment with terlipressin lasts about 14 days unless HRS completely
reverses within a shorter period of time.27 New evidence
suggests that administering terlipressin as a continuous intravenous
infusion improves the adverse effect profile compared with intermittent IV
boluses. A randomized controlled trial of 78 patients with type 1 HRS
showed a similar response rate, for both partial and complete response,
between continuous infusion and intermittent boluses of terlipressin, but
patients receiving a continuous infusion experienced less total adverse
events (35.29% versus 62.16%; p<0.025), although individual adverse
events did not significantly differ between the groups.41
Patients in the continuous infusion group also received lower daily doses
of terlipressin (2.23±0.65 mg/day versus 3.51±1.77 mg/day; p<0.05). Of
note, the intermittent bolus group trended towards a higher 90-day survival
compared with the continuous infusion group, even though the results did
not reach statistical significance (69% versus 53%, p=0.255).
Several case reports describe administering terlipressin continuous
infusion on an outpatient basis as a bridge to liver transplantation. 42,43 Terlipressin continuous infusion was administered for
a median of 21 to 22 days, and doses ranged from 1.7 mg to 3.4 mg over
24 hours. Thus, terlipressin continuous administration may not only
improve the safety profile, but also serve as an outpatient bridge to
liver transplantation in some patients.
When initiating terlipressin, providers should monitor for several adverse
effects. The common adverse effects, especially with intermittent IV bolus
therapy, consist of diarrhea, abdominal pain, circulatory overload, and
cardiovascular ischemic complications, including myocardial infarction. 22,44 Due to cardiac effects, patients should receive an
electrocardiogram (ECG) prior to the initiation of terlipressin.
Although the evidence for vasopressin in HRS remains limited, some
institutions may use it as a substitute for terlipressin. Providers may
initiate vasopressin at 0.01 units/min and titrate based on mean arterial
pressure.45 In the 2005 observational study, the mean
vasopressin dose was 0.23 ± 0.19 units/min in patients who responded to
treatment.26 Vasopressin is an option only for critically ill
patients in the intensive care unit.45 Patients receiving
vasopressin may develop severe skin necrosis, thrombosis, hyponatremia,
anaphylaxis, bronchospasm, urticaria, and ischemia of the gastrointestinal
tract.25 Patients should receive periodic ECGs due to an
increased risk for myocardial infarction, especially in patients with prior
vascular disease.46
Administering IV norepinephrine at doses of 0.5 to 3 mg/h in
combination with albumin should increase mean arterial pressure by 10
mmHg.7,22,27
Patients receive norepinephrine via a central venous line, and thus,
must be admitted to an intensive care unit.22
Providers should monitor for skin necrosis and extravasation.47
At infusion initiation, blood pressure should be measured every 2 minutes
until target blood pressure is achieved, and then, blood pressure should be
measured every 5 minutes.
In patients with HRS, midodrine is typically administered orally at doses
of 7.5 to 12.5 mg three times a day and octreotide subcutaneously at doses
of 100 to 200 µg three times a day.27 Some institutions use a
continuous infusion of octreotide at 50 mg/h, which can be administered on
an internal medicine unit.45 But the evidence for the continuous
infusion is limited and dates back to a 2003 study revealing similar
effects on renal function between octreotide and placebo.48 The
doses of midodrine and octreotide are typically titrated to achieve an
increase of 15 mmHg in mean arterial pressure.9
The combination of midodrine plus octreotide plus albumin is only
administered when terlipressin or norepinephrine are contraindicated or
unavailable.
27
Providers should monitor blood pressure and heart rate because midodrine
may cause hypertension and decrease heart rate.49 Octreotide may
contribute to biliary tract abnormalities, cardiac conduction
abnormalities, hyperglycemia or hypoglycemia, and hypothyroidism. 50 Providers may monitor glucose levels and ECG readings;
following total and/or free T4 levels is recommended mainly for chronic
therapy with octreotide.
Pharmacist role in managing patients with HRS
Pharmacists play an important role in the care of patients with HRS and
ensure the appropriate use of drug therapy. For example, the literature extensively documents
pharmacists’ impact on recognizing appropriate indications and dosing of
albumin. A retrospective cohort study revealed that a pharmacist-driven
albumin protocol improved the appropriate use of albumin for indications
such as large volume paracentesis, spontaneous bacterial peritonitis, and
type 1 HRS.51 Implementing the protocol decreased the
inappropriate use of albumin by 51.3% over 5.7 months, which saved about
$137,000 per year. Another study found that introducing an evidence-based
protocol in conjunction with a pharmacist-led audit and feedback decreased
the overall inappropriate use of albumin by 79.3%, which summed up to an
annual savings of $211,600.52 The services with noteworthy
reduction in inappropriate use of albumin were: pulmonology (reduced by
93%), surgery (reduced by 92%), nephrology (reduced by 86%), and critical
care (reduced by 78.5%). In another project, pharmacists’ daily monitoring
of albumin use reduced inappropriate prescribing by 54%.53
Pharmacists’ involvement impacted the utilization of albumin in the
following units: critical care, solid organ transplant, adult step-down,
and cardiology.
Pharmacists may identify risk factors, including nephrotoxic medications,
for AKI and HRS. A cross-sectional survey-based study of 117 physicians and
135 pharmacists determined that a higher proportion of physicians
identified risk factors for AKI compared with pharmacists, while
pharmacists were more likely to identify AKI-causing medications compared
with physicians.54 Only half of the respondents who encountered
AKI cases in their practice performed an AKI risk assessment. Thus,
pharmacists may fill the gap by identifying risk factors for AKI and HRS,
notifying physicians of AKI-causing medications that should be temporarily
or permanently discontinued, and assessing the prognostic risk factors for
outcomes in patients with HRS.
Pharmacists may select the appropriate agents for managing HRS, monitor
for response to therapy, and assess any potential safety concerns.
Pharmacists familiar with current evidence on HRS treatments can
effectively select and advise prescribers on the most appropriate agents
and corresponding durations of therapy for individual patients. During
therapy, pharmacists can monitor for a response, any safety concerns, and
necessary laboratory values for selected treatments. For patients
experiencing recurrence, pharmacists can assist providers with medication
selection and prolonged treatment, especially when patients transition from
inpatient to outpatient settings.
Summary
Hepatorenal syndrome remains a high mortality condition, especially among
patients with cirrhosis, and causes up to 11% to 20% of all AKI cases. The
ICA provides definitions for HRS and divides HRS into type 1 and type 2.
Type 1 HRS is a more severe type, marked by worse morbidity and mortality
outcomes. The 2015 and 2019 proposals to redefine HRS recommend
reevaluating current cutoffs for SCr values and reclassifying type 1 and
type 2 HRS as HRS-AKI, HRS-AKD, and HRS-CKD. Factors such as disease
classification, cardiac function, biomarkers, and infection may aid in
predicting the prognosis for patients with HRS.
The management of HRS involves pharmacologic and non-pharmacologic
interventions. Non-pharmacologic options consist of paracentesis, TIPS, and
liver transplantation, while pharmacologic options involve agents such as
albumin, terlipressin, norepinephrine, midodrine, and octreotide. Liver
transplantation remains the definitive treatment for HRS, because curing
liver disease reverses HRS. The evidence supports combining albumin with
terlipressin or norepinephrine as the first-line therapy for managing HRS.
These combinations may improve survival and reverse HRS. Midodrine plus
octreotide plus albumin should be reserved for situations when terlipressin
or norepinephrine are contraindicated or unavailable, because this
combination has worse outcomes for reversing HRS. A continued need exists
for further research on optimizing available pharmacological treatments and
developing new therapies for HRS. Pharmacists play a crucial role in taking
care of patients with HRS through ensuring the appropriate use and dosing
of pharmacologic therapies, especially albumin, identifying AKI-causing
medications, and recognizing risk factors for causing HRS and prognostic
factors for predicting outcomes with HRS. Pharmacists also monitor for
response to therapy, assess any potential safety concerns, and assist with
the transition to an outpatient setting.
Resources
Guideline from the European Association for the Study of the Liver (EASL):
management of decompensated cirrhosis:
https://easl.eu/publication/management-of-decompensated-cirrhosis-guideline/
Case Studies
Case study 1:
BK, a 56-year old woman with acute liver failure due to autoimmune
hepatitis, is awaiting liver transplantation. She developed jaundice and
delirium warranting her admission to an internal medicine unit in a
hospital. Her notable labs are: temperature 37.1˚C, blood pressure 110/55
mmHg, HR 60 beats per minute,
albumin 2.4 mg/dL, total bilirubin 15.4 mg/dL, ALT 1040 IU/L, AST 738
IU/L, SCr 3.6 mg/dL.
According to clinic records from 9 days ago, her labs were: total bilirubin
7.9 mg/dL, ALT 1844 IU/L, AST 1451 IU/L, SCr 0.57 mg/dL. She currently
takes only prednisone. Her providers believe that she developed AKI and
HRS. What initial pharmacologic therapy for HRS should be administered on
an internal medicine floor?
Answer: Adding albumin to a vasoconstrictor improves the rate of HRS
reversal, decreases SCr levels, increases arterial pressure, and suppresses
RAAS. A vasoconstrictor, depending on the agent, may reverse HRS and
improve mortality. Available vasoconstrictor choices consist of
terlipressin, norepinephrine, or the combination of midodrine and
octreotide. Terlipressin has been extensively studied, but is not available
in the United States. Norepinephrine is administered through a central
venous line and requires continuous monitoring, and thus, must be used only
in an intensive care unit. Because the patient is admitted to an internal
medicine floor, the combination of midodrine plus octreotide remains the
only vasoconstrictor option. Providers administer this combination only if
terlipressin or norepinephrine is contraindicated or unavailable. The
combination of midodrine plus octreotide yields inferior clinical outcomes
compared with other vasoconstrictor therapies. Thus, due to the patient’s
location, BK should receive albumin plus midodrine plus octreotide.
Providers may admit BK to an intensive care unit to administer
norepinephrine and albumin to improve HRS outcomes.
Case study 2:
DS, a 54-year old man, was admitted to an intensive care unit with symptoms
of worsening jaundice and abdominal pain, rapid cognitive decline, and
epigastric pain. His diagnoses consist of acute liver failure due to
chronic alcoholic liver disease and brain abscess. DS underwent abdominal
paracentesis, which eventually caused spontaneous bacterial peritonitis.
The medical team initiated appropriate empiric broad-spectrum antibiotics.
His SCr increased from 2.4 mg/dL to 8.5 mg/dL over 3 days, and his current
blood pressure is 86/50 mmHg. The medical team diagnosed type 1 HRS and
plans to initiate pharmacologic treatment. Provide a recommendation on an
agent(s) to initiate, dosing, and monitoring parameters.
Answer: Adding albumin 25% to a vasoconstrictor improves the rate of HRS
reversal, decreases SCr levels, increases arterial pressure, and suppresses
RAAS. The recommended dosing of albumin 25% consists of 1 g/kg IV (up to
100 g) on the first day, followed by 20 to 40 g per day on the following
days. Because a recent meta-analysis showed a dose-response relationship
between a cumulative dose of albumin and survival of patients with type 1
HRS, providers should administer albumin at the higher end of the
recommended range – 40 g per day if DS tolerates higher fluid intake.
Providers may measure central venous pressure or use other measures for
assessing blood volume to titrate the dose of albumin and avoid fluid
overload. DS should also receive a vasoconstrictor. Because terlipressin is
not available in the United States and DS is admitted to the intensive care
unit, norepinephrine is the best choice. The evidence reveals similar
positive outcomes for survival and HRS reversal between terlipressin and
norepinephrine. The recommended dose for norepinephrine is 0.5 to 3 mg/h as
a continuous IV infusion, administered via a central venous line. The
combination of norepinephrine and albumin should increase mean arterial
pressure by 10 mmHg. The combination should be administered until SCr is
within 0.3 mg/dL of the baseline SCr, and treatment should be discontinued
after 14 days if no response.
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