Pharmacotherapy for Variceal Hemorrhage

1. Overview of Pharmacologic Management

The management of variceal hemorrhage is a time-sensitive process that spans primary prophylaxis, acute hemorrhage control, and secondary prevention. The primary goals of pharmacotherapy are to reduce portal pressure, achieve rapid and sustained hemostasis, and prevent rebleeding and other complications of cirrhosis.

Key Therapeutic Elements

• Primary Prophylaxis: Nonselective β-blockers (NSBBs) are the cornerstone for patients with compensated cirrhosis and clinically significant portal hypertension (CSPH) to prevent a first bleed.
• Acute Hemorrhage: Immediate initiation of a vasoactive agent (e.g., octreotide, terlipressin) and intravenous antibiotics is critical upon suspicion of a bleed, followed by endoscopic variceal ligation (EVL) within 12 hours.
• Secondary Prophylaxis: After an acute bleed, the combination of an NSBB plus serial EVL is the standard of care to prevent recurrence. Transjugular intrahepatic portosystemic shunt (TIPS) is reserved for high-risk patients or those who fail standard therapy.

2. Nonselective β-Blockers (NSBBs)

NSBBs are the foundation of medical therapy for portal hypertension. They decrease portal pressure through a dual mechanism: β1-receptor blockade reduces cardiac output, while β2-receptor blockade leads to unopposed α-adrenergic activity, causing splanchnic vasoconstriction and reducing portal inflow. Carvedilol offers an additional mechanism through α1-blockade, which reduces intrahepatic resistance.

Dosing and Selection of NSBBs

Monitoring and Contraindications

Therapy should be titrated to a resting heart rate of 55–60 bpm (for propranolol/nadolol) while maintaining a systolic blood pressure (SBP) ≥ 90 mm Hg. Key contraindications include reactive airway disease (asthma/COPD), severe hypotension, and high-degree AV block.

3. Vasoactive Agents in Acute Bleeding

In an acute variceal bleed, immediate pharmacologic reduction of portal pressure is essential to facilitate endoscopy and achieve hemostasis. These agents should be started as soon as a bleed is suspected and continued for 2-5 days.

Agent Selection and Dosing

• Octreotide (Somatostatin Analog): The most commonly used agent in North America. It works by inhibiting the release of vasodilatory peptides like glucagon, leading to indirect splanchnic vasoconstriction.
  • Dosing: 50 mcg IV bolus, followed by a continuous infusion of 50 mcg/hour.
• Terlipressin (Vasopressin Analog): The preferred agent in many parts of the world, including Europe. It is a direct splanchnic vasoconstrictor via V1-receptor agonism.
  • Dosing: 2 mg IV every 4 hours for the first 48 hours, then reduced to 1 mg IV every 4 hours.

Both agents have similar efficacy in controlling bleeding. The choice is often dictated by local availability, cost, and side effect profiles. Terlipressin carries a higher risk of ischemic complications and hyponatremia, while octreotide can cause hyperglycemia.

4. Antibiotic Prophylaxis

Bacterial infections are present in up to 50% of patients with cirrhosis hospitalized for GI bleeding and are a major predictor of rebleeding and mortality. Prophylactic antibiotics are a standard of care and should be initiated on admission.

• Mechanism: Prevents bacterial translocation from the gut, reducing the risk of spontaneous bacterial peritonitis (SBP) and other infections that can worsen portal hypertension.
• Recommended Agent: Intravenous ceftriaxone 1 g daily is the preferred agent, especially in hospitalized patients or regions with high quinolone resistance.
• Duration: Typically administered for 5 to 7 days.

5. Adjunctive Therapies and Coagulopathy Management

Management of adjunctive issues like coagulopathy requires a judicious approach to avoid exacerbating portal hypertension.

A. Coagulopathy and Transfusion Strategy

While patients with cirrhosis are coagulopathic, routine correction with fresh frozen plasma (FFP) or platelets is not recommended unless there is active, severe bleeding. The cornerstone of resuscitation is blood product transfusion.

• Restrictive Transfusion: A restrictive strategy, targeting a hemoglobin of 7 g/dL, is superior to a liberal strategy. Over-transfusion can increase portal pressure and worsen bleeding.
• FFP/Platelets: Reserve for patients with massive hemorrhage and significant coagulopathy (e.g., INR > 2.5) or thrombocytopenia (e.g., platelets < 50,000/mcL) who are undergoing procedures.

B. Proton Pump Inhibitors (PPIs)

PPIs have no role in controlling variceal bleeding itself. Their use should be reserved for patients who have undergone endoscopy and have a co-existing peptic ulcer or severe post-banding ulceration.

6. Integrative Escalation Algorithm

This algorithm outlines the typical sequence of interventions for a patient presenting with acute variceal hemorrhage.

7. Monitoring Plan

Close monitoring is essential to gauge efficacy and detect adverse effects early.

• Efficacy Monitoring:
  • Clinical: Cessation of hematemesis/melena, stabilization of heart rate and blood pressure.
  • Laboratory: Stable hemoglobin, minimal ongoing transfusion requirements.
• Safety Monitoring:
  • Vasoactive Agents: Bradycardia, hypertension (terlipressin), hyperglycemia (octreotide), hyponatremia (terlipressin), and signs of digital or mesenteric ischemia.
  • NSBBs: Symptomatic bradycardia (<55 bpm), hypotension (SBP <90 mm Hg), worsening fatigue or encephalopathy.
  • Antibiotics: Renal function, development of C. difficile-associated diarrhea.
• Frequency: Vital signs should be monitored hourly during the acute phase and vasoactive infusion, then spaced to every 4-8 hours once stable. Laboratory tests are typically performed daily or as dictated by ICU protocols.

8. Summary of Clinical Decision Points & Pearls

• Primary Prophylaxis: Initiate an NSBB (propranolol, nadolol, or carvedilol) in patients with compensated advanced liver disease and large varices to prevent the first bleed and other decompensation events.
• Acute Bleed Triad: Upon suspicion of a variceal bleed, immediately start the therapeutic triad: a vasoactive agent, prophylactic IV antibiotics, and arrange for early EVL (within 12 hours).
• Transfuse with Caution: Adhere to a restrictive RBC transfusion strategy, targeting a hemoglobin of approximately 7 g/dL to avoid increasing portal pressure and rebleeding risk.
• Plan for Failure: For refractory bleeding, use balloon tamponade or a self-expanding metal stent as a bridge to definitive therapy. Pursue early/preemptive TIPS in selected high-risk patients to improve survival.
• Titrate to Effect: In critically ill patients with altered organ function, titrate all medications (especially NSBBs and vasoactive infusions) to hemodynamic and clinical endpoints rather than relying on standard dosing.