Varices

Portal Hypertension Revisited

• Increased structural resistance
  • Fibrous tissue
  • Vascular distortion
• Intrahepatic vasoconstriction
  • Decreased nitric oxide bioavailability
• Splanchnic arterial vasodilation

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Pathophysiology

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Risk of Variceal Bleed

• Varices can be categorized into high verus low risk
  • High risk includes:
    • Medium and large varices
    • Small varices with red wale marks (indicating high risk of bleed)

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Esophagogastroduodenoscopy

• Abbreviated EGD
• Identifies presence of varices
  • Will also be used to identify sources of gastric bleeding
• Can be used to preemtively eliminate varices, as well as treat those that are bleeding

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Primary Prevention of a Bleed

• Recommended for patients with medium/large varices at high risk for bleeding
  • First line → nonselective β-blockers
  • Alternative → endoscopic variceal ligation (EVL)

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Primary Prevention of Variceal Hemorrhage

Therapy	Dosing	Goals
Propranolol	•No ascites = Max  320 mg •Ascites = Max 160 mg	HR of 55-60 Stop if  SBP < 90
Nadolol	•No ascites = Max 160 mg •Ascites = Max 80 mg	HR of 55-60 Stop if SBP < 90
Carvedilol	•Regardless of Ascites: •Max  =  6.25 mg BID *Unless hypertensive	Stop if  SBP < 90
OR
EVL	•Every 2-8 weeks until elimination of varices	Variceal eradication

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Recap of Mechanisms

Non- selective β blockers

–β1 blockade:

-↓ cardiac output and splanchnic blood flow

–β 2 blockade:

-prevent splanchnic vasodilation mediated by β2 receptors, allowing unopposed α adrenergic effects

-↓ portal blood flow and ↑ vasoconstriction of splanchnic vascular  bed

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Acute Variceal Hemorrhage (VH)

• Goals:
  • Control bleeding
  • Maintain hemodynamic stability
  • Prevent rebleed
  • Prevent acute complications

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Management of Acute Variceal Bleed

• Protect airway to prevent aspiration
• STAT EGD
  • Blakemore/tamponade if needed
• Modest blood transfusions & fluid resuscitation
  • Goal Hgb >7g/dL
  • Too much can increase portal pressure, ascites, and risk of hemorrhage
• Hold inappropriate home medications
  • Beta blockers
  • Anti-hypertensives
  • NPO if severe bleed
• Start appropriate pharmacotherapy

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Pharmacotherapy for VH

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Octreotide

• Local splanchnic vasoconstrictor
  • Decreases blood to the variceal bleed by “clamping down” the vasculature
• Associated with lower 7-day mortality, but limited data

Agent	Dose	Duration	Monitoring
Octreotide	-50 mcg bolus (can be repeated x1) -50 mcg/hr continuous infusion	-24-72 hours after bleeding has stopped -Maximum 5 days	NA

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Recap of Mechanisms

Octreotide

–↑ vasoconstriction of splanchnic bed

–↓ portal venous  pressure

–↓ splachnic blood flow

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Antibiotics

• With high pressure bleed → increased risk of bacterial infection
  • Use of prophylactic antibiotics to prevent infection in the setting of VH
  • Decreased risk of infection, recurrent hemorrhage, and death
• Given bleeding, IV route is preferred
  • Antibiotics: Ceftriaxone 1g q24 hours
  • Duration: Maximum of 7 days
• Ceftriaxone dosing for infection prevention (1g q24 hours) is different than that of SBP treatment (2g q24 hours)
• Once patients have recovered from a bleed, there is a need to prevent recurrent bleed

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Secondary Prevention of Variceal Hemorrhage (Preventing Rebleed)

Therapy	Dosing	Goals
Propranolol	•No ascites = Max  320 mg •Ascites = Max 160 mg	HR of 55-60 Stop if  SBP < 90
Nadolol	•No ascites = Max 160 mg •Ascites = Max 80 mg	HR of 55-60 Stop if SBP < 90
WITH
EVL	•Every 1-4 weeks until elimination of varices	Variceal eradication Prevention of VH

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The Beta Blocker Controversy in Patients with Cirrhosis

• Initially found to be beneficial, thought to decrease risk of bleed as well as rebleed after recovery from a variceal hemorrhage
• Conflicting evidence emerged in the 2000’s
  • • Are we doing harm with beta blockers in patients with cirrhosis?
• Piecing out the evidence

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Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis – A controlled study
Design	•Randomized controlled trial •Propranolol arm (n=38); placebo arm (n=36)
Population	•Cirrhosis, admitted for GI bleed and stabilized
Results	•Propranolol group = 96% free of recurrent GI bleed at 1 year •Placebo group = 50% free of recurrent GI bleed at 1 year •P < 0.0001
Conclusion	•Propranolol is effective in preventing recurrent GI bleeding in patients with cirrhosis

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Harm With Beta Blockers

Author	Patients	Design	Outcome	Results
Serste 2010	Refractory ascites (n=151)	Case-control	1 year survival	19% propranolol vs 64% no propranolol, NNH = 2
Serste 2011	Refractory ascites (n=10)	Crossover	Paracentesis induced circulatory dysfunction (PICD)	8 patients developed PICD on propranolol, 1 patient developed PICD after propranolol discontinued
Mandorfer 2014	Patients receiving paracentesis (n=607)	Retrospective	Transplant free survival	Subanalysis – patients with SBP had increased risk of death if receiving beta blocker (HR 1.58, CI 1.098-2.274)

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Benefit with Beta Blockers

Author	Patients	Design	Outcome	Results
Leithead 2015	Cirrhosis (n=322)	Retrospective	Mortality	Beta blockers were associated with decreased mortality in overall analysis and in subgroup analysis of patients with refractory ascites (HR 0.35, CI 0.14 to 0.86)
Bossen 2016	Cirrhosis with ascites (n=1198)	Retrospective	Mortality	Beta blockers were associated with no difference in mortality in overall analysis and in subgroup analysis of patients with refractory ascites
Bang 2016	Decompensated cirrhosis (n=3719)	Retrospective	Mortality	Propranolol was associated with decreased mortality when used at doses less than 160 mg/day (HR 0.7, CI 0.6-0.9)

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The Window Hypothesis

• Early Cirrhosis
  • Beta blockers not indicated
  • Cardiac reserve, SNS activity, and RAAS activity at baseline
    • Low risk of SBP
• Decompensated Cirrhosis (Medium to Large Varices)
  • BB indicated for primary and secondary prophylaxis of VH
  • Decreased cardiac reserve, increased SNS and RAAS
  • Increased risk of SBP
• End-Stage Cirrhosis
  • BB decrease survival
  • Cardiac reserve critically impaired, SNS and RAAS maximally stimulated
  • Easy gut bacteria translocation

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Discontinuation of Beta Blockers

• Refractory ascites
• Systolic BP < 100 mmHg
• Mean arterial pressure ≤ 82 mmHg
• Serum sodium < 120 mEq
• Severe alcoholic hepatitis
• AKI
• HRS
• SBP
• Sepsis
• Poor follow up or nonadherence