Can Giapreza (angiotensin II) be used in an adult with acute liver failure?

Can Giapreza Be Used in Acute Liver Failure?

Yes, Giapreza (angiotensin II) can be used in acute liver failure when patients develop vasodilatory shock requiring vasopressor support, as the drug's clearance is not dependent on hepatic function and case reports demonstrate safety and efficacy in this population.

Pharmacokinetic Rationale for Use in Liver Failure

• The clearance of angiotensin II is not dependent on hepatic function, making the pharmacokinetics of Giapreza unaffected by hepatic impairment 1
• Angiotensin II has a plasma half-life of less than one minute and is metabolized by aminopeptidase A and angiotensin converting enzyme 2 in plasma, erythrocytes, and major organs including intestine, kidney, liver, and lung 1
• This rapid, multi-organ metabolism means that even severe hepatic dysfunction does not significantly impair drug clearance 1

Clinical Context: When Vasopressors Are Needed in Acute Liver Failure

• Acute liver failure patients often develop vasodilatory shock requiring vasopressor support, particularly when complicated by sepsis or systemic inflammatory response 2
• The primary indication for Giapreza is vasodilatory shock in patients who remain hypotensive despite fluid resuscitation and conventional vasopressor therapy 1
• In the ATHOS-3 trial, 91% of subjects had septic shock and 97% were receiving norepinephrine at baseline, with 83% requiring two or more vasopressors 1

Evidence Supporting Use in Liver Failure

• Case reports demonstrate successful use of angiotensin II in patients with decompensated cirrhosis and septic shock, including a patient with a Model for End-Stage Liver Disease (MELD) score of 36 and Sequential Organ Failure Assessment (SOFA) score of 14 2
• Angiotensin II has been used successfully during liver transplantation for combined liver failure-induced distributive shock and septic shock 3
• The liver produces angiotensinogen (a key precursor to angiotensin II), but exogenous angiotensin II administration bypasses this step, making it potentially beneficial when endogenous production is impaired 2

Important Caveat: ATHOS-3 Trial Exclusion

• Liver failure was an exclusion criterion in the pivotal ATHOS-3 trial, meaning the formal evidence base does not include this population 2
• However, this exclusion appears to have been precautionary rather than based on safety concerns, as the pharmacokinetic profile supports use in hepatic impairment 1
• Subsequent case reports and clinical experience have not identified liver-specific safety concerns 2, 3

Dosing and Administration in Liver Failure

• Initiate Giapreza when norepinephrine requirements are escalating (typically ≥0.05 mcg/kg/min) 4
• Start at 20 ng/kg/min and titrate to maintain mean arterial pressure ≥65 mmHg 1
• The median time to reach target MAP in ATHOS-3 was approximately 5 minutes 1
• No dose adjustment is required for hepatic impairment based on pharmacokinetic analysis 1

Monitoring Considerations Specific to Liver Failure

• Monitor for thromboembolism within 48 hours, as this is a known adverse effect (though not specifically increased in liver failure) 1
• Watch for severe hypertension during titration 1
• In acute liver failure patients, continue monitoring arterial ammonia levels as recommended for general supportive care 5
• Assess for signs of end-organ perfusion, particularly renal function, as angiotensin II may improve renal perfusion pressure and glomerular filtration rate 4

Contraindications and Precautions

• Avoid in patients with active thrombosis or high thrombotic risk 1
• Use caution in patients with history of asthma or bronchospasm (these patients were excluded from ATHOS-3) 1
• Patients with Raynaud's syndrome were excluded from the pivotal trial 1

Clinical Algorithm for Use

1. Confirm vasodilatory shock: Patient with acute liver failure requiring norepinephrine ≥0.05 mcg/kg/min despite adequate fluid resuscitation 1, 4
2. Exclude contraindications: Active thrombosis, severe asthma, Raynaud's syndrome 1
3. Initiate Giapreza: Start at 20 ng/kg/min as second-line vasopressor 1
4. Titrate to effect: Target MAP ≥65-75 mmHg while attempting to reduce catecholamine doses 1
5. Monitor closely: Watch for thromboembolism, hypertension, and end-organ perfusion 1

Potential Advantages in Liver Failure

• May reduce catecholamine requirements, potentially improving organ perfusion compared to high-dose norepinephrine 4
• Angiotensin II may improve renal perfusion pressure and glomerular filtration rate, which could be beneficial given the high incidence of acute kidney injury in acute liver failure 4, 6
• Does not rely on hepatic metabolism, making it predictable in liver failure 1