Angiotensin II
Cardiovascular / Critical CareAlso known as: Giapreza
Mechanism
Synthetic human angiotensin II — the body's own powerful blood-pressure-raising hormone, made into a drug for ICU use. Approved in 2017 for patients in severe shock whose blood pressure won't respond to standard vasopressors like norepinephrine and vasopressin. It is essentially a last-resort blood pressure support.
Technical detail
Synthetic human angiotensin II octapeptide (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) identical to endogenous Ang II. Binds AT1 receptor (Gq-coupled GPCR) on vascular smooth muscle: activates PLC/IP3/DAG → Ca2+ release → myosin light chain kinase activation → vasoconstriction. Also stimulates aldosterone secretion (Na+/water retention), ADH release, sympathetic facilitation, and cardiac inotropy. In vasodilatory shock: 20 ng/kg/min IV starting dose, titrated to MAP ≥75 mmHg (range 1.25-200 ng/kg/min). ATHOS-3 Phase III trial (n=344): 69.9% achieved MAP ≥75 or ≥10 mmHg increase at 3 hours vs 23.4% placebo (p<0.001). Metabolized by ACE2 (to Ang 1-7), aminopeptidases, and angiotensinases. Risk of thrombosis (7% in trial) — concurrent VTE prophylaxis required. Half-life ~30 seconds in circulation (continuous infusion required).
Effects
## Detailed Effects — Angiotensin II (Giapreza) ### Cardiovascular System — Vasopressor [Tier 1] - Synthetic human angiotensin II (8-amino acid peptide). The endogenous form is a potent vasoconstrictor and key effector of the renin-angiotensin-aldosterone system (RAAS). - Binds AT1 receptor on vascular smooth muscle → Gq-coupled → IP3/DAG → calcium mobilization → vasoconstriction. Also enhances norepinephrine release from sympathetic nerve terminals. - FDA-approved (Giapreza, 2017) to increase blood pressure in adults with distributive/vasodilatory shock (e.g., septic shock). - **ATHOS-3 Trial (Khanna et al., NEJM 2017, n=321)**: Angiotensin II vs placebo in vasodilatory shock not responding to high-dose catecholamines. Primary endpoint (MAP increase ≥10 mmHg or MAP ≥75 mmHg at 3 hours): 69.9% vs 23.4% (p<0.001). Significant catecholamine-sparing effect. - Target MAP typically 65-75 mmHg in shock resuscitation. ### Renal System [Tier 1-2] - Constricts efferent glomerular arterioles preferentially → maintains glomerular filtration pressure when renal perfusion is low. - In ATHOS-3 subgroup analysis, patients with high renin levels and acute kidney injury had improved renal outcomes with angiotensin II (reduced need for renal replacement therapy). - Stimulates aldosterone release from adrenal zona glomerulosa → sodium and water retention. ### Endocrine / Neurohormonal [Tier 1] - Stimulates ADH (vasopressin) release from posterior pituitary. - Stimulates thirst via circumventricular organ activation. - Activates sympathetic nervous system centrally. ### Adverse Effects [Tier 1] - Thromboembolism: increased venous thrombotic events observed (12.9% vs 5.1% in ATHOS-3). DVT prophylaxis is required. - Excessive vasoconstriction → digital ischemia, mesenteric ischemia (rare but serious). - Tachycardia, hyperglycemia.
Practitioner Guide
## Practitioner Guide — Angiotensin II (Giapreza) ### Clinical Indication - **Distributive/vasodilatory shock** (primarily septic shock) refractory to first-line vasopressors (norepinephrine, vasopressin). - Positioned as a second- or third-line vasopressor when catecholamine requirements are high (norepinephrine-equivalent dose >0.2 mcg/kg/min). - ICU USE ONLY. Central line administration preferred. ### Dosing Protocol - **Starting dose**: 20 ng/kg/min IV infusion. - **Titration**: Increase by 15 ng/kg/min every 5 minutes as needed to achieve target MAP ≥65 mmHg. - **Maintenance range**: 1.25-40 ng/kg/min (most patients stabilize at 5-20 ng/kg/min). - **Maximum dose**: 80 ng/kg/min. - **Weaning**: Once MAP is stable, wean catecholamines first, then wean angiotensin II. Do NOT stop abruptly — taper gradually. ### Preparation - Giapreza vial: 2.5 mg/mL, 1 mL single-dose vial. - Dilute in 0.9% NS to a final volume of 250 mL (concentration 10,000 ng/mL). - Administer via IV infusion pump. Central venous access preferred; peripheral access acceptable short-term. ### When to Choose Angiotensin II Over Other Vasopressors - **ACE-deficient patients**: Patients on chronic ACE inhibitor or ARB therapy may have depleted angiotensin II → RAAS paralysis in sepsis. These patients may respond dramatically to exogenous angiotensin II. - **High-renin state**: Elevated plasma renin activity predicts response to angiotensin II (ATHOS-3 subgroup data). Renin level >3x upper normal = strong predictor of benefit. - **Catecholamine-refractory shock**: When norepinephrine + vasopressin are at high doses and MAP remains below target. - **AKI requiring CRRT**: Angiotensin II may have renal-protective effects by maintaining glomerular filtration pressure. ### Monitoring - Continuous arterial blood pressure monitoring (arterial line). - DVT prophylaxis is MANDATORY — use pharmacologic prophylaxis (heparin or enoxaparin) unless contraindicated. - Monitor extremities for digital ischemia. - Blood glucose monitoring (hyperglycemia common). - Consider renin levels if available — high renin predicts response. ### Storage - Vials: Refrigerate (2-8°C). Do not freeze. - Diluted solution: Stable for 24 hours at room temperature or refrigerated.
Research Summary
## Research Summary — Angiotensin II ### Tier 1: Randomized Controlled Trials - **ATHOS-3 (Khanna et al., NEJM 2017, n=321)**: Pivotal trial. Angiotensin II vs placebo in catecholamine-resistant vasodilatory shock. MAP response at 3 hours: 69.9% vs 23.4% (p<0.001). Significant vasopressor-sparing effect. Led to FDA approval. - **ATHOS-3 Subgroup Analyses**: Patients with elevated renin and AKI requiring CRRT had the greatest benefit — reduced 28-day mortality and reduced dialysis need. ### Tier 2: Systematic Reviews & Meta-Analyses - Systematic reviews of vasopressor strategies in septic shock increasingly include angiotensin II as a third-line option. - Surviving Sepsis Campaign guidelines (2021) include angiotensin II as an option for vasodilatory shock refractory to conventional agents. - Pharmacoeconomic analyses suggest cost-effectiveness in selected patients (high catecholamine requirements, AKI) but not as routine use. ### Tier 3: Case Reports & Practitioner Protocols - Intensivists report dramatic responses in patients on chronic ACEi/ARB therapy who develop septic shock — consistent with RAAS paralysis phenotype. - Renin-guided vasopressor selection is an emerging ICU practice — high renin → add angiotensin II. - Some case reports of use in post-cardiac surgery vasoplegia and anaphylactic shock. ### Gaps - No large trial comparing angiotensin II directly to vasopressin as a second-line agent. - Optimal patient selection criteria (beyond high renin) not fully defined. - Long-term outcomes and thrombotic risk mitigation strategies need further study. ### Active Trials - ACT-IV trial: Phase 3 studying angiotensin II in high-output shock requiring high-dose vasopressors. - Renin-guided vasopressor management trials ongoing. - Studies evaluating angiotensin II + CRRT protocols for septic AKI.