Angiotensin II

Angiotensin II is the effector peptide of the renin-angiotensin system, normally produced when ACE cleaves angiotensin I. Given exogenously it binds the AT1 G-protein-coupled receptor, activating Gq, phospholipase C and IP3-mediated calcium release to constrict arteriolar smooth muscle. It simultaneously stimulates aldosterone release from the adrenal zona glomerulosa and enhances renal sodium reabsorption and vasopressin release. In distributive shock its value is that it works through a pathway entirely separate from catecholamines, so it adds pressure where adrenergic receptors have been desensitised, and it disproportionately helps patients whose endogenous ACE activity has collapsed - measurable as a high angiotensin I to angiotensin II ratio.

Targets: Angiotensin II type 1 receptor (AT1), Aldosterone secretion, Vasopressin release

• · Start at 20 ng/kg/min, titrate every 5 minutes by up to 15 ng/kg/min to reach the MAP target. Maximum 80 ng/kg/min in the first 3 hours, then maintenance should not exceed 40 ng/kg/min. Doses this small are not expressed as fixed micrograms. Wean in decrements of up to 15 ng/kg/min every 5-15 minutes.

Work out your exact syringe units →

• commonThromboembolic events, including deep vein thrombosis— Roughly 13 percent versus 5 percent on placebo in ATHOS-3. Concurrent VTE prophylaxis is recommended.
• commonTachycardia
• commonDelirium
• commonHyperglycaemia
• commonAcidosis
• uncommonPeripheral or digital ischaemia— Potent vasoconstriction can cost fingers and toes, as with any high-dose vasopressor.

• No absolute contraindications on the label, but the thrombosis risk means VTE prophylaxis should be running.
• Use without invasive blood pressure monitoring - the drug is far too potent to titrate off a cuff alone.
• Peripheral infusion, which risks extravasation injury; central venous access is expected.

• cautionACE inhibitors — Blocking ACE increases the response to exogenous angiotensin II, so a lower dose may suffice.
• conflictangiotensin receptor blockers — ARBs occupy the AT1 receptor and blunt or abolish the pressor response, requiring higher doses.
• synergynoradrenaline — The intended pairing - angiotensin II works through a non-catecholamine pathway and lets catecholamine doses come down.

• · Invasive arterial blood pressure with a defined MAP target.
• · Clinical surveillance for thrombosis and for digital or limb ischaemia.
• · Lactate and markers of tissue perfusion.
• · Urine output and renal function.

FDA-approved prescription vasopressor for intensive care use; also approved in the EU. Hospital-only.

• Giapreza (angiotensin II) FDA prescribing information (label)
• Khanna et al. 2017, ATHOS-3, angiotensin II for the treatment of vasodilatory shock (trial)

Angiotensin II acts on the AT1 receptor, a Gq-coupled GPCR. Gq activates phospholipase C beta, which cleaves PIP2 into IP3 and diacylglycerol; IP3 releases calcium from the sarcoplasmic reticulum and DAG activates protein kinase C, and together they produce vascular smooth muscle contraction. That is a completely different second-messenger pathway from catecholamines, which work through Gs and cAMP on alpha and beta adrenoceptors, and different again from vasopressin, which works through V1a and its own Gq pathway. That mechanistic independence is the entire clinical argument: in a patient on 0.5 mcg/kg/min of noradrenaline whose adrenoceptors are downregulated and desensitised by hours of catecholamine exposure and acidosis, adding a third, unrelated vasoconstrictor pathway does something that adding more noradrenaline does not. Beyond vasoconstriction, AT1 activation stimulates aldosterone release from the zona glomerulosa and vasopressin release from the posterior pituitary, so there is a neurohormonal component on top of the direct pressor effect. There is a further mechanistic wrinkle that predicts who responds: in septic shock, ACE activity in the pulmonary endothelium falls, so patients accumulate angiotensin I and cannot make angiotensin II. Those patients have a high angiotensin I to II ratio and are exactly the ones who respond dramatically to exogenous angiotensin II, because you are replacing a hormone they cannot synthesise rather than adding a drug to a full system. The AT2 receptor, by contrast, is counter-regulatory and vasodilatory, which is part of why the net effect at low doses is more modest than the receptor pharmacology alone would suggest.

Thrombosis is the specific harm, both arterial and venous, and it is not a theoretical concern: it was more common than placebo in ATHOS-3, and angiotensin II activates platelets and induces PAI-1. Excessive vasoconstriction is the other: a beautiful MAP with a rising lactate and cold, mottled skin means you have traded perfusion for a number. Patients on ARBs will not respond and the temptation is to keep titrating up. Rebound hypotension on abrupt discontinuation happens because the half-life is under a minute, so this drug must be weaned rather than stopped. And the trial was powered for blood pressure: nobody has shown that angiotensin II makes people survive septic shock, only that it raises their blood pressure and spares catecholamines.

1. —Minute 0 — Start at 20 ng/kg/min by continuous central intravenous infusion.
2. —Every 5 minutes as needed — Titrate up by increments of up to 15 ng/kg/min to reach or hold the target blood pressure.
3. —First 3 hours — Ceiling of 80 ng/kg/min during the first 3 hours. Most responders are well below this.
4. —After 3 hours (maintenance) — Maintenance must not exceed 40 ng/kg/min. Doses as low as 1.25 ng/kg/min are usable and are often where patients end up.
5. —Weaning — Once shock has improved, down-titrate every 5 to 15 minutes by up to 15 ng/kg/min based on blood pressure.

• Angiotensin II type 1 receptor (AT1)

  Gq/phospholipase C signalling to IP3 and DAG, raising intracellular calcium in vascular smooth muscle. Direct vasoconstriction, aldosterone secretion, vasopressin release and sodium retention.

• Angiotensin II type 2 receptor (AT2)

  Counter-regulatory: nitric oxide and bradykinin-mediated vasodilation, opposing AT1. Its contribution to the net clinical effect is not well quantified.

• ATHOS-3 Phase 3 · n=344 · 0.02 weeks · 2017

  MAP response at hour 3, defined as a rise of at least 10 mmHg or to at least 75 mmHg without increasing background vasopressors. Reached by 69.9 percent on angiotensin II versus 23.4 percent on placebo (odds ratio 7.95). Powered for blood pressure, not survival.

• ATHOS-3 renal replacement therapy subgroup analysis Post hoc analysis of a phase 3 trial · n=105 · 4.3 weeks · 2018

  Survival through day 28 in the 105 ATHOS-3 patients (45 angiotensin II, 60 placebo) who were on renal replacement therapy for acute kidney injury at randomisation. 28-day survival was 53 percent with angiotensin II versus 30 percent with placebo (p=0.012). This is the strongest survival signal in the whole programme, and it is a post hoc subgroup.

Median time to reach the target MAP was about 5 minutes in ATHOS-3. Blood pressure falls again within minutes of stopping. There is no accumulation and no tail; this is the fastest-acting and fastest-offsetting drug in this entire class.

Angiotensin II is a third-line addition on top of noradrenaline and vasopressin, and the stack is the point: three independent receptor systems rather than escalating one. ACE inhibitors blunt the response and raise the dose required; ARBs block the receptor outright and make the drug close to useless, which matters because a large fraction of shock patients arrive on an ARB. Concurrent VTE prophylaxis is not optional given the thrombosis signal. There is a plausible interaction with sacubitril/valsartan and with ACE2-directed therapies, both of which alter the angiotensin peptide balance, though this is not well studied.

Against noradrenaline: different receptor, different second messenger, additive rather than competing, and useful precisely where noradrenaline has stopped working. Against vasopressin: both are catecholamine-sparing second agents; vasopressin has decades of use and much lower cost, angiotensin II has a cleaner mechanistic rationale in the specific case of ACE dysfunction and a more impressive blood pressure response. Against methylene blue: methylene blue attacks the nitric oxide arm of vasoplegia rather than adding a vasoconstrictor, and the two are not mutually exclusive. Against angiotensin-(1-7), its metabolite: they are functional opposites, and one is made from the other by ACE2.

ICU infusion billed per vial, not per month. It has been consistently one of the most expensive vasopressors per day of therapy, which is a real part of why it is used late rather than early.

• ?No formal distribution, metabolism or excretion studies were conducted for the approved product, so volume of distribution, clearance and protein binding are genuinely uncharacterised rather than simply unfound.
• ?The renin and angiotensin I to II ratio enrichment story is based on post hoc analyses and is not a validated companion diagnostic; assay availability with useful turnaround is limited in most centres.
• ?Whether the survival signal in the renal replacement therapy subgroup is real or a subgroup artefact has never been tested prospectively.

• Angiotensin II for the treatment of vasodilatory shock Khanna A, English SW, Wang XS, et al. (ATHOS-3 Investigators), N Engl J Med, 2017 · PMID 28528561

  The registration trial. Read the primary endpoint carefully: it is a blood pressure endpoint.

• Outcomes in patients with vasodilatory shock and renal replacement therapy treated with intravenous angiotensin II Tumlin JA, Murugan R, Deane AM, et al., Crit Care Med, 2018 · PMID 29509568

  The AKI-on-dialysis subgroup where the effect looks largest.

• Initiating angiotensin II at lower vasopressor doses in vasodilatory shock: an exploratory post-hoc analysis of the ATHOS-3 clinical trial Wieruszewski PM, Bellomo R, Busse LW, et al., Crit Care, 2023 · PMID 37147690

  Argues for earlier introduction rather than as a last resort.

• Angiotensin II for catecholamine-resistant vasodilatory shock in patients with acute kidney injury: a post hoc analysis of the ATHOS-3 trial Chaba A, Bellomo R, et al., Shock, 2025 · PMID 39671552

  The most recent re-analysis of the renal subgroup.

• Angiotensinogen (UniProt P01019), angiotensin-2 peptide annotation UniProtKB

  Source of the DRVYIHPF sequence given above.