Giapreza: A Synthetic Human Angiotensin II: Rx for Vasoplegia in CV Surgery?

Editor’s Note:

I was having a conversation with my heart surgeon here in the upper Midwest- when he mentioned a newer medication- Giaprezza (A Synthetic Human Angiotensin II: as potential Rx for Vasoplegia associated post CPP in CV Surgery).

Since I needed to educate myself on this drug, I thought I would look it up and put it out there for the rest of the community.  Any thought or anecdotal observations you may wish to share would be greatly appreciated.

Thank you Dr. M  🙂

Vasoplegia RX

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Vasoplegia is a ubiquitous phenomenon in all advanced shock states, including septic, cardiogenic, hemorrhagic, and anaphylactic shock. Its pathophysiology is complex, involving various mechanisms in vascular smooth muscle cells such as G protein-coupled receptor desensitization (adrenoceptors, vasopressin 1 receptors, angiotensin type 1 receptors), alteration of second messenger pathways, critical illness-related corticosteroid insufficiency, and increased production of nitric oxide. This review, based on a critical appraisal of the literature, discusses the main current treatments and future approaches. Our improved understanding of these mechanisms is progressively changing our therapeutic approach to vasoplegia from a standardized to a personalized multimodal treatment with the prescription of several vasopressors.

While norepinephrine is confirmed as first line therapy for the treatment of vasoplegia, the latest Surviving Sepsis Campaign guidelines also consider that the best therapeutic management of vascular hyporesponsiveness to vasopressors could be a combination of multiple vasopressors, including norepinephrine and early prescription of vasopressin.

This new approach is seemingly justified by the need to limit adrenoceptor desensitization as well as sympathetic overactivation given its subsequent deleterious impacts on hemodynamics and inflammation. Finally, based on new pathophysiological data, two potential drugs, selepressin and angiotensin II, are currently being evaluated.

Definition(s) of vasoplegia

Known as “vasodilatory shock”, this condition includes multiple and diverse etiologies (e.g., septic, cardiogenic, neurogenic, and anaphylactic shock) and ultimately results in uncontrolled vasodilation, otherwise termed “vasoplegia”. The pathophysiology of vasoplegia is multifactorial and includes activation of several intrinsic vasodilatory pathways and a vascular hyporesponsiveness to vasopressors [1]. Vasoplegia occurring post-surgery is called postoperative vasoplegic syndrome or vasoplegic syndrome. In clinical practice, vasoplegia can be assessed clinically by the vasopressor dosage necessary to maintain mean arterial blood pressure (MAP) and by the drop in diastolic blood pressure reflecting vasoplegia [2]. Invariably, the necessity to use a high-dose vasopressor is highly indicative of vasoplegia, especially in the case of normal cardiac function. For further details, the reader is invited to consult the pathophysiological article published in the same series.

However, vascular responsiveness to vasopressors is probably better suited than vasoplegia for characterizing the state of vessels during shock. While the term vasoplagia refers to the static diameter of the vessel in response to specific intra-luminal and transmural pressures, vascular responsiveness to vasopressors refers to the dynamic response of the vessel to endogenous and/or exogenous vasoconstrictor agents [1].

Vasoplegia treatment

The use of adrenergic vasopressors
Vascular hyporeactivity-associated hypotension is clearly associated, both significantly and independently, with mortality [19]. After volume resuscitation, the use of catecholamines is considered to be the cornerstone of septic shock hemodynamic treatment [20]. This therapeutic class includes dopamine, epinephrine, norepinephrine, and phenylephrine. All of these molecules increase MAP by stimulating the α1 adrenergic receptor. Nevertheless, aside from phenylephrine, all of the above catecholamines stimulate other adrenergic receptors, leading to various hemodynamic, metabolic, and inflammatory effects [2122]. Comparison of the affinity of these different drugs for receptor subtypes as well as the effects associated with receptor stimulation is depicted in Table 1. Hence, the choice of best adrenergic vasopressor should take into account not only its vasopressor effect but also its cardiac, metabolic, microcirculatory, and immune effects.
Norepinephrine as a first line-agent

Norepinephrine is a very potent and reliable vasopressor. It increases MAP without any concomitant increase in heart rate. Generally, cardiac index is increased due to both a rise in end-diastolic stroke volume through a mobilization of splanchnic unstressed volume and to a direct effect on cardiac myocytes due to β1 adrenergic receptor stimulation [24].

Vasopressin as a second line agent or a catecholamine-sparing agent

Patients with severe septic shock often require very high doses of norepinephrine in order to achieve the target MAP, thereby potentially leading to adverse side effects [30]. The SSC suggests adding either vasopressin (up to 0.03 U/min; weak recommendation, moderate quality of evidence) to norepinephrine with the intent of raising MAP to target, or adding vasopressin (up to 0.03 U/min; weak recommendation, moderate quality of evidence) to decrease norepinephrine dosage. The rationale for vasopressin use is that there is a relative vasopressin deficiency in septic shock such that addition of exogenous vasopressin restores vascular tone by acting on non-adrenergic receptors, increases blood pressure, thereby reducing norepinephrine requirements, and possibly has favorable effects on cytokine production [313233].

Phenylephrine use should be limited

Phenylephrine is a pure α1 adrenergic agonist for which clinical trial data are limited. It has the potential to produce splanchnic vasoconstriction. Moreover, in a model of rat septic shock, phenylephrine use has been associated with a detrimental effect on intrinsic cardiac function [39]. Lastly, among patients with septic shock in US hospitals affected by the 2011 norepinephrine shortage, Vail et al. [40] found that the most commonly administered alternative vasopressor was phenylephrine. Patients admitted to these hospitals during times of shortage had higher in-hospital mortality.

Angiotensin II

Activation of the renin–angiotensin–aldosterone system leads to angiotensin II production [50]. Angiotensin II acts by binding to specific GPCRs, namely AT1 and AT2 [51]. The main hemodynamic effects mediated by AT1 receptor activation include vasoconstriction, aldosterone secretion, vasopressin release, and cardiac remodeling [52]. In the ATHOS-3 study, patients with vasodilatory shock who were receiving more than 0.2 μ−1.min−1 of norepinephrine or the equivalent dose of another vasopressor were assigned to receive infusions of either angiotensin II or placebo [53]. The primary end point was MAP response at 3 h after initiation of infusion, with response defined as an increase from baseline of at least 10 mmHg or an increase to at least 75 mmHg, without an increase in dose of background vasopressors. The primary endpoint was reached by more patients in the angiotensin II group than in the placebo group (p < 0.001). At 48 h, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score was greater in the angiotensin II group than in the placebo group (p = 0.01). Serious adverse events were reported in 60.7 % of the patients in the angiotensin II group and in 67.1 % in the placebo group. Death by day 28 occurred in 75/163 patients (46 %) in the angiotensin II group and in 85/158 patients (54 %) in the placebo group (p = 0.12).


Vasoplegia is a common feature of all advanced shock states, with norepinephrine remaining the cornerstone of vasoplegia-induced hypotension. However, given our improved understanding of vasoplegia, management is likely to evolve from a standardized therapy with norepinephrine alone to a multimodal strategy with two or more vasopressors. Based on new pathophysiological data, numerous potential drugs are currently being investigated. Nevertheless, these new potential treatments or therapeutic strategies should be evaluated not only for their ability to increase arterial pressure but also for their capacity to improve survival or decrease major morbidity as well as for their effectiveness/cost ratio.

Medication Guidelines & Dosing

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Dosage Forms & Strengths

injectable solution

  • 2.5mg/mL
  • 5mg/2mL

Indicated to increase blood pressure in adults with septic or other distributive shock

Initial: 20 ng/kg/minute IV by continuous infusion

Titration: Monitor blood pressure response and titrate q5min by increments of up to 15 ng/kg/min prn to achieve or maintain target blood pressure; not to exceed 80 ng/kg/min during the first 3 hr of treatment

Maintenance: Should not exceed 40 ng/kg/min; doses as low as 1.25 ng/kg/min may be used

Once the underlying shock has sufficiently improved, titrate downward q5-15min by increments of up to 15 ng/kg/min based on blood pressure

Administration via central venous line is recommended

Dosage Modifications

Renal or hepatic impairment

  • Clearance of angiotensin II is not dependent on renal or hepatic function; therefore, the pharmacokinetics are not expected to be influenced by impairment


  • azilsartan
  • benazepril
  • candesartan
  • captopril
  • enalapril
  • eprosartan
  • fosinopril
  • irbesartan
  • lisinopril
  • losartan
  • moexipril
  • olmesartan
  • perindopril
  • quinapril
  • ramipril
  • sacubitril/valsartan
  • telmisartan
  • trandolapril
  • valsartan

Adverse Effects


Thromboembolic events (12.9%)


Thrombocytopenia (9.8%)

Tachycardia (8.6%)

Fungal infection (6.1%)

Delirium (5.5%)

Acidosis (5.5%)

Deep vein thrombosis (4.3%)

Hyperglycemia (4.3%)

Peripheral ischemia (4.3%)




Risk of thromboembolism observed in clinical trials; use concurrent venous thromboembolism prophylaxis

Drug interaction overview

  • Coadministration with angiotensin-converting enzyme (ACE inhibitors) may increase response to angiotensin II
  • Coadministration with angiotensin II blockers may decrease response to angiotensin II


Mechanism of Action

Angiotensin II, the major bioactive component of the renin-angiotensin-aldosterone system (RAAS), serves as one of the body’s central regulators of blood pressure

It raises blood pressure by vasoconstriction and increased aldosterone release; direct action of angiotensin II on the vessel wall is mediated by binding to the G-protein-coupled angiotensin II receptor type 1 on vascular smooth muscle cells, which stimulates Ca2+/calmodulin-dependent phosphorylation of myosin and causes smooth muscle contraction


Serum levels are similar at baseline and at 3 hr; after 3 hr, however, the serum level of angiotensin I (precursor of angiotensin II) is reduced ~40%


Metabolized by aminopeptidase A and angiotensin-converting enzyme 2 to angiotensin-(2-8) [angiotensin III] and angiotensin-(1-7), respectively in plasma, erythrocytes, and many of the major organs (ie, intestine, kidney, liver, lung)


Half-life: <1 min


IV Compatibilities

0.9% NaCl

IV Preparation

Inspect solution for particulate matter and discoloration; solution should appear clear

Solution must be diluted before use with 0.9% NaCl to a final concentration of 5,000 or 10,000 ng/mL

Diluted solution concentrations

    • Not fluid restricted
      • 2.5-mg/mL vial in 500 mL 0.9% NaCl = 5,000 ng/mL
  • Fluid restricted
    • 2.5-mg/mL vial in 250 mL 0.9% NaCl = 10,000 ng/mL
    • 5-mg/2 mL vial in 500 mL 0.9% NaCl = 10,000 ng/mL
IV Administration

Administer by continuous IV infusion via central venous line


Unopened vials

  • Refrigerate at 36-46°F (2-8°C)

Diluted solution

  • May store refrigerated or at room temperature
  • Discard prepared solution after 24 hr

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