According to a recent review article, which of the following novel vasopressors has received approval from the US Food and Drug Administration (FDA) for distributive shock? Read the discussion.
(B) Angiotensin II
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The 3 major categories of shock are hemorrhagic, cardiogenic, and distributive, the last of which is most common. Distributive shock is a high cardiac-output vasodilatory state and is often associated with capillary leak. Sepsis is responsible for approximately 94% of distributive shock cases, while the remaining causes include anaphylaxis, adrenal insufficiency, and drug toxicity.
The Surviving Sepsis Campaign lists norepinephrine as the first-line therapy for septic shock. Second-line therapies include arginine vasopressin and epinephrine, which serve to augment the pressor effect of or reduce the dose of norepinephrine. Because catecholamine-mediated vasopressors (norepinephrine, epinephrine, dopamine) may cause arrhythmias, organ dysfunction, and hyperglycemia, investigation of novel vasopressors focuses on noncatecholamine mechanisms. A recent review described prospective controlled trials that determined the effectiveness of 3 new vasopressor agents.
In December 2017, the US Food and Drug Administration (FDA) approved the use of synthetic angiotensin II (Ang II) for blood pressure management in patients with septic shock or other forms of distributive shock. Ang II is derived from the renin–angiotensin–aldosterone system that regulates blood pressure and volume. Ang I is catalyzed by angiotensin-converting enzyme 1 (ACE1) in the lung circulation to produce Ang II, which acts immediately on angiotensin receptors on vascular smooth muscle to evoke vasoconstriction and stimulates adrenal release of aldosterone. The plasma half-life of Ang II is less than 1 minute, metabolized by plasma aminopeptidase A and the ACE2 enzyme. Rapid pharmacokinetics is a favorable characteristic of Ang II in distributive shock.
The authors of a recent review highlighted the Angiotensin II for the Treatment of High-Output Shock (ATHOS) trial and its phase III follow-up (ATHOS-3), which added Ang II infusion to norepinephrine infusion for septic shock. The starting dose of Ang II was 20 ng/kg/min with a maximum dose of 200 ng/kg/min in the ATHOS-3 trial. Both studies demonstrated sustained augmentation of blood pressure for at least 3 hours, with a decrease in norepinephrine requirement, and no increased incidence of cardiac arrythmia or peripheral (digital) ischemia. Post hoc analysis of these trials suggested an improvement in renal function with the addition of Ang II infusion, a greater likelihood of weaning from renal replacement therapy, and an improvement in survival. The manufacturer’s product label suggests a starting dose of 20 ng/kg/min and a maximum of 80 ng/kg/min. Venous and arterial thromboembolism may occur in up to 10% of patients, so concurrent thromboprophylaxis is recommended. The ATHOS-3 study found no difference in the rate of deep venous thrombosis (1.8% vs 0%). More studies are needed to further define the risk, benefit, and cost effects, and whether Ang II may serve as a first-line choice or sole agent.
The next 2 agents, selepressin and terlipressin, are analogues of arginine vasopressin, which is a nonselective vasopressin type 1a (V1a)-, type 1b (V1b)-, and type 2 (V2)-receptor agonist with a half-life of 10 to 35 minutes. Neither agent has FDA approval in the United States. Selepressin is an investigational selective V1a-receptor agonist with a half-life of 1.5 to 2.5 hours. The rationale for its development is that V1b- and V2-receptor activation increases coagulation factors and nitric oxide, along with sodium and fluid retention, which may exacerbate thrombosis, capillary leak, and pulmonary edema. One study of selepressin was deemed acceptable for this review; it included patients with septic shock who were already receiving infusions of norepinephrine. The study reported that 50% of patients receiving 2.5 ng/kg/min of selepressin did not require norepinephrine at 24 hours, while norepinephrine infusion was required in more than 80% of patients receiving 1.25 ng/kg/min of selepressin. At day 7, the cumulative dose requirement of norepinephrine infusion was reduced in the 2.5-ng group compared with that in the 1.25-ng group. The major finding of this study was that by day 7, patients in the 2.5-ng group had improved survival and ventilator-free days, while length of stay and 28-day survival rates were similar compared with those in the 1.25-ng group. More information on efficacy, side effects, and comparisons with arginine vasopressin infusions is needed for selepressin.
Terlipressin is a nonselective V1a-, V1b-, and V2-receptor agonist similar to arginine vasopressin, but has a longer half-life of 40 minutes. Its use for hepatorenal syndrome and septic shock outside the United States has been described in 11 trials acceptable for this review. Terlipressin has been studied using fixed-dose infusions over 4, 24, and 48 hours and, because of the longer half-life, 1-mg intravenous (IV) boluses. The infusion dose ranged from 78 to 312 µg/h. All included studies demonstrated terlipressin reduced norepinephrine requirements.
One study found that 1-mg IV boluses of terlipressin as the sole therapy was similar to norepinephrine in managing hypotension during the first 6 hours of septic shock. Another study showed that target blood pressure was similar with terlipressin infusion alone compared with norepinephrine in the first 48 hours in patients with acute respiratory distress syndrome. Terlipressin also was more efficacious than norepinephrine in patients with cirrhosis and septic shock. Adverse events found with IV boluses of terlipressin included peripheral ischemia, decreased cardiac index, and decreased oxygen delivery.
As an adjunctive therapy, studies that added 1-mg IV boluses of terlipressin to preexisting norepinephrine infusions found that blood pressure was augmented and sustained at target levels. Those that added terlipressin infusions to norepinephrine also reached target blood pressure. Terlipressin was found to reduce mortality in patients with cirrhosis and septic shock, or hepatorenal syndrome in 2 studies; however, this metric was not the primary study end point. Furthermore, these findings are still considered preliminary. Only 1 study has compared terlipressin with arginine vasopressin, which showed equal efficacy. The risk profile of titrated terlipressin infusions appears to be favorable to bolus doses, but the addition of terlipressin in any form to norepinephrine has been shown to increase the risk of adverse events. Nevertheless, more information is needed for terlipressin as monotherapy and adjunctive therapy, and its efficacy compared to arginine vasopressin.
The authors concluded that the overall quality of evidence supporting these novel vasopressors is limited by the heterogeneity of distributive shock, the concomitant use of multiple vasopressors, few direct comparisons to arginine vasopressin, and the known side effects of vasopressors. Yet, the search for improved agents is still warranted.
- Rodriguez R, Cucci M, Kane S, Fernandez E, Benken S. Novel vasopressors in the treatment of vasodilatory shock: a systematic review of angiotensin II, selepressin, and terlipressin. J Intensive Care Med. 2020;35(4):327-337. doi:10.1177/0885066618818460
- Khanna A, English SW, Wang XS, et al; ATHOS-3 Investigators. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419-430. doi:10.1056/NEJMoa1704154
- Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014;18(5):534. doi:10.1186/s13054-014-0534-9
- FDA approves drug to treat dangerously low blood pressure. News release. US Food and Drug Administration; December 21, 2017. Accessed May 25, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-dangerously-low-blood-pressure