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Angiotensin II: a new therapeutic option for vasodilatory shock.

ABSTRACT: Angiotensin II (Ang II), part of the renin-angiotensin-aldosterone system (RAS), is a potent vasoconstrictor and has been recently approved for use by the US Food and Drug Administration in high-output shock. Though not a new drug, the recently published Angiotensin II for the Treatment of High Output Shock (ATHOS-3) trial, as well as a number of retrospective analyses have sparked renewed interest in the use of Ang II, which may have a role in treating refractory shock. We describe refractory shock, the unique mechanism of action of Ang II, RAS dysregulation in shock, and the evidence supporting the use of Ang II to restore blood pressure. Evidence suggests that Ang II may preferentially be of benefit in acute kidney injury and acute respiratory distress syndrome, where the RAS is known to be disrupted. Additionally, there may be a role for Ang II in cardiogenic shock, angiotensin converting enzyme inhibitor overdose, cardiac arrest, liver failure, and in settings of extracorporeal circulation.

SUBMITTER: Bussard RL

PROVIDER: S-EPMC6067786 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Angiotensin II: a new therapeutic option for vasodilatory shock.

Bussard Rachel L RL Busse Laurence W LW

Therapeutics and clinical risk management 20180726

Angiotensin II (Ang II), part of the renin-angiotensin-aldosterone system (RAS), is a potent vasoconstrictor and has been recently approved for use by the US Food and Drug Administration in high-output shock. Though not a new drug, the recently published Angiotensin II for the Treatment of High Output Shock (ATHOS-3) trial, as well as a number of retrospective analyses have sparked renewed interest in the use of Ang II, which may have a role in treating refractory shock. We describe refractory s ...[more]

PMID: 30100727

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Project description:BackgroundIn patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study.MethodsWe measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes.ResultsMedian baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P < 0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P < 0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P < 0.0001), lower ANG II levels (P < 0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P < 0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses.ConclusionsPatients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction.Trial registrationClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Project description:BackgroundHigh dose vasopressors portend poor outcome in vasodilatory shock. We aimed to evaluate the impact of baseline vasopressor dose on outcomes in patients treated with angiotensin II (AT II).MethodsExploratory post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial data. The ATHOS-3 trial randomized 321 patients with vasodilatory shock, who remained hypotensive (mean arterial pressure of 55-70 mmHg) despite receiving standard of care vasopressor support at a norepinephrine-equivalent dose (NED) > 0.2 µg/kg/min, to receive AT II or placebo, both in addition to standard of care vasopressors. Patients were grouped into low (≤ 0.25 µg/kg/min; n = 104) or high (> 0.25 µg/kg/min; n = 217) NED at the time of study drug initiation. The primary outcome was the difference in 28-day survival between the AT II and placebo subgroups in those with a baseline NED ≤ 0.25 µg/kg/min at the time of study drug initiation.ResultsOf 321 patients, the median baseline NED in the low-NED subgroup was similar in the AT II (n = 56) and placebo (n = 48) groups (median of each arm 0.21 µg/kg/min, p = 0.45). In the high-NED subgroup, the median baseline NEDs were also similar (0.47 µg/kg/min AT II group, n = 107 vs. 0.45 µg/kg/min placebo group, n = 110, p = 0.75). After adjusting for severity of illness, those randomized to AT II in the low-NED subgroup were half as likely to die at 28-days compared to placebo (HR 0.509; 95% CI 0.274-0.945, p = 0.03). No differences in 28-day survival between AT II and placebo groups were found in the high-NED subgroup (HR 0.933; 95% CI 0.644-1.350, p = 0.71). Serious adverse events were less frequent in the low-NED AT II subgroup compared to the placebo low-NED subgroup, though differences were not statistically significant, and were comparable in the high-NED subgroups.ConclusionsThis exploratory post-hoc analysis of phase 3 clinical trial data suggests a potential benefit of AT II introduction at lower doses of other vasopressor agents. These data may inform design of a prospective trial.Trial registrationThe ATHOS-3 trial was registered in the clinicaltrials.gov repository (no. NCT02338843). Registered 14 January 2015.

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Angiotensin II: a new therapeutic option for vasodilatory shock.

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Angiotensin II: a new therapeutic option for vasodilatory shock.

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