What is the clinical evidence from this study?

Study design: RCT. Population: Acute respiratory distress syndrome (ARDS) with refractory vasodilatory shock (n=81). Intervention: Angiotensin II vs. Placebo plus standard vasopressors. Primary outcome: PaO2/FiO2-ratio (P:F) at 48 hours adjusted for baseline P:F (MD 98.4, 95% CI 35.2-161.5, p=0.0028).

January 1, 2023Open Access

Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock

Key Result

Angiotensin-II treatment significantly improved oxygenation in patients with ARDS and refractory vasodilatory shock, increasing the PaO2/FiO2 ratio at 48 hours by a baseline-adjusted mean difference of 98.4 mmHg compared to placebo.

Study Design

Type

RCT (n=81)

Blinding

Double-blind

Randomization

1:1

Multicenter

Yes

Structured PICO

Does angiotensin-II treatment improve oxygenation in patients with ARDS and refractory vasodilatory shock?

Population

81 adults with ARDS and catecholamine-refractory vasodilatory shock were evaluated over 48 hours of treatment and followed for up to 28 days.

Intervention

Synthetic human angiotensin-II started at 20 ng/kg/min and titrated during the first 3 hours to achieve MAP ≥75 mmHg, plus standard vasopressors. Discontinued at 48 hours according to protocol-specified tapering, but could be continued up to 7 days.

Comparator

Saline placebo plus standard vasopressors, titrated to maintain MAP between 65 and 75 mmHg.

Outcome

PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F.surrogate

In patients with ARDS and refractory vasodilatory shock, angiotensin-II treatment significantly improved oxygenation compared to placebo, independent of catecholamine dose reduction.

Main Result

Mean Difference: 98.4 (95% CI 35.2–161.5)

Absolute Event Rate: 265% vs 164%

p-value: p=0.0028

Limitations

Post-hoc subgroup analysis incurs the risk of small-sample bias and type-I errors.
Fluid balance, filling pressures, and serial echocardiography were not measured, meaning volume overload could not be definitively excluded.
Respiratory management, including PEEP titration, lung recruitment, and prone positioning, was not protocolized.
Collecting respiratory data only at hour-3 and hour-48 leaves a significant gap in the clinical course.
The study was underpowered to assess clinical outcomes such as mortality or ventilator-free days in the ARDS subset.

Abstract

Abstract Background The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. Methods Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO 2 /FiO 2 -ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. Results Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg 95%CI 35.2–161.5, p = 0.0028). Similarly, oxygenation index decreased by − 6.0 cmH 2 O/mmHg at hour-48 with angiotensin-II versus − 0.4 cmH 2 O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH 2 O/mmHg, 95%CI − 8.6 to − 1.1, p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% 95%CI 6.5–47.0%, p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. Conclusions In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. Trial Registration : ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

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