Physiologic Response to Angiotensin II Treatment for Coronavirus Disease 2019-Induced Vasodilatory Shock: A Retrospective Matched Cohort Study

Abstract

Objectives: To assess the early physiologic response to angiotensin-II treatment in patients with coronavirus disease 2019-induced respiratory failure and distributive shock.

Design: Retrospective consecutive-sample cohort study.

Setting: Three medical ICUs in New York during the coronavirus disease 2019 outbreak.

Patients: All patients were admitted to the ICU with respiratory failure and were receiving norepinephrine for distributive shock.

Interventions: The treatment groups were patients who received greater than or equal to 1 hour of angiotensin-II treatment. Time-zero was the time of angiotensin-II initiation. Controls were identified using a 2:1 hierarchical process that matched for 1) date and unit of admission; 2) specific organ support modalities; 3) age; 4) chronic lung, cardiovascular, and kidney disease; and 5) sex. Time-zero in the control group was 21 hours post vasopressor initiation, the mean duration of vasopressor therapy prior to angiotensin-II initiation in the treated group.

Measurements and main results: Main outcomes were trajectories of vasopressor requirements (in norepinephrine-equivalent dose) and mean arterial pressure. Additionally assessed trajectories were respiratory (Pao₂/Fio₂, Paco₂), metabolic (pH, creatinine), and coagulation (d-dimer) dysfunction indices after time-zero. We also recorded adverse events and clinical outcomes. Trajectories were analyzed using mixed-effects models for immediate (first 6 hr), early (48 hr), and sustained (7 d) responses. Twenty-nine patients (n = 10 treated, n = 19 control) were identified. Despite matching, angiotensin-II-treated patients had markedly greater vasopressor requirements (mean: 0.489 vs 0.097 µg/kg/min), oxygenation impairment, and acidosis at time-zero. Nonetheless, angiotensin-II treatment was associated with an immediate and sustained reduction in norepinephrine-equivalent dose (6 hr model: β = -0.036 µg/kg/min/hr; 95% CI: -0.054 to -0.018 µg/kg/min/hr, p _interaction=0.0002) (7 d model: β = -0.04 µg/kg/min/d, 95% CI: -0.05 to -0.03 µg/kg/min/d; p _interaction = 0.0002). Compared with controls, angiotensin-II-treated patients had significantly faster improvement in mean arterial pressure, hypercapnia, acidosis, baseline-corrected creatinine, and d-dimer. Three thrombotic events occurred, all in control patients.

Conclusions: Angiotensin-II treatment for coronavirus disease 2019-induced distributive shock was associated with rapid improvement in multiple physiologic indices. Angiotensin-II in coronavirus disease 2019-induced shock warrants further study.

Keywords: angiotensin II; coronavirus disease 2019; norepinephrine; severe acute respiratory syndrome coronavirus-2 infection; shock; vasoconstrictor agents.

Figure 1.

Vasopressor requirements in norepinephrine-equivalent dose (NED) (A and B) and mean arterial pressure (C and D) over time in angiotensin-II (Ang-II)–treated patients versus controls. A and B, Also shows the angiotensin-II dose in Ang-II–treated patients. Markers and error bars indicate mean and sd. Righthand tables indicate interaction coefficients (β), their 95% CIs, and interaction p values from each of the mixed-effects models for time by treatment group. All coefficients are standardized to reflect the difference in rates of change per day, with the control group as the referent. For example, β equals to –0.10 in (A) indicates that the NED decreased in the Ang-II by 0.10 µg/kg/min more per day than it did in the control group over 48 hours. AT2 = angiotensin-II, p_int = p value of the interaction coefficient.

Figure 2.

Markers and error bars indicate mean and sd. Annotations indicate interaction coefficients (β), their 95% CIs, and interaction p values from each of the mixed-effects models for time by treatment group. β reflect the difference in daily rates of change with the control group as the referent. For example, β equals to –0.2 in (C) indicates creatinine decreased in the angiotensin-II group by 0.2 mg/dL/d more than in controls. Paco₂ is adjusted for minute ventilation. Creatinine is adjusted for the patient’s prehospitalization baseline. d-dimer was log-transformed to correct violation of the homoscedastic error assumption for modeling. AT2 = angiotensin-II, p_int = p value of the interaction coefficient, P/F ratio = ratio of Pao₂ to Fio₂, SOFA = Sequential Organ Failure Assessment.