Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial

Rinaldo Bellomo, Lui G Forni, Laurence W Busse, Michael T McCurdy, Kealy R Ham, David W Boldt, Johanna Hästbacka, Ashish K Khanna, Timothy E Albertson, James Tumlin, Kristine Storey, Damian Handisides, George F Tidmarsh, Lakhmir S Chawla, Marlies Ostermann, Rinaldo Bellomo, Lui G Forni, Laurence W Busse, Michael T McCurdy, Kealy R Ham, David W Boldt, Johanna Hästbacka, Ashish K Khanna, Timothy E Albertson, James Tumlin, Kristine Storey, Damian Handisides, George F Tidmarsh, Lakhmir S Chawla, Marlies Ostermann

Abstract

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy.Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS.Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours.Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction).Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).

Keywords: angiotensin I; angiotensin-converting enzyme defect; distributive shock; renin–angiotensin–aldosterone system.

Figures

Figure 1.
Figure 1.
Renin–angiotensin–aldosterone system disturbance hypothesis. The green arrows indicate an increase, the red arrows a decrease, and the red cross marks loss of function. ACE = angiotensin-converting enzyme.
Figure 2.
Figure 2.
Serum angiotensin I and renin concentrations. (A) Serum angiotensin I concentrations. (B) Serum renin concentrations. All values are presented as the median (interquartile range).
Figure 3.
Figure 3.
Kaplan-Meier survival plot according to renin concentrations and treatment with angiotensin II or placebo. (A) Day 28 survival: renin concentration below population median. (B) Day 28 survival: renin concentration above population median. CI = confidence interval; HR = hazard ratio.
Figure 4.
Figure 4.
Cubic splines of mortality and baseline serum renin. Baseline renin is shown with log scale. LJPC501 = angiotensin II.

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