Renin Kinetics and Hemodynamic Response During Treatment of Vasoplegic Shock With Angiotensin II (TENSINTEST): Protocol for a Multicenter Observational Study

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Vasoplegic (distributive) shock (n=121). Intervention: 0- to 6-hour change in relative renin ratio during angiotensin II infusion. Primary outcome: Association between 0- to 6-hour change in relative renin ratio and 28-day organ failure-free days (days without vasopressors, invasive mechanical ventilation, or renal replacement therapy).

Q: What does this research mean for the field?

The Angiotensin II stress test (TENSINTEST) establishes a multicenter protocol to determine whether early 0- to 6-hour renin kinetics can predict clinical responsiveness and organ failure–free days in vasoplegic shock. Novelty: ClaimNovelty.METHODOLOGICAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Andreja Möller Petrun; Katarina Barbara Bajec; Lakhmir S. Chawla; Jan Zmazek; Andrej Markota

doi:10.2196/102437

November 9, 2026JMIR Research ProtocolsOpen Access

Renin Kinetics and Hemodynamic Response During Treatment of Vasoplegic Shock With Angiotensin II (TENSINTEST): Protocol for a Multicenter Observational Study

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Key result

Ongoing TENSINTEST trial evaluates angiotensin II renin kinetics for predicting organ failure-free days.

n=121

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Why the study?

Approximately one-third of patients with vasoplegic shock do not respond to angiotensin II therapy. Because renin is regulated by angiotensin II via negative feedback, a standardized angiotensin II stress test using renin kinetics could help predict treatment responsiveness.

Does an early reduction in relative plasma renin ratio within 6 hours of initiating angiotensin II infusion predict greater 28-day organ failure-free days in critically ill adults with refractory vasodilatory shock?

Key Points

To develop and standardize an angiotensin II stress test using early renin kinetics to predict therapeutic responsiveness and clinical outcomes in patients with distributive shock.
Multicenter observational clinical study measuring plasma renin concentrations immediately before and 6 hours after initiating angiotensin II infusion in patients with vasoplegic shock after adequate fluid resuscitation.
Patients receive norepinephrine base of ≥0.3 mcg/kg/min and vasopressin of 0.03 IU/min before starting third-line angiotensin II infusion.
The primary outcome examines the association between 0- to 6-hour change in relative renin ratio and 28-day organ failure–free days using an adjusted proportional odds ordinal regression model.
Ethical approval was obtained in July 2025, and data collection commenced on August 1, 2025, enrolling 70 patients as of July 2026.
Data collection across participating centers is scheduled for completion in 2027, followed by formal outcome analysis and publication.

Study Design

Type

Observational (n=121)

Blinding

Open-label

Multicenter

Yes

Structured PICO

Does an early reduction in relative plasma renin ratio within 6 hours of initiating angiotensin II infusion predict greater 28-day organ failure-free days in critically ill adults with refractory vasodilatory shock?

P

Population

121 planned adult ICU patients in Slovenia with refractory vasodilatory shock receiving norepinephrine (>=0.3 mcg/kg/min) and vasopressin (0.03 IU/min) who are prescribed angiotensin II, followed for 28 days.

E

Exposure

Venous blood sampling immediately prior to and 6 hours after starting an intravenous angiotensin II infusion to determine direct (active) plasma renin concentration and 0- to 6-hour relative renin ratio kinetics. Angiotensin II is initiated per institutional protocol at 20 ng/kg/min and titrated in 5 ng/kg/min increments every 15 minutes up to a maximum of 40 ng/kg/min to achieve a target MAP of 65-85 mm Hg, added to background norepinephrine (≥0.3 mcg/kg/min) and vasopressin (0.03 IU/min).

O

Outcome

Association between 0- to 6-hour change in relative renin ratio (defined as plasma renin concentration at baseline or 6 hours divided by upper normal limit of 50 mIU/L) and 28-day organ failure-free days (composite of days alive and without vasopressors, invasive mechanical ventilation, or renal replacement therapy).composite

This multicenter observational study protocol outlines the evaluation of 6-hour plasma renin kinetics as a functional biomarker to predict clinical outcomes and personalize angiotensin II therapy in patients with refractory vasodilatory shock.

Limitations

Relatively small sample size and non-optimal sample size estimation due to lack of prior similar prospective studies.
Exclusion of patients with a component of cardiogenic shock limits generalizability to the broader severely ill shock population.
Absence of a control arm prevents determining whether the prognostic significance of renin changes is specific to angiotensin II exposure or applies to other vasopressors.
Enrollment only after reaching the threshold for third-line vasopressor therapy (norepinephrine >=0.3 mcg/kg/min plus vasopressin 0.03 IU/min) limits applicability to earlier stages of vasodilatory shock.
Investigators and ICU staff cannot be blinded due to the nature of the study
Formal sample size calculation parameters for the proportional odds model were unavailable, requiring estimation from indirect evidence
Renin secretion is influenced by sodium and extracellular volume status, representing potential biological sources of variability
Patients who die before the 6-hour measurement cannot have a 0- to 6-hour change in relative renin ratio calculated

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Implication

TENSINTEST enrollment remains incomplete; leaves open whether 6-hour renin kinetics predict organ failure-free days in vasoplegic shock.

Abstract

Background Shock is a life-threatening condition that can lead to multiorgan failure and death. Vasopressors are needed for the treatment of vasoplegic (distributive) shock. Angiotensin II (AT II) is a novel vasopressor. Approximately two-thirds of patients respond to AT II, and one-third do not. AT II is part of the renin-angiotensin-aldosterone system (RAAS). Renin is the limiting enzyme of the RAAS, and among other mechanisms, its concentration is regulated by AT II concentration through a negative feedback loop. It might be an indicator of response to AT II therapy. Objective We designed a study with a primary objective of developing and standardizing an AT II stress test, which could help predict the responsiveness to AT II in patients with distributive shock, regardless of its origin. Methods This is an investigator-initiated, multicenter observational clinical study of renin kinetics before and 6 hours after starting an infusion of AT II in patients with vasoplegic shock and adequate fluid resuscitation who are severely ill. Prior to AT II, patients will receive an infusion of norepinephrine base of 0.3 mcg per kilogram per minute or higher, and vasopressin of 0.03 IU per minute according to institutional protocol. Blood samples for serum renin determination will be obtained immediately prior to and after 6 hours of AT II infusion. We hypothesize that patients who demonstrate a negative trend in relative renin ratio (defined as renin plasma concentration at baseline or at 6 hours after treatment with AT II divided by upper normal concentration of plasma renin [50 mU/L]) will have a greater number of 28-day organ failure–free days (days without vasopressors, mechanical ventilation, or renal replacement therapy). The primary analysis will assess the association between early renin reduction and organ failure–free days using an adjusted proportional odds ordinal regression model. Results The research was funded in December 2024. After obtaining ethics approval in July 2025, data collection started on August 1, 2025. As of July 2026, a total of 70 patients had been enrolled. Data collection is expected to be completed in 2027, after which the results will be analyzed and published. Conclusions The goal of our study is to determine whether renin 0-6 h kinetics (difference between renin levels before and 6 hours after starting an AT II infusion) are associated with clinical outcomes in patients who require AT II. Our study could contribute to the development of a more individualized approach to vasopressor therapy and avoidance of inappropriate use of AT II in patients who are not responders, allowing earlier discontinuation of AT II and consideration of alternative therapies.

Discussion

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Cite This Study

Petrun et al. (2026) conducted an observational in Vasoplegic (distributive) shock (n=121). 0- to 6-hour change in relative renin ratio during angiotensin II infusion was evaluated on Association between 0- to 6-hour change in relative renin ratio and 28-day organ failure-free days (days without vasopressors, invasive mechanical ventilation, or renal replacement therapy). Angiotensin II stress test (TENSINTEST) is an ongoing study (70 of 121 planned patients enrolled as of July 2026) evaluating 0- to 6-h renin kinetics and 28-day organ failure-free days.

synapsesocial.com/papers/6af3463ebdf2424ebd04f853 https://doi.org/10.2196/102437

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Renin Kinetics and Hemodynamic Response During Treatment of Vasoplegic Shock With Angiotensin II (TENSINTEST): Protocol for a Multicenter Observational Study

Figures

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Renin Kinetics and Hemodynamic Response During Treatment of Vasoplegic Shock With Angiotensin II (TENSINTEST): Protocol for a Multicenter Observational Study

Figures

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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