2. Academic Validation
  3. Association of Active Renin Content With Mortality in Critically Ill Patients: A Post hoc Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Trial

Association of Active Renin Content With Mortality in Critically Ill Patients: A Post hoc Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Trial

  • Crit Care Med. 2023 Nov 10. doi: 10.1097/CCM.0000000000006095.
Laurence W Busse 1 2,  Christopher L Schaich 3,  Mark C Chappell 3,  Michael T McCurdy 4,  Erin M Staples 5,  Caitlin C Ten Lohuis 2,  Jeremiah S Hinson 6,  Jonathan E Sevransky 1 2,  Richard E Rothman 7,  David W Wright 8 9,  Greg S Martin 1 2,  Ashish K Khanna 1 2 3 4 5 6 7 8 9 10 11 12,  Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Investigators
Affiliations

Affiliations

  • 1 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA.
  • 2 Emory Critical Care Center, Emory Healthcare, Atlanta, GA.
  • 3 Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC.
  • 4 Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD.
  • 5 Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
  • 6 Department of Emergency Medicine, Johns Hopkins School of Medicine, Baltimore, MD.
  • 7 Department of Emergency Medicine, Johns Hopkins University, The Johns Hopkins Hospital, Baltimore, MD.
  • 8 Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA.
  • 9 Grady Marcus Trauma and Emergency Care Center, Atlanta, GA.
  • 10 Department of Anesthesiology, Section of Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
  • 11 Outcomes Research Consortium, Cleveland, OH.
  • 12 Perioperative Outcomes and Informatics Collaborative, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC.
PMID: 37947484 DOI: 10.1097/CCM.0000000000006095
Abstract

Objective: Sepsis is a leading cause of mortality. Predicting outcomes is challenging and few biomarkers perform well. Defects in the renin-angiotensin system (Ras) can predict clinical outcomes in sepsis and may outperform traditional biomarkers. We postulated that Ras dysfunction (elevated active Renin, angiotensin 1-7 [Ang-(1-7)], and angiotensin-converting Enzyme 2 (ACE2) activity with depressed Ang-II and ACE activity) would be associated with mortality in a cohort of septic patients.

Design: Post hoc analysis of patients enrolled in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized controlled trial.

Setting: Forty-three hospitals across the United States.

Patients: Biorepository samples of 103 patients.

Interventions: We analyzed day 0 (within 24 hr of respiratory failure, septic shock, or both) and day 3 samples (n = 103 and 95, respectively) for assessment of the Ras. The association of Ras values with 30-day mortality was determined using COX proportional hazards regression with multivariable adjustments for age, sex, VICTAS treatment arm, systolic blood pressure, Sequential Organ Failure Assessment Score, and vasopressor use.

Measurements and main results: High baseline active Renin values were associated with higher 30-day mortality when dichotomized to the median of 188.7 pg/mL (hazard ratio [HR] = 2.84 [95% CI, 1.10-7.33], p = 0.031) or stratified into quartiles (Q1 = ref, HRQ2 = 2.01 [0.37-11.04], HRQ3 = 3.22 [0.64-16.28], HRQ4 = 5.58 [1.18-26.32], p for linear trend = 0.023). A 1-sd (593.6 pg/mL) increase in Renin from day 0 to day 3 was associated with increased mortality (HR = 3.75 [95% CI, 1.94-7.22], p < 0.001), and patients whose Renin decreased had improved survival compared with those whose Renin increased (HR 0.22 [95% CI, 0.08-0.60], p = 0.003). Ang-(1-7), ACE2 activity, Ang-II and ACE activity did not show this association. Mortality was attenuated in patients with Renin over the median on day 0 who received the VICTAS intervention, but not on day 3 (p interaction 0.020 and 0.137, respectively). There were no additional consistent patterns of mortality on the Ras from the VICTAS intervention.

Conclusions: Baseline serum active Renin levels were strongly associated with mortality in critically ill patients with sepsis. Furthermore, a greater relative activation in circulating Renin from day 0 to day 3 was associated with a higher risk of death.

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