Highlight
– In a randomized controlled trial of 156 patients undergoing emergency acute-abdomen surgery, phenylephrine and norepinephrine produced broadly similar effects on RAAS components and similar rates of postoperative complications (AKI, myocardial injury, 30-day mortality).
– Norepinephrine, but not phenylephrine, was associated with an immediate postoperative rise in plasma renin; by 24 hours both groups had reductions in angiotensin II and aldosterone.
– Elevated preoperative renin (upper quartile) was associated with greater intraoperative vasopressor requirement and higher incidence of postoperative AKI, suggesting preoperative renin could be a risk biomarker.
Background
Acute abdominal emergencies require rapid resuscitation and often general anesthesia with vasopressor support to maintain organ perfusion. Norepinephrine (NE) is the most widely recommended first-line vasopressor in critically ill patients because of a favorable balance of vasoconstriction and preserved cardiac output; phenylephrine (PE) is a pure alpha-1 agonist that raises systemic vascular resistance but can reduce heart rate and cardiac output. How choice of vasopressor affects the renin-angiotensin-aldosterone system (RAAS) and downstream outcomes such as acute kidney injury (AKI) after noncardiac emergency surgery is incompletely characterized. The RAAS is central to blood pressure control and sodium/water balance; perioperative modulation could plausibly influence renal perfusion and complications.
Study design
Design and setting
This was a randomized controlled trial conducted in the Anesthesiology Department at the Affiliated Hospital of Xuzhou Medical University. The trial randomized patients to intraoperative vasopressor management with either phenylephrine or norepinephrine to maintain mean arterial pressure (MAP) between 70–80 mm Hg during emergency abdominal surgery under general anesthesia.
Population
One hundred fifty-six adult patients (age ≥18) undergoing emergency acute-abdomen surgery were enrolled. Randomization allocated patients to a PE group or an NE group.
Interventions and endpoints
Interventions were titrated PE or NE infusions targeting intraoperative MAP 70–80 mm Hg. Primary physiological measurements were plasma renin, angiotensin II, and aldosterone sampled perioperatively and at 24 hours postoperation. Clinical endpoints included intraoperative vasopressor requirements, incidence of postoperative AKI, myocardial injury, and 30-day mortality. AKI criteria followed standard definitions (reference to KDIGO guidelines in the original paper).
Key findings
RAAS components
– Immediate postoperative period: Plasma renin increased significantly in the NE group (median difference 21 μIU/mL, IQR 5–51; p = 0.020) but not in the PE group (median difference 7 μIU/mL, IQR −1 to 33; p = 0.336).
– At 24 hours: Plasma renin levels were significantly decreased compared with baseline in both groups. Angiotensin II and aldosterone levels were reduced at 24 hours in both groups.
Interpretation: NE produced an early renin rise whereas PE did not, consistent with known beta-adrenergic stimulation of renin release by NE’s beta-1 component. By 24 hours, the downstream hormones were lower in both arms, possibly reflecting volume resuscitation, surgical stress responses, medication effects, and physiological feedback.
Clinical outcomes
– AKI incidence: No statistically significant difference between groups (relative risk [RR] 1.50, 95% CI 0.65–3.47; p = 0.569).
– Myocardial injury: No significant difference (RR 1.11, 95% CI 0.64–1.93; p = 0.497).
– 30-day mortality: No difference (RR 1.00, 95% CI 0.44–2.27; p = 1.000).
Although point estimates suggest numerically higher AKI with PE (RR 1.50), confidence intervals were wide and crossed unity, indicating the study was likely underpowered to detect modest differences in these clinical endpoints.
Prognostic role of baseline renin
Patients with baseline renin in the upper quartile required more vasopressor support intraoperatively and had a higher incidence of postoperative AKI. This association suggests that a high preoperative renin state may identify patients with more severe vasodilatory physiology or relative hypovolemia and higher vulnerability to renal injury.
Expert commentary and interpretation
Biological plausibility
The differential early renin response aligns with adrenergic pharmacology: norepinephrine has modest beta-1 agonism stimulating renin release from juxtaglomerular cells, while phenylephrine’s pure alpha-1 activity tends to decrease renin release via increased afferent arteriolar pressure and direct alpha effects. The subsequent fall in angiotensin II and aldosterone at 24 hours likely reflects integrated effects of fluid resuscitation, neurohormonal suppression after initial surgical stress, and potentially perioperative medication exposures.
Clinical implications
– Vasopressor selection: In this emergency abdominal surgery population, NE and PE produced similar postoperative complication rates and RAAS trajectories at 24 hours, supporting practice that NE remains the preferred agent for most patients because of its hemodynamic profile and guideline endorsement. PE may still be useful for specific indications (e.g., tachyarrhythmias where pure alpha stimulation avoids beta effects), but this trial does not identify a clear advantage for renal protection.
– Preoperative renin as a biomarker: The association between high baseline renin and greater vasopressor need and AKI suggests utility for risk stratification. If externally validated, a single preoperative renin measurement could help personalize hemodynamic targets, fluid strategies, and monitoring intensity.
Limitations
– Sample size and power: The trial enrolled 156 patients and was likely underpowered for clinical endpoints with low-to-moderate event rates (AKI, myocardial injury, mortality). Wide confidence intervals prevent definitive conclusions about equivalence for these outcomes.
– Single-center setting: Conducted at the Affiliated Hospital of Xuzhou Medical University, the findings may not generalize to other health systems or patient populations with different baseline comorbidity, surgical case mix, or perioperative practices.
– Timing and assays: RAAS sampling timing and the nature of renin measurement (immunoreactive renin concentration vs plasma renin activity) influence interpretation. Perioperative factors (volume status, vasoactive or RAAS-modulating drugs, anesthesia depth) can confound hormone levels.
– Unmeasured confounders: Differences in surgical complexity, intraoperative fluid volumes, or concomitant medications may affect renal outcomes; randomization helps but cannot eliminate all imbalances in smaller trials.
How this fits with existing evidence
Norepinephrine is recommended as first-line vasopressor for shock in international guidelines and large trials have favored NE over dopamine because of fewer arrhythmias (De Backer et al., NEJM 2010; Surviving Sepsis Campaign 2021). Phenylephrine is a commonly used alternative vasoconstrictor but has been associated in some settings with reductions in cardiac output and organ perfusion compared with NE. This randomized study adds mechanistic RAAS data and suggests that, despite early hormonal differences, clinically important postoperative outcomes are similar between PE and NE in this surgical emergency population.
Practical takeaways for clinicians
– Use norepinephrine as the default vasopressor in emergency abdominal surgeries requiring persistent vasopressor support, consistent with current critical care guidance, unless specific clinical circumstances (e.g., severe tachyarrhythmia) favor phenylephrine.
– Be aware that NE can acutely elevate renin via beta-1 stimulation; this is a physiological response and was not associated with worse outcomes in this trial.
– Consider preoperative renin measurement in high-risk patients as a hypothesis-generating strategy for risk stratification; however, routine adoption requires external validation and standardized assay use.
Conclusions and research priorities
This randomized controlled trial indicates that phenylephrine and norepinephrine yield broadly similar effects on RAAS components by 24 hours and similar rates of postoperative complications after emergency acute-abdomen surgery, while norepinephrine produces an early rise in plasma renin. Elevated preoperative renin was associated with increased vasopressor need and higher AKI incidence, identifying a potential biomarker for perioperative risk stratification.
Future research should prioritize larger multicenter trials to determine whether vasopressor choice meaningfully influences renal outcomes, standardized renin and RAAS assays to permit reproducible measurements, and prospective studies testing renin-guided hemodynamic strategies to reduce AKI and other complications.
Funding and clinicaltrials.gov
Funding and trial registration are reported in the original publication (Chen et al., Crit Care Med. 2025). Readers should consult the paper for specific funder acknowledgments and registry identifiers.
References
1. Chen J, Wang X, Yin T, et al. Phenylephrine Vs. Norepinephrine on the Renin-Angiotensin-Aldosterone System and Postoperative Complications in Acute Abdomen Emergency Surgery: A Randomized Controlled Trial. Crit Care Med. 2025 Dec 1;53(12):e2629-e2641. doi:10.1097/CCM.0000000000006912 IF: 6.0 Q1 .
2. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779-789.
3. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143.
4. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1–138.
5. Hall JE. Guyton and Hall Textbook of Medical Physiology. 13th ed. Philadelphia: Elsevier; 2015. (Physiology of the renin–angiotensin system and adrenergic regulation of renin release.)