UMEM Educational Pearls

Bottom Line:

This multicenter trial demonstrated improved physiological outcomes such as lactate clearance and renin clearance in septic shock by using early multimodal vasopressor strategy but was not powered to detect mortality benefit. Further studies looking at more patient specific outcomes with this strategy are needed.

When caring for a critically ill ICU boarder in the ED, remember to add vasopressin early for escalating norepinephrine requirements (0.2-0.3 mcg/kg/min NEE).

Additional Information

TRICYCLE trial - Critical Care, Sept 2026

Background:

Vasopressor use in critically ill patients is common and typically follows a stepwise additive approach (norepinephrine, then vasopressin, then epinephrine and adjuncts). However, circulatory shock represents a failure of multiple hormonal mechanisms involved in vascular tone and macroperfusion. We typically don't use only one type of blood pressure medicine to treat hypertension; why do we use only one vasopressor to treat shock? The evidence remains mixed with a recent meta-analysis from AJEM showing decreased hospital length of stay but no mortality difference with the early addition of vasopressin. 

The authors of the TRICYCLE paper sought to see if the use of early multimodal vasopressor therapy in septic shock would accelerate improvement in biomarkers and decrease overall vasopressor requirement in septic shock.

Patients: 18+ years old with sepsis and hypotension requiring vasopressors to maintain MAP of 65 mmHg or greater and serum lactate > 2 mmol/L despite adequate volume resuscitation. Patients needed a vasopressor requirement of minimum 0.15 mcg/kg/min norepinephrine equivalent dose and a cardiac index of greater than 2.3 L/min/m2. 

Exclusions included death in 24 hrs, pregnancy, need for surgery or inter-hospital transfer, liver failure with MELD > 30, mesenteric ischemia, active bleeding or expected need for MTE, and VA-ECMO.

Intervention: “Tricycle therapy” defined as initiation of norepinephrine at 0.15 mcg/kg/min, vasopressin at 0.015 IU/min, and angiotensin II at 20 ng/kg/min, titrated by a defined regimen to a MAP 65-75 mmHg.

Control: Conventional vasopressor titration starting with norepinephrine, then adding vasopressin at higher doses of norepinephrine, and then adding additional vasopressors. In both groups, additional inotropes and vasopressors could be used at the treating physician's discretion.

Outcome: Primary outcome was change in plasma renin concentration (another tissue perfusion marker with growing evidence of association with ICU mortality) within 72 hours. Secondary outcomes included change in lactate concentration within 72 hours and change in SOFA score between days 1 and 3. There were several exploratory outcomes as well including mortality.

Results:

79 total patients were randomized with similar baseline characteristics between the groups except baseline renin and lactate concentrations were higher in the intervention group. Renin declined 2.61%/hour in the intervention group vs. 1.67%/hour in the control group (p=0.015), with 72-hour reduction of 46.9% in intervention vs. 33.2% in control group. Lactate declined similarly with 72-hour reduction of 30.9% in intervention vs. 21.7% in control (p=0.006 for per hour comparison). SOFA score changed by -3 in intervention vs. 0 in control (p=0.018). 

There was no difference in mortality and renal replacement therapy. There was a statistically significant decrease in norepinephrine equivalent dose requirements at 24 hours in the intervention vs. control group (81.9% vs. 52.3%, p<0.0004). Tachyarrhythmias were statistically significantly less in the intervention vs. control group (15.6% vs. 68.6%, p< 0.01).

Discussion:

Overall, this trial was more exploratory but did find improved lactate and renin clearance with an initial multimodal approach to vasopressors in patients with septic shock. However, larger trials are needed to look at outcomes such as incidence of tachyarrhythmias, need for renal replacement therapy, or other patient-related outcomes prior to using this approach clinically.

However, this paper falls in line with other evidence supporting the early use of vasopressin in your ED ICU boarders (typically around norepinephrine doses of 0.2-0.3 mcg/kg/min) as noted in Surviving Sepsis 2026 Guidelines, supporting this multi-mechanism approach.

References

• Kalamar Ž, Landoni G, Gorenjak M, Cestar I, Fluher J, Horvat M, Jerenec K, Kit B, Marinšek M, Puklavec N, Svenšek F, Radoni? R, Šundali? S, Brajkovi? AV, Vujevi? A, Erjavc N, Petek D, Košir AS, Homšak E, Knehtl MC, Markota A. Early multimodal vasopressor strategy in septic shock: results of the TRICYCLE randomized controlled trial. Crit Care. 2026 Sep 7;30(1):508. doi: 10.1186/s13054-026-06323-z. PMID: 42827265; PMCID: PMC13633629.
• Mamede I, Arêa L, Carvalhal G, Bessa R, Lenzi M, Dos Santos MCF. Early vasopressin plus norepinephrine versus delayed or no vasopressin in septic shock: A systematic review and meta-analysis. Am J Emerg Med. 2026 Jan;99:225-231. doi: 10.1016/j.ajem.2025.10.003. Epub 2025 Oct 5. Erratum in: Am J Emerg Med. 2026 Jul;105:202. doi: 10.1016/j.ajem.2026.04.001. PMID: 41067173.
• Gleeson, P. J., Crippa, I. A., Mongkolpun, W., Cavicchi, F. Z., Van Meerhaeghe, T., Brimioulle, S., Taccone, F. S., Vincent, J.-L., & Creteur, J. (2019). Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients*. Critical Care Medicine, 47(2), 152–158. https://doi.org/10.1097/CCM.0000000000003544
• Prescott, H. C., Antonelli, M., Alhazzani, W., Møller, M. H., Alshamsi, F., Azevedo, L. C. P., Belley-Cote, E., De Waele, J., Derde, L., Dionne, J. C., Evans, L., Gershengorn, H. B., Hodgson, C. L., Honarmand, K., Kesecioglu, J., McIntyre, L., Mer, M., Nunnally, M. E., Oczkowski, S. J. W., … Coopersmith, C. M. (2026). Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026. Critical Care Medicine, 54(4), 725–812. https://doi.org/10.1097/CCM.0000000000007075