TRICYCLE: Triple Vasopressors Improve Septic Shock Markers

Key Takeaways

• In the TRICYCLE trial of adults with septic shock requiring vasopressors, starting angiotensin II, vasopressin, and norepinephrine together produced a significantly faster decline in plasma renin than stepwise escalation.
• Concurrent treatment was also associated with a significantly faster lactate decline and a greater reduction in SOFA score at 72 hours.
• Tachyarrhythmias were less frequent with concurrent treatment (15.6% vs 68.6%). Mortality did not differ significantly between groups.
• This was a phase II trial that was not powered to detect differences in mortality, and it does not show that the physiologic changes improve patient-centered outcomes.

After fluid resuscitation, rising norepinephrine requirements in septic shock pose a sequencing dilemma: when to add vasopressors with different mechanisms. Angiotensin II and vasopressin are alternatives to further norepinephrine escalation, but whether to start them together rather than sequentially remains uncertain. Investigators compared the two approaches in adults with persistent vasopressor-dependent shock.

The phase II, single-blind, randomized TRICYCLE trial, published in Critical Care, enrolled 79 adults with septic shock at intensive care units in Slovenia and Croatia. Participants had persistent hypotension requiring vasopressors to maintain a mean arterial pressure of at least 65 mmHg and a lactate above 2 mmol/L despite 20–30 mL/kg of fluid resuscitation within three hours, with a norepinephrine requirement of at least 0.15 µg/kg/min. Thirty-eight participants received angiotensin II, vasopressin, and norepinephrine simultaneously at equipotent starting doses. Forty-one received stepwise management, in which norepinephrine was increased first, followed by vasopressin and then angiotensin II or other vasopressors. The primary endpoint was the change in plasma renin over 72 hours. Change in lactate over 72 hours and change in SOFA score from day 1 to day 3 were prespecified secondary endpoints.

Plasma renin declined by 2.61% per hour with concurrent treatment versus 1.67% per hour with stepwise escalation (P=0.015), meeting the primary endpoint. Lactate declined by 1.53% per hour versus 1.01% per hour (P=0.006). At 72 hours, SOFA score had fallen by 3 points with concurrent treatment versus 0 points with stepwise escalation (P=0.018).

Norepinephrine-equivalent (NEE) requirements fell faster during the first 24 hours with concurrent treatment (6.87% per hour vs 3.03% per hour, P<0.0004). Over the full 72 hours, NEE declined at a similar rate in both groups.

Tachyarrhythmias occurred in 5 of 32 patients (15.6%) with concurrent treatment versus 24 of 35 (68.6%) with stepwise escalation (P<0.01), a difference in an adverse event rather than proof of patient-centered benefit. Tachyarrhythmia data were available for 67 of the 79 participants. Mortality did not differ significantly between groups, and a nonsignificant mortality comparison from a trial not powered for mortality establishes neither benefit nor equivalent survival.

The authors noted several limitations. Baseline renin and lactate were higher in the concurrent-treatment group, which may account for part of the faster decline. Angiotensin II was permitted in the control group for refractory hypotension, and vasopressin was given to 23 of 41 control patients (56.1%). Because concurrent treatment combines angiotensin II and vasopressin, the trial cannot separate their individual contributions, and the entry threshold for norepinephrine requirement leaves less severe shock uncertain.

The investigators concluded that early multimodal vasopressor therapy showed promising physiological effects, but it remains uncertain whether those effects improve patient-centered outcomes.