Timing and Dose Offer Different Perspectives: Response to Wieruszewski and Khanna

By
Žiga Kalamar
Giovanni Landoni
Andrej Markota
October 12, 2026

Critical Care

Overview

The authors argue that TRICYCLE evaluated early multimodal vasopressor therapy, contesting the characterization of its intervention as salvage therapy. They emphasize that the trial’s 5.2-hour median interval was measured from earliest hospital presentation with sepsis or septic shock—not from vasopressor-threshold attainment—and that vasopressor dose alone does not establish shock duration or treatment timing.

Background

The optimal initiation point for non-catecholamine vasopressors remains unresolved. TRICYCLE and ATHOS-3 enrolled patients at different points in their clinical course, despite comparable vasopressor doses at randomization. TRICYCLE measured time from earliest documented hospital presentation, whereas ATHOS-3 required more than 0.2 µg/kg/min norepinephrine-equivalent support for 6–48 hours. The authors distinguish chronological timing from dose when defining early multimodal therapy.

Data Highlights

Study or measure	Reported timing or threshold	Interpretation in the source
TRICYCLE intervention group	Median 5.2 h from earliest documented hospital presentation with sepsis or septic shock to randomization	This interval is not the duration of vasopressor-dependent shock before randomization.
TRICYCLE control group	Median 7.1 h from earliest documented hospital presentation with sepsis or septic shock to randomization	The starting point differs from shock-onset timing used in other studies.
TRICYCLE eligibility window	Enrollment permitted up to 12 h after reaching the vasopressor eligibility threshold	This was the maximum permitted window, not the actual threshold-to-randomization interval.
ATHOS-3 eligibility	>0.2 µg/kg/min norepinephrine-equivalent support for 6–48 h	Patients were enrolled after a specified period of vasopressor support.

Key Findings

TRICYCLE’s 5.2-hour median interval for the intervention group began at earliest documented hospital presentation with sepsis or septic shock, which could precede vasopressor-dependent shock.
The protocol allowed enrollment up to 12 hours after the vasopressor eligibility threshold; the authors clarify that this was a maximum allowance, not the observed threshold-to-randomization interval.
TRICYCLE and ATHOS-3 had comparable vasopressor doses at randomization but different enrollment timing and clinical starting points.
The two studies cited by Wieruszewski and Khanna measured timing from shock onset, limiting direct comparison with TRICYCLE’s hospital-presentation-based interval.
The authors state that dose reflects both elapsed time and the velocity and severity of hemodynamic deterioration; rapidly progressive shock can require high norepinephrine doses within a brief interval.
The source reports that a prior meta-analysis associated non-catecholaminergic vasopressors with improved survival across diverse vasodilatory shock populations, and that a subsequent study associated early addition with improved survival even among patients receiving high-dose norepinephrine.

Clinical Implications

The authors caution against using a high vasopressor dose alone as evidence that multimodal therapy was delayed, or treating an upper dose ceiling as the sole criterion for defining therapy as early. They call for future trials to describe timing relative to preceding vasopressor exposure more comprehensively and to clarify the optimal initiation window.

Conclusion

The authors characterize TRICYCLE as an evaluation of early multimodal vasopressor therapy under its prespecified framework. Their central distinction is that treatment timing and vasopressor dose are related but are not interchangeable measures.