To clarify how TRICYCLE defined treatment timing and to contest the characterization of its multimodal vasopressor intervention as salvage therapy.
Approach:
Timing in TRICYCLE: The authors distinguish the interval from first documented hospital presentation with sepsis or septic shock to randomization from the interval after reaching the vasopressor eligibility threshold.
Comparison with ATHOS-3: They compare enrollment timing and vasopressor doses in TRICYCLE and ATHOS-3, noting that the trials used different timing reference points.
Dose and treatment timing: They argue that vasopressor dose alone does not establish how long a patient has been in shock, because deterioration can occur at different rates.
Key Findings:
In TRICYCLE, median time from earliest documented hospital presentation to randomization was 5.2 hours in the intervention group and 7.1 hours in the control group.
The protocol permitted enrollment up to 12 hours after the vasopressor eligibility threshold; this was a maximum window, not the actual threshold-to-randomization interval.
ATHOS-3 enrolled patients after 6–48 hours of norepinephrine-equivalent support above 0.2 µg/kg/min. Vasopressor doses at randomization were comparable between the trials, but enrollment timing differed.
The authors state that a high vasopressor dose alone should not be interpreted as evidence of delayed treatment and that a fixed dose ceiling could exclude patients whose shock progresses rapidly.
Interpretation:
The authors consider TRICYCLE’s intervention early within its prespecified framework. They argue that defining early therapy solely by a vasopressor dose cutoff conflates dose with elapsed time and shock progression.
Limitations:
Direct comparison of treatment timing across TRICYCLE and other studies is constrained by differing clinical starting points.
The reported TRICYCLE interval from hospital presentation may include time before vasopressor-dependent shock.
Conclusion:
The authors agree that future trials should report timing relative to prior vasopressor exposure more comprehensively and clarify the optimal initiation window. They do not consider an upper vasopressor dose ceiling the sole or necessarily most suitable criterion for defining early therapy.
