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

At a Glance

Key Highlights

• In TRICYCLE, median time from earliest documented hospital presentation with sepsis or septic shock to randomization was 5.2 hours in the intervention group and 7.1 hours in the control group.
• TRICYCLE allowed enrollment up to 12 hours after the vasopressor eligibility threshold; this was the maximum permitted window, not the observed interval from threshold attainment to randomization.
• ATHOS-3 enrolled patients after more than 0.2 µg/kg/min norepinephrine-equivalent support for 6–48 hours, so its timing reference differed from TRICYCLE’s.
• Similar vasopressor doses at randomization do not establish comparable shock duration or stage.
• The authors argue that a fixed vasopressor dose ceiling alone is not a suitable criterion for defining early multimodal therapy.

Guideline-Based Recommendations

Diagnosis

Management

• The authors do not consider an upper vasopressor dose ceiling to be the sole, or necessarily the most suitable, criterion for characterizing multimodal vasopressor therapy as early.
• The article reports that prior studies associated non-catecholaminergic vasopressors with improved survival across diverse vasodilatory shock populations, including established shock, and associated early addition with improved survival among patients receiving high-dose norepinephrine.

Monitoring & Follow-up

• Future trials should describe treatment timing relative to preceding vasopressor exposure more comprehensively and clarify the optimal initiation window.
• The authors note that broader assessment of disturbances affecting the renin–angiotensin system may help refine patient phenotyping.

Risks

• A fixed dose ceiling could exclude patients treated early whose shock progresses rapidly, potentially omitting a clinically important subgroup.
• Comparisons of treatment timing are constrained when studies use different clinical starting points, such as hospital presentation versus shock onset or duration of vasopressor exposure.

Patient & Prescribing Data

Patients with sepsis or septic shock requiring vasopressor support; TRICYCLE and ATHOS-3 used different enrollment timing criteria.

TRICYCLE’s median interval from earliest documented hospital presentation to randomization was 5.2 hours for intervention and 7.1 hours for control. ATHOS-3 required more than 0.2 µg/kg/min norepinephrine-equivalent support for 6–48 hours before enrollment.

Clinical Best Practices

• Distinguish vasopressor dose from elapsed time when describing whether multimodal therapy was initiated early.
• When reporting trial timing, specify the clinical event used as the starting point and the interval from vasopressor eligibility to randomization.
• Do not infer shock duration or stage from vasopressor dose at randomization alone.

Related Resources & Content

• TRICYCLE trial
• TRICYCLE protocol
• ATHOS-3 trial
• References 5–8 cited in the article