Timing and dose do not tell the same story: a reply to Wieruszewski and Khanna

We thank Wieruszewski and Khanna for their comments regarding the timing of multimodal vasopressor therapy in the TRICYCLE trial given that the optimal timing for initiation of non-catecholamine vasopressors remains an important unanswered question [1]. However, we respectfully disagree with the characterization of the TRICYCLE intervention as salvage rather than an early intervention. Wieruszewski and Khanna base this interpretation primarily on the baseline vasopressor dose and the maximum permitted time between eligibility threshold and randomization. In the TRICYCLE trial [2] the median time to randomization in the intervention group was 5.2 h and more importantly, the reported time to randomization was calculated from the earliest documented hospital presentation with sepsis or septic shock, not from the moment the norepinephrine-equivalent eligibility threshold was reached. Therefore, a patient could be admitted with sepsis, subsequently deteriorate to septic shock, and only later meet the vasopressor criterion for study inclusion. The protocol [3] permitted enrollment within 12 h of reaching the vasopressor eligibility threshold. Importantly, this 12-h interval defined the outer limit for eligibility rather than the actual delay from reaching the vasopressor threshold to randomization. The reported median time of 5.2 h should therefore not be considered the duration of vasopressor-dependent shock before randomization. On the contrary, it represents a relatively short interval from the earliest documented hospital presentation with sepsis or septic shock to enrollment. Regarding the comparison with ATHOS-3, although vasopressor doses at randomization were similar, the timing of enrollment was not. In TRICYCLE, the median time from the earliest documented hospital presentation with sepsis or septic shock to randomization was 5.2 h in the intervention group and 7.1 h in the control group (2), whereas ATHOS-3 required 6–48 h of > 0.2 µg/kg/min norepinephrine-equivalent vasopressor support before enrollment [4]. Importantly, two of the studies cited by Wieruszewski and Khanna in support of earlier adjunctive vasopressor initiation [5, 6] define timing from shock onset, whereas the 5.2 h interval in TRICYCLE was measured from the earliest hospital presentation with sepsis or septic shock and could therefore include a period before the development of vasopressor-dependent shock. The timing observed in TRICYCLE was therefore broadly consistent with and in some patients likely shorter than, the early treatment windows cited by Wieruszewski and Khanna, although direct comparison is limited by the different clinical starting points. Thus, similar vasopressor doses at randomization should not be interpreted as reflecting a similar duration or stage of shock.

This distinction is also relevant to the proposed use of an upper vasopressor dose ceiling. Vasopressor dose reflects not only elapsed time but also the rate and severity of hemodynamic deterioration. Patients with rapidly progressive septic shock may reach high norepinephrine requirements within a short period, whereas others may remain below a given threshold for substantially longer. In this context, the relatively short time to randomization observed in TRICYCLE illustrates why a high vasopressor dose should not automatically be interpreted as evidence of late treatment. A rigid dose ceiling could therefore exclude patients who are treated early but whose shock progresses rapidly, potentially excluding a clinically important subgroup in whom timely multimodal vasopressor therapy may be particularly relevant. This matters clinically: in a previous meta-analysis of randomized trials, the use of non-catecholaminergic vasopressors was associated with improved survival across a range of vasodilatory shock populations, including patients with established shock [7], and their early addition was subsequently associated with improved survival even in patients receiving high-dose norepinephrine [8].

We agree that a more comprehensive evaluation of renin–angiotensin system disturbances may help refine patient phenotyping in future studies. This however does not alter the distinction between vasopressor dose and chronological timing when defining early multimodal therapy.

We agree that future trials should report treatment timing in relation to prior vasopressor exposure in greater detail and further establish the optimal window for multimodal vasopressor initiation. However, we do not believe that an upper vasopressor dose ceiling is the only or necessarily the most appropriate way to define “early” therapy. In our view, TRICYCLE tested early multimodal vasopressor therapy within the prespecified clinical framework, while also reinforcing that defining “early” therapy requires more than a single vasopressor dose cutoff.

Author contributions

ŽK, GL, and AM drafted the manuscript. All authors critically revised the manuscript, read, and approved the final version.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

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Competing interests

Author GL has received speaker fees from Medis, Paion and Viatris, and consultancy fees from Paion and Viatris. Author AM has received speaker fees from Medis. These disclosures are unrelated to the present work.