Dear editor

We thank Zhang et al for their interest in our article and for raising the methodological issue regarding the temporal relationship between rescue sedation and the 5‑minute PAED assessment. We are grateful for this opportunity to clarify our study procedures.

We would like to respond to the core methodological concern by clarifying the actual sequence of events in our trial protocol:

The 5‑Minute PAED Score Was Assessed Prior to Any Rescue Sedation

In our protocol, the primary outcome—the PAED score at 5 minutes after awakening—was assessed immediately upon the child’s emergence from anesthesia. This assessment occurred at the prespecified time point before any decision regarding rescue sedation was made. Only after this 5‑minute assessment was completed did we observe whether the child’s PAED score remained >10 for an additional 3 consecutive minutes, or whether the child exhibited severe movement posing a risk of self‑injury or surgical‑site bleeding. If either criterion was met, rescue sedation was then administered.

The temporal sequence is clearly defined in the protocol:

T = 0 min: Emergence from anesthesia (spontaneous eye opening, eye opening on verbal command, first response to verbal command, or spontaneous crying). T = 5 min: PAED score assessed and recorded as the primary outcome. Following the 5‑minute assessment: A 3‑minute observation period began. Only if the PAED score remained >10 for the entire 3‑minute observation period, or if severe movement occurred after the 5‑minute assessment, was rescue sedation initiated.

Therefore, the 5‑minute PAED score that defined the primary outcome was always obtained before any rescue medication was administered. The rescue sedation protocol did not, and could not, affect the primary outcome measurement, because the primary assessment was completed before the rescue decision was made.

Data Confirm the Temporal Clarity

We have compiled the requested data regarding rescue sedation timing (Table 1). The results confirm that all rescue sedations were administered after the 5‑minute PAED assessment, consistent with our protocol.

Table 1 Rescue Sedation Administration and Timing

The mean time from emergence to rescue sedation was 9.00±1.53 minutes in the propofol group and 8.50±0.71 minutes in the ciprofol group. Critically, all rescue sedations were administered after the 5‑minute PAED assessment (mean: 8.5–9.0 minutes post‑emergence), confirming that the primary outcome was measured before any rescue intervention.

Interpretation of the Rescue Sedation Data

A closer examination of the rescue sedation data reveals that the numbers of children receiving rescue sedation and those meeting the primary EA definition are not expected to be identical, as the two are governed by different criteria. This apparent discrepancy is informative and warrants explanation.

In the ciprofol group, three children met the primary outcome definition of EA (PAED >10 at 5 minutes). However, rescue sedation was administered in only two of these three children, because the rescue protocol required PAED >10 to persist for ≥3 consecutive minutes. The remaining child’s PAED score fell to ≤10 before the 3‑minute observation period ended and therefore did not meet the criterion for rescue sedation. This difference reflects the distinction between the instantaneous primary outcome definition and the sustained agitation threshold required for rescue intervention, and it further supports the observation that ciprofol was associated with a shorter duration of agitation and a smoother emergence profile.

In the propofol group, 7 children received rescue sedation, while 6 met the primary EA definition (PAED >10 at 5 minutes). It is important to note that this discrepancy is explained by the two independent triggers for rescue in our protocol: (1) PAED >10 sustained for ≥3 consecutive minutes, and (2) severe movement after the 5‑minute assessment posing a risk of self‑injury or surgical‑site bleeding. One child in the propofol group did not have a PAED score >10 at 5 minutes (and thus was not counted as EA), but developed severe movements during the observation period that met the safety‑based rescue criterion. This finding further supports that the propofol group not only had numerically more EA cases, but also more clinically significant agitation events requiring active intervention, consistent with the smoother emergence profile observed with ciprofol.

Summary

In summary, the 5‑minute PAED score that defined the primary outcome was always assessed before any rescue sedation was administered. The timing data confirm that all rescue sedations occurred after the primary assessment (mean: 8.5–9.0 minutes post‑emergence). The observed differences between the number of EA cases and rescue sedation events are explained by the distinct criteria governing each measure—primary EA is defined by a single time‑point PAED score >10, whereas rescue sedation requires either sustained agitation (≥3 minutes) or safety‑threatening severe movement. These data collectively support the validity of our primary outcome and further reinforce the finding that ciprofol is associated with a smoother emergence profile compared with propofol.

We believe these clarifications fully address the concerns raised and demonstrate that our primary outcome was not influenced by rescue sedation.