Analgesia-first sedation, protocol-directed sedation (PS), or PS with daily sedative interruption in mechanically ventilated adults: A 3-arm pilot RCT

Introduction: Analgesia‐first sedation (AFS) is recommended in the 2013 PAD guidelines but has not been compared to protocol‐directed sedation (PS) or both PS + daily sedation interruption (DSI) nor rigorously evaluated in North America. In this single‐center, pilot study of AFS (vs. PS or PS+DSI) in mechanically ventilated (MV) adults, we sought to determine the feasibility, protocol compliance, clinician workload, safety, and sample size needed to inform a future, large, multicenter RCT evaluating AFS. Methods: Critically ill adults expected to be MV ≥ 48 hours and receiving continuous IV (CIV) sedative and/or opioid therapy were randomized, in a concealed fashion, to AFS, PSD or PDS+ DI. All patients were managed to a similar sedation (RASS ‐3 to ‐ 1) and pain (CPOT ≤ 3) goal and the same spontaneous breathing trial protocol. AFS patients were managed with IV fentanyl (bolus ± CIV) titrated hourly; propofol was permitted if CPOT ≤ 3 or RASS ≥ 0. Patients in the PS arm received CIV midazolam and fentanyl (bolus ± CIV) titrated hourly. Patients in the PS+DSI arm had sedatives/opioids interrupted each morning; restarted only when RASS ≥1 and/or CPOT>3. Measurement and Results: Over a 3‐year period 86 patients [AFS (N=27), PS (N=28), PS+DSI (N=31) were enrolled. Lack of CIV sedative use was the most common barrier to enrollment. ICU study days where compliance to all study interventions was met was high, and similar, between the groups [AFS=95%, PD= 99%, PS+DSI=96%]. Nurse perception of study workload (10‐points Visual Analog Scale) was higher with AFS [4 (2‐6)] vs. PS [1 (1‐3.5)] or PS+DIS [2 (1‐5)]; (p=0.002). Baseline characteristics were similar between the 3 groups [overall cohort: 65±5 yrs, APACHE II score 24 ± 8, medical diagnosis (81%). Days free of MV over 28 days [AFS 24 (23, 26); PS 24 (20,26), and PS+DSI 24 (21,26)], days in the ICU [AFS 7(4,14); PS 8 (3,15), PS+DSI 7 (3,15) and ICU days spent free of coma and delirium were similar between the 3 groups. Unplanned extubations were rare, and similar, between the 3 groups [AFS (n=1); PS (n=0), PS+DIS (n=1)]. Conclusion: AFS is a safe and feasible intervention to evaluate in an RCT in North America. Future RCTs comparing AFS to PDS and/or PDS+DSI will need to be large (as differences in efficacy are small), screen large numbers of patients for enrollment, and account for the greater clinician workload required to manage patients receiving AFS.