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Abstract

Introduction: Early Goal-Directed Sedation (EGDS) represents the administration of a sedative regimen soon after initiation of ventilation to maintain targeted light sedation through frequent sedative titration, awakening and monitoring of sedation depth. The impact of sedative choice on EGDS and the external validity of EGDS remains unclear. Our objectives is to 1)Test the feasibility of achieving EGDS with dexmedetomidine (DEX) compared with standard sedatives chosen by treating clinician, propofol and/or midazolam (CnS) and 2) test the feasibility of delivering EGDS in Malaysian ICUs. Methods: A Prospective randomized controlled pilot trial conducted in 10 tertiary, regional and rural ICUs. After obtaining institutional ethics approval, critically ill adult expected to be mechanically ventilated and needing intravenous sedation > 24 hours were included. Exclusions included acute global or regional brain injury, suspected prolonged weakness and imminent death. EGDS was delivered to all patients with adequate analgesia following randomization. Light sedation (RASS -2 to +1) was targeted in all patients throughout the study period. Subjects were randomized to receive EGDS with DEX as a primary sedative starting at 1 mcg/kg/hr or sedative agents CnS as chosen by treating clinician. Propofol rescue in EGDS+DEX was permitted. Primary outcome was number of RASS in target (-2 to +1) in the first 48 hrs following intubation. Feasibility outcome was time to randomization. Efficacy outcome was dose and duration of rescue sedatives and opioids given. RASS was measured every 2-4 hours and CAM-ICU measured daily (during light sedation). Results: Sixty subjects were randomized, 30 in each group. Mean ±SD age was (48 ± 19 vs 52 ± 17), APACHEII (18 ± 8 vs 20 ± 6) in EGDS+DEX vs EGDS+CnS respectively. Median [IQR] time to randomization was 5.5 [2.4-11.5] vs 7.6 [3.3-11.8] hours following initiation of mechanical ventilation. Midazolam was given on 7/151(4.6%) and propofol on 6/151(4.0%) study days in the EGDS-DEX group. Fentanyl was used in comparable proportion in both groups 19(63.3%) vs 21(70%) while morphine to significantly more patients in EGDS+CnS vs EGDS+DEX 14(46.6%) vs 4(13.3%), P=0.006. The number of RASS (-2 to +1) in the first 48 hours in the EGDS+DEX 115/127(91%) vs 93(137)68% P=0.001 in the EGDS-CnS. Comparable proportion of patients 29% vs 33% had one or more positive CAM-ICU with significant trend to lower days with positive CAM-ICU 10(7%) vs 24(13%) P=0.06, lower physical restraint use 6(20%) vs 14(46.6%) P=0.03 in the EGDS+DEX vs EGDS+CnS respectively. The median [IQR] time to extubation was 53[39-78] vs 65[46-141] hrs P=0.09, ICU stay 3[1.9-2.5] vs 4[3-8] days P=0.09, Hospital stay 9[6-12] vs 13[7.5-14.5] days P=0.07 with comparable proportion of patients received vasopressors 52% vs 54% and 16% vs 15% dialysis in the EGDS+DEX vs EGDS+CnV respectively throughout the study period. Conclusions: Early Goal-Directed Sedation delivered shortly after initiation of ventilation achieved significantly more light sedation targets with a dexmedetomidine based algorithm than with standard sedatives. EGDS+DEX reduced early deep sedation, use of physical restraints with a trend to lower delirium days, ventilation time, ICU and hospital stay. EGDS+DEX, administered in the context of randomized trial, delivered effective sedation with minimal need for rescue sedation and reduced overall opioid use. The administration of EGDS in Malaysian ICUs was safe and feasible. This data supports the validity of EGDS in non Australian ICUs for inclusion in future large scale clinical trial.