Benefit-Risk Balance of Ketamine versus Midazolam + Fentanyl for Sedation-Analgesia in Mechanically Ventilated Patients: Randomised Controlled Trial

Objective: Ketamine has interesting pharmacological properties for sedation-analgesia in intensive care. However, there are few studies on its benefit-risk balance. The aim of this study was to evaluate the efficacy and safety of ketamine compared with midazolam + fentanyl in mechanically ventilated patients. Methods: Randomised, non-inferiority, open-label, multicentre controlled trial. Patients aged 18 years or older requiring invasive mechanical ventilation for at least 24 hours were randomised to receive, after rapid sequence intubation, ketamine at a starting dose of 0. 5 mg/kg/h (n = 191) or midazolam 0. 2mg/kg/h + fentanyl 1μg/kg/h (n =191). Infusion rates were subsequently adjusted to achieve a RASS score between -2 and +1. The primary endpoint was the percentage of time spent in the RASS range -2 to +1 without the use of an alternative sedative; secondary endpoints included level of analgesia, adverse events (AEs), length of stay and mechanical ventilation, and cost of sedation. Results: In total, 73. 5% of patients in the ketamine group vs. 71. 3% in the midazolam group were within the target RASS range, a difference of 2. 2% 95% CI: -3. 2% to 7. 5%; p = 0. 18. The most frequently observed AEs in the ketamine group were hypersalivation (21. 2% vs. 2. 3%; p<0. 001), psychodysleptic phenomena (19. 8% vs. 2. 6%;p<0. 001) and hallucinations (9. 42% vs. 1. 04%; p<0. 001). Delirium was the only AE more frequent in the Midazolam group than in the Ketamine group (23. 5% vs 43. 4%; p < 0. 0001). However, the risk of arterial hypertension (7. 3% vs 4. 2%; p = 0. 188), diarrhoea (0% vs 5%; p = 0. 05) and self-extubation (3. 1% vs 4. 2%; p = 0. 452) did not differ between the 2 groups. The length of stay in intensive care between the 2 groups was 6. 3 ± 1. 6 days vs 7. 3 ± 1. 7 days (p < 0. 001) and that of mechanical ventilation 4. 1 ± 0. 94 days vs 4. 84 ± 0. 85 days (p < 0. 001). The daily cost of sedative treatment was lower with ketamine than with midazolam (32. 4 ± 0. 8 vs 43 ± 6. 3; p<0. 001). Conclusion: In this study, the efficacy of ketamine was not inferior to that of the midazolam + fentanyl combination, but its safety was poorer. Its low cost is a real advantage in our context.