Sedative Pharmacodynamics in Patients Supported With Extracorporeal Membrane Oxygenation

Introduction: In patients supported with venovenous extracorporeal membrane oxygenation (VV ECMO), sedation is used to blunt respiratory drive. However, previous studies have shown a poor correlation between sedation scores and respiratory effort. This study evaluated the pharmacodynamic (PD) effects of commonly used sedatives (propofol and fentanyl) in sedation scores and respiratory effort of patients receiving VV ECMO support. Methods: This was a prospective, single-center, open-label PD study of propofol and fentanyl in patients with VV ECMO at the Toronto General Hospital. Sedative plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Patients’ sedation profile was measured with processed electroencephalography [patient state index (PSI)]; Riker-sedation agitation scale (SAS) was used to calculate the PSI area under the curve for deep sedation (SAS 1-2) prediction. Respiratory effort was measured using airway occlusion pressure (Pocc) and occlusion pressure during the first 0.1 seconds (P0.1). The primary outcome was the association of sedative concentrations with PSI, P0.1 and Pocc. Results: One hundred six evaluations were performed in 11 patients supported with VV ECMO. Mean (SD) age was 43 (±13) years, and 55% were female. Patients were followed for a median (IQR) of 146 (116-146) hours, all patients were sedated with propofol and fentanyl before ECMO cannulation, ten patients (91%) were paralyzed at the time of cannulation, and no patient was paralyzed beyond day one post-cannulation. The area under the curve for detecting deep sedation with PSI was 0.97 (95% CI 0.94-0.97), with an optimal PSI cut-off point of 62. However, oversedation with PSI <40 was encountered in 74% of the observations. PSI strongly correlated with propofol concentrations (correlation coefficient R= -0.7, p<0.001) but weakly correlated with fentanyl concentrations (R= -0.17, p= 0.02). Regarding respiratory effort, 34 observations were excluded due to neuromuscular blockade use, P0.1 and Pocc ranged between -14 to 0 [median (IQR) 0 (-1.5 to 0)] and -45 to 0 [median (IQR) 0 (-6.0 to 0)] cm H2O, respectively. Multiple linear regression showed a weak correlation between propofol concentrations and P0.1 (R= 0.3, p=0.01) andPocc (R= 0.35, p=0.01), and no significant association with fentanyl concentrations (p=0.4), sweep gas (p=0.4), or PaCO2 (p=0.2). Conclusion: There was a strong correlation between propofol concentrations and PSI but a weak correlation between propofol concentrations and respiratory effort, with variable respiratory drive observed across the range of sedative plasma concentrations. No significant correlation was found for fentanyl with PSI or respiratory effort.