Faculty Bibliography

The continued and growing success of lung allotransplantation has intensified the worldwide shortage of donor organs. Yet, xenotransplantation remains a daunting challenge. Additional molecular incompatibilities and unforeseen complications will continue to be discovered. Progress has been made, notably on the generation of alpha-Gal double knockout pigs. Progressive increases in organ survival times have been seen for most organs after significant investments of time and money. The lung continues to be an organ with the lowest supply of cadaveric donors and the least potential for expanded living donation or mechanical alternatives. As such, the impetus for xenotransplantation is strong. The lung appears to be exquisitely sensitive to xenograft rejection and resistant to strategies that have been moderately successful in other organs. A complex program involving genetically modified donor organs, recipient preparation for antibody removal or tolerance promotion, and multitargeted drug therapy will likely be required for successful clinical application.

OBJECTIVE:To determine the pharmacokinetics of sufentanil in patients undergoing coronary artery bypass graft surgery. DESIGN/METHODS:Prospective, multigroup study. SETTING/METHODS:University-affiliated hospital. PARTICIPANTS/METHODS:Patients with good left ventricular function undergoing elective surgery (n = 103). INTERVENTIONS/METHODS:Sufentanil was administered by target-controlled infusion, with target effect-site concentrations ranging from 0.4 to 4.5 ng/mL. Isoflurane was administered as required to maintain stable hemodynamics. Sufentanil pharmacokinetics were determined by population modeling. The potential effects of gender, weight, different premedications (lorazepam, morphine-scopolamine, or clonidine), and coinduction with propofol on sufentanil pharmacokinetics were explored. MEASUREMENTS AND MAIN RESULTS/RESULTS:The first model determined was a simple 3-compartment model, without any covariates, which had these parameters: V(1) = 5.7 L, V(2) = 18.1 L, V(3) = 225 L, Cl(1) = 0.69 L/min, Cl(2) = 3.1 L/min, and Cl(3) = 1.4 L/min. The overall predictive ability during the entire pre-cardiopulmonary bypass period of this model was excellent, with virtually no bias (median prediction error, -0.4%) and good precision (median absolute prediction error, 18.4%). More complex models with the various premedications used or coinduction with propofol as covariates did not improve the predictive accuracy or precision compared with the simple 3-compartment model. Similarly, including either gender or weight as a covariate did not improve predictive ability. CONCLUSION/CONCLUSIONS:The authors have determined a pharmacokinetic model for sufentanil that can be used to maintain desired target concentrations of sufentanil before cardiopulmonary bypass, with a high degree of accuracy and acceptable variability. Concomitantly administered medications (lorazepam, morphine-scopolamine, clonidine, or propofol) do not appear to have any clinically important effects on distribution-phase sufentanil pharmacokinetics.

UNLABELLED:In this controlled study, we compared clonidine with conventional premedication in 35 patients undergoing coronary artery bypass grafting (CABG). After premedication with clonidine 5 microg/kg p.o. (Group C, n = 11), lorazepam 60 microg/kg p.o. (Group L, n = 13), or morphine 0.1 mg/kg plus scopolamine 6 microg/kg i.m. (Group M, n = 11), sedation, anxiety, and quality of premedication were graded. After the administration of sufentanil 2.0 microg/kg over 12.5 min, a computer-assisted infusion device targeted a sufentanil effect-site concentration of 0.75 ng/mL. Hemodynamic variables, end-tidal isoflurane concentration (ET-ISO), the electroencephalographic spectral edge, and the serum sufentanil concentration (SUF) were measured. There were no intergroup differences in anxiety, sedation, quality of premedication, the dose of sufentanil causing unconsciousness, or the electroencephalographic (EEG) response to induction. Intraoperative SUF was stable, with no intergroup difference. The average prebypass ET-ISO was lower in Group C than in Group M. The ET-ISO and peak ET-ISO after intense surgical stimulation were lower in Group C versus Groups L and M. Mean arterial blood pressure was lower in Group C versus Groups L and M. There were no intergroup differences in pharmacologic intervention, time to extubation, or intensive care unit stay. Clonidine produces sedation, anxiolysis, and quality of premedication comparable to conventional premedication. Compared with other drugs, clonidine does not alter the dose of sufentanil inducing unconsciousness or EEG slowing, but it uniquely reduces isoflurane requirements. IMPLICATIONS/CONCLUSIONS:In patients undergoing coronary artery bypass grafting, clonidine produces sedation and relieves anxiety as effectively as conventional premedication. Clonidine does not uniquely alter the dose of sufentanil inducing unconsciousness or electroencephalographic slowing, but it significantly reduces isoflurane requirements.