Faculty Bibliography

OBJECTIVE:Deep sternal wound infection is a dreaded complication of coronary artery bypass surgery, particularly in patients with diabetes. This study determines whether skeletonization of internal thoracic artery conduits compared with pedicled harvesting reduces the risk of deep sternal wound infection in patients with diabetes undergoing bilateral internal thoracic artery grafting. METHODS:We reviewed prospectively gathered data on all patients who have undergone coronary artery bypass grafting and received bilateral internal thoracic artery grafts at our institution since 1990. We compared patients with diabetes who received skeletonized (n = 79) versus conventional pedicled (n = 36) internal thoracic artery conduits. RESULTS:The proportion of patients taking insulin (19.0% vs 14.0% for skeletonized vs conventional grafts, respectively, P =.6) or oral hypoglycemic agents (68.4% vs 69.4%, P =.9), as well as the prevalence of type I diabetes (2.5% vs 8.3%, P =.18), were similar in both groups. Patients who received skeletonized grafts were more likely to receive a free rather than an in situ right internal thoracic artery graft (93.7% vs 30.6%, P <.001). The prevalence of deep sternal wound infection was significantly lower in patients who received skeletonized grafts compared with patients who received conventional grafts (1.3% vs 11.1%, P =.03). Patients in the skeletonized group were also less likely to develop any (superficial or deep) sternal wound infection postoperatively (5.1% vs 22.2%, P =.03). There was no significant difference in the prevalence of deep sternal wound infection between patients with diabetes who received skeletonized internal thoracic arteries and patients without diabetes who underwent conventional internal thoracic artery grafting (n = 578) (1.2% vs 1.6%, respectively, P =.8). CONCLUSIONS:Skeletonization of internal thoracic artery conduits lowers the risk of deep sternal wound infection in patients with diabetes undergoing bilateral internal thoracic artery grafting. We no longer consider diabetes a contraindication to bilateral internal thoracic artery grafting, provided the internal thoracic arteries are skeletonized.

Hyperosmotic stress initiates adaptive responses, including phosphorylation of myosin light chain (MLC) and concomitant activation of Na+-K+-Cl- cotransporter (NKCC). Because the small GTPase Rho is a key regulator of MLC phosphorylation, we investigated 1) whether Rho is activated by hyperosmotic stress, and if so, what the triggering factors are, and 2) whether the Rho/Rho kinase (ROK) pathway is involved in MLC phosphorylation and NKCC activation. Rho activity was measured in tubular epithelial cells by affinity pulldown assay. Hyperosmolarity induced rapid (<1 min) and sustained (>20 min) Rho activation that was proportional to the osmotic concentration and reversed within minutes upon restoration of isotonicity. Both decreased cell volume at constant ionic strength and elevated total ionic strength at constant cell volume were capable of activating Rho. Changes in [Na+] and [K+] at normal total salinity failed to activate Rho, and Cl- depletion did not affect the hyperosmotic response. Thus alterations in cellular volume and ionic strength but not individual ion concentrations seem to be the critical triggering factors. Hyperosmolarity induced mono- and diphosphorylation of MLC, which was abrogated by the Rho-family blocker Clostridium toxin B. ROK inhibitor Y-27632 suppressed MLC phosphorylation under isotonic conditions and prevented its rise over isotonic levels in hypertonically stimulated cells. ML-7 had a smaller inhibitory effect. In contrast, it abolished the hypertonic activation of NKCC, whereas Y-27632 failed to inhibit this response. Thus hyperosmolarity activates Rho, and Rho/ROK pathway contributes to basal and hyperosmotic MLC phosphorylation. However, the hypertonic activation of NKCC is ROK independent, implying that the ROK-dependent component of MLC phosphorylation can be uncoupled from NKCC activation.

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.