Effect of oral clonidine premedication on anesthetic requirement, hormonal response, hemodynamics, and recovery in coronary artery bypass graft surgery patients.

STUDY OBJECTIVE: To examine how premedication with clonidine affects opioid use, hemodynamic effects, hormonal responses, and recovery effects. DESIGN: Double blind, placebo-controlled study. SETTING: Operating room and surgical intensive care unit of a university medical center. PATIENTS: 54 patients undergoing elective coronary artery bypass graft (CABG) surgery. INTERVENTIONS: Patients received approximately 5 micrograms/kg of oral clonidine or a placebo together with 40 micrograms/kg lorazepam 90 minutes prior to titrated sufentanil induction of anesthesia. Thirty minutes prior to cardiopulmonary bypass, a second dose of either approximately 5 micrograms/kg clonidine or placebo was given as a slurry via a nasogastric tube. MEASUREMENTS AND MAIN RESULTS: Opioid use, hemodynamic effects, hormonal responses, and recovery effects were recorded. Values for ten hemodynamic variables were compiled on the evening prior to surgery, prior to induction, and during seven additional events and compared. Catecholamines and beta-endorphins were measured prior to induction, after intubation, and after sternotomy. The amount of sufentanil used for induction, maintenance, and total opioid were compared. The times to awakening and response to verbal commands were compared. The two groups exhibited similar patient demographics, cardiopulmonary bypass time, and duration of surgery. Patients receiving clonidine required significantly (p < 0.04) less sufentanil for induction (clonidine: 2.19 +/- 0.95 micrograms/kg vs. placebo: 2.93 +/- 1.07 micrograms/kg) and total amount of sufentanil (clonidine: 9.1 +/- 3.9 micrograms/kg vs. placebo: 11.7 +/- 4.6 micrograms/kg). Patients receiving clonidine required significantly (p < 0.01) less isoflurane (9.7 +/- 6.8 MAC min vs. 19.7 +/- 9.9 MAC min) to maintain heart rate (HR) and mean arterial pressure (MAP) to within 15% of baseline without significant differences in other vasoactive drugs. Catecholamine concentrations were significantly (p < 0.02) lower in patients receiving clonidine without any difference in beta-endorphin concentrations. Patients receiving clonidine had significantly (p < 0.02) lower HR, systolic arterial pressure, MAP, and systemic vascular resistance prior to induction than patients receiving placebo without differences in other hemodynamic variables. CONCLUSION: Clonidine decreases opioid use and lowers hormonal response while maintaining stable hemodynamics in patients undergoing CABG with sufentanil anesthesia.

Cystic fibrosis transmembrane conductance regulator mutations that disrupt nucleotide binding.

Increasing evidence suggests heterogeneity in the molecular pathogenesis of cystic fibrosis (CF). Mutations such as deletion of phenylalanine at position 508 (delta F508) within the cystic fibrosis transmembrane conductance regulator (CFTR), for example, appear to cause disease by abrogating normal biosynthetic processing, a mechanism which results in retention and degradation of the mutant protein within the endoplasmic reticulum. Other mutations, such as the relatively common glycine-->aspartic acid replacement at CFTR position 551 (G551D) appear to be normally processed, and therefore must cause disease through some other mechanism. Because delta F508 and G551D both occur within a predicted nucleotide binding domain (NBD) of the CFTR, we tested the influence of these mutations on nucleotide binding by the protein. We found that G551D and the corresponding mutation in the CFTR second nucleotide binding domain, G1349D, led to decreased nucleotide binding by CFTR NBDs, while the delta F508 mutation did not alter nucleotide binding. These results implicate defective ATP binding as contributing to the pathogenic mechanism of a relatively common mutation leading to CF, and suggest that structural integrity of a highly conserved region present in over 30 prokaryotic and eukaryotic nucleotide binding domains may be critical for normal nucleotide binding.

Role of calcium in inactivation of calcium/calmodulin dependent protein kinase II after cerebral ischemia.

Transient cerebral ischemia demonstrates an increase in activated oxygen species in the brain that could lead to eventual neuronal cell death. Neuronal cells respond to oxygen free radicals through the restructuring of the cytoskeleton and membranes, mobilization of calcium and gene expression which play a role in cell injury. Ten min of bilateral carotid artery occlusion resulted in a decrease in calcium/calmodulin dependent protein kinase II (CaM kinase II) phosphorylation and activity detected in the brain immediately following ischemia and was partially restored within 24 h of reperfusion. Pretreatment of animals with an anesthetic dose of pentobarbital (40 mg/kg) resulted in partial protection of inactivation of CaM kinase II following ischemia. CaM kinase II activity was maintained following pretreatment of animals with alpha-phenyl N-tert-butyl nitrone (PBN), which traps oxygen free radicals. Infusion of superoxide dismutase or catalase prior to ischemia, blocked CaM kinase II inactivation. Blockage of calcium uptake with bepridil resulted in a marked protection of CaM kinase II inactivation. In addition, trifluoperazine, a calmodulin antagonist also diminished the inhibition of CaM kinase II phosphorylation in our model. These results suggest that ischemia and reperfusion injury results in the generation of activated oxygen and the mobilization of calcium which inactivate CaM kinase II. These results indicate that changes associated with protein kinase activity in the brain following an ischemic insult may have profound effects upon neurodegeneration and neuronal survival.

Defining the dose range for esmolol used in electroconvulsive therapy hemodynamic attenuation.

We evaluated the clinical effectiveness of esmolol, an ultra-short-acting, beta-adrenergic receptor blocking drug, to control the sinus tachycardia and increase in arterial blood pressure induced by electroconvulsive therapy (ECT). Each of 20 patients, ASA physical status I-III, participated in a double-blind, randomized Latin-Square study involving two matched-pair trials (placebo versus esmolol given as a 500-micrograms/kg bolus followed by either 300 micrograms.kg-1.min-1 [high dose], 200 micrograms.kg-1.min-1 [medium dose], or 100 micrograms.kg-1.min-1 [low dose] infusion of esmolol) during ECT. Each patient acted as his or her own control (total number of ECT procedures were 160). We administered a 1-min bolus of placebo (normal saline) or esmolol at the rate of 500 micrograms.kg-1.min-1 followed by either high-, medium-, or low-dose esmolol or placebo for an additional 3 min. We then induced anesthesia with methohexital (1 mg/kg) and succinylcholine (0.5 mg/kg) IV. Ninety seconds after the administration of succinylcholine, the electrical stimulus was applied to induce seizure. The infusion of placebo or esmolol was discontinued 3 min after the electrical stimulus. Significant decreases were found in mean heart rate from minute 3 until minute 7 and in the maximum heart rate. The mean of each patient's maximum heart rate after seizure changed from 147 +/- 18 bpm in placebo patients to 112 +/- 20 bpm in high-dose esmolol patients; to 121 +/- 23 bpm in medium-dose esmolol patients; and to 124 +/- 20 bpm in low-dose esmolol patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium/calmodulin dependent protein kinase II mRNA in the gerbil brain after cerebral ischemia.

The effect of transient cerebral ischemia on the expression of Ca2+/calmodulin dependent protein kinase II (CaM kinase II) mRNA in the gerbil brain was analyzed by Northern blots using cDNA clones for CaM kinase II. Ten minutes of bilateral carotid occlusion and 30 min of reperfusion resulted in reduced protein levels for alpha and beta subunits of the CaM kinase II, decreasing to 35% of control levels at 24 h. Recovery of immunoreactivity was detected in the cortex after 48 h. Eight to twelve hours after ischemia, the cortex showed a decrease in alpha and beta CaM kinase II mRNA levels. By 12-24 h of reperfusion the level of CaM kinase II mRNA was reduced to 26% of the control mRNA levels. CaM kinase II mRNA levels recovered by 48 h after ischemia, coinciding with the increase in CaM kinase II protein immunoreactivity. These results suggest that CaM kinase II is involved in neuronal survival through the reorganization of the neuroarchitecture and that the regulation of this role is controlled at the level of gene expression.

The expanding physician supply and health policy: the clouded outlook.

Our conclusions about consensus and policy follow: -The interested parties from the citizenry to the leaders of specialty societies are definitely not of one mind whether the increasing number of physicians is to be viewed as boon or bane. -If over the next few years the much enlarged supply of physicians is seen as creating more problems than it is solving, the step from consensus to policy will still prove difficult. -The absence of early consensus or specific action does not imply that the future supply of physicians is not being influences. The cutbacks in federal support for medical students are certain to have a dampening effect sooner or later on the numbers that will seek admission to medical school. -The marker signals that physicians' incomes are lagging behind other professionals and that government is increasing its control over medical practice will also have an effect on many premedical students, some of whom will choose other careers. -The changes in payment mechanisms and the delivery of heath care will have important long-term consequences for the effective demand for physician services, which in turn will influence future medical school enrollments.