Preoperative exposure to calcium channel blockers suggests increased blood product use following cardiac surgery.

PURPOSE: In this study the authors reviewed the medical records of a random sample of patients undergoing coronary artery bypass grafting (CABG) during the preceding ten years at University Medical Center. The purpose of this study was to evaluate the impact of exposure to calcium channel blockers (CCB's) on blood product use following cardiopulmonary bypass (CPB). DESIGN: Retrospective medical record review. SETTING: University hospital. PARTICIPANTS: 527 patients undergoing CABG or re-do CABG. INTERVENTIONS: The medical records of approximately 50% of patients undergoing CABG or re-do CABG at University Medical Center between 1988 and 1998 were randomly selected by the medical records librarian for review. Preoperative medications, bypass time and temperature, and blood product use were recorded. RESULTS: Of the 527 patients studied, 309 (59%) had no exposure to CCB's. 218 (41%) were on CCB's at the time of admission. Patients who were on CCB's had an average 12.5 (+/- 1.0) blood product units transfused following bypass whereas those not on CCB's had an average 8.7 (+/- 0.6) units transfused (p < 0.001). Use of packed red blood cells (p < 0.001), fresh frozen plasma (p = 0.018) and platelets (p = 0.023) were each individually significantly increased. CONCLUSIONS: In this study, it appeared that patients exposed to CCB's before cardiac revascularization received significantly more blood products than those who were not exposed to CCB's. Because of the limitations imposed by retrospective studies, further prospective studies are warranted to define the clinical significance of CCB use in the perioperative period.

Ethical decisions in perioperative elder care.

Settings involving the extremes of age and illness are the most complex in ethical deliberation and require sound principles that can be clearly applied to individual situations. This article discusses how one's view of the aging process effects clinical decision making. The basic principles of medical ethics (autonomy, beneficence, nonmaleficence, and justice) are discussed along with alternative ethical paradigms that may be more appropriate to the elderly population. Issues such as informed consent, do not resuscitate orders in the operating room, and controversies in end-of-life palliative care specifically impact the role of the anesthesiologist. Anesthesiologists, as medical professionals in a health care team, have a great stake in ethical decision making and the ethics of health care policy.

Dihydropyridine ligand binding decreases earlier in adolescent than in infant swine after global cerebral ischemia.

BACKGROUND AND PURPOSE: Voltage-dependent calcium channels (VDCCs) are thought to play a major role in the alteration of calcium homeostasis during ischemia. Tissue functional state as well as responsiveness to therapy with calcium channel blockers may be a function of regional changes in the density of VDCCs. This study determined whether VDCCs are altered by global ischemia in infant and adolescent swine. METHODS: We employed the radioligand 3HPN200-110 to quantify the binding characteristics of VDCCs in cerebral cortex, caudate, and hippocampus by equilibrium binding analysis. Adolescent and infant pigs underwent 3, 5, 10, and 20 minutes of global cerebral ischemia without reperfusion by ligation of the brachiocephalic and left subclavian arteries combined with hypotension to a mean arterial blood pressure of 50 mm Hg. Brain cortex, hippocampus, and caudate samples were taken during ischemia and frozen immediately in liquid nitrogen, and crude synaptosomal membranes were isolated by differential centrifugation/filtration. 3HPN200-110 equilibrium binding assays were performed in the presence or absence of 1.0 mumol/L unlabeled nitrendipine to determine total and nonspecific binding. RESULTS: Infant cortex maximal binding (Bmax) increased to 176% of control after 5 minutes of global cerebral ischemia and remained significantly elevated (172% of control) after 10 minutes before falling to near control levels by 20 minutes. Adolescent cortex Bmax increased to 157% of control levels after 5 minutes but did not remain elevated, falling to 131% of control by 10 minutes and near control by 20 minutes. Infant caudate and hippocampus binding were significantly elevated after 10 (124% and 149% of control, respectively) and 20 (115% and 120% of control, respectively) minutes of ischemia. Adolescent caudate and hippocampus binding was either not significantly different from control levels (hippocampus at 10 minutes) or less than control after 10 and 20 minutes of global cerebral ischemia. The decrease in binding following the initial upregulation, which appeared earlier in the adolescent than the infant pigs, may indicate decreased tolerance to ischemia in the adolescent. CONCLUSIONS: The binding of 3HPN200-110 in brain is altered during 20 minutes of global cerebral ischemia, and these changes are region- and age-dependent.

Inhibition of [3H]isradipine binding to L-type calcium channels by the optical isomers of isoflurane. Lack of stereospecificity.

BACKGROUND: The dose-dependent myocardial depression of volatile general anesthetics such as isoflurane has been linked to blockade of L-type Ca2+ channels. The effects of (+)- and (-)-isoflurane on the inhibition of [3H]isradipine binding to L-type Ca2+ channels in membranes prepared from mouse heart were examined. In addition, because there is a stereo-specific effect of these isomers on sleep time in mice, the potential contribution of L-type Ca2+ channels to isoflurane-induced sleep was assessed by determining whether a similar stereoselectivity would be manifested at these sites in cerebral cortical membranes. METHODS: The effects of isoflurane stereoisomers on the binding of an L-type Ca2+ channel ligand ([3H]isradipine) were studied in cardiac and brain cortical membranes. Their potencies and effects on the Kd and Bmax of [3H]isradipine were measured. RESULTS: Pharmacologically relevant concentrations of (+)- and (-)-isoflurane inhibited [3H]isradipine binding. The IC50 values for (+)-isoflurane were 0.48 +/- 0.02% and 0.40 +/- 0.01% in heart and brain membranes, respectively. The values for (-)-isoflurane were not significantly different from the respective values for the (+)-isomer. Saturation analysis demonstrated (+)- and (-)-isoflurane inhibited [3H]isradipine binding by significantly reducing Bmax and increasing Kd, but there were no significant differences between these isomers in either tissue. CONCLUSIONS: The stereoisomers of isoflurane are equipotent as inhibitors of [3H]isradipine binding to L-type Ca2+ channels. This lack of stereoselectivity between (+)- and (-)-isoflurane indicates that the [3H]isradipine site on L-type Ca2+ channels in brain does not contribute to the differences in isoflurane-induced sleep time reported for these stereoisomers. Taken with a lack of stereoselectivity at L-type Ca2+ channels in heart, an optically resolved isomer of isoflurane may have clinical advantages compared to the current racemic mixture.

Increased activation of L-type voltage-dependent calcium channels is associated with glycine enhancement of N-methyl-D-aspartate-stimulated dopamine release in global cerebral ischemia/reperfusion.

We investigated the relationships among N-methyl-D-aspartate, glycine, L-type voltage-dependent calcium channels, and [3H]dopamine release in a canine model of global cerebral ischemia/reperfusion. The binding of [3H]PN200-110 ([3H]isradipine) to L-type voltage-dependent calcium channels, that open as a consequence of N-methyl-D-aspartate-induced changes in membrane potential, was approximately doubled in striatal membranes prepared from ischemic animals relative to controls, and remained significantly elevated at 30 min and 2 h of reperfusion. These changes coincided temporally with changes in the ability of the voltage-sensitive calcium channel blocker nitrendipine to inhibit glycine enhancement of N-methyl-D-aspartate-stimulated [3H]dopamine release in striatal slices prepared from the same animals. Compared with nonischemic controls, N-methyl-D-aspartate-stimulated [3H]dopamine release was increased in ischemic animals and remained increased throughout reperfusion up to at least 24 h. Glycine enhanced N-methyl-D-aspartate-stimulated release in all treatment groups. The enhancement of N-methyl-D-aspartate-stimulated dopamine release by glycine was reduced by the inclusion of nitrendipine in striatal slices from ischemic and 30-min reperfused animals. These data suggest that glycine may facilitate opening of the voltage-dependent calcium channels activated by N-methyl-D-aspartate and that this facilitation is blocked by the antagonist nitrendipine.

Effect of intracarotid and intraventricular morphine on regional cerebral blood flow and metabolism in pentobarbital-anesthetized dogs.

Potent opiate analgesics, administered either epidurally, intrathecally, or intravenously, are a common adjunct to pain control in the perioperative period. Little is known, however, of the effects of opiate agonists on cerebral blood flow (CBF) and metabolism. Current studies are complicated by the hypotensive effects of these compounds and their route of administration. To circumvent these difficulties we studied the effects of intraventricular and intracarotid morphine sulfate, in doses that do not affect arterial blood pressure, on regional CBF and total cerebral oxygen consumption (CMRO2) in pentobarbital-anesthetized dogs. Five dogs received 0.04 mg/kg morphine via intracarotid injection. Five additional dogs received 0.2 mg/kg morphine via ventricular cisternal infusion over 5 min, and five control dogs received mock cerebrospinal fluid at the same infusion rate. CBF was measured using the radiolabeled microsphere technique. Intracarotid morphine decreased neurohypophyseal blood flow to 58% of control, but it did not alter blood flow to any other brain region, except caudate nucleus, or cause a change in CMRO2. Infusion of mock cerebrospinal fluid in the cerebral ventricles did not alter CBF or CMRO2. Ventricular-cisternal perfusion of morphine caused a transient increase in CBF (24 +/- 2 to 37 +/- 6 mL min-1 100 kg-1) but had no effect on spinal cord blood flow or CMRO2. Neurohypophyseal blood flow, however, decreased to 40% of control levels (480 +/- 76 to 176 +/- 42 mL min-1 100 kg-1) after 2 min and gradually returned to control levels at 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Alteration of voltage-dependent calcium channels in canine brain during global ischemia and reperfusion.

Elevated intracellular calcium (iCa2+) plays an important role in the pathophysiology of ischemic brain damage. The mechanisms by which iCa2+ increases are uncertain. Recent evidence implicates the voltage-dependent calcium channel (VDCC) as a likely site for the alteration in Ca2+ homeostasis during ischemia. The purpose of this study was to determine whether VDCCs are altered by global ischemia and reperfusion in a canine cardiac arrest, resuscitation model. We employed the radioligand, [3H]PN200-110, to quantitate the equilibrium binding characteristics of the VDCCs in the cerebral cortex. Twenty-five adult beagles were separated into four experimental groups: (a) nonischemic controls, (b) those undergoing 10-min ventricular fibrillation and apnea, (c) those undergoing 10-min ventricular fibrillation and apnea followed by spontaneous circulation and controlled respiration for 2 and (d) 24 h. Brain cortex samples were taken prior to killing of the animal, frozen immediately in liquid nitrogen, and crude synaptosomal membranes isolated by differential centrifugation/filtration. After 10 min of ischemia the maximal binding (Bmax) of [3H]PN200-110 increased to greater than 250% of control values (control Bmax 11.16 +/- 0.98; ischemic 28.35 +/- 2.78 fmol/mg protein; p less than 0.05). Bmax returned to near control values after 2 h of reperfusion but remained significantly greater than the control at 24 h. Although the affinity constant (Kd) (control = 0.12 +/- 0.03 nM) appeared to increase with ischemia and normalize with reperfusion, the changes were not statistically significant. We conclude that the binding of [3H]PN200-110 to L-type VDCCs is increased after 10 min of global ischemia/anoxia produced by ventricular fibrillation and apnea in the dog.(ABSTRACT TRUNCATED AT 250 WORDS)

Halothane depresses D600 binding to bovine heart sarcolemma.

Volatile anesthetics exert their negative inotropic effects by interfering with Ca2+ homeostasis in the myocardial cell. The mechanism of this dose-dependent action is uncertain. 3H-D600 (3H-Gallopamil), a Ca(2+)-channel antagonist, binds to the voltage-dependent Ca2+ channels (VDCC) in a specific, saturable, and reversible manner. We used this ligand to study the effect of halothane on the binding characteristics of the VDCC in purified bovine heart sarcolemma. Cardiac sarcolemmal vesicles were isolated from fresh bovine heart by differential centrifugation and filtration. 3H-D600 equilibrium binding assays were performed in the presence or absence of 1.0 mM unlabeled D600 to determine total and nonspecific binding in room air and at 0.7, 1.3, and 2.5% (vol/vol) halothane. Halothane produced a significant dose-dependent and reversible depression of 3H-D600 specific binding in bovine heart sarcolemma. Depression was completely reversed when halothane had evaporated from the samples prior to filtration. Halothane 1.3% (vol/vol) produced a 40% reduction in the maximum binding capacity. The dissociation constant was not affected by any concentration of halothane. One mechanism by which the volatile anesthetics may induce negative inotropism is through the reduction of functional VDCCs in the heart, leading to reduction of Ca2+ entry. The results of this study support this hypothesis.

Comparison of thermal clearance measurement of regional cerebral blood flow with radiolabelled microspheres.

A thermal clearance technique for measuring cerebral blood flow is described and compared with the radiolabelled microsphere technique. The thermal technique involves measurement of the rewarming curve generated after bolus infusion of 4-5 ml of ice-cold saline into the common carotid artery with a subdural thermistor placed on the parietal cortex. Evaluation of the biexponential decay curves obtained with this technique demonstrated a close correlation with total hemispheric, parietal, and parietal gray blood flow determined by simultaneous microsphere measurement. Despite significant correlations (p less than 0.001), scatter in the data produced a broad 95% confidence interval, thus making interpretation of blood flow with the thermal clearance technique impossible. Furthermore, instrumentation with the thermal probe, which required opening of the dura, blunted the cerebral blood flow response to hypercapnia. We conclude that the major limitations of the thermal clearance technique include: nonhomogeneous clearance function, significant variability, and depression of CO2 reactivity. These limitations must be addressed before this technique can be used reliably in the laboratory.

Effect of lidoflazine on cerebral blood flow following twelve minutes total cerebral ischemia.

Lidoflazine, a calcium channel blocker, was administered to dogs following twelve minutes of cerebral ischemia, induced by aortic cross-clamping. The effects of lidoflazine (1 mg/kg i.v.) on cerebral blood flow following ischemia was studied in 15 anesthetized, mechanically ventilated dogs. Cerebral blood flow was measured with the radiolabelled microsphere technique before and 10, 30, 60, 90 and 150 minutes following ischemia. Cerebral blood flow increased in all brain regions following ischemia, but by 60 minutes had decreased to control values. Lidoflazine had no effect on this reperfusion phenomenon, or on the distribution of blood flow within the brain. Regional cerebral blood flow was also not altered by lidoflazine therapy. Our data demonstrate that this dose of lidoflazine has no effect on regional or total cerebral blood flow following 12 minutes of cerebral ischemia in dogs. These data do not support perfusion preservation as a mechanism of amelioration of neurologic injury after ischemia by this calcium channel blocker.

Determination of cerebral cortical blood flow: a thermal technique.

A mathematical model for tissue thermodilution was developed to study cerebral cortical perfusion before and after controlled perfusion arrest. Cerebral cortical perfusion rates are readily determined by this method. A thermistor was introduced into the subdural space and secured in direct contact with the frontal cortex in 12 dogs on ketamine and gallamine anesthesia. A 22-gauge angiocath was placed in the right superior thyroid artery and directed into the carotid artery on the same side as the thermistor. The dogs were placed on cardiac bypass using a circuit from the right atrium to the pulmonary artery and a second circuit from the left ventricular apex to the left femoral artery. Arterial pressure, central venous pressure (CVP), intracranial pressure (ICP), and left atrial pressure (LAP) were monitored directly. A heat exchanger was used to maintain a constant blood temperature of 37 C in the output of the left side bypass circuit. Thermal flow curves were generated in the cerebral cortex by injecting 2 to 4 cc of cold saline into the common carotid artery through the injection catheter. Preliminary evaluation of this flow method in comparison to radioactive microspheres indicates that this method can be used in a reliable and reproducible fashion to determine cerebral cortical blood flow.

Effect of flunarizine on canine cerebral cortical blood flow and vascular resistance post cardiac arrest.

Twelve dogs were anesthetized and instrumental for determination of CVP, arterial pressure, intracranial pressure, left atrial pressure, and frontal cerebral cortical blood flow (CCBF) by the thermal method. A catheter was introduced into the venous return of the cerebral confluence to allow determination of cerebral A-V oxygen saturation differences. The animals were placed on cardiac bypass using a circuit from the right atrium to the pulmonary artery and a second circuit from the left ventricular apex to the left femoral artery. A heat exchanger was used to maintain a constant blood temperature of 37 C in the output of the left side bypass circuit. All animals were heparinized during bypass. Ventricular fibrillation was induced after completion of the bypass surgery. Two dogs served as controls. Pre-arrest determinations of hemoglobin, glucose, CCBF, and cerebral A-V oxygen differences were taken. Full circulatory arrest was carried out for 20 minutes by shutting off the cardiac bypass. Resuscitation was achieved by resumption of bypass perfusion. Acid-base balance was corrected quickly, and pre-arrest perfusion pressure was achieved and maintained for 90 minutes. All pressure parameters were monitored continuously. All pre-arrest determinations were repeated at 20, 40, 60, and 90 minutes post resuscitation. Five dogs were treated with 6 microgram/kg flunarizine administered IV drip over 10 minutes immediately post reperfusion. Five dogs were not treated post arrest. Treated animals had a prompt return of CCBF rates equal to or greater than pre-arrest flow, which persisted throughout the period of post-arrest observation. Untreated animals had markedly reduced CCBF and increased resistance. CCBF uniformly proceeded to near zero flow by 90 minutes. The ICP was not significantly altered by treatment.

Canine cerebral cortical blood flow and vascular resistance post cardiac arrest.

seven dogs were anesthetized and instrumented for determination of central venous pressure (CVP), arterial pressure, intracranial pressure (ICP), left atrial pressure (LAP), and frontal cerebral cortical blood flow by the thermal method. A catheter was introduced into the venous return of the cerebral confluence to allow determination of cerebral A-V oxygen saturation differences. The animals were placed on cardiac bypass using a circuit from the right atrium to the pulmonary artery, and a second circuit from the left ventricular apex to the left femoral artery. A heat exchanger was used to maintain a constant blood temperature of 37 C in the output of the left-side bypass circuit. All animals were heparinized during bypass. Ventricular fibrillation was induced after completion of the bypass surgery. Two dogs served as controls for stability of the measured parameters on prolonged bypass. Pre-arrest determinations of hemoglobin, cerebral cortical blood flow, and cerebral A-V oxygen saturation differences were taken. Full circulatory arrest was carried out for 20 minutes in 5 dogs by shutting off the cardiac bypass. Resuscitation was achieved by resumption of bypass perfusion. Acid-base balance was corrected and pre-arrest perfusion pressures were achieved and maintained for 90 minutes. All pressure parameters were monitored continuously. Pre-arrest determinations were repeated at 20, 40, 60, and 90 minutes post resuscitation. A 50% reduction in cerebral cortical blood flow 20 minutes post resuscitation progressed to near zero flow 90 minutes post resuscitation. The changes in net cerebral perfusion pressure produced by the slowly rising intracranial pressure do not account for this flow reduction. Calculation of cerebral vascular resistance reveals a ten-fold increase in resistance post-arrest and -resuscitation.

Peripheral vs central circulation times during CPR: a pilot study.

The circulation time during closed chest cardiac compression was studied using Cardio-Green injected in either the right antecubital vein or right subclavian vein during CPR. Arterial blood was obtained from a right femoral arterial catheter at 30-second intervals for five minutes following injection. Six patients, in two groups, comprised the study population. The arterial sample for Cardio-Green after central venous injection revealed a high concentration of the dye at 30 seconds and an emerging second peak at five minutes. After peripheral injection, no peak concentration of the dye was achieved during the five-minute sampling method. Our preliminary study indicates reduced concentrations and significant delay in arrival of injected agents that are introduced at a peripheral intravenous site during closed chest compression.

Mitochondrial O2 use and ATP synthesis: kinetic effects of Ca++ and HPO4(-2) modulated by glucocorticoids.

We have studied the effect of increased Ca++ on rat liver mitochondrial O2 consumption and modulation of the effects of the Ca++ by varying levels of HPO4(-2). Moreover, we have studied the acute in vitro effects of glucocorticoids on this system. Our data indicate that: 1) 200 microM Ca++ produces uncoupled respiration by mitochondria and blocks ATP synthesis: 2) HPO4(-2) increases the velocity and duration of uncoupled O2 consumption induced by Ca++. The HPO4(-2) effect fits Michaelis-Menton kinetics, indicating a specific site for the action of HPO4(-2) with a Km (1/2 saturation constant) of 5 mM; 3) dexamethasone acts acutely (without prefeeding) as an allosteric inhibitor of the HPO4(-2) system; and 5) uptake kinetics done with tritium-labeled dexamethasone into fresh intact human leukocytes demonstrate equilibration into the cell within 60 sec with a very large Vmax of transport at the plasma membrane. Critically ill patients with reduced tissue perfusion have lowered ionized calcium blood levels. This reflects movement of this ion into the cytosol as the plasma membrane Ca++ pump begins to fail. Clinical implications of our study are that: 1) administration of therapeutic Ca++ in hypoperfused patients with low serum Ca++ levels may be contraindicated because this will only increase the Ca++ load on the mitochondria and further depress ATP synthesis; 2) glucocorticoids administered to these patients offer partial protection of the mitochondria from uncoupling and improve ATP synthesis; and 3) effective doses of glucocorticoids are probably near optimum at four to five times the K.

His electrocardiographic characterization of terminal arrhythmias of hemorrhagic shock in dogs.

Pulseless idioventricular rhythm is the agonal arrhythmia identified in three models of hemorrhagic shock used in this study. This arrhythmia is preceded by atrial and then junctional arrest demonstrated by His electrocardiography in all nine dogs studied. Two additional dogs were used as controls. Acid-base and electrolyte changes were not sufficient to cause the progressive failure of conduction system function seen so consistently. Patients receiving cardiopulmonary resuscitation who have profound bradycardia without pulses may have been in shock prior to cardiopulmonary arrest.