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Experiments were performed on nine dogs instrumented with pulmonary artery Swan-Ganz catheters and catheters placed into the distal aorta and posterior caval vein. Electromagnetic flowmeter probes were placed around the portal vein and hepatic artery, and the portal vein was cannulated. A week later, systemic and splanchnic circulatory variables were studied before and after 10 mg/kg of midazolam given intravenously. Three minutes after injection, heart rate increased 26% (P less than 0.006), cardiac index decreased 15% (P less than 0.001), portal flow increased 19% (P greater than 0.05), and hepatic arterial flow decreased slightly (P less than 0.002). Later, portal blood flow decreased 17% below baseline values (P less than 0.006). The biphasic response of portal blood flow to midazolam is probably related to redistribution of blood within the splanchnic system (blood mobilization from spleen and intestine). It is suggested that because maintenance of cardiac output during midazolam anesthesia depends on compensatory mechanisms, failure to increase cardiac output with compensatory increases in heart rate, contractility, and blood volume mobilization from the splanchnic circulation could result in decreased cardiac output.

Sustaining the circulation during cardiac operations requires use of extracorporeal circulation with a cardiopulmonary bypass (CPB) pump perfusion system. The safety of this procedure is remarkable when one ponders the technological, physiologic, and pathologic problems that have been encountered, solved, or ignored. [1] The perfusion pressure during CPB is one of the physiologic variables that usually becomes very abnormal, especially at the initiation of CPB. It is common for the perfusion pressure to decrease significantly to very low levels (20–30 mmHg) at the start of extracorporeal circulation. This degree of hypotension in normal man would certainly produce shock (inadequate tissue perfusion), but does not do so during the altered physiologic state of CPB. Nevertheless, there are valid reasons for concern when the perfusion pressure is diminished during CPB. We address these concerns as they apply to two organ systems: the brain and the heart.

The development of cardiopulmonary bypass (CPB) has been essential to the remarkable improvements in the surgical management of cardiac diseases. Although advances in technique and equipment have substantially reduced morbidity and mortality related to CPB, unpredictable transient and permanent central nervous system complications continue to occur. The exact causes of central nervous system injury following uncomplicated open heart surgery are not known.

This study was designed to test the hypothesis that acute hypovolemia would compromise the compensatory hemodynamic mechanisms to midazolam and decrease its metabolic clearance. Experiments were performed on seven chronically instrumented female beagle dogs. Animals received a single intravenous dose of midazolam, 10 mg/kg, 4 days apart during normovolemic (N) and hypovolemic (H) states in a random sequence. Hypovolemia was achieved by the withdrawal of 26 ml/kg of blood, equivalent to one-third of the calculated blood volume. Midazolam plasma concentrations were determined at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 h after midazolam injection. Elimination half-life (t 1/2 beta) was significantly longer and total clearance was significantly lower during H than during N. Initial distribution half-life, central compartment volume, total volume of distribution, and plasma protein binding were similar in both N and H states. Midazolam caused a significant decrease in systolic blood pressure (SBP) and an increase in heart rate (HR) during N, and produced significant decreases in SBP, diastolic blood pressure (DBP), and mean arterial pressure (MAP) during H. Midazolam led to similar per cent decreases in blood pressure and cardiac output in states N and H; however, the absolute values of blood pressure and cardiac output were significantly (P less than 0.001) lower in the hypovolemic state than in the normovolemic state. These data suggest that the hypotensive effects of midazolam, like those of other intravenous induction agents, could be potentiated by volume depletion.

Stressful surgical stimuli, such as endotracheal intubation, surgical incision, organ manipulation and emergence from anesthesia, elicit adrenergic responses that precipitate transient but intense increases in heart rate and blood pressure. Although this response is well tolerated in healthy patients, patients with ischemic heart disease are at significant risk of myocardial ischemia and infarction owing to the sudden increase in myocardial oxygen demand. Parenteral beta blockers are effective in blunting this adrenergic response, but the duration of action of these agents is long-lasting and the degree of beta blockade is often difficult to predict. Further, long-acting parenteral beta blockers may cause adverse effects, the reversal of which presents a difficult clinical problem in patients with ischemic heart disease. The availability of esmolol, an ultrashort-acting parenteral beta-adrenergic antagonist with a half-life of 9 minutes, brings obvious advantages to the perioperative management of hypertension and tachycardia. With esmolol treatment, the difficulties of therapy with long-lasting beta blockers are avoided. Also, to blunt the adrenergic response, the anesthesiologist will have an alternative to increasing the depth of anesthesia, which can accentuate cardiovascular depression and prolong awakening and postoperative respiratory depression. Clinical studies performed during the perioperative period reveal that esmolol is safe and effective in this setting. Esmolol has been shown to be safe and efficacious in patients in ASA classifications I through IV and patients undergoing carotid endarterectomy and coronary artery bypass surgery. The pharmacokinetic profile, rapid onset and elimination half-life make this agent particularly well suited to treat the very intense but transient adrenergic responses to surgical stress in patients undergoing cardiac and noncardiac surgery.

B ENZODIAZEPINES are not contraindicated as induction agents for coronary artery surgery; in fact, in my opinion they are indicated. It has been shown in many studies that diazepam, midazolam, and even lorazepam are effective induction agents for patients with heart disease.‘“3 The reason that benzodiazepines are effective induction agents is that they produce relatively rapid hypnotic and amnestic effects with minimal hemodynamic perturbations. The hypnotic and amnestic properties of these anesthetics are predictable, reliable, and reproducible. This combination of hypnosis and amnesia is unique to the benzodiazepines and is not a characteristic of alternative drugs such as thiopental, etomidate, and especially opioids. The relatively rapid onset of hypnosis and amnesia are important aspects of the pharmacology of benzodiazepines when used for induction in patients with coronary artery disease, and these characteristics make benzodiazepines very valuable induction agents. In contrast to opioids, benzodiazepines produce no muscle rigidity (they are muscle relaxants) and the airway is easily maintained. This makes the transition from consciousness to unconsciousness free of troublesome ventilation problems during this crucial phase of patient management. However, because benzodiazepines do not have analgesic properties, it is imperative that other anesthetic drugs be administered to provide analgesia. This can be accomplished by the judicious combination of opioids or inhalation anesthetics. This brings us to a cautionary note. It is well known that the combination of benzodiazepines and opioids can produce a supra-additive hypotension that presents a common problem in cardiac anesthesia.34 This unwanted side effect occurs in patients given

The incidence of transient post cardiac surgery neurologic dysfunction varies between 0 and 4096.1–14 Slogoff has shown that this incidence depends on the retrospective vs. prospective and sensitivity vs. specificity of the studies.14 (Table). Hypotension has been implicated as a precipitating cause by a number of investigators2,3,5,6,11 while others have failed to show a correlation of hypotension with cerebral dysfunction.8,14 We wished to examine the relationship of cerebral blood flow and perfusion pressure during cardiopulmonary bypass (CPB). If cerebral autoregulation is lost during CPB, it is possible that hypotension could produce decreased cerebral perfusion. The reduced perfusion could then produce central nervous system (CNS) hypoxia and contribute to CNS damage if the oxygen delivery were insufficient to meet oxygen demand. We used a method of cerebral blood flow determination during CPB first reported by McKay et al. 16 and recently used by Henriksen et al.17

Cardiopulmonary bypass (CPB) alters systemic hemodynamics and affects several biochemical systems involved in cardiovascular regulation. We investigated the changes in levels of circulating epinephrine (E) and norepinephrine (NE) and related them to events during CPB. Twenty-eight patients undergoing various surgical procedures were studied. Plasma E and NE were determined by radioenzymatic assay at eight stages of the operation. A ninefold increase in arterial E (from 75 +/- 13 to 708 +/- 117.3 pg/ml) occurred from prebypass (stage 1) measurements to the end of aortic cross-clamping (stage 4). The values at stage 4 were significantly higher (p less than 0.05) than at all other stages. E decreased rapidly, to 360 +/- 84.3 pg/ml, after myocardial and pulmonary reperfusion (stage 5). Arterial NE increased twofold from stage 1 to stage 4 (from 426 +/- 66.9 to 825 +/- 84.2, p less than 0.05). The increase in NE from initial CPB values (stage 2) to 30 minutes of aortic cross-clamping (stage 3) was associated with an increase in mean blood pressure (r = 0.51, p = 0.02). The peak increases in catecholamines occurred when the heart and lungs were excluded from the circulation, which suggests that either or both contributed to the increase. Because the increase in E was markedly greater than that in NE, the predominant humoral response to CPB appears to be adrenomedullary release of E. This significant increase in catecholamines could jeopardize myocardial protective measures during CPB.

In order to investigate the ability of a computer-assisted continuous infusion (CACI) system to maintain constant plasma levels of sufentanil during cardiopulmonary bypass (CPB) using pharmacokinetic data derived from healthy surgical patients to determine the infusion rate, ten patients were anaesthetized with diazepam, enflurane and oxygen until ten minutes prior to the expected time of initiation of CPB. At that point, an infusion of sufentanil, aimed to reach a central compartment concentration of 5 ng.ml-1, was started via CACI. Plasma concentrations of sufentanil, haematocrit, total protein and albumin concentrations, and nasopharyngeal and CPB inflow temperatures were obtained at predetermined intervals before and up to 90 min after the initiation of CPB. Plasma concentrations of sufentanil reached 3.8 +/- 0.4 ng.ml-1 before CPB and approached the 5.0 ng.ml-1 set point (4.7 +/- 0.4 ng.ml-1) over the 90 min of CPB. In conclusion, our results show that it is possible to obtain stable plasma levels of sufentanil on CPB using a pharmacokinetically driven infusion scheme; however, our data suggest that use of such a system may lead to accumulation of drug during CPB.

Calcium entry blocking drugs (CaEBs) produce vasodilation and, in high doses, modify alpha adrenergic receptor function. Previous laboratory data suggested that CaEBs might alter the response to alpha-adrenergic stimulation. The authors tested the hypothesis that CaEB therapy altered alpha-adrenergic responsiveness in patients chronically treated with CaEBs. Twenty-six consenting patients with coronary artery disease were given a phenylephrine challenge before anesthesia induction and during cardiopulmonary bypass while the aorta was cross-clamped. A log dose response curve was constructed for each patient, and the ED30 (dose producing 30% increase in systemic vascular resistance) was calculated. Nine patients not treated with CaEB served as controls, and 17 patients were treated with nifedipine (n = 7) or diltiazem (n = 10). Mean ED30 was increased approximately three-fold in the CaEB treated groups compared to the control group. However, there was no statistical difference in the ED30 or phenylephrine dose response slopes between CaEB treated and untreated patients. In awake patients, ED30 correlated with nifedipine levels (R = 0.953, P = 0.01). There was a significant (P less than .02) shift in the ED30 from prior to anesthesia to during aortic cross-clamp and cardiopulmonary bypass; ED30 was approximately 50% less and correlated with CaEB level (R = 0.713, P = 0.03). Hemodynamic variables were not different between groups at any interval. Our data suggest that vascular responsiveness to phenylephrine in patients treated with CaEBs is diminished, but similar to that in untreated patients. Vascular responsiveness decreases in awake patients with increasing nifedipine levels.

The pharmacokinetics of esmolol, a new, ultra-short-acting beta adrenergic blocking drug, were studied in 19 patients undergoing coronary artery surgery. Esmolol was administered as a continuous infusion, and blood concentrations were measured at intervals up to 40 min after discontinuation of the infusion. In all patients, a bi-exponential equation best described the esmolol concentration--time curve. Half-lives for the distribution and elimination phases were 1.34 +/- 0.77 min and 9.9 +/- 4.55 min (mean +/- SD), respectively. The mean values for V beta and V epsilon were 1.9 +/- 1.24 l X kg-1 and 0.41 +/- 0.31 l X kg-1, respectively, and the total clearance was 128 +/- 41 ml X kg-1 X min-1.

There are conflicting reports regarding blood volume change following alcohol administration. Variations have been reported which are of sufficient magnitude that they could influence any acute circulatory study in which large volumes of alcohol are administered. In these experiments a simple method utilizing a single injection of radioiodinated serum albumin (RISA) was devised. This technique minimizes errors inherent in methods employing multiple injections of RISA. In eight dogs, hematocrit, blood alcohol, and plasma volume were determined at intervals following oral administration of 2 g/kg ethanol (40% v/v in saline) or an equal volume of saline. Blood alcohol peaked at 152 mg/100 ml 3 hr following ingestion. During the 6 hr experimental period there were no significant alterations in hematocrit or plasma volume in either the saline or alcohol treated dogs. These data support the view that blood volume fluctuations are inconsequential in acute cardiovascular experiments performed during 6 hr following ingestion of ethyl alcohol as described above.

UNLABELLED Efforts to reduce controlled-substance abuse by anesthesiologists have focused on education and tighter regulation of controlled substances. However, the efficacy of these approaches remains to be determined. Our hypotheses were that the reported incidence of controlled-substance abuse is unchanged from previous reports and that the control and accounting process involved in distribution of operating room drugs has tightened. We focused our survey on anesthesiology programs at American academic medical centers. Surveys were sent to the department chairs of the 133 US anesthesiology training programs accredited at the end of 1997. There was a response rate of 93%. The incidence of known drug abuse was 1.0% among faculty members and 1.6% among residents. Fentanyl was the controlled substance most often abused. The number of hours of formal education regarding drug abuse had increased in 47% of programs. Sixty-three percent of programs surveyed had tightened their methods for dispensing, disposing of, or accounting for controlled substances. The majority of programs (80%) compared the amount of controlled substances dispensed against individual provider usage, whereas only 8% used random urine testing. Sixty-one percent of departmental chairs indicated that they would approve of random urine screens of anesthesia providers. IMPLICATIONS This survey indicates that the frequency of controlled substance abuse among anesthesiologists has changed little in the past few years, despite an increase in the control and accounting procedures for controlled substances as well as increased mandatory education.

Cerebral blood flow was measured in 20 patients by xenon 133 clearance methodology during nonpulsatile hypothermic cardiopulmonary bypass to determine the effect of age on regional cerebral blood flow during these conditions. Measurements of cerebral blood flow at varying perfusion pressures were made in patients arbitrarily divided into two age groups at nearly identical nasopharyngeal temperature, hematocrit value, and carbon dioxide tension and with equal cardiopulmonary bypass flows of 1.6 L/min/m2. The range of mean arterial pressure was 30 to 110 mm Hg for group I (less than or equal to 50 years of age) and 20 to 90 mm Hg for group II (greater than or equal to 65 years of age). There was no significant difference (p = 0.32) between the mean arterial pressure in group I (54 +/- 28 mm Hg) and that in group II (43 +/- 21 mm Hg). The range of cerebral blood flow was 14.8 to 29.2 ml/100 gm/min for group I and 13.8 to 37.5 ml/100 gm/min for group II. There was no significant difference (p = 0.37) between the mean cerebral blood flow in group I (21.5 +/- 4.6 ml/100 gm/min) and group II (24.3 +/- 8.1 ml/100 gm/min). There wasmore » a poor correlation between mean arterial pressure and cerebral blood flow in both groups: group I, r = 0.16 (p = 0.67); group II, r = 0.5 (p = 0.12). In 12 patients, a second cerebral blood flow measurements was taken to determine the effect of mean arterial pressure on cerebral blood flow in the individual patient. Changes in mean arterial pressure did not correlate with changes in cerebral blood flow (p less than 0.90). We conclude that age does not alter cerebral blood flow and that cerebral blood flow autoregulation is preserved in elderly patients during nonpulsatile hypothermic cardiopulmonary bypass.« less

The effect of intravenous (IV) nitroglycerin (NTG) on perioperative myocardial ischemia as detected by single pass radionuclide angiocardiography was studied in 20 patients scheduled for elective coronary artery bypass grafting (CABG). Ten patients, selected at random, received IV NTG 1 microgram.kg-1.min-1 (NTG group) and 10 others, IV saline (control group). Anesthetic induction consisted of midazolam 0.2 mg.kg-1, vecuronium 0.1 mg.kg-1, and 50% N{sub 2}O in O{sub 2}. ECG leads I, II, and V5 were monitored for ST segment changes. Single pass radionuclide angiocardiography (RNA) was performed at 5 times: prior to induction, prior to tracheal intubation, and at 1, 3.5, and 6 min following intubation. The presence of new regional wall motion abnormalities (RWMA) was determined from each RNA study as compared with the preinduction measurement. Apart from one patient in the control group who developed a new v wave after intubation, there was no evidence of ischemia by pulmonary capillary wedge pressure. No ECG evidence of ischemia was detected in any patient. Despite this, new regional wall motion abnormalities were observed in 3 patients in the control group and 1 patient in the NTG group. Blood pressure and heart rate responses of patients with new RWMA were not significantlymore » different from other patients. The low incidence of ischemia in this population precludes a definitive statement regarding the efficacy of IV NTG, but the lower incidence of RWMA in the NTG group suggests a protective effect.« less

Acutely ill patients with myocardial infarction may require immediate cardiac catheterization and coronary angioplasty to achieve myocardial reperfusion. To determine the feasibility of using general anesthesia under these circumstances, a randomized clinical trial was performed. Of 50 patients, 25 received anesthesia and 25 receive intravenous sedation. There were transient increases in heart rate and blood pressure after tracheal intubation in the anesthetized patients, followed by significant and sustained decreases below baseline values once steady state anesthesia was attained. Arterial oxygenation was significantly improved in anesthetized patients. There were no serious complications due to anesthesia, but the small sample size limited the power of the study to detect differences in morbidity or mortality. Patients strongly preferred anesthesia. These results show that general anesthesia is feasible in patients undergoing interventional cardiac catheterization during acute myocardial infarction, when pain, anxiety or agitation do not respond adequately to conventional measures.

Phenylephrine (Phe) is frequently administered as an intravenous (IV) bolus to increase blood pressure, yet the acute time course and hemodynamic effects of bolus Phe in patients with myocardial disease have not been reported. Therefore 50 randomized IV bolus doses of Phe (50, 100, 150, or 200 micrograms) were given to 18 patients during anesthesia for elective coronary artery surgery. Esophageal Doppler techniques were used to continuously monitor cardiac output (CO); mean arterial pressure (MAP), CO, and calculated systemic vascular resistance (SVR) were recorded every 5 seconds for a total of 2 minutes. The hemodynamic changes (mean +/- SEM) for each of the four doses of Phe (50, 100, 150, 200 micrograms) were maximal at about 42 seconds after the drug was given. They consisted of an increase in MAP (11.6 +/- 2.1, 15.6 +/- 2.4, 14.7 +/- 2.4, 18.0 +/- 1.5 mm Hg); increase in SVR (766 +/- 190, 930 +/- 310, 950 +/- 344, 1732 +/- 824 dynes.sec.cm-5); and a decrease in CO (-.58 +/- .11, -.68 +/- .13, -.73 +/- .20, -.77 +/- .18 L.min-1). Hypertension, increased age, low preoperative ejection fraction, high baseline CO, and low baseline SVR significantly (P less than 0.05) decreased hemodynamic responses to Phe (see text). In conclusion, bolus IV Phe in patients with myocardial disease increases MAP and SVR and simultaneously decreases CO; these peak hemodynamic events occur approximately 42 seconds after Phe administration.

Recent studies have demonstrated the presence of physiologically active beta 2 receptors in the myocardium. We hypothesized that activation of cardiac beta 2 receptors by endogenously released epinephrine and norepinephrine during surgical stress would add to the positive chronotropic response mediated by beta 1 stimulation. Twenty patients scheduled for coronary artery bypass grafting were studied. Ten patients received a beta 1-selective antagonist (atenolol, 6; metoprolol, 4) and ten patients received a nonselective beta 1 and beta 2 antagonist (propranolol) preoperatively. An isoproterenol dose-heart rate response test was performed. After stabilization, general anesthesia was induced followed by tracheal intubation and surgery. Hemodynamic data were recorded before induction, 1 min after induction, 5 min after intubation, 1 min before and after skin incision, 1 min before and after sternotomy. The ten patients on cardioselective beta-blocker drugs had significantly greater increases in heart rate during isoproterenol administration than did the non-cardioselectively blocked group of patients. Heart rate responses to tracheal intubation and surgical stress were not significantly different between the two groups at any point. We conclude that changes in heart rate during perioperative stress are primarily mediated through activation of beta 1 receptors in the myocardium and that patients on either cardioselective or noncardioselective beta-blockers have similar protection to adrenergic-mediated stressful hemodynamic events.

Eighteen patients with normal left ventricular function scheduled for elective myocardial revascularization were anesthetized with fentanyl (52-58 micrograms/kg). At the beginning of hypothermic cardiopulmonary bypass (CPB) they were assigned to a control (C) group (n = 6) that did not receive further anesthesia, or to a group given either 1% isoflurane (n = 6) or 2% isoflurane (n = 6). Blood samples for measurement of total plasma cortisol concentrations were obtained before, during, and after CPB. Hemodynamic measurements before and after CPB were not different among groups. Patients in group C required higher infusion rates of sodium nitroprusside (P less than or equal to 0.05) and patients given 2% isoflurane received more phenylephrine (P less than or equal to 0.05) to keep mean arterial pressure at 50 +/- 10 mm Hg during CPB. Isoflurane caused a dose-related decrease in total plasma cortisol concentrations during and after CPB. We conclude that increased depth of anesthesia attenuates the cortisol (stress) response to cardiopulmonary bypass.