Calcium inhibits the cardiac stimulating properties of dobutamine but not of amrinone.

To contrast the effect of increasing blood calcium concentrations on the cardiovascular actions of intravenous beta-adrenergic agonists and phosphodiesterase inhibitors, 46 patients recovering from aortocoronary bypass surgery received either dobutamine or amrinone both in the presence and absence of a calcium infusion. Cardiac output, systemic arterial pressure, pulmonary arterial pressure, central venous pressure, pulmonary artery occlusion pressure, heart rate, and blood ionized calcium concentration were measured before and during infusions of dobutamine (2.5 and 5.0 micrograms/kg/min) and amrinone (0.75 mg/kg bolus + 10 micrograms/kg/min or 2.25 mg/kg bolus + 20 micrograms/kg/min). After the initial dobutamine infusion period, patients were randomly and blindly assigned to receive either a calcium or placebo infusion, and the dobutamine infusions were repeated. Because of the long duration of amrinone's actions, the amrinone maintenance infusion was continued while randomized, blinded infusion of either calcium or placebo was added. Dobutamine (5 micrograms/kg/min) increased cardiac output from 7.1 +/- 0.3 L/min to 9.1 +/- 0.4 L/min, and increased heart rate from 93 +/- 4 beats/min to 107 +/- 4 beats/min. Systemic vascular resistance decreased and stroke volume increased. Dobutamine had no significant effects on other hemodynamic values. Amrinone (2.25 mg/kg bolus + 20 micrograms/kg/min) increased cardiac output from 5.6 +/- 0.4 L/min to 6.9 +/- 0.5 L/min, and increased heart rate from 87 +/- 3 beats/min to 98 +/- 3 beats/min. Amrinone decreased mean arterial pressure, systemic vascular resistance, pulmonary artery occlusion pressure, central venous pressure, and pulmonary artery pressure. Calcium infusion increased arterial pressure (8 to 13 percent) but had no significant effects on any other hemodynamic parameters. Calcium reduced the increase in cardiac output produced by dobutamine by 30 percent, but it did not alter the cardiotonic actions of amrinone. Thus, calcium inhibits the cardiotonic actions of certain beta-adrenergic agonists, most likely by interfering with signal transduction through the beta-adrenergic receptor complex.

Amrinone in cardiac surgical patients with left-ventricular dysfunction. A prospective, randomized placebo-controlled trial.

STUDY OBJECTIVE: To evaluate the efficacy of amrinone for facilitating weaning from cardiopulmonary bypass (CPB). DESIGN: Prospective, randomized, double-blind, placebo-controlled trial with epinephrine as "rescue" therapy. SETTING: Operating room of a large, metropolitan tertiary-care center. PATIENTS: Thirty-nine patients with preoperative left ventricular dysfunction undergoing cardiac surgery. Thirty-three patients underwent aortocoronary bypass grafting; six patients underwent valve replacement for severe mitral or aortic regurgitation. INTERVENTIONS: Patients received either amrinone (1.5 mg/kg loading dose plus 10 micrograms/kg/min maintenance infusion; n = 20) or placebo (n = 19) in a randomized double-blind fashion shortly (median, 10.5 min; range, 2 to 24 min) before separation from CPB. Inotropic drugs (other than the study drug) were withheld prior to separation from CPB unless safety considerations demanded that the protocol be broken. Patients who could not be weaned from CPB, as well as those with a cardiac index of 2.2 L/min/m2 or less after weaning from CPB, received epinephrine (60 to 120 ng/kg/min) by infusion. MEASUREMENTS AND RESULTS: Fourteen of 19 patients receiving placebo but only 1 of the 20 patients receiving amrinone (p = 0.00001) required epinephrine infusion to separate from bypass. The cardiac index of 4 patients receiving placebo (but no patients with amrinone) failed to exceed 2.2 L/min/m2 despite epinephrine infusion, requiring the protocol to be broken (p < 0.08). Blood concentrations of amrinone determined (only in the amrinone group) after separation from CPB confirmed that the dosage of amrinone produced an effective blood concentration. Fourteen of 19 patients receiving placebo and 17 of 20 patients receiving amrinone required an infusion of phenylephrine titrated to maintain systolic blood pressure less than 90 mm Hg. Seven patients (four with amrinone and three with placebo) required antiarrhythmic drug therapy. The outcome at 3 months was similar in the 2 groups. CONCLUSIONS: Amrinone by itself is an effective agent to facilitate weaning from CPB, and therapy with amrinone reduced the need for individualized titration of epinephrine. Amrinone is as effective as individualized titration of epinephrine (after CPB) to improve cardiac function. Patients in the group receiving amrinone had no greater need for vasoconstricting agents than did patients in the group receiving placebo; however, proactive administration of amrinone before separation from CPB appears to offer no greater benefit to high-risk patients than selective administration of drugs (epinephrine) only to those patients who demonstrate the need for drug support at the time of weaning.

Effects of amrinone on cardiac index, venous oxygen saturation and venous admixture in patients recovering from cardiac surgery.

The hemodynamic and oxygen transport effects of low-dose (0.75 mg/kg loading dose + 10 micrograms/kg/min infusion, n = 12) and high-dose (2.25 mg/kg loading dose + 20 micrograms/kg/min infusion, n = 12) amrinone were evaluated in extubated patients 24 h after CABG. At both doses, amrinone significantly (p less than 0.05) increased HR, but decreased mean arterial, mean pulmonary artery, central venous and pulmonary artery occlusion pressures. High-dose amrinone significantly decreased systemic vascular resistance. Arterial oxygen saturation decreased significantly following both low- (97.8 +/- 0.4 to 95.6 +/- 0.9 percent) and high- (98.8 +/- 3.4 to 93.9 +/- 1.2 percent) dose amrinone. Pulmonary shunt increased significantly following low-dose amrinone and markedly increased Qs/Qt after high-dose amrinone. Although amrinone significantly increased cardiac index in a dose-dependent fashion (low:3.0 +/- 0.2 to 3.3 +/- 0.3 L/min/m2; high:2.7 +/- 0.2 to 3.4 +/- 0.2 L/min/m2), mixed venous oxygen saturation did not change. Thus, mixed venous oxygen saturation may not predict the hemodynamic response to amrinone infusion in postoperative surgical patients.

Relative efficacy and potency of beta-adrenoceptor agonists for generating cAMP in human lymphocytes.

BACKGROUND: Dopexamine and dobutamine are traditionally described as having primarily beta 2-adrenergic agonist properties; norepinephrine is generally classified as beta 1-selective; and epinephrine, isoproterenol, and dopamine are considered mixed beta 1- and beta 2-receptor agonists. Much of this selectivity is designated from studies conducted with intact cardiovascular systems in which indirect actions (eg, norepinephrine release from presynaptic nerve terminals) are not separated from direct agonist-receptor interactions. OBJECTIVE: To assess the relative efficacy and potency of dopamine, dobutamine, dopexamine, epinephrine, isoproterenol, and norepinephrine for directly stimulating cyclic adenosine monophosphate (cAMP) production in human lymphocytes, a model of beta 2-adrenoceptor function. DESIGN: Open-label, prospective paired studies of lymphocytes from nine healthy human volunteers (seven men). SETTING: Experimental laboratory of a large, university-affiliated medical center. INTERVENTIONS: Concentration-response curves were generated for each adrenergic agonist; maximal cAMP production was used to compare efficacy. For the agonists that more than doubled basal cAMP concentrations, EC50 calculations were used to compare potency. MEASUREMENTS AND MAIN RESULTS: Isoproterenol and epinephrine produced the greatest concentrations of cAMP of the agonists tested. cAMP production was increased by isoproterenol at concentrations 1/10 to 1/10,000 that of the other agonists. Norepinephrine stimulated cAMP production only one third as much as epinephrine and isoproterenol, but more than double the level of dopamine, dobutamine, and dopexamine. EC50 concentrations for norepinephrine were 10-fold higher than epinephrine and 50-fold higher than isoproterenol. CONCLUSIONS: Epinephrine and isoproterenol are the most efficacious and potent direct-acting beta 2-adrenergic receptor agonists using this lymphocyte cAMP model. Norepinephrine exhibits significant effects on the beta-receptors on lymphocytes, suggesting beta 2-adrenoceptor effects with high concentrations of this drug. The very low cAMP levels generated by dopamine, dobutamine, and dopexamine (even in high concentrations) support other evidence that these agents have little direct effect on the beta 2-adrenoceptor.

Coronary revascularization in patients with bilateral internal carotid occlusions.

Coronary revascularization that is neurologically uneventful in patients with bilateral totally occluded internal carotid arteries has not been previously reported. We performed saphenous vein coronary artery bypass grafting on three such patients and observed them for 6 to 23 months. Preoperatively two of our patients had chronic stable symptoms of cerebrovascular insufficiency, and one had received cerebral revascularization via a superficial temporal-to-middle cerebral artery bypass. Controversy exists regarding proper cerebral protective maneuvers during coronary revascularization for patients with advanced cerebrovascular disease. Cerebral protection for our patients during cardiopulmonary bypass included hypothermia and high perfusion flows and pressures. Two patients also received prophylactic sodium thiopental. None of these three patients had a stroke perioperatively or during the follow-up period. We believe that these case histories strongly suggest that the functional state of the cerebral collateral circulation, as judged by preoperative neurological symptoms, predicts neurological outcome after coronary revascularization better than the specific occlusive anatomy of the extracranial carotid arteries.

Renal dose dopamine does not alter the response to beta-adrenergic stimulation by isoproterenol in healthy human volunteers.

OBJECTIVES: To determine if renal dose dopamine (3 microg/kg/min) alters the heart rate (HR) by itself, or if a dopamine infusion alters the HR response to bolus doses of the beta-adrenergic agonist isoproterenol in healthy human subjects. DESIGN: Prospective study. SETTING: Clinical laboratory of a university-affiliated academic medical center. SUBJECTS: A total of 15 healthy nonpregnant women and men aged 21 to 44 years. INTERVENTIONS: Subjects were monitored continuously with bedside ECG, pulse oximetry, and ambulatory ECG recording to measure the maximal HR response to separate injections of 10, 20, and 30 ng/kg of isoproterenol, given before, during, and after the infusion of 3 microg/kg/min of dopamine. MEASUREMENTS AND MAIN RESULTS: Dopamine in the absence of isoproterenol did not alter baseline HR significantly (62.7+/-2.2 beats/min without dopamine; 65.4+/-2.2 with dopamine; p=0.15). All three doses of isoproterenol increased HR significantly above baseline, both in the presence and absence of dopamine (p<0.001). Dopamine infusion resulted in a higher HR following isoproterenol only for the 20-ng/kg dose. The incremental increases in HR, defined as the difference between peak HR following isoproterenol and baseline HR, were not increased during dopamine infusion for any of the doses of isoproterenol. Nausea was reported by 5 of the 15 subjects during the dopamine infusion. CONCLUSIONS: In healthy human subjects, infusion of 3 microg/kg/min of dopamine does not significantly increase the HR when combined with beta-adrenergic stimulation using isoproterenol, suggesting neither an additive nor antagonistic interaction between the two drugs. While our study did not demonstrate an increase in HR in healthy subjects, the risk of increasing the chronotropic response to beta-adrenergic inotropic medications with "renal dose" dopamine in critically ill patients needs to be investigated. The frequency of nausea during dopamine infusion also may influence consideration of using dopamine to augment splanchnic blood flow and renal function in conscious patients.

Hemodynamic and renal effects of dopexamine and dobutamine in patients with reduced cardiac output following coronary artery bypass grafting.

OBJECTIVE: Dopexamine hydrochloride is a novel synthetic adrenergic agonist that combines the renal effects of dopamine with the hemodynamic effects of dobutatmine. Our study is designed to compare the hemodynamic, diuretic, and natriuretic effects of dopexamine and dobutamine in patients with reduced cardiac index following heart surgery. DESIGN: Prospectively randomized, blinded study. SETTING: Operating room and intensive care unit of a large, urban, academic medical center. PATIENTS: Twenty-eight patients undergoing elective coronary artery bypass grafting (CABG) with preoperative ejection fraction of at least 40 percent gave informed consent. The study group consisted of the ten patients who had a cardiac index < or = 2.5 L/min/m2 (while receiving no inotropic medication) immediately after separation from cardiopulmonary bypass. INTERVENTIONS AND MEASUREMENTS: Study patients were randomly given a starting dose of either 5 micrograms/kg/min of dobutamine (n = 5) or 2 micrograms/kg/min of dopexamine (n = 5). During the initial 30 min following separation from bypass, dosages were titrated incrementally to maintain cardiac index > or = 3.0/L/min/m2. Further titrations of the drug were done only if cardiac index fell below 3.0 L/min/m2 or if sustained tachycardia occurred during the 24-h study period. Data were collected at 5- and 10-min intervals for the first 30 min after separation from bypass, hourly for the next 8 h, then every 2 h for the remainder of the study period. RESULTS: Both drugs increased cardiac index by more than 50 percent over baseline (dobutamine 2.2 +/- 0.1 to 3.5 +/- 0.2 [p < 0.05]; dopexamine, 2.3 +/- 0.1 to 3.5 +/- 0.1 [p < 0.05] L/min/m2). The mean dose required to maintain cardiac index > or = 3.0L/min/m2 was 1.5 micrograms/kg/min for dopexamine and 3.5 micrograms/kg/min for dobutamine. There were no significant differences in either urinary output or net sodium excretion in the dopexamine group compared with the dobutamine group, and tachycardia (heart rate > 120 beats/min) was more common in the dopexamine group. CONCLUSIONS: Our study demonstrates that dopexamine produces hemodynamic, diuretic, and natriuretic effects similar to dobutamine in patients with reduced cardiac index following CABG.

Pharmacologic cardiovascular support.

The availability of newer and better inotropic agents has led to their widespread application in critically ill medical and surgical patients. Although the elective use of inotropic drugs has been associated with adverse outcomes in patients with cardiomyopathy and chronic heart failure, inotropic drugs used as part of treatment protocols designed to optimize oxygen delivery to tissues have been shown to improve outcome in critical illness. Future research must be aimed toward better definition of clinical settings in which outcome can be improved with inotropes and toward identifying safer agents with fewer adverse side effects.

Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of inotropic need, theoretical concepts of inotropic administration.

Clinical myocardial dysfunction following cardiopulmonary bypass commonly occurs in patients with good preoperative ventricular function. Following separation from cardiopulmonary bypass, ventricular function improves initially, but then begins to worsen and reaches a nadir between 4 and 6 hours after surgery with full recovery occurring around 24 hours postoperatively. However, in patients with preoperative ventricular dysfunction, the depression of ventricular function is more severe and recovery is longer. Despite this high frequency of myocardial dysfunction, many patients do well without requiring pharmacologic intervention after cardiopulmonary bypass to augment contractility and peripheral perfusion. Factors that may predict the need for inotropic support in patients following cardiopulmonary bypass include low ejection fraction, older age, cardiac enlargement, female sex, the length of cardiopulmonary bypass and the duration of aortic cross-clamping. The patient with preoperative ventricular dysfunction has many of these preoperative and intraoperative predictors for inotropic support. The pharmacologic regimen to support the myocardium during the recovery period following cardiopulmonary bypass must take into consideration the pathophysiologic processes of chronic congestive heart failure and reperfusion injury. Reduction of cyclic adenosine monophosphate (cAMP) levels is a fundamental problem in congestive heart failure and results from either down-regulation of beta-receptors or a defect in the G-regulatory proteins controlling adenylyl cyclase production. This diminishes the effectiveness of agents dependent on cAMP to produce an inotropic response. However, amplification of the reduced cAMP produced by beta-agonists may occur in association with the inhibition of cAMP breakdown resulting from phosphodiesterase inhibitors. All inotropic agents are usually effective in reversing the reperfusion-induced stunned myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac conduction interactions of propranolol and verapamil with halothane in pentobarbitone-anaesthetized dogs.

We have studied the effects of propranolol 0.25 mg kg-1 and verapamil 0.075 mg kg-1 on cardiac conduction and refractoriness in 21 dogs anaesthetized with pentobarbitone 30 mg kg-1 using His bundle electrocardiography and programmed stimulation. After baseline studies under pentobarbitone and halothane (1.3 MAC) anaesthesia, the dogs were allocated randomly to two groups: group 1 received verapamil followed by propranolol; group 2 received propranolol followed by verapamil; the drugs were given in a continuous infusion over 10 min. The atrial-His (AH) interval, the atrioventricular node effective (AVERP), and functional (AVFRP) refractory periods, were prolonged by verapamil in both groups, but not the His-ventricle (HV) interval or the ventricular effective refractory period (VERP). AVFRP and VERP were prolonged by propranolol in both groups. Corrected sinus node recovery times were normal after each drug. Heart rate and the rate required to produce Wenckebach were decreased by each drug. The combination of verapamil and propranolol during halothane anaesthesia in dogs has significant cardiac conduction effects; however, no spontaneous AV block occurred during the study.

Sufentanil is preferable to etomidate during rapid-sequence anesthesia induction for aortocoronary bypass surgery.

To evaluate rapid-sequence anesthetic induction techniques for aortocoronary bypass grafting, 20 patients scheduled for elective surgery were randomly assigned to receive bolus injections of either etomidate, 0.4 mg/kg, intravenously (IV), or sufentanil, 5 micrograms/kg, IV, with succinylcholine, 1 mg/kg, IV. Patients in the two groups had similar demographic characteristics and baseline (preinduction) hemodynamic values. Following induction and intubation, 8 of 9 etomidate patients required a pharmacologic intervention to treat hypertension and tachycardia, whereas only 1 of 11 sufentanil patients required additional treatment (P less than 0.001). Three of 9 etomidate patients had ST segment changes of new myocardial ischemia following induction and intubation; two other etomidate patients developed Q waves on their postoperative electrocardiograms, indicative of a perioperative myocardial infarction. No sufentanil patient demonstrated either ischemia or infarction. It is concluded that sufentanil-succinylcholine provides more stable hemodynamics and fewer ischemic myocardial events than etomidate-succinylcholine in patients undergoing myocardial revascularization surgery.

Premedication determines the circulatory responses to rapid sequence induction with sufentanil for cardiac surgery.

Thirty-three patients undergoing elective aortocoronary bypass were allocated randomly to receive morphine 0.1 mg kg-1 i.m. and either lorazepam 50 micrograms kg-1 by mouth or hyoscine 6 micrograms kg-1 i.m. before rapid sequence induction of anaesthesia with sufentanil 5 micrograms kg-1 i.v.and suxamethonium 1 mg kg-1 i.v. Following induction and tracheal intubation, patients premedicated with hyoscine had a significantly higher mean heart rate, mean arterial pressure, cardiac index and left ventricular stroke-work index than patients premedicated with lorazepam. The incidence of new myocardial ischaemia was low in both groups.

Pulmonary artery wedge pressure measurement during experimental pulmonary hypertension: comparison of techniques in relation to catheter-induced hemorrhage.

Two methods of wedging a pulmonary artery catheter were studied in dogs with experimental pulmonary hypertension secondary to left atrial balloon inflation. In Group 1 (N = 8), the catheter tips were located in a branch of the pulmonary artery so that wedge pressures were obtained with balloon inflation. In Group 2 (N = 8), the catheter tips were positioned 1 to 2 cm beyond the pulmonic valve and readvanced into a branch of the pulmonary artery for each wedge pressure determination. In both groups, wedge pressures were obtained using a balloon inflation volume of 0.8 mL. With left atrial hypertension, the pressure gradient across the inflated balloon (calculated as mean pulmonary artery pressure minus pulmonary artery wedge pressure) was lower than baseline (P < .05). Wedge pressures were determined every five minutes. After two hours, the lungs were removed and studied grossly for hemorrhage. The incidence of pulmonary hemorrhage was 50% in Group 1 dogs, but 0% in Group 2 dogs (P < .03). It is concluded that locating the catheter tip in the proximal pulmonary artery and readvancing it for each wedge pressure determination significantly reduces the risk of catheter-induced pulmonary hemorrhage in this model.

Factors that predict the use of positive inotropic drug support after cardiac valve surgery.

UNLABELLED: Left ventricular dysfunction is common after cardiac surgery and is often treated with positive inotropic drugs (PIDs). We hypothesized that the use of PIDs after cardiac valve surgery would have significant associations with the valvular pathophysiology and surgical procedure, and unlike the case for patients undergoing coronary artery surgery, would be unrelated to duration of cardiopulmonary bypass (CPB) or of aortic clamping. One hundred forty-nine consenting patients undergoing cardiac valve surgery were studied. Patients with hepatic or renal failure, or New York Heart Association class IV cardiac symptoms, were excluded. Patients were considered to have received PIDs if they received an infusion of amrinone, dobutamine, epinephrine, or dopamine (> or = 5 microg x kg[-1] x min[-1]). PIDs were received by 78 patients (52%). In a univariate model, older age, history of congestive heart failure, decreasing left ventricular ejection fraction, longer durations of CPB, and concurrent coronary artery surgery significantly increased the likelihood of PID support. There was also significant variation by anesthesiologist in the administration of PIDs. The specific diseased valve and valvular stenosis or insufficiency did not influence the likelihood of receiving PID support. In a multivariable model, age, history of congestive heart failure, decreasing left ventricular ejection fraction, and anesthesiologist were significantly associated with the likelihood of PID support, but duration of CPB and concurrent coronary artery surgery were not. In conclusion, patient age and ventricular function, as well as physician preferences, predicted the need for inotropic drug support; however, neither the specific valvular lesion, nor duration of CPB were strongly predictive in a multivariable model. IMPLICATIONS: We evaluated factors related to use of positive inotropic drugs after cardiac valve surgery. The likelihood of a patient receiving these drugs increases with advancing age and with more severe preoperative left ventricular dysfunction, but was not influenced by the specific diseased valve or the duration of cardiopulmonary bypass.

Cardiopulmonary effects of hypertonic saline in canine oleic acid-induced pulmonary edema.

Vasoactive drugs may increase intrapulmonary shunt in patients with permeability edema. Because 7.5% hypertonic saline solution has cardiotonic properties, we studied its hemodynamic and pulmonary effects in a canine model of oleic acid-induced lung injury. Immediately after saline infusion, there were increases in cardiac output (2.0 +/- 0.1 to 3.4 +/- 0.2 L/min; p less than .001) and intrapulmonary shunt (50.3 +/- 4.4 to 57.3 +/- 3.2%; p less than .01) without alteration in arterial or mixed venous oxygen tension. Although arterial oxygen content decreased from 16.4 +/- 1.1 to 14.4 +/- 0.9 ml/dl (p less than .001), paralleling the change in hemoglobin concentration, oxygen delivery to the tissues increased from 327 +/- 23 to 486 +/- 36 ml/min (p less than .001). These effects were transient, inasmuch as all values returned to preinfusion levels within 30 min. Tissue oxygen consumption increased proportionately with cardiac output, and the directional change in arterial oxygenation was similar to the change in mixed venous oxygen tension. We conclude that tissue oxygen delivery improves after hypertonic saline infusion despite changes in intrapulmonary shunt and oxygen consumption. However, any benefit appears to be transient.

Efficacy of noninvasive transcutaneous cardiac pacing patients undergoing cardiac surgery.

Noninvasive transcutaneous cardiac pacing (NTP) is a rapid, safe, and easily utilized form of emergency cardiac pacing, with hemodynamics similar to right ventricular endocardial pacing. Although the technique has proven effective for hemodynamically significant bradycardias and early use during cardiopulmonary resuscitation, NTP under anesthetic conditions has been poorly characterized. In particular, it is unknown to what degree the multiple physiologic perturbations of cardiac surgery and cardiopulmonary bypass (CPB) affect myocardial thresholds and the efficacy of the unit itself. Patients undergoing procedures utilizing CPB (n = 23) were studied in an effort to address these issues. All patients were able to be paced at all points throughout the 24-h study interval, although four patients developed hemodynamic instability during this period causing their exclusion from additional investigation. Only one patient requested discontinuation from the study due to discomfort. A statistically significant increase in mean current requirements for capture was demonstrated over time (P less than 0.0001), with baseline thresholds being significantly less than other study points (P less than or equal to 0.05). Thresholds following chest wall closure were significantly greater than all other study points (P less than or equal to 0.05), possibly due to accumulation of pericardial and mediastinal air. Multiple measured variables changed significantly during the study, but only increases in cardiac output and core temperature were related to statistically significant increases in current thresholds (P less than or equal to 0.05). Increasing age and pump time were of borderline importance. NTP represents an effective pacing alternative in cardiac surgical patients.

A pharmacokinetic and pharmacodynamic evaluation of milrinone in adults undergoing cardiac surgery.

Milrinone can reverse acute postischemic myocardial dysfunction after cardiopulmonary bypass, although neither the appropriate bolus dose nor its pharmacokinetics has been established for cardiac surgical patients. Consenting patients undergoing cardiac surgery received milrinone (25, 50, or 75 micrograms/kg) in an open-label, dose-escalating study if their cardiac index was < 3 L.min-1.m-2 after separation from bypass. Heart rate, mean arterial blood pressure, pulmonary capillary wedge pressure, and cardiac index were determined before and after the administration of milrinone. Timed blood samples were obtained for measurement of milrinone plasma concentrations and pharmacokinetic analysis. Twenty-nine of 60 consenting patients had cardiac indices < 3 L.min-1.m-2 after separation from bypass, received milrinone, and completed the protocol. All three bolus doses of milrinone significantly increased cardiac index. The 50- and 75-micrograms/kg doses produced significantly larger increases in cardiac index than the 25-micrograms/kg dose; however, the 75-micrograms/kg dose did not produce a significantly larger increase in cardiac index than did the 50-micrograms/kg dose. Two of 10 patients receiving milrinone 25 micrograms/kg, but no patient receiving either 50 or 75 micrograms/kg, required early epinephrine rescue when the cardiac index failed to increase by > 15%. The 75-micrograms/kg dose was associated with a case of ventricular tachycardia. The three-compartment model better described milrinone drug disposition than the two-compartment model by both visual inspection and Schwartz-Bayesian criterion. There was only limited evidence of dose-dependence, so data from all three doses are reported together (and normalized to the 50-micrograms/kg dose). Data from one patient was discarded (samples mislabeled). Using mixed-effects nonlinear regression (for n = 28), the following volumes were determined for the three compartments: V1 = 11.1 L, V2 = 16.9 L, and V3 = 363 L. Similarly, the following clearances were estimated for the three compartments: Cl1 = 0.067 L/min, Cl2 = 1.05 L/min, and Cl3 = 0.31 L/min. The 50-micrograms/kg loading dose appeared more potent than the 25-micrograms/kg dose, and, as potent, but with possibly fewer side-effects than the 75-micrograms/kg dose. The short context-sensitive half-times of 6.7 or 10.2 min after 1- or 10-min bolus infusions underscore the need for prompt institution of a maintenance infusion when milrinone concentrations must be maintained.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiac electrophysiologic effects of fentanyl and combinations of fentanyl and neuromuscular relaxants in pentobarbital-anesthetized dogs.

The effects of fentanyl, both alone and in combination with pancuronium bromide or succinylcholine, on atrioventricular (AV) node and ventricular conduction times and refractory periods were studied. Twenty-four pentobarbital-anesthetized dogs were instrumented both with an intraaortic catheter to measure cardiac conduction times and, through a thoracotomy, with atrial and ventricular epicardial pacing electrodes to provide premature stimulation that would allow measurement of atrial and ventricular refractoriness. Fentanyl prolonged the RR interval in both low- (100 micrograms/kg) and high-dose (400 micrograms/kg) groups by 26 and 45%, respectively, and prolonged AV node conduction time by 28 and 25%, respectively. During atrial pacing at a rate sufficient to capture the atria, AV node conduction time lengthened in the low- and high-dose groups by 27 and 25%, respectively. Fentanyl also significantly lengthened AV node effective and functional refractory periods and ventricular effective refractory periods in both groups. Pancuronium (0.1 mg/kg) administered after fentanyl shortened RR intervals in the low- and high-dose groups by 14 and 22%, respectively, and shortened AV conduction times by 18 and 20%, respectively, but did not restore all values to baseline. Pancuronium significantly shortened AV node refractory periods in the low-dose but not the high-dose group. When administered after fentanyl, succinylcholine (2 mg/kg) significantly shortened the RR interval in the low- and high-dose groups by 14 and 12%, respectively. Succinylcholine shortened AV node conduction slightly but without significance and had no effect on cardiac refractoriness. His-Purkinje conduction remained unaffected by any drug intervention. These data demonstrate that fentanyl depresses cardiac conduction; subsequent administration of pancuronium and succinylcholine partially reverses this effect.

High-frequency jet ventilation produces auto-PEEP.

Positive-pressure ventilation can increase dead space by trapping gas, especially at high frequencies. Under conditions of high airway resistance and high pulmonary compliance, gas trapping can increase alveolar pressure without affecting proximal airway pressure, due to impedance to expiratory gas flow. The difference between alveolar pressure and proximal airway pressure at end-expiration has been called auto-PEEP. Using a mechanical test lung, we altered compliance and resistance under a variety of high-frequency jet ventilator settings to evaluate the generation of auto-PEEP. High driving pressures and prolonged inspiratory times significantly increased gas trapping. This effect was most pronounced when both airway resistance and pulmonary compliance were elevated. These findings support the concept that high-frequency jet ventilation (HFJV) may have deleterious side-effects in patients with chronic obstructive pulmonary disease.