Less isoflurane is required after than before cardiopulmonary bypass to maintain a constant bispectral index value.

OBJECTIVE: To test whether patients require less volatile anesthetic after cardiopulmonary bypass (CPB). DESIGN: Prospective, observational clinical study. SETTING: Cardiovascular operating rooms of a large teaching hospital. PARTICIPANTS: Twenty adult patients undergoing surgery with CPB. INTERVENTIONS: Subjects received a computer-controlled fentanyl infusion designed to maintain effect site concentrations of 3 ng/mL, combined with a variable amount of isoflurane. MEASUREMENTS AND MAIN RESULTS: The end-tidal isoflurane concentration associated with a target bispectral index of 55 was recorded during skin preparation, after sternotomy, during rewarming, and after separation from CPB. Adjusted, geometric mean (95% confidence intervals), end-tidal isoflurane concentrations associated with a bispectral index of 55 were 0.46% (0.38% to 0.58%) during skin preparation, 0.47% (0.39% to 0.58%) after sternotomy, 0.35% (0.29% to 0.42%) during rewarming, and 0.36% (0.31% to 0.43%) after separation from CPB. The last 2 concentrations (recorded near the end and after CPB) were significantly (p < 0.05) less than the first 2 concentrations (recorded before CPB). CONCLUSION: Because the level of surgical stimulation was relatively constant and minimal at the times of the measurements, these results are consistent with a reduced need for isoflurane after compared with before CPB.

Pharmacokinetics of dopamine in healthy male subjects.

BACKGROUND: Dopamine is an agonist of alpha, beta, and dopaminergic receptors with varying hemodynamic effects depending on the dose of drug being administered. The purpose of this study was to measure plasma concentrations of dopamine in a homogeneous group of healthy male subjects to develop a pharmacokinetic model for the drug. Our hypothesis was that dopamine concentrations can be predicted from the infusion dose using a population-based pharmacokinetic model. METHODS: Nine healthy male volunteers aged 23 to 45 yr were studied in a clinical research facility within our academic medical center. After placement of venous and arterial catheters, dopamine was infused at 10 microg x kg(-1) x min(-1) for 10 min, followed by a 30-min washout period. Subsequently, dopamine was infused at 3 microg x kg(-1) x min(-1) for 90 min, followed by another 30-min washout period. Timed arterial blood samples were centrifuged, and the plasma was analyzed by high-performance liquid chromatography. Mixed-effects pharmacokinetic models using NONMEM software (NONMEM Project Group, University of California, San Francisco, CA) were used to determine the optimal compartmental pharmacokinetic model for dopamine. RESULTS: Plasma concentrations of dopamine varied from 12,300 to 201,500 ng/l after 10 min of dopamine infusion at 10 microg x kg(-1) x min(-1). Similarly, steady-state dopamine concentrations varied from 1,880 to 18,300 ng/l in these same subjects receiving 3-microg x kg(-1) x min(-1) infusions for 90 min. A two-compartment model adjusted for body weight was the best model based on the Schwartz-Bayesian criterion. CONCLUSIONS: Despite a homogeneous population of healthy male subjects and weight-based dosing, there was 10- to 75-fold intersubject variability in plasma dopamine concentrations, making standard pharmacokinetic modeling of less utility than for other drugs. The data suggest marked intraindividual and interindividual variability in dopamine distribution and/or metabolism. Thus, plasma dopamine concentrations in patients receiving dopamine infusion at identical rates may vary profoundly. Our data suggest that dosing dopamine based on body weight does not yield predictable blood concentrations.

Comparison of a prototype esophageal oximetry probe with two conventional digital pulse oximetry monitors in aortocoronary bypass patients.

OBJECTIVE: Pulse oximetry (SpO2) is the non-invasive standard for monitoring arterial oxygen saturation in patients undergoing anesthesia, but is subject to external interference by motion artifact, peripheral vasoconstriction, and low cardiac output. We hypothesized that oximetry signals could be acquired from the esophagus when peripheral pulse oximetry is unobtainable. Therefore, we tested an esophageal stethoscope which incorporates transverse oximetry photodetectors and emitters in patients undergoing coronary bypass surgery. METHODS: Immediately after induction of general anesthesia in 10 coronary artery bypass (CABG) patients, Criticare and Nellcor digital probes were positioned on the left hand, concurrent with placement of an esophageal SpO2 probe. A computer recorded 5,910 matched oximetry signals every 15 sec during an average of 2.5 hrs. All SpO2 measurements were before, and immediately after non-pulsatile, hypothermic cardiopulmonary bypass. Data represent the percentage (median value [range]) of the total monitored time that a SpO2 value was displayed. RESULTS: The Nellcor (99.8%, range 6.5-100%) and Criticare (99.7%, range 36.6-100%) acquired and displayed saturation signals more frequently (p = 0.003) than the esophageal monitor (75.3%, range 42.1-95.8%). The two standard digital oximeters had a mean difference of 0.9%, with a standard deviation of the differences of 0.9. The esophageal probe had a mean difference of -5.2% and -4.8%, with standard deviation of differences of 8.0 and 7.7 (compared to the Nellcor and Criticare monitors, respectively). A second-generation prototype shielded from electrocautery interference was tested in an additional 4 patients. The shielded prototype displayed signals more frequently (96.7%, range 68.4-100%) than the original esophageal prototype. CONCLUSIONS: Digital pulse oximetry failure is common in CABG patients, probably because of marginal cardiac output and peripheral vasoconstriction associated with hypothermia. Our study could not confirm that esophageal technology, which utilizes the esophagus as a site of transflectance oximetry, was superior to conventional digital pulse oximetry.

Plasma bupivacaine concentrations and effects of epinephrine after superficial cervical plexus blockade in patients undergoing carotid endarterectomy.

OBJECTIVE: To determine if epinephrine (EPI) added to a solution of bupivacaine (BUP) injected for use in superficial cervical plexus blockade (SCPB) lowers plasma BUP concentrations after injection and whether this addition of EPI resulted in tachycardia, cardiac arrhythmias, or both. DESIGN: Randomized, unblinded prospective clinical interventional study. PARTICIPANTS: Patients scheduled to undergo carotid endarterectomy using SCPB consenting to study. SETTING: University-affiliated tertiary care hospital operating room. INTERVENTIONS: Twenty patients were given SCPB with BUP 0.5% and were randomized to receive either no EPI or 1:300,000 EPI. This study block was followed by a second period in which 20 patients were given SCPB with BUP 0.25% randomized to receive either no EPI or 1:300,000 EPI. Continuous electrocardiogram monitoring was performed during and after the block and analyzed for heart rate and rhythm changes. MEASUREMENTS AND MAIN RESULTS: Arterial plasma BUP concentrations were measured 2.5 to 120 minutes after initiation of SCPB. Plasma BUP concentrations were highest in the 0.5% no EPI group, followed by the 0.5% EPI, 0.25% no EPI, and 0.25% EPI groups. The use of EPI did not significantly affect heart rate or change the incidence of cardiac arrhythmias. CONCLUSIONS: BUP 0.25% consistently produced the lowest plasma BUP concentrations, particularly when EPI was added to the solution. BUP 0.5% without EPI can produce plasma BUP concentrations previously reported to be associated with central nervous system effects. The use of EPI in this setting does not produce untoward cardiac side effects.

Effects of cardiopulmonary bypass and deep hypothermic circulatory arrest on the thyroid axis during and after repair of congenital heart defects: preservation by deep hypothermia?

UNLABELLED: Thyroid function is altered by cardiopulmonary bypass (CPB) in children. To better understand the cause of altered thyroid hormone levels, we compared the effects on the pituitary-thyroid axis of CPB in 23 children undergoing elective repair of congenital heart defects. Twelve patients underwent CPB with moderate hypothermia without a period of deep hypothermic circulatory arrest (DHCA), and eleven underwent CPB with DHCA. Nine blood samples were collected from each patient before, during, and after CPB. Free T3 (FT3), free T4 (FT4), total T3 (TT3), total T4 (TT4), thyrotropin (TSH), and albumin were measured; concentrations of each decreased significantly with the onset of CPB (P < 0.05). There was a greater decline in hormone than in albumin concentrations, which suggests that factors in addition to hemodilution were present (P < 0.05). TSH concentrations in the DHCA group began to increase during cooling, exceeding baseline values after rewarming and after separation from CPB. Patients undergoing CPB without DHCA had persistently low TSH concentrations (P < 0.05). By Postoperative Days 1 and 2, TSH concentrations in both groups were similar and significantly lower than baseline values (P < 0.001). FT3, FT4, TT3, TT4, and albumin all increased during CPB after an initial decrease. Of these, only albumin and FT4 recovered to their baseline values after the initial decrease. Nevertheless, by Postoperative Day 1, both groups demonstrated the "sick" euthyroid syndrome and could not be distinguished from one another. This study demonstrates greater pituitary release of TSH in children undergoing repair of congenital heart defects with DHCA compared with CPB alone, the cause of which could not be determined in this study. However, despite the increase in TSH in the DHCA group, the thyroid hormone concentrations failed to increase appropriately. IMPLICATIONS: Early after deep hypothermia circulatory arrest, thyrotopin concentrations increase appropriately, responding to decreased concentrations of T3; however, all children undergoing cardiopulmonary bypass eventually develop a "sick" euthyroid syndrome by Postoperative Day 1. Whether this difference represents better protection of neuroendocrine function by deep hypothermic circulatory arrest (relative to cardiopulmonary bypass alone) remains speculative.

Dobutamine antagonizes epinephrine's biochemical and cardiotonic effects: results of an in vitro model using human lymphocytes and a clinical study in patients recovering from cardiac surgery.

BACKGROUND: Patients may receive more than one positive inotropic drug to improve myocardial function and cardiac output, with the assumption that the effects of two drugs are additive. The authors hypothesized that combinations of dobutamine and epinephrine would produce additive biochemical and hemodynamic effects. METHODS: The study was performed in two parts. Phase 1 used human lymphocytes in an in vitro model of cyclic adenosine monophosphate (cAMP) generation in response to dobutamine (10(-8) to 10(-4) M) or epinephrine (10(-9) M to 10(-5) M), and dobutamine and epinephrine together. Phase 2 was a clinical study in patients after aortocoronary artery bypass in which isobolographic analysis compared the cardiotonic effects of dobutamine (1.25, 2.5, or 5 microg x kg(-1) x min(-1)) or epinephrine (10, 20, or 40 ng x kg(-l) x min(-1)), alone or in combination. RESULTS: In phase 1, dobutamine increased cAMP production 41%, whereas epinephrine increased cAMP concentration approximately 200%. However, when epinephrine (10(-6) M) and dobutamine were combined, dobutamine reduced cAMP production at concentrations between 10(-6) to 10(-4) M (P = 0.001). In patients, 1.25 to 5 microg x kg(-1) x min(-1) dobutamine increased the cardiac index (CI) 15-28%. Epinephrine also increased the CI with each increase in dose. However, combining epinephrine with the two larger doses of dobutamine (2.5 and 5microg x kg(-1) x mi(-1)) did not increase the CI beyond that achieved with epinephrine and the lowest dose of dobutamine (1.25 microg x kg(-1) x min(-1)). In addition, the isobolographic analysis for equieffective concentrations of dobutamine and epinephrine suggests subadditive effects. CONCLUSIONS: Dobutamine inhibits epinephrine-induced production of cAMP in human lymphocytes and appears to be subadditive by clinical and isobolographic analyses of the cardiotonic effects. These findings suggest that combinations of dobutamine and epinephrine may be less than additive.

A multicenter, randomized, blind comparison of amrinone with milrinone after elective cardiac surgery.

UNLABELLED: Amrinone and milrinone are phosphodiesterase inhibitors with positive inotropic effects useful for the treatment of ventricular dysfunction after cardiac surgery. Forty-four patients undergoing elective cardiac surgery at four centers received either amrinone (n = 22) or milrinone (n = 22) in a randomized, blind fashion. Immediately after separation from cardiopulmonary bypass (CPB), two bolus doses of either amrinone 0.75 mg/kg or milrinone 25 microg/kg were administered over 30 s, separated by 5 min. Hemodynamic measurements were recorded before each dose and at the end of the 10-min study. Both amrinone and milrinone increased the cardiac index (48% vs 52%, P = not significant [NS] for amrinone and milrinone, respectively). There was a small increase in mean arterial pressure (MAP) after amrinone administration (from 68 +/- 3 to 72 +/- 3 mm Hg at 10 min, P < 0.05) with no significant change in MAP after milrinone administration. Central venous pressure was significantly higher in the amrinone group at baseline and 5 min (12 vs 10 mm Hg and 11 vs 10 mm Hg, respectively; P < 0.05). Systemic and pulmonary vascular resistances decreased significantly and to a similar extent after either amrinone or milrinone administration. Phenylephrine was required in 11 of 22 patients receiving amrinone and in 11 of 22 patients receiving milrinone to maintain arterial blood pressure. The proportion of patients requiring an intravascular volume infusion (15 of 22 vs 17 of 22, P = NS) and the total fluid volume infused were similar (402 +/- 57 vs 350 +/- 49 mL, P = NS for amrinone and milrinone, respectively). Amrinone and milrinone seem to have similar hemodynamic effects after CPB, with the exception of blood pressure, although the need for vasopressor support of blood pressure did not differ. Selection between these two drugs may include nonhemodynamic considerations such as cost. IMPLICATIONS: Amrinone and milrinone are drugs that improve cardiac contraction. Their effects have never been directly compared in patients. We found that amrinone and milrinone produced similar hemodynamic effects in adult patients undergoing cardiac surgery. Choice between the two drugs can be based on nonhemodynamic considerations such as cost.

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.

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.

Rocuronium versus succinylcholine for rapid-sequence induction using a variation of the timing principle.

STUDY OBJECTIVE: To determine if, using a variation of the "timing" principle, 0.6 mg/kg of rocuronium can achieve an onset time and intubating conditions similar to those achieved with succinylcholine. STUDY DESIGN: Prospective, randomized, double-blind clinical comparison. SETTING: Operating room in a university medical center. PATIENTS: 42 ASA physical status I and II patients undergoing general anesthesia for elective surgery. INTERVENTIONS: All patients were fitted with a Grass FT-10 force transducer attached to the thumb. Supramaximal stimulation was applied to the ulnar nerve with a variable current peripheral nerve stimulator. 22 patients (succinylcholine group) received a placebo bolus injection followed 20 seconds later by thiopental 4 to 5 mg/kg and succinylcholine 1 mg/kg; 20 additional patients (rocuronium group) received a bolus dose of rocuronium 0.6 mg/kg followed 20 seconds later by thiopental 4 to 5 mg/kg and a placebo bolus injection. MEASUREMENTS AND MAIN RESULTS: We measured the onset time from administration of the muscle relaxant to 95% twitch reduction and assessed the quality of intubating conditions 60 seconds after the induction of anesthesia. There was a significant difference in the mean onset time of rocuronium (72 sec) versus succinylcholine (42 sec, p < 0.0001). However, there was no significant difference in intubating conditions 60 seconds after administration of thiopental. CONCLUSION: Rocuronium given 20 seconds prior to thiopental provides intubating conditions equivalent to thiopental-succinylcholine for rapid-sequence inductions, circumventing rocuronium's longer onset time to 95% neuromuscular blockade.

Treatment of hypotension after hyperbaric tetracaine spinal anesthesia. A randomized, double-blind, cross-over comparison of phenylephrine and epinephrine.

BACKGROUND: Despite many advantages, spinal anesthesia often is followed by undesirable decreases in blood pressure, for which the ideal treatment remains controversial. Because spinal anesthesia-induced sympathectomy and management with a pure alpha-adrenergic agonist can separately lead to bradycardia, the authors hypothesized that epinephrine, a mixed alpha- and beta-adrenergic agonist, would more effectively restore arterial blood pressure and cardiac output after spinal anesthesia than phenylephrine, a pure alpha-adrenergic agonist. METHODS: Using a prospective, double-blind, randomized, cross-over study design, 13 patients received sequential infusions of epinephrine and phenylephrine to manage hypotension after hyperbaric tetracaine (10 mg) spinal anesthesia. Blood pressure, heart rate, and stroke volume (measured by Doppler echocardiography using the transmitral time-velocity integral) were recorded at baseline, 5 min after injection of tetracaine, and before and after management of hypotension with epinephrine and phenylephrine. Cardiac output was calculated by multiplying stroke volume x heart rate. RESULTS: Five min after placement of a hyperbaric tetracaine spinal anesthesia, significant decrease in systolic (from 143 +/- 6 mmHg to 125 +/- 5 mmHg; P < 0.001), diastolic (from 81 +/- 3 to 71 +/- 3; P < 0.001), and mean (from 102 +/- 4 to 89 +/- 3; P < 0.001) arterial pressures occurred. Heart rate (75 +/- 4 beats/min to 76 +/- 4 beat/min; P = 0.9), stroke volume (115 +/- 17 to 113 +/- 13; P = 0.9), and cardiac output (8.0 +/- 1 l/m to 8.0 +/- 1l/m; P = 0.8) did not change significantly after spinal anesthesia. Phenylephrine was effective at restoring systolic blood pressure after spinal anesthesia (120 +/- 6 mmHg to 144 +/- 5 mmHg; P < 0.001) but was associated with a decrease in heart rate from 80 +/- 5 beats/min to 60 +/- 4 beats/min (P < 0.001) and in cardiac output from 8.6 +/- 0.7 l/m to 6.2 +/- 0.7 l/m (P < 0.003). Epinephrine was effective at restoring systolic blood pressure after spinal anesthesia (119 +/- 5 mmHg to 139 +/- 6 mmHg; P < 0.001) and was associated with an increase in stroke volume from 114 +/- 12 ml to 142 +/- 17 (P < 0.001) and cardiac output from 7.8 +/- 0.6 l/m to 10.8 +/- 1.1 l/m (P < 0.001). CONCLUSIONS: Epinephrine management of tetracaine spinal-induced hypotension increases heart rate and cardiac output and restores systolic arterial pressure but does not restore mean and diastolic blood pressure. Phenylephrine management of tetracaine spinal-induced hypotension decreases heart rate and cardiac output while restoring systolic, mean, and diastolic blood pressure.

Pharmacodynamics and pharmacokinetics of milrinone administration to increase oxygen delivery in critically ill patients.

OBJECTIVES: The positive inotropic and vasodilator actions of phosphodiesterase (PDE) inhibitor drugs may offer therapeutic alternatives to beta-agonists in critically ill patients. We hypothesized that milrinone administration would increase cardiac index (CI) and oxygen delivery (Do2) in ICU patients, and that a pharmacokinetic model previously developed in cardiac surgery patients may be used to predict milrinone plasma concentrations in a medical-surgical ICU population. SETTING: ICU in two tertiary-care, university medical centers. DESIGN AND INTERVENTIONS: A prospective, open-label, multicenter, dose-escalating study in three successive groups of eight ICU patients who received a 10-min loading dose of milrinone (25 micrograms/kg [LOW], 50 micrograms/kg [MED], and 75 micrograms/kg [HIGH]). In addition, all patients then received a milrinone infusion of 0.5 microgram/kg/min for 1 h. MEASUREMENTS: Hemodynamic measurements included heart rate (HR); mean arterial, pulmonary artery, central venous, and pulmonary artery occlusion pressures; and thermodilution cardiac output. Oxygen transport indexes included arterial and venous blood oxygen tensions to determine Do2 and oxygen consumption (Vo2). Data were analyzed by univariate repeated measures analysis of covariance, with baseline values utilized as covariate regressors. RESULTS: Twenty-four adult ICU patients 20 to 84 years of age completed the study. The three groups did not differ, except that the patients in the MED group were significantly older (67 +/- 4 years, mean +/- SEM) compared with either the patients in the LOW (48 +/- 7 years) or HIGH (47 +/- 6 years) group. While HR did not change in the LOW group (90 +/- 4 to 93 +/- 3 beats/min), HR increased significantly in the HIGH group (94 +/- 5 to 112 +/- 8 beats/min) (baseline to 60 min infusion time points). All milrinone doses increased both CI and Do2. At the end of the 10-min loading dose, CI increased 0.3 L/min/m2 in the LOW group, 1.1 L/min/m2 in the MED group, and 0.9 L/min/m2 in the HIGH group. Do2 increased 8% in the LOW group, 33% in the MED group, and 23% in the HIGH group, similar to the changes in CI. Mixed venous oxygen saturation increased 3 to 5% during the 10-min loading dose of milrinone. During this same time period, mean arterial pressure decreased 6 to 16% and pulmonary artery pressures decreased 9 to 15%. Peak plasma milrinone concentrations increased as a function of the loading dose (159 +/- 9 ng/mL in the LOW group, 302 +/- 33 ng/ml in the MED group, and 411 +/- 45 ng/mL in the HIGH group). However, milrinone concentrations were similar in all three groups after the 1-h infusion; 113 +/- 14 ng/ml (LOW), 147 +/- 22 ng/mL (MED), and 119 +/- 14 ng/ml (HIGH). In all patients with final plasma milrinone concentrations greater than 100 ng/mL (15/23), the CI increased by at least 0.4 L/min/m2 (range, 0.4 to 1.8 L/min/m2). CONCLUSIONS: Our study confirms that a milrinone loading dose of 50 micrograms/kg/min followed by an infusion of 0.5 microgram/kg/min achieves adequate plasma concentrations of 100 ng/mL or greater, which significantly increases both CI and Do2. In addition, a previously established pharmacokinetic model of milrinone disposition is confirmed in this mixed ICU population.

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.

Effect of pH and lidocaine on beta-adrenergic receptor binding. Interaction during resuscitation?

Epinephrine and other beta-adrenergic receptor (beta AR) agonists are often administered during cardiopulmonary resuscitation, a time when acid-base abnormalities and arrhythmias also commonly occur. We tested whether beta 2AR binding is influenced by pH or the antiarrhythmic drug lidocaine, and whether pH might influence the interaction of lidocaine with beta 2ARs. With institutional review board approval and informed consent, 32 venous blood samples were obtained from volunteers. Lymphocytes (which bear beta 2ARs similar to those found in heart) were isolated by density gradient centrifugation. Specific binding of the beta AR ligand 3H-dihydroalprenolol (3H-DHA) was determined with lidocaine concentrations ranging from 10(-6) to 10(-2) mol/L (n = 18 experiments), and with and without lidocaine (n = 10 experiments), 100 mumol/L, and with and without QX314 (a permanently charged lidocaine derivative), 1 mmol/L (n = 4 experiments). Data are presented as percent of control-specific binding measured at a pH of 7.4. Statistical analysis consisted of Spearman's rank-test. 3H-DHA-specific binding increased (p < .001) with pH. Thus, alkaline conditions favored binding of 3H-DHA to the receptor. Lidocaine inhibited 3H-DHA binding to beta 2ARs in a concentration-dependent manner. The concentration that inhibited specific binding of 3H-DHA by 50% was 3.1 x 10(-4) mol/L (95% confidence limits, 1.3 x 10(-4) to 7.5 x 10(-4) mol/L). Lidocaine potency at inhibiting beta 2AR binding also increased with increasing pH; thus, there was limited benefit (in terms of increasing binding to beta 2ARs) to increasing pH when lidocaine was present. QX314, despite being present in a 10-fold greater concentration than lidocaine, had no effect on 3H-DHA binding at any tested pH. The affinity of beta 2 ARs for both 3H-DHA and lidocaine increased with pH. Thus, the response to beta 2AR agonists (when no lidocaine is present) might be expected to be greater with normal or alkalotic pH than under acidotic conditions, supporting the correction of metabolic acidosis to achieve optimal effects from beta 2AR agonists during resuscitation.

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)

Sodium nitroprusside: twenty years and counting.

SNP remains an effective, reliable, and commonly used drug for the rapid reduction of significant arterial hypertension regardless of the etiology, for afterload reduction in the face of low CO when blood volume is normal or increased, and for intraoperative induced hypotension. After establishing indwelling arterial monitoring, an initial infusion rate of 0.3-0.5 micrograms.kg-1.min-1 is begun with titration as needed up to 2.0 micrograms.kg-1.min-1. Higher rates for brief periods of time (10 min) are acceptable. The use of alternative drugs to reduce the dose or shorten the duration of infusion should be considered when the 2.0 micrograms.kg-1.min-1 range is exceeded (Table 1). SNP should not be used by individuals unfamiliar with its potency and metabolic pathways, as the many reports of adverse reactions testify. Careful attention to infusion rates, particularly in patients at risk for depleted thiosulfate stores, is mandatory, and the use of other drugs in conjunction with or instead of SNP should always be considered. As with many therapeutic interventions, SNP requires careful administration to appropriately selected patients by a clinician who knows its inherent hazards. Despite its toxicity, SNP is popular because it is often the most (in some cases, the only) effective drug in some difficult clinical circumstances.

Magnesium antagonizes the actions of lysophosphatidyl choline (LPC) in myocardial cells: a possible mechanism for its antiarrhythmic effects.

Patients with cardiac arrhythmias, ischemia, and infarction may benefit from administration of supplemental magnesium. However, the exact mechanisms for magnesium's beneficial effects remain unknown. Lysophosphatidyl choline (LPC), an amphipathic phospholipid released from cardiac cell membranes during ischemia, increases free intracellular calcium concentrations ([Ca]i) and has been implicated as a cause of cardiac arrhythmias and coronary artery spasm during myocardial ischemia. We postulated that magnesium acts by inhibiting cellular calcium overload induced by mediators such as LPC. Myocardial cells from male Sprague-Dawley rats were isolated from ventricular tissue samples and [Ca]i determined using the fluorescent dye, fura-2/acetoxymethyl ester, measured in a spectrofluorometer. The increase in [Ca]i after exposure to 100 and 200 microM LPC was recorded in cells suspended in modified Dulbecco's phosphate buffered saline solution with 0.2, 2.0, and 20 mM magnesium chloride. Differences were determined by analysis of variance with P < 0.05 considered significant. LPC significantly increased [Ca]i in the 100 microM (506 +/- 76 nM) and 200 microM (675 +/- 81 nM) concentrations, compared to baseline (301 +/- 25 nM). MgCl2 at both the 2.0 and 20 mM concentrations significantly blunted the increase in [Ca]i in myocardial cells exposed to LPC, whereas 0.2 mM MgCl2 was ineffective. LPC is a potent lipid mediator which increases myocyte [Ca]i in a concentration-dependent manner. Magnesium concentrations > or = 2.0 mM effectively antagonize the increase in [Ca]i induced by LPC. Thus, magnesium may limit intracellular calcium overload stimulated by ischemic-induced LPC release.

Calcium entry attenuates adenylyl cyclase activity. A possible mechanism for calcium-induced catecholamine resistance.

In experimental animals, coadministration of calcium (Ca) salts with beta-adrenergic receptor agonists reduces the increased blood pressure and cyclic AMP (cAMP) produced by beta-adrenergic receptor agonists alone. In patients, coadministration of these drugs reduces the increased cardiac output and blood glucose produced by selective administration of beta-adrenergic agonists. The mechanism by which Ca might produce catecholamine resistance remains unclear. Healthy volunteers donated venous blood from which lymphocytes were isolated. The cAMP production was measured by radioimmunoassay under control conditions and after incubation with epinephrine or colforsin (forskolin) in the presence and absence of inhibitors. Epinephrine and colforsin produced concentration-dependent increases in cAMP production. Extracellular Ca concentration over the range from 0 to 8 mM did not inhibit basal cAMP production or that stimulated by either colforsin or epinephrine. The calcium channel agonist Bay K 8644 (50 microM) combined with normal extracellular Ca concentration significantly attenuated colforsin-induced increases in cAMP production. When barium was substituted for Ca in the extracellular fluid, the cAMP response to colforsin was restored, despite Bay K 8644. Inhibition of Ca channel permeability with cadmium or cobalt ions partially restored colforsin-stimulated cAMP production, despite the presence of extracellular Ca and Bay K 8644. These results suggest that entry of Ca ions through Ca channels attenuates adenylyl cyclase. The inhibition appears specific for Ca ions over other permeant divalent cations, and favors a possible physiologic role for the recently cloned Ca-inhibited adenylyl cyclase.