Dose-related cardiovascular effects of amrinone and epinephrine in reversing bupivacaine-induced cardiovascular depression

Background: To ascertain the efficacy of amrinone and epinephrine in reversing bupivacaine-induced cardiovascular depression, we investigated the time course of recovery of cardiac function with 3 doses of both agents after bupivacaine administration. Methods: In sevoflurane-anaesthetized dogs, bupivacaine was infused intravenously at 1 mg . kg^?1 . min^?1 until mean arterial pressure fell to 60 mmHg or less. The 3 doses of amrinone (1, 2, and 4 mg . kg^?1) or the 3 doses of epinephrine (2, 5, and 10 μg . kg^?1) were administered as a bolus in randomized order in each dog. Results: Amrinone improved maximum left ventricular dP/dt, a time constant of left ventricular isovolemic relaxation and cardiac index persistently and dose-relatedly. Amrinone increased heart rate and decreased left ventricular end-diastolic pressure and systemic vascular resistance index. Amrinone at 1 and 2 mg . kg^?1 significantly increased mean arterial pressure, but amrinone at 4 mg . kg^?1 did not. Epinephrine increased mean arterial pressure, maximum left ventricular dP/dt, and systemic vascular resistance dose-relatedly. The duration of action of epinephrine, peaking at 1 min and subsequently decreasing by 10 min after administration, did not differ among the groups. Epinephrine at all doses failed to improve a time constant of left ventricular isovolemic relaxation and cardiac index. ECG evidence of serious ventricular dysrhythmias was seen in 1 out of 6 dogs after administrating each dose of amrinone and in 3, 3 and 5 out of 6 dogs after administrating 2, 5 and 10 μg . kg^?1 of epinephrine, respectively. Conclusion: Bolus amrinone may have a certain efficacy in reversing bupivacaine-induced cardiovascular depression, and improving cardiac contractility and relaxation dose-relatedly. In contrast to amrinone, bolus epinephrine remains indispensable for resuscitation, causing a rapid, massive, transient and doserelated rise in blood pressure. However, the use of amrinone may be limited predominantly by a decrease in systemic vascular resistance, while the use of epinephrine may be limited predominantly by the generation of serious ventricular dysrhythmias and lack of effectiveness on cardiac index and on cardiac relaxation.     

Amrinone reverses cardiac depression and augments coronary vasodilation with isoflurane in the isolated heart

Amrinone is a positive inotropic and vasodilatory agent and may be administered during anesthesia with isoflurane. The authors' aims were 1) to examine if amrinone produces coronary artery vasodilation through an increase in metabolic demand or through a direct vasodilatory effect or through both and 2) to test if amrinone attenuates cardiac depression and enhances coronary artery vasodilation produced with exposure to isoflurane. The effects of these drugs were examined in 11 isolated perfused guinea pig hearts. Variables measured were: heart rate (HR), atrioventricular conduction time (AVCT), isovolumetric peak left ventricular pressure (LVP), coronary flow, percent O2 extraction, myocardial O2 consumption (MVO2), and the ratio of O2 delivery (DO2) to MVO2. Each heart was exposed for 10-min periods to 10, 50, 100, and 500 microM amrinone alone, and to 0.5 or 1% isoflurane before, during, and after amrinone. Initial control values were: heart rate 216 +/- 5 beats per min; AVCT 56 +/- 1 ms; peak LVP 86 +/- 3 mmHg; coronary flow 6.3 +/- 0.3 ml.min-1.g-1 (11.4 +/- 0.7 ml.min-1.g-1 with adenosine bolus), percent O2 extraction 52 +/- 3%; DO2 107 +/- 3 microliters.min-1.g-1; MVO2 56 +/- 4 microliters.min-1.g-1; and DO2/MVO2 1.75 +/- 0.08. Amrinone 500 microM alone increased (P less than 0.05) heart rate by 9%, LVP by 13%, coronary flow by 18%, and MVO2 by 23%; AVCT decreased by 3%.(ABSTRACT TRUNCATED AT 250 WORDS)     

RETRACTED ARTICLE: Amrinone improves contractility of fatigued diaphragm in dogs

The effects of amrinone, a bipyridine derivative, on diaphragmatic contractility and fatigue were examined in 36 anaesthetized, mechanically ventilated dogs divided into four groups. In Group Ia (n = 8), dogs without diaphragmatic fatigue were given a bolus injection (0.75 mg · kg^?1) followed by continuous infusion (10 μg · kg^?1 · min^?1) of amrinone iv. In Group Ib (n = 8), animals without fatigue received infusion only of maintenance fluid. In Group IIa (n = 10) and Group IIb (n = 10), diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After producing fatigue, amrinone (0.75 mg · kg^?1 loading dose plus 10 μg · kg^?1 · min^?1 maintenance dose) iv were administered in Group IIa. Only maintenance fluids were administered in Group IIb during this period. Diaphragmatic contractility was assessed in each group by measuring transdiaphragmatic pressure (Pdi). Compared with Group Ib, Pdi at any stimuli in Group Ia did not differ. After producing fatigue, in Group IIa and Group IIb, Pdi decreased at low-frequency (10–30 Hz) stimulation (P < 0.05), whereas no change in Pdi was observed at high-frequency (50–100 Hz) stimulation. In Group IIa, Pdi to each stimulus increased during amrinone infusion compared with Group IIb (P < 0.05). In Group IIb, the speed of recovery from fatigue was relatively slower at low-frequency stimulation. The integrated diaphragmatic electric activity (Edi) did not change throughout the experiment. These results indicate that amrinone improves contractility in the fatigued diaphragm.     

Amrinone improves postischemic myocardial metabolism in the rat heart-lung preparation

Amrinone, a phosphodiesterase inhibitor, is a non-glycosidic noncatecholamine with both vasodilator and positive inotropic effects. We were interested in assessing the effect of amrinone on postischemic cardiac performance in the isolated heart-lung preparation. Twenty-four male Wistar-ST rats were used. They were randomly divided into three groups. Amrinone, 10 μg·ml⁻¹ or 100 μg·ml⁻¹ was administered 8 min after the start of perfusion except in the control group. Ten minutes after the start of perfusion, all hearts were made globally ischemic for 8 min. Subsequently, the preparations were reperfused for 10 min. At the end of the experimental period, the hearts were freeze-clamped, and then myocardial high-energy phosphates, lactate, pyruvate, and glycogen were measured. Hemodynamic parameters in all groups decreased significantly during ischemia. However, there were no significant differences among the groups. The myocardial ATP level in the 100 μg·ml⁻¹ group was significantly higher than that in the control group. Adenosine diphosphate (ADP) and adenosine monophosphate (AMP) levels in the 100 μg·ml⁻¹ group were significantly lower than those in the control group. Myocardial lactate, pyruvate, and glycogen levels were not significantly different among the groups. This result suggests that amrinone improves postischemic myocardial metabolism. Although we could not measure coronary flow, amrinone might increase coronary flow with direct coronary vasodilation which would have increased the myocardial ATP and energy charge levels.     

Normothermic cardiopulmonary bypass and cardioplegia reduce inotropic requirements and creatine kinase-MB after coronary artery bypass graft surgery

Purpose To determine whether normothermic cardiopulmonary bypass (CPB) and cardioplegia preserve myocardial function, reduce inotropic requirements, and reduce markers of myocardial ischemia following coronary artery bypass graft surgery (CABG). Methods We retrospectively reviewed the charts of 171 consecutive patients undergoing elective CABG by a single surgeon from April 1994 to December 1995. Hypothermic CPB with intermittent cold cardioplegia was used in 83 patients and normothermic CPB with intermittent warm cardioplegia in 88 patients. Demographic, surgical, hemodynamic, and inotropic requirements and laboratory data were reviewed. Results The duration of CPB was significantly shorter in the normothermic group (113±27vs 90±21 min;P<0.0001). After CPB the cardiac index was similar between groups, but significantly larger doses of both dopamine and dobutamine were required (8vs 5μg·kg⁻¹·min⁻¹,P<0.0001), and significantly more patients required norepinephrine administration in the hypothermic group (18%vs 6%;P=0.01). Postoperative peak values of creatine kinase MB fraction (CK-MB) were significantly lower in the normothermic group (80±60vs 55±54 IU·I⁻¹;P<0.0001). Conclusion Normothermic CPB and cardioplegia reduce inotropic requirements and CK-MB following CABG.     

Amrinone in perioperative low cardiac output syndrome

Amrinone has been shown to have a beneficial effect on left ventricular function in low output syndrome (LOS), but its use after open-heart surgery has not been extensively revised. We studied 10 patients with LOS post-cardiopulmonary bypass (CPB), who failed to respond to conventional treatment (vasoactive drugs plus intraaortic balloon pump) and were treated with amrinone, 0.75 mg.kg-1 followed by a continuous infusion of 5 to 10 micrograms.kg-1-min-1. One patient failed to respond to the treatment and subsequently died, but in the other nine patients blood pressure and cardiac index increased, left filling pressure decreased and they were successfully weaned from the CBP and survived. These results suggest that amrinone, either alone or combined with other inotropic drugs and mechanical support, is a valuable drug in the management of LOS after CPB.     

Hemodynamic effects of dobutamine and dopexamine after cardiopulmonary bypass in pediatric cardiac surgery*

Background: After surgical repair of congenital heart disease, inotropic support is sometimes necessary to wean from cardiopulmonary bypass. In pediatric cardiac surgery, dobutamine and dopamine are often used as inotropic support. Dopexamine is a synthetic catecholamine, which has positive inotropic and vasodilating properties. Because the hemodynamic effects of catecholamines are modified after cardiopulmonary bypass, the aim of this study was to investigate the effects of dobutamine and dopexamine on cardiac index and systemic vascular resistance index after cardiopulmonary bypass in pediatric cardiac surgery. Methods: The study was performed in a prospective, randomized, and double‐blinded cross‐over design. The investigation included 11 children for elective, noncomplex congenital heart surgery. After weaning from cardiopulmonary bypass and a 20‐min period of steady state, children received either 2.5 μg·kg^?1·min^?1 dobutamine or 1 μg·kg^?1·min^?1 dopexamine for 20 min. Cardiac index (transpulmonary thermodilution), mean arterial pressure, central venous pressure, stroke volume, systemic vascular resistance, and central venous oxygen saturation were determined. The primary outcome variable was cardiac index. Results: No difference in cardiac index was observed between the two groups (P = 0.594). Both drugs increased cardiac index, dopexamine from 3.9 ± 0.6 to 4.7 ± 0.8 l·min^?1·m^?2 (P = 0.003) and dobutamine from 4.1 ± 0.7 to 4.8 ± 0.7 l·min^?1·m^?2 (P = 0.004). During treatment with dobutamine, children presented with significantly higher mean arterial pressure (P = 0.003) and systemic vascular resistance index (P = 0.026). Conclusions: This trial demonstrates that low‐dose dobutamine and dopexamine both increase cardiac index during pediatric cardiac surgery but with different hemodynamic effects.     

Prophylactic amrinone for weaning from cardiopulmonary bypass

This prospective, randomised, double-blind, controlled clinical study was performed at a single tertiary referral centre to test the hypothesis that the prophylactic administration of amrinone before separation of a patient from cardiopulmonary bypass decreases the incidence of failure to wean, and to identify those patients who could be predicted to benefit from such pre-emptive management. Two hundred and thirty-four patients, scheduled to undergo elective cardiac surgery, were randomly allocated to receive either a bolus dose of 1.5 mg x kg(-1) amrinone over 15 min, followed by an infusion of 10 microg x kg(-1) x min(-1), or a bolus of placebo of equal volume followed by an infusion of placebo. Treatment with amrinone or placebo was initiated upon release of the aortic cross-clamp, before weaning from cardiopulmonary bypass. Anaesthetic technique, monitoring and myocardial preservation methods were standardised for both groups. Significantly fewer patients failed to wean in the group that received prophylactic amrinone than in the control group (7 vs. 21%, p = 0.002). Amrinone improved weaning success regardless of left ventricular ejection fraction, although this benefit was statistically significant only in the group with left ventricular ejection fractions > 55%. Of the 32 patients who failed to wean from cardiopulmonary bypass, 14 had normal pre-operative left ventricular ejection fractions.     

Comparative effect of amrinone, aminophylline and diltiazem on rat airway smooth muscle

We investigated the effect of amrinone, a phosphodiesterase III inhibitor, on rat airway smooth muscle, and thereafter, compared its activity with aminophylline and diltiazem. Amrinone produced relaxation of the acetylcholine-induced airway contraction in a dose-related manner. This bronchodilatory activity of amrinone was similar to that of aminophylline, but smaller than that of diltiazem. The 50% relaxant effect (ED50) of amrinone, aminophylline and diltiazem were 3.6 x 10(-4) M, 1.4 x 10(-4) M and 1.4 x 10(-5) M, respectively. Diltiazem was the most potent airway relaxant, and amrinone was less potent in these experiments. Taken together in its positive inotropic and chronotropic effects and anti-inflammatory activity, however, amrinone could be beneficial for treatment of patients suffering from asthma or heart failure with cardiac asthma.     

Arrhythmogenic potential of dopexamine hydrochloride during halothane anaesthesia in dogs

Dopexamine hydrochloride (Dopacard®) is the novel synthetic catecholamine designed for use in the acute management of a low cardiac output status. In addition to dopaminergic receptor stimulation, dopexamine hydrochloride is a potent β₂ adrenoreceptor agonist with negligible direct β₁ and no alpha adrenergic effect. The objective of this study was to compare the arrhythmogenic effects of dopexamine hydrochloride and dopamine in dogs anaesthetized with halothane (1.2 MAC). The starting dose for dopexamine hydrochloride was 3.5 μg · kg^?1 min^?1 and for dopamine was 5 μg · kg^?1 min^?1. Concentrations of the drugs were increased until four or more premature ventricular contractions within 15 seconds were produced. All dogs developed ventricular tachycardia when dopamine was administered in concentrations ranging between 18–20 μg · kg^?1 · min^?1. Unlike dopamine, dopexamine hydrochloride even at concentrations as high as 50 μg · kg^?1· min^?1 did not induce any atrial or ventricular ectopic beats. Lack of β_-1 and alpha adrenergic agonist effects is a likely explanation for low arrhythmogenicity of dopexamine hydrochloride. Both drugs increase cardiac output; dopexamine hydrochloride primarily by a dose-related increase in heart rate and increased aflerload. At the maximal concentration dopexamine hydrochloride increased heart rate from 114 to 150 beat · min^?1, mean arterial pressure decreased from 81 mmHg to 45 mmHg and SVR decreased from 2418 to 962 dyne · sec^?1cm^?5. Myocardial contractility increased only moderately, as evaluated by dP/dt, which increased from 1290 to 1696 mmHg · sec^?1. Dopamine had a more marked inotropic effect: the dP/dt increased, at the maximal concentration, from 1480 to 2570 mmHg · sec^?1. Dopamine also produced vasoconstriction: SVR increased from 2325 to 2683 dyne · sec · cm^?5 and mean arterial pressure from 86 mmHg to 110 mmHg. In conclusion, dopexamine hydrochloride is less arrhythmogenic than dopamine, has less of an inotropic effect, and a greater effect on aflerload.     

Timely use of a CentriMag heart assist device improves survival in postcardiotomy cardiogenic shock

Abstract Background: Postcardiotomy cardiogenic shock (PCS) is often fatal despite inotropic and circulatory support. We compared our experience with the CentriMag left ventricular assist device (LVAD) for patients with PCS at two time periods: in the operating room (OR) after unsuccessful weaning from cardiopulmonary bypass (CPB) and after transfer to the intensive care unit (ICU). Methods: We reviewed 22 patients’ records (13 men, nine women; age, 65 ± 12 years) who underwent open heart surgery (January 2004 to September 2009) and required LVAD support for PCS despite maximal inotropic and intra‐aortic balloon pump (IABP) support. In ten patients who could not be weaned from CPB despite high‐dose inotropic therapy (≥ 3 agents) and IABP support, the CentriMag was implanted in the OR (immediate group). The other 12 patients were weaned from CPB with high‐dose inotropic therapy and IABP but became increasingly unstable or had a cardiac arrest in the ICU, and the CentriMag was implanted for circulatory support (delayed group). Results: Preoperatively, the average ejection fraction was 40%± 12%, the creatinine level was 1.6 ± 0.6 mg/dL, and the European Systematic Coronary Risk Evaluation was 13.1 ± 4.6. The duration of CentriMag support was 5 ± 3 days. The immediate group had significantly better survival (7/10 vs. 2/12, p = 0.027), higher cardiac index (2.4 ± 0.3 L/min/m² vs. 1.7 ± 0.3 L/min/m², p = 0.001), and lower pulmonary capillary wedge pressure (20 ± 6 mmHg vs. 29 ± 8 mmHg, p = 0.024) than the ICU group. No perioperative complications related to device implantation occurred. Conclusion: In patients with PCS, timely placement of a CentriMag LVAD may increase the chance of eventual recovery. (J Card Surg 2011;26:548‐552)     

The effects of amrinone and calcium chloride on pulmonary vasculature and biventricular function in ethchlorvynol-induced lung injury in sheep

The effects of amrinone and CaCl₂ on pulmonary vasculature and biventricular function in sheep with acute lung injury (ALI) were studied. Seven sheep were ventilated with a tidal volume of 10–12 ml.kg^-1 with end-tidal C0₂ of 40 ± 5 mmHg (5.3 ± 0.7 kPa) after acute lung injury was induced with up to 30 mg kg^-1 of ethchlorvynol (ECV). Biventricular function and hemodynamic profiles were estimated with a rapid computerized thermodilution method and modified pulmonary artery catheters after acute lung injury, following a loading dose (1 mg kg^-1) and maintenance dose (5 μg kg^-1 min-1 ) of amrinone and after a bolus dose of CaCl₂ (20 mg kg^-1). ECV successfully induced acute lung damage in sheep, causing significant increases in pulmonary artery pressure (PAP) and pulmonary vascular resistance index (PVRI). Amrinone reversed the unfavorable changes induced by ECV, significantly reducing PAP, PVRI and left ventricular end-diastolic volume (LVEDV). CaCl₂, however, reversed the effect of amrinone and increased PAP, PVRI, and LVEDV but decreased left ventricular ejection fraction.     

Pharmacokinetics of amrinone in neonates and infants

OBJECTIVE: To evaluate the pharmacokinetics of amrinone and its metabolites in neonates and infants after reconstructive surgery for congenital heart disease. DESIGN: Prospective study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Fifteen neonates aged less than 1 month with transposition of the great arteries and 14 infants aged 2 to 6 months with complete atrioventricular septal defect. INTERVENTIONS: Amrinone, loading dose of 2 mg/kg, was administered before weaning from cardiopulmonary bypass, followed by a maintenance infusion of 7.5 microg/kg/min. MEASUREMENTS AND MAIN RESULTS: Blood samples to determine plasma concentrations of amrinone, N-acetylamrinone, and N-glycolylamrinone were drawn before amrinone administration, frequently after the loading dose, every 6 hours during the maintenance infusion, and until 48 hours after the end of the infusion. Amrinone clearance was 2.4 +/- 0.9 mL/kg/min in neonates and 3.2 +/- 1.2 mL/kg/min in infants (p < 0.05). The volume of distribution at steady-state was smaller (p < 0.05) in neonates than in infants. The elimination half-life of amrinone was 10.7 +/- 6.7 hours in neonates and 6.1 +/- 1.4 hours in infants (p < 0.05). There was a linear correlation between the clearance of amrinone and the body surface area (r = 0.67; p < 0.05). The ratio of the plasma concentration of N-acetylamrinone to that of amrinone did not differ between neonates and infants. CONCLUSIONS: Amrinone is eliminated at a slower rate in neonates than in infants. The rate of acetylation of amrinone appears to be similar; the differences in the elimination capacity of amrinone are mainly due to the immature renal function in neonates.     

Epidural and intravenous bolus morphine for postoperative analgesia in infants

Purpose

To compare two doses of bolus epidural morphine with bolus iv morphine for postoperative pain after abdominal or genitourinary surgery in infants.

Methods

Eighteen infants were randomly assigned to bolus epidural morphine (0.025 mg · kg^?1 or 0.050 mg · kg^?1) or bolus iv morphine (0.050–0.150 mg · kg^?1). Postoperative pain was assessed and analgesia provided, using a modified infant pain scale. Monitoring included continuous ECG, pulse oximetry, impedance and nasal thermistor pneumography. The CO₂ response curves and serum morphine concentrations were measured postoperatively.

Results

Postoperative analgesia was provided within five minutes by all treatment methods. Epidural groups required fewer morphine doses (3.8 ± 0.8 for low dose [LE], 3.5 ± 0.8 for high dose epidural [HE] vs. 6.7 ± 1.6 for iv, P < 0.05) and less total morphine (0.11 ± 0.04 mg · kg^?1 for LE, 0.16 ± 0.04 for HE vs 0.67 ± 0.34 for iv, P < 0.05) on POD1 Dose changes were necessary in all groups for satisfactory pain scores. Pruritus, apnoea, and haemoglobin desaturation occurred in all groups. CO₂ response curve slopes, similar preoperatively (range 36–41 ml · min^?1 · mmHg ETco ₂ ^?1 · kg^?1) were generally depressed (range, 16–27 ml · min^?1 · mmHg ETco ₂ ^?1 · kg^?1) on POD1. Serum morphine concentrations, negligible in LE (<2 ng · ml^?1), were similar in the HE and iv groups (peak 8.5 ± 12.5 and 8.6 ± 2.4 ng · ml^?1, respectively).

Conclusion

Epidural and iv morphine provide infants effective postoperative analgesia, although side effects are common. Epidural morphine gives satisfactory analgesia with fewer doses (less total morphine); epidural morphine 0.025 mg · kg^?1 is appropriate initially. Infants receiving epidural or iv morphine analgesia postoperatively need close observation in hospital with continuous pulse oximetry.     

Nicardipine to control mean arterial pressure during extracorporeal membrane oxygenation

The authors present the use of nicardipine to control mean arterial pressure (MAP) in a 19–month-old boy who required venoarterial extracorporeal membrane oxygenation for 11 days for treatment of hydrocarbon aspiration. Nicardipine is an intravenously administered dihydropyridine calcium channel antagonist whose primary physiological action includes vasodilatation. Unlike other calcium channel blockers, it has limited effects on the inotropic and dromotropic function of the myocardium. Nicardipine was started at 5 μg·kg^?1·min^?1 and within five min lowered the MAP from a maximum value of 108 mmHg back to the baseline range of 60 to 80 mmHg. Once the MAP had returned to baseline values, infusion requirements varied from 1 to 3 μg·kg^?1·min^?1 to maintain the MAP at 60 to 80 mmHg during the 11 days of ECMO. No increase in dose requirements were noted during the 11 days.     

Amrinone and dobutamine as primary treatment of low cardiac output syndrome following coronary artery surgery: a comparison of their effects on hemodynamics and outcome.

This study was undertaken in order to compare the effectiveness of amrinone and dobutamine as primary treatment of a low cardiac output (CO) after coronary artery bypass graft (CABG) surgery. Thirty patients with preoperative left ventricular dysfunction participated in this open-label randomized study. Patients were included if they failed to separate from cardiopulmonary bypass (CPB) without inotropic support or if they had a cardiac index (CI) less than 2.4 L/min/m2 after CPB regardless of the blood pressure, in the presence of adequate filling pressures. The treatment objectives were to separate from CPB and achieve a CI > or = 2.4 L/min/m2 and a mean arterial pressure > or = 70 mmHg. Patients treated with amrinone received 0.75 mg/kg followed by 10 micrograms/kg/min; when the objectives were not achieved within five minutes, another 0.75 mg/kg was given. Patients treated with dobutamine received an initial infusion of 5 micrograms/kg/min increased stepwise to 15 micrograms/kg/min if necessary. Eleven of 15 amrinone versus 6 of 15 dobutamine patients achieved the predefined treatment objectives with the test drug alone (P = NS). Comparisons of hemodynamics in patients treated solely with amrinone (n = 7) or dobutamine (n = 6) after CPB showed no significant differences between the treatment groups. The incidence of myocardial ischemia as detected by Holter monitor was 36% with amrinone and 33% with dobutamine. Two patients suffered ventricular fibrillation and two had significant supraventricular tachyarrhythmias (heart rate > 130/min) during treatment with dobutamine alone, whereas no significant arrhythmias occurred in the amrinone group (P = NS). Six dobutamine patients (40%) had postoperative myocardial infarction (MI) as opposed to none among the amrinone patients (P = 0.017). These results indicate that amrinone compares favorably with dobutamine as a primary treatment of low CO after CABG. Further study in a larger number of patients will be required in order to determine if the lower incidence of MI in the amrinone group was due to the treatment drug.     

Clevidipine compared with nitroglycerin for blood pressure control in coronary artery bypass grafting: a randomized double-blind study

Purpose

We tested the hypothesis that clevidipine, a rapidly acting dihydropyridine calcium channel blocker, is not inferior to nitroglycerin (NTG) in controlling blood pressure before cardiopulmonary bypass (CPB) during coronary artery bypass grafting (CABG).

Methods

In this double-blind study from October 4, 2003 to April 26, 2004, 100 patients undergoing CABG with CPB were randomized at four centres to receive intravenous infusions of clevidipine (0.2-8 μg·kg^?1·min^?1) or NTG (0.4 μg·kg^?1·min^?1 to a clinician-determined maximum dose rate) from induction of anesthesia through 12 hr postoperatively. The study drug was titrated in the pre-CPB period with the aim of maintaining mean arterial pressure (MAP) within ± 5 mmHg of a clinician-predetermined target. The primary endpoint was the area under the curve (AUC) for the total time each patient’s MAP was outside the target range from drug initiation to the start of CPB, normalized per hour (AUC_MAP-D). The predefined non-inferiority criterion for the primary endpoint was a 95% confidence interval (CI) upper limit no greater than 1.50 for the geometric means ratio between clevidipine and NTG.

Results

Total mean [standard deviation (SD)] dose pre-bypass was 4.5 (4.7) mg for clevidipine and 6.9 (5.4) mg for NTG (P < 0.05). The geometric mean AUC_MAP-D for clevidipine was 283 mmHg·min·hr^?1 (n = 45) and for NTG was 292 mmHg·min·hr^?1 (n = 48); the geometric means ratio was 0.97 (95% CI 0.74 to 1.27). The geometric mean AUC_MAP-D during aortic cannulation was 357.7 mmHg·min·hr^?1 for clevidipine compared with 190.5 mmHg·min·hr^?1 for NTG. Mean (SD) heart rate with clevidipine was 76.0 (13.8) beats·min^?1 compared with 81.5 (14.4) beats·min^?1 for NTG. There were no clinically important differences between groups in adverse events.

Conclusion

During CABG, clevidipine was not inferior to NTG for blood pressure control pre-bypass.     

Stress hormone responses to major intra-abdominal surgery during and immediately after sevoflurane-nitrous oxide anaesthesia in elderly patients

We studied the responses of plasma epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), cortisol, and antidiuretic hormone (ADH) during and immediately after sevoflurane-nitrous oxide anaesthesia supplemented with vecuronium in seven elderly patients (mean 76.6 ± 1.7 SEM) who underwent major intra-abdominal surgery. The plasma concentrations of norepinephrine, ACTH, cortisol, and ADH increased in response to surgical procedures (P <0.05). The plasma concentration of ADH increased to a peak concentration of 189.1 ± 20.7 pg · ml^?1 30 min after skin incision (P < 0.05). the plasma concentrations of epinephrine, norepinephrine, ACTH, and cortisol increased to peak concentrations of 408.6 ± 135.5 pg · ml^?1, 635.7 ± 167.8 pg · ml^?1, 222.6 ± 48.0 pg · ml^?1, and 113.6 ± 67.5 μg · dI^?1, respectively immediately after tracheal extubation (P <0.05). We conclude that, in the elderly patients, the responses of stress hormones to major intraabdominal surgery were preserved during sevoflurane-nitrous oxide anaesthesia sufficient to prevent increases in arterial pressure and heart rate. The strongest responses of epinephrine, norepinephrine, ACTH, and cortisol were elicited immediately after treacheal extubation.     

Ketamine concentrations during cardiopulmonary bypass

Purpose

To describe the serum concentrations of ketamine following a clinically relevant dosing schedule during cardiopulmonary bypass (CPB).

Methods

Design: Prospective case series. Setting: Tertiarycare teaching hospital. Patients: Six patients undergoing coronary artery bypass grafting and over age 60 yr. Intervention: Following induction of anaesthesia each patient received a bolus of ketamine 2 mg· kg^?1 followed by an infusion of 50 μg· kg^?1 · min^?1 which ran continuously until two hours after bypass. Main Outcome Measures: Ketamine serum concentrations were measured at five minutes after bolus, immediately following aortic cannulation, 10 and 20 min on CPB, termination of CPB, termination of the drug infusion and three and six hours after infusion termination.

Results

At the time of aortic cannulation, ketamine concentrations were 3.11 ± 0.81μg · ml^?1, these levels decreased by one third with the initiation of CPB. By the end of CPB the concentrations had returned to levels roughly equivalent to those observed at the time of aortic cannulation. Following cessation of the infusion, ketamine concentration declined in a log-linear fashion with a half-life averaging 2.12 hr. (range 1.38–3.09 hr).

Conclusions

This dosage regimen maintained general anaesthetic concentrations of ketamine throughout the operative period. These levels should result in brain tissue concentrations in excess of those previously shown to be neuroprotective in animals. Thus we conclude that this infusion regimen would be reasonable to use in order to assess the potential neuroprotective effects of ketamine in humans undergoing CPB.     

Amrinone before termination of cardiopulmonary bypass: haemodynamic variables and oxygen utilization in the postbypass period

One hundred patients were randomly allocated to receive saline or amrinone, 0.75 mg.kg-1, ten minutes before separation from cardiopulmonary bypass (CPB) after elective coronary artery bypass grafting, in order to determine the effects of this agent on haemodynamic variables and O2 utilization. Anaesthesia and CPB were managed in a standard fashion. Before induction of anaesthesia, at pericardiotomy, then at 1, 10, 20 and 30 min after CPB, haemodynamic profiles, haematocrit, and O2 saturation of arterial and mixed venous blood were measured. Incremental doses of ephedrine or phenylephrine, or an infusion of norepinephrine with phentolamine were administered when required. The groups were demographically similar and surgical variables were also similar. Haemodynamic measurements were similar between groups at all times; however, a higher dose of phenylephrine was given immediately before weaning from CPB in the amrinone group, and more patients in this group received phenylephrine in the first 30 min after CPB. Mixed venous saturation (SvO2) was higher in the amrinone patients at all times after CPB, leading to lower calculated oxygen consumption (VO2) (P less than 0.05). Insufficient dosage may explain the lack of haemodynamic effect, while possible reasons for the higher SvO2 and lower VO2 are either reduced whole body VO2 or peripheral shunting.