Mutsuhito Kikura

Comparison of the Effect-site keOs of Propofol for Blood Pressure and EEG Bispectral Index in Elderly and Younger Patients

BACKGROUND Drug effect lags behind the blood concentration. The goal of this investigation was to determine the time course of plasma concentration and the effects of propofol demonstrated by electroencephalogram or blood pressure changes and to compare them between elderly and young or middle-aged patients. METHODS A target-controlled infusion was used to rapidly attain and maintain four sequentially increasing, randomly selected plasma propofol concentrations from 1 to 12 microg/ml in 41 patients aged 20-85 yr. The target concentration was maintained for about 30 min. Bispectral index (BIS), spectral edge frequency, and systolic blood pressure (SBP) were used as measures of propofol effect. Because the time courses of these measures following the started drug infusion showed an exponential pattern, the first-order rate constant for equilibration of the effect site with the plasma concentration (k(eO)) was estimated by fitting a monoexponential model to the effect versus time data resulting from the pseudo-steady-state propofol plasma concentration profile. RESULTS The half-times for the plasma-effect-site equilibration for BIS were 2.31, 2.30, 2.29, and 2.37 min in patients aged 20-39, 40-59, 60-69, and 70-85 yr, respectively (n = 10 or 11 each). The half-times for SBP were 5.68, 5.92, 8.87, and 10.22 min in the respective age groups. All were significantly longer than for BIS (P < 0.05). The propofol concentration at half of the maximal decrease of SBP was significantly greater (P < 0.05) in the elderly than in the younger patients. CONCLUSIONS The effect of propofol on BIS occurs more rapidly than its effect on SBP. Age has no effect on the rate of BIS reduction with increasing propofol concentration, whereas with increasing age, SBP decreases to a greater degree but more slowly.

Pharmacokinetics of Intravenous Milrinone in Patients Undergoing Cardiac Surgery

Background:Milrinone is a phosphodiesterase inhibitor with positive inotropic and vasodilator effects that are useful in the treatment of ventricular dysfunction after cardiac surgery. However, the pharmacokinetics of the drug have been investigated only in healthy volunteers and in patients with ch

Comparison of effects of sevoflurane/nitrous oxide and enflurane/nitrous oxide on myocardial contractility in humans : load-independent and noninvasive assessment with transesophageal echocardiography

Background:Few studies have been reported on the direct depressive effects of sevoflurane on myocardial contractility in humans. Direct assessment of contractile state is possible by examining the slope of left ventricular end-systolic wall stress (LVESWS) versus velocity of circumferential fiber shortening with heart rate corrected (Vcfc) relationship with echocardiography. Using this contractile index, the effects of sevoflurane/nitrous oxide were compared with that of enflurane/nitrous oxide on myocardial contractility in humans. Methods:Twenty-eight subjects were studied during either sevoflurane/nitrous oxide or enflurane/nitrous oxide anesthesia. Systolic, diastolic, and mean arterial blood pressure, heart rate, and transesophageal echocardiographic data were determined at 0.9 MAC and 1.35 MAC of sevoflurane or enflurane, both with 60% N2O, and at 1.6 MAC of sevoflurane with 60% N2O. Furthermore, another 28 awake subjects were studied with transthoracic echocardiography to examine the contractile state at awake state, and echocardiograms, heart rate, and arterial blood pressure were recorded. Results:Heart rate did not changed significantly in either group. Enflurane/nitrous oxide produced significantly greater decrease in arterial blood pressure than did sevoflurane/nitrous oxide. The Vcfc at each anesthetic dose in both anesthetic groups was significantly less than that in the awake subjects group. Sevoflurane/nitrous oxide produced no significant change in Vcfc at 1.5 MAC, whereas enflurane/nitrous oxide caused significant dose-related decrease in Vcfc. Vcfc produced by sevoflurane/nitrous oxide was significantly greater than that produced by enflurane/nitrous oxide. There was no significant difference in LVESWS (index of afterload) between the groups. With respect to the LVESWS-Vcfc relationship, myocardial contractility was significantly depressed in both the sevoflurane and the enflurane groups compared to the awake subjects group. However, myocardial contractility produced by enflurane/nitrous oxide was significantly less than that by sevoflurane/nitrous oxide at equiMAC concentration. Conclusions:The results of the present study suggest that sevoflurane has fewer depressant effects on cardiac function than does enflurane.

Optimal propofol plasma concentration during upper gastrointestinal endoscopy in young, middle-aged, and elderly patients.

BACKGROUND Suitable propofol plasma concentrations during gastroscopy have not been determined for suppressing somatic and hemodynamic responses in different age groups. METHODS Propofol sedation at target plasma concentrations from 0.5 to 4.0 microgram/ml were performed randomly in three groups of patients (23 per group) who were undergoing elective outpatient gastroscopy: ages 17-49 yr (group 1), 50-69 yr (group 2), and 70-89 yr (group 3). Plasma propofol concentration in which 50% of patients do not respond to these different stimuli were determined by logistic regression: verbal command (Cp50ls), somatic response to gastroscopy (Cp50endo), and gag response to gastroscopy (Cp50gag). Hemodynamic responses were also investigated in the different age groups. RESULTS Cp50ls concentrations were 2.23 microgram/ml (group 1), 1.75 microgram/ml (group 2), and 1.40 microgram/ml (group 3). The Cp50endo values in groups 1 and 2 were 2.87 and 2.34 microgram/ml, respectively, which were significantly higher than their respective Cp50ls values. Cp50endo value in group 3 was 1.64 microgram/ml, which was close to its Cp50ls value. Because of a high degree of interpatient variability, Cp50gag could not be defined. Systolic blood pressure response decreased with increasing propofol concentrations. CONCLUSIONS The authors determined the propofol concentration necessary for gastroscopy and showed that increasing age reduces it. Propofol concentration that suppresses somatic response induces loss of consciousness in almost all young patients.

The effect of milrinone on hemodynamics and left ventricular function after emergence from cardiopulmonary bypass

Although milrinone effectively increases cardiac function, few studies have specifically evaluated its efficacy during cardiac surgery.We investigated the effects of milrinone on hemodynamics and left ventricular function in cardiac surgical patients who were already treated with catecholamines. Thirty-seven patients undergoing cardiac surgery were studied. Immediately after emergence from cardiopulmonary bypass (CPB), patients were randomly assigned to a control group (n = 10) or to one of these milrinone groups: milrinone 50 micro g/kg intravenously (n = 8), 50 micro g/kg + 0.5 micro g [centered dot] kg-1 [centered dot] min-1 (n = 10), or 75 micro g/kg + 0.75 micro g [centered dot] kg-1 [centered dot] min-1 (n = 9). Hemodynamics and transesophageal echocardiogram were recorded while constant filling pressures were maintained by volume reinfusion from the CPB reservoir. Arterial blood samples were obtained for the measurement of milrinone plasma concentrations and to determine the dose response curve. In all three milrinone groups, cardiac index and velocity of circumferential fiber shortening (Vcfc) significantly increased from the baseline, and both were significantly higher at 5 and 10 min than those in the control group. The plasma concentration of milrinone with half of maximum increase in Vcfc was 139.3 ng/mL based on the dose-response curve. Thus, milrinone improves hemodynamics and left ventricular function when constant loading conditions are maintained. (Anesth Analg 1997;85:16-22)

Investigation of effective anesthesia induction doses using a wide range of infusion rates with undiluted and diluted propofol.

Background: The influence of infusion rate on the induction dose–response relation has not been investigated over a wide range of infusion rates. In this study, the authors defined the effect of different propofol infusion rates on the times and doses necessary to reach clinical induction of anesthesia. Methods: The subjects of the study were 250 patients classified as American Society of Anesthesiologists physical status I or II aged 25–55 yr. For induction with undiluted propofol, 180 patients were allocated randomly to one of two groups of 90 patients each (A and B). Each group was further divided into nine subgroups (10 patients each) that were administered propofol infusion at rates of 10, 15, 20, 30, 40, 60, 100, 200, and 300 mg · kg−1 · h−1. The remaining 70 patients (group C) were allocated randomly into seven subgroups (10 patients each), and these groups were induced with diluted propofol (0.5 mg/ml) at the rates of 10, 15, 30, 60, 100, 200, and 300 mg · kg−1 · h−1. Group B was given crystalloid at the same infusion rates as group C via a catheter in the opposite arm. Induction time, induction dose, plasma arterial propofol concentration at loss of consciousness, and percentage decrease of systolic blood pressure were measured. A previously reported three-compartment model with an effect-site rate constant for propofol of 0.456/min was used to predict the induction time and dose at each infusion rate. Results: The differences between predicted induction time and dose and the observed time and dose could be explained by factoring in the lag time from infusion site to central compartment (lag timecirculation) and the amount of propofol in transit during this time (residual dosecirculation). Residual dosecirculation and lag timecirculation correlated with infusion time from 20 to 60 s for undiluted and from 0 to 40 s for diluted propofol. At the infusion rates greater than 80 mg · kg−1 · h−1, rapid circulation because of incomplete mixing in the central compartment decreased the excess induction time and dose. The use of diluted propofol significantly attenuated the decrease in systolic blood pressure provoked by the residual dosecirculation. Conclusions: Induction dose and time are dependent on infusion rate in a complex manner, and residual dosecirculation was a factor in overdose and hemodynamic depression. Hypotension during induction was attenuated by diluted propofol.

Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after cardiopulmonary bypass.

There are no clinically available alternatives for reversing heparin in protamine-allergic patients. This study examined the ability of methylene blue, hexadimethrine, and vancomycin to reverse circulating heparin so that these compounds can be carefully examined in future placebo-controlled studies in humans. Heparin activity in blood obtained from extracorporeal circuits was reversed by adding protamine (13.5, 27.0, 81.1, 135.1, and 270.3 micro gram/mL), methylene blue (13.5, 27.0, 135.1, 202.7, 270.3, 337.8, 405.4, 473.0, 540.5, and 810.8 micro gram/mL), hexadimethrine (6.8, 13.5, 20.3, 27.0, 81.1, and 135.1 micro gram/mL), or vancomycin (13.5, 27.0, 135.1, 270.3, 540.5, and 810.8 micro gram/mL), and activated clotting times (ACTs) were measured with kaolin (n = 18). Heparinase-ACT was obtained to determine complete reversal. Heparin concentrations were 3.3 +/- 0.3 U/mL with ACT values of 485 +/- 97 s. The ACT at a protamine concentration of 81.1 micro gram/mL and at hexadimethrine concentrations of 81.1 and 135.1 micro gram/mL was not statistically different from heparinase-ACT; however, methylene blue or vancomycin did not reverse the anticoagulation at any concentrations. Hexadimethrine can reverse heparin-induced anticoagulation after cardiopulmonary bypass as well as protamine, although methylene blue or vancomycin did not neutralize heparin in vitro. (Anesth Analg 1996;83:223-7)

The effects of milrinone on platelets in patients undergoing cardiac surgery.

Although amrinone produces thrombocytopenia, no information is available regarding the acute effects of milrinone on platelets.Therefore, we evaluated the effects of milrinone on platelet number and function in cardiac surgical patients. Twenty-seven patients were studied during cardiac surgery requiring cardiopulmonary bypass (CPB). Patients were randomized to receive no milrinone (n = 10), or milrinone (n = 17) at a loading dose of 50-75 micro gram/kg in the CPB circuit followed by 0.5-0.75 micro gram centered dot kg-1 centered dot min-1 for 12-24 h. Bleeding times and blood samples for coagulation studies were obtained prior to induction, and at 2 and 24 h after CPB. In both groups, platelet counts decreased significantly from the baseline at 2 and 24 h after CPB, and bleeding time increased significantly from the baseline at 2 and 24 h after CPB. No significant thromboelastoplasty (TEG) changes were observed in either group, and there were no significant differences in platelet aggregation or chest tube drainage between the groups. Acute milrinone administration did not cause significant changes in platelet number of function in patients undergoing cardiac operations requiring CPB, beyond the usual adverse effects of cardiac surgery and CPB. (Anesth Analg 1995;81:44-8)

The efficacy of preemptive Milrinone or Amrinone therapy in patients undergoing coronary artery bypass grafting

UNLABELLED Acute deterioration in ventricular function and oxygen transport is common after cardiac surgery. We hypothesized that milrinone or amrinone may reduce their occurrence and catecholamine requirements and increase cellular enzyme levels in patients undergoing coronary artery bypass. In 45 patients, we randomly administered milrinone 50 microg/kg plus 0.5 microg x kg(-1) x min(-1) infusion for 10 h, amrinone 1.5 mg/kg plus 10 microg x kg(-1) x min(-1) infusion for 10 h, or placebo at release of aortic cross-clamp. Hemodynamic variables, dopamine requirement, and laboratory values were recorded. At the postoperative nadir, stroke volume index was higher in the Milrinone and Amrinone groups (mean +/- SD, 27.8 +/- 4.0 and 26.1 +/- 3.2 vs. 20.4 +/- 5.1 mL x min (-1) x m(-2) per beat, P < 0.0001), and oxygen transport index was higher (354.7 +/- 57.8 and 353.7 +/- 91.2 vs 283.0 +/- 83.9 mL. min(-1) x m(-2), P = 0.009). The postoperative dopamine requirement was less (6.6 +/- 2.7 and 6.8 +/- 2.6 vs 10.4 +/- 2.0 mg/kg, P < 0.008), and postoperative serum lactate, alanine and aspartate aminotransferase, lactate dehydrogenase, creatinine kinase, C-reactive protein, and glucose levels were less (P < 0.01). The mean postoperative heart rate was faster in the Milrinone group than in the Amrinone and Placebo groups (96.8 +/- 10.3 vs. 86.9 +/- 9.5 and 87.8 +/- 10.8 bpm, P < 0.01). Milrinone and amrinone administered preemptively reduce postoperative deterioration in cardiac function and oxygen transport, dopamine requirement, and increases in serum lactate, glucose, and enzyme levels, although milrinone may increase heart rate. IMPLICATIONS Preemptive milrinone or amrinone administration before separation from cardiopulmonary bypass in cardiac surgical patients not only ameliorates postoperative deterioration in cardiac function and oxygen transport, but also reduces dopamine requirement and increases serum lactate, glucose, and cellular enzyme levels, although milrinone may increase heart rate.

Relation between Initial Blood Distribution Volume and Propofol Induction Dose Requirement

BackgroundPropofol induction dose is variable and depends on many factors, including initial volume of distribution and early disposition. The authors hypothesized that preadministration blood distribution volumes, cardiac output (CO), and hepatic blood flow (HBF) could be examined to establish a propofol induction dose. MethodsPropofol dose required to reach loss of consciousness, when infused at infusion rate per lean body mass (LBM) of 40 mg · kg−1 · h−1, was determined in 75 patients aged 11–85 yr. CO, blood volume (BV), central blood volume (CBV), and HBF were measured with indocyanine green pulse spectrophotometry. Univariate least squares linear regression analysis was used to individually analyze the relation between propofol induction dose and patient characteristics, including LBM, baseline distribution volumes, CO, and HBF. Stepwise multiple linear regression models were used to select important predictors of induction dose. ResultsAlthough there was a significant correlation between the induction dose and each of the eight variables of age, sex, LBM, hemoglobin, CO, BV, CBV, and HBF, only factors of age (partial r = −0.655), LBM (partial r = 0.325), CBV (partial r = 0.540), and HBF (partial r = 0.357) were independently associated with the induction dose (R2 = 0.85) when all variables were included in a multivariate model. ConclusionsAt a constant propofol infusion rate of 40 mg · kg−1 · h−1 as a function of LBM in patients with American Society of Anesthesiologists physical status I or II, the induction dose can be determined from four variables: age, LBM, CBV, and HBF.