Tadayoshi Kurita

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.

Influence of Cardiac Output on Plasma Propofol Concentrations during Constant Infusion in Swine

Background As propofol is a high-clearance drug, plasma propofol concentrations can be influenced by cardiac output (CO), which can easily change in response to several factors. If propofol is metabolized in the lungs, the difference between pulmonary and arterial propofol concentrations might also be affected by CO. The objective of the current study was to assess how much plasma propofol concentrations are affected by CO and to determine how much the lungs take part in propofol elimination and in concentration changes affected by CO in anesthetized swine. Methods Thirteen swine were studied. Propofol was administered via a peripheral vein at a rate of 6 mg · kg−1 · h− 1, and blood samples were simultaneously collected from pulmonary and femoral arteries at 0, 2, 3.5, 5, 7, 10, 20, and 30 min and at 20-min intervals up to 270 min. After 90 min of sampling (baseline 1), CO increased in response to a continuous infusion of dobutamine (20 &mgr;g · kg−1 · min− 1; high-CO state); the infusion was then stopped, and CO was allowed to return to baseline (baseline 2). Finally, CO decreased with the administration of propranolol (2.0–4.0 mg administered intravenously; low-CO state). Each hemodynamic status was maintained for 1 h. Results As CO increased 36% from baseline 1, plasma propofol concentrations decreased by 18% from baseline 1, and as CO decreased 42% from baseline 1, plasma propofol concentrations increased by 70% from baseline 1. Plasma propofol concentrations can be expressed by the following equation: plasma propofol concentration (micrograms per milliliter) = 6.51/CO (l/min) + 1.11 (r = 0.78, P < 0.0001). No significant differences were observed between plasma propofol concentrations in pulmonary and femoral arteries in any state, and CO caused no apparent differences between pulmonary and arterial propofol concentrations. Conclusions An inverse relation was observed between CO and propofol concentrations. The lungs appear to have a minor effect on plasma propofol concentrations during constant infusion in anesthetized swine.

Auditory Evoked Potential Index Predicts the Depth of Sedation and Movement in Response to Skin Incision during Sevoflurane Anesthesia

Background The auditory evoked potential (AEP) index, which is a single numerical parameter derived from the AEP in real time and which describes the underlying morphology of the AEP, has been studied as a monitor of anesthetic depth. The current study was designed to evaluate the accuracy of AEPindex for predicting depth of sedation and anesthesia during sevoflurane anesthesia. Methods In the first phase of the study, a single end-tidal sevoflurane concentration ranging from 0.5 to 0.9% was assigned randomly and administered to each of 50 patients. The AEPindex and the Bispectral Index (BIS) were obtained simultaneously. Sedation was assessed using the responsiveness portion of the observer’s assessment of alertness–sedation scale. In the second phase of the study, 10 additional patients were included, and the 60 patients who were scheduled to have skin incisions were observed for movement in response to skin incision at the end-tidal sevoflurane concentrations between 1.6 and 2.6%. The relation among AEPindex, BIS, sevoflurane concentration, sedation score, and movement or absence of movement after skin incision was determined. Prediction probability values for AEPindex, BIS, and sevoflurane concentration to predict depth of sedation and anesthesia were also calculated. Results The AEPindex, BIS, and sevoflurane concentration correlated closely with the sedation score. The prediction probability values for AEPindex, BIS, and sevoflurane concentration for sedation score were 0.820, 0.805, and 0.870, respectively, indicating a high predictive performance for depth of sedation. AEPindex and sevoflurane concentration successfully predicted movement after skin (prediction probability = 0.910 and 0.857, respectively), whereas BIS could not (prediction probability = 0.537). Conclusions Auditory evoked potential index can be a guide to the depth of sedation and movement in response to skin incision during sevoflurane anesthesia.

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.

Influence of hemorrhage on propofol pseudo-steady state concentration.

Background A small induction dose has been recommended in cases of hemorrhagic shock. However, the influence of hemorrhage on the amplitude of plasma propofol concentration has not yet been fully investigated during continuous propofol infusion. The authors hypothesized that the effect of hemorrhage on plasma propofol concentration is variously influenced by the different stages of shock. Methods After 120 min of steady state infusion of propofol at a rate of 2 mg · kg−1 · h−1, nine instrumented immature swine were studied using a stepwise increasing hemorrhagic model (200 ml of blood every 30 min until 1 h, then additional stepwise bleeding of 100 ml every 30 min thereafter, to the point of circulatory collapse). Hemodynamic parameters and plasma propofol concentration were recorded at every step. Results Before total circulatory collapse, it was possible to drain 976 ± 166 ml (mean ± SD) of blood. Hemorrhage of less than 600 ml (19 ml/kg) was not accompanied by a significant change in plasma propofol concentration. At individual peak systemic vascular resistance, when cardiac output and mean arterial pressure decreased by 31% and 14%, respectively, plasma propofol concentration increased by 19% of its prehemorrhagic value. At maximum heart rate, when cardiac output and mean arterial pressure decreased by 46% and 28%, respectively, plasma propofol concentration increased by 38%. In uncompensated shock, it increased to 3.75 times its prehemorrhagic value. Conclusions During continuous propofol infusion, plasma propofol concentration increased by less than 20% during compensated shock. However, it increased 3.75 times its prehemorrhagic concentration during uncompensated shock.

Comparison of Predicted Induction Dose with Predetermined Physiologic Characteristics of Patients and With Pharmacokinetic Models Incorporating those Characteristics as Covariates

Background The relationship between patient characteristics and anesthesia induction dose at a high administration rate is unclear. This study was designed to investigate the relation between induction dose and patient characteristics and to compare it to the predicted induction dose using the previously reported pharmacokinetic model. Methods Diluted propofol (0.5 mg/ml) dose required to reach loss of consciousness, when infused at an infusion rate per lean body mass (LBM) of 150 mg · kg−1 · h−1 (high rate), was determined in 82 patients, ages 10–85 yr. Cardiac output, blood volume, central blood volume (CBV), and hepatic blood flow were measured with indocyanine green pulse spectrophotometry. Stepwise multiple linear regression models were used to investigate the relations between the patient characteristics and induction dose. These were compared with our previously reported parameters at the rate of 40 mg · kg−1 · h−1 (low rate) and with predicted induction doses with two previously reported pharmacokinetic models. Results Significant factors for predicting the induction dose at a high rate were age, LBM, and CBV. Induction dose with one pharmacokinetic model was 1.5 times that of the measured one and the other was half that of the measured one at a high rate. At a low rate, one pharmacokinetic model provided an accurate induction dose. Conclusions The prediction of induction dose from physiologic characteristics of patients provides reasonable accuracy at both high and low administration rates of propofol. A previously reported pharmacokinetic model that incorporated patient characteristics provides the same accurate induction dose at a low rate.

Influence of Fluid Infusion Associated with High-volume Blood Loss on Plasma Propofol Concentrations

BackgroundIt is common clinical practice to use fluid infusion to manage high-volume blood loss until a blood transfusion is performed. The authors investigated the influence of fluid infusion associated with blood loss on the pseudo-steady state propofol concentration. MethodsTwenty-seven swine were assigned to a lactated Ringer’s solution group, a hydroxyethyl starch group, or a threefold lactated Ringer’s solution group (n = 9 in each group). After 180 min of steady state infusion of propofol at a rate of 2 mg · kg−1 · h−1, hemorrhage and infusion were induced by stepwise bleeding followed by fluid infusion every 30 min. In each of the first two steps, 400 ml blood was collected; thereafter, 200 ml was collected at each step. Just after each bleeding step, fluid infusion was rapidly performed using a volume of lactated Ringer’s solution or hydroxyethyl starch equivalent to the blood withdrawn, or a threefold volume of lactated Ringer’s solution. Hemodynamic parameters and the plasma propofol concentration were recorded at each step. ResultsAlthough the plasma propofol concentration in the lactated Ringer’s solution group increased with hemorrhage and infusion, it decreased in both the hydroxyethyl starch and the threefold lactated Ringer’s solution groups. The propofol concentration in the hydroxyethyl starch group could be expressed by the following equation: Plasma Propofol Concentration Decrease (%) = 0.80 × Hematocrit Decrease (%) (r2 = 0.83, P < 0.0001). ConclusionsWhen high-volume blood loss is managed by isovolemic hemodilution, the plasma propofol concentration during continuous propofol infusion decreases linearly with the hematocrit decrease.

Lithium dilution cardiac output measurements using a peripheral injection site comparison with central injection technique and thermodilution.

Objective. The lithium dilution technique for the measurement of cardiac output by the central injection of lithium chloride was introduced by Linton et al. in 1993. In the present report, we compare lithium dilution cardiac output measurement (LD) by the peripheral injection of lithium chloride (pLD) and by central venous injection (cLD), cardiac output determined by electromagnetic flowmetry (EM), and conventional thermodilution cardiac output measurement (TD) on ten swine. Methods. The animals were monitored with a pulmonary artery catheter, a femoral artery catheter, and an electromagnetic flowmeter placed around the ascending aorta. cLD, pLD, TD, and EM were determined at the baseline, then in a hyperdynamic state produced by dobutamine administration, at a second baseline, and finally in a hypodynamic state induced by propranolol during deep anesthesia. Data were analyzed by linear regression analysis and the comparison method described by Bland and Altman; bias and precision were calculated using the method of Sheiner and Beal. Results. The correlation coefficient between pLD and EM (0.86) was significantly less than that between cLD and EM (0.96), however it was not significantly different from that between TD and EM (0.85). The precision value of pLD (0.14) was the same as that of TD (0.14). Conclusion. The results of the present study indicate that pLD is a reliable technique.

Landiolol, an ultra short-acting beta1-adrenoceptor antagonist, does not alter the minimum alveolar anesthetic concentration of isoflurane in a swine model.

BACKGROUND:We previously reported that landiolol, an ultra–short-acting β1-adrenoceptor antagonist, does not alter the electroencephalographic effect of isoflurane. Here, we investigated the influence of landiolol on the minimum alveolar anesthetic concentration (MAC) of isoflurane required to prevent movement in response to a noxious stimulus in 50% of subjects. METHODS:Ten swine (29.0 ± 3.4 kg) were anesthetized by inhalation of isoflurane. MAC was determined using the dewclaw clamp technique, in which movement in response to clamping is recorded. After determination of MAC in the baseline period, an infusion of landiolol (0.125 mg · kg−1 · min−1 for 1 min, then 0.04 mg · kg−1 · min−1) was started. After a 20-min stabilization period, MAC was again assessed (0.04 mg · kg−1 · min−1 landiolol). The infusion of landiolol was then increased from 0.04 to 0.2 mg · kg−1 · min−1, and after a 20-min stabilization period, MAC was again assessed (0.2 mg · kg−1 · min−1 landiolol). Finally, the infusion of landiolol was stopped, and after a 20-min stabilization period, MAC was assessed for a fourth time (Baseline 2). RESULTS:Landiolol clearly attenuated the increases in heart rate and mean arterial blood pressure that occurred in response to the dewclaw clamp, but did not alter the MAC of isoflurane. CONCLUSIONS:Landiolol does not alter the antinociceptive effect of isoflurane. This result, combined with that from our previous work, also suggests that landiolol does not influence the anesthetic potency of inhaled anesthetics.

The influence of hemorrhagic shock on the minimum alveolar anesthetic concentration of isoflurane in a swine model.

BACKGROUND:Although hemorrhagic shock decreases the minimum alveolar concentration (MAC) of inhaled anesthetics, it minimally alters the electroencephalographic (EEG) effect. Hemorrhagic shock also induces the release of endorphins, which are naturally occurring opioids. We tested whether the release of such opioids might explain the decrease in MAC. METHODS:Using the dew claw-clamp technique in 11 swine, we determined the isoflurane MAC before hemorrhage, after removal of 30% of the estimated blood volume (21 mL/kg of blood over 30 min), after fluid resuscitation using a volume of hydroxyethylstarch equivalent to the blood withdrawn, and after IV administration of 0.1 mg/kg of the &mgr;-opioid antagonist naloxone. RESULTS:Hemorrhagic shock decreased the isoflurane MAC from 2.05% ± 0.28% to 1.50% ± 0.51% (P = 0.0007). Fluid resuscitation did not reverse MAC (1.59% ± 0.53%), but additional administration of naloxone restored it to control levels (1.96% ± 0.26%). The MAC values decreased depending on the severity of the shock, but the alterations in hemodynamic variables and metabolic changes accompanying fluid resuscitation or naloxone administration did not explain the changes in MAC. CONCLUSIONS:Consistent with previous reports, we found that hemorrhagic shock decreases MAC. In addition, we found that naloxone administration reversed the effect on MAC, and we propose that activation of the endogenous opioid system accounts for the decrease in MAC during hemorrhagic shock. Such an activation would not be expected to materially alter the EEG, an expectation consistent with our previous finding that hemorrhagic shock minimally alters the EEG.