Kenichi Masui

Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory.

Background: In animal models, neonatal exposure to volatile anesthetics induces neuroapoptosis, leading to memory deficits in adulthood. However, effects of neonatal exposure to desflurane are largely unknown. Methods: Six-day-old C57BL/6 mice were exposed to equivalent doses of desflurane, sevoflurane, or isoflurane for 3 or 6 h. Minimum alveolar concentration was determined by the tail-clamp method as a function of anesthesia duration. Apoptosis was evaluated by immunohistochemical staining for activated caspase-3, and by TUNEL. Western blot analysis for cleaved poly-(adenosine diphosphate-ribose) polymerase was performed to examine apoptosis comparatively. The open-field, elevated plus-maze, Y-maze, and fear conditioning tests were performed to evaluate general activity, anxiety-related behavior, working memory, and long-term memory, respectively. Results: Minimum alveolar concentrations at 1 h were determined to be 11.5% for desflurane, 3.8% for sevoflurane, and 2.7% for isoflurane in 6-day-old mice. Neonatal exposure to desflurane (8%) induced neuroapoptosis with an anatomic pattern similar to that of sevoflurane or isoflurane; however, desflurane induced significantly greater levels of neuroapoptosis than almost equivalent doses of sevoflurane (3%) or isoflurane (2%). In adulthood, mice treated with these anesthetics had impaired long-term memory, whereas no significant anomalies were detected in the open-field and the elevated plus-maze tests. Although performance in a working memory task was normal in mice exposed neonatally to sevoflurane or isoflurane, mice exposed to desflurane had significantly impaired working memory. Conclusions: In an animal model, neonatal desflurane exposure induced more neuroapoptosis than did sevoflurane or isoflurane and impaired working memory, suggesting that desflurane is more neurotoxic than sevoflurane or isoflurane.

On-line monitoring of end-tidal propofol concentration in anesthetized patients

Background:Propofol (2,6-diisopropylphenol) has some volatility, so it can be detected in expired breath of individuals receiving intravenous propofol. This study measured volatile propofol exhaled by patients and investigated the relation between exhaled and plasma propofol concentrations. Methods:Nineteen patients with American Society of Anesthesiologists physical status I or II who were undergoing elective surgery participated in this two-part study. In study 1 (n = 11), anesthesia was induced with 2 mg/kg propofol, 0.1 mg/kg vecuronium, and 2 &mgr;g/kg fentanyl. After intubation, propofol was administered continuously for 60 min at each of three rates: 3, 6, and 9 mg · kg−1 · h−1. Blood samples were obtained just before each change in the infusion rate, and the plasma concentrations of propofol were measured. The exhaled propofol concentration was measured continuously by means of proton transfer mass spectrometry. End-tidal propofol concentrations during blood sampling were averaged and compared with plasma propofol concentrations. In study 2 (n = 8), after induction of anesthesia, patients received a bolus injection of 2 mg/kg propofol, and the exhaled propofol concentration was measured. Results:Volatile propofol was detected in expired gas from all study patients. From study 1, the authors obtained 24 paired data points, i.e., concentrations of end-tidal and plasma propofol. With Bland-Altman analysis, bias ± precision was 5.2 ± 10.4 with 95% limits of agreement of −15.1 and 25.6. In study 2, the exhaled propofol concentration curve showed an obvious peak in all patients. Conclusions:Agreement between plasma and exhaled propofol concentrations suggests that proton transfer mass spectrometry can be used for real-time propofol monitoring.

The performance of compartmental and physiologically based recirculatory pharmacokinetic models for propofol: a comparison using bolus, continuous, and target-controlled infusion data.

BACKGROUND: With the growing use of pharmacokinetic (PK)-driven drug delivery and/or drug advisory displays, identifying the PK model that best characterizes propofol plasma concentration (Cp) across a variety of dosing conditions would be useful. We tested the accuracy of 3 compartmental models and 1 physiologically based recirculatory PK model for propofol to predict the time course of propofol Cp using concentration-time data originated from studies that used different infusion schemes. METHODS: Three compartmental PK models for propofol, called the “Marsh,” the “Schnider,” and the “Schüttler” models, and 1 physiologically based recirculatory model called the “Upton” model, were used to simulate the time course of propofol Cp. To test the accuracy of the models, we used published measured plasma concentration data that originated from studies of manual (bolus and short infusion) and computer-controlled (target-controlled infusion [TCI] and long infusion) propofol dosing schemes. Measured/predicted (M/P) propofol Cp plots were constructed for each dataset. Bias and inaccuracy of each model were assessed by median prediction error (MDPE) and median absolute prediction error (MDAPE), respectively. RESULTS: The M/P propofol Cp in the 4 PK models revealed bias in all 3 compartmental models during the bolus and short infusion regimens. In the long infusion, a worse M/P propofol Cp at higher concentration was seen for the Marsh and the Schüttler models than for the 2 other models. Less biased M/P propofol Cp was found for all models during TCI. In the bolus group, after 1 min, a clear overprediction was seen for all 3 compartmental models for the entire 5 min; however, this initial error resolved after 4 min in the Schnider model. The Upton model did not predict propofol Cp accurately (major overprediction) during the first minute. During the bolus and short infusion, the Marsh model demonstrated worse MDPE and MDAPE compared with the 3 other models. During short infusion, MDAPE for the Schnider and Schüttler models was better than the Upton and the Marsh models. All models showed similar MDPE and MDAPE during TCI simulations. During long infusion, the Marsh and the Schüttler models underestimated the higher plasma concentrations. CONCLUSION: When combining the performance during various infusion regimens, it seems that the Schnider model, although still not perfect, is the recommended model to be used for TCI and advisory displays.

Early Phase Pharmacokinetics but Not Pharmacodynamics Are Influenced by Propofol Infusion Rate

Background:Conventional compartmental pharmacokinetic models wrongly assume instantaneous drug mixing in the central compartment, resulting in a flawed prediction of drug disposition for the first minutes, and the flaw affects pharmacodynamic modeling. This study examined the influence of the administration rate and other covariates on early phase kinetics and dynamics of propofol by using the enlarged structural pharmacokinetic model. Methods:Fifty patients were randomly assigned to one of five groups to receive 1.2 mg/kg propofol given with the rate of 10 to 160 mg · kg−1 · h−1. Arterial blood samples were taken frequently, especially during the first minute. The authors compared four basic pharmacokinetic models by using presystemic compartments and the time shift of dosing, LAG time. They also examined a sigmoidal maximum possible drug effect pharmacodynamic model. Patient characteristics and dose rate were obtained to test the model structure. Results:Our final pharmacokinetic model includes two conventional compartments enlarged with a LAG time and six presystemic compartments and includes following covariates: dose rate for transit rate constant, age for LAG time, and weight for central distribution volume. However, the equilibration rate constant between central and effect compartments was not influenced by infusion rate. Conclusions:This study found that a combined pharmacokinetic-dynamic model consisting of a two-compartmental model with a LAG time and presystemic compartments and a sigmoidal maximum possible drug effect model accurately described the early phase pharmacology of propofol during infusion rate between 10 and 160 mg · kg−1 · h−1. The infusion rate has an influence on kinetics, but not dynamics. Age was a covariate for LAG time.

Effect of remifentanil on plasma propofol concentration and bispectral index during propofol anaesthesia

BACKGROUND Propofol and remifentanil are commonly administered together in clinical anaesthesia, but the effect of remifentanil on the plasma concentration of propofol has yet to be established. The aim of the present study was to investigate the effect of remifentanil on plasma propofol concentrations (Cp) in the absence of surgical stimulation. METHODS Thirty-eight patients undergoing elective gynaecologic surgery were randomly assigned to receive one of the three remifentanil doses (0, 0.5, or 1.0 µg kg⁻¹ min⁻¹). Anaesthesia was induced by a target-controlled infusion of propofol. After tracheal intubation, saline or remifentanil infusion was administered for 15 min. Mean arterial pressure (MAP), heart rate (HR), and bispectral index (BIS) were recorded and cardiac index (CI), blood volume, and indocyanine green disappearance ratio (K-ICG) were measured using a dye densitogram analyser before and 15 min after saline or remifentanil infusion. Cp was measured using high-performance liquid chromatography. RESULTS HR, K-ICG, and BIS were significantly decreased in the remifentanil 0 µg kg⁻¹ min⁻¹ group. The decrease in MAP, HR, CI, and K-ICG was significantly lower in the remifentanil 0.5 and 1.0 µg kg⁻¹ min⁻¹ groups compared with the remifentanil 0 µg kg⁻¹ min⁻¹ group. Cp was significantly increased after remifentanil administration, but this had no influence on BIS. CONCLUSIONS Remifentanil reduced the CI and increased the Cp, which may be related to a decrease in the K-ICG, but had no significant effect on the BIS.

Effect of landiolol on bispectral index and spectral entropy responses to tracheal intubation during propofol anaesthesia

BACKGROUND beta1-Adrenoceptor antagonists suppress the haemodynamic and arousal responses to tracheal intubation. The Entropy Module shows two spectral entropy-based indices, response entropy (RE) and state entropy (SE). The difference between RE and SE (RE-SE) may reflect nociception during general anaesthesia. In the present study, we investigated the effect of landiolol on entropy indices in response to tracheal intubation. METHODS A total of 60 patients were randomly assigned to receive saline (Group S), remifentanil (Group R), or landiolol (Group L). Anaesthesia was induced by propofol target-controlled infusion. Two minutes after the induction of anaesthesia, infusion with vecuronium bromide and remifentanil, landiolol, or saline was initiated. Tracheal intubation was performed 7 min after anaesthesia induction. Arterial pressure, heart rate (HR), bispectral index (BIS), and entropy indices were recorded. RESULTS In Group S, RE increased significantly after tracheal intubation, but there was no significant increase in BIS or SE. These increases in RE were abolished in Groups R and L. RE-SE increased significantly after tracheal intubation in Group S, whereas no increase in RE-SE was observed in Groups R and L. Increases in mean arterial pressure and HR after tracheal intubation were suppressed in Groups R and L compared with Group S. CONCLUSIONS RE increased in response to tracheal intubation, whereas BIS and SE did not. Landiolol and remifentanil suppressed the increase in RE after tracheal intubation with significant inhibition of RE-SE difference.

Effects of a Short-acting β1 Receptor Antagonist Landiolol on Hemodynamics and Tissue Injury Markers in Patients With Subarachnoid Hemorrhage Undergoing Intracranial Aneurysm Surgery

Sympathetic activation after subarachnoid hemorrhage (SAH) can induce tachycardia as well as cardiac and brain injury. We examined the effects of β1 receptor antagonist landiolol on hemodynamics and the levels of tissue injury markers in patients with SAH. Fifty-six SAH patients undergoing intracranial aneurysm surgery with tachycardia (≥90 beats per minute) randomly allocated to landiolol (L) or control (C) group were examined. In L group, landiolol was continuously administered during anesthesia. In C group, landiolol was not administered except bolus dose used in cases that exhibited uncontrolled tachycardia. Hemodynamics, the incidence of electrocardiographic abnormality, and levels of B-type natriuretic peptide, troponin T, S-100β, 8-Hydroxy-2′-deoxyguanosine, interleukin-6 (IL-6), and IL-1 receptor antagonist were compared. Heart rate values from time of intubation to the end of anesthesia were significantly lower in L group than in C group, whereas blood pressure was similar between the groups. Although the incidence of bradycardia (<60 beats per minute) was significantly higher in L group than in C group (57% vs. 18%, respectively), bradycardia could be recovered without any adverse effects. The serum S-100β levels 24 hours after operation were significantly lower in L group than in C group, whereas there were no significant differences in the incidence of electrocardiographic abnormality and levels of B-type natriuretic peptide, troponin T, 8-Hydroxy-2′-deoxyguanosine, IL-6, and IL-1 receptor antagonist between groups. We conclude that landiolol can be effectively used in the treatment of tachycardia in SAH patients and significantly reduced the serum S-100β levels 24 hours after the operation.

Pulse wave transit time measurements of cardiac output in patients undergoing partial hepatectomy: a comparison of the esCCO system with thermodilution.

BACKGROUND: Measuring cardiac output accurately during anesthesia is thought to be helpful for safely controlling hemodynamics. Several minimally invasive methods to measure cardiac output have been developed as alternatives to thermodilution with pulmonary artery catheterization. We evaluated the reliability of a novel pulse wave transit time method of cardiac output assessment to trend with thermodilution cardiac output in patients undergoing partial hepatectomy. METHODS: Thirty-one patients (ASA physical status II or III) undergoing partial hepatectomy under general anesthesia were evaluated. Cardiac output measurements by pulse wave transit time method and by thermodilution were recorded after induction of anesthesia, after a change in body positioning to 20° head up, after a change to 20° head down, after volume challenge with 10 mL·kg−1 hydroxyethyl starch 6%, during the Pringle maneuver, and immediately after Pringle maneuver release. Trending was assessed using Bland-Altman analysis and concordance analysis. RESULTS: The direction of change between consecutive pulse wave transit time measurements and the corresponding thermodilution measurements showed a concordance rate of 96.0% (lower 95% confidence interval = 64%), with limits of agreement −1.51 and 1.61 L·min−1. CONCLUSIONS: The pulse wave transit time method had good concordance but fairly wide limits of agreement with regard to trending in patients with changes in preload and systemic vascular resistance. There are potential inaccuracies when vasopressors are used to treat hypotension associated with decreased systemic vascular resistance. The study limitations are that the cardiac output data were collected in a nonblinded fashion, and an existing intraarterial catheter was used, although the system requires only routine, noninvasive cardiovascular monitors. This is a promising technique that currently has limitations and will require further improvements and clinical assessment.

Predictive performance of eleven pharmacokinetic models for propofol infusion in children for long-duration anaesthesia

Background Predictive performance of eleven published propofol pharmacokinetic models was evaluated for long-duration propofol infusion in children. Methods Twenty-one aged three-11 yr ASA I-II patients were included. Anaesthesia was induced with propofol or sevoflurane, and maintained with propofol, remifentanil, and fentanyl. Propofol was continuously infused at rates of 4-14 mg kg  - 1 h - 1 after an initial bolus of 1.5-2.0 mg kg  - 1 . Venous blood samples were obtained every 30-60 min for five h and then every 60-120 min after five h from the start of propofol administration, and immediately after the end of propofol administration. Model performance was assessed with prediction error (PE) derivatives including divergence PE, median PE (MDPE), and median absolute PE (MDAPE) as time-related PE shift, measures for bias, and inaccuracy, respectively. Results We collected 85 samples over 270 (130) (88-545), mean (SD) (range), min. The Short model for children, and the Schüttler general-purpose model had acceptable performance (-20%≤MDPE ≤ 20%, MDAPE ≤ 30%, -4% h - 1  ≤   divergence PE ≤ 4% h - 1 ). The Short model showed the best performance with the maximum predictive performance metric. Two models developed only using bolus dosing (Shangguan and Saint-Maurice models) and the Paedfusor of the remaining nine models had significant negative divergence PE (≤-6.1% h - 1 ). Conclusions The Short model performed well during continuous infusion up to 545 min. This model might be preferable for target-controlled infusion for long-duration anaesthesia in children.

Hypnotic effects and pharmacokinetics of a single bolus dose of propofol in Japanese macaques (Macaca fsucata fsucata)

OBJECTIVE To describe the hypnotic effects of a single bolus dose of propofol in Japanese macaques, and to develop a pharmacokinetic model. STUDY DESIGN Prospective experimental trial. ANIMALS Four male macaques (5-6 years old, 8.0-11.2 kg). METHODS The macaque was restrained and 8 mg kg(-1) of propofol was administrated intravenously at 6 mg kg(-1) minute(-1) . Behavioural changes without stimuli (first experiment) then responses to external stimuli (the second experiment) were assessed every 2 minutes for 20 minutes. Venous blood samples were collected before and at 1, 5, 15, 30, 60, 120 and 210 minutes after drug administration, and plasma concentrations of propofol were measured (third experiment). Pharmacokinetic modelling was performed using NONMEM VI. RESULTS Macaques were recumbent without voluntary movement for a mean 14.0 ± 2.7 SD (range 10.5-16.2) or 10.0 ± 3.4 (7.2-14.5)minutes and recovered to behave as pre-administration by 25.1 ± 3.6 (22.1-30.1) or 22.2 ± 1.5 (21.1-24.3) minutes after the end of propofol administration without or with stimuli, respectively. Respiratory and heart rates were stable throughout the experiments (28-68 breaths minute(-1) and 72-144 beats minute(-1) , respectively). Our final pharmacokinetic model included three compartments and well described the plasma concentration of propofol. The population pharmacokinetic parameters were: V(1)=10.4 L, V(2)=8.38 L, V(3)=72.7 L, CL(1)=0.442 L minute(-1), CL(2)=1.14 L minute(-1), CL(3)= 0.313 L minute(-1), (the volumes of distribution and the clearances for the central, rapid and slow peripheral compartments, respectively). CONCLUSIONS Intravenous administration of propofol (8 mg kg(-1)) at 6 mg kg(-1)minute(-1) to Japanese macaques had a hypnotic effect lasting more than 7 minutes. A three-compartment model described propofol plasma concentrations over more than 3 hours. CLINICAL RELEVANCE The developed pharmacokinetic parameters may enable simulations of administration protocols to maintain adequate plasma concentration of propofol.OBJECTIVE To describe the hypnotic effects of a single bolus dose of propofol in Japanese macaques, and to develop a pharmacokinetic model. STUDY DESIGN Prospective experimental trial. ANIMALS Four male macaques (5-6 years old, 8.0-11.2 kg). METHODS The macaque was restrained and 8 mg kg-1 of propofol was administrated intravenously at 6 mg kg-1 minute-1. Behavioural changes without stimuli (first experiment) then responses to external stimuli (the second experiment) were assessed every 2 minutes for 20 minutes. Venous blood samples were collected before and at 1, 5, 15, 30, 60, 120 and 210 minutes after drug administration, and plasma concentrations of propofol were measured (third experiment). Pharmacokinetic modelling was performed using NONMEM VI. RESULTS Macaques were recumbent without voluntary movement for a mean 14.0 ± 2.7 SD (range 10.5-16.2) or 10.0 ± 3.4 (7.2-14.5) minutes and recovered to behave as pre-administration by 25.1 ± 3.6 (22.1-30.1) or 22.2 ± 1.5 (21.1-24.3) minutes after the end of propofol administration without or with stimuli, respectively. Respiratory and heart rates were stable throughout the experiments (28-68 breaths minute-1 and 72-144 beats minute-1, respectively). Our final pharmacokinetic model included three compartments and well described the plasma concentration of propofol. The population pharmacokinetic parameters were: V1 = 10.4 L, V2=8.38 L, V3=72.7 L, CL1= 0.442 L minute-1, CL2= 1.14 L minute-1, CL3= 0.313 L minute-1, (the volumes of distribution and the clearances for the central, rapid and slow peripheral compartments, respectively). CONCLUSIONS Intravenous administration of propofol (8 mg kg-1) at 6 mg kg-1 minute-1 to Japanese macaques had a hypnotic effect lasting more than 7 minutes. A three-compartment model described propofol plasma concentrations over more than 3 hours. CLINICAL RELEVANCE The developed pharmacokinetic parameters may enable simulations of administration protocols to maintain adequate plasma concentration of propofol.