Shinju Obara

Mechanism of injection pain with long and longmedium chain triglyceride emulsive propofol

Purposet has been suggested that long-medium chain triglyceride (LCT/MCT) emulsive propofol causes less injection pain than long chain triglyceride (LCT) emulsive propofol because of the decreased propofol concentration in the aqueous phase. Alternatively, LCT propofol generates bradykinin causing the injection pain and activates complement, but these effects when using LCT/MCT propofol have not been examined. To identify the mechanism for reduced pain with LCT/MCT propofol, injection pain, bradykinin generation and complement activation with use of both propofol products were compared.MethodsTwo hundred adult patients randomly allocated to two groups were given 1.5 mg·kg-1 iv of either LCT propofol or LCT/MCT propofol at a rate of 200 mg·min-1 in a double-blind manner and were asked to grade pain scores. In another study, bradykinin and activated complement 3 (C3a) concentrations were measured using blood obtained from 13 healthy volunteers mixed with saline, LCT propofol or LCT/MCT propofol.ResultsThere was a significant difference in pain scores between groups, showing a lower incidence of injection pain in the LCT/MCT propofol group. The bradykinin concentrations in blood mixed with LCT and LCT/MCT propofol were significantly higher than in blood mixed with saline. The C3a concentrations showed similar results.ConclusionsLCT/MCT propofol causes less pain on injection compared with LCT propofol. Bradykinin generation and complement activation are similar with both LCT and LCT/MCT propofol. Thus, the reason for less pain on injection with LCT/MCT propofol may be attributed to a decreased concentration of propofol in the aqueous phase.RésuméObjectifOn a pensé qu’une émulsion de propofol avec une chaîne mi-longue de triglycéride (CLT/CMT) cause moins de douleur à l’injection qu’une émulsion à chaîne longue (CLT) parce que la concentration de propofol diminue pendant la phase aqueuse. Aussi, le propofol avec CLT génère de la bradykinine, causant de la douleur à l’injection, et active le complément, mais ces effets n’ont pas été étudiés avec le propofol CLT/CMT. Pour définir le mécanisme qui réduit la douleur avec le propofol CLT/CMT, nous avons comparé la douleur à l’injection, la génération de bradykinine et l’activation du complément avec l’usage des deux produits de propofol.MéthodeDeux cents patients adultes ont été répartis au hasard en deux groupes et ont reçu 1,5 mg·kg-1 iv de propofol CLT ou CLT/CMT à 200 mg·min-1 en double aveugle. On a demandé aux patients d’évaluer leur douleur. Dans une autre étude, les concentrations de bradykinine et de complément 3 activé (C3a) ont été mesurées dans des échantillons sanguins, obtenus de 13 volontaires sains, mêlés à une solution salée, à du propofol CLT ou CLT/CMT.RésultatsOn a noté une différence significative de scores de douleur, montrant une plus faible incidence avec le propofol CLT/CMT. Les concentrations de bradykinine dans le sang mêlé au propofol CLT et CLT/CMT ont été significativement plus élevées que dans le sang mêlé à la solution saline. Les concentrations de C3a ont montré des résultats similaires.ConclusionLe propofol CLT/CMT cause moins de douleur à l’injection que le propofol CLT. La génération de bradykinine et l’activation de complément sont similaires avec le propofol CLT et CLT/CMT. Par conséquent, la diminution de la douleur avec le propofol CLT/CMT peut être attribuée à la plus faible concentration de propofol pendant la phase aqueuse.

AZD-3043: A Novel, Metabolically-Labile Sedative/Hypnotic Agent with Rapid and Predictable Emergence from Hypnosis

Background: Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the &ggr;-aminobutyric acid type A (GABAA) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile. Methods: The effects of AZD-3043, propofol, and propanidid were studied on GABAA receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. Results: AZD-3043 potentiated GABAA receptor-mediated chloride currents and inhibited [35S]tert-butylbicyclophosphorothionate binding to GABAA receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. Conclusions: AZD-3043 is a positive allosteric modulator of the GABAA receptor in vitro and a sedative–hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative–hypnotic agent with rapid and predictable recovery.

Correlation between augmentation index and pulse wave velocity in rabbits

Purpose Pulse wave velocity (PWV) is a direct measure of large arterial stiffness. Augmentation index (AIx) is a surrogate measure of arterial rigidity that could be affected by the ventricular ejection and peripheral haemodynamics in addition to the properties of large arteries. In clinical studies, it is still controversial whether PWV depends on AIx or not. We investigated a relationship between PWV and AIx in young normal rabbits when mean arterial pressure (MAP) level was altered using vasoactive drugs. Materials and methods Pulse waves were simultaneously recorded in the ascending, proximal and distal abdominal aortas in response to intravenous infusion of angiotensin II or sodium nitroprusside in fifteen normal rabbits anaesthetized with pentobarbital sodium. Changes in intravascular diameters were measured using an intravascular ultrasound imaging system in the proximal thoracic and proximal abdominal aortas to determine pressure-strain elastic modulus (Ep). Results PWV from the ascending aorta to the bifurcation of the common iliac arteries and AIx at the ascending aorta were changed with MAP level in response to vasoactive drugs. Significant and positive correlation was observed between PWV and MAP. AIx was correlated significantly with systolic, diastolic and mean arterial pressures. PWV and AIx showed significant and positive correlation mainly with Ep in the proximal thoracic and proximal abdominal aortas, respectively. There was significant correlation between PWV and AIx (r = 0.66, P < 0.001). Conclusion AIx was changed dependently on PWV when the MAP level was changed with vasoactive drugs, which was partly associated with the change in Ep.

The effects of propofol ]on local field potential spectra, action potential firing rate, and their temporal relationship in humans and felines

Propofol is an intravenous sedative hypnotic, which, acting as a GABAA agonist, results in neocortical inhibition. While propofol has been well studied at the molecular and clinical level, less is known about the effects of propofol at the level of individual neurons and local neocortical networks. We used Utah Electrode Arrays (UEAs) to investigate the effects of propofol anesthesia on action potentials (APs) and local field potentials (LFPs). UEAs were implanted into the neocortex of two humans and three felines. The two human patients and one feline received propofol by bolus injection, while the other two felines received target-controlled infusions. We examined the changes in LFP power spectra and AP firing at different levels of anesthesia. Increased propofol concentration correlated with decreased high-frequency power in LFP spectra and decreased AP firing rates, and the generation of large-amplitude spike-like LFP activity; however, the temporal relationship between APs and LFPs remained relatively consistent at all levels of propofol. The probability that an AP would fire at this local minimum of the LFP increased with propofol administration. The propofol-induced suppression of neocortical network activity allowed LFPs to be dominated by low-frequency spike-like activity, and correlated with sedation and unconsciousness. As the low-frequency spike-like activity increased and the AP–LFP relationship became more predictable firing rate encoding capacity is impaired. This suggests a mechanism for decreased information processing in the neocortex that accounts for propofol-induced unconsciousness.

Disposition of Remifentanil in Obesity: A New Pharmacokinetic Model Incorporating the Influence of Body Mass

Background: The influence of obesity on the pharmacokinetic (PK) behavior of remifentanil is incompletely understood. The aim of the current investigation was to develop a new population PK model for remifentanil that would adequately characterize the influence of body weight (among other covariates, e.g., age) on the disposition of remifentanil in the general adult population. We hypothesized that age and various indices of body mass would be important covariates in the new model. Methods: Nine previously published data sets containing 4,455 blood concentration measurements from 229 subjects were merged. A new PK model was built using nonlinear mixed-effects modeling. Satisfactory model performance was assessed graphically and numerically; an internal, boot-strapping validation procedure was performed to determine the CIs of the model. Results: Body weight, fat-free body mass, and age (but not body mass index) exhibited significant covariate effects on certain three-compartment model parameters. Visual and numerical assessments of model performance were satisfactory. The bootstrap procedure showed satisfactory CIs on all of the model parameters. Conclusions: A new model estimated from a large, diverse data set provides the PK foundation for remifentanil dosing calculations in adult obese and elderly patients. It is suitable for use in target-controlled infusion systems and pharmacologic simulation.

Enhancing a sedation score to include truly noxious stimulation: The Extended Observer's Assessment of Alertness and Sedation (EOAA/S)

BACKGROUND Although the Modified Observers Assessment of Alertness and Sedation (MOAA/S) is frequently used in sedation-related drug and device studies, a major shortcoming is that it does not differentiate between lighter and deeper levels of general anaesthesia because the only noxious stimulus of the MOAA/S is a trapezius squeeze. The primary aim of this investigation was to expand the MOAA/S score to include truly noxious stimulation, thereby extending the dynamic range of the assessment to include sedation states consistent with deeper levels of general anaesthesia. METHODS Twenty healthy volunteers received target controlled infusions of fentanyl (target=0.8 ng ml(-1)) and propofol (starting at 0.5 µg ml(-1) and gradually increasing to 5 µg ml(-1)). At each propofol concentration, a MOAA/S score was obtained before and after tetanic electrical stimulation. The tetanic electrical stimulation current was gradually increased until the subject responded or until 50 mA was delivered without a response. A pharmacodynamic model was constructed to characterize the concentration-effect relationship between propofol and the MOAA/S scores. RESULTS All subjects required a significantly higher propofol concentration to produce unresponsiveness to tetanic electrical stimulation at 50 mA compared with a standardized trapezius squeeze. The pharmacodynamic model adequately characterized the concentration-effect relationship. CONCLUSIONS The Extended Observers Assessment of Alertness and Sedation (or EOAA/S) extends the range of the widely used MOAA/S score to include truly noxious stimulation, thereby enabling the identification of drug-induced central nervous system depression representative of surgical anaesthesia.

Changes in femoral vein blood flow velocity by intermittent pneumatic compression: calf compression device versus plantar-calf sequential compression device

Intermittent pneumatic compression has become widely used to prevent deep venous thrombosis potentially causing fatal pulmonary embolism. Although uniform compression has been commonly applied, a new method of sequential compression from plantar to calf has recently been developed. In this report, changes in maximum blood flow velocity in the femoral vein were compared with compression of only the calf uniformly and compression from plantar to calf sequentially in 10 healthy adult volunteers. A compression pressure of 60 mm Hg was applied for 5 min, and the velocity was measured before and after this treatment by ultrasound echography. There was no statistically significant difference in the change in maximum velocity between calf compression and plantar-calf sequential compression. The maximum velocity increased significantly with both compressions. However, plantar-calf sequential compression tended to have a greater effect. Although the results did not demonstrate an advantage of plantar-calf sequential compression compared with calf compression only, if the former compression is applied for a long time, it may have a greater effect.

Current state of emergency medicine in Fukushima 4 years after the Great East Japan Earthquake

On 11 March 2011, a huge tsunami exceeding 13 m in height generated by the Great East Japan Earthquake widely damaged the Pacific coastal area of Fukushima Prefecture. The tsunami induced loss of the power supply to nuclear reactors 1–4 at the Fukushima Daiichi Nuclear Power Plant (see figure 1; F1 on map). Steam explosions of the reactor buildings ensued, and the eastern part of Fukushima Prefecture was widely contaminated by scattered radioactive materials. At that time, we were engaged in the forefront of emergency medical care at Fukushima Medical University Hospital for the victims of this disaster. Fukushima Prefecture has two nuclear power plants, and we had prepared for radiation accidents before the Great East Japan Earthquake. We learned how to measure radiation activity and decontaminate radioactive materials. However, these actions were not useful for this disaster because our training involved learning how to treat only two to three patients involved in radiation accidents in nuclear power plants. We were thus unprepared for this large-scale disaster. The most urgent problem for us was the sudden closing of hospitals around F1. We had to accept large numbers of patients from these hospitals, and many of the patients were transported with only the clothes on their backs. Because the communication system in Fukushima Prefecture completely collapsed, dozens of patients were transported by the Japan Self-Defense Force and arrived at our hospital without any information. These patients required radioactivity screening, but we could not take rapid action because of the lack of trained staff members and danger involved in handling radioactivity measuring devices. In many cases, these patients had to undergo long-distance …

To what extent does aortic pulse wave velocity estimate early atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic rabbits?

Pulse wave velocity (PWV), an index of arterial stiffness, is dependent not only on structural alterations in arterial wall but also on distending pressure, which could be related to wall distensibility. We investigated the efficacy of aortic PWV (AoPWV) for detecting early to moderate atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. Pressure waves were recorded at the ascending, and proximal and distal abdominal aortas in 13 male normal and KHC rabbits aged 12 months under pentobarbital anesthesia when angiotensin II or sodium nitroprusside was infused intravenously. AoPWV was compared between the two rabbit groups at different mean arterial pressure (MAP) levels. Vascular diameter (Dm) was measured using an intravascular ultrasound imaging system in the proximal thoracic and proximal abdominal aortas to determine pressure–strain elastic modulus (Ep). AoPWV was correlated to MAP in the two rabbit groups (P<0.001). AoPWV was slightly but significantly greater (<0.5 m s−1) in the KHC rabbit group than in the normal rabbit group at MAP level >80 mm Hg (P<0.01). The value of h/Dm (h, wall thickness) was significantly high in the KHC rabbit group at any MAP level (P<0.001) in these aortic regions. There was no significant difference in Ep and Dm between the two rabbit groups at any MAP level. AoPWV showed only a slight but significant increase in the young KHC rabbits at different MAP levels, which was mainly due to the increased h/Dm. AoPWV could underestimate aortic stiffness due to early to moderate atherosclerosis if AoPWV was adjusted for arterial pressure level.

Anesthetic management for ascending aorta replacement in a patient who refused autologous transfusion for religious reasons.

We report on the anesthetic management of a 69-year-old female Jehovah’s Witness undergoing cardiopulmonary bypass to replace the ascending aorta; the patient refused transfusion of stored autologous or allogeneic blood products for religious reasons. The strategy involved preoperative hematopoiesis with recombinant human erythropoietin and iron, intraoperative acute normovolemic hemodilution, the use of a cell-saver system, administration of high-dose tranexamic acid, controlled hypotension, avoidance of low body temperature, simplification of the surgery, and lower blood dilution during cardiopulmonary bypass.