bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial Depressant Effects of Sevoflurane
Authors: Park Wyun Kon , Pancrazio Joseph J. , Suh Chang Kook , Lynch Carl III
Published: November 2003

Background

The effects of anesthetic concentrations of sevoflurane were studied in isolated myocardial tissue to delineate the mechanisms by which cardiac function is altered.

Methods

Isometric force of isolated guinea pig ventricular papillary muscle was studied at 37 degrees C in normal and 26 mM K+ Tyrode's solution at various stimulation rates. Normal and slow action potentials were evaluated using conventional microelectrodes. Effects of sevoflurane on sarcoplasmic reticulum function in situ were also evaluated by its effect on rapid cooling contractures, which are known to activate Ca2+ release from the sarcoplasmic reticulum, and on concentrations of rat papillary muscle. Finally, Ca2+ and K+ currents of isolated guinea pig ventricular myocytes were examined using the whole-cell patch clamp technique.

Results

Sevoflurane equivalent to 1.4% and 2.8% depressed guinea pig myocardial contractions to approximately 85 and approximately 65% of control, respectively, although the maximum rate of force development at 2 or 3 Hz and force in rat myocardium after rest showed less depression. In the partially depolarized, beta-adrenergically stimulated myocardium, sevoflurane selectively depressed late peak force without changing early peak force, whereas it virtually abolished rapid cooling contractures. Sevoflurane did not alter the peak amplitude or maximum depolarization rate of normal and slow action potentials, but action potential duration was significantly prolonged. In isolated guinea pig myocytes at room temperature, 0.7 mM sevoflurane (equivalent to 3.4%) depressed peak Ca2+ current by approximately 25% and increased the apparent rate of inactivation. The delayed outward K+ current was markedly depressed, but the inwardly rectifying K+ current was only slightly affected by 0.35 mM sevoflurane.

Conclusions

These results suggest that the direct myocardial depressant effects of sevoflurane are similar to those previously described for isoflurane. The rapid initial release of Ca2+ from the sarcoplasmic reticulum is not markedly decreased, although certain release pathway, specifically those induced by rapid cooling, appear to be depressed. Contractile depression may be partly related to the depression of Ca2+ influx through the cardiac membrane. The major electrophysiologic effect of sevoflurane seems to be a depression of the delayed outward K+ current, which appears to underlie the increased action potential duration.
Concurrent Spinal Infusion of MK801 Blocks Spinal Tolerance and Dependence Induced by Chronic Intrathecal Morphine in the Rat
Authors: Dunbar Stuart , Yaksh Tony L.
Published: November 2003

Background

MK801, an N-methyl-D-aspartate receptor antagonist, has recently been reported to attenuate tolerance to, and withdrawal from morphine. This study analyzes tolerance and withdrawal in a chronic intrathecal coinfusion model of morphine and MK801.

Methods

Intrathecal catheters, attached to 7-day miniosmotic infusion pumps, were implanted in rats and infused with saline, 20 nM/h morphine, MK801 (10 and 3 nM/h) + morphine; and 10 nM/h MK801. Analgesia was measured on the hot plate daily. On the day 7, groups received 3 mg/kg intraperitoneal naloxone and six signs of withdrawal were assessed: vocalization to air motion or light touch, abnormal posture, spontaneous vocalization, escape attempts, "wet dog shakes," and ejaculation. Similar groups were tested only on days 1 and 7. Intrathecal morphine dose-response curves were obtained on day 8. A separate morphine-tolerant group received 10 nM MK801 on day 7. Rats from each group received 10 nM intrathecal morphine 1 week later.

Results

Coinfusion of MK801 with morphine resulted in a dose-dependent preservation of effect, and attenuated three of six signs of withdrawal. Coinfusion of MK801 (10 and 3 nM/h) prevented the reduction of potency observed with morphine alone. ED50 values (maximum percent effect, nM morphine) were: saline (16), morphine (496), MK801 (10 nM/h) + morphine (4), and 10 nM/h MK801 (0.3). Acute administration of MK801 was ineffective in restoring sensitivity to morphine. One week after cessation of infusion, there was no significant difference between groups.

Conclusions

Chronic spinal MK801 attenuates tolerance to, and withdrawal from spinal morphine in a dose-dependent fashion, supporting the hypothesis that N-methyl-D-aspartate receptor activity plays a role in the reorganization of spinal function produced by chronic opioid receptor activation. Chronic intrathecal MK801 appears to sensitize the spinal cord to intrathecal morphine.
Dose-dependent Increases in the Renal Sympathetic Nerve Activity during Rapid Increase in Isoflurane Concentration in Intact, Lower Airway-deafferented, and Baroreceptor-deafferented Rabbits
Authors: Okamoto Hirotsugu , Hoka Sumio , Kawasaki Toshihiro , Okuyama Tomoko , Takahashi Shosuke
Published: November 2003

Background

The inhalation of high concentrations of isoflurane has been reported to increase the heart rate and the concentration of serum catecholamines. Although the precise mechanisms for the sympathetic activation of isoflurane have yet to be clearly elucidated, they are considered to possibly originate from the stimulation of airway sensory afferents, the baroreceptor reflex, or the direct stimulation of the central nervous system. To determine how these three mechanisms contribute to sympathetic augmentation, the effects of lower airway deafferentation and baroreceptor deafferentation on the isoflurane-induced changes in the renal sympathetic nerve activity (RSNA) in tracheally intubated rabbits were examined.

Methods

Twenty rabbits were given basal anesthesia. After tracheotomy and during mechanical ventilation, the changes in the heart rate, mean arterial pressure, and RSNA in response to random exposures to 1%, 2%, 3%, and 4% isoflurane were examined. The animals were assigned to one of three groups; 1, the intact group (n = 6); 2, the baroreceptor-deafferented group (n = 9), in which the sinoaortic plus vagal nerves were cut; and 3, the lower airway-deafferented group (n = 5), which underwent a bilateral vagotomy. The exposure to isoflurane was for 10 min in group 1 and 5 min in groups 2 and 3. At least 1 h was allowed for the recovery interval between exposures to isoflurane.

Results

The inhalation of isoflurane caused dose-dependent increases in RSNA in all three groups. RSNA during high concentrations of isoflurane began to increase at 1 min, reaching the maximum at 4 or 5 min in group 1 (2.8- and 3.8-fold at 3% and 4% isoflurane, respectively) and group 3 (2.8- and 4.5-fold at 3% and 4% isoflurane, respectively), but it reached the peak at 2 or 3 min in group 2 (1.7- and 2.4-fold at 3% and 4% isoflurane, respectively) after the initiation of inhalation, in association with early slight increases followed by decreases of mean arterial pressure in groups 1 and 2 but only gradual decreases of mean arterial pressure in group 3. The increases in RSNA in group 3 were similar to group 1, however, those in group 2 were significantly attenuated compared with group 1.

Conclusions

The inhalation of isoflurane caused an increase of RSNA in intact, baroreceptor-deafferented, and lower airway-deafferented rabbits. The extent of the increases in RSNA was greater in intact and lower airway-deafferented rabbits than in baroreceptor-deafferented rabbits. Therefore, it is suggested that isoflurane may increase the efferent sympathetic nerve activity via the direct stimulation of the central nervous system and via the arterial baroreceptor reflex reflecting the reduction in arterial blood pressure. The stimulation of the vagally innervated airway may not contribute to the increase in the sympathetic nerve activity by isoflurane.
Antagonism of the Antinocifensive Action of Halothane by Intrathecal Administration of GABA-A Receptor Antagonists
Authors: Mason Peggy , Owens Casey A. , Hammond Donna L.
Published: November 2003

Background

The hind brain and the spinal cord, regions that contain high concentrations of gamma-aminobutyric acid (GABA) and GABA receptors, have been implicated as sites of action of inhalational anesthetics. Previous studies have established that general anesthetics potentiate the effects of gamma-aminobutyric acid at the GABAA receptor. It was therefore hypothesized that the suppression of nocifensive movements during anesthesia is due to an enhancement of GABAA receptor-mediated transmission within the spinal cord.

Methods

Rats in which an intrathecal catheter had been implanted 1 week earlier were anesthetized with halothane. Core temperature was maintained at a steady level. After MAC determination, the concentration of halothane was adjusted to that at which the rats last moved in response to tail clamping. Saline, a GABAA, a GABAB, or glycine receptor antagonist was then injected intrathecally. The latency to move in response to application of the tail clamp was redetermined 5 min later, after which the halothane concentration was increased by 0.2%. Response latencies to application of the noxious stimulus were measured at 7-min intervals during the subsequent 35 min. To determine whether these antagonists altered baseline response latencies by themselves, another experiment was conducted in which the concentration of halothane was not increased after intrathecal administration of GABAA receptor antagonists.

Results

Intrathecal administration of the GABAA receptor antagonists bicuculline (0.3 micrograms) or picrotoxin (0.3, 1.0 micrograms) antagonized the suppression of nocifensive movement produced by the small increase in halothane concentration. In contrast, the antinocifensive effect of the increase in halothane concentration was not attenuated by the GABAB receptor antagonist CGP 35348 or the glycine receptor antagonist strychnine. By themselves, the GABAA receptor antagonists did not alter response latency in rats anesthetized with sub-MAC concentrations of halothane.

Conclusions

Intrathecal administration of bicuculline or picrotoxin, at doses that do not change the latency to pinch-evoked movement when administered alone, antagonized the suppression of noxious-evoked movement produced by halothane concentrations equal to or greater than MAC. These results suggest that enhancement of GABAA receptor-mediated transmission within the spinal cord contributes to halothane's ability to suppress nocifensive movements.
Pharmacokinetics of Propofol in Adult Patients Undergoing Coronary Revascularization
Authors: Bailey James M. , Mora Christina T. , Shafer Stephen L.
Published: November 2003

Background

Propofol is increasingly used for cardiac anesthesia and for perioperative sedation. Because pharmacokinetic parameters vary among distinct patient populations, rational drug dosing in the cardiac surgery patient is dependent on characterization of the drug's pharmacokinetic parameters in patients actually undergoing cardiac procedures and cardiopulmonary bypass (CPB). In this study, the pharmacokinetics of propofol was characterized in adult patients undergoing coronary revascularization.

Methods

Anesthesia was induced and maintained by computer-controlled infusions of propofol and alfentanil, or sufentanil, in 41 adult patients undergoing coronary artery bypass graft surgery. Blood samples for determination of plasma propofol concentrations were collected during the predefined study periods and assayed by high-pressure liquid chromatography. Three-compartment model pharmacokinetic parameters were determined by nonlinear extended least-squares regression of pooled data from patients receiving propofol throughout the perioperative period. The effect of CPB on propofol pharmacokinetics was modeled by allowing the parameters to change with the institution and completion of extracorporeal circulation and selecting the optimal model on the basis of the logarithm of the likelihood. Predicted propofol concentrations were calculated by convolving the infusion rates with unit disposition functions using the estimated parameters. The predictive accuracy of the parameters was evaluated by cross-validation and by a prospective comparison of predicted and measured levels in a subset of patients.

Results

Optimal pharmacokinetic parameters were: central compartment volume = 6.0 l; second compartment volume = 49.5 l; third compartment volume = 429.3 l; Cl1 (elimination clearance) = 0.68 l/min; Cl2 (distribution clearance) = 1.97 l/min1; and Cl3 (distribution clearance) = 0.70 l/min. The effects of CPB were optimally modeled by step changes in V1 and Cl1 to values of 15.9 and 1.95, respectively, with the institution of CPB. Median absolute prediction error was 18% in the cross-validation assessment and 19% in the prospective evaluation. There was no evidence for nonlinear kinetics. Previously published propofol pharmacokinetic parameter sets poorly predicted the observed concentrations in cardiac surgical patients.

Conclusions

The pharmacokinetics of propofol in adult patients undergoing cardiac surgery with CPB are dissimilar from those reported for other adult patient populations. The effect of CPB was best modeled by an increase in V1 and Cl1. Predictive accuracy of the derived pharmacokinetic parameters was excellent as measured by cross-validation and a prospective test.
Comparison of the Effects of Etomidate, Propofol, and Thiopental on Respiratory Resistance after Tracheal Intubation
Authors: Eames Wendell O. , Rooke Alec G. , Sai-Chuen Wu Rick , Bishop Michael J.
Published: November 2003

Background

Tracheal intubation frequently results in reversible bronchoconstriction. Propofol has been reported to minimize this response in healthy patients and in asthma patients, but may be unsuitable for hemodynamically unstable patients for whom etomidate may be preferable. The current study examined respiratory resistance after tracheal intubation after induction with either thiopental, etomidate, or propofol. A supratherapeutic dose of etomidate was used to test the hypothesis that the bronchoconstrictive response could be minimized by deep intravenous anesthesia.

Methods

Seventy-seven studies were conducted in 75 patients. Anesthesia was induced with either 2.5 mg/kg propofol, 0.4 mg/kg etomidate, or 5 mg/kg thiopental. Respiratory resistance was measured at 2 min after induction.

Results

Respiratory resistance at 2 min was 8.1 +/- 3.4 cmH2O.1(-1).s (mean +/- SD) for patients receiving propofol versus 11.3 +/- 5.3 for patients receiving etomidate and 12.3 +/- 7.9 for patients receiving thiopental (P < or = 0.05 for propofol vs. either etomidate or thiopental).

Conclusions

Respiratory resistance after tracheal intubation is lower after induction with propofol than after induction with thiopental or after induction with high-dose etomidate.
Thoracic Epidural Anesthesia Via the Lumbar Approach in Infants and Children
Authors: Blanco D. , Llamazares J. , Rincon R. , Ortiz M. , Vidal F.
Published: November 2003

Background

In upper abdominal or chest surgery, the segmental approach to thoracic epidural space has the advantage of reducing the total dose of local anesthetic needed. This approach, however, is associated with greater risk of neurologic damage or dural puncture. The aim of this study was to assess the success and the degree of difficulty in advancing a 19-G catheter from the lumbar epidural space to the thoracic level in patients aged 0-96 months.

Methods

In 39 patients undergoing abdominal surgery, the cutaneous distance between the L4-L5 and T10-T11 interspaces was measured, and an appropriate length of 19-G catheter was inserted into the epidural space through an 18-G Tuohy needle with bevel directed cephalad. The intent was to advance the full length of catheter measured to reach the objective. The tips were observed radiologically, and all those positioned cephalad to the T12 level were considered well placed. The degree of difficulty in advancing the catheter was classified as easy, difficult, or impossible. Complications reported were vascular and/or spinal puncture and difficulty removing the catheter.

Results

The catheter tip reached T10-T12 in 7 patients, L2 in 1, L3 in 8, and L4-L5 in 23. Forty-eight percent of the catheters described as easily advanced remained at the L4-L5 level, and only 22% reached the desired level. Difficult insertions occurred in eight patients, in whom the objective was never reached. One case of intravascular insertion was reported. All catheters were removed without difficulty.

Conclusions

The 19-G catheter is inappropriate for use in reaching the thoracic epidural space by the lumbar approach. Easy entrance of a catheter is not a reliable sign of having reached the desired level.
Concentration-Effect Relationships of Eltanolone Given as a Bolus Dose or Constant Rate Intravenous Infusion to Healthy Male Volunteers
Authors: Wessen Arne , Parivar Kourosh M. , Widman Marianne , Nilsson Anders , Hartvig Per
Published: November 2003

Background

The primary purpose of this study was to evaluate concentration-effect relationships of the new steroid anesthetic eltanolone during recovery from a bolus dose and constant rate intravenous infusion in healthy male volunteers.

Methods

Ten subjects received a bolus dose of 0.75 mg/kg eltanolone over 20 s. A 2-h constant rate intravenous infusion of eltanolone was given to five subjects at a rate of 2 mg.kg-1.h-1 and to another five subjects at a rate of 3.5 mg.kg-1.h-1. Recovery performance was assessed as the time required to reach different end-points and by means of three different psychomotor tests.

Results

A low interindividual variability was found in the serum concentration of eltanolone at the pharmacodynamic end-points during recovery. The Cp50 value for "eye opening" was 382 micrograms/L (95% confidence interval, 285-489) after a bolus dose corresponding to a median time of 16 min (range 8-25). After eltanolone infusion, the Cp50 value for "eye opening" was 507 micrograms/L (95% confidence interval, 425-605) and the corresponding median time was 21 min (range 8-25) in the low-dose group and 49 min (range 31-66) in the high-dose group. The Cp50 values at the same effect end-points in the bolus group were less than those in the infusion groups, probably because of insufficient equilibration time between serum and the effect compartment.

Conclusions

Recovery characteristics of eltanolone were predictable because of a relatively low interindividual variability in serum concentrations but with a slow blood:effect compartment equilibration.
Reduction in the Shivering Threshold Is Proportional to Spinal Block Height
Authors: Leslie Kate , Sessler Daniel I
Published: November 2003

Background

Hypothermia is nearly as common, and may be as severe, during spinal and epidural anesthesia as during general anesthesia. The authors have proposed that thermoregulatory failure results when regional anesthesia increases apparent leg skin temperature to a level far exceeding actual leg skin temperature. Extensive dermatomal blocks will alter thermal input to the hypothalamus from a greater skin-surface area more than less extensive ones and thus might be expected to impair central thermoregulatory control more. Accordingly, they tested the hypothesis that reduction in the shivering threshold is directly related to the number of dermatomes blocked during spinal anesthesia.

Methods

Eleven men, aged 62 +/- 6 yr (mean +/- SD), undergoing urologic surgery were studied. Ice-cold lactated Ringer's solution was administered intravenously before spinal blockade and the shivering threshold (triggering core temperature) was established. Spinal anesthesia then was induced using a randomly assigned dose of 0.5% bupivacaine (2-4 ml). Again, sufficient cold lactated Ringer's solution was given to induce shivering. Tympanic membrane, ambient and skin temperatures were measured, and extent of block was defined by loss of temperature discrimination. Presence of shivering was evaluated by a blinded observer. Mean upper-body skin and ambient temperatures, cooling rates and intravenous fluid volumes at the two thresholds were compared using paired, two-tailed t tests (P < 0.05). Linear regression defined the relationship between reduction in shivering threshold and the number of dermatomes blocked.

Results

There were no significant differences between mean upper-body skin and ambient temperatures, cooling rates or intravenous fluid volumes at the control and spinal shivering thresholds. Spinal anesthesia reduced the shivering threshold in direct relation to the number of dermatomes blocked: delta threshold = 0.74 - 0.06 (dermatomes blocked); r2 = 0.58, P < 0.006.

Conclusions

Extensive spinal blockade impairs central thermoregulatory control more than less extensive blockade. Clinicians can thus anticipate more core hypothermia during extensive than during restricted spinal blockade.
Induction, Recovery, and Safety Characteristics of Sevoflurane in Children Undergoing Ambulatory Surgery
Authors: Lerman Jerrold , Davis Peter J. , Welborn Leila G. , Orr Rosemary J. , Rabb Mary , Carpenter Rob , Motoyama Etsuro , Hannallah Rafaat , Haberkern Charles M.
Published: November 2003

Background

Sevoflurane is an inhalational anesthetic with characteristics suited for use in children. To determine whether the induction, recovery, and safety characteristics of sevoflurane differ from those of halothane, the following open-labeled, multicenter, randomized, controlled, phase III study in children undergoing ambulatory surgery was designed.

Methods

Three hundred seventy-five children, ASA physical status 1 or 2, were randomly assigned in a 2:1 ratio to receive either sevoflurance or halothane, both in 60% N2O and 40% O2. Anesthesia was induced using a mask with an Ayre's t piece or Bain circuit in four of the centers and a mask with a circle circuit in the fifth center. Maximum inspired concentrations during induction of anesthesia were 7% sevoflurane and 4.3% halothane. Anesthesia was maintained by spontaneous ventilation, without tracheal intubation. End-tidal concentrations of both inhalational anesthetics were adjusted to 1.0 MAC for at least 10 min before the end of surgery. Induction and recovery characteristics and all side effects were recorded. The plasma concentration of inorganic fluoride was measured at induction of and 1 h after anesthesia.

Results

During induction of anesthesia, the time to loss of the eyelash reflex with sevoflurane was 0.3 min faster than with halothane (P < 0.001). The incidence of airway reflex responses was similar, albeit infrequent with both anesthetics. The total MAC.h exposure to sevoflurane was 11% less than the exposure to halothane (P < 0.013), although the end-tidal MAC multiple during the final 10 min of anesthesia was similar for both groups. Early recovery as evidenced by the time to response to commands after sevoflurane was 33% more rapid than it was after halothane (P < 0.001), although the time to discharge from hospital was similar for both anesthetics. The mean ( +/- SD) plasma concentration of inorganic fluoride 1 h after discontinuation of sevoflurane was 10.3 +/- 3.5 microM. The overall incidence of adverse events attributable to sevoflurane was similar to that of halothane, although the incidence of agitation attributable to sevoflurane was almost threefold greater than that attributable to halothane (P < 0.004).

Conclusions

Sevoflurane compared favorably with halothane. Early recovery after sevoflurane was predictably more rapid than after halothane, although this was not reflected in a more rapid discharge from the hospital. The incidence of adverse events was similar for both anesthetics. Clinically, the induction, recovery, and safety characteristics of sevoflurane and halothane are similar. Sevoflurane is a suitable alternative to halothane for use in children undergoing minor ambulatory surgery.
Magnetic Resonance Imaging of Cerebrospinal Fluid Volume and the Influence of Body Habitus and Abdominal Pressure
Authors: Hogan Quinn H. , Prost Robert , Kulier Alexander , Taylor Mary Lou , Liu Spencer , Mark Leighton
Published: November 2003

Background

Although the cerebrospinal fluid (CSF) is the pathway of anesthetic delivery and the diluent for neuraxially administered drugs, little is known about its volume, including variability among individuals, longitudinal distribution, or influence of body habitus. Models made to investigate subarachnoid anesthetic distribution lack valid dimensions. CSF volume was measured in volunteers, and the effect of obesity and abdominal compression on CSF volume was evaluated using magnetic resonance imaging.

Methods

Low thoracic and lumbosacral axial magnetic resonance images of 25 healthy volunteers were obtained at 8-mm intervals by fast spin-echo sequence, which highlights CSF. A repeat image series was performed in 15 subjects during external abdominal compression. In two subjects, images were obtained without compression for the entire vertebral column. Dural sac and spinal cord areas were determined in a blinded fashion for each image using video/digital analysis. Area of the sac minus area of the cord constituted area of CSF and roots ("CSF/root"); this area multiplied by 8 mm resulted in CSF/root volume per section.

Results

There is great interindividual variability in CSF/root volume. From the T11-T12 disc to the sacral terminus of the dural sac, the mean volume for all subjects is 49.9 +/- 12.1 ml (mean +/- SD; range 28.0-81.1 ml). This volume was significantly less in relatively obese subjects (42.9 +/- 9.5 ml) than in nonobese subjects (53.5 +/- 12.9 ml). Abdominal compression decreased CSF/root volume by 3.6 +/- 3.2 ml. Sections through intervertebral foramina showed the biggest decrease with abdominal compression, with a lesser change in sections with veins and no change in the absence of these anatomic features. Total vertebral CSF/root volume in two subjects was 94.84 and 120.01 ml, respectively.

Conclusions

CSF volume is widely variable between individuals. The decreased CSF volume that results from increased abdominal pressure, such as with obesity or pregnancy, may produce more extensive neuraxial blockade through diminished dilution of anesthetic. The mechanism by which increased abdominal pressure decreases CSF volume is probably inward movement of soft tissue in the intervertebral foramen, which displaces CSF.
Cardiovascular Responses during Sedation after Coronary Revascularization
Authors: Wahr Joyce A. , Plunkett Jerill J. , Ramsay James G. , Reeves John , Jain Uday , Ley Catherine , Wilson Robert , Mangano Dennis T.
Published: November 2003

Background

Propofol sedation offers advantages for titration and rapid emergence in the critically ill patient, but concern for adverse hemodynamic effects potentially limits its use in these patients. The current study compares the cardiovascular effects of sedation with propofol versus midazolam during the first 12 h after coronary revascularization.

Methods

Three hundred fifty-one patients undergoing coronary revascularization were anesthetized using a standardized sufentanil/midazolam regimen, and assigned randomly to 12 h of sedation with either propofol or midazolam while tracheally intubated. The incidence and characteristics of hemodynamic episodes, defined as heart rate less than 60 or greater than 100 beats/min or systolic blood pressure greater than 140 or less than 90 mmHg, were determined using data electronically recorded at 1-min intervals. The presence of myocardial ischemia was determined using continuous three-channel Holter electrocardiography (ECG) and of myocardial infarctions (MI) using 12-lead ECG (Q wave MI, Minnesota Code) or creatine kinase isoenzymes (CK-MB) analysis (non-Q wave MI, peak CK-MB > 70 ng/ml, or CK-MB > 70 IU/I).

Results

Ninety-three percent of patients in both treatment groups had at least one hemodynamic episode during the period of postoperative sedation. Propofol sedation resulted in a 17% lower incidence of tachycardia (58% vs. 70%, propofol vs. midazolam; P = 0.04), a 28% lower incidence of hypertension (39% vs. 54%; P = 0.02), and a greater incidence of hypotension (68% vs. 51%; P = 0.01). Despite these hemodynamic effects, the incidence of myocardial ischemia did not differ between treatment groups (12% propofol vs. 13% midazolam; P = 0.66), nor did its severity, as measured by ischemic minutes per hour monitored (8.7 +/- 5.8 vs. 6.2 +/- 4.6 min/h, propofol vs. midazolam; P = 0.19) or ischemic area under the curve (6.8 +/- 4.0 vs. 5.3 +/- 4.2; P = 0.37). The incidence of cardiac death (one per group), Q wave MI (propofol, n = 7; midazolam, n = 3; P = 0.27), or non Q wave MI (propofol, n = 16; midazolam, n = 18; P = 0.81) did not differ between treatment groups.

Conclusions

Hemodynamic episodes occur frequently in the first 12 h after coronary revascularization. Compared with a standard sedation regimen (midazolam), propofol sedation appears to modulate postoperative hemodynamic responses by reducing the incidence and severity of tachycardia and hypertension and increasing the incidence of hypotension. Both sedation regimens appear similarly safe with respect to myocardial ischemia. These findings indicate that propofol infusion provides effective sedation without deleterious hemodynamic effects in patients recovering from cardiac surgery.
Rapid Rewarming Causes an Increase in the Cerebral Metabolic Rate for Oxygen that Is Temporarily Unmatched by Cerebral Blood Flow
Authors: Enomoto Sakae , Hindman Bradley J. , Dexter Franklin , Smith Tom , Cutkomp Johann
Published: November 2003

Background

Jugular venous hemoglobin desaturation during the rewarming phase of cardiopulmonary bypass is associated with adverse neuropsychologic outcome and may indicate a pathologic mismatch between cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). In some studies, rapid rewarming from hypothermic cardiopulmonary bypass results in greater jugular venous hemoglobin desaturation. The authors wished to determine if rewarming rate influences the temperature dependence of CBF and CMRO2.

Methods

Anesthetized New Zealand white rabbits, cooled to 25 degrees C on cardiopulmonary bypass, were randomized to one of two rewarming groups. In the fast group (n = 9), aortic blood temperature was made normothermic within 4 min. In the slow group (n = 9), aortic blood temperature was made normothermic over 25 min. Cerebral blood flow (microspheres) and CMRO2 (Fick) were determined at baseline (25 degrees C), and at brain temperatures of 28 degrees, 31 degrees, 34 degrees, and 37 degrees C during rewarming.

Results

Systemic physiologic variables appeared similar between groups. At a brain temperature of 28 degrees C, CMRO2 was 47% greater in the fast rewarming group than in the slow group (2.2 +/- 0.5 vs. 1.5 +/- 0.2 ml O2.100 g-1. min-1, respectively; P = 0.01), whereas CBF did not differ (48 +/- 18 vs. 49 +/- 8 ml.100 g-1.min-1, respectively; P = 0.47). Throughout rewarming, CBF increased as a function of brain temperature but was indistinguishable between groups. Cerebral metabolic rate for oxygen differences between groups decreased as brain temperatures increased.

Conclusions

Cerebral venous hemoglobin desaturation with rapid rewarming is caused by an increase in CMRO2 that is temporarily greater than the increase in CBF. This mismatch may indicate a transient abnormality in flow-metabolism coupling, or the effect of temperature gradients on oxygen transfer from hemoglobin to brain.
Prolonged Regional Nerve Blockade
Authors: Curley Joanne , Castillo Jenny , Hotz Joyce , Uezono Megumi , Hernandez Sonia , Lim Jeong-Ok , Tigner Joseph , Chasin Mark , Langer Robert , Berde Charles
Published: November 2003

Background

Biodegradable microspheres are a useful method of drug delivery because they are both injectable and biodegradable, eliminating the need for surgical implantation or removal. Previous work has characterized implantable preparations of local anesthetics in polymer pellets for prolonged regional anesthesia. In this article, the authors characterize injectable suspensions of bupivacaine-polymer microspheres and examine whether they can produce prolonged blockade of the sciatic nerve in rats.

Methods

Microspheres were prepared using polylactic-co-glycolic acid polymers loaded with 75% w/w bupivacaine by a solvent evaporation method. Bupivacaine release from microspheres was determined in vitro by ultraviolet spectroscopy and scintillation counting. Sensory and motor blockade of the rat sciatic nerve were assessed in vivo after injection of microsphere suspensions.

Results

Depending on the type of microspheres, the dose, and the additive used, mean duration of sciatic nerve block ranged from 10 h to 5.5 days. Incorporation of 0.05% w/w dexamethasone into the microspheres resulted in significant prolongation of block (up to 13-fold), and only preparations that contained dexamethasone produced blocks lasting beyond 1 day. Bupivacaine was released in a controlled manner in vitro. Dexamethasone does not substantially slow bupivacaine release from microspheres in vitro.

Conclusions

Prolonged percutaneous blockade of peripheral nerves is feasible. The recovery from blockade is complete, and plasma bupivacaine levels are far below the range associated with systemic toxicity. The mechanisms underlying the dexamethasone block-prolonging effect are under investigation.
Thiopental Uncouples Hippocampal and Cortical Synchronized Electroencephalograpbic Activity
Authors: MacIver Bruce M. , Mandema Jaap W. , Stanski Donald R. , Bland Brian H.
Published: November 2003

Background

Thiopental produces a concentration-dependent continuum of effects on the cortical electroencephalogram (EEG) that has been linked to behavioral measures of anesthetic depth. The complexity of the response, however, limits a clear insight into the neurophysiologic actions of thiopental. The current study investigated thiopental actions on cortical EEG and hippocampal electrical activity, to determine whether similar effects occur on both structures and to compare synchronized activity between these structures.

Methods

Thiopental was administered intravenously via an implanted catheter in freely moving rats. Arterial blood oxygen/carbon dioxide concentration, thiopental concentrations, and temperature were monitored and controlled. Neocortical EEG was recorded from implanted dural surface electrodes and hippocampal neuron electrical activity was recorded from stereotaxically placed microelectrodes. Pharmacokinetic models were used to determine effect site concentrations.

Results

Thiopental produced an increase in EEG frequency and amplitude at low concentrations (15-20 micrograms/ml total plasma, approximately 10 microM unbound), which produced a loss of righting reflex. This was followed by a frequency decrease and burst suppression activity at higher concentrations (50-80 micrograms/ml, approximately 60 microM), which produced a loss of tail pinch and corneal reflexes. Higher concentrations of thiopental ( > 60 micrograms/ml) uncoupled synchronized burst discharges recorded in hippocampus and cortex. Isoelectric EEG activity was associated with concentrations of 70-90 micrograms/ml (approximately 80 microM) and a deep level of anesthesia; motor reflexes were abolished, although cardiovascular reflexes remained. In all frequency bands, similar concentration-EEG effect relationships were observed for cortical and hippocampal signals, only differing in the magnitude of response. A reversed progression of effects was observed on recovery.

Conclusions

The results confirm earlier findings in humans and animals and demonstrate that both the hippocampus and neocortex exhibit burst suppression and isoelectric activity during thiopental anesthesia. Thiopental-induced synchronized burst activity was depressed by progressively higher concentrations. The lost synchronization suggests a depression of synaptic coupling between cortical structures contributes to anesthesia.
Differential Nerve Block
Authors: Jaffe Richard A. , Rowe Michael A.
Published: November 2003

Background

Clinically, differential block is manifested by the loss of small fiber mediated sensation (e.g., temperature) two or more dermatomes beyond the sensory limit for large fiber mediated sensations. These observations support the belief that sensitivity to local anesthetics is inversely proportional to axon diameter. This study reports the first measurements of differential sensitivity to lidocaine in individual myelinated and unmyelinated mammalian dorsal root axons.

Methods

Lumbar dorsal roots and vagus nerves were isolated from anesthetized adult rats and maintained in vitro in a perfusion/recording chamber at 37 +/- 0.3 degrees C. Using single fiber techniques, evoked action potentials in individual myelinated and unmyelinated axons were digitized and recorded for subsequent analysis. Axons were exposed to lidocaine at 150, 260, or 520 microM. Sensitivity to local anesthetic was assessed by measuring the incidence of conduction block and the magnitude of conduction velocity slowing under steady-state conditions.

Results

Data were obtained from 77 dorsal root axons and 41 vagal axons. The estimated steady-state EC50 lidocaine concentration for myelinated dorsal root axons (232 microM) was comparable to that for unmyelinated axons (228 microM). Similarly, the incidence of conduction block was not significantly different among dorsal root axon groups. However, unmyelinated dorsal root axons were significantly less sensitive to the conduction velocity slowing effect of lidocaine than their myelinated counterparts (P < 0.01). The incidence of conduction block in short (mean length 13.5 mm) dorsal root axons was not significantly different from that in long (mean length 22.4 mm) axons. Compared with dorsal root axons, the estimated EC50s for vagal myelinated and unmyelinated axons (345 and 285 microM, respectively), while lower were not significantly different. However, the incidence of conduction block at 260 microM lidocaine was significantly lower (16.7% vs. 56.7%; P < 0.05) in vagal myelinated axons.

Conclusions

Although no difference in sensitivity to the conduction blocking effects of lidocaine could be demonstrated among dorsal root axons, myelinated axons were more sensitive to the conduction velocity slowing effects of lidocaine. This differential effect cannot explain clinical observations of differential nerve block. Differential sensory block with lidocaine may depend on factors (e.g., physiologic function) related only indirectly to individual axon conduction velocity (diameter).
Effect of Volatile Anesthetics with and without Verapamil on Intracellular Activity in Vascular Smooth Muscle
Authors: Namba Hitoshi , Tsuchida Hideaki
Published: November 2003

Background

Although halothane and isoflurane inhibit receptor agonist-induced smooth muscle contraction by inhibiting Ca2+ influx via the L-type voltage-dependent Ca2+ channels, their effects on pharmacomechanical coupling remained to be clarified. The intracellular action of both anesthetics was studied during agonist-induced contractions using the Ca2+ channel blocker verapamil.

Methods

Isolated spiral strips of rat thoracic aorta with endothelium removed were suspended for isometric tension recordings in physiologic salt solution. Cytosolic concentration of Ca2+ ([Ca2+]i) was measured concomitantly using fura-2-Ca2+ fluorescence. Muscle contraction was evoked by the receptor agonists with 30 nm norepinephrine or 10 microM prostaglandin F2 alpha (PGF2 alpha), followed by exposure to halothane, at 0%, 1%, 2%, and 3% or isoflurane, at 2% and 4%. The effects of the anesthetics were compared with those of 0.1-1 microM verapamil (n = 8 for each condition). To clarify the intracellular action of the volatile anesthetics on agonist-induced contractions, this procedure was repeated for the anesthetics only in the presence of 1 microM verapamil (n = 8 for each condition). The effects of both anesthetics were also examined in nonreceptor-mediated contractions evoked with a 1-microM dose of the protein kinase C activator, 12-deoxyphorbol 13-isobutylate, which increases the Ca2+ sensitivity of the contractile elements (n = 8 for each).

Results

Halothane, isoflurane, and verapamil suppressed norepinephrine-and PGF2 alpha-induced increases in muscle tension and [Ca2+]i in a concentration-dependent manner. The Ca2+-tension regression lines suggested that the volatile anesthetics reduced Ca2+ sensitivity of the contractile elements during PGF2 alpha-induced contraction. Pretreatment of the muscle strip with verapamil revealed that halothane and isoflurane released Ca2+ during norepinephrine-induced contraction and that [Ca2+]i-tension relationship was modulated during PGF2 alpha-induced contractions. Halothane at 2% and 3% and isoflurane at 4% suppressed 12-deoxyphorbol 13-isobutylate-induced increases in muscle tension, whereas they enhanced increases in [Ca2+]i, indicating that both anesthetics suppressed Ca2+ sensitivity during 12-deoxyphorbol 13-isobutylate-induced contraction.

Conclusions

Verapamil pretreatment unmasked the intracellular action of the anesthetics. Halothane and isoflurane influenced pharmacomechanical coupling during agonist-induced contraction.
Electroencephalographic Burst Suppression Is Not Required to Elicit Maximal Neuroprotection from Pentobarbital in a Rat Model of Focal Cerebral Ischemia
Authors: Warner David S. , Takaoka Seiji , Wu Bo , Ludwig Paula S. , Pearlstein Robert D. , Brinkhous Ann D. , Dexter Franklin MD
Published: November 2003

Background

Barbiturates have previously been demonstrated to reduce focal cerebral ischemic brain damage. However, the dose of drug required to elicit maximal neuroprotection has not been defined. The authors' hypothesized that doses of pentobarbital substantially lower than those required to cause electroencephalographic burst suppression would result in maximal magnitudes of reduction of cerebral infarct volume.

Methods

Wistar rats underwent 90 min of filament occlusion of the middle cerebral artery while either awake (control), or anesthetized with intravenous sodium pentobarbital administered to preserve an active electroencephalogram (15-23 mg.kg-1.h-1) or a pattern of burst suppression (45-60 mg.kg-1.h-1; n = 17). During ischemia and for the first 6 h of recirculation, brain temperature was rigorously controlled at 38.0 +/- 0.2 degrees C. Rats were allowed a recovery interval of 7 days after which neurologic function and cerebral infarct volume were assessed. In nonischemic rats undergoing a similar anesthetic protocol, the cerebral metabolic rate of glucose utilization was measured at each anesthetic depth.

Results

Relevant physiologic values were similar between groups. Total infarct volume (mean +/- SD) was smaller in the active electroencephalogram group than in the control group (124 +/- 68 mm3 versus 163 +/- 66 mm3; P < 0.05). Increasing the dose of pentobarbital (burst suppression) did not further decrease infarct volume (128 +/- 54 mm3). Neurologic score and infarct volume were positively correlated (P < 0.001). Cerebral metabolic rate of glucose utilization was reduced by 56% in the burst suppression group versus 43% in the active electroencephalogram pentobarbital group (P < 0.001).

Conclusions

Sodium pentobarbital administered at either dose (active electroencephalogram or burst suppression) resulted in an approximately equal to 25% reduction of cerebral infarct size, indicating that burst suppression is not required to elicit maximal neuroprotective efficacy.
Etomidate and Thiopental Inhibit the Release of Endothelium-derived Hyperpolarizing Factor in the Human Renal Artery
Authors: Kessler Paul , Lischke Volker , Hecker Markus
Published: November 2003

Background

Endothelium-derived hyperpolarizing factor is thought to be a cytochrome P450-derived arachidonic acid metabolite that hyperpolarizes vascular smooth muscle cells by opening Ca(2+)-activated K+ channels (K+Ca channels). In the rabbit carotid artery both volatile and intravenous anesthetics inhibit the acetylcholine-stimulated release of endothelium-derived hyperpolarizing factor. Because the release of this factor may help to maintain vascular tone in humans under conditions of a failing nitric oxide synthesis, e.g., in atherosclerosis, the effects of two intravenous anesthetics, thiopental and etomidate, on the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine were investigated in human isolated renal artery segments.

Methods

The segments were suspended in Krebs-Henseleit solution (37 degrees C) containing the cyclooxygenase inhibitor diclofenac (1 microM) and preconstricted with norepinephrine (6 microM). Relaxations caused by acetylcholine (1 microM) were compared in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (0.1 mM) in control segments and in segments exposed to etomidate or thiopental (0.03-0.3 mM). In addition, the effects of the two anesthetics on the relaxant response to the nitric oxide donors glyceryl trinitrate (3 microM) and sodium nitroprusside (0.1 microM) were examined.

Results

The relaxant response to acetylcholine, which was resistant to both nitric oxide synthase and cyclooxygenase blockade, was markedly reduced by the K+Ca channel antagonist tetrabutyl ammonium (3 mM) and the cytochrome P450 inhibitor clotrimazole (30 microM). Both etomidate and thiopental, at a concentration of 0.3 mM, selectively attenuated the relaxant response to acetylcholine in N(G)-nitro-L-arginine-treated segments, but did not affect relaxations elicited by glyceryl trinitrate or sodium nitroprusside.

Conclusions

Etomidate and thiopental inhibit the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine in the human renal artery, an effect that appears to be attributable to the cytochrome P450-inhibiting properties of these anesthetics.
Mass Spectrometry Provides Warning of Carbon Monoxide Exposure Via Trifluoromethane
Authors: Woehlck Harvey J. , Dunning Marshall , Nithipatikom Kasem , Kulier Alexander H. , Henry Daniel W.
Published: November 2003

Background

The chemical breakdown of isoflurane, enflurane, or desflurane in dried carbon dioxide absorbents may produce carbon monoxide. Some mass spectrometers can give false indications of enflurane during anesthetic breakdown.

Methods

During clinical anesthesia with isoflurane or desflurane, the presence of carbon monoxide in respiratory gas was confirmed when enflurane was inappropriately indicated by a clinical mass spectrometer that identified enflurane at mass to charge ratio = 69. In vitro, isoflurane, enflurane, or desflurane in oxygen was passed through dried carbon dioxide absorbents at 35, 45, and 55 degrees C. Gases were analyzed by gas chromatography and by mass spectrometry.

Results

Mass spectrometry identified several clinical incidents in which 30-410 ppm carbon monoxide was measured in respiratory gas. Trifluoromethane was produced during in vitro breakdown of isoflurane or desflurane. Although these inappropriately indicated quantities of "enflurane" correlated (r2 > 0.95) to carbon monoxide concentrations under a variety of conditions, this ratio varied with temperature, anesthetic agent, absorbent type, and water content.

Conclusions

Trifluoromethane causes the inappropriate indication of enflurane by mass spectrometry, and indicates isoflurane and desflurane breakdown. Because the ratio of carbon monoxide to trifluoromethane varies with conditions, this technique cannot be used to quantitatively determine the amount of carbon monoxide to which a patient is exposed. If any warning of anesthetic breakdown results from this technique then remedial steps should be taken immediately to stop patient exposure to carbon monoxide. No warning can be provided for the breakdown of enflurane by this technique.