bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrathecal Adenosine Administration
Authors: Rane Kerstin , Segerdahl Marta , Goiny Michel , Sollevi Alf
Published: November 2003

Background

Several animal studies show antinociceptive effects of intrathecally administered adenosine and its analogs. However, there is no clinical experience regarding the effects of intrathecal adenosine in humans.

Methods

The side effects and analgesic effects of intrathecal adenosine (500-2,000 microg) on experimental pain were studied in 12 healthy volunteers. Before and after adenosine was given, the authors evaluated the cold pain rating of the foot (submersion in ice water for 1 min), the forearm ischemic pain rating during a 30-min tourniquet test, and the thermal and tactile pain thresholds on healthy and inflamed skin after application of mustard oil (4 min) to the calf. The areas of secondary allodynia surrounding the inflammation were also determined. The cerebrospinal fluid level of adenosine was determined before and after injection.

Results

Intrathecal adenosine caused a 1,000- to 2,000-fold elevation of the cerebrospinal fluid concentration. One volunteer experienced transient (30 min) lumbar pain after injection at a dose of 2,000 microg. There were no other complications in any other volunteers. Adenosine reduced, in a non-dose-dependent manner, the areas of secondary allodynia after skin inflammation (brush, P < 0.06; and von Frey hair, P < 0.03) and reduced the forearm tourniquet ischemic pain rating (P = 0.01). Tactile pain thresholds were significantly reduced by mustard oil inflammation during control, whereas adenosine treatment prevented this reduction. The ice water-induced cold pain rating was not influenced by adenosine.

Conclusions

An intrathecal adenosine injection of 1,000 microg lacked side effects in healthy volunteers. The compound attenuated different types of experimental pain.
Intraoperative Modulation of Alveolar Macrophage Function during Isoflurane and Propofol Anesthesia
Authors: Kotani Naoki , Hashimoto Hiroshi , Sessler Daniel I. , Kikuchi Atsuhiro , Suzuki Akiko , Takahashi Satoshi , Muraoka Masatoshi , Matsuki Akitomo
Published: November 2003

Background

Alveolar macrophages are a critical part of the defense against pulmonary infection. Thus the authors determined time-dependent changes in alveolar macrophage functions in patients having surgery who were anesthetized with isoflurane or propofol.

Methods

Patients anesthetized with propofol (n = 30) or isoflurane (n = 30) during orthopedic surgery were studied. Alveolar macrophages were harvested by bronchoalveolar lavage immediately, and 2, 4, and 6 h after induction anesthesia and at the end of surgery. The fraction of aggregated and nonviable macrophages was determined. Then phagocytosis was measured by ingestion of opsonized and unopsonized particles. Finally, microbicidal activity was determined as the ability of the macrophages to kill Listeria monocytogenes directly.

Results

Demographic and morphometric characteristics of the patients given propofol and isoflurane were similar, as were their levels of pulmonary function and hemodynamic responses. The fraction of alveolar macrophages ingesting opsonized and unopsonized particles, and the number of particles ingested, decreased significantly over time, with the decrease slightly but significantly greater during isoflurane anesthesia. Microbicidal function decreased progressively during anesthesia and surgery, with the decrease almost twice as great during isoflurane compared with propofol anesthesia. The fraction of aggregated macrophages and recovered neutrophils increased over time in the patients given each anesthetic.

Conclusions

Pulmonary immunologic function changed progressively during anesthesia and surgery. The data from this study suggest that pulmonary defenses are modulated by the type of anesthesia and by the duration of anesthesia and surgery.
Effects of Mild Perioperative Hypothermia on Cellular Immune Responses
Authors: Beilin Benzion , Shavit Yehuda , Razumovsky Jacob , Wolloch Yaacov , Zeidel Alexander , Bessler Hanna
Published: November 2003

Background

Unintentional perioperative hypothermia is a common complication of anesthesia and surgery associated with adverse effects on several systems, including impaired wound healing and more frequent wound infections. Mild hypothermia affects various immune functions. In the current study, the authors sought to determine whether immune alterations in the perioperative period might be induced, at least in part, by impaired thermoregulation during this period.

Methods

Sixty patients undergoing abdominal surgery were randomly assigned to two thermal care groups: routine care or forced-air warming. The patients' anesthetic care was standardized. Venous blood samples were collected 90 min before induction of anesthesia and immediately, 24 h, and 48 h after surgery. White cells were separated and frozen. Peripheral blood mononuclear cells were used to test cytokine production (interleukins [IL] -1beta, -2, and -6; tumor necrosis factor-alpha [TNF-alpha]), mitogens-induced proliferation, and natural killer NK cell cytotoxicity. Plasma cortisol levels were also determined.

Results

Patients in the normothermia group maintained normal body core temperature, whereas temperature decreased by approximately 1 degree C in the hypothermia group. Mitogenic responses were suppressed in cells from patients in the hypothermia but not in the normothermia group 24 and 48 h after surgery. Proinflammatory cytokine (IL-1beta, IL-6, TNF-alpha) production increased in both groups, although the production of IL-1beta was significantly higher in the normothermia group 24 h after surgery. Production of IL-2 was suppressed in the hypothermia but not in the normothermia group at 24 h.

Conclusions

Mild perioperative hypothermia suppressed mitogen-induced activation of lymphocytes and reduced the production of certain cytokines, IL-1beta and IL-2, and in this way may contribute to the immune alterations observed in the perioperative period.
A Prospective Evaluation of Clinical Tests for Placement of Laryngeal Mask Airways
Authors: Joshi Shailendra , Sciacca Robert R. , Solanki Daneshvari , Young William L , Mathru Mali M.
Published: November 2003

Background

Reliable tests of correct anatomic placement of the laryngeal mask airway (LMA) may enhance safety during use and minimize the need for fiberoptic instrumentation during airway manipulation through the device. This study assessed the correlation between the outcomes of nine clinical tests to place the LMA and the anatomic position of the device as graded on a standard fiberoptic scale.

Methods

During 150 anesthetics, the outcome of nine clinical tests of correct placement was individually scored as satisfactory (positive) or unsatisfactory (negative) for clinical use of the LMA. Anatomic placement was assessed (by fiberoptic evaluation) by an anesthesiologist, who was blinded to the placement of the device, as grade 1, vocal cords not seen; grade 2, cords plus the anterior epiglottis seen; grade 3, cords plus the posterior epiglottis seen; and grade 4, only vocal cords seen. The outcomes of clinical tests were correlated with fiberoptic grade.

Results

Tests that correlated with the fiberoptic grade were the ability to generate an airway pressure of 20 cm water, the ability to ventilate manually, a black line on the LMA in midline, anterior movement of the larynx, outward movement of the LMA on inflation of the cuff, and movements of the reservoir bag with spontaneous breathing. Two tests, ability to generate airway pressure of 20 cm water and ability to ventilate manually, correlated with fiberoptic grades 4 and 3 combined (i.e., the epiglottis was supported by the LMA) and grade 2 (the epiglottis was not supported by the LMA). Tests with poor correlation with fiberoptic grade were the presence of resistance at the end of insertion, inability to advance LMA after inflation of the cuff, and presence of a capnographic trace.

Conclusions

The outcome of clinical tests correlates with the anatomic placement of LMAs, as judged by fiberoptic examination. Two tests that best correlated with the fiberoptic grade were the ability to generate airway pressure of 20 cm water and the ability to ventilate manually.
Inhaled Nitric Oxide, Almitrine Infusion, or Their Coadministration as a Treatment of Severe Hypoxemic Focal Lung Lesions
Authors: Payen Didier , Muret Jane , Beloucif Sadek , Gatecel Claire , Kermarrec Nathalie , Guinard Nathalie , Mateo Joaquim
Published: November 2003

Background

The partition of pulmonary blood flow between normal and shunting zones is an important determinant of oxygen tension in arterial blood (PaO2). The authors hypothesized that the combination of inhaled nitric oxide (iNO) and almitrine infusion might have additional effects related to their pharmacologic properties to improve PaO2. Such a combination was tested in patients with hypoxia caused by focal lung lesions, distinct from the acute respiratory distress syndrome.

Methods

Fifteen patients with hypoxic focal lung lesions despite optimal therapy were included and successively treated with (1) 5 ppm iNO, (2) low-dose almitrine infusion (5.5 +/- 1.7 microg x kg(-1) min(-1)) during iNO, and (3) almitrine infusion alone (with NO turned off). Then iNO was reintroduced and we studied the effect of the coadministration in reducing the fractional concentration of oxygen in inspired gas (FI(O2)) and positive end-expiratory pressure (PEEP) levels. Changes in blood gases and pulmonary and systemic hemodynamics were measured.

Results

Systemic hemodynamic variables remained stable in all protocol conditions. Use of iNO improved arterial oxygenation and decreased intrapulmonary shunt. Almitrine similarly improved PaO2 but increased pulmonary artery pressure and right atrial pressure. Coadministration of iNO and almitrine improved PaO2 compared with each drug alone and with control. All patients responded (that is, they had at least a +30% increase in PaO2) to this coadministration. When the drug combination was continued, FI(O2) and PEEP could be reduced over 8 h. The hospital mortality rate was 33% and unrelated to hypoxia.

Conclusions

In hypoxemic focal lung lesions, iNO or low-dose almitrine markedly improved PaO2 to a similar extent. Furthermore, the coadministration amplified the PaO2 increase at a level that allowed reductions in FI(O2) and PEEP levels.
Effects of Halothane and Isoflurane on β-adrenoceptor-mediated Responses in the Vascular Smooth Muscle of Rat Aorta
Authors: Tanaka Satoru , Tsuchida Hideaki
Published: November 2003

Background

Although previous studies have proposed that anesthetics may influence signal transduction systems, their effects on the beta-adrenoceptor-mediated system have not been fully characterized in vascular smooth muscle. The aim of this study was to determine how halothane and isoflurane affect beta-adrenoceptor-mediated vasodilation in rat aorta and what mechanisms were involved.

Methods

Isometric tension and the intracellular calcium ion concentration ([Ca2+]i) were measured concomitantly in rat aortic strips from which the endothelium was removed. Strips precontracted with norepinephrine were dilated with the beta-adrenoceptor agonist, isoproterenol; the adenylyl cyclase activator, forskolin; or the membrane-permeable dibutyryl cyclic adenosine monophosphate (cAMP) with or without halothane or isoflurane. The effects of the anesthetics on each vasodilator were compared with the control responses. Beta-adrenoceptor binding characteristics and affinity for agonists were determined with [125I]-iodocyanopindolol with and without halothane or isoflurane. Furthermore, concentrations of cAMP induced by either isoproterenol or forskolin were measured with or without the anesthetics using an enzyme immunoassay procedure.

Results

Halothane and isoflurane attenuated vasodilation and [Ca2+]i decreases induced by isoproterenol, whereas both anesthetics only slightly affected vasodilation and [Ca2+]i decreases induced by forskolin and dibutyryl cAMP. Halothane and isoflurane had no effect on beta-adrenoceptor binding characteristics and affinity for agonists. Three percent halothane or 4% isoflurane significantly reduced cAMP levels induced by isoproterenol but not by forskolin.

Conclusions

Halothane and isoflurane, at clinically relevant concentrations, can interfere with beta-adrenoceptor-mediated responses in the rat aorta at the steps after the agonist-receptor binding but before the adenylyl cyclase activation.
Effect of Intravenous Anesthetics on Spontaneous and Endotoxin-stimulated Cytokine Response in Cultured Human Whole Blood
Authors: Larsen Brita , Hoff Gudrun , Wilhelm Wolfram , Buchinger Heiko , Wanner Guido A. , Bauer Michael
Published: November 2003

Background

Various anesthetics have been suggested to interfere with the immune system. The ability of leukocytes to express surface receptors and mediators is fundamental to a successful host defense. Therefore, the effects of intravenous anesthetics on cytokine release by leukocytes and expression of surface molecules known to modulate this response were determined.

Methods

Concentration-dependent effects of thiopentone, etomidate, propofol, ketamine, midazolam, and fentanyl on spontaneous and endotoxin (lipopolysaccharide; 1 microg/ml)-stimulated cytokine release were studied in whole blood from volunteers (n = 6) cultured for 25 h. In addition, expression of the lipopolysaccharide-recognition molecule CD14 and the major histocompatibility complex class II molecule human leukocyte locus A system-DR (HLA-DR) on monocytes were assessed using flow cytometry.

Results

All anesthetics studied elicited only minor effects on spontaneous cytokine release even at pharmacologic concentrations. However, expression density of CD14 was reduced in the presence of thiopentone, etomidate, and propofol, whereas HLA-DR was unaffected. Lipopolysaccharide-stimulated tumor necrosis factor response was inhibited by thiopentone (12.8% [median]; 7.6-18.8 [25-75 percentile]) of control, and ketamine (46.4% [median]; 44.4-56.4 [25-75 percentile]), at pharmacologic concentrations, whereas it was augmented even in the presence of low concentrations of propofol (172.3% [median]; 120.5-200.7 [25-75 percentile]). Ketamine additionally decreased the concentration of interleukin (IL)-1beta (14.8% [median]; 12.0-18.0 [25-75 percentile]). Release of IL-1 receptor antagonist (IL-1ra) was inhibited by thiopentone, etomidate, and propofol, whereas the same anesthetics increased IL-10 concentration simultaneously. Midazolam and fentanyl did not alter the concentrations of any cytokine.

Conclusions

These results suggest a complex modulation of the cytokine response by the studied anesthetics in cultured whole blood. Although effects on spontaneous cytokine release by leukocytes were negligible, some anesthetics affected their ability to respond to lipopolysaccharide.
Systolic Pressure Variation as a Guide to Fluid Therapy in Patients with Sepsis-induced Hypotension
Authors: Tavernier Benoit , Makhotine Olivier , Lebuffe Gilles , Dupont Jacques , Scherpereel Philippe
Published: November 2003

Background

Monitoring left ventricular preload is critical to achieve adequate fluid resuscitation in patients with hypotension and sepsis. This prospective study tested the correlation of the pulmonary artery occlusion pressure, the left ventricular end-diastolic area index measured by transesophageal echocardiography, the arterial systolic pressure variation (the difference between maximal and minimal systolic blood pressure values during one mechanical breath), and its delta down (dDown) component (= apneic - minimum systolic blood pressure) with the response of cardiac output to volume expansion during sepsis.

Methods

Preload parameters were measured at baseline and during graded volume expansion (increments of 500 ml) in 15 patients with sepsis-induced hypotension who required mechanical ventilation. Each volume-loading step (VLS) was classified as a responder (increase in stroke volume index > or = 15%) or a nonresponder. Successive VLSs were performed until a nonresponder VLS was obtained.

Results

Thirty-five VLSs (21 responders) were performed. Fluid loading caused an overall significant increase in pulmonary artery occlusion pressure and end-diastolic area index, and a significant decrease in systolic pressure variation and delta down (P < 0.01). There was a significant difference between responder and nonresponder VLSs in end-diastolic area index, systolic pressure variation, and dDown, but not in pulmonary artery occlusion pressure. Receiver-operator curve analysis showed that dDown was a more accurate indicator of the response of stroke volume index to volume loading than end-diastolic area index and pulmonary artery occlusion pressure. A dDown component of more than 5 mmHg indicated that the stroke volume index would increase in response to a subsequent fluid challenge (positive and negative predictive values: 95% and 93%, respectively).

Conclusion

The dDown component of the systolic pressure variation is a sensitive indicator of the response of cardiac output to volume infusion in patient with sepsis-induced hypotension who require mechanical ventilation.
A Randomized Study of Combined Spinal-Epidural Analgesia versus Intravenous Meperidine during Labor
Authors: Gambling David R. , Sharma Shiv K. , Ramin Susan M. , Lucas Michael J. , Leveno Kenneth J. , Wiley Jackie , Sidawi Elaine J.
Published: November 2003

Background

Combined spinal-epidural (CSE) analgesia produces rapid-onset pain relief and allows ambulation in early labor. Epidural local anesthetics may contribute to an increase in operative deliveries by decreasing perineal sensation and causing motor weakness. Operative delivery rates might be reduced with CSE, by avoiding or delaying administration of local anesthetics. This study compares the operative delivery rates associated with a CSE technique and those associated with intravenous meperidine for labor analgesia.

Methods

Healthy parturients at full term were assigned randomly to receive CSE or intravenous meperidine analgesia. The CSE group received 10 microg intrathecal sufentanil, followed by epidural bupivacaine and fentanyl at their next request for analgesia. Parturients receiving intravenous meperidine had 50 mg on demand (maximum, 200 mg in 4 h). Labor and delivery outcomes in both groups were recorded and compared.

Results

An intent-to-treat analysis of 1,223 women indicated that CSE does not increase the rate of cesarean delivery for dystocia in nulliparous and parous women (CSE, 3.5% vs. intravenous meperidine, 4; P=not significant) or in nulliparous women alone (CSE, 7% vs. intravenous meperidine, 8%; P=not significant). Profound fetal bradycardia that necessitated emergency cesarean delivery within 1 h of the time the mother received sufentanil occurred in 8 of 400 parturients (compared with 0 of 352 who received meperidine; P < 0.01). However, the method of fetal monitoring differed between the two groups. Despite this, neonatal outcomes were similar overall.

Conclusions

Combined spinal-epidural analgesia during labor does not increase the cesarean delivery rate for dystocia in healthy parturient patients at full term, regardless of parity. However, an unexpected increase in the number of cesarean deliveries for profound fetal bradycardia after intrathecal sufentanil was observed. Further investigation is warranted.
Bupivacaine 0.01% and/or Epinephrine 0.5 [micro sign]g/ml Improve Epidural Fentanyl Analgesia after Cesarean Section
Authors: Cohen Shaul , Lowenwirt Isaac , Pantuck Carol B. , Amar David , Pantuck Eugene J.
Published: November 2003

Background

The authors studied the addition of bupivacaine and epinephrine, separately and together, to epidural fentanyl to determine whether this improved postcesarean analgesia and reduced the incidence of side effects.

Methods

After elective cesarean section, 100 parturient patients who received fentanyl (3 microg/ml) epidurally for 48 h were allocated randomly in a double-blinded manner to four groups to receive, in addition to the study solution, 0.01% bupivacaine, 0.5 microg/ml epinephrine, both, or neither. A neurologic assessment of breast-fed neonates was made at 2 and 48 h of life. Plasma fentanyl concentrations were determined in a subset of patients at intervals after treatment.

Results

Patients receiving fentanyl alone made more attempts at patient-controlled analgesia (P < 0.01), required a greater total dose of fentanyl (P < 0.01), reported more pain (P < 0.003) and less satisfaction (P < 0.003), and had more nausea and urinary retention (P < 0.05) than all other groups. Patients who received bupivacaine with or without epinephrine had better overall satisfaction scores than those who did not receive bupivacaine (P < 0.001), and they required less fentanyl (P < 0.02) than patients who received fentanyl with only epinephrine. Motor blockade or orthostatic hypotension did not develop in any patient, and all patients could ambulate without difficulty. Neurobehavioral scores, which were similar among all neonates, were within the normal range. Plasma concentrations of fentanyl increased after epinephrine-containing solutions were discontinued.

Conclusions

During the conditions of this study, the addition of epinephrine and bupivacaine to a 3-microg/ml epidural fentanyl solution for postcesarean section pain relief provided superior analgesia compared with fentanyl alone or fentanyl with epinephrine. Whether increasing the concentration of fentanyl alone might improve the efficacy of fentanyl remains unclear.
Effect of Various Lithotomy Positions on Lower-extremity Blood Pressure
Authors: Halliwill John R. , Hewitt Scott A. , Joyner Michael J. , Warner Mark A.
Published: November 2003

Background

Compartment syndrome of a lower extremity from hypoperfusion is a rare but potentially devastating complication of the lithotomy position during surgery. The aim of this study is to determine the effects of various lithotomy positions on lower-extremity blood pressures.

Methods

Blood pressure in eight young, healthy people was studied for 10 lithotomy positions. Blood pressure measurements were taken in both the upper arm (brachial artery) and the lower extremity (dorsalis pedis). The heart-to-ankle height gradient in each position was measured, and a predicted lower-extremity systolic pressure was calculated. The measured and predicted lower-extremity systolic blood pressures were compared with repeated measures analysis of variance.

Results

As a group, the mean systolic blood pressures in the lower extremities correlated closely with the predicted values. However, the difference between measured and predicted pressures varied among the 10 positions (P < 0.05).

Conclusions

Although lower-extremity systolic blood pressures in the young, healthy volunteers correlated with predicted values, there was an additional reduction in pressure associated with the lithotomy position. This surprising finding suggests that a lengthy procedure necessitating the use of a lithotomy position for only a portion should be planned so the remainder of the procedure can take place before establishing the position or so the position can be changed to an alternative position when it is no longer needed.
Interaction of Intrathecally Infused Morphine and Lidocaine in Rats (Part I)
Authors: Saito Yoji , Kaneko Megumi , Kirihara Yumiko , Sakura Shinichi , Kosaka Yoshihiro
Published: November 2003

Background

Synergistic antinociception of opioids and local anesthetics has been established in bolus injections but not in long-term use. The somatic and visceral antinociceptive effects of intrathecally infused morphine or lidocaine were characterized, and the nature of the interaction of those agents in rats was evaluated.

Methods

Intrathecal catheters were implanted in rats. Morphine (0.3 to 10 microg x kg(-1) x h(-1)), lidocaine (30-1,000 microg x kg(-1) x h(-1)), a combination of those, or saline was infused intrathecally at a constant rate of 1 microl/h for 6 days. The tail flick and colorectal distension tests were used to measure the somatic and visceral antinociceptive effects, respectively. Nociceptive tests and motor function tests were repeated on days 1, 2, 3, 4, and 6. Isobolographic analysis was performed on the results of the tail flick test to determine the magnitude of the interaction.

Results

Intrathecally infused morphine produced dose-dependent antinociceptive effects in both the tail flick and the colorectal distension tests. Morphine showed a lower peak percentage maximum possible effect (%MPE) in the colorectal distension test than in the tail flick test. Intrathecal lidocaine also produced dose-dependent antinociceptive effects. Lidocaine infusion at 1,000 microg x kg(-1) x h(-1) caused motor impairment. Coinfusion of morphine 0.3 microg x kg(-1) x h(-1) and lidocaine 200 microg x kg(-1) x h(-1), which had no effects by themselves, significantly increased the percentage maximum possible effects (P < 0.01). Coinfused lidocaine potentiated the duration and the magnitude of morphine antinociception. Isobolographic analysis of the tail flick test on day 1 showed a synergistic interaction between morphine and lidocaine.

Conclusions

Morphine and lidocaine intrathecally coadministered synergistically potentiated the antinociceptive effects of each other. That coinfusion dramatically potentiated visceral antinociception, whereas the infusion of morphine alone showed little visceral antinociception.
Recovery from Sevoflurane Anesthesia
Authors: Ebert Thomas J. , Robinson Brian J. , Uhrich Toni D. , Mackenthun Arden , Pichotta Philip J.
Published: November 2003

Background

Sevoflurane has a lower blood:gas partition coefficient than isoflurane, which may cause a more rapid recovery from anesthesia; it also might cause faster emergence times than for propofol-based anesthesia. We evaluated a database that included recovery endpoints from controlled, randomized, prospective studies sponsored by Abbott Laboratories that compared sevoflurane to isoflurane or propofol when extubation was planned immediately after completion of elective surgery in adult patients.

Methods

Sevoflurane was compared to isoflurane in eight studies (N=2,008) and to propofol in three studies (N=436). Analysis of variance was applied using least squares method mean values to calculate the pooled mean difference in recovery endpoints between primary anesthetics. The effects of patient age and case duration also were determined.

Results

Sevoflurane resulted in statistically significant shorter times to emergence (-3.3 min), response to command (-3.1 min), orientation (-4.0 min) and first analgesic (-8.9 min) but not time to eligibility for discharge (-1.7 min) compared to isoflurane (mean difference). Times to recovery endpoints increased with increasing case duration with isoflurane but not with sevoflurane (patients receiving isoflurane took 4-5 min more to emerge and respond to commands and 8.6 min more to achieve orientation during cases longer than 3 hr in duration than those receiving sevoflurane). Patients older than 65 yr had longer times to orientation, but within any age group, orientation was always faster after sevoflurane. There were no differences in recovery times between sevoflurane and propofol.

Conclusions

Recovery from sevoflurane was 3-4 min faster than with isoflurane in all age groups, and the difference was magnified in longer-duration surgical cases (> 3 hr).
Halothane Attenuates Calcium Sensitization in Airway Smooth Muscle by Inhibiting G-proteins
Authors: Kai Tetsuya , Jones Keith A. , Warner David O.
Published: November 2003

Background

Halothane directly relaxes airway smooth muscle partly by decreasing the Ca2+ sensitivity. In smooth muscle, receptor stimulation is thought to increase Ca2+ sensitivity via a cascade of heterotrimeric and small monomeric guanine nucleotide-binding proteins (G-proteins). Whether this model is applicable in the airway and where halothane acts in this pathway were investigated.

Methods

A beta-escin-permeabilized canine tracheal smooth muscle preparation was used. Exoenzyme C3 of Clostridium botulinum, which inactivates Rho monomeric G-proteins, was used to evaluate the involvement of this protein in the Ca2+ sensitization pathway. The effects of halothane on different stimulants acting at different levels of signal transduction were compared: acetylcholine on the muscarinic receptor, aluminum fluoride (AIF4-) on heterotrimeric G-proteins, and guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) on all G-proteins.

Results

Exoenzyme C3 equally attenuated acetylcholine- and AIF4--induced Ca2+ sensitization, suggesting that these pathways are both mediated by Rho. Halothane applied before stimulation equally attenuated acetylcholine- and AIF4--induced Ca2+ sensitization. However, when added after Ca2+ sensitization was established, the effect of halothane was greater during Ca2+ sensitization induced by acetylcholine compared with AIF4-, which, along with the previous result, suggests that halothane may interfere with dissociation of heterotrimeric G-proteins. Halothane applied during GTPgammaS-induced Ca2+ sensitization had no significant effect on force, suggesting that halothane has no effect downstream from monomeric G-proteins.

Conclusion

Halothane inhibits increases in Ca2+ sensitivity of canine tracheal smooth muscle primarily by interfering with the activation of heterotrimeric G-proteins, probably by inhibiting their dissociation.
Obstetric Postanesthesia Care Unit Stays
Authors: Cohen Sheila E. , Hamilton Catherine L. , Riley Edward T. , Walker Dean S. , Macario Alex , Halpern Jerry W.
Published: November 2003

Background

Obstetric patients may have long postanesthesia care unit (OB-PACU) stays after surgery because of residual regional block or other conditions. This study evaluated whether modified discharge criteria might allow for earlier discharge without compromising patient safety.

Methods

Data were prospectively collected for 6 months for all patients (N=358) who underwent cesarean section or tubal ligation and recovered in the OB-PACU. Regional anesthesia was used in 94% of patients. The duration of anesthesia and PACU stays, the presence and treatment of events in the PACU, and the regression of neural blockade were recorded. Discharge from the OB-PACU required a 60-min minimum stay, stable vital signs, adequate analgesia, and ability to flex the knees. After completion of prospective data collection, events that kept patients in the PACU after 60 min were reevaluated as to whether patients needed to stay in the PACU for medical reasons. "Needed to stay" events included bleeding, cardiorespiratory problems, sedation, dizziness, and pain. "Safe to leave" conditions included pruritus, nausea, and residual neural blockade. The cumulative duration of OB-PACU stays not clearly justifiable for medical reasons was calculated.

Results

Residual block and spinal opioid side effects accounted for the majority of "unnecessary" stays. Annually, 429 h of PACU time could have been saved using the revised criteria. Complications did not develop subsequently in any patient deemed "safe to leave."

Conclusions

In many obstetric patients, the duration of PACU stays could safely be shortened by continuing observation in a lower-acuity setting. This may result in greater flexibility and more efficient use of nursing personnel.
Population Pharmacokinetics of Piritramide in Surgical Patients
Authors: Bouillon Thomas , Kietzmann Daniela , Port Rudiger , Meineke Ingolf , Hoeft Andreas
Published: November 2003

Background

Piritramide is a synthetic opioid used for postoperative analgesia in several European countries. The authors present a mixed-effects model of its population pharmacokinetics in patients undergoing surgery.

Methods

After institutional approval and informed patient consent was obtained, 29 patients who were classified as American Society of Anesthesiologists physical status I or II and aged 21-82 yr were enrolled in the study. They received 0.2 mg/kg piritramide as an intravenous bolus before anesthesia was induced. Central venous blood samples were drawn for as long as 48 h after administration of the drug. The plasma concentration of piritramide was determined by gas chromatography. The concentration-time data were analyzed by mixed-effects modeling. Target-controlled infusions and intermittent bolus regimens were simulated to identify a regimen suitable for patient-controlled analgesia based on population pharmacokinetics and published pharmacodynamic data.

Results

The pharmacokinetics of piritramide were described adequately by a linear three-compartment model. Patient age and weight were significant covariates. The values of the pharmacokinetic parameters are: V1 = 50.5 [1], V2 = 150 x (1 + 9.32 x 10(-3) x (age - 47 yr)) [l], V3 = 212 x (1 + 6.37 x 10(-3) x (age - 47 yr)) [l], Cl1 = 0.56 x (1 - 6.14 x 10(-3) x (age - 47 yr)) [l/min], Cl2 = 8.25 x (1 + 2.02 x 10(-2) x (Wt - 74 kg)) [l/min], Cl3 = 0.80 [l/min]. The age of 47 yr and the weight of 74 kg refer to the median values for these factors in the patients studied. Rapid distribution, slow distribution, and elimination half-lives for the median patient are 0.05, 1.34, and 10.43 h, respectively. The context-sensitive half-time after a 24-h infusion is predicted at 10.5 h in a 75-yr-old patient compared with 7 h for the median patient.

Conclusions

Piritramide is distributed extensively and eliminated slowly. The pharmacokinetic profile of the drug allows for intermittent bolus administration even when constant effect compartment concentrations are desirable, e.g., for PLA.
Milrinone Modulates Endotoxemia, Systemic Inflammation, and Subsequent Acute Phase Response after Cardiopulmonary Bypass (CPB)
Authors: Mollhoff Thomas , Loick Heinz M. , Van Aken Hugo , Schmidt Christoph , Rolf Norbert , Tjan Tonny D. T. , Asfour Boulos , Berendes Elmar
Published: November 2003

Background

Compromised splanchnic perfusion and the resulting intestinal mucosal injury leads to a decreased mucosal barrier function, which allows translocation of intestinal flora and endotoxemia. The authors evaluated the effects of milrinone on splanchnic oxygenation, systemic inflammation, and the subsequent acute-phase response in patients undergoing coronary artery bypass grafting.

Methods

This open, placebo-controlled randomized clinical study enrolled 22 adult patients in two groups. Before induction of anesthesia, baseline values were obtained and patients were randomized to receive milrinone (30 microg/kg bolus administered progressively in 10 min, followed by a continuous infusion of 0.5 microg x kg(-1) x min(-1)) or saline. The following parameters were determined: hemodynamics; systemic oxygen delivery and uptake; arterial, mixed venous and hepatic venous oxygen saturation; intramucosal pH (pHi); and mixed and hepatic venous plasma concentrations of endotoxin, interleukin 6, serum amyloid A, and C-reactive protein.

Results

Milrinone did not prevent gastrointestinal acidosis as measured by pHi, but its perioperative administration resulted in significantly higher pHi levels compared with control. Venous and hepatic venous endotoxin and the interleukin 6 concentration were reduced significantly in the milrinone group. Serum amyloid A values were attenuated in the milrinone group 24 h after surgery. No significant differences could be seen in routinely measured oxygen transport-derived variables.

Conclusions

Perioperative administration of low-dose milrinone may have antiinflammatory properties and may improve splanchnic perfusion in otherwise healthy patients undergoing routine coronary artery bypass grafting.
Volume Kinetics of Ringer's Solution in Hypovolemic Volunteers
Authors: Drobin Dan , Hahn Robert G.
Published: November 2003

Background

The amount of Ringer's solution needed to restore normal blood volumes is thought to be three to five times the volume of blood lost. This therapy can be optimized by using a kinetic model that takes accounts for the rates of distribution and elimination of the infused fluid.

Methods

The authors infused 25 ml/kg Ringer's acetate solution into 10 male volunteers who were 23 to 33 yr old (mean, 28 yr) when they were normovolemic and after 450 ml and 900 ml blood had been withdrawn. One-volume and two-volume kinetic models were fitted to the dilution of the total venous hemoglobin and plasma albumin concentrations.

Results

Withdrawal of blood resulted in a progressive upward shift of the dilution-time curves of both markers. The two-volume model was statistically justified in 56 of the 60 analyzed data sets. The hemoglobin changes indicated that the body fluid space expanded by the infused fluid had a mean total volume of 10.7 l(+/-0.9 SEM). The elimination rate constant (kr) decreased with the degree of hypovolemia and was 133 ml/min (22 ml/min [SEM]), 100 ml/min (39 ml/min [SEM]), and 34 ml/min (7 ml/min [SEM]), respectively (P < 0.01). Plasma albumin indicated a slightly larger body fluid space expanded by the infused fluid, but kr was less (P < 0.02). Hypovolemia reduced the systolic and diastolic blood pressures by approximately 10 mmHg (P < 0.05).

Conclusions

The dilution of the blood and the retention of infused Ringer's solution in the body increases in the presence of hypovolemia, which can be attributed chiefly to a reduction of the elimination rate constant.
Reducing Myoclonus after Etomidate
Authors: Doenicke Alfred W. , Roizen Michael F. , Kugler Johann , Kroll Heike , Foss Joseph , Ostwald Philipp
Published: November 2003

Background

The authors hypothesized that myoclonus after etomidate is dose-related, could be suppressed when small doses of etomidate were administered before induction, and is unassociated with seizure-like activity on electroencephalogram (EEG).

Methods

Three studies were performed. In the first study, 36 men were randomly assigned to receive 0.025, 0.050, 0.075, 0.100, 0.200, or 0.300 mg/kg of etomidate. In a second crossover study, eight men were randomly allocated to receive either a pretreatment dose of 0.050 mg/kg etomidate or placebo 50 s before 0.300 mg/kg etomidate was injected. EEG was recorded for subjects in the first two studies. In a third study, 60 patients were randomly allocated to one of three pretreatment doses of etomidate: 0.030, 0.050, or 0.075 mg/kg before 0.300 mg/kg was given.

Results

In Study 1, myoclonus was not observed after 0.025 or 0.050 mg/kg etomidate. One volunteer had myoclonus after 0.075 mg/kg and another after 0.100 mg/kg etomidate; three had myoclonus after 0.200 mg/kg; and five after 0.300 mg/kg. Incidence of myoclonus was dose-related (P < or = 0.01). In Study 2, two volunteers (25%) with etomidate pretreatment had mild myoclonus compared to six (75%) with placebo pretreatment (P < or = 0.05). EEG changes, other than delta waves, were not seen during myoclonic epochs. In Study 3, myoclonus was less likely after the small pretreatment doses (0.030 or 0.050 mg/kg) than after the large dose (0.075 mg/kg, P < or = 0.01).

Conclusions

Incidence and intensity of myoclonus after induction with etomidate are dose-related, suppressed by pretreatment, and unassociated with seizure-like EEG activity.
Isoflurane Increases the Apparent Agonist Affinity of the Nicotinic Acetylcholine Receptor
Authors: Raines Douglas E. , Zachariah Vinu T.
Published: November 2003

Background

Volatile general anesthetics increase agonist-mediated ion flux through the gamma-aminobutyric acid(A), glycine, and 5-hydroxytryptamine3 (5-HT3) receptors. This action reflects an anesthetic-induced increase in the apparent agonist affinity of these receptors. In contrast, volatile anesthetics block ion flux through the nicotinic acetylcholine receptor (nAcChoR). The authors tested the hypothesis that in addition to blocking ion flux through the nAcChoR, isoflurane also increases the apparent affinity of the nAcChoR for agonist.

Methods

Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana. The apparent agonist affinity of the nAcChoR was determined using a new stopped-flow fluorescence assay. This assay derives the apparent agonist affinity of the nAcChoR from the apparent rates with which agonists convert nAcChoRs from the resting state to the desensitized state.

Results

Isoflurane significantly increased the apparent affinity (decreased the apparent dissociation constant) of acetylcholine for the nAcChoR at clinically relevant concentrations. The apparent dissociation constant decreased exponentially with the isoflurane concentration from a control value of 44+/-4 microM to 1.0+/-0.1 microM in the presence of 1.5 mM isoflurane, the highest concentration studied.

Conclusions

Isoflurane increases the apparent agonist affinity of the nAcChoR; however, this effect is poorly resolved in ion flux studies because isoflurane also causes channel blockade. The lack of saturation of isoflurane's effect on the apparent agonist affinity even at relatively high isoflurane concentrations argues against a single site of anesthetic action. However, it is consistent with isoflurane interactions with several receptor sites that exhibit a range of anesthetic affinities, sites within the membrane lipid, or both.
Ionic Mechanisms Mediating the Differential Effects of Methohexital and Thiopental on Action Potential Duration in Guinea Pig and Rabbit Isolated Ventricular Myocytes
Authors: Martynyuk Anatoly E. , Morey Timothy E. , Raatikainen Pekka M.J. , Seubert Christoph N. , Dennis Donn M.
Published: November 2003

Background

Commonly used barbiturate anesthetics may significantly influence cardiac electrophysiologic characteristics. The authors evaluated thiopental (a thiobarbiturate) and methohexital (an oxybarbiturate), two compounds with similar physicochemical properties but different structures, to determine whether they have distinct effects on the major ionic currents that determine action potential duration (APD) in ventricular myocytes.

Methods

The effects of thiopental and methohexital (50 microM) on APD at 50% (APD50) and 90% (APD90) repolarization were studied in guinea pig and rabbit single ventricular myocytes using the patch-clamp technique in a whole-cell configuration. The ionic mechanisms underlying the APD changes were evaluated by measuring the anesthetics' effects on the L-type calcium inward current, the inward rectifier potassium current, and the delayed rectifier potassium current in guinea pig cells and on the transient outward potassium current in rabbit cells.

Results

Thiopental and methohexital caused opposite effects on APD. Whereas thiopental prolonged APD50 and APD90 in guinea pig and rabbit ventricular myocytes, methohexital shortened them. Thiopental markedly depressed both the inward and outward components of the inward rectifier potassium current, whereas methohexital caused minimal inhibition of the inward component and no change in the outward component. The delayed rectifier potassium current was inhibited by thiopental but significantly potentiated by methohexital. Neither thiopental nor methohexital significantly affected the transient outward potassium current or the L-type calcium inward current.

Conclusions

Despite their similar lipid solubilities, molecular weights, and pKa values, thiopental increased and methohexital decreased the APD in ventricular myocytes by predominantly inhibiting the inward rectifier potassium current and the delayed rectifier potassium current and by increasing the delayed rectifier potassium current, respectively. These characteristics suggest distinct structure-specific actions of barbiturates on the function of myocardial ionic channels.
Inhibitory Effects of Diazepam and Midazolam on Ca2+and K+Channels in Canine Tracheal Smooth Muscle Cells
Authors: Yamakage Michiaki , Matsuzaki Takashi , Tsujiguchi Naoki , Honma Yasuyuki , Namiki Akiyoshi
Published: November 2003

Background

Benzodiazepines have a direct bronchodilator action in airway smooth muscle, but the mechanisms by which these agents produce muscle relaxation are not fully understood. The current study was performed to identify the effects of the benzodiazepines diazepam and midazolam on Ca2+ and K+ channels in canine tracheal smooth muscle cells.

Methods

Whole-cell patch-clamp recording techniques were used to evaluate the effects of the benzodiazepines diazepam (10(-8) to 10(-3) M) and midazolam (10(-8) to 10(-3) M) on inward Ca2+ and outward K+ channel currents in dispersed canine tracheal smooth muscle cells. The effects of the antagonists flumazenil (10(-5) M) and PK11195 (10(-5) M) on these channels were also studied.

Results

Each benzodiazepine tested significantly inhibited Ca2+ currents in a dose-dependent manner, with 10(-6) M diazepam and 10(-5) M midazolam each causing approximately 50% depression of peak voltage-dependent Ca2+ currents. Both benzodiazepines promoted the inactivated state of the channel at more-negative potentials. The Ca2+-activated and voltage-dependent K+ currents were inhibited by diazepam and midazolam (> 10(-5) M and > 10(-4) M, respectively). Flumazenil and PK11195 had no effect on these channel currents or on the inhibitory effects of the benzodiazepines.

Conclusions

Diazepam and midazolam had inhibitory effects on voltage-dependent Ca2+ channels, which lead to muscle relaxation. However, high concentrations of these agents were necessary to inhibit the K+ channels. The lack of antagonized effects of their antagonists is related to the non-gamma-aminobutyric acid-mediated electrophysiologic effects of benzodiazepines on airway smooth muscle contractility.
Bound Volatile General Anesthetics Alter Both Local Protein Dynamics and Global Protein Stability
Authors: Johansson Jonas S. , Zou Helen , Tanner Jonathan W.
Published: November 2003

Background

Recent studies have demonstrated that volatile general anesthetic agents such as halothane and isoflurane may bind to discrete sites on protein targets. In the case of bovine serum albumin, the sites of halothane and chloroform binding have been identified as being located in the IB and IIA subdomains. This structural information provides a foundation for more detailed studies into the potential mechanisms of anesthetic action.

Methods

The effect of halothane and isoflurane and the nonimmobilizer 1,2-dichlorohexafluorocyclobutane on the mobility of the indole ring in the tryptophan residues of albumin was investigated using measurements of fluorescence anisotropy. Myoglobin served as a negative control. In addition, the effect of bound anesthetic agents on global protein stability was determined by thermal denaturation experiments using near-ultraviolet circular dichroism spectroscopy.

Results

The fluorescence anisotropy measurements showed that halothane and isoflurane decreased the mobility of the indole rings in a concentration-dependent manner. The calculated dissociation constants were 1.6+/-0.4 and 1.3+/-0.3 mM for isoflurane and halothane, respectively. In contrast, both agents failed to increase the fluorescence anisotropy of the tryptophan residues in myoglobin, compatible with lack of binding. The nonimmobilizer 1,2-dichlorohexafluorocyclobutane caused no change in the fluorescence anisotropy of albumin. Binding of the anesthetic agents stabilized the native folded form of albumin to thermal denaturation. Analysis of the thermal denaturation data yielded dissociation constant values of 0.98+/-0.10 mM for isoflurane and 1.0+/-0.1 mM for halothane.

Conclusions

Attenuation of local side-chain dynamics and stabilization of folded protein conformations may represent fundamental modes of action of volatile general anesthetic agents. Because protein activity is crucially dependent on inherent flexibility, anesthetic-induced stabilization of certain protein conformations may explain how these important clinical agents change protein function.