bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidural, Cerebrospinal Fluid, and Plasma Pharmacokinetics of Epidural Opioids (Part 2)
Authors: Bernards Christopher M. , Shen Danny D. , Sterling Emily S. , Adkins Jason E. , Risler Linda , Phillips Brian , Ummenhofer Wolfgang 
Published: November 2003

Background
The ability of epinephrine to improve the efficacy of epidurally administered drugs is assumed to result from local vasoconstriction and a consequent decrease in drug clearance. However, because drug concentration in the epidural space has never been measured, our understanding of the effect of epinephrine on epidural pharmacokinetics is incomplete. This study was designed to characterize the effect of epinephrine on the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids.

Methods
Morphine plus alfentanil, fentanyl, or sufentanil was administered epidurally with and without epinephrine (1:200,000) to pigs. Opioid concentration was subsequently measured in the epidural space, central venous plasma, and epidural venous plasma, and these data were used to calculate relevant pharmacokinetic parameters.

Results
The pharmacokinetic effects of epinephrine varied by opioid and by sampling site. For example, in the lumbar epidural space, epinephrine increased the mean residence time of morphine but decreased that of fentanyl and sufentanil. Epinephrine had no effect on the terminal elimination half-life of morphine in the epidural space, but it decreased that of fentanyl and sufentanil. In contrast, in the lumbar intrathecal space, epinephrine had no effect on the pharmacokinetics of alfentanil, fentanyl, or sufentanil, but it increased the area under the concentration-time curve of morphine and decreased its elimination half-life.

Conclusions
The findings indicate that the effects of epinephrine on the spinal pharmacokinetics of these opioids are complex and often antithetical across compartments and opioids. In addition, the data clearly indicate that the pharmacokinetic effects of epinephrine in spinal "compartments" cannot be predicted from measurements of drug concentration in plasma, as has been assumed for decades.
Use of Discharge Abstract Databases to Differentiate among Pediatric Hospitals Based on Operative Procedures
Authors: Dexter Franklin , Wachtel Ruth E. , Yue Jack C. 
Published: November 2003

Introduction
A pediatric hospital may aim to show governmental agencies, charitable organizations, and philanthropic individuals how its clinical services differ from those of nonpediatric surgical facilities and of other pediatric hospitals. Yet, it is unknown how to use existing databases to quantify where infants and young children undergo surgery, and to use that information to differentiate among facilities.

Methods
Discharge abstracts were used to study inpatient and outpatient operative procedures performed between January and June 2001 in children 0-2 yr old at hospitals or hospital-affiliated outpatient surgery centers in Iowa.

Results
Of the 93 facilities performing at least one procedure, the 90 performing 15 or fewer different types of procedures provided surgical care for 80% of procedures. Among procedures performed at these 90 facilities, less than 0.15% were physiologically complex (more than seven American Society of Anesthesiologists' basic units). In contrast, at the larger and smaller pediatric hospitals, the percentages were 26% and 7%, respectively. These pediatric hospitals performed 181 and 73 different types of procedures, respectively; 64% of the physiologically complex procedures performed statewide were performed at the larger pediatric hospital. The smaller pediatric hospital was no more similar to the larger pediatric hospital in its relative volumes of each type of procedure than it was to the other 91 facilities.

Conclusions
Statewide discharge abstract data can be used by a hospital to quantify how its surgical practice differs from that of other hospitals (e.g., to show that it provides a more diverse, comprehensive, and physiologically complex selection of procedures in younger patients).
Hand-cleansing during Postanesthesia Care
Authors: Pittet Didier , Stéphan François , Hugonnet Stéphane , Akakpo Christophe , Souweine Bertrand , Clergue François 
Published: November 2003

Background
Transmission of microorganisms from the hands of healthcare workers is the main source of cross-infection and can be prevented by hand-cleansing. The authors assessed the compliance rate with hand-cleansing practices in the postanesthesia care unit and investigated factors associated with noncompliance.

Methods
Patient care activities, indications for and compliance of postanesthesia care unit staff with hand-cleansing, defined as either washing hands with soap and water or rubbing hands with alcohol, were monitored at the time of patient admission and during their stay. Multivariate analysis identified predictors of noncompliance with hand-cleansing on admission after adjustment for confounders.

Results
A total of 3,143 patient care activities, including 1,091 opportunities for hand-cleansing at high or medium risk for cross-transmission, were recorded among 187 patients. The higher the workload, the higher the number of indications for hand-cleansing and the lower the compliance. Average compliance with hand-cleansing at postanesthesia care unit admission was 19.6%. Independent predictors for noncompliance included caring for patients older than 65 yr (odds ratio, 2.23; 95% confidence interval, 1.40-3.57) and those recovering from clean/clean-contaminated surgery (odds ratio, 2.27; 95% confidence interval, 1.11-4.76), as well as high intensity of patient care (odds ratio, 1.01 per patient care activity; 95% confidence interval, 1.0-1.02). Compliance with hand-cleansing for patients already admitted to the postanesthesia care unit was 12.5%.

Conclusions
Failure to cleanse hands during patient care is common in the postanesthesia care unit and is associated with identifiable factors. The close relation between the intensity of patient care and noncompliance argues that hand-cleansing should not be viewed as a problematic individual behavior only, and system change must be considered in prevention strategies.
Anaphylactic and Anaphylactoid Reactions Occurring during Anesthesia in France in 1999–2000
Authors: Mertes Paul Michel , Laxenaire Marie-Claire , Alla François 
Published: November 2003

Background
Anaphylactic and anaphylactoid reactions occurring during anesthesia remain a major cause of concern for anesthesiologists. The authors report the results of a 2-yr survey of such reactions observed during anesthesia in France.

Methods
Between January 1, 1999, and December 31, 2000, 789 patients who experienced immune-mediated (anaphylaxis) or nonimmune-mediated (anaphylactoid) reactions were referred to one of the 40 participating centers. Anaphylaxis was diagnosed on the basis of clinical history, skin tests, and/or specific immunoglobulin E assay.

Results
Anaphylactic and anaphylactoid reactions were diagnosed in 518 cases (66%) and 271 cases (34%), respectively. The most common causes of anaphylaxis were neuromuscular blocking agents (NMBAs) (n = 306, 58.2%), latex (n = 88, 16.7%), and antibiotics (n = 79, 15.1%). Rocuronium (n = 132, 43.1%) and succinylcholine (n = 69, 22.6%) were the most frequently incriminated NMBAs. Cross-reactivity between NMBAs was observed in 75.1% of cases of anaphylaxis to an NMBA. No difference was observed between anaphylactoid and anaphylactic reactions when the incidences of atopy, asthma, or drug intolerance were compared. However, atopy, asthma, and food allergy were significantly more frequent in the case of latex allergy when compared with NMBA allergy. Clinical manifestations were more severe in anaphylaxis. The positive predictive value of tryptase for the diagnosis of anaphylaxis was 92.6%; the negative predictive value was 54.3%. The diagnostic value of specific NMBA immunoglobulin E assays was confirmed.

Conclusions
These results further corroborate the need for systematic screening in the case of anaphylactoid reaction during anesthesia and for the constitution of allergoanesthesia centers to provide expert advice to anesthesiologists and allergists.
Awareness: Monitoring versus Remembering What Happened
Authors: Kerssens Chantal , Klein Jan , Bonke Benno 
Published: November 2003

Background
Awareness during anesthesia is foremost assessed with postoperative interviews, which may underestimate its incidence. On-line monitors such as the Bispectral Index and patient response to verbal command are not necessarily commonly used. This study investigated response to command during deep sedation (Bispectral Index 60-70) and the ability of prevailing monitoring techniques to indicate awareness and predict recall.

Methods
The authors systematically assessed the response to command using the isolated forearm technique while monitoring electroencephalographic and hemodynamic variables. Fifty-six elective surgical patients were repeatedly given verbal instructions to squeeze the observer's hand during target-controlled infusion with propofol and alfentanil. After recovery, conscious recall was assessed with a short structured interview.

Results
Overall, 1,082 commands were given. No response was observed to 887 (82%) commands, an equivocal response was observed to 56 (5%) commands, and an unequivocal response was observed to 139 (13%) commands. Of the 37 patients (66%) with an unequivocal response to command ("awareness"), nine (25%) reported conscious recall after recovery. Their reports provided valuable insights as to how awareness may be adequately addressed. Hemodynamic variables poorly predicted awareness, whereas parameters derived from the encephalogram, especially the Bispectral Index, were highly significant predictors (P < 0.0001). Electroencephalographic parameters did not discriminate between patients with or without conscious recall, whereas heart rate and responsiveness to command did.

Conclusions
The incidence of awareness is underestimated when conscious recall is taken as evidence. Awareness can be monitored on-line with behavioral and modern neurophysiologic measures. Providing feedback during intra-anesthetic awareness helps patients to cope with a potentially stressful situation.
Effects of Sevoflurane, Propofol, and Adjunct Nitrous Oxide on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans
Authors: Kaisti Kaike K. , Långsjö Jaakko W. , Aalto Sargo , Oikonen Vesa , Sipilä Hannu , Teräs Mika , Hinkka Susanna , Metsähonkala Liisa , Scheinin Harry 
Published: November 2003

Background
Anesthetic agents, especially volatile anesthetics and nitrous oxide (N2O), are suspected to perturb cerebral homeostasis and vascular reactivity. The authors quantified the effects of sevoflurane and propofol as sole anesthetics and in combination with N2O on regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV) in the living human brain using positron emission tomography.

Methods
15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine rCBF, rCMRO2 and rCBV, respectively, in eight healthy male subjects during the awake state (baseline) and at four different anesthetic regimens: (1) sevoflurane alone, (2) sevoflurane plus 70% N2O (S+N), (3) propofol alone, and (4) propofol plus 70% N2O (P+N). Sevoflurane and propofol were titrated to keep a constant hypnotic depth (Bispectral Index 40) throughout anesthesia. End-tidal carbon dioxide was strictly kept at preinduction level.

Results
The mean +/- SD end-tidal concentration of sevoflurane was 1.5 +/- 0.3% during sevoflurane alone and 1.2 +/- 0.3% during S+N (P < 0.001). The measured propofol concentration was 3.7 +/- 0.7 microg/ml during propofol alone and 3.5 +/- 0.7 microg/ml during P+N (not significant). Sevoflurane alone decreased rCBF in some (to 73-80% of baseline, P < 0.01), and propofol in all brain structures (to 53-70%, P < 0.001). Only propofol reduced also rCBV (in the cortex and cerebellum to 83-86% of baseline, P < 0.05). Both sevoflurane and propofol similarly reduced rCMRO2 in all brain areas to 56-70% and 50-68% of baseline, respectively (P < 0.05). The adjunct N2O counteracted some of the rCMRO2 and rCBF reductions caused by drugs alone, and especially during S+N, a widespread reduction (P < 0.05 for all cortex and cerebellum vs. awake) in the oxygen extraction fraction was seen. Adding of N2O did not alter the rCBV effects of sevoflurane and propofol alone.

Conclusions
Propofol reduced rCBF and rCMRO2 comparably. Sevoflurane reduced rCBF less than propofol but rCMRO2 to an extent similar to propofol. These reductions in flow and metabolism were partly attenuated by adjunct N2O. S+N especially reduced the oxygen extraction fraction, suggesting disturbed flow-activity coupling in humans at a moderate depth of anesthesia.
Sevoflurane Confers Additional Cardioprotection after Ischemic Late Preconditioning in Rabbits
Authors: Müllenheim Jost , Ebel Dirk , Bauer Mirco , Otto Florian , Heinen André , Frässdorf Jan , Preckel Benedikt , Schlack Wolfgang 
Published: November 2003

Background
Sevoflurane exerts cardioprotective effects that mimic the early ischemic preconditioning phenomenon (EPC) by activating adenosine triphosphate-sensitive potassium (KATP) channels. Ischemic late preconditioning (LPC) is an important cardioprotective mechanism in patients with coronary artery disease. The authors investigated whether the combination of LPC and sevoflurane-induced preconditioning results in enhanced cardioprotection and whether opening of KATP channels plays a role in this new setting.

Methods
Seventy-three rabbits were instrumented with a coronary artery occluder. After recovery for 10 days, they were subjected to 30 min of coronary artery occlusion and 120 min of reperfusion (I/R). Controls (n = 14) were not preconditioned. LPC was induced in conscious animals by a 5-min period of coronary artery occlusion 24 h before I/R (LPC, n = 15). Additional EPC was induced by a 5-min period of myocardial ischemia 10 min before I/R (LPC+EPC, n = 9). Animals of the sevoflurane (SEVO) groups inhaled 1 minimum alveolar concentration of sevoflurane for 5 min at 10 min before I/R with (LPC+SEVO, n = 10) or without (SEVO, n = 15) additional LPC. The KATP channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg) was given intravenously 10 min before sevoflurane administration (LPC+SEVO+5-HD, n = 10).

Results
Infarct size of the area at risk (triphenyltetrazolium staining) was reduced from 45 +/- 16% (mean+/-SD, control) to 27 +/- 11% by LPC (P < 0.001) and to 27 +/- 17% by sevoflurane (P = 0.001). Additional sevoflurane administration after LPC led to a further infarct size reduction to 14 +/- 8% (LPC+SEVO, P = 0.003 vs. LPC; P = 0.032 vs. SEVO), similar to the combination of LPC and EPC (12 +/- 8%; P = 0.55 vs. LPC+SEVO). Cardioprotection induced by LPC+SEVO was abolished by 5-HD (LPC+SEVO+5-HD, 41 +/- 19%, P = 0.001 vs. LPC+SEVO).

Conclusions
Sevoflurane administration confers additional cardioprotection after LPC by opening of KATP channels.
Sevoflurane Inhibits Guanosine 5′-[γ-thio]triphosphate–stimulated, Rho/Rho-kinase–mediated Contraction of Isolated Rat Aortic Smooth Muscle
Authors: Yu Jingui , Ogawa Koji , Tokinaga Yasuyuki , Hatano Yoshio 
Published: November 2003

Background
The Rho/Rho-kinase signaling pathway plays an important role in mediating Ca2+ sensitization of vascular smooth muscle. The effect of anesthetics on Rho/Rho-kinase-mediated vasoconstriction has not been determined to date. This study is designed to examine the possible inhibitory effects of sevoflurane on the Rho/Rho-kinase pathway by measuring guanosine 5'-[gamma-thio]triphosphate (GTP gamma S)-stimulated contraction and translocation of RhoA (one of the three Rho subtypes) and Rock-2 (one of the two Rho-kinase subtypes) from the cytosol to the membrane in rat aortic smooth muscle.

Methods
GTP gamma S-induced contraction of rat aortic endothelium-denuded rings was measured using an isometric force transducer, and GTP gamma S-stimulated membrane translocation of RhoA and Rock-2 in smooth muscle cells was detected with Western blotting in the presence and absence of sevoflurane.

Results
GTP gamma S (10(-4) m) induced a sustained contraction, which was significantly inhibited by the Rho-kinase inhibitor, Y27632 (3 x 10(-6) m). Before treatment with GTP gamma S, RhoA and Rock-2 were detected primarily in the cytosolic fraction. GTP gamma S (10(-4) m) stimulated the translocation of RhoA and Rock-2 from the cytosol to the membrane, which was sustained for more than 60 min. Sevoflurane (1.7, 3.4, and 5.1%) concentration dependently inhibited the GTP gamma S-induced constriction of rat aortic smooth muscle with a reduction of constriction of 52-75% (P < 0.01, n = 8), and attenuated the translocation of RhoA and Rock-2 by 31-66% and 34-78%, respectively (P < 0.05-0.01, respectively; n = 4).

Conclusion
The current findings show that sevoflurane depresses the GTP gamma S-stimulated contraction and translocation of both Rho and Rho-kinase from the cytosol in a concentration-dependent manner, indicating that sevoflurane is able to inhibit vasoconstriction mediated by the Rho/Rho-kinase pathway in rat aortic smooth muscle.
Pharmacologic Interaction between Cannabinoid and either Clonidine or Neostigmine in the Rat Formalin Test
Authors: Yoon Myung Ha , Choi Jeong Il 
Published: November 2003

Background
Although spinal cannabinoid receptor agonist (WIN 55,212-2) has been shown to encounter various models of pain, the role of two subtypes of cannabinoid receptor for the antinociceptive effect of cannabinoids has not been investigated at the spinal level. Spinal alpha 2 receptor agonist (clonidine) and cholinesterase inhibitor (neostigmine) are also active in the modulation of nociception. The authors examined the properties of drug interaction after coadministration of WIN 55,212-2-clonidine, and intrathecal WIN 55,212-2-neostigmine, and further clarified the role of cannabinoid 1 and 2 receptors in cannabinoid-induced antinociception at the spinal level.

Methods
Catheters were inserted into the intrathecal space of male Sprague-Dawley rats, and 50 microl of 5% formalin solution was injected into the hind paw to evoke the pain. Isobolographic analysis was used for evaluation of pharmacologic interaction.

Results
Intrathecal 55,212-2, clonidine, and neostigmine dose-dependently suppressed the flinching observed during phase 1 and 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of WIN 55,212-2-clonidine or WIN 55,212-2-neostigmine mixture in both phases. The antinociceptive effect of WIN 55,212-2 was antagonized by cannabinoid 1 receptor antagonist (AM 251) but not by cannabinoid 2 receptor antagonist (AM 630). No antinociceptive effect was seen after intrathecal administration of cannabinoid 2 receptor agonist (JWH 133).

Conclusions
Intrathecal 55,212-2, clonidine, and neostigmine attenuate the facilitated state and acute pain. WIN 55,212-2 interacts synergistically with either clonidine or neostigmine. The antinociception of WIN 55,212-2 is mediated through the cannabinoid 1 receptor, but not the cannabinoid 2 receptor, at the spinal level.
A Model of the Ventilatory Depressant Potency of Remifentanil in the Non–steady State
Authors: Bouillon Thomas , Bruhn Joergen , Radu-Radulescu Lucian , Andresen Corina , Cohane Carol , Shafer Steven L. 
Published: November 2003

Background
The C50 of remifentanil for ventilatory depression has been previously determined using inspired carbon dioxide and stimulated ventilation, which may not describe the clinically relevant situation in which ventilatory depression occurs in the absence of inspired carbon dioxide. The authors applied indirect effect modeling to non-steady state Paco2 data in the absence of inspired carbon dioxide during and after administration of remifentanil.

Methods
Ten volunteers underwent determination of carbon dioxide responsiveness using a rebreathing design, and a model was fit to the end-expiratory carbon dioxide and minute ventilation. Afterwards, the volunteers received remifentanil in a stepwise ascending pattern using a computer-controlled infusion pump until significant ventilatory depression occurred (end-tidal carbon dioxide [Peco2] > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 ng/ml. Remifentanil pharmacokinetics and Paco2 were determined from frequent arterial blood samples. An indirect response model was used to describe the Paco2 time course as a function of remifentanil concentration.

Results
The time course of hypercarbia after administration of remifentanil was well described by the following pharmacodynamic parameters: F (gain of the carbon dioxide response), 4.30; ke0 carbon dioxide, 0.92 min-1; baseline Paco2, 42.4 mmHg; baseline minute ventilation, 7.06 l/min; kel,CO2, 0.08 min-1; C50 for ventilatory depression, 0.92 ng/ml; Hill coefficient, 1.25.

Conclusion
Remifentanil is a potent ventilatory depressant. Simulations demonstrated that remifentanil concentrations well tolerated in the steady state will cause a clinically significant hypoventilation following bolus administration, confirming the acute risk of bolus administration of fast-acting opioids in spontaneously breathing patients.
Pharmacodynamic Effect of Morphine-6-glucuronide versus Morphine on Hypoxic and Hypercapnic Breathing in Healthy Volunteers
Authors: Romberg Raymonda , Olofsen Erik , Sarton Elise , Teppema Luc , Dahan Albert 
Published: November 2003

Background
Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is generally associated with less respiratory depression than morphine. Because M6G will be on the market in the near future, the authors assessed the time profile and relative potency of M6G's effect versus morphine's effect on carbon dioxide-driven and hypoxic breathing.

Methods
In nine healthy female volunteers, the effects of 0.2 mg/kg intravenous M6G, 0.13 mg/kg intravenous morphine, and intravenous placebo were tested on ventilation at a fixed end-tidal pressure of carbon dioxide (Petco2) of 45 mmHg (Vi45) and on the acute hypoxic ventilatory response (AHR). All subjects participated in all three arms of the study. Respiratory studies were performed at 1-h intervals for 7 h after drug infusion. The data were analyzed using a population dose-driven approach, which uses a dose rate in function of time as input function driving the pharmacodynamics, and a population pharmacokinetic-pharmacodynamic (PK/PD) approach in which fixed pharmacokinetic parameter values from the literature were used as input function to the respiratory model. From the latter analysis, the authors obtained the blood effect-site equilibration half-life (t1/2ke0) and the effect-site concentration producing 25% depression of Vi45 and AHR (C25). Values reported are mean +/- SE.

Results
Placebo had no effect on Vi45 or AHR over time. Both analysis approaches yielded good descriptions of the data with comparable model parameters. M6G PK/PD model parameters for Vi45 were t1/2ke0 2.1 +/- 0.2 h and C25 528 +/- 88 nm and for AHR were t1/2ke0 1.0 +/- 0.1 h and C25 873 +/- 81 nm. Morphine PK/PD model parameters for Vi45 were t1/2ke0 3.8 +/- 0.9 h and C25 28 +/- 6 nm and for AHR were t1/2ke0 4.3 +/- 0.6 h and C25 16 +/- 2 nm.

Conclusions
Morphine is more potent in affecting hypoxic ventilatory control than M6G, with a potency ratio ranging from 1:19 for Vi45 to 1:50 for AHR. At drug concentrations causing 25% depression of Vi45, M6G caused only 15% depression of AHR, whereas morphine caused greater than 50% depression of AHR. Furthermore, the speed of onset/offset of M6G is faster than morphine by a factor of approximately 2. The authors discuss some of the possible mechanisms for the observed differences in opioid behavior.