bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety of Chronic Intrathecal Morphine Infusion in a Sheep Model
Authors: Gradert Tamara Lee , Baze Wallace B. , Satterfield William C. , Hildebrand Keith R. , Johansen Mary J. , Hassenbusch Samuel J.
Published: November 2003

Background

The safety of chronically administered intrathecal morphine has been questioned. Therefore, the authors examined the behavioral and neurologic effects and neurotoxicity of continuous intrathecal morphine administration in sheep.

Methods

Groups of three sheep were implanted with intrathecal infusion systems for the continuous administration of morphine (3, 6, 9, 12, or 18 mg/day) or saline at a fixed infusion rate of 1.92 ml/day beginning approximately 7 days after implantation. Sheep were examined daily for any changes in behavior or neurologic function. After 28-30 days, the animals were humanely killed. Cerebrospinal fluid samples were collected and analyzed for protein, erythrocytes and leukocytes, and morphine content. The spinal cord and meninges with the catheter in situ was removed en bloc and fixed in formalin for histologic analysis.

Results

Unilateral hind-leg gait deficits were observed in two of three animals in each of the 12- and 18-mg/day dose groups. Gross and microscopic evaluation of spinal cord tissue from these animals revealed intradural-extramedullary inflammatory masses that compressed the spinal cord at the catheter-tip and mid-catheter areas. This inflammation was ipsilateral to extremities that exhibited gait deficits and had acute and chronic cellular components.

Conclusions

The toxicity of intrathecal morphine seems to be dependent on the amount of morphine infused, although the effects of dose versus concentration cannot be clearly distinguished in this study. Intrathecal morphine doses of 12- 18 mg/day produced inflammatory masses extending from the catheter tip down the length of the catheter within the subarachnoid space. Doses of 6-9 mg/day produced mild-to-moderate inflammation 5 cm cranial to the catheter tip. A dose of 3 mg/day produced no neurotoxicity and spinal histopathologic changes that were equivalent to those observed in the saline-treated animals.
Plasticity in Action of Intrathecal Clonidine to Mechanical but Not Thermal Nociception after Peripheral Nerve Injury
Authors: Paqueron Xavier , Conklin Dawn , Eisenach James C.
Published: November 2003

Background

Intrathecal clonidine reduces tactile allodynia in animal models of neuropathic pain, and this effect is blocked by atropine. However, the role of tonic spinal cholinergic activity and its interaction with alpha2-adrenergic systems in normal and neuropathic conditions and to different sensory methods has not been systematically examined. The authors examined cholinergic receptor involvement in thermal and mechanical sensitivity in normal and neuropathic animals and its interaction with intrathecal clonidine.

Methods

Normal rats and rats that received L5/L6 spinal nerve ligation were tested with acute radiant heat, paw pressure, and punctate mechanical stimulation before and after the intrathecal administration of saline, the muscarinic receptor antagonist, atropine, or a toxin to destroy cholinergic neurons, and then after intrathecal clonidine.

Results

Atropine, the cholinergic neuronal toxin, and saline did not alter baseline withdrawal thresholds. In nerve-injured rats, neither saline nor atropine altered antinociception from clonidine to a thermal stimulus, but atropine reduced the effect of clonidine to von Frey filament withdrawal threshold (34 +/- 5.6 vs. 14 +/- 5.8 g [mean +/- SEM], saline vs. atropine; P < 0.05) and to withdrawal threshold to paw pressure after clonidine (174 +/- 18 g vs. 137 +/- 16 g, saline vs. atropine; P < 0.05).

Conclusions

These data suggest that after nerve injury, mechanical but not thermal antinociception from intrathecal clonidine relies on a muscarinic interaction, because only mechanical antinociception was antagonized by atropine. These results do not favor a regulation of nociceptive transmission by a tonic release of acetylcholine in nerve-injured rats.
Protocol for the Sequence Analysis of Ryanodine Receptor Subtype 1 Gene Transcripts from Human Leukocytes
Authors: Kraev Natasha , Loke Julian C. P. , Kraev Alexander , MacLennan David H.
Published: November 2003

Background

The search for novel mutations in the ryanodine receptor subtype 1 (RYR1) gene causing malignant hyperthermia and central core disease is hampered by the fact that the gene contains 106 exons. Searching for novel mutations in complementary DNA (cDNA) requires an invasive muscle biopsy. Accordingly, an alternate source of RYR1 cDNA was sought for sequence analysis.

Methods

Leukocytes were isolated from human blood and used for extraction of RNA and reverse transcription of messenger RNA into cDNA. A detailed protocol was developed in which overlapping fragments of RYR1 cDNA were amplified by polymerase chain reaction in a series of steps and used for double-strand sequencing.

Results

The sequences of full-length leukocyte RYR1 cDNA obtained from four human blood samples were shown to be identical to the sequence of a human muscle RYR1 cDNA. The incidence of aberrant splicing was more pronounced in the blood-derived cDNAs, but this could be minimized by adequate sample preparation. Protocols to sequence alternatively spliced products were also developed. Several silent nucleotide polymorphisms were detected, and minor revisions were made to the RYR1 sequence.

Conclusions

Because there are no differences in RYR1 transcript structure between muscle and leukocytes, aside from those that may be ascribed to RNA splicing aberrations during processing, leukocytes seem to be an adequate substitute tissue for screening the RYR1 gene for previously undiscovered mutations in families with malignant hyperthermia or central core disease.
Detection of a Novel Ryanodine Receptor Subtype 1 Mutation (R328W) in a Malignant Hyperthermia Family by Sequencing of a Leukocyte Transcript
Authors: Loke Julian C. P. , Kraev Natasha , Sharma Parveen , Du GuoGuang , Patel Leena , Kraev Alexander , MacLennan David H.
Published: November 2003

Background

To determine whether malignant hyperthermia (MH) susceptibility in a Canadian pedigree is associated with a mutation in the ryanodine receptor subtype 1 (RYR1) gene, the complete RYR1 transcript obtained from the leukocytes of one MH-susceptible family member was sequenced, using a newly developed protocol.

Methods

RNA was extracted from leukocytes and converted into complementary DNA. Overlapping fragments of RYR1 complementary DNA were amplified by the polymerase chain reaction and used for double-strand sequencing to find a single mutation likely to be causal of MH susceptibility. Inheritance of the mutation in the family was studied by restriction endonuclease analysis and/or sequencing of genomic DNA and compared to available caffeine halothane contracture test data. The mutation was introduced into rabbit RYR1 complementary DNA, the complementary DNA was expressed in human embryonic kidney line 293 cells, and Ca2+ release by the mutant Ca2+ release channel was measured following the addition of caffeine and halothane.

Results

A novel arginine 328 to tryptophan mutation in RYR1 was detected by direct sequencing of the RYR1 transcript from leukocytes of one MH-susceptible individual. A causal role for this mutation in MH is indicated by cosegregation of the mutation with the MH-susceptible phenotype within the family and by the demonstration that the mutant channel has increased sensitivity to both caffeine and halothane.

Conclusions

The feasibility of using complete RYR1 transcripts from leukocytes for sequence analysis offers an efficient and noninvasive method for scanning RYR1 for novel mutations.
Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner
Authors: Mertens Martijn J. , Olofsen Erik , Engbers Frank H. M. , Burm Anton G. L. , Bovill James G. , Vuyk Jaap
Published: November 2003

Background

Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia. The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and evaluated this in relation to previously published data on propofol and alfentanil.

Methods

With ethics committee approval and informed consent, 30 unpremedicated female patients with American Society of Anesthesiologists physical status class I or II, aged 18-65 yr, scheduled to undergo lower abdominal surgery, were randomly assigned to receive a target-controlled infusion of propofol with constant target concentrations of 2, 4, or 6 microg/ml. The target concentration of remifentanil was changed in response to signs of inadequate anesthesia. Arterial blood samples for the determination of remifentanil and propofol concentrations were collected after blood-effect site equilibration. The presence or absence of responses to various perioperative stimuli were related to the propofol and remifentanil concentrations by response surface modeling or logistic regression, followed by regression analysis. Both additive and nonadditive interaction models were explored.

Results

With blood propofol concentrations increasing from 2 to 7.3 microg/ml, the C(50) of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy, from 4.4 ng/ml to 1.2 ng/ml for intubation, and from 6.3 ng/ml to 0.4 ng/ml for intraabdominal surgery. With blood remifentanil concentrations increasing from 0 to 7 ng/ml, the C(50) of propofol for the return to consciousness decreased from 3.5 microg/ml to 0.6 microg/ml.

Conclusions

Propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner.
Spontaneous Breathing Improves Lung Aeration in Oleic Acid–induced Lung Injury
Authors: Wrigge Hermann , Zinserling Jörg , Neumann Peter , Defosse Jerome , Magnusson Anders , Putensen Christian , Hedenstierna Göran
Published: November 2003

Background

Experimental and clinical studies have shown reduction in intrapulmonary shunt with improved oxygenation by spontaneous breathing with airway pressure release ventilation (APRV) in acute lung injury. The mechanisms of these findings are not clear. The authors hypothesized that spontaneous breathing results in better aeration of lung tissue and that improvement in oxygenation can be explained by these changes. This hypothesis was studied in a porcine model of oleic acid-induced lung injury.

Methods

Two hours after induction of lung injury, 24 pigs were randomly assigned to APRV with or without spontaneous breathing at a positive end-expiratory pressure of 5 cm H(2)O. Hemodynamics, spirometry, and end-expiratory lung volume by nitrogen washout were measured at baseline, after 2 h of lung injury, and after 2 and 4 h of mechanical ventilation in the specific mode. Finally, spiral computed tomography of the chest was performed at end-expiratory lung volume in 22 pigs.

Results

Arterial carbon dioxide tension and mean and end-inspiratory airway pressures were comparable between settings. Four hours of APRV with spontaneous breathing resulted in improved oxygenation compared with APRV without spontaneous breathing (arterial oxygen tension, 144 +/- 65 vs. 91 +/- 50 mmHg, P < 0.01 for interaction time x mode), higher end-expiratory lung volume (786 +/- 320 vs. 384 +/- 148 ml, P < 0.001), and better aeration. End-expiratory lung volume and venous admixture were both correlated with the amount of lung reaeration (r(2) = 0.62 and r(2) = 0.61, respectively).

Conclusions

The results support the hypothesis that spontaneous breathing during APRV improves oxygenation mainly by recruitment of nonaerated lung and improved aeration of the lungs.
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.
Mouth Opening
Authors: Calder Ian , Picard John , Chapman Martin , O'Sullivan Caoimhe , Crockard H. Alan
Published: November 2003

Background

The authors hypothesized that craniocervical extension occurs during normal mouth opening.

Methods

Twenty volunteers were studied. Interdental distance was measured at four different degrees of craniocervical extension.

Results

Interdental distance increased from 28 mm (95% confidence interval, 25-30) in slight flexion to 46 mm (95% confidence interval, 42-49) at full extension. Nearly maximal mouth opening was obtained with 26 degrees (95% confidence interval, 22-30) of craniocervical extension from neutral.

Conclusion

Craniocervical extension is an integral part of complete mouth opening in conscious subjects. Fixation of the craniocervical junction by disease, an internal or external fixation device, or technique may restrict mouth opening, with consequences for airway management.
Participation of Children in Clinical Research
Authors: Tait Alan R. , Voepel-Lewis Terri , Malviya Shobha
Published: November 2003

Background

Given the initiatives of the National Institutes of Health and other agencies to include children in research, it is important to understand the factors that influence their participation. This study was designed to identify factors that influence parents' decisions to consent to their child's participation in clinical research.

Methods

This survey study consisted of 505 parents who had been approached for permission to allow their child to participate in a clinical anesthesia or surgery study at a large tertiary care children's hospital. Regardless of whether the parents consented to (consenters, n = 411), or declined (nonconsenters, n = 94) their child's participation in a study, they were offered the opportunity to complete a questionnaire eliciting information regarding factors that had influenced their decision.

Results

Consenters exhibited less uncertainty in their decision making, were more trusting of the medical system, had greater understanding of the research, and believed that the environment in which consent was sought was less pressured than nonconsenters. Predictors of consent included low perceived risk, degree to which the parent read the consent document, characteristics of the consent document, parental understanding, perceived importance of the study, and perceived benefits.

Conclusions

Identification of factors that influence parents' decisions to allow their child to participate in a clinical research study will be important by way of developing strategies to improve the manner in which study information is disclosed and to ensure that parents are truly informed.
Cardiopulmonary Bypass Has Minimal Effects on the Pharmacokinetics of Fentanyl in Adults
Authors: Hudson Robert J. , Thomson Ian R. , Jassal Rajive , Peterson David J. , Brown Aaron D. , Freedman Jeffrey I.
Published: November 2003

Background

Although fentanyl has been widely used in cardiac anesthesia, no complete pharmacokinetic model that has assessed the effect of cardiopulmonary bypass (CPB) and that has adequate predictive accuracy has been defined. The aims of this investigation were to determine whether CPB had a clinically significant impact on fentanyl pharmacokinetics and to determine the simplest model that accurately predicts fentanyl concentrations during cardiac surgery using CPB.

Methods

Population pharmacokinetic modeling was applied to concentration-versus-time data from 61 patients undergoing coronary artery bypass grafting using CPB. Predictive ability of models was assessed by calculating bias (prediction error), accuracy (absolute prediction error), and measured:predicted concentration ratios versus time. The predictive ability of a simple three-compartment model with no covariates was initially compared to models with premedication (lorazepam vs. clonidine), sex, or weight as covariates. This simple model was then compared to 18 CPB-adjusted models that allowed for step changes in pharmacokinetic parameters at the start and/or end of CPB. The predictive ability of the final model was assessed prospectively in a second group of 29 patients.

Results

None of the covariate (premedication, sex, weight) models nor any of the CPB-adjusted models significantly improved prediction error or absolute prediction error, compared to the simple three-compartment model. Thus, the simple three-compartment model was selected as the final model. Prospective assessment of this model yielded a median prediction error of +3.8%, with a median absolute prediction error of 15.8%. The model parameters were as follows: V1, 14.4 l; V2, 36.4 l; V3, 169 l; Cl1, 0.82 l. min-1; Cl2, 2.31 l x min-1; Cl3, 1.35 l x min-1.

Conclusions

Compared to other factors that cause pharmacokinetic variability, the effect of CPB on fentanyl kinetics is clinically insignificant. A simple three-compartment model accurately predicts fentanyl concentrations throughout surgery using CPB.
Effect of Nitroglycerin Inhalation on Patients with Pulmonary Hypertension Undergoing Mitral Valve Replacement Surgery
Authors: Yurtseven Nurgul , Karaca Pelin , Kaplan Mehmet , Ozkul Vedat , Tuygun Abdullah K. , Aksoy Tamer , Canik Sevim , Kopman Ercument
Published: November 2003

Background

The aim of this study was to investigate the postoperative hemodynamic effects of nitroglycerin inhalation on patients with pulmonary hypertension undergoing mitral valve replacement surgery.

Methods

Twenty patients who underwent mitral valve replacement surgery were included in the study. In the surgical intensive care unit, at T0 (before the inhalation of nitroglycerin), basal systemic and pulmonary hemodynamics were recorded. Then, 2.5 microg x kg-1 x min-1 nitroglycerin liquid nebulized by a 2-l gas flow of 40% oxygen and air mixture was administered to the patients who were diagnosed as having pulmonary hypertension (mean pulmonary arterial pressures > 25 mmHg). The same parameters were measured at the first (T1), third (T2), and fifth (T3) hours after the beginning of this treatment and 1 h after the end of nitroglycerin inhalation (T4).

Results

There were no statistically significant differences at T0, T1, T2, T3, or T4 with respect to heart rate, mean arterial pressure, systemic vascular resistance, cardiac index, mixed venous oxygen saturation, arteriovenous oxygen content difference, or arterial carbon dioxide tension. However, mean pulmonary artery pressure, pulmonary vascular resistance, and intrapulmonary shunt fraction were significantly lower, and the arterial oxygen tension/fraction of inspired oxygen ratio was higher at T1, T2, and T3 when compared to that of T0 and T4.

Conclusion

The results suggest that nitroglycerin inhalation produces a significant reduction in both mean pulmonary artery pressure and pulmonary vascular resistance in patients after mitral valve operations without reducing mean arterial pressure and systemic vascular resistance. Therefore, it might be a safe and useful therapeutic intervention during the postoperative course.
Severe Bradycardia during Spinal and Epidural Anesthesia Recorded by an Anesthesia Information Management System
Authors: Lesser Jonathan B. , Sanborn Kevin V. , Valskys Rytis , Kuroda Max
Published: November 2003

Background

Bradycardia and asystole can occur unexpectedly during neuraxial anesthesia. Risk factors may include low baseline heart rate, first-degree heart block, American Society of Anesthesiologists physical status 1, beta-blockers, male gender, and high sensory level. Anesthesia information management systems automatically record large numbers of physiologic variables that are combined with data input from the anesthesiologist to form the anesthesia record. Such large databases can be scanned for episodes of bradycardia.

Methods

To select spinal and epidural anesthetics that did not also involve general anesthesia, 57,240 automated anesthesia records were scanned. Obstetrical patients and patients younger than age 12 yr were excluded. The electronic records selected were then scanned for episodes of moderate (heart rate < 50 and >/= 40 beats/min) or severe (heart rate < 40 beats/min) bradycardia.

Results

A total of 6,663 cases (11.6%) met the inclusion criteria. Among the 677 cases of bradycardia (10.2%) were 46 cases of severe bradycardia (0.7%). In the final multivariate logistic regression analysis, baseline heart rate less than 60 beats/min (P </= 0.0001) and male gender (P </= 0.05) contributed significantly to risk for a severe bradycardia episode (odds ratio [OR]), 14.1 and 95% confidence interval [CI], 6.9-28.0, and OR, 2.1 and 95% CI, 1-4.3, respectively). For the 631 episodes of moderate bradycardia (9.5%), the final multivariate model included baseline heart rate less than 60 beats/min (OR, 16.2; 95% CI, 12.4-22.0), age younger than 37 yr (OR, 1.4; 95% CI, 1.1-1.7), male gender (OR, 1.4; 95% CI, 1.2-1.8), nonemergency status (OR, 1.7; 95% CI, 1.2-2.4), beta-blockers (OR, 1.6; 95% CI, 1.1-2.3), and case duration (OR, 2.0; 95% CI, 1.6-2.4) as significant risk factors. Time of occurrence of a bradycardia event was distributed widely across the entire duration of a case.

Conclusions

Moderate or severe bradycardia may occur at any time during neuraxial anesthesia, regardless of the duration of anesthesia. Low baseline heart rate increases the risk for bradycardia.
Calreticulin Mediates Anesthetic Sensitivity in Drosophila melanogaster
Authors: Gamo Sumiko , Tomida Junya , Dodo Katsuyuki , Keyakidani Dai , Matakatsu Hitoshi , Yamamoto Daisuke , Tanaka Yoshiharu
Published: November 2003

Background

Various species, e.g., Caenorhabditis elegans, Drosophila melanogaster, and mice, have been used to explore the mechanisms of action of general anesthetics in vivo. The authors isolated a Drosophila mutant, ethas311, that was hypersensitive to diethylether and characterized the calreticulin (crc) gene as a candidate of altered anesthetic sensitivity.

Methods

Molecular analysis of crc included cloning and sequencing of the cDNA, Northern blotting, and in situ hybridization to accomplish the function of the gene and its mutation. For anesthetic phenotype assay, the 50% anesthetizing concentrations were determined for ethas311, revertants, and double-mutant strains (wild-type crc transgene plus ethas311).

Results

Expression of the crc 1.4-kb transcript was lower in the mutant ethas311 than in the wild type at all developmental stages. The highest expression at 19 h after pupation was observed in the brain of the wild type but was still low in the mutant at that stage. The mutant showed resistance to isoflurane as well as hypersensitivity to diethylether, whereas it showed the wild phenotype to halothane. Both mutant phenotypes were restored to the wild type in the revertants and double-mutant strains.

Conclusion

ethas311 is a mutation of low expression of the Drosophila calreticulin gene. The authors demonstrated that hypersensitivity to diethylether and resistance to isoflurane are associated with low expression of the gene. In Drosophila, calreticulin seems to mediate these anesthetic sensitivities, and it is a possible target for diethylether and isoflurane, although the predicted anesthetic targets based on many studies in vitro and in vivo are the membrane proteins, such as ion channels and receptors.