bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose-Response Relationship of Intrathecal Morphine for Postcesarean Analgesia
Authors: Palmer Craig M. , Emerson Scott , Volgoropolous Dimitri , Alves Diane
Published: November 2003

Background

This series investigated the quality of analgesia and the incidence and severity of side effects of intrathecal morphine for post-cesarean analgesia administered over a dose range of 0.0-0.5 mg.

Methods

ONE hundred eight term parturients undergoing cesarean delivery at term and given spinal anesthesia were randomized to receive a single dose of intrathecal morphine (0.0, 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, 0.4, or 0.5 mg). A patient-controlled analgesia (PCA) device provided free access to additional analgesics. PCA morphine use, incidence and severity of side effects, and need for treatment interventions were recorded for 24 h. Data were analyzed with analysis of variance and linear regression analysis for trends among groups.

Results

Patient-controlled analgesia use differed significantly between groups; PCA use was higher in the control group than in groups receiving 0.075, 0.1, 0.3, 0.4, or 0.5 mg. Twenty-four-hour PCA morphine use was 45.7 mg lower (95% CI, 4.8-86.6 mg lower) in the 0.075-mg group than the control group. There was no difference in PCA morphine use between the 0.075- and 0.5-mg groups (95% CI, 36.8 mg lower to 45.0 mg higher); despite a fivefold increase in intrathecal morphine dose, PCA morphine use remained constant. There was no difference between control and treatment groups or among treatment groups with respect to nausea and vomiting. Pruritus and the need for treatment interventions increased in direct proportion to the dose of intrathecal morphine (linear regression, P = 0.001 and P = 0.0002, respectively).

Conclusions

These data indicate there is little justification for use of more than 0.1 mg for post-cesarean analgesia. For optimal analgesia, augmentation [corrected] of intrathecal morphine with systemic opioids may be necessary.
Population Pharmacokinetic Modeling in Very Premature Infants Receiving Midazolam during Mechanical Ventilation
Authors: Lee Toong C. , Charles Bruce G. , Harte Glen J. , Gray Peter H. , Steer Peter A. , Flenady Vicki J.
Published: November 2003

Background

Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants.

Methods

Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program.

Results

Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL.

Conclusions

Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.
The Pulmonary First-pass Uptake of Five Nondepolarizing Muscle Relaxants in the Pig
Authors: Beaufort Ton M. , Proost Johannes H. , Houwertjes Martin C. , Roggeveld Jan , Wierda Mark J.K. H.
Published: November 2003

Background

It is not known whether the lungs influence the early pharmacokinetics of muscle relaxants and, if they do, whether differences in pulmonary uptake contribute to the differences in potency and/or onset time among muscle relaxants. Because the lungs are uniquely positioned, receive the entire cardiac output, have a large capillary surface area, and can temporarily store various basic drugs, the authors determined whether substantial pulmonary first-pass uptake of muscle relaxants occurs.

Methods

In 14 pigs, rocuronium, vecuronium, Org 9487, Org 7617, or d-tubocurarine were administered simultaneously with indocyanin green within 1 s into the right ventricle, and then arterial blood was sampled every 1.2 s (in the first min). The tibialis muscle response was registered mechanomyographically.

Results

The maximum block was 93% (68-100% [median and range]). Onset times ranged from 83 s (78-86 s) for rocuronium to 182 s (172-192 s) for d-tubocurarine. Fraction-versus-time outflow curves showed that the peak of muscle relaxants and indocyanin green occurred almost simultaneously. Pulmonary first-pass retention was negligible. The retention of muscle relaxants at 95% passage of indocyanin green was -9% (-31 to 18%). The difference in the mean transit time between muscle relaxant and indocyanin green was 1.0 (0.8 to 1.4), 0.2 (-0.8 to 0.3), 0.3 (0.2 to 0.4), 0.5 (0.2 to 1.3), and -2.2 s for rocuronium, vecuronium, Org 9487, Org 7617, and d-tubocurarine, respectively.

Conclusions

There is no substantial pulmonary first-pass uptake of rocuronium, vecuronium, Org 9487, Org 7617, or d-tubocurarine in pigs. Therefore, differences in pulmonary first-pass uptake do not contribute to the differences in potency and/or onset time among muscle relaxants.
Dexamethasone Changes Brain Monoamine Metabolism and Aggravates Ischemic Neuronal Damage in Rats
Authors: Tsubota Shinzo , Adachi Naoto , Chen Junfeng , Yorozuya Toshihiro , Nagaro Takumi , Arai Tatsuru
Published: November 2003

Background

Glucocorticoids have been reported to aggravate ischemic brain damage. Because changes in the activities of various neuronal systems are closely related to the outcome of ischemic damage, the authors evaluated the effects of dexamethasone on the monoaminergic systems and ischemic neuronal damage.

Methods

The right middle cerebral artery was occluded for 2 h, and the tissue concentrations of monoamines and their metabolites were determined in the cerebral cortex and the striatum of rats. The turnover of 5-hydroxytryptamine was compared in animals injected with saline and those injected with dexamethasone twice (2 mg/kg in each injection) by evaluating the probenecid-induced accumulation of 5-hydroxyindoleacetic acid. The turnovers of norepinephrine and dopamine were estimated from the alpha-methyl-p-tyrosine-induced depletion of norepinephrine and dopamine, respectively. The effect of dexamethasone on the infarct volume was evaluated by triphenyltetrazolium chloride stain in rats subjected to 2 h of occlusion.

Results

Dexamethasone did not affect the cortical 5-hydroxytryptamine or 5-hydroxyindoleacetic acid contents. However, it suppressed the turnover of the cortical 5-hydroxytryptamine on both sides. Dexamethasone reduced the turnover of the striatal 5-hydroxytryptamine and facilitated the dopamine turnover. In rats subjected to 2 h of occlusion and 2 h of reperfusion, the infarct volume was 10.5 times greater in the group that received dexamethasone than in the animals that received saline.

Conclusions

Dexamethasone suppresses the inhibitory serotonergic system and facilitates the excitatory dopaminergic system in the rat telencephalon. This may be a mechanism by which dexamethasone aggravates ischemic neuronal injury.
Vanilloid Receptor Agonists Potentiate the In Vivo Local Anesthetic Activity of Percutaneously Injected Site 1 Sodium Channel Blockers
Authors: Kohane Daniel S. , Kuang Yu , Lu Nu T. , Langer Robert , Strichartz Gary R. , Berde Charles B.
Published: November 2003

Background

Capsaicin, the pungent ingredient in chili peppers, is a vanilloid with noxious and analgesic effects that inhibits tetrodotoxin-resistant sodium currents. Because tetrodotoxin-resistant currents are found primarily in small-diameter nociceptor afferents of the peripheral nerves, their inhibition may lead to selective analgesia. Therefore, the authors evaluated the interactions between tetrodotoxin, a site 1 sodium channel blocker, and capsaicin on nerve blockade in vivo.

Methods

Percutaneous sciatic nerve injections with 0 to 9.9 mM capsaicin, 0 to 120 microM tetrodotoxin, or both were administered to male Sprague-Dawley rats. Thermal nociceptive and motor blockade were measured. Data were expressed as medians with 25th and 75th percentiles.

Results

Capsaicin produced a transient increase in thermal latency with no effect on motor strength. Tetrodotoxin reduced motor strength for a longer duration than nociception. The interaction between tetrodotoxin and capsaicin was synergistic, as evidenced by (1) supraadditive prolongation of both nociceptive and motor block, with the effect of capsaicin reversed by the vanilloid antagonist capsazepine, and (2) synergism in the frequency that rats achieved maximal block shown by isobolographic analysis. The combination of tetrodotoxin and capsaicin showed less motor predominance than tetrodotoxin did alone. Similar interactions were found between tetrodotoxin and resiniferatoxin (another vanilloid), and between capsaicin and saxitoxin (another site 1 sodium channel blocker), but much less so between bupivacaine and capsaicin.

Conclusions

Site 1 sodium channel blockers and vanilloids have synergistic effects on nerve blockade in vivo. These interactions may be useful in developing prolonged local anesthetics and elucidating mechanisms of functionally selective nerve blockade.
GAS-1
Authors: Kayser Ernst-Bernhard , Morgan Phil G. , Sedensky Margaret M.
Published: November 2003

Background

Mutations in several genes of Caenorhabditis elegans confer altered sensitivities to volatile anesthetics. A mutation in one gene, gas-1(fc21), causes animals to be immobilized at lower concentrations of all volatile anesthetics than in the wild-type, and it does not depend on mutations in other genes to control anesthetic sensitivity. gas-1 confers different sensitivities to stereoisomers of isoflurane, and thus may be a direct target for volatile anesthetics. The authors have cloned and characterized the gas-1 gene and the mutant allele fc21.

Methods

Genetic techniques for nematodes were as previously described. Polymerase chain reaction, sequencing, and other molecular biology techniques were performed by standard methods. Mutant rescue was done by injecting DNA fragments into the gonad of mutant animals and scoring the offspring for loss of the mutant phenotype.

Results

The gas-1 gene was cloned and identified. The protein GAS-1 is a homologue of the 49-kDa (IP) subunit of the mitochondrial NADH:ubiquinone-oxidoreductase (complex I of the respiratory chain). gas-1(fc21) is a missense mutation replacing a strictly conserved arginine with lysine.

Conclusions

The function of the 49-kDa (IP) subunit of complex I is unknown. The finding that mutations in complex I increase sensitivity of C elegans to volatile anesthetics may implicate this physiologic process in the determination of anesthetic sensitivity. The hypersensitivity of animals with a mutation in the gas-1 gene may be caused by a direct anesthetic effect on a mitochondrial protein or secondary effects at other sites caused by mitochondrial dysfunction.
Causes of Nitrous Oxide Contamination in Operating Rooms
Authors: Kanmura Yuichi , Sakai Junya , Yoshinaka Heiji , Shirao Kazusada
Published: November 2003

Background

To reduce the ambient concentration of waste anesthetic agents, exhaust gas scavenging systems are standard in almost all operating rooms. The incidence of contamination and the factors that may increase the concentrations of ambient anesthetic gases have not been evaluated fully during routine circumstances, however.

Methods

Concentrations of nitrous oxide (N2O) in ambient air were monitored automatically in 10 operating rooms in Kagoshima University Hospital from January to March 1997. Ambient air was sampled automatically from each operating room, and the concentrations of N2O were analyzed every 22 min by an infrared spectrophotometer. The output of the N2O analyzer was integrated electronically regarding time, and data were displayed on a monitor in the administrative office for anesthesia supervisors. A concentration of N2O > 50 parts per million was regarded as abnormally high and was displayed with an alarm signal. The cause of the high concentration of N2O was then sought.

Results

During the 3-month investigation, N2O was used in 402 cases. Abnormally high concentrations of N2O were detected at some time during 104 (25.9%) of those cases. The causes were mask ventilation (42 cases, 40.4% of detected cases), unconnected scavenging systems (20 cases, 19.2%), leak around uncuffed pediatric endotracheal tube (13 cases, 12.5%), equipment leakage (12 cases, 11.5%), and others (17 cases, 16.4%).

Conclusions

N2O contamination was common during routine circumstances in our operating rooms. An unconnected scavenging system led to the highest concentrations of N2O recorded. Proper use of scavenging systems is necessary if contamination by anesthetic gas is to be limited.
Benzodiazepine Premedication
Authors: van Vlymen Janet M. , Sa Rego Monica M. , White Paul F.
Published: November 2003

Background

Women awaiting needle-guided breast biopsy procedures may experience high anxiety levels. A randomized, double-blind, placebo-controlled study was designed to evaluate the ability of midazolam and diazepam (in a lipid emulsion [Dizac]) to improve patient comfort during needle localization and breast biopsy procedures.

Methods

Ninety women received two consecutive doses of a study medication, one before the mammographic needle localization and a second before entering the operating room. Patients were assigned randomly to receive saline, 2.0 ml intravenously, at the two time points; midazolam, 1.0 mg intravenously and 2.0 mg intravenously; or diazepam emulsion, 2.0 mg intravenously and 5.0 mg intravenously, respectively. Patients assessed their anxiety levels before the needle localization, before entering the operating room, and on arrival in the operating room. Patients completed a questionnaire evaluating their perioperative experience at the time of discharge.

Results

Patient satisfaction during needle localization was significantly improved in both benzodiazepine treatment groups (vs. saline). The incidence of moderate-to-severe discomfort during needle localization was lower in the midazolam (20%) and diazepam emulsion (6%) groups compared with the saline group (70%) (P<0.05). The preoperative visual analogue scale anxiety scores were similar in all three groups. In the operating room, however, anxiety scores were 55% and 68% lower after midazolam (21+/-19) and diazepam emulsion (15+/-14) compared with saline (46+/-28). Finally, there was no difference in the time to achieve home-readiness or actual discharge time among the three groups.

Conclusions

Premedication with midazolam or diazepam emulsion improved patients' comfort during needle localization procedures and significantly reduced intraoperative anxiety levels before breast biopsy procedures without prolonging discharge times. Use of diazepam emulsion may be an effective alternative to midazolam in this population.
The Effect of Graded Postischemic Spinal Cord Hypothermia on Neurological Outcome and Histopathology after Transient Spinal Ischemia in Rat
Authors: Kakinohana Manabu , Taira Yutaka , Marsala Martin
Published: November 2003

Background

Previous data have shown that postischemic brain hypothermia is protective. The authors evaluated the effect of postischemic spinal hypothermia on neurologic function and spinal histopathologic indices after aortic occlusion in the rat.

Methods

Spinal ischemia was induced by aortic occlusion lasting 10 min. After ischemia, spinal hypothermia was induced using a subcutaneous heat exchanger. Three studies were conducted. In the first study, the intrathecal temperature was decreased to 34, 30, or 27 degrees C for 2 h beginning with initial reperfusion. In the second study, hypothermia (target intrathecal temperature 27 degrees C) was initiated with reflow and maintained for 15 or 120 min. In the third study, the intrathecal temperature was decreased to 27 degrees C for 2 h starting 5, 60, or 120 min after normothermic reperfusion. Animals survived for 2 or 3 days, at which time they were examined and perfusion fixed with 4% paraformaldehyde.

Results

Normothermic ischemia followed by normothermic reflow resulted in spastic paraplegia and spinal neuronal degeneration. Immediate postischemic hypothermia (27 degrees C for 2 h) resulted in decreasing motor dysfunction. Incomplete protection was noted at 34 degrees C. Fifteen minutes of immediate cooling (27 degrees C) also provided significant protection. Delay of onset of post-reflow hypothermia (27 degrees C) by 5 min or more failed to provide protection. Histopathologic analysis revealed temperature-dependent suppression of spinal neurodegeneration, with no effect of delayed cooling.

Conclusions

These findings indicate that the immediate period of reperfusion (0-15 min) represents a critical period that ultimately defines the degree of spinal neuronal degeneration. Hypothermia, when initiated during this period, showed significant protection, with the highest efficacy observed at 27 degrees C.
Interaction of Bupivacaine and Tetracaine with the Sarcoplasmic Reticulum Ca2+Release Channel of Skeletal and Cardiac Muscles
Authors: Komai Hirochika , Lokuta Andrew J.
Published: November 2003

Background

Although various local anesthetics can cause histologic damage to skeletal muscle when injected intramuscularly, bupivacaine appears to have an exceptionally high rate of myotoxicity. Research has suggested that an effect of bupivacaine on sarcoplasmic reticulum Ca2+ release is involved in its myotoxicity, but direct evidence is lacking. Furthermore, it is not known whether the toxicity depends on the unique chemical characteristics of bupivacaine and whether the toxicity is found only in skeletal muscle.

Methods

The authors studied the effects of bupivacaine and the similarly lipid-soluble local anesthetic, tetracaine, on the Ca2+ release channel-ryanodine receptor of sarcoplasmic reticulum in swine skeletal and cardiac muscle. [3H]Ryanodine binding was used to measure the activity of the Ca2+ release channel-ryanodine receptors in microsomes of both muscles.

Results

Bupivacaine enhanced (by two times at 5 mM) and inhibited (66% inhibition at 10 mM) [3H]ryanodine binding to skeletal muscle microsomes. In contrast, only inhibitory effects were observed with cardiac microsomes (about 3 mM for half-maximal inhibition). Tetracaine, which inhibits [3H]ryanodine binding to skeletal muscle microsomes, also inhibited [3H]ryanodine binding to cardiac muscle microsomes (half-maximal inhibition at 99 microM).

Conclusions

Bupivacaine's ability to enhance Ca2+ release channel-ryanodine receptor activity of skeletal muscle sarcoplasmic reticulum most likely contributes to the myotoxicity of this local anesthetic. Thus, the pronounced myotoxicity of bupivacaine may be the result of this specific effect on Ca2+ release channel-ryanodine receptor superimposed on a nonspecific action on lipid bilayers to increase the Ca2+ permeability of sarcoplasmic reticulum membranes, an effect shared by all local anesthetics. The specific action of tetracaine to inhibit Ca2+ release channel-ryanodine receptor activity may in part counterbalance the nonspecific action, resulting in moderate myotoxicity.
Influence of Atracurium on the Diaphragm Mean Action Potential Conduction Velocity in Canines
Authors: Goldman Ernesto , Sinderby Christer , Lindstrom Lars , Grassino Alex
Published: November 2003

Background

It has been shown that progressive neuromuscular blockade (NMB) affects the electromyogram power spectrum and compound muscle action potential duration in skeletal muscle. These measures are linked to the mean muscle action potential conduction velocity (APCV), but no studies have confirmed a relation between the mean APCV and NMB. The aim of this study was to determine whether diaphragm mean APCV is affected by NMB.

Methods

The effects of NMB on diaphragm mean APCV were evaluated in five mongrel dogs. Progressive NMB was induced by slow intravenous infusion of atracurium. During spontaneous breathing, the diaphragm mean APCV was determined by electromyogram signals, in the time and frequency domains. The magnitude of NMB was quantified by the amplitude of the compound muscle action potential and by changes in muscle shortening during supramaximal stimulation of the phrenic nerve.

Results

Progressive NMB was associated with a decrease in diaphragm mean APCV. At approximately 70% reduction in the compound muscle action potential amplitude, diaphragm mean APCV had decreased more than 20%. Recovery after NMB was characterized by a restoration of the mean APCV to control values.

Conclusion

This study shows that progressive NMB paralyzes motor units within the diaphragm in an orderly manner, and the blockade first affects muscle fibers with high APCV before it affects fibers with lower APCV.
Primary and Secondary Hyperalgesia in a Rat Model for Human Postoperative Pain
Authors: Zahn Peter K. , Brennan Timothy J.
Published: November 2003

Background

Previously, the authors developed and characterized a rat model for postoperative pain to learn more about pain produced by incisions. In this study, the responses to heat and mechanical stimuli were evaluated directly on or adjacent to the incision and at varying distances from the incision.

Methods

Rats were anesthetized with halothane and incisions were made at different locations in the plantar aspect of the foot. The response frequency to a blunt mechanical stimulus, the withdrawal threshold to von Frey filaments (15-522 mN), and the withdrawal latency to radiant heat were measured. Rats were tested before surgery, 2 h later, and then daily through postoperative day 9.

Results

After plantar incision, persistent hyperalgesia was observed immediately adjacent to or directly on the incision to punctate and blunt mechanical stimuli, respectively. The withdrawal threshold to punctate stimuli applied 1 cm from the incision was decreased through postoperative day 1. In a transitional area, between the distant and adjacent sites, the withdrawal threshold was intermediate and the duration of hyperalgesia was transient. Heat hyperalgesia was persistent but present when the stimulus was applied to the site of injury but not to a distant site.

Conclusion

Robust primary hyperalgesia to punctate and blunt mechanical stimuli was present. Hyperalgesia distant to the wound, or secondary hyperalgesia, occurred in response to punctate mechanical stimuli, was short-lived, and required greater forces. These results suggest that the most persistent pain behaviors in this model are largely primary hyperalgesia.
Epidural Catheter Tip Position and Distribution of Injectate Evaluated by Computed Tomography
Authors: Hogan Quinn
Published: November 2003

Background

The distribution of solutions injected into the epidural space has not been determined. The author therefore examined the site of catheter tips and the spread of contrast material in the epidural space using computed tomographic (CT) imaging in patients receiving successful epidural analgesia.

Methods

Lumbar epidural catheters were placed in 20 female patients by a midline technique. Anesthetic effect was determined by motor and sensory examinations during analgesic infusion. CT images were obtained for identification of the catheter tip and after radiographic contrast injection of 4 ml and then an additional 10 ml.

Results

Catheter tips were most often found lateral to the dura in the intervertebral foramen. In these subjects with normally functioning epidural analgesia, there was remarkable interindividual variability in patterns of spread, including various amounts of anterior passage, layering along the dura, and compression of the dura creating a posterior fold. Accumulation becomes more symmetric with increasing injectate volume. Spread through the intervertebral foramina was seen in all subjects. Air and fat in the region of the catheter interfered with solution spread in three subjects, but only over a limited area. Asymmetry in anesthetic effect was attributable to catheter position. No substantial barriers to solution spread were observed.

Conclusions

A variety of catheter tip positions and patterns of solution spread underlie normal epidural anesthesia. Nonuniform distribution of injectate is common and is compatible with uniform anesthesia. Posterior midline structures play a minimal role in impeding distribution of injectate. A far lateral catheter position is a more common cause of asymmetric block than anatomic barriers to solution spread.
Dose Response of Intravenous Heparin on Markers of Thrombosis during Primary Total Hip Replacement
Authors: Sharrock Nigel E. , Go George , Sculco Thomas P. , Salvati Eduardo A. , Westrich Geoffrey H. , Harpel Peter C.
Published: November 2003

Background

Thrombogenesis in total hip replacement (THR) begins during surgery on the femur. This study assesses the effect of two doses of unfractionated intravenous heparin administered before femoral preparation during THR on circulating markers of thrombosis.

Methods

Seventy-five patients undergoing hybrid primary THR were randomly assigned to receive blinded intravenous injection of either saline or 10 or 20 U/kg of unfractionated heparin after insertion of the acetabular component. Central venous blood samples were assayed for prothrombin F1+2 (F1+2), thrombin-antithrombin complexes (TAT), fibrinopeptide A (FPA), and D-dimer.

Results

No changes in the markers of thrombosis were noted after insertion of the acetabular component. During surgery on the femur, significant increases in all markers were noted in the saline group (P < 0.0001). Heparin did not affect D-dimer or TAT. Twenty units per kilogram of heparin significantly reduced the increase of F1+2 after relocation of the hip joint (P < 0.001). Administration of both 10 and 20 U/kg significantly reduced the increase in FPA during implantation of the femoral component (P < 0.0001). A fourfold increase in FPA was noted in 6 of 25 patients receiving 10 U/kg of heparin but in none receiving 20 U/kg (P = 0.03). Intraoperative heparin did not affect intra- or postoperative blood loss, postoperative hematocrit, or surgeon's subjective assessments of bleeding. No bleeding complications were noted.

Conclusions

This study demonstrates that 20 U/kg of heparin administered before surgery on the femur suppresses fibrin formation during primary THR. This finding provides the pathophysiologic basis for the clinical use of intraoperative heparin during THR.
Pharmacokinetics of Prilocaine after Intravenous Administration in Volunteers
Authors: van der Meer Auke Dirk , Burm Anton G. L. , Stienstra Rudolf , van Kleef Jack W. , Vletter Arie A. , Olieman Wim
Published: November 2003

Background

Prilocaine exists in two stereoisomeric configurations, the enantiomers S(+)- and R(-)-prilocaine. The drug is clinically used as the racemate. This study examined the pharmacokinetics of the enantiomers after intravenous administration of the racemate.

Methods

Ten healthy male volunteers received 200 mg racemic prilocaine as a 10-min intravenous infusion. Blood samples were collected for 8 h after the start of the infusion. Plasma concentrations were measured by stereoselective high-performance liquid chromatography (HPLC). Unbound fractions of the enantiomers in blank blood samples, spiked with racemic prilocaine, were determined using equilibrium dialysis.

Results

The unbound fraction of R(-)-prilocaine (mean +/- SD, 70%+/-8%) was smaller (P < 0.05) than that of S(+)-prilocaine (73%+/-5%). The total plasma clearance of R(-)-prilocaine (2.57+/-0.46 l/min) was larger (P < 0.0001) than that of S(+)-prilocaine (1.91+/-0.30 l/min). The steady-state volume of distribution of R(-)-prilocaine (279+/-94 l) did not differ from that of S(+)-prilocaine (291+/-93 l). The terminal half-life of R(-)-prilocaine (87+/-27 min) was shorter (P < 0.05) than that of S(+)-prilocaine (124+/-64 min), as was the mean residence time of R(-)-prilocaine (108+/-30 min) compared with S(+)-prilocaine (155+/-59 min; P < 0.005).

Conclusions

The pharmacokinetics of prilocaine are enantioselective. The difference in clearance is most likely a result of a difference in intrinsic metabolic clearance. The difference in the pharmacokinetics of the enantiomers of prilocaine does not seem to be clinically relevant.
Pharyngeal Mucosal Pressures, Airway Sealing Pressures, and Fiberoptic Position with the Intubating versus the Standard Laryngeal Mask Airway
Authors: Keller Christian , Brimacombe Joseph
Published: November 2003

Background

The tube of the intubating laryngeal mask (ILM) is more rigid than the standard laryngeal mask airway (LMA), and the authors have tested the hypothesis that pharyngeal mucosal pressures, airway sealing pressures, and fiberoptic position are different when the two devices are compared.

Methods

Twenty anesthetized, paralyzed adults were randomly allocated to receive either the LMA or ILM for airway management. Microchip sensors were attached to the size 5 LMA or ILM at locations corresponding to the pyriform fossa, hypopharynx, base of tongue, posterior pharynx, and distal and proximal oropharynx. Mucosal pressures, airway sealing pressures, and fiberoptic positioning were recorded during inflation of the cuff from 0 to 40 ml in 10-ml increments.

Results

Airway sealing pressures were higher for the ILM (30 vs. 23 cm H2O), but epiglottic downfolding was more common (56% vs. 26%). Pharyngeal mucosal pressures were much higher for the ILM at five of six locations. Mean mucosal pressures in the distal oropharynx for the ILM were always greater than 157 cm H2O, regardless of cuff volume. There was no correlation between mucosal pressures and airway sealing pressures at any location for the LMA, but there was a correlation at three of six locations for the ILM.

Conclusions

The ILM provides a more effective seal than the LMA, but pharyngeal mucosal pressures are higher and always exceed capillary perfusion pressure. The ILM is unsuitable for use as a routine airway and should be removed after its use as an airway intubator.
Pharmacokinetic Modeling of M6G Formation after Oral Administration of Morphine in Healthy Volunteers
Authors: Lotsch Jorn , Weiss Michel , Ahne Gabi , Kobal Gerd , Geisslinger Gerd
Published: November 2003

Background

Morphine is metabolized to two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide (M6G). Under the conditions of long-term oral morphine administration, the accumulation of M6G may contribute to the analgesic effects, but it may also cause respiratory depression.

Methods

Five healthy male volunteers (ages 25-34 yr) received 90 mg MST (morphine sulfate 5H2O sustained-released tablet, equivalent to 67.8 mg oral morphine). Multiple plasma and urine samples were taken for as long as 14 and 36 h, respectively. Individual pharmacokinetics after intravenous administration of morphine and M6G were available from a previous investigation. A new model that considers the M6G-plasma profile as a sum of the input from the first-pass metabolism of morphine and the input from systemically available morphine was applied to the plasma concentration versus time curves of M6G. The concentrations of M6G at the effect site after long-term morphine administration were simulated.

Results

The fraction of morphine absorbed from the gut was 82+/-14%. Of this, 42+/-8% passed through the liver, resulting in an oral bioavailability of morphine of 34+/-9%. Of the total amount of M6G, 71+/-7% was formed during the first-pass metabolism, and 29+/-7% was formed by metabolism of systemic morphine. After 36 h, the amounts of M6G and morphine excreted in the urine were 92+/-17% and 9+/-3%, respectively. Simulation of effect-site concentrations of M6G indicated that after multiple oral dosing of morphine in patients with normal liver and renal function, M6G might reach concentrations two times greater than that of morphine.

Conclusions

M6G may contribute to the analgesic and side effects seen with long-term morphine treatment. The current model of morphine and M6G pharmacokinetics after oral administration of morphine may serve as a pharmacokinetic basis for experiments evaluating the analgesic contribution of M6G with long-term oral dosing of morphine.
Fentanyl and Morphine, but not Remifentanil, Inhibit Acetylcholine Release in Pontine Regions Modulating Arousal
Authors: Mortazavi Steven , Thompson Janel , Baghdoyan Helen A. , Lydic Ralph
Published: November 2003

Background

Opioids inhibit the rapid eye movement (REM) phase of sleep and decrease acetylcholine (ACh) release in medial pontine reticular formation (mPRF) regions contributing to REM sleep generation. It is not known whether opioids decrease ACh release by acting on cholinergic cell bodies or on cholinergic axon terminals. This study used in vivo microdialysis to test the hypothesis that opioids decrease ACh levels at cholinergic neurons in the laterodorsal tegmental nuclei (LDT) and LDT axon terminals in the mPRF.

Methods

Nine male cats were anesthetized with halothane, and ACh levels within the mPRF or LDT were assayed using microdialysis and high-pressure liquid chromatography (HPLC). ACh levels were analyzed in response to dialysis of the mPRF and LDT with Ringer's solution (control), followed by dialysis with Ringer's solution containing morphine sulfate (MSO4) or naloxone. ACh in the mPRF also was measured during either dialysis delivery or intravenous infusion of remifentanil and during dialysis delivery of fentanyl.

Results

Compared with dialysis of Ringer's solution, microdialysis with MSO4 decreased ACh by 23% in the mPRF and by 30% in the LDT. This significant decrease in ACh was antagonized by naloxone. MSO4 and fentanyl each caused a dose-dependent decrease in mPRF ACh when delivered by dialysis. Remifentanil delivered by continuous intravenous infusion or by dialysis into the mPRF did not alter mPRF ACh.

Conclusions

Morphine inhibits ACh at the cholinergic cell body region (LDT) and the terminal field in the mPRF. ACh in the mPRF was not altered by remifentanil and was significantly decreased by fentanyl. Thus, MSO4 and fentanyl disrupt cholinergic neurotransmission in the LDT-mPRF network known to modulate REM sleep and cortical electroencephalographic activation. These data are consistent with the possibility that inhibition of pontine cholinergic neurotransmission contributes to arousal state disruption by opioids.
Mild Therapeutic Hypothermia for Postischemic Vasoconstriction in the Perfused Rat Liver
Authors: Zar Harvey A. , Tanigawa Koichi , Kim Young-Myeong , Lancaster Jack R.
Published: November 2003

Background

Mild hypothermia, a promising therapy being evaluated for various clinical situations, may suppress the formation of reactive oxygen species during reperfusion and may ameliorate microcirculatory perfusion failure (the "no-reflow phenomenon").

Methods

Isolated rat livers underwent 30 min of perfusion, 2.5 h of ischemia, and 3 h of reperfusion. The temperature was maintained at 34 degrees C (mild hypothermia, n = 5) or 38 degrees C (normothermia, n = 6) for all three periods by perfusion of a modified Krebs Henseleit solution, air surface cooling, or both. A third group of livers was normothermic before and during ischemia and mildly hypothermic during reperfusion (reperfusion hypothermia, n = 6). Control livers had 3 h of perfusion at normothermia. Chemiluminescence (a measure of the generation of reactive oxygen species) and hepatic vascular resistance were monitored simultaneously to evaluate the effect of temperature on the formation of reactive oxygen species and the development of no reflow. Also measured were thiobarbituric acid reactive species and lactate dehydrogenase, as indicators of oxidative stress and cell injury.

Results

Mild hypothermia decreased formation of reactive oxygen species and postischemic increases in vascular resistance. Reperfusion hypothermia also decreased postischemic increases in vascular resistance, but not as effectively as did mild hypothermia. Levels of thiobarbituric acid reactive species were lower for reperfusion hypothermia than for mild hypothermia at only 0 and 30 min of reperfusion. Lactate dehydrogenase was significant only at 0 min of reperfusion for the normothermic group. Oxygen consumption did not change.

Conclusion

The prevention of hepatic vascular injury by suppression of oxidative stress may be an important protective mechanism of mild hypothermia.
Acute Lung Injury after Instillation of Human Breast Milk into Rabbits' Lungs
Authors: O'Hare Brendan , Chin Christopher , Lerman Jerrold , Endo Junko
Published: November 2003

Background

The authors compared the lung injury in rabbits that occurred after tracheal instillation of human breast milk (HBM) acidified to pH 1.8 with hydrochloric acid (HCl), HBM at its native pH (7.0), and HBM acidified with gastric juice to pH 1.8 and 3.0.

Methods

The alveolar-to-arterial oxygen tension gradient and dynamic compliance were recorded before and hourly for 4 h after intratracheal instillation of 0.8 ml/kg HBM acidified with HCI (pH 1.8), HBM at its native pH (7.0), HBM acidified with gastric juice (pH 1.8 or 3.0), or 5% dextrose solution acidified with gastric juice (pH 1.8) as a control in 30 adult rabbits. The circulating neutrophil count and phagocyte oxidant activity were determined before and 1 and 4 h after instillation.

Results

The alveolar-to-arterial oxygen tension gradient increased and dynamic compliance decreased significantly in all groups after instillation of HBM compared with baseline values and those in the control group. The severity of the lung injury after instillation of HBM at all pH values (1.8, 3.0, and 7.0) and after acidification with gastric juice or HCl was similar. The circulating neutrophil count increased steadily for 4 h after instillation (P < 0.013), whereas spontaneous phagocyte oxidant burst activity peaked at 1 h (P < 0.007) and returned to baseline by 4 h after instillation.

Conclusions

The severity of the lung injury after tracheal instillation of 0.8 ml/kg HBM in rabbits is similar at pH values between 1.8 and 7.0 after acidification with HCl or gastric juice. Tracheal instillation of HBM increases the circulating neutrophil count and phagocyte oxidant burst activity.
Recirculatory and Compartmental Pharmacokinetic Modeling of Alfentanil in Pigs
Authors: Kuipers Jette A. , Boer Fred , Olofsen Erik , Olieman Wim , Vletter Arie A. , Burm Anton G. L. , Bovill James G.
Published: November 2003

Background

Cardiac output (CO) is likely to influence the pharmacokinetics of anesthetic drugs and should be accounted for in pharmacokinetic models. The influence of CO on the pharmacokinetic parameters of alfentanil in pigs was evaluated using compartmental and recirculatory models.

Methods

Twenty-four premedicated pigs were evaluated during halothane (0.6-2%) anesthesia. They were assigned randomly to one of three groups. One group served as control. In the other groups, the baseline CO was decreased or increased by 40% by pharmacologic intervention (propranolol or dobutamine). Boluses of alfentanil (2 mg) and indocyanine green (25 mg) were injected into the right atrium. Blood samples were taken for 150 min from the right atrium and aortic root. Arterial concentration-time curves of indocyanine green and alfentanil were analyzed using compartmental models (two-stage and mixed-effects approach) and a recirculatory model, which can describe lung uptake and early distribution.

Results

The CO of individual pigs varied from 1.33 to 6.44 l/min. Three-compartmental modeling showed that CO is a determinant of the central compartment volume (V1, r2 = 0.54), fast peripheral compartment volume (V2, r2 = 0.29), steady state distribution volume (Vss, r2 = 0.29), fast distribution clearance (Cl12, r2 = 0.39), and elimination clearance (Cl10, r2 = 0.51). Recirculatory modeling showed that CO is a determinant of total distribution volume (r2 = 0.48), elimination clearance (r2 = 0.54), and some distribution clearances. The pulmonary distribution volume was independent of CO.

Conclusions

Cardiac output markedly influences the pharmacokinetics of alfentanil in pigs. Therefore, accounting for CO enhances the predictive value of pharmacokinetic models of alfentanil.
Epidural Analgesia during Labor and Maternal Fever
Authors: Philip John MD , Alexander James M. , Sharma Shiv K. , Leveno Kenneth J. , McIntire Donald D. , Wiley Jackie
Published: November 2003

Background

In recent observational studies, epidural analgesia during labor at patient request has been associated with maternal fever. The authors report a secondary analysis of fever in women who were randomized to receive either epidural or patient-controlled intravenous analgesia during labor.

Methods

Maternal tympanic temperature was measured during spontaneous labor in 715 women at term who were randomized to either epidural analgesia with bupivacaine and fentanyl or to patient-controlled intravenous analgesia with meperidine. Intent-to-treat analysis of women with fever (temperature > or = 38.0 degrees C) versus those without was performed using Student t test and Fisher exact test to determine statistical significance (P < 0.05).

Results

Epidural analgesia was associated with maternal fever (odds ratio = 4.0; 95% confidence interval = 2.0-7.7), as was nulliparity (odds ratio = 4.1; 95% confidence interval = 1.8-9.1) and labor longer than 12 h (odds ratio = 5.4; 95% confidence interval = 2.9-9.9). These factors were all independent variables for maternal fever when analyzed using logistic regression.

Conclusions

Epidural analgesia is associated with maternal fever. However, nulliparity and dysfunctional labor are also significant cofactors in the fever attributed to epidural analgesia.
Spinal versus Epidural Anesthesia for Cesarean Section in Severely Preeclamptic Patients
Authors: Hood David D. , Curry Regina
Published: November 2003

Background

Selection of spinal anesthesia for severely preeclamptic patients requiring cesarean section is controversial. Significant maternal hypotension is believed to be more likely with spinal compared with epidural anesthesia. The purpose of this study was to assess, in a large retrospective clinical series, the blood pressure effects of spinal and epidural anesthesia in severely preeclamptic patients requiring cesarean section.

Methods

The computerized medical records database was reviewed for all preeclamptic patients having cesarean section between January 1, 1989 and December 31, 1996. All nonlaboring severely preeclamptic patients receiving either spinal or epidural anesthesia for cesarean section were included for analysis. The lowest recorded blood pressures were compared for the 20-min period before induction of regional anesthesia, the period from induction of regional anesthesia to delivery, and the period from delivery to the end of operation.

Results

Study groups included 103 women receiving spinal anesthesia and 35 receiving epidural anesthesia. Changes in the lowest mean blood pressure were similar after epidural or spinal anesthesia. Intraoperative ephedrine use was similar for both groups. Intraoperative crystalloid administration was statistically greater for patients receiving spinal versus epidural anesthesia (1780 +/- 838 vs. 1359 +/- 674 ml, respectively). Neonatal Apgar scores and incidence of maternal intensive care unit admission or postoperative pulmonary edema were also similar.

Conclusion

Although we cannot exclude the possibility that the spinal and epidural anesthesia groups were dissimilar, the magnitudes of maternal blood pressure declines were similar after spinal or epidural anesthesia in this series of severely preeclamptic patients receiving cesarean section. Maternal and fetal outcomes also were similar.
ATX II, A Sodium Channel Toxin, Sensitizes Skeletal Muscle to Halothane, Caffeine, and Ryanodine
Authors: Fletcher Jeffrey E. , Adnet Pascal J. , Reyford Hugo , Wieland Steven J. , Stewart Sherri L. , Rosenberg Henry
Published: November 2003

Background

The function or expression of subtypes of the sodium ion (Na+) channel is altered in biopsies or cultures of skeletal muscle from many persons who are susceptible to malignant hyperthermia (MH). ATX II, a specific Na+ channel toxin from a sea anemone, causes delayed inactivation of the channel similar to that seen in cell cultures of MH muscle. ATX II was added to skeletal muscle to determine whether altered Na+ channel function could increase the sensitivity of normal skeletal muscle to agents (halothane, caffeine, ryanodine) to which MH muscle is hypersensitive.

Methods

Studies were performed of fiber bundles from the vastus lateralis muscle of persons who were deemed not MH susceptible (MH-) or MH susceptible (MH+) according to the MH diagnostic test and of strips of diaphragm muscle from rats. Preparations in a tissue bath containing Krebs solution were connected to a force transducer. ATX II was introduced 5 min before halothane, caffeine, or ryanodine.

Results

ATX II increased the magnitude of contracture to halothane in preparations from most MH-, but not MH+, human participants. After ATX II treatment, preparations from 9 of 24 MH- participants generated contractures to halothane, 3%, that were of the same magnitude as those from MH+ participants. Preparations from four of six ATX II-treated healthy participants also gave responses of the same magnitude as those of MH-susceptible participants to a graded halothane challenge (0.5-3%). The contractures to bolus doses of halothane in specimens from male participants were more than three times larger than the contractures in specimens from female participants. In rat muscle, ATX II increased the magnitude of contracture to caffeine (2 mM) and decreased the time to produce a 1-g contracture to ryanodine (1 microM).

Conclusions

ATX II, which causes delayed inactivation of the Na+ channel in cell cultures similar to that reported in cultures of MH+ skeletal muscle, increased the sensitivity of normal muscle to three agents to which MH+ muscle is hypersensitive. The increased sensitivity to halothane, 3%, occurred in most (79%), but not all, MH- participants, and this effect was most evident in male participants. Therefore, abnormal function of the Na+ channel, even if it is a secondary event in MH, may contribute to a positive contracture test result for MH.