bluuebunny/crossref_metadata_2025 huggingface dataset:
Sevoflurane Selectively Increases Coronary Collateral Blood Flow Independent of KATPChannels In Vivo
Authors: Kersten Judy R. , Schmeling Todd , Tessmer John , Hettrick Douglas A. , Pagel Paul S. , Warltier David C.
Published: November 2003

Background

Volatile anesthetic agents produce coronary vasodilation via activation of adenosine triphosphate-sensitive potassium (KATP) channels. The authors tested the hypothesis that sevoflurane selectively increases coronary collateral blood flow and assessed the role of KATP channel activation in this process.

Methods

Experiments were conducted in dogs 8 weeks after long-term implantation of a left anterior descending coronary artery (LAD) ameroid constrictor to stimulate coronary collateral growth. Dogs were instrumented for measurement of retrograde LAD blood flow (an index of large coronary collateral blood flow) and LAD tissue flow (via radioactive microspheres; an index of small collateral blood flow). Coronary collateral perfusion and normal (left circumflex coronary artery [LCCA]) zone tissue blood flow were determined in four groups of dogs pretreated with intracoronary glyburide (50 microg/kg) or vehicle in the presence or absence of sevoflurane (1 minimum alveolar concentration). Dose-response relationships to the KATP channel agonist nicorandil were established in each dog using doses (25, 50, and 100 microg/min) previously shown to increase coronary collateral blood flow.

Results

Sevoflurane increased blood flow through large and small collaterals and increased collateral vascular conductance in the presence of glyburide but did not affect LCCA blood flow or conductance. In contrast, nicorandil increased blood flow through small but not large collaterals. Nicorandil also increased LCCA blood flow and conductance, actions that were attenuated by glyburide.

Conclusions

The results demonstrate that sevoflurane selectively increases large and small coronary collateral blood flow via mechanism(s) independent of KATP channel activation.
Pulmonary Airway Resistance with the Endotracheal Tube versus Laryngeal Mask Airway in Paralyzed Anesthetized Adult Patients
Authors: Berry Alison , Brimacombe Joseph , Keller Christian , Verghese Chandi
Published: November 2003

Background

The hypothesis that airway resistance is less with the laryngeal mask airway than with the endotracheal tube was tested.

Methods

Thirty-six paralyzed, anesthetized adult patients with no respiratory disease (American Society of Anesthesiologists physical status 1-3; age, 18-80 yr) were randomly allocated (9 men, 9 women in each group) to receive either a size-4 laryngeal mask airway or an endotracheal tube (men, 9-mm ID; women, 8-mm ID). A pulmonary monitor with flow transducer and esophageal balloon was used to measure peak airway pressure and mean airway resistance (device resistance plus pulmonary airway resistance) at three different tidal volumes (5, 10, and 15 ml/kg). Device resistance was measured in vitro with the distal end of the endotracheal tube or laryngeal mask airway open to the atmosphere and using the same ventilator settings. Pulmonary airway resistance was derived by subtracting the mean device resistance from the mean airway resistance.

Results

Peak airway pressure, mean airway resistance, device resistance, and pulmonary airway resistance were greater for the endotracheal tube (all P < 0.0001).

Conclusions

The laryngeal mask airway triggers less bronchoconstriction than does the endotracheal tube in paralyzed anesthetized adult patients. This may have implications for maintaining intraoperative pulmonary function and reducing the risk for atelectasis and pulmonary infection.
The Comparative Pharmacodynamics of Remifentanil and Its Metabolite, GR90291, in a Rat Electroencephalographic Model
Authors: Cox Eugene H. , Langemeijer Mariska W. E. , Gubbens-Stibbe Josy M. , Muir Keith T. , Danhof Meindert
Published: November 2003

Background

The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model.

Methods

Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood.

Results

Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6).

Conclusions

Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.
Comparison of European and North American Malignant Hyperthermia Diagnostic Protocol Outcomes for Use in Genetic Studies
Authors: Fletcher Jeffrey E. , Rosenberg Henry , Aggarwal Mukta
Published: November 2003

Background

Halothane and caffeine diagnostic protocols and an experimental ryanodine test from the North American Malignant Hyperthermia (MH) Group (NAMHG) and the European MH Group (EMHG) have not been compared in the same persons until now.

Methods

The outcomes of the NAMHG and EMHG halothane and caffeine contracture tests were compared in 84 persons referred for diagnostic testing. In addition, the authors assessed the experimental ryanodine protocol in 50 of these persons.

Results

Although the NAMHG and EMHG halothane protocols are slightly different methodologically, each yielded outcomes in close (84-100%) agreement with diagnoses made by the other protocol. Excluding 23 persons judged to be equivocal (marginally positive responders) by the EMHG protocol resulted in fewer persons classified as normal and MH susceptible (42 and 19, respectively) than those classified by the NAMHG protocol (48 and 34, respectively). For the 61 persons not excluded as equivocal, the diagnoses were identical by both protocols, with the exception of one person who was diagnosed as MH susceptible by the NAMHG protocol and as "normal" by the EMHG protocol. The NAMHG protocol produced only two equivocal diagnoses. Therefore, a normal or MH diagnosis by the NAMHG protocol was frequently associated with an equivocal diagnosis by the EMHG protocol. The time to 0.2-g contracture after the addition of 1 microM ryanodine completely separated populations, which was in agreement with the EMHG protocol and, except for one person, with the NAMHG protocol.

Conclusions

Overall, the NAMHG and EMHG protocols and the experimental ryanodine test yielded similar diagnoses. The EMHG protocol reduced the number of marginal responders in the final analysis, which may make the remaining diagnoses slightly more accurate for use in genetic studies.
Behavioral and Physiological Effects of Remifentanil and Alfentanil in Healthy Volunteers
Authors: Black Matthew L. , Hill Joanna L. , Zacny James P.
Published: November 2003

Background

The subjective and psychomotor effects of remifentanil have not been evaluated. Accordingly, the authors used mood inventories and psychomotor tests to characterize the effects of remifentanil in healthy, non-drug-abusing volunteers. Alfentanil was used as a comparator drug.

Methods

Ten healthy volunteers were enrolled in a randomized, double-blinded, placebo-controlled, crossover trial in which they received an infusion of saline, remifentanil, or alfentanil for 120 min. The age- and weight-adjusted infusions (determined with STANPUMP, a computer modeling software package) were given to achieve three predicted constant plasma levels for 40 min each of remifentanil (0.75, 1.5, and 3 ng/ml) and alfentanil (16, 32, and 64 ng/ml). Mood forms and psychomotor tests were completed, and miosis was assessed, during and after the infusions. In addition, analgesia was tested at each dose level using a cold-pressor test.

Results

Remifentanil had prototypic micro-like opioid subjective effects, impaired psychomotor performance, and produced analgesia. Alfentanil at the dose range tested had more mild effects on these measures, and the analgesia data indicated that a 40:1 potency ratio, rather than the 20:1 ratio we used, may exist between remifentanil and alfentanil. A psychomotor test administered 60 min after the remifentanil infusion was discontinued showed that the volunteers were still impaired, although they reported feeling no drug effects.

Conclusions

The notion that the pharmacodynamic effects of remifentanil are extremely short-lived after the drug is no longer administered must be questioned given our findings that psychomotor effects were still apparent 1 h after the infusion was discontinued.
Comparison of Three Solutions of Ropivacaine/Fentanyl for Postoperative Patient-controlled Epidural Analgesia
Authors: Liu Spencer S. , Moore James M. , Luo Amy M. , Trautman Walter J. , Carpenter Randall L.
Published: November 2003

Background

Ropivacaine, 0.2%, is a new local anesthetic approved for epidural analgesia. The addition of 4 microg/ml fentanyl improves analgesia from epidural ropivacaine. Use of a lower concentration of ropivacaine-fentanyl may further improve analgesia or decrease side effects.

Methods

Thirty patients undergoing lower abdominal surgery were randomized in a double-blinded manner to receive one of three solutions: 0.2% ropivacaine-4 microg fentanyl 0.1% ropivacaine-2 microg fentanyl, or 0.05% ropivacaine-1 microg fentanyl for patient-controlled epidural analgesia after standardized combined epidural and general anesthesia. Patient-controlled epidural analgesia settings and adjustments for the three solutions were standardized to deliver equivalent drug doses. Pain scores (rest, cough, and ambulation), side effects (nausea, pruritus, sedation, motor block, hypotension, and orthostasis), and patient-controlled epidural analgesia consumption were measured for 48 h.

Results

All three solutions produced equivalent analgesia. Motor block was significantly more common (30 vs. 0%) and more intense with the 0.2% ropivacaine-4 microg fentanyl solution. Other side effects were equivalent between solutions and mild in severity. A significantly smaller volume of 0.2% ropivacaine-4 microg fentanyl solution was used, whereas the 0.1% ropivacaine-2 microg fentanyl group used a significantly greater amount of ropivacaine and fentanyl.

Conclusions

Lesser concentrations of ropivacaine and fentanyl provide comparable analgesia with less motor block despite the use of similar amounts of ropivacaine and fentanyl. This finding suggests that concentration of local anesthetic solution at low doses is a primary determinant of motor block with patient-controlled epidural analgesia after lower abdominal surgery.
Clinical Isoflurane Metabolism by Cytochrome P450 2E1
Authors: Kharasch Evan D. , Hankins Douglas C. , Cox Kathy
Published: November 2003

Background

Some evidence suggests that isoflurane metabolism to trifluoroacetic acid and inorganic fluoride by human liver microsomes in vitro is catalyzed by cytochrome P450 2E1 (CYP2E1). This investigation tested the hypothesis that P450 2E1 predominantly catalyzes human isoflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1.

Methods

Twenty-two elective surgery patients who provided institutionally-approved written informed consent were randomized to receive disulfiram (500 mg orally, N = 12) or nothing (controls, N = 10) the evening before surgery. All patients received a standard isoflurane anesthetic (1.5% end-tidal in oxygen) for 8 hr. Urine and plasma trifluoroacetic acid and fluoride concentrations were quantitated in samples obtained for 4 days postoperatively.

Results

Patient groups were similar with respect to age, weight, gender, duration of surgery, blood loss, and delivered isoflurane dose, measured by cumulative end-tidal isoflurane concentrations (9.7-10.2 MAC-hr). Postoperative urine excretion of trifluoroacetic acid (days 1-4) and fluoride (days 1-3) was significantly (P<0.05) diminished in disulfiram-treated patients. Cumulative 0-96 hr excretion of trifluoroacetic acid and fluoride in disulfiram-treated patients was 34+/-72 and 270+/-70 micromoles (mean +/- SD), respectively, compared to 440+/-360 and 1500+/-800 micromoles in controls (P<0.05 for both). Disulfiram also abolished the rise in plasma metabolite concentrations.

Conclusions

Disulfiram, a selective inhibitor of human hepatic P450 2E1, prevented 80-90% of isoflurane metabolism. These results suggest that P450 2E1 is the predominant P450 isoform responsible for human clinical isoflurane metabolism in vivo.
Effects of Isoflurane Anesthesia on Pulmonary Vascular Response to K (ATP)+Channel Activation and Circulatory Hypotension in Chronically Instrumented Dogs
Authors: Fujiwara Yoshihiro , Murray Paul A.
Published: November 2003

Background

The objective of this study was to evaluate the effects of isoflurane anesthesia on the pulmonary vascular responses to exogenous adenosine triphosphate-sensitive potassium (K+ ATP) channel activation and circulatory hypotension compared with responses measured in the conscious state. In addition, the extent to which K+ ATP channel inhibition modulates the pulmonary vascular response to circulatory hypotension in conscious and isoflurane-anesthetized dogs was assessed.

Methods

Fifteen conditioned, male mongrel dogs were fitted with instruments for long-term monitoring to measure the left pulmonary vascular pressure-flow relation. The dose-response relation to the K+ ATP channel agonist, lemakalim, and the pulmonary vascular response to circulatory hypotension were assessed in conscious and isoflurane-anesthetized (approximately 1.2 minimum alveolar concentration) dogs. The effect of the selective K+ ATP channel antagonist, glibenclamide, on the pulmonary vascular response to hypotension was also assessed in conscious and isoflurane-anesthetized dogs.

Results

Isoflurane had no effect on the baseline pulmonary circulation, but it attenuated (P<0.05) the pulmonary vasodilator response to lemakalim. Reducing the mean systemic arterial pressure to approximately 50 mm Hg resulted in pulmonary vasoconstriction (P<0.05) in the conscious state, and this response was attenuated (P<0.05) during isoflurane. Glibenclamide had no effect on the baseline pulmonary circulation, but it potentiated (P<0.05) the pulmonary vasoconstrictor response to hypotension in conscious and isoflurane-anesthetized dogs.

Conclusions

These results indicate that K+ ATP-mediated pulmonary vasodilation and the pulmonary vasoconstrictor response to hypotension are attenuated during isoflurane anesthesia. Endogenous K+ ATP channel activation modulates the pulmonary vasoconstrictor response to hypotension in the conscious state, and this effect is preserved during isoflurane anesthesia.
Mechanisms of Bronchoprotection by Anesthetic Induction Agents
Authors: Brown Robert H. , Wagner Elizabeth M.
Published: November 2003

Background

Propofol and ketamine have been purported to decrease bronchoconstriction during induction of anesthesia and intubation. Whether they act on airway smooth muscle or through neural reflexes has not been determined. We compared propofol and ketamine to attenuate the direct activation of airway smooth muscle by methacholine and limit neurally mediated bronchoconstriction (vagal nerve stimulation).

Methods

After approval from the institutional review board, eight sheep were anesthetized with pentobarbital, paralyzed, and ventilated. After left thoracotomy, the bronchial artery was cannulated and perfused. In random order, 5 mg/ml concentrations of propofol, ketamine, and thiopental were infused into the bronchial artery at rates of 0.06, 0.20, and 0.60 ml/min. After 10 min, airway resistance was measured before and after vagal nerve stimulation and methacholine given via the bronchial artery. Data were expressed as a percent of baseline response before infusion of drug and analyzed by analysis of variance with significance set at P< or =0.05.

Results

Systemic blood pressure was not affected by any of the drugs (P>0.46). Baseline airway resistance was not different among the three agents (P = 0.56) or by dose (P = 0.96). Infusion of propofol and ketamine into the bronchial artery caused a dose-dependent attenuation of the vagal nerve stimulation-induced bronchoconstriction to 26+/-11% and 8+/-2% of maximum, respectively (P<0.0001). In addition, propofol caused a significant decrease in the methacholine-induced bronchoconstriction to 43+/-27% of maximum at the highest concentration (P = 0.05)

Conclusions

The local bronchoprotective effects of ketamine and propofol on airways is through neurally mediated mechanisms. Although the direct effects on airway smooth muscle occur at high concentrations, these are unlikely to be of primary clinical relevance.
Continuous Arterial PO(2) and PCO(2) Measurements in Swine during Nitrous Oxide and Xenon Elimination
Authors: Calzia Enrico , Stahl Wolfgang , Handschuh Thomas , Marx Thomas , Froba Gebhardt , Georgieff Michael , Radermacher Peter
Published: November 2003

Background

During nitrous oxide (N2O) elimination, arterial oxygen tension (PaO2) decreases because of the phenomenon commonly called diffusive hypoxia. The authors questioned whether similar effects occur during xenon elimination.

Methods

Nineteen anesthetized and paralyzed pigs were mechanically ventilated randomly for 30 min using inspiratory gas mixtures of 30% oxygen and either 70% N2O or xenon. The inspiratory gas was replaced by a mixture of 70% nitrogen and 30% oxygen. PaO2 and carbon dioxide tensions were recorded continuously using an indwelling arterial sensor.

Results

The PaO2 decreased from 119+/-10 mm Hg to 102+/-12 mm Hg (mean+/-SD) during N2O washout (P<0.01) and from 116+/-9 mm Hg to 110+/-8 mm Hg during xenon elimination (P<0.01), with a significant difference (P<0.01) between baseline and minimum PaO2 values (deltaPaO2, 17+/-6 mm Hg during N2O washout and 6+/-3 mm Hg during xenon washout). The PaCO2 value also decreased (from 39.3+/-6.3 mm Hg to 37.6+/-5.8 mm Hg) during N2O washout (P<0.01) and during xenon elimination (from 35.4+/-1.6 mm Hg to 34.9+/-1.6 mm Hg; P< 0.01). The deltaPaCO2 was 1.7+/-0.9 mm Hg in the N2O group and 0.5+/-0.3 mm Hg in the xenon group (P<0.01).

Conclusion

Diffusive hypoxia is unlikely to occur during recovery from xenon anesthesia, probably because of the low blood solubility of this gas.
Relative Analgesic Potencies of Ropivacaine and Bupivacaine for Epidural Analgesia in Labor
Authors: Polley Linda S. , Columb Malachy O. , Naughton Norah N. , Wagner Deborah S. , van de Ven Cosmas J. M.
Published: November 2003

Background

The minimum local analgesic concentration (MLAC) has been defined as the median effective local analgesic concentration in a 20-ml volume for epidural analgesia in the first stage of labor. The aim of this study was to assess the relative analgesic potencies of epidural bupivacaine and ropivacaine by determining their respective minimum local analgesic concentrations.

Methods

Seventy-three parturients at < or = 7 cm cervical dilation who requested epidural analgesia were allocated to one of two groups in this double-blinded, randomized, prospective study. After a lumbar epidural catheter was placed, 20 ml of the test solution was given, either ropivacaine (n = 34) or bupivacaine (n = 39). The concentration of local anesthetic was determined by the response of the previous patient in that group to a higher or lower concentration using up-down sequential allocation. Analgesic efficacy was assessed using 100-mm visual analog pain scores with < or = 10 mm within 30 min defined as effective. An effective result directed a 0.01% wt/vol decrement for the next patient. An ineffective result directed a 0.01% wt/vol increment.

Results

The minimum local analgesic concentration of ropivacaine was 0.111% wt/vol (95% confidence interval, 0.100-0.122), and the minimum local analgesic concentration of bupivacaine was 0.067% wt/vol (95% confidence interval, 0.052-0.082). Ropivacaine was significantly less potent than bupivacaine, with a potency ratio of 0.6 (95% confidence interval, 0.49-0.74). No difference in motor effects was observed.

Conclusion

Ropivacaine was significantly less potent than bupivacaine for epidural analgesia in the first stage of labor.
Comparison of Adenosine and Remifentanil Infusions as Adjuvants to Desflurane Anesthesia
Authors: Zarate Eduardo , Sa Rego Monica M. , White Paul F. , Duffy Larry , Shearer Vance E. , Griffin James D. , Whitten Charles W.
Published: November 2003

Background

Because adenosine has been alleged to produce both anesthetic and analgesic sparing effects, a randomized, double-blinded study was designed to compare the perioperative effects of adenosine and remifentanil when administered as intravenous adjuvants during general anesthesia for major gynecologic procedures.

Methods

Thirty-two women were assigned randomly to one of two drug treatment groups. After premedication with 0.04 mg/kg intravenous midazolam, anesthesia was induced with 2 micro/kg intravenous fentanyl, 1.5 mg/kg intravenous propofol, and 0.6 mg/kg intravenous rocuronium, and maintained with desflurane, 2%, and nitrous oxide, 65%, in oxygen. Before skin incision, an infusion of either remifentanil (0.02 microg x kg(-1) x min(-1)) or adenosine (25 microg x kg(-1) x min(-1)) was started and subsequently titrated to maintain systolic blood pressure, heart rate, or both within 10-15% of the preincision values.

Results

Adenosine and remifentanil infusions were effective anesthetic adjuvants during lower abdominal surgery. Use of adenosine (mean +/- SEM, 166+/-17 microg x kg(-1) x min(-1)) was associated with a significantly greater decrease in systolic blood pressure and higher heart rate values compared with remifentanil (mean +/- SEM, 0.2+/-0.03 microg kg(-1) x min(-1)). Total postoperative opioid analgesic use was 45% and 27% lower in the adenosine group at 0-2 h and 2-24 h after surgery, respectively.

Conclusions

Adjunctive use of a variable-rate infusion of adenosine during desflurane-nitrous oxide anesthesia was associated with acceptable hemodynamic stability during the intraoperative period. Compared with remifentanil, intraoperative use of adenosine was associated with a decreased requirement for opioid analgesics during the first 24 h after operation.
Factors Affecting the Pharmacokinetic Characteristics of Rapacuronium
Authors: Fisher Dennis M. , Kahwaji Raymond , Bevan David , Bikhazi George , Fragen Robert J. , Angst Martin S. , Ornstein Eugene , Matteo Richard S.
Published: November 2003

Background

Rapacuronium is a new nondepolarizing muscle relaxant with rapid onset and offset. As part of a study to determine its neuromuscular effects, the authors sampled plasma sparsely to determine the influence of age, gender, and other covariates on its pharmacokinetic characteristics.

Methods

Of 181 patients receiving a single bolus dose of 0.5-2.5 mg/kg rapacuronium, 43 (aged 24-83 yr) had plasma sampled 3 or 4 times to determine plasma concentrations of rapacuronium and its metabolite, ORG9488. Pharmacokinetic analysis was performed using a population approach (mixed-effects modeling) to determine the influence of demographic characteristics and preoperative laboratory values on the pharmacokinetic parameters.

Results

Rapacuronium's weight-normalized plasma clearance was 7.03 x (1 - 0.0507 x (HgB - 13)) ml x kg(-1) x min(-1), where HgB is the patient's preoperative value for hemoglobin (g/100 ml); however, rapacuronium's blood clearance (11.4+/-1.4 ml x kg(-1) x min(-1), mean +/- SD) did not vary with hemoglobin. Rapacuronium's weight-normalized pharmacokinetic parameters were not influenced by age, gender, or other covariates examined. Plasma concentrations of ORG9488 were typically less than 14% those of rapacuronium during the initial 30 min after rapacuronium administration.

Conclusions

In this patient population, neither age nor gender influence elimination of rapacuronium. This finding contrasts to an age-related decrease in plasma clearance observed in a study of 10 healthy volunteers and in a pooled analysis of the pharmacokinetic data from 206 adults in multiple clinical studies. Even if ORG9488 has a potency similar to that of rapacuronium, its plasma concentrations after a single bolus dose of rapacuronium are sufficiently small to contribute minimally to neuromuscular blockade.
The Pharmacokinetics of Milrinone in Pediatric Patients after Cardiac Surgery
Authors: Bailey James M. , Miller Bruce E. , Lu Wei , Tosone Steven R. , Kanter Kirk R. , Tam Vincent K. H.
Published: November 2003

Background

Milrinone has been shown to increase cardiac output in children after cardiac surgery, but pharmacokinetic analysis has not been used to identify effective dose regimens. The purpose of this study was to characterize the pharmacokinetics of milrinone in infants and children and to apply the results to the issue of dosing.

Methods

Twenty children were studied after they underwent repair of congenital cardiac defects. Control hemodynamic measurement was made after the children were separated from cardiopulmonary bypass, and each patient was given a loading dose of 50 microg/kg progressively in 5 min. Hemodynamic measurements were recorded again at the end of the loading dose and when a blood sample was taken to determine milrinone plasma concentrations. Further blood samples were taken during the next 16 h for milrinone plasma concentration analysis. The pharmacokinetics of milrinone were analyzed using the population pharmacokinetic program NONMEM.

Results

The loading dose of milrinone resulted in a mean decrease in mean blood pressure of 12% and a mean increase in cardiac index of 18% at a mean peak plasma concentration of 235 ng/ml. The pharmacokinetics of milrinone were best described by a three-compartment model. In the optimal model, all volumes and distribution clearances were proportional to weight, and weight-normalized elimination clearance was proportional to age; ie., Cl1 = 2.5 x weight x (1 + 0.058 x age) where Cl1 is expressed as ml/min, and the units of weight and age are kg and months, respectively.

Conclusions

A loading dose of 50 microg/kg effectively increases cardiac index in children after cardiac surgery. Simulations indicate that the peak plasma concentration can be maintained by following the loading dose of 50 microg/kg with an infusion of approximately 3 microg x kg(-1) x min(-1) for 30 min and then a maintenance infusion, which may require adjustment for age.
Lumbar Sympathetic Blocks Speed Early and Second Stage Induced Labor in Nulliparous Women
Authors: Leighton Barbara L. , Halpern Stephen H. , Wilson Donna B.
Published: November 2003

Background

Rapid cervical dilation reportedly accompanies lumbar sympathetic blockade, whereas epidural analgesia is associated with slow labor. The authors compared the effects of initial lumbar sympathetic block with those of epidural analgesia on labor speed and delivery mode in this pilot study.

Methods

At a hospital not practicing active labor management, full-term nulliparous patients whose labors were induced randomly received initial lumbar sympathetic block or epidural analgesia. The latter patients received 10 ml bupivacaine, 0.125%; 50 microg fentanyl; and 100 microg epinephrine epidurally and sham lumbar sympathetic blocks. Patients to have lumbar sympathetic blocks received 10 ml bupivacaine, 0.5%; 25 microg fentanyl; and 50 microg epinephrine bilaterally and epidural catheters. Subsequently, all patients received epidural analgesia.

Results

Cervical dilation occurred more quickly (57 vs. 120 min/cm cervical dilation; P = 0.05) during the first 2 h of analgesia in patients having lumbar sympathetic blocks (n = 17) than in patients having epidurals (n = 19). The second stage of labor was briefer in patients having lumbar sympathetic blocks than in those having epidurals (105 vs. 270 min; P < 0.05). Nine patients having lumbar sympathetic block and seven having epidurals delivered spontaneously, whereas seven patients having lumbar sympathetic block and seven having epidurals had instrument-assisted vaginal deliveries. Cesarean delivery for fetal bradycardia occurred in one patient having lumbar sympathetic block. Cesarean delivery for dystocia occurred in five patients having epidurals compared with no patient having lumbar sympathetic block (P = not significant). Visual analog pain scores differed only at 60 min after block.

Conclusions

Nulliparous parturients having induced labor and receiving initial lumbar sympathetic blocks had faster cervical dilation during the first 2 h of analgesia, shorter second-stage labors, and a trend toward a lower dystocia cesarean delivery rate than did patients having epidural analgesia. The effects of lumbar sympathetic block on labor need to be determined in other patient groups. These results may help define the tocodynamic effects of regional labor analgesia.
Cardiopulmonary Resuscitation
Authors: Hevesi Zoltan G. , Thrush David N. , Downs John B. , Smith Robert A.
Published: November 2003

Background

Conventional cardiopulmonary resuscitation (CPR) includes 80-100/min precordial compressions with intermittent positive pressure ventilation (IPPV) after every fifth compression. To prevent gastric insufflation, chest compressions are held during IPPV if the patient is not intubated. Elimination of IPPV would simplify CPR and might offer physiologic advantages, but compression-induced ventilation without IPPV has been shown to result in hypercapnia. The authors hypothesized that application of continuous positive airway pressure (CPAP) might increase CO2 elimination during chest compressions.

Methods

After appropriate instrumentation and measurement of baseline data, ventricular fibrillation was induced in 18 pigs. Conventional CPR was performed as a control (CPR(C)) for 5 min. Pauses were then discontinued, and animals were assigned randomly to receive alternate trials of uninterrupted chest compressions at a rate of 80/min without IPPV, either at atmospheric airway pressure (CPR(ATM)) or with CPAP (CPR(CPAP)). CPAP was adjusted to produce a minute ventilation of 75% of the animal's baseline ventilation. Data were summarized as mean +/- SD and compared with Student t test for paired observations.

Results

During CPR without IPPV, CPAP decreased PaCO2 (55+/-28 vs. 100+/-16 mmHg) and increased SaO2 (0.86+/-0.19 vs. 0.50+/-0.18%; P < 0.001). CPAP also increased arteriovenous oxygen content difference (10.7+/-3.1 vs. 5.5+/-2.3 ml/dl blood) and CO2 elimination (120+/-20 vs. 12+/-20 ml/min; P < 0.01). Differences between CPR(CPAP) and CPR(ATM) in aortic blood pressure, cardiac output, and stroke volume were not significant.

Conclusions

Mechanical ventilation may not be necessary during CPR as long as CPAP is applied. Discontinuation of IPPV will simplify CPR and may offer physiologic advantage.
Local Anesthetic Inhibition of Baseline Potassium Channels with Two Pore Domains in Tandem
Authors: Kindler Christoph H. , Yost Spencer C. , Gray Andrew T.
Published: November 2003

Background

Recently, a new structural family of potassium channels characterized by two pore domains in tandem within their primary amino acid sequence was identified. These tandem pore domain potassium channels are not gated by voltage and appear to be involved in the control of baseline membrane conductances. The goal of this study was to identify mechanisms of local anesthetic action on these channels.

Methods

Oocytes of Xenopus laevis were injected with cRNA from five cloned tandem pore domain baseline potassium channels (TASK, TREK-1, TOK1, ORK1, and TWIK-1), and the effects of several local anesthetics on the heterologously expressed channels were assayed using two-electrode voltage-clamp and current-clamp techniques.

Results

Bupivacaine (1 mM) inhibited all studied tandem pore potassium channels, with TASK inhibited most potently. The potency of inhibition was directly correlated with the octanol: buffer distribution coefficient of the local anesthetic, with the exception of tetracaine, to which TASK is relatively insensitive. The approximate 50% inhibitory concentrations of TASK were 709 microM mepivacaine, 222 microM lidocaine, 51 microM R(+)-ropivacaine, 53 microM S(-)-ropivacaine, 668 microM tetracaine, 41 microM bupivacaine, and 39 microM etidocaine. Local anesthetics (1 mM) significantly depolarized the resting membrane potential of TASK cRNA-injected oocytes compared with saline-injected control oocytes (tetracaine 22+/-6 mV rs. 7+/-1 mV, respectively, and bupivacaine 31+/-7 mV vs. 6+/-4 mV).

Conclusions

Local anesthetics inhibit tandem pore domain baseline potassium channels, and they could depolarize the resting membrane potential of cells expressing these channels. Whether inhibition of these channels contributes to conduction blockade or to the adverse effects of local anesthetics remains to be determined.
Speed of Onset and Offset and Mechanisms of Ventilatory Depression from Sevoflurane
Authors: Dahan Albert , Olofsen Erik , Teppema Luc , Sarton Elise , Olievier Cees
Published: November 2003

Background

Inhalational anesthetics depress breathing dose dependently. The authors studied the dynamics of ventilation on changes in end-tidal sevoflurane partial pressure. To learn more about the mechanisms of sevoflurane-induced respiratory depression, the authors also studied its influence on the dynamic ventilatory response to carbon dioxide.

Methods

Experiments were performed in cats anesthetized with alpha chloralose-urethane. For protocol 1, step changes in end-tidal sevoflurane partial pressure were applied and inspired ventilation was measured. Breath-to-breath inspired ventilation was related to the sevoflurane concentration in a hypothetical effect compartment based on an inhibitory sigmoid Emax model. For protocol 2, step changes in the end-tidal partial pressure of carbon dioxide were applied at 0, 0.5, and 1% end-tidal sevoflurane. The inspired ventilation-end-tidal partial pressure of carbon dioxide data were analyzed using a two-compartment model of the respiratory controller, which consisted of a fast peripheral and slow central compartment. Values are the mean +/- SD.

Results

In protocol 1, the effect-site half-life of respiratory changes caused by alterations in end-tidal sevoflurane partial pressure was 3.6+/-1.0 min. In protocol 2, at 0.50% sevoflurane, the central and peripheral carbon dioxide sensitivities decreased to 43+/-20% and 36+/-18% of control. At 1% sevoflurane, the peripheral carbon dioxide sensitivity decreased further, to 12+/-13% of control, whereas the central carbon dioxide sensitivity showed no further decrease.

Conclusions

Steady state inspired ventilation is reached after 18 min (i.e., 5 half-lives) on stepwise changes in end-tidal sevoflurane. Anesthetic concentrations of sevoflurane have, in addition to an effect on pathways common to the peripheral and central chemoreflex loops, a selective effect on the peripheral chemoreflex loop. Sevoflurane has similar effects on ventilatory control in humans and cats.
Effect of Systemic Morphine on the Responses of Convergent Neurons to Noxious Heat Stimuli Applied over Graded Surface Areas
Authors: Gall Olivier , Bouhassira Didier , Chitour Djamel , Le Bars Daniel
Published: November 2003

Background

Stimulus intensity is a major determinant of the antinociceptive activity of opiates. This study focused on the influence of the spatial characteristics of nociceptive stimuli, on opiate-induced depressions of nociceptive transmission at the level of the spinal cord.

Methods

Anesthetized rats were prepared to allow extracellular recordings to be made from convergent neurons in the lumbar dorsal horn. The effects of systemic morphine (1 and 10 mg/kg) were compared with those of saline for thermal stimuli of constant intensity, applied to the area of skin surrounding the excitatory receptive field (1.9 cm2) or to a much larger adjacent area (18 cm2).

Results

The responses (mean +/- SD) elicited by the 1.9-cm2 stimulus were not modified by 1 mg/kg intravenous morphine, although they were decreased by the 10-mg/kg dose (to 11+/-4% of control values compared with saline; P < 0.05). In contrast, when the 18-cm2 stimulus was applied, 1 mg/kg intravenous morphine produced a paradoxical facilitation of the neuronal responses (159+/-36% of control values; P < 0.05) and 10 mg/kg intravenous morphine resulted in a weaker depression of the responses (to 42+/-24% of control values; P < 0.05) than was observed with the smaller stimulus.

Conclusions

Doses of systemic morphine in the analgesic range for rats had dual effects on nociceptive transmission at the level of the spinal cord, depending on the surface area that was stimulated. Such effects are difficult to explain in terms of accepted pharmacodynamic concepts and may reflect an opioid-induced depression of descending inhibitory influences triggered by spatial summation.
Differential Effects of Lidocaine and Mexiletine on Relaxations to ATP-sensitive K+Channel Openers in Rat Aortas
Authors: Kinoshita Hiroyuki , Ishikawa Toshizo , Hatano Yoshio
Published: November 2003

Background

In cardiac myocytes, lidocaine reduces but mexiletine increases adenosine triphosphate (ATP)-sensitive K+ currents, suggesting that these class Ib antiarrhythmic drugs may differentially modify the activity of ATP-sensitive K+ channels. The effects of lidocaine and mexiletine on arterial relaxations induced by K+ channel openers have not been studied. Therefore, the current study was designed to evaluate whether lidocaine and mexiletine may produce changes in relaxations to the ATP-sensitive K+ channel openers cromakalim and pinacidil in isolated rat thoracic aortas.

Methods

Rings of rat thoracic aortas without endothelia were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative fashion. During submaximal contractions to phenylephrine (3 x 10(-7) M), relaxations to cromakalim (10(-7) to 3 x 10(-5) M), pinacidil (10(-7) to 3 x 10(-5) M), or diltiazem (10(-7) to 3 x 10(-4) M) were obtained. Lidocaine (10(-5) to 3 x 10(-4) M), mexiletine (10(-5) to 10(-4) M) or glibenclamide (5 x 10(-6) M) was applied 15 min before addition of phenylephrine.

Results

During contractions to phenylephrine, cromakalim and pinacidil induced concentration-dependent relaxations. A selective ATP-sensitive K+ channel antagonist, glibenclamide (5 x 10(-6) M), abolished these relaxations, whereas it did not alter relaxations to a voltage-dependent Ca2+ channel inhibitor, diltiazem (10(-7) to 3 x 10(-4) M). Lidocaine (more than 10(-5) M) significantly reduced relaxations to cromakalim or pinacidil in a concentration-dependent fashion, whereas lidocaine (3 x 10(-4) M) did not affect relaxations to diltiazem. In contrast, mexiletine (more than 10(-5) M) significantly augmented relaxations to cromakalim or pinacidil. Glibenclamide (5 x 10(-6) M) abolished relaxations to cromakalim or pinacidil in arteries treated with mexiletine (10(-4) M).

Conclusions

These results suggest that lidocaine impairs but mexiletine augments vasodilation mediated by ATP-sensitive K+ channels in smooth muscle cells.
Surgical Subspecialty Block Utilization and Capacity Planning
Authors: Strum David P. , Vargas Luis G. , May Jerrold H.
Published: November 2003

Background

Operational inefficiencies in the use of operating rooms (ORs) are hidden by traditional measures of OR utilization. To better detect these inefficiencies, the authors defined two new terms, underutilization and overutilization, and illustrated how these measures might be used to evaluate the use of surgical subspecialty ORs. The authors also described capacity planning (optimizing surgical subspecialty block time allotments) using a minimal cost analysis (MCA) model.

Methods

The authors evaluated post hoc all surgeries performed over 6 yr at a large teaching hospital. To prepare utilization estimates, surgical records were categorized relative to budgeted OR block time for each subspecialty. Surgical cases beginning and ending during budgeted OR block time were categorized as budgeted utilization, budgeted time not used for surgery was underutilization, and cases beginning before/after budgeted block time were classified as overutilization. Cases that overlapped budgeted and nonbudgeted OR block time were parsed and the portions were assigned appropriately. Probability distributions were fitted to the historical patterns of surgical demand, and MCA block time budgets were estimated that minimized the costs of underutilization and overutilization for each subspecialty. To illustrate the potential savings if these MCA budgets were implemented, the authors compared actual operational costs to the estimated MCA budget costs and expressed the savings as a percentage of actual costs.

Results

The authors analyzed data from 58,251 surgical cases and 10 surgical subspecialty blocks. Classic utilization for each block-day by surgical subspecialty ranged from 44-113%. Average daily block-specific underutilization ranged from 16 to 60%, whereas overutilization ranged from 4 to 49%.

Conclusions

Underutilization and overutilization are important measures because they may be used to evaluate the quality of OR schedules and the efficiency of OR utilization. Overutilization and underutilization also allow capacity planning using an MCA model This study indicated that the potential savings, if the MCA budgets were to be implemented, would be significant.
Ineffectiveness of Burst Suppression Therapy in Mitigating Perioperative Cerebrovascular Dysfunction
Authors: Roach Gary W. , Newman Mark F. , Murkin John M. , Martzke Jeff , Ruskin Adam , Li Juliet , Guo Annie , Wisniewski Amy , Mangano Dennis T.
Published: November 2003

Background

Cerebral injury is among the most common and disabling complications of open heart surgery. Attempts to provide neuroprotection have yielded conflicting results. We assessed the potential of propofol-induced burst suppression during open heart surgery to provide cerebral protection as determined by postoperative neuropsychologic function.

Methods

Two hundred twenty-five patients undergoing valve surgery were randomized to receive either sufentanil or sufentanil plus propofol titrated to electroencephalographic burst suppression. Blinded investigators performed neurologic and neuropsychologic testing at baseline, postoperative day (POD) 1 (neurologic testing only), PODs 5-7, and PODs 50-70. Neuropsychologic tests were compared with the results of 40 nonsurgical patients matched for age and education.

Results

Electroencephalographic burst suppression was successfully achieved in all 109 propofol patients. However, these patients sustained at least as many adverse neurologic outcomes as the 116 controls: POD 1, 40% versus 25%, P = 0.06; PODs 5-7, -18% versus 8%, P = 0.07; PODs 50-70, -6% versus 6%, P = 0.80. No differences in the incidence of neuropsychologic deficits were detected, with 91% of the propofol patients versus 92% of the control patients being impaired at PODs 5-7, decreasing to 52 and 47%, respectively, by PODs 50-70. No significant differences in the severity of neuropsychologic dysfunction, depression, or anxiety were noted.

Conclusions

Electroencephalographic burst suppression surgery with propofol during cardiac valve replacement did not significantly reduce the incidence or severity of neurologic or neuropsychologic dysfunction. The authors' results suggest that neither cerebral metabolic suppression nor reduction in cerebral blood flow reliably provide neuroprotection during open heart surgery. Other therapeutic approaches must be evaluated to address this important medical problem.
Women Emerge from General Anesthesia with Propofol/Alfentanil/Nitrous Oxide Faster than Men
Authors: Gan Tong J. , Glass Peter S. , Sigl Jeff , Sebel Peter , Payne Fredrick , Rosow Carl , Embree Patricia
Published: November 2003

Background

Recovery from general anesthesia is governed by pharmacodynamic and pharmacokinetic factors. Gender has not previously been recognized as a factor influencing the time to emergence from general anesthesia.

Methods

This multicenter study was originally designed to measure the effects of the bispectral index on intraoperative anesthetic management and patient recovery. We compared the wake-up and recovery times of 274 adults after propofol/alfentanil/nitrous oxide anesthesia. Patients were randomly assigned to have the titration of propofol performed with or without the use of bispectral index monitoring. Specific guidelines were given for the titration of drugs. The aim in all cases was to provide a safe anesthetic with the fastest possible recovery.

Results

There was a significant reduction in propofol dose, time to eye opening, and response to verbal command when the anesthetic was titrated using the bispectral index. Unexpectedly, gender proved to be a highly significant independent predictor for recovery time. Women woke significantly faster than men: the time from end of anesthesia to eye opening was 7.05 versus 11.22 min, P < 0.05, and response to verbal command was 8.12 versus 11.67 min, P < 0.05. These differences were significant at all four study sites and in each treatment group. Men consistently had prolonged recovery times compared to women, P < 0.001. There was no difference in the dose of anesthetic used between gender.

Conclusions

Gender appears to be an important variable in recovery from general anesthesia. These findings may explain the increased reported incidence of awareness in women (three times more frequent) and support the need to include gender as a variable in pharmacokinetic and pharmacodynamic studies of anesthetic drugs.