bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and Pharmacodynamics of Inhaled versus Intravenous Morphine in Healthy Volunteers
Authors: Dershwitz Mark , Walsh John L. , Morishige Richard J. , Connors Patricia M. , Rubsamen Reid M. , Shafer Steven L. , Rosow Carl E.
Published: November 2003

Background

A new pulmonary drug delivery system produces aerosols from disposable packets of medication. This study compared the pharmacokinetics and pharmacodynamics of morphine delivered by an AERx prototype with intravenous morphine.

Methods

Fifteen healthy volunteers were enrolled. Two subjects were administered four inhalations of 2.2 mg morphine each at 1-min intervals or 4.4 mg over 3 min by intravenous infusion. Thirteen subjects were given twice the above doses, i.e., eight inhalations or 8.8 mg intravenously over 7 min. Arterial blood sampling was performed every minute during administration and at 2, 5, 7, 10, 15, 20, 45, 60, 90, 120, 150, 180, and 240 min after administration. The effect of morphine was assessed by measuring pupil diameter and ventilatory response to a hypercapnic challenge. Pharmacokinetic and pharmacodynamic analyses were performed simultaneously using mixed-effect models.

Results

The pharmacokinetic data after intravenous administration were described by a three-exponent decay model preceded by a lag time. The pharmacokinetic model for administration by inhalation consisted of the three-exponent intravenous pharmacokinetic model preceded by a two-exponent absorption model. The authors found that, with administration by inhalation, the total bioavailability was 59%, of which 43% was absorbed almost instantaneously and 57% was absorbed with a half-life of 18 min. The median times to the half-maximal miotic effects of morphine were 10 and 5.5 min after inhalation and intravenous administration, respectively (P < 0.01). The pharmacodynamic parameter ke0 was approximately 0.003 min-1.

Conclusions

The onset and duration of the effects of morphine are similar after intravenous administration or inhalation via this new pulmonary drug delivery system. Morphine bioavailability after such administration is 59% of the dose loaded into the dosage form.
Predictive Accuracy of Target-controlled Propofol and Sufentanil Coinfusion in Long-lasting Surgery
Authors: Pandin Pierre C. , Cantraine Francis , Ewalenko Patricia , Deneu Stéphane C. , Coussaert Eddy , d’Hollander Alain A.
Published: November 2003

Background

The predictive accuracy of target concentration infusions of propofol has been documented only for less than 4 h, and no prospective study of sufentanil target controlled infusion is available. The authors investigated the predictive accuracy of pharmacokinetic models for propofol and sufentanil coadministered during long-lasting surgery.

Methods

Ten patients, American Society of Anesthesiologists physical status I and II, were studied during extended cervicofacial surgery. Target controlled infusion of propofol and sufentanil was administered during surgery using decisional algorithms, taking into consideration pain assessment, hemodynamic changes, and peroperative blood losses. Intrasubject data analysis included calculation of performance error, median performance error, median absolute performance error, divergence, and wobble.

Results

The range of plasma target concentrations was 2-5 microgram/ml for propofol and 0.2-1 ng/ml for sufentanil. Median performance error was -12.1% for propofol and -10% for sufentanil. The wobble values were 11.6% and 22.3% for propofol and sufentanil, respectively. The pharmacokinetic sets used slightly overpredicted the concentrations, with negative values of divergence of 2.92% and 0.22% units/h for propofol and sufentanil, for a mean infusion period of 762 min.

Conclusions

This prospective study demonstrates the predictive accuracy of the pharmacokinetic model for sufentanil infusion and confirms that for propofol during long-lasting surgery using standardized rules for the management of target controlled infusion and blood loss replacement.
Efficacy of Preoxygenation with Tidal Volume Breathing
Authors: Nimmagadda Usharani , Salem M. Ramez , Joseph Ninos J. , Lopez Gilbert , Megally Mahfouz , Lang David J. , Wafai Yaser
Published: November 2003

Background

Preoxygenation before tracheal intubation is intended to increase oxygen reserves and delay the onset of hypoxemia during apnea. Various systems are used for preoxygenation. Designed specifically for preoxygenation, the NasOral system uses a small nasal mask for inspiration and a mouthpiece for exhalation. One-way valves in the nasal mask and the mouthpiece ensure unidirectional flow. This investigation compares the efficacy of preoxygenation using the standard circle system with the NasOral system and five different resuscitation bags.

Methods

Twenty consenting, healthy volunteers were studied in the supine position for 5-min periods of tidal volume breathing using the circle absorber system, the NasOral system, and five resuscitation bags in a randomized order. Data were collected during room air breathing and at 30-s intervals during 5 min of oxygen administration. Inspired oxygen, end-tidal oxygen, and end-tidal nitrogen were measured by mass spectrometry.

Results

At 2. 5 min of oxygenation, end-tidal oxygen plateaued at 88.1 +/- 4.8 and 89.3 +/- 6.4% (mean +/- SD) for the circle absorber and NasOral systems, respectively. This was associated with inverse decreases in end-tidal nitrogen. At no time did these end-tidal oxygen or nitrogen values differ from each other. Three of the resuscitation bags (one disk type and two duck-bill type with one-way exhalation valves) delivered inspired oxygen more than 90%, and the end-tidal oxygen plateaued between 77 and 89% at 2 min of tidal volume breathing. The other two resuscitation bags (both duck-bill bags without exhalation valves) delivered inspired oxygen less than 40%, and the end-tidal oxygen values ranged between 21.8 +/- 5.0 and 31.9 +/- 8.7%.

Conclusions

The circle absorber and NasOral systems were equally effective in achieving maximal preoxygenation during tidal volume breathing. Resuscitation bags differed markedly in effectiveness during preoxygenation; those with duck-bill valves without one-way exhalation valves were the least effective. Thus, the use of these bags should be avoided for preoxygenation.
Facilitated Uptake of Fentanyl, but Not Alfentanil, by Human Pulmonary Endothelial Cells
Authors: Waters Christopher M. , Krejcie Tom C. , Avram Michael J.
Published: November 2003

Background

Extensive pulmonary uptake of lipophilic basic amines, such as fentanyl, attenuates early blood drug concentrations after rapid intravenous administration. The basis of this phenomenon is poorly understood. The authors tested the hypothesis that fentanyl uptake into cultured human lung microvascular endothelial (HMVE-L) cells occurs by facilitated uptake in addition to passive diffusion. The authors compared fentanyl and alfentanil uptake with that of antipyrine, a diffusible marker of pulmonary tissue water. In addition, the authors determined the effect of verapamil, a nonspecific inhibitor of drug transport, and UIC2, a blocking antibody of the P-glycoprotein drug transporter, on the uptake of these drugs.

Methods

Human lung microvascular endothelial cells were incubated, with varying concentrations of antipyrine and fentanyl or alfentanil in the absence or presence of varying verapamil concentrations or of UIC2. Supernatants were collected and cells were rinsed and dissolved. Supernatant and cell-associated antipyrine, fentanyl, and alfentanil concentrations were measured. The data were fit to a model of cellular uptake that allowed for passive diffusion and facilitated uptake.

Results

Alfentanil uptake by HMVE-L cells was indistinguishable from that of antipyrine for the concentration ranges studied. In contrast, at low concentrations, fentanyl sequestration into HMVE-L cells was substantially greater than that of antipyrine. Facilitated fentanyl uptake was blocked by verapamil, but not by UIC2, in a concentration-dependent manner.

Conclusions

The differential HMVE-L uptake of fentanyl and alfentanil is consistent with the observed differences in the pulmonary uptake of these drugs. This suggests that specific fentanyl uptake and sequestration by HMVE-L cells may be the mechanisms of its extensive pulmonary uptake.
Cause-specific Mortality Risks of Anesthesiologists
Authors: Alexander Bruce H. , Checkoway Harvey , Nagahama Sonia I. , Domino Karen B.
Published: November 2003

Background

The health-related effects of the operating room environment are unclear. The authors compared mortality risks of anesthesiologists to those of internal medicine physicians between 1979 and 1995.

Methods

The Physician Master File database, a listing of all US physicians, was used to identify anesthesiologists and general internists. The cohort of internists (n = 40,211) was a stratified random sample of all internists, frequency-matched to the cohort of anesthesiologists (n = 40,242) by gender, decade of birth, and US citizenship. The National Death Index was used to confirm death status and to determine specific causes of death. Mortality risks, adjusted for age, gender, and race, were compared using the Cox proportional hazards regression model.

Results

The standardized mortality ratios for all physicians were well below 1.0, except for suicide. The all-cause mortality ratios, and the risks of death caused by cancer and heart disease, did not differ between anesthesiologists and internists. Anesthesiologists had an increased risk of death from suicide (rate ratio [RR] = 1.45, 95% confidence interval [CI] = 1.07 - 1.97), drug-related death (RR = 2.79, 95% CI = 1.87 - 4.15), death from other external causes (RR = 1.53, 95% CI = 1.05 - 2.22), and death from cerebrovascular disease (RR = 1.39, 95% CI = 1.08 - 1.79). Male anesthesiologists had an increased risk of death from HIV (RR = 1.82, 95% CI = 1.09 - 3.02) and viral hepatitis (RR = 7.98, 95% CI = 1.0 - 63.84). Although the risk to anesthesiologists of drug-related deaths was highest in the first 5 years after medical school graduation, it remained increased over that of internists throughout the career.

Conclusions

Substance abuse and suicide represent significant occupational hazards for anesthesiologists. New methods to combat substance abuse among anesthesiologists should be developed.
Transdermal Nitroglycerine Enhances Spinal Neostigmine Postoperative Analgesia following Gynecological Surgery
Authors: Lauretti Gabriela R. , Oliveira Ana-Paula M. , Julião Maria-do-Carmo C. , Reis Marlene P. , Pereira Newton L.
Published: November 2003

Background

Intrathecal neostigmine causes analgesia by inhibiting the breakdown of acetylcholine. Experimental data suggest that the production of endogenous nitric oxide is necessary for tonic cholinergic inhibition of spinal pain transmission. The purpose of this study was to determine whether association of transdermal nitroglycerine would enhance analgesia from a low dose of intrathecal neostigmine in patients undergoing gynecologic surgery during spinal anesthesia.

Methods

Forty-eight patients were randomized to one of four groups. Patients were premedicated with use of 0.05-0.1 mg/kg intravenous midazolam and received 15 mg bupivacaine plus 1 ml test drug intrathecally (saline or neostigmine, 5 microgram). Twenty to 30 min after the spinal puncture, a transdermal patch of either 5 mg nitroglycerin or placebo was applied. The control (Con) group received spinal saline and transdermal placebo. The neostigmine group received spinal neostigmine and transdermal placebo. The nitroglycerin group received spinal saline and a transdermal nitroglycerine patch. Finally, the neostigmine-nitroglycerin group received spinal neostigmine and transdermal nitroglycerine. Pain and adverse effects were evaluated using a 10-cm visual analog scale.

Results

Patients in the groups were similar regarding age, weight, height, and American Society of Anesthesiologists status. Sensory level to pin prick at 10 min, surgical duration, anesthetic duration, and visual analog scale score for pain at the time of administration of first rescue medication were statistically the same for all groups. The time to administration of first rescue analgesic (min) was longer in the neostigmine-nitroglycerin group (550 min; range, 458-1,440 min; median, 25-75th percentile) compared with the other groups (P < 0.001). The neostigmine-nitroglycerin group required fewer rescue analgesics in 24 h than did the control group (P < 0.0005), whereas the neostigmine group required less analgesics compared with the control group (P < 0.02). The incidence of perioperative adverse effects (nausea, vomiting, headache, back pain) was similar among groups (P > 0.05).

Conclusion

Although neither intrathecal 5 microgram neostigmine alone nor transdermal nitroglycerine alone (5 mg/day) delayed the time to administration of first rescue analgesics, the combination of both provided an average of 14 h of effective postoperative analgesia after vaginoplasty, suggesting that transdermal nitroglycerin and the central cholinergic agent neostigmine may enhance each other's antinociceptive effects at the dose studied.
Oral Clonidine Premedication Does Not Change Efficacy of Simulated Epidural Test Dose in Sevoflurane-anesthetized Children
Authors: Shiga Makoto , Nishina Kahoru , Mikawa Katsuya , Uesugi Takanobu , Maekawa Nobuhiro , Obara Hidefumi
Published: November 2003

Background

Caudal epidural anesthesia is often used as an adjunct to general anesthesia and for postoperative pain relief in children. In anesthetized children, epinephrine and isoproterenol are reliable indicators to detect accidental intravascular injection of a test dose. Oral clonidine, a useful premedicant in pediatric anesthesia, modifies hemodynamic responses to sympathomimetics, including catecholamines. The aim of the current study was to determine whether oral clonidine premedication alters the efficacy of a simulated intravascular test dose containing epinephrine or isoproterenol in sevoflurane-anesthetized children.

Methods

One hundred twenty children (aged 1-7 yr) were randomly divided into six groups; control-saline, control-epinephrine, control-isoproterenol, clonidine-saline, clonidine-epinephrine, and clonidine-isoproterenol. The three clonidine groups received oral clonidine 4 microg/kg [DOSAGE ERROR CORRECTED] as premedication, whereas the three control groups did not receive any premedication. Anesthesia was maintained with sevoflurane at a level of 1.2 minimum alveolar concentration. After hemodynamics were stable, 0.1 ml/kg of 1% lidocaine containing epinephrine 0.5 mg/kg or isoproterenol 75 ng/kg was intravenously given to the two epinephrine or isoproterenol groups, respectively, to simulate intravascular injection of a test dose. The saline groups received saline alone instead of the test dose. Heart rate, blood pressure, and T-wave amplitude of electrocardiogram were recorded before and after administration of study drugs for subsequent analysis.

Results

Test solution containing epinephrine increased heart rate, systolic blood pressure, and T-wave amplitude. Oral clonidine had no effect on elevation of these variables in response to epinephrine. The isoproterenol-containing test dose produced a prominent increase in heart rate and a less pronounced increase in systolic blood pressure and T-wave amplitude. Oral clonidine also failed to modify isoproterenol-induced hemodynamic and T-wave changes. Calculated sensitivity and specificity of epinephrine or isoproterenol were all 100% based on a new heart rate criterion (positive if >/= 10 beats/min) and were unaltered by oral clonidine premedication.

Conclusions

Epinephrine or isoproterenol is a reliable marker to detect accidental intravascular injection of a test dose with 100% sensitivity and specificity based on a new heart rate criterion in sevoflurane-anesthetized children. These data suggest that oral clonidine premedication does not alter the efficacy of a simulated epidural test dose containing epinephrine or isoproterenol.
Analgesic Effects of Caudal and Intramuscular S (+)-Ketamine in Children
Authors: Koinig Herbert , Marhofer Peter , Krenn Claus G. , Klimscha Walter , Wildling Eckart , Erlacher Wolfgang , Nikolic Ajsa , Turnheim Klaus , Semsroth Margot
Published: November 2003

Background

Previous studies suggest that caudal administration of ketamine cause effective analgesia. The purpose of the current study was to compare the clinical effectiveness and plasma concentrations of S(+)-ketamine after caudal or intramuscular administration in children to distinguish between local and systemic analgesia.

Methods

After induction of general anesthesia, 42 patients, aged 1 to 7 yr, scheduled to undergo inguinal hernia repair randomly received a caudal (caudal group) or intramuscular (intramuscular group) injection of 1 mg/kg S(+)-ketamine. Intraoperatively, heart rate (HR), mean arterial pressure (MAP) and arterial oxygen saturation were measured. Postoperative measurements included duration of analgesia, a four-point sedation score, and hemodynamic and respiratory monitoring for 6 h in the recovery room. Analgesic requirements in the recovery room were assessed by an independent blinded observer using an observational pain/discomfort scale (OPS). Plasma samples for determination of ketamine concentrations were obtained before and 10, 20, 30, 45, 60, 90, 120, and 180 min after injection of S(+)-ketamine.

Results

A significantly longer duration of analgesia (P < 0.001) was observed after caudal administration (528 min [220-1,440 min]; median [range]) when compared with intramuscular administration (108 min [62-1,440 min]) of S(+)-ketamine. Plasma levels of ketamine were significantly lower from 10 to 45 min after caudal administration than after intramuscular injection.

Conclusion

Caudal S(+)-ketamine provides good intra- and postoperative analgesia in children. Despite similar plasma concentrations during most of the postoperative observation period, caudal S(+)-ketamine provided more effective analgesia than did intramuscular S(+)-ketamine, indicating a local analgesic effect.
The Role of Human Lungs in the Biotransformation of Propofol
Authors: Dawidowicz Andrzej L. , Fornal Emilia , Mardarowicz Marek , Fijalkowska Anna
Published: November 2003

Background

The metabolism of propofol is very rapid, and its transformation takes place mainly in the liver. There are reports indicating extrahepatic metabolism of the drug, and the alimentary canal, kidneys, and lungs are mentioned as the most probable places where the process occurs. The aim of this study was to determine whether the human lungs really take part in the process of propofol biotransformation.

Methods

Blood samples were taken from 55 patients of American Society of Anesthesiologists grade 1-3 scheduled for elective intracranial procedures (n = 47) or for pulmonectomy (n = 8). All patients were premedicated with diazepam (10 mg) administered orally 2 h before anesthesia. Propofol total intravenous anesthesia was performed at the following infusion rates: 12 mg. kg-1. h-1, 9 mg. kg-1. h-1, and 6 mg. kg-1. h-1. Fentanyl and pancuronium bromide were also administered intermittently. After tracheal intubation, the lungs were ventilated to normocapnia with an oxygen-air mixture (fraction of inspired oxygen = 0.33). Blood samples for propofol and 2,6-diisopropyl-1, 4-quinol analysis were taken simultaneously from the right atrium and the radial artery, or the pulmonary artery and the radial artery. The concentration of both substances were measured with high-performance liquid chromatography and gas chromatography-mass spectroscopy.

Results

The concentration of propofol in the central venous system (right atrium or pulmonary artery) is greater than in the radial artery, whereas the opposite is observed for propofol's metabolite, 2,6-diisopropyl-1,4-quinol. Higher propofol concentrations are found in blood taken from the pulmonary artery than in the blood collected from the radial artery.

Conclusions

Human lungs take part in the elimination of propofol by transforming the drug into 2,6-diisopropyl-1,4-quinol.
Adenosine-induced Ventricular Asystole to Induce Transient Profound Systemic Hypotension in Patients Undergoing Endovascular Therapy
Authors: Hashimoto Tomoki , Young William L. , Aagaard Beverly D. , Joshi Shailendra , Ostapkovich Noeleen D. , Pile-Spellman John
Published: November 2003

Background

Adenosine-induced asystole has been used to induce transient systemic hypotension for various vascular procedures. Dose-response characteristics of adenosine-induced ventricular asystole have not been determined.

Methods

During endovascular embolization of cerebral arteriovenous malformations, the authors performed a series of adenosine test injections to establish a dose-response relation in each patient. After an interval of 3-10 min, the dose was escalated by 10-20 mg for each injection to achieve an end point of 20-30 s of stable mean arterial pressure (MAP) reduction to 25-30 mmHg. All patients received constant infusion of nitroprusside (approximately 1 microgram. kg-1. min-1) throughout the procedure.

Results

The authors studied four adult patients (age, 22-44 yr; two patients had two separate procedures) and one pediatric patient (age, 4 yr). Twenty-three adenosine injections resulted in measurable asystole. The adenosine dose was 0. 98 +/- 0.40 mg/kg (mean +/- SD), and the dose range was 0.24-1.76 mg/kg (6-90 mg). The duration of asystole, MAP < 30 mmHg, and MAP < 50 mmHg, were 8 +/- 3 s, 18 +/- 12 s, and 50 +/- 29 s, respectively. The minimum MAP and the MAP for the first 20 s were 16 +/- 3 mmHg and 30 +/- 9 mmHg, respectively. There was a linear relation between adenosine dose and the duration of hypotension with MAP < 30 mmHg and MAP < 50 mmHg.

Conclusions

In the dose range studied, a series of adenosine test injections can be used to determine optimal adenosine dose for induction of transient profound hypotension.
Isosulfan Blue Affects Pulse Oximetry
Authors: Vokach-Brodsky Lindsey , Jeffrey Stefanie S. , Lemmens Harry J. M. , Brock-Utne John G.
Published: November 2003

Background

Certain vital dyes are known to cause pulse oximetry (Spo2) desaturation. The authors studied the effect of isosulfan blue (IB) on Spo2.

Methods

Thirty-three women, aged 34-81 yr, who were undergoing surgery for breast cancer were studied. IB, 5 ml (50 mg), was injected intraparenchymally around the tumor area by the surgeon. A pulse oximeter was used to continuously record Spo2 values up to 130 min after IB injection. Friedman repeated-measures analysis of ranks was used to analyze the baseline Spo2 and values at 5, 10, 20, 30, 40, 50, and 60 min.

Results

Spo2 values were significantly different from baseline values at 5, 10, 20, 30, 40, 50, and 60 min (P < 0.05). In a typical patient, a maximum Spo2 decrease of 3% can be anticipated 25 min after injection of IB.

Conclusions

After peritumoral administration of IB, 50 mg, a significant interference with Spo2 will occur.
Low- and Medium-molecular-weight Hydroxyethyl Starches
Authors: Jamnicki Marina , Bombeli Thomas , Seifert Burkhardt , Zollinger Andreas , Camenzind Vladimir , Pasch Thomas , Spahn Donat R.
Published: November 2003

Background

High-molecular-weight hydroxyethyl starch (HES) compromises blood coagulation more than medium-molecular-weight HES. The authors compared medium molecular weight HES (200 kd [HES200]) and low-molecular-weight HES (70 kd [HES70]).

Methods

In a prospective, double-blind, randomized-sequence crossover study, 22 male volunteers received 15 ml/kg HES200 and HES70. Blood samples were taken before and 5 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after infusion. The following parameters were analyzed at all time points: prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, antigenetic and functional von Willebrand factor, platelets, Thrombelastograph analysis parameters (reaction time, coagulation time, maximum amplitude, angle alpha, and clot lysis 30 and 60 min after maximum amplitude), ionized calcium, hematocrit, HES plasma concentration, molecular weight (weight average and number average), molar substitution, and polydispersity (weight average/number average). Repeated-measures analysis of variance (P < 0.05) was used to compare the response of the aforementioned parameters to the infusion of HES70 and HES200.

Results

Both HES solutions had a significant impact on all parameters. A slightly greater compromise with HES200 was found in activated partial thromboplastin time (P = 0.010), factor VIII (P = 0.009), antigenetic von Willebrand factor (P = 0.041), functional von Willebrand factor (P = 0.026), maximum amplitude (P = 0.008), and angle alpha (P = 0.003). No difference was established with the other parameters. HES concentration (P < 0.001), weight average (P < 0.001), number average (P < 0.001), and polydispersity (P < 0.001) were higher with HES200. There was no difference with molar substitution (P = 0.091).

Conclusions

Low-molecular-weight hydroxyethyl starch (70 kd) compromises blood coagulation slightly less than HES200, but it is unclear whether this is clinically relevant.
The Effect of Chronic Dexamethasone-induced Hyperglycemia and Its Acute Treatment with Insulin on Brain Glucose and Glycogen Concentrations in Rats
Authors: Thompson Matthew D. , Gallagher William J. , Iaizzo Paul A. , Lanier William L.
Published: November 2003

Background

In the rat model of forebrain ischemia, long-term dexamethasone treatment is reported to cause hyperglycemia and worsen postischemic functional and histologic injury. This effect was assumed to result from glucose enhancement of intraischemic lactic acidosis within the brain. Short-term insulin therapy restored normoglycemia but did not return histologic injury completely to baseline values. Using a nonischemic rat model, the current study attempted to identify a metabolic basis for such outcome data.

Methods

Fifty-eight halothane-anesthetized (1.3% inspired) Sprague-Dawley rats were assigned randomly to be administered either no treatment (N = 18) or 2 mg/kg intraperitoneal dexamethasone (N = 40). The latter were administered dexamethasone 3 h before the study only (N = 8) or for 3 h before the study plus daily for 1 day (N = 8), 2 days (N = 8), or 4 days (N = 16). Of the rats treated with dexamethasone for 4 days, one half (N = 8) were administered an insulin-containing saline infusion subsequently to restore normoglycemia short-term. All other rats (N = 50) were administered an infusion of saline without insulin. Plasma glucose was quantified, and brains were excised after in situ freezing. Brain glucose and glycogen concentrations were measured using enzymatic fluorometric analyses.

Results

After 4 days of dexamethasone treatment, plasma glucose was 159% greater than in rats administered placebo (i.e., 22.01 +/- 4.66 vs. 8.51 +/- 1.65 micromol/ml; mean +/- SD; P < 0.0001). Brain glucose concentrations increased parallel to plasma glucose. An insulin infusion for 27 +/- 5 min restored normoglycemia but resulted in a brain-to-plasma glucose ratio that was 32% greater than baseline values (P < 0.01). Neither dexamethasone nor the combination of dexamethasone plus insulin affected brain glycogen concentrations.

Conclusions

In a nonischemic rat model, dexamethasone alone had no independent effect on the brain-to-plasma glucose ratio. However, short-term insulin therapy caused a dysequilibrium between plasma and brain glucose, resulting in an underestimation of brain glucose concentrations when normoglycemia was restored. The dysequilibrium likely was caused by the rapid rate of glucose reduction. The magnitude of the effect may account for the failure of insulin to reverse dexamethasone enhancement of neurologic injury completely in a previous report that used the rat model of forebrain ischemia.
Alterations in Ascending Dorsal Horn Neurons by a Surgical Incision in the Rat Foot
Authors: Vandermeulen Erik P. , Brennan Timothy J.
Published: November 2003

Background

Little is known about the mechanisms of pain caused by a surgical incision. The authors have developed a rat model of postoperative pain characterized by decreased withdrawal thresholds to punctate mechanical stimuli after plantar incision. The present studies examined the response characteristics of dorsal horn neurons receiving input from the plantar aspect of the foot before and after a plantar incision placed adjacent to the low threshold area of the receptive field (RF).

Methods

Individual dorsal horn neurons from the lumbar enlargement were antidromically identified and characterized as low threshold, wide dynamic range (WDR), and high threshold (HT) based on their responses to brush and pinch. Thresholds (in millinewtons), the pinch RF, and stimulus-response functions (SRFs) to von Frey filaments characterized the neurons. SRFs were analyzed using area under the curve. Changes in background activity, punctate mechanical thresholds, SRFs, and RF were recorded after an incision was made adjacent to the most sensitive area of the RF.

Results

In all cells, an incision increased background activity; this remained elevated in 3 of 9 HT and 16 of 28 WDR neurons 1 h later. The SRFs were enhanced in 10 of 27 WDR neurons and in 2 of 8 HT cells after incision. Only the WDR neurons were responsive to filaments that produced withdrawal responses after incision in behavioral experiments. Increases in the RFs outside of the injured area occurred after incision in 15 of 29 WDR and 2 of 9 HT cells.

Conclusion

A plantar incision caused dorsal horn cell activation and central sensitization. Because the threshold of HT neurons did not decrease to the range of the withdrawal responses in behavioral experiments, particular WDR dorsal horn neurons likely contribute to the reduced withdrawal threshold observed in behavioral experiments. Both WDR and HT neurons are capable of transmitting enhanced responses to strong punctate mechanical stimuli after incision.
Evaluation of Transesophageal Echocardiography for Diagnosis of Traumatic Aortic Injury
Authors: Goarin Jean-Pierre , Cluzel Philippe , Gosgnach Marilyn , Lamine Khaled , Coriat Pierre , Riou Bruno
Published: November 2003

Background

Traumatic aortic injury is a frequent cause of death after blunt trauma, but few patients survive to reach a trauma center. The role of transesophageal echocardiography (TEE) in the diagnosis of traumatic aortic injury remains debated.

Methods

Over a 9-yr period, 209 blunt trauma patients (mean age, 34 +/- 13 yr) were suspected of having traumatic aortic injury because of enlarged mediastinum and/or sudden deceleration, and underwent TEE and angiography (aortography and/or contrast-enhanced computed tomography.

Results

Traumatic aortic injury was diagnosed in 42 patients (20%). Angiography (aortography and/or contrast-enhanced computed tomography) was less accurate (sensitivity, 83%; specificity, 100%) than TEE (sensitivity, 98%; specificity, 100%) for the diagnosis of aortic injury because it failed to diagnose most minor injuries (intramural hematoma or limited intimal flap, n = 7). However, when considering only patients with major aortic injury (n = 33; i.e., those who might need surgery), angiography (sensitivity, 97%; specificity, 100%) and TEE (sensitivity, 97%; specificity, 100%) were equivalent.

Conclusion

Transesophageal echocardiography is an accurate method for diagnosis of traumatic aortic injury. Nevertheless, the clinical implications of limited aortic injuries diagnosed by the technique have yet to be determined.
An Investigation of Learning during Propofol Sedation and Anesthesia Using the Process Dissociation Procedure
Authors: Stapleton Clare L. , Andrade Jackie
Published: November 2003

Background

Many studies have shown that patients may remember words learned during apparently adequate anesthesia. Performance on memory tests may be influenced by explicit and implicit memory. We used the process dissociation procedure to estimate implicit and explicit memory for words presented during sedation or anesthesia.

Methods

We investigated intraoperative learning in 72 women undergoing pervaginal oocyte collection during propofol and alfentanil infusion. One word list was played once before infusion, another was played 10 times during surgery. Venous blood was taken for propofol assay at the end of the intraoperative list. Behavioral measures of anesthetic depth (eyelash reflex, hand squeeze response to command) were recorded and used to adjust the dose of anesthetic where clinically appropriate. On recovery, memory was assessed using an auditory word stem completion test with inclusion and exclusion instructions.

Results

The mean blood propofol concentration was 2.5 microg/ml (median, 2.3 microg/ml; range, 0.7-6.1 microg/ml). Mean alfentanil dose was 2.1 mg (median, 2.0 mg; range, 1.2-3.4 mg). Comparison of target and distractor hits in the inclusion condition showed memory for preoperative words only. However, the process dissociation procedure estimates showed explicit (mean, 0.18; P < 0.001) and implicit (mean, 0.05; P < 0.05) memory for the preoperative words, and a small amount of explicit memory for the intraoperative words (mean, 0.06; 95% confidence interval, 0.01-0.10). Memory performance did not differ between the 17 patients who consistently responded to command and eyelash reflex and the 32 patients who remained unresponsive. Blood propofol concentration and alfentanil dose did not correlate with memory for the intraoperative list.

Conclusions

There was no unprompted recall of surgery, but the process dissociation procedure showed memory for words presented during surgery. This memory was apparently explicit but did not correlate with the measures of depth of anesthesia used.
Effects of Halothane on Excitatory Neurotransmission to Medullary Expiratory Neurons in a Decerebrate Dog Model
Authors: Stuth Eckehard A. E. , Krolo Mirko , Stucke Astrid G. , Tonkovic-Capin Mislav , Tonkovic-Capin Viseslav , Hopp Francis A. , Kampine John P. , Zuperku Edward J.
Published: November 2003

Background

The activity of canine expiratory (E) neurons in the caudal ventral respiratory group is primarily dependent on N-methyl-D-aspartic acid (NMDA) receptor-mediated excitatory chemodrive inputs and modulated by an inhibitory mechanism mediated via gamma-aminobutyric acidA (GABA(A)) receptors. In an intact canine preparation, halothane depressed the activity of these neurons mainly by reduction in overall glutamatergic excitation. A new decerebrate preparation allows comparison of the effects of halothane on these synaptic mechanisms with an anesthetic-free baseline state.

Methods

Two separate studies were performed in decerebrate, vagotomized, paralyzed, mechanically ventilated dogs during hypercapnic hyperoxia. In study 1, the effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded E neuronal activity was studied before and during complete GABA(A) receptor blockade by localized pressure ejection of bicuculline. Complete blockade of the inhibitory mechanism allowed differentiation between the effects of halothane on overall GABA(A)-mediated inhibition and on overall NMDA receptor-mediated excitation. In study 2, the effect of 1 MAC halothane on the dose response of neurons to localized picoejection of the glutamate agonist NMDA was used to estimate halothane effect on postsynaptic glutamatergic excitatory neurotransmission.

Results

In study 1, the spontaneous activity of 14 E neurons was depressed 38.6 +/- 20.6% (mean +/- SD) by 1 MAC halothane. Overall excitation was depressed 31.5 +/- 15.5%. The GABAergic inhibition showed a 11.7 +/- 18.3% enhancement during halothane. In study 2, the spontaneous activity of 13 E neurons was again significantly depressed by 1 MAC halothane (27.9 +/- 10.6%), but the postsynaptic response of the neurons to exogenous NMDA was not significantly depressed by halothane (3.3 +/- 38.4%).

Conclusions

Together these results suggest that in our E neuron paradigm, halothane exerted its depressive effect mainly via reduction of glutamatergic presynaptic mechanisms.
Intramuscular Rapacuronium in Infants and Children
Authors: Denman William T. , Kaplan Richard F. , Goudsouzian Nishan G. , Uejima Tetsu , Barcelona Sandra L. , Cote Charles J. , Ginsberg Brian , Hannallah Raafat S.
Published: November 2003

Background

This multicenter, assessor, blinded, randomized study was conducted to confirm and extend a pilot study in which intramuscular rapacuronium was given to infants and children to confirm efficacy and to evaluate tracheal intubating conditions.

Methods

Ninety-six pediatric patients were studied in two groups: infants aged 1 to 12 months (n = 46) and children aged 1 to 3 yr (n = 50). Infants received 2.8 mg/kg and children 4.8 mg/kg of intramuscular rapacuronium during 1 minimum alveolar concentration halothane anesthesia. These two groups were studied in three subgroups, depending on the time (1.5, 3, or 4 min) at which tracheal intubation was attempted after the administration of intramuscular rapacuronium into the deltoid muscle. Neuromuscular data collected included onset time, duration of action, and recovery data during train-of-four stimulation at 0.1 Hz. Data were analyzed by the Cochran-Mantel-Haenszel procedure.

Results

The tracheal intubating conditions were deemed acceptable in 17, 36, and 64% of infants and 20, 47, and 71% of children at 1.5, 3, or 4 min, respectively. The mean values for % of control twitch height (T1) 2 min after rapacuronium in both groups were similar. The mean (SD) time required to achieve more than or equal to 95% twitch depression in infants was 6.0 (3.7) versus 5.5 (3.8) min in children.

Conclusions

Only 27% of patients achieved clinically acceptable tracheal intubating conditions at 1.5 or 3 min after administration of 2.8 mg/kg and 4.8 mg/kg rapacuronium during 1 minimum alveolar concentration halothane anesthesia. Tracheal intubation conditions at 4 min were acceptable in 69% of subjects. The duration of action of 4.8 mg/kg of rapacuronium in children was longer than 2.8 mg/kg of rapacuronium in infants.
Recirculatory Pharmacokinetics and Pharmacodynamics of Rocuronium in Patients
Authors: Kuipers Jette A. , Boer Fred , Olofsen Erik , Bovill James G. , Burm Anton G. L.
Published: November 2003

Background

Recirculatory models are capable of accurately describing first-pass pharmacokinetics and the influence of cardiac output (CO), which is important for drugs with a fast onset of effect. The influence of CO on pharmacokinetic and pharmacodynamic parameters of rocuronium in patients was evaluated using a recirculatory pharmacokinetic model.

Methods

Fifteen patients were included to study rocuronium pharmacokinetics and pharmacodynamics. Bolus doses of rocuronium (0.35 mg/kg) and indocyanine green (25 mg) were injected simultaneously via a peripheral intravenous catheter. Blood samples were taken for 240 min from the radial artery. The force of contraction of the adductor pollicis after a train-of-four at 2 Hz every 12 s was measured. Arterial concentration-time curves of rocuronium and indocyanine green were analyzed using a recirculatory model. Pharmacodynamics were described using a sigmoid maximum effect (Emax) model.

Results

The CO of the patients varied from 2.43 to 5.59 l/min. Total distribution volume of rocuronium was 17.3 +/- 4.8 l (mean +/- SD). The CO showed a correlation with the fast tissue clearance (Cl(T_f); r2 = 0.51), with the slow tissue clearance (Cl(T_s); r2 = 0.31) and with the mean transit times of rocuronium except for the mean transit time of the slow tissue compartment. The blood-effect site equilibration constant (k(e0)) was strongly correlated with CO (r2 = 0.70).

Conclusions

Cardiac output influences the pharmacokinetics, including k(e0), for rocuronium in patients. For drugs with a fast onset of effect, a recirculatory model, which includes CO, can give a good description of the relation between concentration and effect, in contrast to a conventional compartmental pharmacokinetic model.
Evidence for Susceptibility to Malignant Hyperthermia in Patients with Exercise-induced Rhabdomyolysis
Authors: Wappler Frank , Fiege Marko , Steinfath Markus , Agarwal Kamayni , Scholz Jens , Singh Surjit , Matschke Jakob , Schulte am Esch Jochen
Published: November 2003

Background

Malignant hyperthermia (MH), heat stroke, and exercise-induced rhabdomyolysis (ER) were suspected to be related syndromes. However, it is not known whether individuals with history of ER have an increased incidence of susceptibility to MH. To establish an association between ER and susceptibility to MH, the authors determined the MH status in patients with a history of MH-like episodes induced by physical stress.

Methods

Twelve unrelated patients with ER, 18 patients with anesthesia-induced MH, and 28 controls were investigated with the in vitro contracture test (IVCT) according to the European MH Group protocol and the ryanodine contracture test. In addition, all patients were screened for genetic mutations, and histology was performed on muscle specimens.

Results

Ten ER patients had positive IVCT results, one patient had a negative test result, and one patient showed equivocal responses. Samples from patients with positive IVCT results showed pronounced contractures after exposition to ryanodine, as opposed to specimens from patients with negative IVCT results, which developed contractures slowly. Three ER patients had mutations at the ryanodine receptor gene. All anesthesia-induced MH patients had positive IVCT results, two of them presented the C1840T mutation. The control patients had normal contracture test results and no typical MH mutations. Histologic examination determined no specific myopathies in any patient.

Conclusions

Regarding these results, the authors recommend performing muscle biopsies for histologic examination and IVCT in patients with ER. In addition, the patient should be seen by a neurologist and screened for genetic abnormalities to shed light on the genetics of MH.
Effect of Drugs Used for Neuropathic Pain Management on Tetrodotoxin-resistant Na+Currents in Rat Sensory Neurons
Authors: Bräu Michael E. , Dreimann Marc , Olschewski Andrea , Vogel Werner , Hempelmann Gunter
Published: November 2003

Background

Tetrodotoxin-resistant Na(+) channels play an important role in generation and conduction of nociceptive discharges in peripheral endings of small-diameter axons of the peripheral nervous system. Pathophysiologically, these channels may produce ectopic discharges in damaged nociceptive fibers, leading to neuropathic pain syndromes. Systemically applied Na(+) channel--blocking drugs can alleviate pain, the mechanism of which is rather unresolved. The authors investigated the effects of some commonly used drugs, i.e., lidocaine, mexiletine, carbamazepine, amitriptyline, memantine, and gabapentin, on tetrodotoxin-resistant Na+ channels in rat dorsal root ganglia.

Methods

Tetrodotoxin-resistant Na(+) currents were recorded in the whole-cell configuration of the patch-clamp method in enzymatically dissociated dorsal root ganglion neurons of adult rats. Half-maximal blocking concentrations were derived from concentration-inhibition curves at different holding potentials (-90, -70, and -60 mV).

Results

Lidocaine, mexiletine, and amitriptyline reversibly blocked tetrodotoxin-resistant Na(+) currents in a concentration- and use-dependent manner. Block by carbamazepine and memantine was not use-dependent at 2 Hz. Gabapentin had no effect at concentrations of up to 3 mm. Depolarizing the membrane potential from -90 mV to -60 mV reduced the available Na(+) current only by 23% but increased the sensitivity of the channels to the use-dependent blockers approximately fivefold. The availability curve of the current was shifted by 5.3 mV to the left in 300 microm lidocaine.

Conclusions

Less negative membrane potential and repetitive firing have little effect on tetrodotoxin-resistant Na(+) current amplitude but increase their sensitivity to lidocaine, mexiletine, and amitriptyline so that concentrations after intravenous administration of these drugs can impair channel function. This may explain alleviation from pain by reducing firing frequency in ectopic sites without depressing central nervous or cardiac excitability.
Critical Hematocrit in Intestinal Tissue Oxygenation during Severe Normovolemic Hemodilution
Authors: van Bommel Jasper , Siegemund Martin , Pieter Henny C. , Trouwborst Adrianus , Ince Can
Published: November 2003

Background

A critical point in oxygen supply for microvascular oxygenation during normovolemic hemodilution has not been identified. The relation between organ microvascular oxygen partial pressure (microPO2) and organ oxygen consumption (VO2) during a decreasing oxygen delivery (DO2) is not well understood. The present study was designed to determine the systemic hematocrit and organ DO2 values below which organ microPO2 and VO2 cannot be preserved by regulatory mechanisms during normovolemic hemodilution.

Methods

Eighteen male Wistar rats were randomized between an experimental group (n = 12), in which normovolemic hemodilution was performed with pasteurized protein solution (PPS), and a control group (n = 6). Systemic hemodynamic and intestinal oxygenation parameters were monitored. Intestinal microPO2 was measured using the oxygen-dependent quenching of palladium-porphyrin phosphorescence.

Results

Baseline values in hemodilution and control group were similar. Hemodilution decreased hematocrit to 6.2 +/- 0.8% (mean +/- SD). Constant central venous pressure measurements suggested maintenance of isovolemia. Despite an increasing mesenteric blood flow, intestinal DO2 decreased immediately. Initially, microPO2 was preserved, whereas mesenteric venous PO2 (P(mv)O2) decreased; below a hematocrit of 15%, microPO2 decreased significantly below P(mv)O2. Critical DO2 was 1.5 +/- 0.5 ml x kg(-1) x min(-1) for VO2, and 1.6 +/- 0.5 ml x kg(-1) x min(-1) for microPO2. Critical hematocrit values for VO2 and microPO2 were 15.8 +/- 4.6% and 16.0 +/- 3.5%, respectively.

Conclusions

Intestinal microPO2 and VO2 were limited by a critical decrease in DO2 and hematocrit at the same time. Beyond these critical points not only shunting of oxygen from the microcirculation could be demonstrated, but also a significant correlation between intestinal microPO2 and VO2.