bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Midazolam in Neonates Undergoing Extracorporeal Membrane Oxygenation
Authors: Mulla Hussain , McCormack Peter , Lawson Graham , Firmin Richard K. , Upton David Robert 
Published: November 2003

Background
Although the pharmacokinetics of midazolam in critically ill children has been described, there are no such reports in extracorporeal membrane oxygenation.

Methods
The pharmacokinetics of midazolam and 1-hydroxy midazolam after continuous infusion (50-250 microg. kg(-1). h(-1)) were determined in 20 neonates undergoing extracorporeal membrane oxygenation. Patients were randomized into two groups: group 1 (n = 10) received midazolam extracorporeally (into the circuit), and group 2 received drug via central or peripheral access. Blood samples for determination of plasma concentrations were taken at baseline, 2, 4, 6, 12, 18, and 24 h, then every 12 h. Population pharmacokinetic analysis and model building was conducted using WinNonMix (Pharsight Corporation, Mountain View, CA). The 1-hydroxy midazolam/midazolam metabolic ratio was determined as a surrogate marker of cytochrome P450 3A activity.

Results
The parameter estimates (n = 19) were based on a one-compartment model with time-dependent change in volume of distribution. Volume (mean +/- standard error) expanded monoexponentially from the onset of extracorporeal membrane oxygenation to a maximum value, 0.8 l +/- 0.5 and 4.1 +/- 0.5 l/kg, respectively. Consequently, plasma half-life was substantially prolonged (median [range]) from onset to steady-state: 6.8 (2.2-39.8) and 33.3 (7.4-178) h, respectively. Total body clearance was determined as (mean +/- standard error) 1.4 +/- 0.15 ml. kg-1. min-1. The median metabolic ratio was 0.17 (0.03-0.9). No significant differences were observed between the two groups with respect to parameter estimates. Simulations of plasma concentration profiles revealed excess levels at conventional doses.

Conclusions
These results reveal significantly increased volume of distribution and plasma half-life in neonates receiving extracorporeal membrane oxygenation. Altered kinetics may reflect sequestration of midazolam by components of the extracorporeal membrane oxygenation circuit.
Performance of Noninvasive Partial CO2Rebreathing Cardiac Output and Continuous Thermodilution Cardiac Output in Patients Undergoing Aortic Reconstruction Surgery
Authors: Kotake Yoshifumi , Moriyama Kiyoshi , Innami Yasushi , Shimizu Hideyuki , Ueda Toshihiko , Morisaki Hiroshi , Takeda Junzo 
Published: November 2003

Background
In the partial CO(2) rebreathing method, monitored changes in CO(2) elimination and end-tidal CO(2) in response to a brief rebreathing period are used to estimate cardiac output. However, dynamic changes in CO(2) production during ischemia and reperfusion may affect the accuracy of these estimates. This study was designed to compare measurements of cardiac output as produced by the partial CO(2) rebreathing (NICO), bolus (BCO), and continuous thermodilution (CCO) methods of monitoring cardiac output.

Methods
Cardiac output was continuously monitored using both NICO and CCO in 28 patients undergoing aortic reconstruction. BCO measurements were taken at the following intervals when hemodynamic stability was achieved: (1) after anesthetic induction; (2) during aortic cross-clamp; (3) at reperfusion of the iliac artery; and, (4) during peritoneal closure.

Results
The bias and precision (1 SD) derived from all the measurements between NICO and BCO was -0.58 +/- 0.9 l/min, whereas for CCO and BCO it was 0.38 +/- 1.17 l/min. The bias between NICO and BCO was small after anesthetic induction and during cross-clamp, but increased following reperfusion. The bias between CCO and BCO was relatively small until reperfusion but increased significantly at peritoneal closure.

Conclusions
Results indicate that in aortic reconstruction surgery the performance of NICO monitoring is comparable with that of CCO; however, the direction of bias in these continuous measurement devices is the opposite.
Using the Time of Maximum Effect Site Concentration to Combine Pharmacokinetics and Pharmacodynamics
Authors: Minto Charles F. , Schnider Thomas W. , Gregg Keith M. , Henthorn Thomas K. , Shafer Steven L. 
Published: November 2003

Background
To simulate the time course of drug effect, it is sometimes necessary to combine the pharmacodynamic parameters from an integrated pharmacodynamic-pharmacodynamic study (e.g., volumes, clearances, k(e0) [the effect site equilibration rate constant], C(50) [the steady state plasma concentration associated with 50% maximum effect], and the Hill coefficient) with pharmacokinetic parameters from a different study (e.g., a study examining a different age group or sampling over longer periods of time). Pharmacokinetic-pharmacodynamic parameters form an interlocked vector that describes the relationship between input (dose) and output (effect). Unintended consequences may result if individual elements of this vector (e.g., k(e0)) are combined with pharmacokinetic parameters from a different study. The authors propose an alternative methodology to rationally combine the results of separate pharmacokinetic and pharmacodynamic studies, based on t(peak), the time of peak effect after bolus injection.

Methods
The naive approach to combining separate pharmacokinetic and pharmacodynamic studies is to simply take the k(e0) from the pharmacodynamic study and apply it naively to the pharmacokinetic study of interest. In the t(peak) approach, k(e0) is recalculated using the pharmacokinetics of interest to yield the correct time of peak effect. The authors proposed that the t(peak) method would yield better predictions of the time course of drug effect than the naive approach. They tested this hypothesis in three simulations: thiopental, remifentanil, and propofol.

Results
In each set of simulations, the t(peak) method better approximated the postulated "true" time course of drug effect than the naive method.

Conclusions
T(peak) is a useful pharmacodynamic parameter and can be used to link separate pharmacokinetic and pharmacodynamic studies. This addresses a common difficulty in clinical pharmacology simulation and control problems, where there is usually a wide choice of pharmacokinetic models but only one or two published pharmacokinetic-pharmacodynamic models. The results will be immediately applicable to target-controlled anesthetic infusion systems, where linkage of separate pharmacokinetic and pharmacodynamic parameters into a single model is inherent in several target-controlled infusion designs.
Anesthetic Preconditioning
Authors: Kevin Leo G. , Katz Peter , Camara Amadou K. S. , Novalija Enis , Riess Matthias L. , Stowe David F. 
Published: November 2003

Background
Anesthetic preconditioning (APC) is protective for several aspects of cardiac function and structure, including left ventricular pressure, coronary flow, and infarction. APC may be protective, however, only if the duration of ischemia is within a certain, as yet undefined range. Brief ischemia causes minimal injury, and APC would be expected to provide little benefit. Conversely, very prolonged ischemia would ultimately cause serious injury with or without APC. Previous investigations used a constant ischemic time as the independent variable to assess ischemia-induced changes in dependent functional and structural variables. The purpose of the study was to define the critical limits of efficacy of APC by varying ischemic time.

Methods
Guinea pig hearts (Langendorff preparation; n = 96) underwent pretreatment with sevoflurane (APC) or no treatment (control), before global ischemia and 120 min reperfusion. Ischemia durations were 20, 25, 30, 35, 40, and 45 min.

Results
At 120 min reperfusion, developed (systolic-diastolic) left ventricular pressure was increased by APC compared with control for ischemia durations of 25-40 min. Infarction was decreased by APC for ischemia durations of 25-40 min, but not 20 or 45 min. APC improved coronary flow and vasodilator responses for all ischemia durations longer than 25 min, and decreased ventricular fibrillation on reperfusion for ischemia durations longer than 30 min.

Conclusions
Although APC protects against vascular dysfunction and dysrhythmias after prolonged ischemia, protection against contractile dysfunction and infarction in this model is restricted to a range of ischemia durations of 25-40 min. These results suggest that APC may be effective in a subset of patients who have cardiac ischemia of intermediate duration.
Embolism Bubble Adhesion Force in Excised Perfused Microvessels
Authors: Suzuki Akira , Eckmann David M. 
Published: November 2003

Background
The mechanics of gas embolism bubble adhesion to the vessel wall is poorly understood. New strategies to treat gas embolism may result from an understanding of adhesion forces, including the molecular determinants of bubble adhesion. The authors conducted experiments to measure the adhesion force of bubbles contacting the vessel wall.

Methods
Microbubbles were injected into excised arterioles. Bubbles resided for 5, 10, 20, or 30 min with the endothelium intact or damaged and with a physiologic salt solution, physiologic salt solution with 5% bovine serum albumin, or rat serum as the perfusate. Inflow pressure was raised until the bubble dislodged. The differential pressure across the microbubble, deltaP, was recorded at the moment of bubble movement. Bubble diameter, D, and length, L, were determined by videomicroscopy. The adhesion force per unit surface area of a bubble contacting the vessel wall, K = deltaPD/4 L, was calculated for each experiment.

Results
K at 10 min contact time (physiologic salt solution, 141 +/- 29; serum, 153 +/- 57 dyne/cm2) was higher than at 5 min (physiologic salt solution, 56 +/- 22; serum, 71 +/- 29 dyne/cm2), 20 min (physiologic salt solution, 46 +/- 29) and 30 min (physiologic salt solution, 14 +/- 5) (P < 0.05). Endothelium removal reduced K at 10 min (physiologic salt solution, 68 +/- 46; serum, 60 +/- 14 dyne/cm2) (P < 0.05). K was higher with 5% bovine serum albumin present at 10 min (349 +/- 149, P < 0.05), correlating with in vivo estimates.

Conclusions
The adhesion force developed between a microbubble and the vessel wall depends on multiple factors, including bubble residence time, presence of the endothelium, and perfusion solution.
Interaction between the Spinal Melanocortin and Opioid Systems in a Rat Model of Neuropathic Pain
Authors: Vrinten Dorien H. , Gispen Willem Hendrik , Kalkman Cor J. , Adan Roger A. H. 
Published: November 2003

Background
The authors recently demonstrated that administration of the melanocortin-4 receptor antagonist SHU9119 decreased neuropathic pain symptoms in rats with a sciatic chronic constriction injury. The authors hypothesised that there is a balance between tonic pronociceptive effects of the spinal melanocortin system and tonic antinociceptive effects of the spinal opioid system. Therefore, they investigated a possible interaction between these two systems and tested whether opioid effectiveness could be increased through modulation of the spinal melanocortin system activity.

Methods
In chronic constriction injury rats, melanocortin and opioid receptor ligands were administered through a lumbar spinal catheter, and their effects on mechanical allodynia were assessed by von Frey probing.

Results
Naloxone (10-100 microg) dose-dependently increased allodynia (percent of maximum possible effect of -67 +/- 9%), which is in agreement with a tonic antinociceptive effect of the opioid system. SHU9119 decreased allodynia (percent of maximum possible effect of 60 +/- 13%), and this effect could be blocked by a low dose of naloxone (0.1 microg), which by itself had no effect on withdrawal thresholds. Morphine (1-10 microg) dose-dependently decreased allodynia (percent of maximum possible effect of 73 +/- 14% with the highest dose tested). When 0.5 microg SHU9119 (percent of maximum possible effect of 47 +/- 14%) was given 15 min before morphine, there was an additive antiallodynic effect of both compounds.

Conclusions
Together, these data confirm that there is an interaction between the spinal melanocortin and opioid systems and that combined treatment with melanocortin-4 receptor antagonists and opioids might possibly contribute to the treatment of neuropathic pain.
Pronociceptive Actions of Isoflurane
Authors: Flood Pamela , Daniel Danette 
Published: November 2003

Background
Low concentrations of inhaled anesthetics present in the early postoperative period can increase pain sensitivity. Changes in pain threshold associated with inhaled anesthetics have been reported in male mice, rats, and humans.

Methods
The authors compared the pain-enhancing effects of isoflurane in male and female mice in response to a thermal stimulus and studied the consequences of hormonal manipulation.

Results
Isoflurane produced a larger increase in pain sensitivity in female mice. Both castration and oophorectomy resulted in an increase in baseline pain sensitivity and potentiated pain enhancement by isoflurane. At stages of the estrus cycle when estrogen was low, female mice showed greater pain enhancement from isoflurane than at high estrogen stages. Treatment with exogenous estrogen reduced isoflurane-induced pain sensitivity. Exogenous testosterone treatment had a similar effect, which did not occur when enzymatic conversion to estrogen was prevented.

Conclusions
Because both estrogen and testosterone reduce the pronociceptive action of isoflurane, intact females may exhibit a larger increase in pain sensitivity because of their cyclical estrogen levels. Testosterone is effective in the male because of conversion to estrogen. Enhanced pain sensitivity is clearly undesirable in the postoperative setting. If these findings also apply to humans, the menstrual cycle may be an important factor in determining pain levels after emergence from general anesthesia.
Risk Factors for Clinically Relevant Pulmonary Embolism and Deep Venous Thrombosis in Patients Undergoing Primary Hip or Knee Arthroplasty
Authors: Mantilla Carlos B. , Horlocker Terese T. , Schroeder Darrell R. , Berry Daniel J. , Brown David L. 
Published: November 2003

Background
Prevention of thromboembolic complications after elective lower extremity arthroplasty has increasingly relied on routine thromboprophylaxis in all patients. Not all patients are at equal risk, however, and prophylaxis is not devoid of complications. The aim of this study was to examine the risk factors for clinically relevant pulmonary embolism and deep venous thrombosis after elective primary hip or knee arthroplasty in a large patient population.

Methods
During the 10-yr study period, 116 of 9,791 patients undergoing primary hip or knee arthroplasty at the authors' institution who experienced pulmonary embolism or deep venous thrombosis within 30 days of surgery were matched at a 1:1 ratio with patients undergoing the same surgery with the same surgeon who did not experience an adverse event. Medical records were reviewed, with data abstracted using a standardized data collection form.

Results
Increased body mass index (P = 0.031; odds ratio = 1.5 for each 5-kg/m2 increase) and American Society of Anesthesiologists physical status classification of 3 or greater (P = 0.005; odds ratio = 2.6) were found to independently increase the likelihood of pulmonary embolism or deep venous thrombosis. In addition, use of antithrombotic prophylaxis was found to decrease the likelihood of these thromboembolic events (P = 0.050; odds ratio = 0.2 for aspirin or subcutaneous heparin, and odds ratio = 0.4 for warfarin or low-molecular-weight heparin).

Conclusions
In patients undergoing primary elective lower extremity arthroplasty, obesity, poor American Society of Anesthesiologists physical status classification, and lack of thromboprophylaxis are independent risk factors for clinically relevant thromboembolic events.
Prospective, Randomized Trial Comparing General with Spinal Anesthesia for Cesarean Delivery in Preeclamptic Patients with a Nonreassuring Fetal Heart Trace
Authors: Dyer Robert A. , Els Ilse , Farbas Josef , Torr Gregory J. , Schoeman Leann K. , James Michael F. 
Published: November 2003

Background
There are no randomized studies on neonatal outcome after spinal versus general anesthesia for cesarean delivery in preeclamptic patients with a nonreassuring fetal heart trace. This study examined both markers of neonatal hypoxia and maternal hemodynamics.

Methods
Seventy patients were randomized to general (n = 35) or spinal anesthesia (n = 35). The general anesthesia group received thiopentone, magnesium sulfate, and suxamethonium intravenously before intubation, followed by 50% nitrous oxide in oxygen, 0.75-1.5% isoflurane, and morphine after delivery. The target end-tidal partial pressure of carbon dioxide (Pco2) was 30-34 mmHg. The spinal anesthesia group received 1.8 ml hyperbaric bupivacaine plus 10 microg fentanyl at the L3-L4 interspace. Heart rate and blood pressure were measured at specific time points. Hypotension was treated with ephedrine. Maternal arterial and neonatal umbilical arterial blood gas samples were taken at delivery. Resuscitation requirements were recorded.

Results
In both groups, hemodynamic measures remained within acceptable limits. Spinal anesthesia patients required more ephedrine (13.7 vs. 2.7 mg). Maternal Paco2 was lower in the spinal group (28.9 vs. 32.4 mmHg). One-minute Apgar scores were lower after general anesthesia. Base deficit was greater (7.13 vs. 4.68 mEq/l) and neonatal umbilical arterial pH was lower (7.20 vs. 7.23) after spinal anesthesia. Post hoc analysis showed that if maternal diastolic blood pressure on admission was greater than 110 mmHg, neonatal umbilical arterial base deficit was greater after spinal anesthesia. There was no difference in the number of patients with Apgar scores less than 7 at 1 or 5 min or umbilical arterial pH less than 7.2 or in the requirements for resuscitation.

Conclusions
In preeclamptic patients with a nonreassuring fetal heart trace, spinal anesthesia for cesarean delivery was associated with a greater mean neonatal umbilical arterial base deficit and a lower median umbilical arterial pH. The clinical significance remains to be established. Maternal hemodynamics were similar and acceptable with either anesthetic technique.
Urgent Adenotonsillectomy
Authors: Brown Karen A. , Morin Isabelle , Hickey Chantal , Manoukian John J. , Nixon Gillian M. , Brouillette Robert T. 
Published: November 2003

Background
The aim of this study was to determine the frequency and type of respiratory complications after urgent adenotonsillectomy (study group) for comparison with a control group of children undergoing a sleep study and adenotonsillectomy for obstructive sleep apnea syndrome. A second aim was to assess risk factors predictive of respiratory complications after urgent adenotonsillectomy.

Methods
The perioperative course of children who underwent adenotonsillectomy between January 1, 1999, and March 31, 2001, was reviewed. Two groups of children were identified from two different databases: the hospital database for surgical procedures (the study group) and the sleep laboratory database (the control group). The retrospective chart review focused on the preoperative status (including an evaluation for obstructive sleep apnea), anesthetic management, and need for postoperative respiratory interventions.

Results
A total of 64 consecutive cases for urgent adenotonsillectomy were identified, and 54 children met the inclusion criteria. Thirty-three children (60%) had postoperative respiratory complications necessitating a medical intervention; 11 (20.3%) required a major intervention (reintubation, ventilation, and/or administration of racemic epinephrine or Ventolin), and 22 (40.7%) required a minor intervention (oxygen administration). Six children (11.1%) required reintubation in the recovery room for respiratory compromise. Risk factors for respiratory complications were an associated medical condition (odds ratio, 8.15; 95% confidence interval, 1.81-36.73) and a preoperative saturation nadir less than 80% (odds ratio, 5.54; 95% confidence interval, 1.15-26.72). Sixteen (49%) of the medical interventions were required within the first postoperative hour. Atropine administration, at induction, decreased the risk of postoperative respiratory complications (odds ratio, 0.18; 95% confidence interval, 0.11-1.050.

Control Group
Of 75 children who underwent a sleep study and adenotonsillectomy, 44 had sleep apnea and were admitted to hospital after elective adenotonsillectomy. Sixteen (36.4%) children had postoperative respiratory complications necessitating a medical intervention. Six percent of the children (n = 3) required a major medical intervention. No child required reintubation for respiratory compromise.

Conclusions
Severe obstructive sleep apnea syndrome and an associated medical condition are risk factors for postadenotonsillectomy respiratory complications. Risk reductions strategies should focus on their assessment.
Effects of Subanesthetic Doses of Ketamine on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans
Authors: Långsjö Jaakko W. , Kaisti Kaike K. , Aalto Sargo , Hinkka Susanna , Aantaa Riku , Oikonen Vesa , Sipilä Hannu , Kurki Timo , Silvanto Martti , Scheinin Harry 
Published: November 2003

Background
Animal experiments have demonstrated neuroprotection by ketamine. However, because of its propensity to increase cerebral blood flow, metabolism, and intracranial pressure, its use in neurosurgery or trauma patients has been questioned.

Methods
15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine quantitative regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV), respectively, on selected regions of interest of nine healthy male volunteers at baseline and during three escalating concentrations of ketamine (targeted to 30, 100, and 300 ng/ml). In addition, voxel-based analysis for relative changes in rCBF and rCMRO2 was performed using statistical parametric mapping.

Results
The mean +/- SD measured ketamine serum concentrations were 37 +/- 8, 132 +/- 19, and 411 +/- 71 ng/ml. Mean arterial pressure was slightly elevated (maximally by 15.3%, P < 0.001) during ketamine infusion. Ketamine increased rCBF in a concentration-dependent manner. In the region-of-interest analysis, the greatest absolute changes were detected at the highest ketamine concentration level in the anterior cingulate (38.2% increase from baseline, P < 0.001), thalamus (28.5%, P < 0.001), putamen (26.8%, P < 0.001), and frontal cortex (25.4%, P < 0.001). Voxel-based analysis revealed marked relative rCBF increases in the anterior cingulate, frontal cortex, and insula. Although absolute rCMRO2 was not changed in the region-of-interest analysis, subtle relative increases in the frontal, parietal, and occipital cortices and decreases predominantly in the cerebellum were detected in the voxel-based analysis. rCBV increased only in the frontal cortex (4%, P = 0.022).

Conclusions
Subanesthetic doses of ketamine induced a global increase in rCBF but no changes in rCMRO2. Consequently, the regional oxygen extraction fraction was decreased. Disturbed coupling of cerebral blood flow and metabolism is, however, considered unlikely because ketamine has been previously shown to increase cerebral glucose metabolism. Only a minor increase in rCBV was detected. Interestingly, the most profound changes in rCBF were observed in structures related to pain processing.