Intravenous Administration Of Fentanyl Research Articles

Anesthetic management during minimally invasive cardiac surgery with the Port-Access system for closure of atrial septal defect.

a ratio of pulmonary to systemic blood flow (Qp/Qs) of 2.7 6 0.9 and a pulmonary artery mean pressure of 15 6 3mmHg (mean 6 standard deviation) (Table 1). All patients underwent preoperative assessment of the aorta, iliac arteries, and femoral arteries by angiography. The patients were premedicated with oral diazepam (5mg) and intramuscular pethidine (35mg) and atropine (0.5mg). Anesthesia was induced by intravenous administration of midazolam (2 to 4mg), fentanyl (5μg·kg21), and vecuronium (0.15mg·kg21), followed by endotracheal intubation with a standard single-lumen tube. Anesthesia was maintained with sevoflurane and nitrous oxide in oxygen in combination with fentanyl (15 to 20μg·kg21 in total), propofol, and vecuronium. Nitrous oxide was used only before CPB, and propofol was infused continuously during CPB at 4mg·kg21·h21. Intraoperative monitoring included five-lead electrocardiography, pulse oximetry, capnography, urinary output measurement, and nasopharyngeal and bladder temperature. After the induction of anesthesia, the bilateral brachial arteries were cannulated to measure the pressure difference, and a central venous catheter was inserted through the right internal jugular vein. In our institution, we usually use the brachial artery for intravascular blood pressure measurement, since the brachial artery can provide more accurate estimation of aortic pressure than the radial artery [4,5]. Simultaneously, a 5Fr sheath was placed in the right internal jugular vein by the anesthesiologist. A transesophageal echocardiography (TEE) probe was placed. TEE examination was performed to determine the diameter of the ascending aorta and to exclude severe atherosclerosis of the ascending and descending aorta as well as major aortic valve insufficiency. Defibrillator pads were placed over the right lateral and left posterior chest wall. The Port-Access cannulae/catheter-based system (Endovascular CPB system: Heartport) consists of a set

Inhibition by neuropeptide Y of fentanyl-induced muscular rigidity at the locus coeruleus in rats

The aim of this study was to evaluate the effects of centrally administered neuropeptide Y (NPY) on muscular rigidity induced by fentanyl in Sprague–Dawley rats. They were anesthetized with ketamine (120 mg/kg, i.p.) and their lungs were mechanically ventilated. Intravenous administration of fentanyl (100 μg/kg) consistently evoked a significant increase in the electromyographic activity (EMG) recorded from the sacrococcygeus dorsalis lateralis muscle. This implied muscular rigidity was appreciably attenuated by intracerebroventricular administration of NPY (4 nmol/2.5 μl). Microinjection of NPY (40 or 160 pmol/50 nl) into the bilateral locus coeruleus (LC) elicited an inhibition of the EMG activation induced by fentanyl in a dose-dependent manner. Microinjection of 160 pmol NPY plus antiserum against NPY (NPY Ab, 1:20) into the LC failed to suppress fentanyl-induced muscular rigidity. However, this implied muscular rigidity was not affected by NPY plus normal rabbit serum (NRS, 1:20). In addition, NPY Ab or NRS per se had no substantial effect on the rigidity. Microinjection of NPY (160 pmol) into the areas adjacent to the LC did not attenuate the rigidity. Our results suggest that the centrally administered NPY attenuated fentanyl-induced muscular rigidity by acting at the LC, but endogenous NPY may not be involved in this process.

Pharmacokinetics of fentanyl after intravenous and transdermal administration in goats

Abstract Objective To evaluate disposition of fentanyl in goats after IV and transdermal administration. Animals 8 healthy 2-year-old goats weighing 31.8 to 53.6 kg (mean ± SD, 40.4 ± 7.5 kg). Procedure Each goat was given 2 treatments consisting of fentanyl administered IV (2.5 μg/kg of body weight) and via a transdermal patch (50 μg/h). There was a 2-month interval between treatments. Blood samples were collected at specified times and analyzed in duplicate to determine plasma fentanyl concentrations. Pharmacokinetic values were calculated, using a computerized modeling program. Results Administration of fentanyl was tolerated by all goats. Intravenous administration of fentanyl resulted in a transitory increase in rectal temperature that was not clinically important. Terminal elimination half-life after IV administration was 1.20 ± 0.78 h, volume of distribution at steady state was 1.51 ± 0.39 L/kg, and systemic clearance was 2.09 ± 0.62 L/kg/h. Transdermal administration of fentanyl resulted in variable plasma concentrations, with peak plasma concentrations ranging from 1.12 to 16.69 ng/ml (mean ± SD, 6.99 ± 6.03 ng/ml) and time to peak concentration ranging from 8 to 18 hours (mean ± SD, 13 ± 4.5 hours). After removal of the transdermal patch, mean ± SD terminal elimination half-life was 5.34 ± 5.34 hours. Conclusions and Clinical Relevance Intravenous administration of fentanyl (2.5 μg/kg) in goats results in a relatively short half-life that will limit its use for management of pain. Transdermal administration of fentanyl (50 μg/h) in goats results in variable plasma concentrations that may exceed those anticipated on the basis of a theoretical delivery rate, but stable plasma concentrations of fentanyl may not be achieved. (Am J Vet Res 1999;60:986–991)

Postoperative Epidural Fentanyl Analgesia

In Response: Dr. dos Santos expresses two concerns in his letter: "methodological considerations … which may bring into question the conclusions" and available literature that was not quoted in the area of concern, i.e., the mechanisms of postoperative analgesia after epidural or intravenous fentanyl administration. Regarding the methodological concern, it would have been helpful if Dr. dos Santos had been more specific regarding which of the studies he thought had problems with the number of the patients enrolled, bias from inappropriate blinding methods and pain scoring, diluent of a given dose of fentanyl, and the position of the epidural catheter in relation to the area of nociception. Moreover, references to support his observations in this area are needed. Although the power of analysis may be a problem in some studies, this may not be the case in the five studies cited to support our observation that analgesia after epidural administration for postoperative analgesia is primarily supraspinal. Moreover, the authors of these studies used blinding techniques so that bias could be avoided. Regarding his observation of "diluent volume," there are no data in the literature that suggest that the volume in which a dose of fentanyl is administered in the epidural space will affect the vascular absorption or the arachnoid penetration. Birnbach et al. [1] showed that increasing diluent volumes of fentanyl given epidurally reduced the onset time of analgesia without changing the duration after bolus doses. They concluded that one should expect both a shorter onset and a shorter duration of analgesia when large volumes of diluted fentanyl were given epidurally. As discussed in the "Physical and Chemical Properties of Opioids in the Epidural Space" section of the article [2], vascular absorption, arachnoid penetration, and dosing are the three factors that appear to determine the spinal and supraspinal effects. Finally, Dr. dos Santos comments on the "site of the epidural catheter" as another factor that may affect the results. As discussed in the article, Guinard et al. [3] clearly showed that the position of the catheter in relation to the area of nociception (surgical incision) or the route of administration (epidural versus intravenous) had no influence on the quality of analgesia, incidence of side effects, or opioid consumption in patients who underwent thoracic surgery and received fentanyl for postoperative analgesia. Thus, the belief that the position of the catheter will influence the quality of analgesia after epidural fentanyl is not founded. The results of the studies that Dr. dos Santos believes demonstrated clinical advantages of epidural fentanyl need to be taken with reservations. Two of the cited studies addressed intraoperative variables [4,5]. Thus, their results are not applicable to postoperative analgesia. Two others evaluated analgesia either during labor [6] or after cesarean delivery [7]. The results of studies in these two groups should not be extrapolated to the postoperative population due to the analgesic effects of progesterone that will reduce opioid consumption [8]. Moreover, the study by Cooper et al. [7] can be criticized because the protocol design did not allow for titration of the fentanyl doses during the study. This shortcoming is reflected in the analysis of pain scores during movement between the epidural and the intravenous groups. If patient-controlled analgesia had been adequately used by allowing patients to titrate their doses, there should not be differences in the pain scores between the two groups; the differences should be seen in opioid consumption. Nevertheless, analysis of their results suggest that contrary to their conclusion, there were no differences in opioid consumption. The cumulative doses of fentanyl (the best indicator) in the epidural and the intravenous groups were similar, and there was only a single difference in the mean hourly doses of fentanyl used at the 4- to 8-h interval. Fentanyl consumption during the rest of the intervals was similar between the two groups. Thus, this study does not support the notion that there are advantages in using epidural fentanyl over intravenous fentanyl for postcesarean delivery analgesia. We concur with Dr. dos Santos' observation that a meta analysis may help to address the spinal versus supraspinal question. However, in the end, clinicians must ask themselves whether epidural use of fentanyl alone is justified for postoperative epidural analgesia in view of the results of the studies reported. Oscar A. de Leon-Casasola, MD Mark J. Lema, PhD, MD Department of Anesthesiology; Roswell Park Cancer Institute; Buffalo, NY 14263

Continuous intravenous fentanyl administration attenuates plasma cortisol levels in neonates with respiratory failure. • 1024

Previous studies in adults and surgical neonates have demonstrated that high dose opioid anesthesia attenuates plasma cortisol levels. We have observed that once administration of continuous fentanyl sedation has begun in neonates with respiratory failure, there is often a deterioration in cardiovascular status. Our objective was to determine the effect of continuously administered fentanyl on the secretion of cortisol and ACTH in neonates with respiratory failure.

Perioperative Sympatholysis

Perioperative Sympatholysis

Transient facial palsy in sphenoidal electrode placement.

Sphenoidal electrode (SE) insertion can cause pain, for which local anesthesia with lidocaine or intravenous administration of fentanyl has been advocated by different epilepsy treatment centers. Transient facial palsies have been observed after SE insertion. Their frequency of occurrence, distribution, and duration have not been well characterized, however. We hypothesized that this complication is due to the effect of local anesthesia on the peripheral branches of the seventh cranial nerve. To test this hypothesis, we compared the incidence and characteristics of facial palsy during SE insertions performed with either local anesthesia or after intravenous fentanyl administration. We performed a retrospective study in two patient groups. Group A consisted of 25 patients aged 28 +/- 8.2 years who underwent a prolonged video-EEG (VEEG) monitoring study with SE after subcutaneous infusion of 1% lidocaine in the insertion area. Group B included 25 patients aged 30.1 +/- 8.9 years whose SE were inserted after intravenous administration of 100-200 micrograms fentanyl. Blood pressure (BP) was monitored every 3-5 min throughout the procedure. Five patients (20%) from group A had a transient facial palsy; in 4, it was complete and in 1 it was partial; 1 patient had a bilateral facial palsy. Paresis lasted 1-7 min (mean 3.2 min). In all patients, the recovery was complete. None of the patients in group B had complications (p = 0.025, Fisher's exact test). Transient facial palsy is a relatively frequent complication of SE insertion when SE are placed under local anesthesia; patients should be forewarned of its possible occurrence.

A comparison of sympathetic adrenal nerve responses to intravenous high-dose morphine and fentanyl administration in rats

We compared the effects of intravenous morphine (5 mg·kg(-1)) and fentanyl, (50μg·kg(-1)) on systolic blood pressure (SBP), heart rate (HR), and efferent sympathetic adrenal nerve action potentials (SANA) in rats. We also determined the extent of the reflex responses of these parameters of 9% carbon dioxide (CO2) challenge during the above narcotic anesthesia. In the morphine group, SBP was elevated and the elevated levels were maintained, while changes in SBP in the fentanyl group were not significant. In the morphine group, SANA showed initial stimulation and subsequent depression, while in the fentanyl group, SANA showed sustained depression. CO2 challenge induced only very small changes in SBP and HR, suggesting that during high-dose narcotic anesthesia the hypercapnic stimulus may not be reflected in circulatory parameters. In both groups, hypercapnia increased SANA to 30% of the baseline values from the pre-challenge level. However, these values were only 91% and 56% of the baseline value in the morphine and the fentanyl, groups, respectively.

A comparison of sympathetic adrenal nerve responses to intravenous high-dose morphine and fentanyl administration in rats

A comparison of sympathetic adrenal nerve responses to intravenous high-dose morphine and fentanyl administration in rats

Tussive Effect of Intravenous Fentanyl Administration and Antitussive Effect of Lidocaine

Tussive Effect of Intravenous Fentanyl Administration and Antitussive Effect of Lidocaine

Epidural and Intravenous Fentanyl Produce Equivalent Effects During Major Surgery

BACKGROUND The benefit of epidural versus intravenous fentanyl administration for postoperative analgesia is controversial. In the current study, the intraoperative effects of epidural versus intravenous fentanyl administration were compared during major surgery. METHODS Twenty elective patients scheduled for thoracoabdominal esophagectomy under general anesthesia with propofol infusion were randomly allocated to receive either intravenous or epidural boluses of 50-100 micrograms fentanyl in a double-blind fashion to maintain hemodynamic stability. Plasma cortisol and fentanyl, as well as total urinary catecholamines, were obtained at the end of the operations. RESULTS Hemodynamic variations were similar except that patients receiving epidural fentanyl had a lower incidence of heart rate reduction (> 20% reduction from baseline, P < 0.05). There were no differences in mean intraoperative fentanyl (1,115 +/- 430 and 1,010 +/- 377 micrograms, epidural and intravenous, respectively) or propofol (2,281 +/- 645 and 2,452 +/- 1,169 mg) doses, number of boluses of fentanyl (nine in both groups), plasma fentanyl concentration (1.13 +/- 0.4 and 1.02 +/- 0.46 ng/ml), or number of anesthesiologists correctly identifying the site of fentanyl administration. Similarly, there were no differences in plasma glucose (8.9 +/- 1.8 and 9.3 +/- 1.8 mM) and cortisol (696 +/- 446 and 846 +/- 257 mM), or urinary epinephrine (12 +/- 3.7 and 13.1 +/- 9.2, micrograms/sample) and norepinephrine (42.7 +/- 26.7 and 39.1 +/- 27.6, micrograms/sample). CONCLUSIONS There appears to be no clinical advantage to epidural administration of fentanyl over intravenous administration during anesthesia for major surgery.

Biopharmaceutics of a New Transdermal Fentanyl Device

Compared with conventional routes of delivering potent analgesics to postoperative patients, transdermal administration of fentanyl offers the advantages of simplicity and noninvasive delivery. The only available form of transdermal fentanyl, the Duragesic system, has been implicated in preventable patient deaths when used for postoperative analgesia and is contraindicated in the management of postoperative pain. We examined the biopharmaceutics of a new transdermal fentanyl device developed by Cygnus and intended for use as a postoperative analgesic to see whether the new formulation offers pharmacokinetic advantages that might permit safe use in postoperative patients. We studied 15 consenting male adult surgical patients. Patients received 650 or 750 micrograms intravenous fentanyl as part of the induction of anesthesia. Plasma fentanyl concentrations were measured over the following 24-h period. On the first postoperative day, 24 h after the intravenous dose of fentanyl, a transdermal fentanyl device was placed on the upper torso of the patient for 24 h and then removed. Plasma fentanyl concentrations were measured for 72 h after application of the transdermal fentanyl device. From the concentration versus time profile for the 24 h after intravenous fentanyl administration we determined each patient's clearance and unit disposition function by moment analysis and constrained numeric deconvolution, respectively. From the concentration versus time profile for the 72 h after application of the transdermal device we determined the amount of fentanyl absorbed and the rate of absorption, again by moment analysis and constrained numeric deconvolution. The residual fentanyl in the transdermal fentanyl device was measured, permitting calculation of the absolute bioavailability of transdermally administered fentanyl. Of the 14 subjects who received transdermal fentanyl, 3 had clinically significant fentanyl toxicity, mandating early removal of the device. The range during the plateau from 12 to 24 h in subjects still wearing the device was 0.34-6.75 ng/ml, a 20-fold range in concentration. In subjects wearing the device for 24 h, the terminal half-life of fentanyl after removal of the device was 16 h. The bioavailability of transdermally administered fentanyl was 63 +/- 35% coefficient of variation. The rate of fentanyl absorption from 12-24 h ranged from 10 to 230 micrograms/h in subjects still wearing the device. In two subjects, the rate within the first 6 h briefly exceeded 300 micrograms/h. Both of these subjects demonstrated fentanyl toxicity, requiring early removal of the device. The Cygnus transdermal fentanyl device shows great variability in the rate of fentanyl absorption, resulting in highly variable plasma fentanyl concentrations. Some persons may rapidly absorb fentanyl from the device in the first few hours after application, leading to fentanyl toxicity. The variability in effect of the Cygnus transdermal fentanyl device is appreciably greater than that reported for the currently available Duragesic transdermal fentanyl device, which is contraindicated for postoperative analgesia.

Subtypes of Guanine-Nucleotide-Binding Regulatory Proteins at the Locus coeruleus Involved in Fentanyl-Induced Muscular Rigidity in the Rat.

Previous results from our laboratory have established that the G(o) subtype of guanine nucleotide (GTP)-binding regulatory protein at the locus coeruleus (LC) may participate in the elicitation of muscular rigidity by fentanyl. The present study further examined the involvement of other subtypes of GTP-binding regulatory proteins at the LC in this process, using Sprague-Dawley rats anesthetized with ketamine (120 mg/kg, i.p., with 30 mg/kg/h i.v. infusion supplements) and under mechanical ventilation. Intravenous administration of fentanyl (100 &mgr;g/kg) induced a significant increase in electromyographic signals recorded from the sacrococcygeus dorsi lateralis muscle. Power spectral analysis revealed that this was accomplished by a decrease in the mean power frequency and an increase in the root mean square values of the signals. The above responses were appreciably antagonized by pretreating animals with bilateral microinjection into the LC of pertussis toxin (80 or 160 fmol), N-ethylmaleimide (16 pmol) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (100 or 200 fmol); but not by cholera toxin (120 or 240 fmol), forskolin (240 or 480 pmol) or N-ethylmaleimide at a higher dose (32 pmol). These results suggest that, in addition to G(o) protein, fentanyl-induced muscular rigidity may also involve other pertussis toxin-sensitive GTP-binding regulatory proteins, possibly G(i) and G(p) subtypes, in the signal transduction processes following activation of &mgr;-opioid receptors at the LC. Copyright 1995 S. Karger AG, Basel

Buccal Absorption of Fentanyl Is pH-Dependent in Dogs

Analgesia and sedation have been achieved noninvasively by fentanyl administration through the oral and nasal mucosa. In theory, the transmucosal bioavailability and absorption of fentanyl could be improved by converting more fentanyl to the unionized form by adjusting the surrounding pH. The authors tested this hypothesis in dogs. Under general anesthesia, each of six mongrel dogs was given fentanyl on repeated occasions, first intravenously (once), then by application to the buccal mucosa (six times). Buccal fentanyl administration was accomplished by placement of a pH-buffered solution of fentanyl into a specially constructed cell, which was clamped to the dog's buccal mucosa for 60 min. Fentanyl solutions with pHs of 6.6, 7.2, and 7.7 were studied to span a tenfold difference in the unionized fraction of fentanyl. Femoral arterial blood samples were sampled frequently and analyzed for fentanyl using a radioimmunoassay. Peak plasma concentration and the time of its occurrence for each buccal study were noted from the plasma concentration verses time profile. Terminal elimination half-life, bioavailability, and permeability coefficients were calculated using standard pharmacokinetic techniques. The variables peak plasma concentration, bioavailability, and permeability coefficient increased three- to fivefold as the pH of the fentanyl buccal solution increased and more fentanyl molecules became unionized. There was no difference in terminal elimination half-life after intravenous fentanyl (244 +/- 68 min) or buccal fentanyl administration (pH 7.7, 205 +/- 89 min; pH 7.2, 205 +/- 65 min; pH 6.6, 196 +/- 48 min). In all buccal studies regardless of pH, time to peak plasma concentration occurred within 10 min of removal of the fentanyl solutions from the buccal mucosa. The buccal absorption, bioavailability, and permeability of fentanyl are markedly increased as the pH of the fentanyl solution becomes more basic. Most likely, this is because of an increase in the fraction of unionized fentanyl.

Epidural and Intravenous Fentanyl Produce Equivalent Effects during Major Surgery

The benefit of epidural versus intravenous fentanyl administration for postoperative analgesia is controversial. In the current study, the intraoperative effects of epidural versus intravenous fentanyl administration were compared during major surgery. Twenty elective patients scheduled for thoracoabdominal esophagectomy under general anesthesia with propofol infusion were randomly allocated to receive either intravenous or epidural boluses of 50-100 micrograms fentanyl in a double-blind fashion to maintain hemodynamic stability. Plasma cortisol and fentanyl, as well as total urinary catecholamines, were obtained at the end of the operations. Hemodynamic variations were similar except that patients receiving epidural fentanyl had a lower incidence of heart rate reduction (> 20% reduction from baseline, P < 0.05). There were no differences in mean intraoperative fentanyl (1,115 +/- 430 and 1,010 +/- 377 micrograms, epidural and intravenous, respectively) or propofol (2,281 +/- 645 and 2,452 +/- 1,169 mg) doses, number of boluses of fentanyl (nine in both groups), plasma fentanyl concentration (1.13 +/- 0.4 and 1.02 +/- 0.46 ng/ml), or number of anesthesiologists correctly identifying the site of fentanyl administration. Similarly, there were no differences in plasma glucose (8.9 +/- 1.8 and 9.3 +/- 1.8 mM) and cortisol (696 +/- 446 and 846 +/- 257 mM), or urinary epinephrine (12 +/- 3.7 and 13.1 +/- 9.2, micrograms/sample) and norepinephrine (42.7 +/- 26.7 and 39.1 +/- 27.6, micrograms/sample). There appears to be no clinical advantage to epidural administration of fentanyl over intravenous administration during anesthesia for major surgery.

Neural control of small intestinal giant migrating contractions

We investigated the neural mechanisms of control of giant migrating contractions (GMCs) in five conscious dogs. After control recordings, a Thiry-Vella loop was prepared from the middle segment, and the remaining two segments were reanastomosed. GMCs were stimulated by intravenous administration of fentanyl and erythromycin lactobionate, oral administration of loperamide and erythromycin stearate, and gastric or intraluminal administration of cider vinegar in the loop. In the intact state, the agents stimulated GMCs in all three segments, and they propagated uninterruptedly from the point of their origin to the terminal ileum. The propagation velocity of GMCs increased, whereas that of migrating motor complexes (MMCs) decreased distally. After Thiry-Vella loop formation, the agents stimulated GMCs independently in the three segments, and they propagated only to the end of the segment in which they started. In the intact small intestine, the GMCs produced ascending and descending inhibition of spontaneous phase II contractions but did not interrupt the caudad propagation of the ongoing MMC. After Thiry-Vella loop formation, the ascending inhibition was unaltered, but the descending inhibition occurred only in the segment containing the GMC. We conclude that the propagation of GMCs in the small intestine is controlled by the enteric nerves. The extrinsic nerves control the ascending inhibition produced by GMCs, whereas the enteric nerves control the descending inhibition.

Involvement of G oα subtype of guanine nucleotide-binding regulatory protein at the locus coeruleus in fentanyl-induced muscular rigidity in the rat

Previous work from our laboratory suggested that locus coeruleus (LC) and the coerulospinal noradrenergic pathway are intimately related to the elicitation of muscular rigidity by fentanyl. The present study attempted to identify the subtype of guanine nucleotide-binding regulatory protein that may participate in this process, using Sprague-Dawley rats anesthetized with ketamine and under mechanical ventilation. Immunofluorescent staining with a polyclonal antiserum directed against a 39-kDa protein that corresponds to the α subunit of G o revealed the presence of G oα immunoreactivity in neurons of the LC. Bilateral microinjection of the same G oα antiserum into the LC also significantly blunted the enhanced electromyographic activity recorded from the sacrococcygeus dorsalis lateralis muscle induced by intravenous administration of fentanyl (100 μg/kg). These results suggest that G oα protein at the LC may participate in the signal transduction process that underlies muscular rigidity induced by high-dose fentanyl.

Prospective Evaluation of Epidural and Intravenous Administration of Fentanyl for Pain Control and Restoration of Ventilatory Function Following Multiple Rib Fractures

Department of Surgery, Division of Trauma, and Department of Anesthesiology, University Hospital, University of California, San Diego, California

Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration

An encephalopathy developed in three infants in the intensive care unit after heavy sedation with midazolam and fentanyl for 4 to 11 days. The affected infants had poor social interaction, decreased visual attentiveness, dystonic postures, and choreoathetosis. Symptoms cleared completely in 5 days to 4 weeks. Retrospective review of records of all children treated in the intensive care unit with prolonged intravenous administration of midazolam revealed that 45 children could be assessed neurologically on withdrawal of sedation. Three children had definite and two had possible neurologic sequelae (5/45, 11.1%). All had received concomitant intravenous fentanyl therapy. Neurologic sequelae were significantly associated with young age, female gender, low serum albumin concentration, and concomitant administration of aminophylline. This encephalopathy may represent a benzodiazepine withdrawal syndrome, a prolonged agonist action on the benzodiazepine receptor, or the combined effects of multiple toxic, metabolic, and infectious insults to the central nervous system of infants in the intensive care unit. Prolonged use of intravenous midazolam sedation necessitates careful dosing, monitoring, and discontinuation, particularly in infants and young children.

Absorption and Bioavailability of Oral Transmucosal Fentanyl Citrate

Oral transmucosal fentanyl citrate (OTFC) is a novel, noninvasive dosage form of fentanyl used to provide children and adults with sedation, anxiolysis, and analgesia. In order to determine the bioavailability and absorption of fentanyl from OTFC, 12 volunteers were given intravenous fentanyl citrate or OTFC 15 micrograms/kg on each of two occasions. On a third occasion, the authors assessed oral administration (gastrointestinal absorption) by giving eight of the same volunteers the same dose of a solution of fentanyl citrate to swallow. In each study, arterial blood samples were taken over 24 h for analysis of plasma fentanyl. After intravenous (iv) administration of fentanyl, clearance (mean +/- standard deviation) was 0.67 +/- 0.15 l/min; volume of distribution at steady state was 287 +/- 79 l; and the terminal elimination half-life was 425 +/- 102 min. Peak plasma concentrations of fentanyl were higher (3.0 +/- 1.0 vs. 1.6 +/- 0.6 ng/ml, P = 0.01) and occurred sooner (22 +/- 2.5 vs. 101 +/- 48.8 min, P = 0.003) after OTFC than after oral solution administration. Plasma concentrations of fentanyl after OTFC decreased rapidly, to less than 1.0 ng/ml within 75-135 min after the beginning of administration. Peak absorption rate was greater (11.1 +/- 4.3 vs. 3.6 +/- 2.1 micrograms/min, P = 0.004) and occurred much sooner after OTFC than after oral solution administration (19 +/- 2.6 vs. 87.5 +/- 38.1 min, P = 0.001). Systemic bioavailability was greater after OTFC administration than after the oral solution (0.52 +/- 0.1 vs. 0.32 +/- 0.1, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)