Doses Of Intravenous Fentanyl Research Articles

Comparison of intranasal naloxone and intranasal nalmefene in a translational model assessing the impact of synthetic opioid overdose on respiratory depression and cardiac arrest

IntroductionUsing a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the μ-opioid receptor antagonists naloxone and nalmefene.MethodsThis translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µ-opioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment.ResultsFollowing simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene.ConclusionSimulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl.

Attenuation of hemodynamic pressor response to laryngoscopy and endotracheal intubation by intravenous fentanyl in elective surgery under general anesthesia: A randomized controlled trial using three different doses

Background: Direct laryngoscopy and endotracheal intubation elicit hemodynamic pressor responses which may be hazardous in high risk patients. Fentanyl, a low cost synthetic opioid, when used judiciously, may be a good option to attenuate this stress response. Aims and Objectives: The present study has been conducted to compare the efficacy of three different doses of intravenous fentanyl in attenuation of hemodynamic pressor response to laryngoscopy and endotracheal intubation in elective surgery under general anesthesia. Materials and Methods: It was a double-blinded randomized controlled trial. A total of 90 patients of American Society of Anesthesiologists physical status I and II, 55 male and 35 female, aged between 20 and 55 years, were randomized into three groups receiving 2, 3, and 4 μg/kg of injection fentanyl, respectively, administered intravenously 5 min before direct laryngoscopy and endotracheal intubation. Results: There were significant differences in hemodynamic variables among all three groups at 1, 3, 5, and 10 min after endotracheal intubation. Just after endotracheal intubation; heart rate, mean arterial pressure, and diastolic arterial pressure – all these variables showed significance between 3 μg/kg and 4 μg/kg groups only. Incidence of nausea/vomiting showed statistical significance between 2 μg/kg and 4 μg/kg groups only. Conclusion: In our double-blinded randomized controlled trial, 4 μg/kg of injection fentanyl administered 5 min before laryngoscopy and intubation, has showed superior efficacy in suppressing hemodynamic stress responses associated with it. Further, larger trials are needed to confirm our findings.

Emergence agitation in children after sevoflurane anaesthesia: a comparative evaluation of ketamine and varying doses of fentanyl

Introduction: Sevoflurane, inhalational anaesthetic of choice in children, is associated with high incidence of emergence agitation (EA). But that “one drug” which can significantly reduce or prevent EA still eludes us. Thus we aimed at studying the efficacy of intravenous ketamine and varying doses of intravenous fentanyl on postoperative emergence agitation in children receiving sevoflurane anaesthesia. Materials and methods : This prospective, double blind, randomized comparative study was conducted on 114 children, 2-10 years, with ASA physical status I-II. They were undergoing herniotomy under sevoflurane anaesthesia and were randomly divided into Group A receiving ketamine 0.5 mg/kg, Group B fentanyl 2mcg/kg and Group C fentanyl 3mcg/kg at the time of induction. Postoperatively emergence agitation was assessed every 5 min during first 60 min of PACU stay using Aono's four point scale . We also observed recovery characteristics including time to extubation, time to emergence, discharge from PACU and postoperative complications. Results: The incidence of EA was significantly low in Group A (31.6%) and Group C (28.9%) compared to group B (65.8%), with no significant difference between Group A and Group C. Incidence of EA was higher in preschool children. A prolonged PACU stay was observed in all children who developed EA, with lesser duration of PACU stay noted in fentanyl 3 mcg/kg group. Conclusion: Intravenous administration of either ketamine 0.5 mg/kg or fentanyl 3mcg/kg i.v. at the time of induction reduces the incidence of EA effectively when compared with fentanyl 2mcg/kg, without delaying recovery. DOI: http://dx.doi.org/10.4038/slja.v23i1.7514

Post-thoracotomy pain relief in pediatric patients epidural versus inter-pleural analgesia

Background For controlling post-thoracotomy pain, thoracic epidural (TE) analgesia is considered a gold standard technique. However, it may be associated with serious complications. Interpleural (IP) analgesia is thought to be a simpler technique. Therefore, the current study aimed to compare the efficacy of simple IP with TE bupivacaine in controlling post-thoracotomy pain in pediatrics. Patients and methods A total of 80 pediatric patients undergoing elective thoracotomy were randomly assigned to either the TE or the IP group. In the TE group, epidural catheter was threaded through the caudal space and the tip was placed at the fourth intercostal space. In the IP group, the surgeon inserted the IP catheter through the IP space under direct vision and directed its tip towards the fourth intercostal space on the paravertebral line. Bupivacaine 1.5 mg/kg in 25% concentration was administered through either TE or IP catheters as intermittent boluses every 6 h, starting from the beginning of skin closure, for 24 h postoperatively. Fentanyl 1 mg/kg intravenous bolus was administered as rescue analgesia to keep the pain score less than 0.4. Hemodynamic parameters and pain scores were recorded at 1, 6, 12, 18, and 24 h. In addition, interleukin-6 was measured at 1, 6, and 24 h beginning from the first injected local anesthetic dose. Total postoperative 24 h fentanyl requirements and time to first postoperative rescue analgesia were recorded. Results CRIES pain score showed no significant difference between the studied groups. Time to first rescue analgesia was significantly shorter in the IP group (2.75 ± 0.93) compared with the TE group (4.17 ± 1.07). Patients of the IP group required higher doses of intravenous fentanyl than did those in the TE group (12.83 ± 3.83 vs. 8.16 ± 3.4μg) (P Conclusion For post-thoracotomy pain in pediatrics, equipotent analgesia can be achieved through TE blockade and the simpler IP technique, but with higher postoperative intravenous fentanyl supplementation to the latter technique.

A method for conducting functional MRI studies in alert nonhuman primates: Initial results with opioid agonists in male cynomolgus monkeys.

Functional MRI (fMRI) has emerged as a powerful technique for assessing neural effects of psychoactive drugs and other stimuli. Several experimental approaches have been developed to use fMRI in anesthetized and awake animal subjects, each of which has its advantages and complexities. We sought to assess whether one particular method to scan alert postanesthetized animals can be used to assess fMRI effects of opioid agonists. To date, the use of fMRI as a method to compare pharmacological effects of opioid drugs has been limited. Such studies are important because mu and kappa opioid receptor agonists produce distinct profiles of behavioral effects related both to clinically desirable endpoints (e.g., analgesia) and to undesirable effects (e.g., abuse potential). This study sought to determine whether we could use our fMRI approach to compare acute effects of behaviorally equipotent (3.2 μg/kg) intravenous doses of fentanyl and U69,593 (doses that do not affect cardiorespiratory parameters). Scans were acquired in alert male cynomolgus macaques acclimated to undergo fMRI scans under restraint, absent excessive stress hormone increases. These opioid agonists activated bilateral striatal and nucleus accumbens regions of interest. At the dose tested, U69,593 induced greater left nucleus accumbens BOLD activation than fentanyl, while fentanyl activated left dorsal caudate nucleus more than U69,593. Our results suggest that our fMRI approach could be informative for comparing effects of opioid agonists.

High-dose dexmedetomidine increases the opioid-free interval and decreases opioid requirement after tonsillectomy in children

Dexmedetomidine, a selective α(2) adrenoreceptor agonist, has analgesic and sedative properties, minimal impact on respiratory parameters, and reportedly decreases analgesic requirements after surgery. Given its pharmacodynamic profile, dexmedetomidine might have a role for postoperative pain control in children undergoing tonsillectomy. In this study, we hypothesized that dexmedetomidine would delay and decrease opioid requirements after tonsillectomy. In a double-blind controlled trial, participants undergoing tonsillectomy were randomized to receive one intravenous dose of fentanyl (1 μg·kg(-1) or 2 μg·kg(-1)) or dexmedetomidine (2 μg·kg(-1) or 4 μg·kg(-1)) immediately after endotracheal intubation. Primary outcomes included requirement for rescue morphine in the initial postoperative period. One hundred and one children were enrolled. During the postoperative period, dexmedetomidine (2 and 4 μg·kg(-1) groups combined) significantly prolonged the opioid-free interval of children who underwent tonsillectomy compared with fentanyl (1 and 2 μg·kg(-1) groups combined) (P < 0.001). Children treated with dexmedetomidine 2 μg·kg(-1) vs dexmedetomidine 4 μg·kg(-1) had similar cumulative incidence curves for time to morphine rescue, whereas there was a small difference in time to first morphine rescue administration when comparing fentanyl 1 μg·kg(-1) vs fentanyl 2 μg·kg(-1). Furthermore, length of stay in the postanesthesia care unit was significantly longer for children treated with dexmedetomidine vs children treated with fentanyl (P = 0.0016). High-dose dexmedetomidine decreases opioid requirements, prolongs the opioid-free interval after tonsillectomy, and prolongs length of stay in the postanesthesia care unit. It is conceivable that these early opioid-sparing effects could benefit patients at risk for respiratory complications early in the postoperative course after tonsillectomy (e.g., patients with obstructive sleep apnea). (ClinicalTrials.gov number, NCT00654511).

D1-dopamine receptor agonists prevent and reverse opiate depression of breathing but not antinociception in the cat

Opioids depress respiration and decrease chest wall compliance. A previous study in this laboratory showed that dopamine-D(1) receptor (D(1)R) agonists restored phrenic nerve activity after arrest by fentanyl in immobilized, mechanically ventilated cats. The reinstated phrenic nerve rhythm was slower than control, so it was not known whether D(1)R agonists can restore spontaneous breathing to levels that provide favorable alveolar gas exchange and blood oxygenation. It was also not known whether the agonists counteract opioid analgesia. In the present study, anesthetized, spontaneously breathing cats were given intravenous doses of fentanyl (18.0 +/- 3.4 microg/kg) that severely depressed depth and rate of respiration, lowered arterial hemoglobin oxygenation (HbO(2)), elevated end-tidal carbon dioxide (ETCO(2)), and abolished the nociceptive hind limb crossed-extensor reflex. Fentanyl (30 microg/kg) also evoked tonic discharges of caudal medullary expiratory neurons in paralyzed mechanically ventilated cats, which might explain decreased chest compliance. The selective D(1)R agonists 6-chloro APB (3 mg/kg) or dihydrexidine (DHD, 1 mg/kg) increased depth and rate of spontaneous breathing after opioid depression and returned HbO(2) and ETCO(2) to control levels. Opioid arrest of the nociceptive reflex remained intact. Pretreatment with DHD prevented significant depression of spontaneous breathing by fentanyl (17.5 +/- 4.3 microg/kg). Tonic firing evoked by fentanyl in expiratory neurons was converted to rhythmic respiratory discharges by DHD (1 mg/kg). The results suggest that D(1)R agonists might be therapeutically useful for the treatment of opioid disturbances of breathing without impeding analgesia.

The Neurologic and Adaptive Capacity Score: a systematic review of its use in obstetric anesthesia research.

The Neurologic and Adaptive Capacity Score: a systematic review of its use in obstetric anesthesia research.

Effects of a bolus injection of adenosine triphosphate on atrioventricular conduction and hemodynamics in patients undergoing coronary artery bypass grafting

Objective: To investigate the effects of adenosine triphosphate (ATP) on atrioventricular (A-V) conduction and hemodynamics in patients undergoing coronary artery surgery. Design: A prospective study. Setting: University teaching hospital. Participants: Patients scheduled for elective coronary artery bypass graft surgery. Interventions: Anesthesia was induced with the same dose of intravenous fentanyl (300 μg) and midazolam (10 mg) for each patient. After the baseline measurement, a bolus dose of 10 mg of ATP (0.19 ± 0.03 mg/kg, mean ± SD) was rapidly injected through a central venous catheter. Right ventricular pacing was conducted at a rate of 40 beats/min during the development of complete A-V block. Measurements and Main Results: ATP induced an A-V block in 10 of 12 patients (2: 1 block in two patients and complete A-V block in eight patients). The onset of the A-V block was rapid (17.1 ± 3.4 seconds) and the duration was short (12.1 ± 7.0 seconds). Radial arterial pressure (AP) decreased with the appearance of the A-V block ( p < 0.01). Heart rate (HR) returned to the baseline value quickly after the restoration of the A-V block, but recovery of radial AP was delayed. HR increased 1 minute after the ATP injection ( p < 0.01). Both HR and radial AP returned to the baseline values 2 minutes after the ATP injection. ST segments on both leads II and V 5 of electrocardiograms decreased more than 0.10 mV 1 minute after the ATP injection in one patient. Conclusion: A bolus injection of 10 mg of ATP successfully induced a transient A-V block in 83% of the 12 patients. The countermeasures, including ventricular pacing, are indispensable to cope with the subsequent hypotension that may lead to myocardial ischemia, especially in patients with ischemic heart disease.

Fentanyl Therapy Controls Autonomic Hyperactivity in Tetanus

Sympathetic overactivity is a well-recognized complication of generalized tetanus in humans. In this clinical situation, a variety of drugs with primary or secondary actions on the cardiovascular system has been used with varying success. We show successful management of severe generalized tetanus in adults associated with autonomic hyperactivity with large doses of intravenous fentanyl.

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.

Attenuation of the Hemodynamic Responses to Chest Physical Therapy

Chest physiotherapy (CPT) is a commonly used technique in mechanically ventilated critically ill patients. This study examines the hemodynamic and metabolic changes associated with CPT and measures the attenuation by two doses of intravenous fentanyl (1.5 micrograms/kg and 3.0 micrograms/kg) on these changes. Heart rate, systolic and mean blood pressures, cardiac output, oxygen consumption (VO2), and carbon dioxide production (VCO2) all increased during CPT. Decreases in arterial pH and VE and increases in PaCO2 were also observed. The higher, but not lower dose, of fentanyl significantly attenuated increases in blood pressure and heart rate during CPT and no substantial hemodynamic changes occurred once CPT had stopped. The increases in VO2 and VCO2 were not attenuated. Short acting narcotics attenuate the hemodynamic responses to stressful stimuli such as CPT.

Reversal of opioid-induced muscular rigidity in rats: Evidence for alpha-2 adrenergic involvement

Compounds from several different pharmacological classes were tested for their ability to reverse the muscular rigidity induced by an intravenous dose of fentanyl that also caused loss of the righting reflex (LOR). Opioid antagonists reversed the entire syndrome—LOR and rigidity but, generally, rigidity could be reversed nonspecifically by doses of compounds that caused LOR by themselves (e.g., CNS depressants). Muscle relaxants and agonists of histamine, which appeared to be acting peripherally, were also effective. On the other hand, serotonergic drugs and dopamine agonists were not. However, dopaminergic antagonists with adrenolytic activity (i.e., chlorpromazine, haloperidol) reversed rigidity, whereas sulpiride did not. Moreover, rigidity reversed by neuroleptics could be restored by piperoxane, an alpha-2 adrenergic antagonist. In addition, clonidine and other alpha-2 agonists selectively reversed only rigidity following systemic or central administration at doses several orders of magnitude lower than other compounds tested. It is proposed that opioid-induced rigidity is reversed by inhibition of sympathoadrenal outflow which can be accomplished selectively, centrally, by alpha-2 agonists.

Blood Pressure Response and Plasma Fentanyl Concentrations during High-and Very High-Dose Fentanyl Anesthesia for Coronary Artery Surgery

We examined whether different plasma fentanyl concentrations could maintain hemodynamic stability during coronary artery surgery. Two randomly selected groups of 10 patients were studied. Patients in group 1 received a single 75-micrograms/kg intravenous dose of fentanyl; patients in group 2 received the same dose but it was followed by an infusion of fentanyl at a rate of 0.75 micrograms/kg/min. The total dose of fentanyl in group 2 was 162 +/- 6.5 micrograms/kg (mean +/- SEM). At some point during surgery, all 10 patients in group 1 and 7 of 10 patients in group 2 had a hypertensive response. Plasma fentanyl concentrations in the two groups were not significantly different in the period 10-45 min after induction of anesthesia. At 60 min, corresponding to the time of aortic root dissection, mean plasma fentanyl concentration was statistically significantly lower in group 1 than in group 2 (13.5 +/- 1.4 ng/ml and 24 +/- 2.3 ng/ml, respectively, P less than 0.01). However, no significant difference was observed in the frequency of hypertensive response between the two groups in the period before cardiopulmonary bypass. During cardiopulmonary bypass, plasma fentanyl concentrations in group 1 were 2-3 times lower than those in group 2, and hypertension was observed in all 10 patients in group 1 but in only 2 patients in group 2 (P less than 0.05). Patients in group 1 were ventilated for 16.6 +/- 1.5 h, and those in group 2 for 19.1 +/- 1.8 h, postoperatively (P greater than 0.05). Six patients in group 1 required vasodilating drugs, whereas eight patients in group 2 required alpha-adrenergic agonists. Although the plasma fentanyl concentrations achieved were not successful in totally suppressing a hypertensive response, this study suggests that a plasma fentanyl concentration might be attainable to effect this.

Cardiovascular Effects of Fentanyl during Enflurane Anesthesia in Man

The cardiovascular effects of three doses of intravenous fentanyl (50, 100, and 200 microgram) were determined in 42 adult patients undergoing intraabdominal surgical procedures with enflurane (2--3%) and nitrous oxide (50%) in oxygen. Fentanyl was administered a minimum of 40 minutes after induction of anesthesia and 30 minutes after initiation of the surgical procedure. Stroke volume, heart rate, cardiac output, mean arterial and central venous blood pressures, and peripheral arterial resistance were determined by computer analysis of the central aortic pulse-pressure curve according to the method of Warner. Measurements were made before and 2, 4, 6, 8, and 10 minutes after fentanyl. Fentanyl (50 microgram) produced increases in stroke volume and cardiac output as well as a decrease in peripheral arterial resistance but did not alter heart rate or mean arterial blood pressure. Fentanyl (100 microgram) did not significantly change any variable at any time. Fentanyl (1l (200 microgram) produced sustained decreases in stroke volume, cardiac output and mean arterial blood pressure and increased central venous pressure but did not alter heart rate or peripheral arterial resistance. The data indicate that fentanyl (50--100 microgram) stimulates or has no effect on cardiovascular dynamics during enflurane-nitrous oxide anesthesia but fentanyl (200 microgram) produces significant cardiovascular depression. Our findings suggest that small doses of intravenous fentanyl may be of benefit during enflurane-nitrous oxide but larger doses should probably be avoided.