High-dose Fentanyl Research Articles

Comparison of meperidine, tramadol and fentanyl for post-spinal shivering prevention during cesarean delivery: A double-blind randomized controlled trial.

To assess the effects of intravenously administered meperidine, fentanyl and tramadol in reducing the incidence, onset time and severity of the shivering response in parturients during cesarean delivery under spinal anesthesia. Secondary outcomes included patient satisfaction and sedation scores. After Ethics board approval and informed written consent, 350 parturients (ASA physical status I or II), between 20 and 40 years of age, undergoing emergency or elective cesarean delivery under spinal anesthesia were recruited. Parturients were then randomly allocated to seven study groups: normal saline (control), low-dose meperidine (0.5 mg/kg), high-dose meperidine (0.75 mg/kg), low-dose fentanyl (0.5 mcg/kg), high-dose fentanyl (0.75 mcg/kg), low-dose tramadol (0.5 mg/kg) and high-dose tramadol (0.75 mg/kg). The incidence, onset time and severity of shivering, along with patient satisfaction and sedation scores were measured. All study drugs showed significant reduction in incidence, onset time and severity of shivering and greater satisfaction scores compared to the control group (P < 0.01). Within each drug class, no significant differences in shivering were found between the high-dose and low-dose groups. Among study drugs, low-dose tramadol was superior due to shivering prevention and significantly reduced sedation. Intravenously administered meperidine, fentanyl and tramadol reduce shivering incidence, onset time and severity in parturients undergoing cesarean delivery following spinal anesthesia. Importantly, low-dose intravenous tramadol (0.5 mg/kg) allowed shivering prevention and low sedation scores, thereby offering greater parturient satisfaction and better maternal-newborn bonding.

Fentanyl-Induced Chest Wall Rigidity as a Cause of Acute Respiratory Failure in the Intensive Care Unit

We aim to report a case of chest wall rigidity induced by high-dose fentanyl infusion sedation and analgesia in the intensive care unit (ICU) for management of pneumonia and asthma. The patient is an 80-year-old woman, who presented to the hospital with complaints of fever and productive cough with yellowish expectoration of 2 days duration. She also had lethargy over the same time period and had sick contacts in the form of two daughters who both had recently recovered from a “flu-like” illness. She was known to have bronchial asthma treated with seretide 25/250 two puffs ON + PO monteleukast 10 mg ON, hypertension treated with PO losartan 50 mg BD, type 2 diabetes mellitus controlled with PO linagliptin 5 mg OM and a previous right thalamic ischemic stroke 5 years ago for which she was on PO clopidogrel 75 mg OM and PO simvastatin. She developed severe ventilator desynchrony characterized by dramatic sudden onset of severe hypercarbia, severely decreased pulmonary compliance and episodic breath holding. She was empirically treated for asthma exacerbation and treated with steroids, bronchodilators and manual ventilation but despite doing so during this episode the patient failed to respond. The patient was clinically evaluated and dynamic hyperinflation was excluded as a cause of the respiratory failure. There was no evidence of pneumothorax and worsening pneumonia. Considerations of insufficient sedation and analgesia led to deepening sedation and analgesia without good response. Ventilation was dramatically improved after small doses of neuromuscular relaxation. This cycle was repeated many times. The patient was kept on high-dose propofol and fentanyl, but there were repeated cycles of sudden persistent severe hypercarbia, severely decreased pulmonary compliance and episodic breath holding. Eventually a suspicion of fentanyl-induced chest wall rigidity was made after excluding causes of airway resistance and reduction in pulmonary compliance. Gradual reduction in fentanyl infusion was associated with a reduction of episodes of reduced lung compliance and improvement in ventilation. Fentanyl is often used for analgesia and sedation in the ICU. It has a good side effect profile but it is not without harm. High doses of fentanyl can lead to dramatic worsening of respiratory mechanics that may be life threatening. Fentanyl-induced chest wall rigidity is an important side effect that needs to be considered in the differential diagnosis of respiratory failure in the ICU. J Med Cases. 2019;10(8):249-252 doi: https://doi.org/10.14740/jmc3351

Effects of low-dose intraoperative fentanyl on postoperative respiratory complication rate: a pre-specified, retrospective analysis

BackgroundFentanyl is one of the most frequently administered intraoperative drugs and may increase the risk of postoperative respiratory complications (PRCs). MethodsWe performed a pre-specified analysis of 145 735 adult non-cardiac surgical cases under general anaesthesia. Using multivariable logistic regression, we evaluated the association of intraoperative fentanyl dose and PRCs within 3 days after surgery (defined as reintubation, respiratory failure, pneumonia, pulmonary oedema, or atelectasis). We examined effect modification by patient characteristics, surgical site, and anaesthetics used. ResultsPRCs within 3 days after surgery occurred in 18 839 (12.9%) patients. In comparison with high intraoperative fentanyl doses [median: 3.85; inter-quartile range (IQR): 3.42–4.50 μg kg−1, quartile 4 (Q4)], low intraoperative fentanyl dose [median: 0.80, IQR: 0.00–1.14 μg kg−1, quartile 1 (Q1)] was significantly associated with lower odds of PRCs [Q1 vs Q4: 10.9% vs 16.2%; adjusted odds ratio (aOR) 0.79; 95% confidence intervals (CI) 0.75–0.84; P<0.001; adjusted absolute risk difference (aARD) −1.7%]. This effect was augmented by thoracic surgery (P for interaction <0.001; aARD −6.2%), high doses of inhalation anaesthetics (P for interaction=0.016; aARD −2.2%) and neuromuscular blocking agents (NMBAs) (P for interaction=0.001; aARD −3.4%). Exploratory analysis demonstrated that compared with no fentanyl, low-dose fentanyl was associated with lower rates of PRCs (decile 2 vs decile 1: aOR 0.82, CI 0.75–0.89, P<0.001). ConclusionsIntraoperative low-dose fentanyl (about 60–120 μg for a 70 kg patient) was associated with lower risk of postoperative respiratory complications compared with both no fentanyl and high-dose fentanyl. Beneficial effects of low-dose fentanyl were magnified in specific patient subgroups. Clinical trial registrationNCT03198208.

Abstract #137: Opioid Induced Hyperalgesia with Intrathecal Infusion of High Dose Fentanyl

Abstract #137: Opioid Induced Hyperalgesia with Intrathecal Infusion of High Dose Fentanyl

The effect of two doses of fentanyl on chest wall rigidity at equipotent doses of isoflurane in dogs

ObjectiveTo evaluate the effect of two doses of fentanyl upon chest wall rigidity of dogs anesthetized at equipotent doses of isoflurane [1.3 minimum alveolar concentration (MACISO) of each dose of fentanyl]. Study designProspective crossover randomized study. AnimalsA group of eight male Beagle dogs, approximately 1 year old and weighing 12.1 ± 1.6 kg (mean ± standard deviation). MethodsThe dogs were anesthetized with isoflurane and instrumented for the measurement of esophageal pressure (PESO), flow (V˙) and volume (V). Chest wall elastance (ECW) was estimated by multiple linear regression of the model. PESO(t) = V˙(t) × RCW + V(t) × ECW + EEPESO where t is time, RCW is chest wall resistance and EEPESO is end-expiratory PESO. Chest wall compliance (CCW) was calculated as 1/ECW and normalized to the body weight of each dog (mL cmH2O−1 kg−1). Anesthesia was maintained at 1.3 MACISO for at least 15 minutes and CCW recorded (CCW-ISO). The dogs were randomly assigned to the lower fentanyl dose [loading dose (33 μg kg−1) and infusion (0.2 μg kg−1 minute−1)] or the higher fentanyl dose [loading dose (102 μg kg−1) and infusion (0.8 μg kg−1 minute−1)]. After 60 minutes of fentanyl infusion, CCW was recorded for each dose (CCW-FENT). During fentanyl infusion, the dogs were maintained at equipotent doses of isoflurane (1.3 MACISO for each fentanyl dose). A two-way analysis of variance followed by a Bonferroni test was used to compare CCW-ISO and CCW-FENT in both treatments and CCW-FENT between treatments. A p value <0.05 was considered significant. ResultsNeither of the fentanyl doses decreased CCW and there was no difference in CCW-FENT between doses. Conclusions and clinical relevanceFentanyl at the studied doses did not result in chest wall rigidity in dogs anesthetized with equipotent doses of isoflurane (1.3 MACISO).

Effects of chronic fentanyl administration on behavioral characteristics of mice.

BackgroundFentanyl, a synthetic opioid categorized as a narcotic analgesic, has a 100‐ to 200‐fold stronger effect than most opioids, such as morphine. Fatal accidents due to chronic use and abuse of fentanyl are a worldwide social problem. One reason for the abuse of fentanyl is its psychostimulant effects that could induce behavioral changes. The effects of chronic fentanyl administration on behavior, however, are unclear.MethodsAdult male C57BL/6J mice were chronically administered fentanyl (0.03 or 0.3 mg/kg/d i.p.), and various behaviors were assessed using a behavioral test battery.ResultsMice chronically administered a high dose of fentanyl (0.3 mg/kg/d) exhibited decreased anxiety‐like behavior as assessed by the open field and elevated plus maze tests. On the other hand, interruption of fentanyl administration led to increased anxiety‐like behavior as observed in the light and dark transition test. The hot plate test revealed that chronic administration of fentanyl reduced pain sensitivity. High‐dose chronic fentanyl administration reduced the locomotor stimulatory effects of cocaine. The results, however, failed to reach the threshold for study‐wide statistical significance.ConclusionChronic fentanyl administration induces some behavioral changes in mice. Although further studies are needed to clarify the underlying mechanisms of the behavioral effects of chronic fentanyl administration, our findings suggest that fentanyl is safe under properly controlled conditions.

Labor Epidural Analgesia and Breastfeeding

(Anesthesiology 2017;V:127) Breastfeeding is paramount for both maternal and neonatal well-being and incurs substantial long-term and short-term health benefits to the infant and the mother. A previous randomized controlled study observed that women receiving high-dose fentanyl labor epidural analgesia (cumulative dose &gt;150 µg) were more likely to stop breastfeeding 6 weeks postpartum compared with women receiving less fentanyl or no fentanyl. In addition, the 24-hour neonatal neurobehavioral scores were also lowest in the neonates of women receiving high-dose epidural fentanyl. A systematic review of 23 studies found the evidence substantiating the association between labor epidural analgesia and breastfeeding success to be inconclusive.

A Study of the Prophylactic and Curative Effect of Melatonin on Postoperative Delirium after Coronary Artery Bypass Grafting Surgery in Elderly Patients

Background: delirium is a common complication after cardiac surgical procedures and is associated with increased morbidity and mortality. Postoperative delirium is associated with an increased length of stay in the intensive care unit, long hospital stay and high hospital charges. Aim of the Work: to investigate the effectiveness of melatonin as a preoperative sedative as well as the preventive and the curative effect of melatonin supplementation in elderly patients undergoing coronary artery bypass surgery on postoperative delirium. Patients and Methods: this prospective, randomized, controlled, double blind study was conducted on a total of 50 patients allocated into 2 equal groups. It was conducted in Ain Shams University hospitals, in the cardiothoracic surgery unit. Results: melatonin has superior sedative effect at 30 min preoperatively compared with placebo (P=0.022). Melatonin succeeded to treat about 56% of delirious patients. The incidence of delirium was 8% in the melatonin group vs. 28% in the control group (P= 0.046). In univariate analysis, predictors of delirium in both groups were age (P= 0.049 in melatonin group, P=0.021 in control group), higher fentanyl dose (P= 0.021 in melatonin group, P=0.047 in control group), lower ejection fraction (P= 0.018 in melatonin group, P=0.008 in control group), longer cardiopulmonary bypass (CPB) times (P= 0.026 in melatonin group, P=0.04 in control group) and longer aortic cross clamping (ACC) times (P= 0.04 in melatonin group, P=0.019 in control group). Conclusion: administration of melatonin significantly decreased the incidence of postoperative delirium (POD) after coronary artery bypass grafting in elderly patients and significantly increased preoperative sedation. Advanced age, higher total intraoperative fentanyl dose, lower ejection fraction and longer CPB and ACC times were independent predictors of POD with or without melatonin supplementation.

A Study of the Prophylactic and Curative Effect of Melatonin on Postoperative Delirium after Coronary Artery Bypass Grafting Surgery in Elderly Patients

Background: delirium is a common complication after cardiac surgical procedures and is associated with increased morbidity and mortality. Postoperative delirium is associated with an increased length of stay in the intensive care unit, long hospital stay and high hospital charges. Aim of the Work: to investigate the effectiveness of melatonin as a preoperative sedative as well as the preventive and the curative effect of melatonin supplementation in elderly patients undergoing coronary artery bypass surgery on postoperative delirium. Patients and Methods: this prospective, randomized, controlled, double blind study was conducted on a total of 50 patients allocated into 2 equal groups. It was conducted in Ain Shams University hospitals, in the cardiothoracic surgery unit. Results: melatonin has superior sedative effect at 30 min preoperatively compared with placebo (P=0.022). Melatonin succeeded to treat about 56% of delirious patients. The incidence of delirium was 8% in the melatonin group vs. 28% in the control group (P= 0.046). In univariate analysis, predictors of delirium in both groups were age (P= 0.049 in melatonin group, P=0.021 in control group), higher fentanyl dose (P= 0.021 in melatonin group, P=0.047 in control group), lower ejection fraction (P= 0.018 in melatonin group, P=0.008 in control group), longer cardiopulmonary bypass (CPB) times (P= 0.026 in melatonin group, P=0.04 in control group) and longer aortic cross clamping (ACC) times (P= 0.04 in melatonin group, P=0.019 in control group). Conclusion: administration of melatonin significantly decreased the incidence of postoperative delirium (POD) after coronary artery bypass grafting in elderly patients and significantly increased preoperative sedation. Advanced age, higher total intraoperative fentanyl dose, lower ejection fraction and longer CPB and ACC times were independent predictors of POD with or without melatonin supplementation.

Comparative study of different methods of anesthesia with transrectal resection of the large bowel in Hirschsprung's disease in young children

Aim. Improvement of the safety of patients and of effectiveness of anesthetic protection for young children with Hirschsprung's disease during transrectal resection of the large bowel by comparative study of various methods of anesthesia and creating an effective and safe anesthesia regimen. Methods. The study included 25 children with Hirschsprung's disease who underwent transrectal resection of the large intestine. All examined patients were divided into two groups depending on the chosen method of anesthesia. In clinical group 1 (n=13) multicomponent endotracheal anesthesia with high doses of fentanyl were selected for anesthesia, in clinical group 2 (n=12), surgical interventions were performed under general anesthesia combined with caudal block. Results. The level of cortisol in patients from group 2 at the 2nd stage of the study significantly decreased by 22%, which indicated the adequacy of this technique of anesthesia. Also, in patients of this group at the 4th stage of the study the level of cortisol and glucose did not change. In patients from group 1 who underwent multicomponent general anesthesia with high doses of fentanyl, at the 4th stage of the study a significant increase occurred in the level of cortisol and glucose by 48.6 and 93.6%, respectively. This indicates the appearance of severe pain 24 hours after the surgery. Conclusion. Caudal anesthesia combined with general anesthesia provides a reliable analgesic effect and miorelaxation in transrectal resection of the colon in Hirschsprung's disease in young children; the combined administration of trimeperidine (promedol) with ropivacain (naropine) into the caudal canal prolongs the analgesic effect up to 24 hours.

Rapid Sequence Intubation in Traumatic Brain-injured Adults.

Deciding on proper medication administration for the traumatic brain injury (TBI) patient undergoing intubation can be daunting and confusing. Pretreatment with lidocaine and/or vecuronium is no longer recommended; however, high-dose fentanyl can be utilized to help blunt the sympathetic stimulation of intubation. Induction with etomidate is recommended; however, ketamine can be considered in the proper patient population, such as those with hypotension. Paralysis can be performed with either succinylcholine or rocuronium, with the caveat that rocuronium can lead to delays in proper neurological examinations due to prolonged paralysis. Recommendations for post-intubation continuous sedation medications include a combination propofol and fentanyl in the normotensive/hypertensive patient population. A combination midazolam and fentanyl or ketamine alone can be considered in the hypotensive patient.

Impact of fellowship training level on colonoscopy quality and efficiency metrics

Previous studies have described variable effects of fellow involvement on the adenoma detection rate (ADR), but few have stratified this effect by level of training. We aimed to evaluate the "fellow effect" on multiple procedural metrics including a newly defined adenoma management efficiency index, which may have a role in documenting colonoscopy proficiency for trainees. We also describe the impact of level of training on moderate sedation use. We performed a retrospective review of 2024 patients (mean age, 60.9 ± 10 years; 94% men) who underwent outpatient colonoscopy between June 2012 and December 2014 at our Veterans Affairs Medical Center. Colonoscopies were divided into 5 groups. The first 2 groups were first-year fellows in the first 6 months and last 6 months of the training year. Second- and third-year fellows and attending-only procedures accounted for 1 group each. We collected data on doses of sedatives used, frequency of adjunctive agent use, procedural times, and location, size, and histology of polyps. We defined the adenoma management efficiency index as average time required per adenoma resected during withdrawal. Of the colonoscopies performed, 1675 involved a fellow and 349 were performed by the attending alone. There was no difference in ADR between fellows according to level of training (P= .8) or between fellows compared with attending-only procedures (P= .67). Procedural times decreased consistently during training and declined further for attending-only procedures. This translated into improvement in the adenoma management efficiency index (fellow groups by ascending level of training: 23.5 minutes vs 18.3 minutes vs 13.7 minutes vs 13.4 minutes vs attending group 11.7 minutes; P< .001). There was no difference in the average doses of midazolam and fentanyl used among fellow groups (P= .16 and P= .1, respectively). Compared with attending-only procedures, fellow involvement was associated with higher doses of fentanyl and midazolam and more frequent use of diphenhydramine and glucagon (P< .0001, P= .0002, P< .0001, and P= .01, respectively). ADR was similar at different stages of fellowship training and comparable with the attending group. Efficiency of detecting and resecting polyps improved throughout training without reaching the attending level. Fellow involvement led to a greater use of moderate sedation, which may relate to a longer procedure duration and an evolving experience in endoscopic technique.

P-Glycoprotein on Blood-Brain Barrier Plays a Vital Role in Fentanyl Brain Exposure and Respiratory Toxicity in Rats.

Fentanyl is a rapid-acting, short duration opioid analgesic agent. In recent years, increased prescription and illicit use of fentanyl drugs have led to major safety concerns and a growing death toll. However, the causes of fentanyl-induced fatal adverse effects have not been thoroughly researched. This study investigated P-glycoprotein (P-gp) modulated blood-brain barrier penetration of fentanyl and its resulting toxicity in vitro and in vivo. ATPase assays were performed together with bi-directional transport assays using Caco-2 cells in the presence and absence of tariquidar, a P-gp inhibitor, to confirm the P-gp substrate property of fentanyl. In vivo determinations of brain pharmacokinetic profile, duration of loss of righting reflex, and respiratory function were further conducted following intravenous administration of low and high doses of fentanyl with and without tariquidar in rats. Fentanyl significantly increased the ATPase activity of P-gp membrane. The efflux ratio of fentanyl on Caco-2 cells was >2, which was remarkably reduced when co-incubated with tariquidar. Using concomitant tariquidar with fentanyl (40 μg/kg) in rats, the unbound brain-to-plasma concentration ratio in rats increased 2.9- fold. The duration of loss of righting reflex was significantly extended, and fentanyl-induced respiratory depression was aggravated. At high fentanyl doses (80 µg/kg), inhibition of P-gp resulted in severe respiratory toxicity in the rats and even death. Collectively, these results gave strong evidence that P-gp plays a vital role in fentanyl blood-brain barrier penetration and the resulting toxicity. Fentanyl requires close monitoring in clinic when administered concomitantly with P-gp inhibitors.

Cardiovascular and respiratory effects of two doses of fentanyl in the presence or absence of bradycardia in isoflurane-anesthetized dogs

ObjectiveTo compare the cardiopulmonary effects of low and high doses of fentanyl before and after the correction of bradycardia in isoflurane-anesthetized dogs. Study designProspective, randomized crossover trial. AnimalsEight healthy male Beagle dogs weighing 11.1 ± 1.3 kg [mean ± standard deviation (SD)] and aged approximately 1 year. MethodsThe dogs were anesthetized with isoflurane [1.3 × minimum alveolar concentration (MAC)] on two occasions and fentanyl was administered intravenously; either low-dose fentanyl, loading dose (33 μg kg–1) and infusion (0.2 μg kg–1 minute–1) or a high-dose, loading dose (102 μg kg–1) and infusion (0.8 μg kg–1 minute–1). Cardiopulmonary variables were measured at three time points in equipotent isoflurane concentrations (1.3 MAC): before fentanyl administration (ISO), during fentanyl-induced bradycardia (ISO–F) and after administration of glycopyrrolate normalized heart rate (ISO–FNHR). Data are mean ± SD. ResultsHeart rate and cardiac index (CI) decreased and systemic vascular resistance index (SVRI) increased at ISO–F in both treatments. Bradycardia and vasoconstriction at ISO–F were greater in high than in low-dose fentanyl (42 ± 7 versus 57 ± 15 beats minute–1 and 3457 ± 1108 versus 2528 ± 968 dyne second cm–5 m–2), respectively. Oxygen delivery index (DO2I) decreased only during high-dose fentanyl. CI and DO2I were higher in both treatments at ISO–FNHR than at ISO–F; however, they were higher only during the high-dose fentanyl than at ISO. SVRI was higher at ISO–F than at ISO and ISO–FNHR in both treatments, and was higher at ISO–F in the high than in the low-dose treatment. Conclusions and clinical relevanceAn overall improvement in cardiovascular function of dogs anesthetized with equipotent isoflurane doses (1.3 MAC) was observed after the treatment of bradycardia only with the high-dose fentanyl.

Low-Dose Bupivacaine Versus High-Dose Bupivacaine Along With Fentanyl for Spinal Anesthesia in Opioid-Dependent Mothers

Background: Spinal anesthesia is the method of choice for cesarean section. In opioid-dependent mothers, more narcotic is necessary for analgesia. Objectives: In this study, low dose bupivacaine was used to reduce adverse effects, and high dose fentanyl was used to improve analgesia. Patients and Methods: This randomized double-blinded study was performed on 60 opioid-dependent pregnant females in 2 similar groups. In the high-dose bupivacaine with low-dose fentanyl (HBLF) group, 10 mg of bupivacaine and 25 µg of fentanyl, and in the low-dose bupivacaine with high-dose fentanyl (LBHF) group, 6 mg of bupivacaine and 50 µg of fentanyl were used for spinal anesthesia. The blood pressure, heart rate, itching, nausea and vomiting, Apgar score at 1 and 5 minutes, and surgeon and patient satisfaction were evaluated during the study. The sensory block onset and reverse were measured to Thorax 5 and Thorax 12, respectively. The patient’s pain was assessed by a verbal analogue scale (VAS) every half an hour. The time of analgesic was determined from anesthesia injection to verbal analogue scale of > 4. The information was analyzed using the SPSS v16 software and P < 0.05 was considered significant. Results: The demographic data and pre-anesthetic hemodynamic status were similar. The blood pressure was decreased in both groups (P = 0.019), yet there was no significant difference between the 2 groups (P = 0.43). There was no difference in heart rate (P = 0.33), itching, nausea, and vomiting, Apgar score at 1 and 5 minutes, and surgeon and patients’ satisfaction, (P value was 0.47, 0.54, 0.85, 0.86, 0.92, and 0.09, respectively). The block onset to T5 in the HBLF group and LBHF group was 4.4 ± 0.9 and 5.3 ± 0.9 minutes, respectively (P = 0.002). The sensory block reverse to T12 in the HBLF group and the LBHF group was 141.2 ± 28.9 and 122.3 ± 24.5 minutes, respectively (P = 0.03). Also, the time of the first analgesic in the HBLF group and the LBHF group was 248.2 ± 31.4 and 282.1 ± 28.6 minutes, respectively (P = 0.02). Conclusions: There was no difference between low-dose and high-dose narcotic groups in complications and satisfaction. In the opioid-addicted mothers, the sensory block at high-dose bupivacaine (10 mg) and low-dose fentanyl (25 µg) was faster and longer. On the other hand, the duration of analgesia in the low-dose bupivacaine (6 mg) and high-dose fentanyl (50 µg) was higher.

Prehospital analgesic choice in injured patients does not impact on rates of vomiting: Experience from a New South Wales primary retrieval service.

This study aimed to explore the analgesic regimes adopted in our contemporary retrieval practice and the incidence of vomiting in ED after prehospital analgesic use. A retrospective review was conducted on trauma patients retrieved by the Hunter Primary Retrieval Service in the Hunter New England Local Health District, New South Wales, Australia, during 2015. Of the 379 patients attended by the service in 2015, 196 of them (mean age 38.6, SD 19.68, years) were selected for this review. Morphine was the most commonly used analgesic (mean 68.37%; 95% CI 61.36-74.81%), followed by fentanyl (mean 48.47%; 95% CI 41.29-55.70%) and ketamine (mean 34.18%; 95% CI 27.57-41.28%). Fourteen (7.14%, 95% CI 3.96-11.69%) patients vomited either prehospital or within the ED. Patients in both the emesis and the non-emesis group were comparable in demographics. None of the three studied analgesics were observed to be significantly associated with higher risk of vomiting than the others in this review, although a higher dose of fentanyl was given to the non-emesis group (P = 0.04). The frequency of vomiting in the retrieved patients observed in our study was less than previously reported in the literature. Opioids still prevailed over ketamine as the preferred initial analgesic, with ketamine most commonly used as an adjunct. Multi-centre trials in this field would be preferable in future in view of the relatively low incidence of vomiting in retrieved trauma patients.

Time course of copeptin during a model of experimental pain and hyperalgesia: A randomised volunteer crossover trial.

A reliable biomarker for quantifying pain or hyperalgesia has yet to be found. A surrogate marker of arginine vasopressin, copeptin, is elevated in a number of states of physiological and psychological stress and may have a role in quantifying pain and/or hyperalgesia. To evaluate copeptin as a biomarker for pain or hyperalgesia developing after 120 min of sustained electrical stimulation. Secondary analysis of a randomised, double-blinded, crossover trial. Single, tertiary university hospital from September 2014 to January 2015. A total of 16 healthy, opioid-naïve white men with no confounding medication or history of pain. Copeptin and cortisol were measured five times during an established model of transdermal electrical stimulation designed to assess pain and hyperalgesia. The primary outcome was the change in copeptin concentration after 120 min of sustained electrical stimulation. Secondary outcomes were copeptin and cortisol concentrations after a subsequent period of rest and analyses of copeptin and cortisol concentrations were made in high-dose and low-dose fentanyl groups separately. Total copeptin concentrations were not significantly elevated after 120 min [9.15 pmol l (interquartile ranges (IQR), 3.45 to 35.45 pmol l); P = 0.150] compared with baseline [6.15 pmol l (IQR, 3.60 to 10.62 pmol l)]. In the high-dose fentanyl group, there was a significant increase in copeptin within individuals [P = 0.001; median, 37.9 pmol l (IQR, 8.1 to 62 pmol l)] after 120 min, and in the low-dose fentanyl group a significant decrease in copeptin concentrations within individuals [P = 0.006; median, 4.7 pmol l (IQR, 3.13 to 9.35 pmol l)]. No correlation between copeptin concentration and either the area under the pain curve or area under the hyperalgesia curve could be found, indicating that the observed differences may be due to other fentanyl-mediated effects. Copeptin concentrations do not appear to be associated directly with pain and hyperalgesia. Instead, some fentanyl-mediated effect or effects appear to have greatly increased copeptin concentrations from baseline to 120 min. Clinicaltrials.gov identifier: NCT02252458.

Fentanyl Suppresses the Survival of CD4+ T Cells Isolated from Human Umbilical Cord Blood through Inhibition of IKKs-mediated NF-κB Activation.

The aim of this study was to investigate the effects and the underlying mechanisms of fentanyl anaesthetic on T lymphocytes isolated from human umbilical cord blood invitro. The percentages of CD4+ , CD8+ and regulatory T (Treg) cells in human umbilical cord blood mononuclear cells (UBMC) treated with fentanyl invitro were analysed by flow cytometry. The levels of cytokines IFN-γ, IL-2, IL-4 and IL-17 secreted by activated CD4+ T cells were measured by ELISA assays. Expressions of MAPK and NF-κB signalling pathway proteins were determined by Western blotting. Effects of fentanyl on IKK and p65 expression promoter activities were analysed by luciferase assay. Fentanyl decreased the percentages and amounts of CD4+ , CD8+ and Foxp3+ Treg T lymphocyte subsets in UBMCs in a dose-dependent manner. Fentanyl inhibited the proliferation and induced apoptosis of activated CD4+ T cells dose dependently. Fentanyl could not reverse the increase of cell proliferation in activated groups to be equivalent with those in inactivated group. Secretions of IFN-γ, IL-2 and IL-4 cytokines were significantly decreased by moderate to high dose of fentanyl compared with controls. No significant differences were observed in protein expressions of MAPK pathway. In addition, fentanyl suppressed the IKKs-mediated activation of NF-κB. This study demonstrates that fentanyl exerts immunosuppressive effects on T lymphocytes obtained from UBMCs. Thus, the clinical application of fentanyl would not only relieve pain caused by surgery but regulate immune responses post-operation possibly through inhibition of IKKs-mediated NF-κB activation.

Maternal patent ductus arteriosus with bidirectional shunt: Obstetric anaesthesia and its challenges.

Sir, During pregnancy and peripartum period, the physiological changes are poorly tolerated by a patient with bidirectional shunt and severe pulmonary hypertension.[1] We describe a case of 27-year-old primigravida at 32 weeks of gestation who presented with respiratory distress, pre-eclampsia and platelet count of 64 × 109/L. She was a known case of uncorrected congenital PDA with severe pulmonary hypertension and Eisenmenger syndrome. With an interdisciplinary approach, high-risk consent was taken for the emergency caesarean section because of worsening maternal condition, after explaining the high incidence of maternal morbidity and mortality to the family. Pre-operatively, she had tachycardia, hypertension and tachypnoea with an oxygen saturation of 82% on room air, which improved to 89%–92% with oxygen supplementation. Arterial blood gas also showed hypoxaemia and metabolic acidosis, with pH 7.40, PaCO2 22, PaO2 42.00, bicarbonate 16.10, base excess – 5.1 and SaO2 80.70%. In the operating room, right radial artery and right internal jugular vein were cannulated for blood pressure and central venous pressure monitoring, respectively. General anaesthesia with rapid sequence induction and cricoid pressure was instituted using fentanyl, etomidate and succinylcholine. Spinal anaesthesia was not given because of the low platelet count. Soon after induction of anaesthesia, the patient developed supraventricular tachyarrhythmia, followed spontaneously by bradycardia and reverted to normal sinus rhythm in few seconds. This may have been due to sympathetic response to laryngoscopy and intubation, although a higher dose of fentanyl was given at induction to avoid this. A live baby boy was delivered, with Apgar score of 7 at 1 min and 8 at 5 min. During the maintenance phase, she was initially given 100% O2 to maintain oxygen saturation, which was tapered down to 50% and supplemented with 50% air during the procedure. According to the echocardiogram findings, she had severe pulmonary hypertension. She was given milrinone (inodilator) and glyceryl trinitrate infusions, titrated according to response from 0.3–0.6 μg/kg/min, and 0.5–8 μg/kg/min, respectively. At the end of surgery, the trachea was extubated after fulfilling the criteria. During transfer from the operating room, she suddenly developed primary postpartum haemorrhage with a blood loss of approximately 1.5 L, for which immediately 1 unit packed cell was transfused. The surgeon requested general anaesthesia to perform balloon tamponade, which was provided with facemask and sevoflurane 2%–3%. The patient was shifted to cardiac care unit, where she deteriorated from the 2nd post-operative day and inspite of the best possible care provided, patient died on the 4th post-operative day. She experienced sudden cardiac arrest, cardiopulmonary resuscitation was performed but she never revived. The cause of death could not be ascertained. The most probable diagnosis was pneumonia as she had a fever, increasing total leucocyte count, tachypnoea, increased oxygen requirement and pulmonary infiltrate on chest X-ray. She may have aspirated during inhalational anaesthesia by facemask that was given for balloon tamponade, or she may have had a community-acquired infections, leading to severe sepsis and acute respiratory distress syndrome. This could have further worsened the pulmonary hypertension resulting in pulmonary hypertensive crisis and cardiac arrest. Another possible cause could be massive pulmonary embolism resulting in sudden death which is also a common cause of mortality in such patients.[2] The pregnancy induced hypercoagulable state further increases the risk of thromboembolic events in patients with Eisenmenger syndrome, and hence prophylactic anticoagulation is recommended. Unfortunately, our patient never received anticoagulation at any stage, though she was considered high risk for thromboembolic episodes. Haemodynamic disturbance with major fluid shifts occurring after delivery can also be considered as cause of death in such patients. Vigilance is mandated in fluid management as postpartum autotransfusion may expose these patients to fluid overload and heart failure.[3] Pregnancy is contraindicated in women with Eisenmenger syndrome,[4] It is a significant cause of mortality, typically from heart failure or thromboembolic events.[5] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Determination of the minimum infusion rate of alfaxalone during its co-administration with fentanyl at three different doses by constant rate infusion intravenously in goats

ObjectiveTo determine the minimum infusion rate (MIR) of alfaxalone required to prevent purposeful movement of the extremities in response to standardized noxious stimulation during its co-administration with fentanyl at three different doses by constant rate infusion (CRI) intravenously (IV) in goats. Study designProspective, blinded, randomized crossover, experimental. AnimalsEight healthy goats; four does and four wethers. MethodsFor induction of anaesthesia, a bolus of fentanyl was administered at 0.005 mg kg-1 (LFent), 0.015 mg kg-1 (MFent) or 0.03 mg kg-1 (HFent) followed by alfaxalone at 2.0 mg kg-1. For maintenance, the goats received alfaxalone at an initial infusion rate of 9.6 mg kg-1 hour-1 and one of three fentanyl treatments: 0.005 mg kg-1 hour-1(LFent), 0.015 mg kg-1 hour-1 (MFent) or 0.03 mg kg-1 hour-1 (HFent). The MIR of alfaxalone was determined during fentanyl CRI by testing for responses to stimulation (clamping on a digit with Vulsellum forceps) every 30 minutes. Some cardiopulmonary parameters were measured. ResultsThe alfaxalone MIR median (range) was 6.7 (6.7–8.6), 2.9 (1.0–6.7) and 1.0 (1.0–4.8) mg kg-1 hour-1 during LFent, MFent and HFent, respectively. Alfaxalone MIR was significantly lower during MFENT and HFENT compared to LFENT. Significantly low oxygen haemoglobin saturation (SaO2) and arterial oxygen partial pressure (PaO2), observed 2 minutes into anaesthesia after all fentanyl treatments, were the most remarkable adverse cardiopulmonary effects observed. Recovery from anaesthesia was severely affected by high doses of fentanyl with excitatory behavioural signs predominant for up to 2 hours post-administration after MFent and HFent. Conclusions and clinical relevanceFentanyl reduces alfaxalone MIR in goats in a dose-dependent manner. Immediate oxygen supplementation after induction of general anaesthesia is recommended to prevent hypoxaemia. Doses of fentanyl equal to or greater than 0.015 mg kg-1 hour-1 tend to be associated with severe excitatory behaviour and should be avoided when fentanyl is administered to goats.