Determination of remifentanil in neonatal dried blood spots by liquid chromatography-tandem mass spectrometry.

Remifentanil is an ultra-short-acting synthetic opioid-class analgesic which might be increasingly used "off-label" as pain management during labour. Side effects in parturients during labour, and in the infant at birth are of particular concern, especially respiratory depression which is concentration-dependent, and can occur at levels as low as 3-5 ng mL-1. The safety of such use, particularly in newborns due to remifentanil placental transfer, has not been fully demonstrated yet, partly due to the lack of a suitable non-invasive analytical method. The aim of our work was to develop a sensitive method to monitor the levels of remifentanil in neonates by a non-invasive sampling of umbi lical cord blood to support efficacy and safety trials. The presented LC-MS method is sensitive enough to reliably quantify remifentanil in just 20 µL of blood at only 0.3 ng mL-1. The dried blood spot sample preparation included solvent extraction with subsequent solid-phase extraction. The method was validated in terms of accuracy, precision, recovery, matrix effect, and stability, and was successfully applied to a small pilot study. The estimated arterial blood concentrations at the time of delivery ranged from 0.2 to 0.3, and up to 0.9 ng mL-1 in neonatal, and maternal samples, respectively.

Effects of different plasma target concentrations of remifentanil on the MACBAR of sevoflurane in children with laparoscopic surgery.

BACKGROUND: To investigate the effects of different plasma target concentrations of remifentanil on the minimum alveolar concentration (MAC) for blocking adrenergic response (BAR) of sevoflurane in children with laparoscopic herniorrhaphy. METHODS: Seventy-five children with 3-7 years old scheduled for laparoscopic herniorrhaphy were randomly divided into group R0, group R1, and group R2 according to different remifentanil plasma target concentration (0, 1, and 2 ngml-1), respectively. The MACBAR of sevoflurane was determined by the up-and-down and sequential method in each group. The concentrations of epinephrine and noradrenaline were also determined at corresponding time points. RESULTS: A total of 52 child patients were used among the anticipated 75 patients. In groups R0, R1, and R2, the MACBAR of sevoflurane was (3.29 ± 0.17) %, (2.12 ± 0.10) % and (1.29 ± 0.11) %, respectively, and a significant difference was found among the three groups (P<0.05). The changes of epinephrine and noradrenaline concentrations in each group before and after insufflation of carbon dioxide pneumoperitoneum showed no significant differences. CONCLUSION: Remifentanil by target-controlled infusion can effectively reduce the MACBAR of sevoflurane during laparoscopic surgery in children. At a similar effect of MACBAR, both the changes of epinephrine and noradrenaline concentrations are not affected by the infusion of different remifentanil target concentrations. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn ( ChiCTR1800019393 , 8, Nov, 2018).

Multiplex detection of 14 fentanyl analogues and U-47700 in biological samples: Application to a panel of French hospitalized patients.

Synthetic opioids (SO) associated with the recent alarming increase of deaths and intoxications in United States of America and Europe are not detected by the usual first-line opiates drug screening assays. We developed a liquid chromatography tandem mass spectrometry analytical method for the multiplex detection of 14 fentanyl analogues (2-furanylfentanyl, 4-ANPP, 4-methoxybutyrylfentanyl, acrylfentanyl, alfentanil, carfentanil, despropionyl-2-fluorofentanyl, fentanyl, methoxyacetylfentanyl, norfentanyl, ocfentanil, remifentanil, sufentanil and valerylfentanyl) and U-47700 in whole blood and urine samples. The method was validated according to the requirements of ISO 15189. A simple and fast liquid-liquid extraction (LLE) with De-Tox Tube-A was performed leading to better recovery of molecules in urine than in blood samples. Depending on the compound, the limits of detection (LODs) ranged from 0.01 to 0.10 ng/mL and from 0.02 to 0.05 ng/mL in whole blood and urine, respectively. Calibration curves were linear in the range 0.5-50.0 ng/mL and the limit of quantification (LOQ) ranged from 0.10 to 0.40 ng/mL in blood. Internal quality controls at 1 and 40 ng/mL showed intra-day and between-day precision and accuracy bias below 10% in urine and 15% in blood. The method was applied to the screening of 211 urine samples from patients admitted in emergency or addiction departments. The presence of legal fentanyl analogues in 5 urine samples was justified by their therapeutic use as analgesics. Only one patient was concerned by fentanyl misuse and addiction whereas no illegal SO was detected. This study is not in favor of a huge misuse of SO in the Lorraine region.

Remifentanil and perioperative glycaemic response in cardiac surgery: an open-label randomised trial.

BACKGROUND: This study investigated whether remifentanil infusion decreased intraoperative hyperglycaemia and insulin resistance compared with intermittent fentanyl administration in patients undergoing elective cardiac surgery. METHODS: This was a randomised, prospective, open-label trial. Patients undergoing elective cardiac surgery (n=116) were randomised to receive either continuous intravenous remifentanil infusion or intermittent fentanyl boluses. Hourly blood glucose values were obtained for 24 h starting from induction of anaesthesia. The difference in percentage of patients with ≥2 intraoperative blood glucose concentrations >10 mM (180 mg dl-1) between the groups was the primary outcome measure. Secondary outcome measures included insulin requirements, select stress hormone and inflammatory cytokine concentrations, and safety events and adverse outcomes. RESULTS: The trial included 106 subjects in the final intention-to-treat analysis. There were fewer patients with ≥2 intraoperative blood glucose values >10 mM (180 mg dl-1) in the remifentanil group (17 [31.5%]) compared with the fentanyl group (33 [63.5%]) (relative risk: 0.50; 95% confidence interval [CI]: 0.32-0.77; P=0.001). The administered intraoperative insulin was a median of 8.1 units (range: 0-46.7) in the fentanyl group and 2.9 units (range: 0-35.1) in the remifentanil group (median difference=5 units; 95% CI: 1-7; P=0.004). Cortisol and adrenocorticotropic hormone were increased less in the remifentanil group (P<0.001), but there was no relative decrease in this group in select inflammatory cytokines. Postoperative measures of glycaemic control and adverse clinical outcomes were not significantly different between groups. CONCLUSIONS: Compared with patients treated with intermittent fentanyl, patients receiving continuous remifentanil infusion had fewer episodes of hyperglycaemia and less need for insulin administration during the intraoperative period of cardiac surgery. CLINICAL TRIAL REGISTRATION: NCT02349152.

Pharmacodynamic Interaction of Remifentanil and Dexmedetomidine on Depth of Sedation and Tolerance of Laryngoscopy.

BACKGROUND: Dexmedetomidine is a sedative with modest analgesic efficacy, whereas remifentanil is an opioid analgesic with modest sedative potency. Synergy is often observed when sedative-hypnotics are combined with opioid analgesics in anesthetic practice. A three-phase crossover trial was conducted to study the pharmacodynamic interaction between remifentanil and dexmedetomidine. METHODS: After institutional review board approval, 30 age- and sex- stratified healthy volunteers were studied. The subjects received consecutive stepwise increasing target-controlled infusions of dexmedetomidine, remifentanil, and remifentanil with a fixed dexmedetomidine background concentration. Drug effects were measured using binary (yes or no) endpoints: no response to calling the subject by name, tolerance of shaking the patient while shouting the name ("shake and shout"), tolerance of deep trapezius squeeze, and tolerance of laryngoscopy. The drug effect was measured using the electroencephalogram-derived "Patient State Index." Pharmacokinetic-pharmacodynamic modeling related the administered dexmedetomidine and remifentanil concentration to these observed effects. RESULTS: The binary endpoints were correlated with dexmedetomidine concentrations, with increasing concentrations required for increasing stimulus intensity. Estimated model parameters for the dexmedetomidine EC50 were 2.1 [90% CI, 1.6 to 2.8], 9.2 [6.8 to 13], 24 [16 to 35], and 35 [23 to 56] ng/ml, respectively. Age was inversely correlated with dexmedetomidine EC50 for all four stimuli. Adding remifentanil did not increase the probability of tolerance of any of the stimuli. The cerebral drug effect as measured by the Patient State Index was best described by the Hierarchical interaction model with an estimated dexmedetomidine EC50 of 0.49 [0.20 to 0.99] ng/ml and remifentanil EC50 of 1.6 [0.87 to 2.7] ng/ml. CONCLUSIONS: Low dexmedetomidine concentrations (EC50 of 0.49 ng/ml) are required to induce sedation as measured by the Patient State Index. Sensitivity to dexmedetomidine increases with age. Despite falling asleep, the majority of subjects remained arousable by calling the subject's name, "shake and shout," or a trapezius squeeze, even when reaching supraclinical concentrations. Adding remifentanil does not alter the likelihood of response to graded stimuli.

Protective effect of remifentanil on myocardial ischemia-reperfusion injury through Fas apoptosis signaling pathway.

OBJECTIVE: The aim of this study was to investigate the protective effect of remifentanil (RFT) on myocardial ischemia-reperfusion (IR) injury through Fas apoptosis signaling pathway. MATERIALS AND METHODS: A total of 36 Sprague-Dawley (SD) rats were randomly divided into 3 groups, including the sham operation (Sham) group, IR model (IR) group and RFT pretreatment (RFT) group, with 12 rats in each group. Myocardial tissues of rats in each group were collected. Hematoxylin and eosin (H&E) staining was used to examine the pathological differences of the myocardium in the three groups. The levels of lactate dehydrogenase (LDH), creatine kinase (CK), superoxide dismutase (SOD) and malondialdehyde (MDA) in the serum of rats in each group were detected by enzyme-linked immunosorbent assay (ELISA). Meanwhile, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was adopted to detect the apoptosis level of myocardial cells in each group. Furthermore, Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting were applied to measure the mRNA and protein expression levels of Fas and its pathway indexes, respectively. RESULTS: Compared with the Sham group, LDH and CK activities and MDA level in the IR group were significantly increased, whereas the level of SOD was remarkably decreased (p<0.05). Compared with the IR group, RFT pretreatment could significantly reduce the release of LDH and CK-muscle/brain (CK-MB), increase SOD level and decrease MDA level (p<0.05). TUNEL results manifested that the apoptosis rate of myocardial cells in the IR group was markedly increased than that of the Sham group (p<0.05). Meanwhile, the apoptosis rate of myocardial cells in the RFT group was notably decreased when compared with that of the IR group (p<0.05). ELISA results demonstrated that the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) proteins in the RTF group were significantly lower than those of the IR group (p<0.05). RT-PCR and Western blotting results indicated that the expressions of Fas, Fas ligand (FasL), and Fas-associated protein with death domain (FADD) in IR and RFT groups were significantly higher than those of the Sham group (p<0.05). However, RTF pretreatment could markedly reduce the levels of Fas, FasL, and FADD (p<0.05). CONCLUSIONS: RFT can reduce the apoptosis of myocardial cells as well as IR-induced oxidative stress and inflammation by inhibiting the Fas/FasL signal transduction pathway.

Performance of the Minto model for the target-controlled infusion of remifentanil during cardiopulmonary bypass.

We studied the predictive performance of the Minto pharmacokinetic model during cardiopulmonary bypass in patients undergoing cardiac surgery. Patients received remifentanil target-controlled infusion using the Minto model during total intravenous anaesthesia with propofol. From 56 patients, 275 arterial blood samples were drawn before, during and after bypass to determine the plasma concentration of remifentanil, and the predicted concentrations were recorded at each time. For pooled data, the median prediction error and median absolute prediction error were 21.3% and 21.8%, respectively, and 22.1% and 22.3% during bypass. Both were 148.4% during hypothermic circulatory arrest and measured concentrations were more than three times greater than predicted (26.9 (17.0) vs. 7.1 (1.6) ng.ml-1 ). The Minto model showed considerable bias but overall acceptable precision during bypass. The target concentration of remifentanil should be reduced when using the Minto model during hypothermic circulatory arrest.