The 90% effective dose (ED90) of remimazolam for inhibiting responses to the insertion of a duodenoscope during ERCP.

BACKGROUND: Compared to midazolam, remimazolam has a faster onset and offset of hypnotic effect, as well as cardiorespiratory stability, this study aims to determine the 90% effective dose (ED90) of remimazolam to inhibit responses to insertion of a duodenoscope during endoscopic retrograde cholangiopancreatography (ERCP). METHODS: A dose-response study was carried out undergoing ERCP who received remimazolam-alfentanil anesthesia using 10 µg/kg of alfentanil between September 2021 and November 2021. The initial dose of remimazolam was 0.2 mg/kg. The dose was then decided based on the responses of earlier patients by exploiting the sequential ascend and descend according to a 9: 1 biased coin design. Upon failure, the dose of remimazolam was increased by 0.025 mg/kg in the next patient. When the insertion was successful, the succeeding patient was randomized to an identical dose or a dose that was lower by 0.025 mg/kg.The ED90 of remimazolam for inhibiting responses to the insertion of a duodenoscope during ERCP was calculated. Adverse events and complications of remimazolam were recorded. RESULTS: A total of 55 elderly patients (age > 65) were included in the study. 45 successfully anesthetized patients, and 10 unsuccessfully. The ED90 of remimazolam was 0.300 mg/kg (95% CI = 0.287-0.320). ED95 was 0.315 (95% CI = 0.312-0.323) and ED99 was 0.323 (95% CI = 0.323-0.325). Among the patients, 9 patients developed hypotension, 2 patients developed bradycardia and 1 patient developed tachycardia, and hypoxia occurred in 2 patients. CONCLUSIONS: A loading dose of 0.300 mg / kg of remimazolam for elderly patients undergoing ERCP can safely, effectively, and quickly induce patients to fall asleep and inhibit responses to the insertion of a duodenoscope. TRIAL REGISTRATION: The study protocol was registered at the website ClinicalTrials.gov on 22/09/2021(NCT05053763).

Low-Dose Alfentanil Inhibits Sufentanil-Induced Cough During Anesthesia Induction: A Prospective, Randomized, Double-Blind Study.

Background: Cough is one of the most common complications following intravenous administration of sufentanil during anesthesia induction. The study aimed to investigate the protective effect of alfentanil, afentanyl derivative with short onset time and short duration, in reducing sufentanil-induced cough. Patients and methods: Eighty patients that scheduled for thyroid surgery under general anesthesia were randomly divided into the alfentanil group and normal saline group, with 40 cases per group. Patients in the alfentanil group received intravenous administration of 2 µg/kg alfentanil prior to sufentanil injection during general anesthesia induction, while the same dose of normal saline was administered in the normal saline group. The outcomes measures included the incidence and severity of cough and common side effects of opioids following the administration of sufentanil during the induction of general anesthesia, intraoperative hemodynamics parameters and major adverse events during anesthesia recovery period. Results: The incidence of cough within one minute after the injection of sufentanil during anesthesia induction was 40% in the normal saline group, and the pretreatment of alfentanil significantly reduced the incidence of sufentanil-induced cough to 5% (p < 0.05). Correspondingly, the patients in the alfentanil group had decreased severity of sufentanil-induced cough compared with the normal saline group (p < 0.05). No significant differences in the incidences of common side effects of opioids (dizziness, nausea and vomiting, chest tightness and respiratory depression) within one minute after sufentanil injection were found (p > 0.05). Furthermore, there were no significant differences between the two groups in intraoperative hemodynamic parameters, extubation time, or the incidences of emergence agitation, respiratory depression, delayed recovery from anesthesia and postoperative nausea and vomiting during Postanesthesia Care Unit stay (p > 0.05). Conclusion: Pretreatment with low-dose alfentanil (2 µg/kg) effectively and safely reduced both the incidence and severity of sufentanil-induced cough during anesthesia induction. Clinical Trial Registration Number: Chinese Clinical Trial Registry (identifier: ChiCTR2300069286).

The 90% effective concentration of alfentanil combined with 0.075% ropivacaine for epidural labor analgesia: a single-center, prospective, double-blind sequential allocation biased-coin design.

PURPOSE: More literature studies have reported that alfentanil is safe and effective for labor analgesia. However, there is no unified consensus on the optimal dosage of alfentanil used for epidural analgesia. This study explored the concentration at 90% of minimum effective concentration (EC90) of alfentanil combined with 0.075% ropivacaine in patients undergoing epidural labor analgesia to infer reasonable drug compatibility and provide guidance for clinical practice. METHODS: In this prospective, single-center, double-blind study, a total of 45 singleton term primiparas with vaginal delivery who volunteered for epidural labor analgesia were recruited. The first maternal was administered with 3 µg/mL alfentanil combined with 0.075% ropivacaine with the infusion of 10 mL of the mixture every 50 min at a background dose of 3 mL/h. In the absence of PCEA, a total of 15 mL of the mixture is injected per hour. The subsequent alfentanil concentration was determined on the block efficacy of the previous case, using an up-down sequential allocation with a bias-coin design. 30 min after epidural labor analgesia, the block of patient failed with visual analog score (VAS) > 3, the alfentanil concentration was increased in a 0.5 µg/mL gradient for the next patient, while the block was successful with VAS ≤ 3, the alfentanil concentration was remained or decreased in a gradient according to a randomized response list for the next patient. EC90 and 95% confidence interval were calculated by linear interpolation and prediction model with R statistical software. RESULTS: In this study, the estimated EC90 of alfentanil was 3.85 µg/mL (95% confidence interval, 3.64-4.28 µg/mL). CONCLUSION: When combined with ropivacaine 0.075%, the EC90 of alfentanil for epidural labor analgesia is 3.85 µg/mL in patients undergoing labor analgesia.

Randomized, Single-Blind, Comparative Study of Remimazolam Besylate vs Propofol for Facial Plastic Surgery.

BACKGROUND: Use of local anesthesia and conscious sedation with a combination of a sedative and anesthetic drug during a surgical procedure is an approach designed to avoid intubation, which produces fewer adverse events compared to general anesthesia. In the present study, a comparison was made between the efficacy and safety of remimazolam besylate and propofol for facial plastic surgery. OBJECTIVES: The objective was to evaluate the clinical efficacy, comfort, and incidence of adverse events of remimazolam compared with propofol combined with alfentanil in outpatient facial plastic surgery. METHODS: In this randomized, single-blind, single-center, comparative study, facial plastic surgery patients were randomly divided into remimazolam-alfentanil (n = 50) and propofol-alfentanil (n = 50) groups for sedation and analgesia. The primary endpoint was the incidence of hypoxemia, while secondary endpoints included efficacy and safety evaluations. RESULTS: There were no significant differences regarding the surgical procedure, sedation and induction times, pain and comfort scores, muscle strength recovery, heart rate, respiratory rate, and blood pressure, but the dosage of alfentanil administered to the remimazolam group (387.5 µg) was lower than that for the propofol group (600 µg). The incidence of hypoxemia (P = .046) and towing of the mandibular (P = .028), as well as wake-up (P = .027) and injection pain (P = .008), were significantly higher in the propofol group than the remimazolam group. CONCLUSIONS: Remimazolam and propofol had similar efficacies for sedation and analgesia during facial plastic surgery, but especially the incidence of respiratory depression was significantly lower in patients given remimazolam.

Prediction methods of drug-drug interactions of non-oral CYP3A4 substrates based on clinical interaction data after oral administrations - Validation with midazolam, alfentanil, and verapamil after intravenous administration and prediction for blonanserin transdermal patch.

Drug-drug interactions (DDI) have been examined for various drugs for oral use, but less for non-oral applications. This study provides DDI prediction methods for non-orally administered CYP3A4 substrates based on clinical DDI data of oral dosages. Gut availability (Fg) and fraction contribution of CYP3A4 to hepatic intrinsic clearance (fmCYP3A4) were predicted by AUC ratio (AUCR) in oral DDI study with/without grapefruit juice, and alteration in intrinsic clearances with/without ketoconazole, respectively. AUCRs of non-orally administered CYP3A4 substrates with/without inhibitors or inducers were predicted with the estimated Fg, fmCYP3A4 and changes in liver CYP3A4 activities with inhibitors/inducers predicted using Simcyp library. DDIs of intravenously administered midazolam and alfentanil with CYP3A4 inhibitors/inducers could be predicted well by this method with predicted AUCRs within ±64% of observed values. Moreover, maximum DDIs with strong CYP3A4 inducers could be predicted by comparing hepatic clearance with hepatic blood flow, as hepatic blood flow indicates the possible maximum hepatic clearance after strong enzyme induction. Predicted AUCRs of midazolam, alfentanil and R- and S-verapamil were less than, but not far from observed ratios, suggesting good conservative prediction. These methods were applied to blonanserin transdermal patch, suggesting much smaller interaction with CYP3A4 inhibitors/inducers compared to oral dosage of blonanserin.

Phenylpiperidine opioid effects on isoflurane minimum alveolar concentration in cats.

Different structurally related phenylpiperidine opioids exhibit different isoflurane-sparing effects in cats. Because minimum alveolar concentration (MAC) in cats is affected only by very high plasma concentrations of some phenylpiperidine opioids, we hypothesized these effects are caused by actions on nonopioid receptors. Using a prospective, randomized, crossover design, six cats were anesthetized with isoflurane, intubated, ventilated, and instrumented. Isoflurane MAC was measured in triplicate using a tail-clamp and bracketing technique. A computer-controlled intravenous infusion using prior pharmacokinetic models targeted plasma concentrations of 60 ng/ml fentanyl, 10 ng/ml sufentanil, or 500 ng/ml alfentanil, and isoflurane MAC was measured in duplicate. Next, naltrexone 0.6 mg/kg was administered to cats hourly during the opioid infusion, and isoflurane MAC was measured in duplicate. Blood was collected during MAC determinations to measure opioid concentrations. Responses were analyzed using repeated measures ANOVA with significance at p < .05. Alfentanil and sufentanil decreased isoflurane MAC by 16.4% and 6.4%, respectively, and these effects were completely reversed by naltrexone. Fentanyl had no significant effect on isoflurane MAC. Alfentanil and sufentanil modestly reduce isoflurane MAC via agonist effects on opioid receptors. However, these effects are too small to justify clinical use of phenylpiperidine opioids as single agents to reduce MAC in cats.

The Influence of Hemorrhagic Shock on the Disposition and Effects of Intravenous Anesthetics: A Narrative Review.

The need to reduce the dose of intravenous anesthetic in the setting of hemorrhagic shock is a well-established clinical dogma. Considered collectively,; the body of information concerning the behavior of intravenous anesthetics during hemorrhagic shock, drawn from animal and human data, confirms that clinical dogma and informs the rational selection and administration of intravenous anesthetics in the setting of hemorrhagic shock. The physiologic changes during hemorrhagic shock can alter pharmacokinetics and pharmacodynamics of intravenous anesthetics. Decreased size of the central compartment and central clearance caused by shock physiology lead to an altered dose-concentration relationship. For most agents and adjuncts, shock leads to substantially higher concentrations and increased effect. The notable exception is etomidate, which has relatively unchanged pharmacokinetics during shock. Increased concentrations lead to increased primary effect as well as increased side effects, notably cardiovascular effects. Pharmacokinetic changes are essentially reversed for all agents by fluid resuscitation. Propofol is unique among agents in that, in addition to the pharmacokinetic changes, it exhibits increased potency during shock. The pharmacodynamic changes of propofol persist despite fluid resuscitation. The persistence of these pharmacodynamic changes during shock is unlikely to be due to increased endogenous opiates, but is most likely due to increased fraction of unbound propofol. The stage of shock also appears to influence the pharmacologic changes. The changes are more rapid and pronounced as shock physiology progresses to the uncompensated stage. Although scant, human data corroborate the findings of animal studies. Both the animal and human data inform the rational selection and administration of intravenous anesthetics in the setting of hemorrhagic shock. The well-entrenched clinical dogma that etomidate is a preferred induction agent in patients experiencing hemorrhagic shock is firmly supported by the evidence. Propofol is a poor choice for induction or maintenance of anesthesia in severely bleeding patients, even with resuscitation; this can include emergent trauma cases or scheduled cases that routinely have mild or moderate blood loss.

Effect of electroacupuncture on sedation requirements during colonoscopy: a prospective placebo-controlled randomised trial.

INTRODUCTION: Propofol provides excellent sedation during colonoscopy. However, its application, namely when used together with an opioid, is associated with cardiopulmonary depression. Acupuncture is used nowadays for the treatment of pain and anxiety, and also to induce sedation. We hypothesised that electroacupuncture (EA) during colonoscopy would have sedative effects, thereby reducing propofol requirements to achieve an adequate level of sedation. METHOD: The study was designed and conducted as a single centre, patient and observer blinded, sham- and placebo-controlled randomised trial. Patients scheduled for elective colonoscopy under deep propofol/alfentanil sedation were randomly assigned to receive unilateral EA, sham-acupuncture (SA) or placebo-acupuncture (PA) at ST36, PC6 and LI4. The primary outcome parameter was the total dosage of propofol. Secondary outcomes included the patients' and endoscopists' satisfaction levels evaluated by questionnaires. RESULTS: The dosage of propofol required (median [IQR]) was not significantly different between the three groups (EA group 147 µg/kg/min [109-193] vs SA group 141 µg/kg/min [123- 180] vs PA group 141 µg/kg/min [112-182]; P=0.776). There was also no significant difference in alfentanil consumption (P=0.634). Global satisfaction (median [IQR]) among patients (EA group 6.6 [6.0-7.0] vs SA group 6.8 [6.0-7.0] vs PA group 6.5 [6.0-7.0]; P=0.481) and endoscopists (6.0 [5.0-6.0] for all groups; P=0.773) did not significantly differ between the three groups. There was no significant difference in the number of cardiorespiratory events. CONCLUSION: For colonoscopy, the applied mode of EA did not show any propofol-sparing sedative effect compared with sham or placebo acupuncture. TRIAL REGISTRATION: The trial is registered in the Netherland's Trial Registry (NTR4325).

Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults.

BACKGROUND: The application of modeling and simulation approaches in clinical pharmacology studies has gained momentum over the last 20 years. OBJECTIVES: The objective of this study was to develop six empirical models from clearance data obtained from children aged > 2 years and adults to evaluate the suitability of the models to predict drug clearance in children aged ≤ 2 years (preterm, term, and infants). METHODS: Ten drugs were included in this study and administered intravenously: alfentanil, amikacin, busulfan, cefetamet, meperidine, oxycodone, propofol, sufentanil, theophylline, and tobramycin. These drugs were selected according to the availability of individual subjects' weight, age, and clearance data (concentration-time data for these drugs were not available to the author). The chosen drugs are eliminated by extensive metabolism by either the renal route or both the renal and hepatic routes. The six empirical models were (1) age and body weight-dependent sigmoidal maximum possible effect (Emax) maturation model, (2) body weight-dependent sigmoidal Emax model, (3) uridine 5'-diphospho [body weight-dependent allometric exponent model (BDE)], (4) age-dependent allometric exponent model (ADE), (5) a semi-physiological model, and (6) an allometric model developed from children aged > 2 years to adults. The model-predicted clearance values were compared with observed clearance values in an individual child. In this analysis, a prediction error of ≤ 50% for mean or individual clearance values was considered acceptable. RESULTS: Across all age groups and the ten drugs, data for 282 children were compared between observed and model-predicted clearance values. The validation data consisted of 33 observations (sum of different age groups for ten drugs). Only three of the six models (body weight-dependent sigmoidal Emax model, ADE, and semi-physiological model) provided reasonably accurate predictions of clearance (> 80% observation with ≤ 50% prediction error) in children aged ≤ 2 years. In most instances, individual predicted clearance values were erratic (as indicated by % error) and were not in agreement with the observed clearance values. CONCLUSIONS: The study indicated that simple empirical models can provide more accurate results than complex empirical models.

The effectiveness of a low-dose esketamine versus an alfentanil adjunct to propofol sedation during endoscopic retrograde cholangiopancreatography: A randomised controlled multicentre trial.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is one of the most complex gastrointestinal endoscopic procedures. Currently, it is still unclear which sedation regimen best facilitates an ERCP. The N-methyl-D-aspartate receptor antagonist esketamine has anaesthetic, analgesic and sympathomimetic properties and is known to cause less cardiorespiratory depression than other sedatives. It could therefore be an ideal adjunct to propofol for deep sedation. OBJECTIVE: To assess the effectiveness of esketamine versus alfentanil as an adjunct to propofol target-controlled infusion (TCI) for deep sedation during ambulant ERCP. DESIGN: A randomised controlled multicentre study. SETTING: Endoscopic intervention suite at an academic and general hospital in the Netherlands. PARTICIPANTS: Adult, American Society of Anesthesiologists Physical Status I to III patients scheduled to undergo ERCP. INTERVENTION: Consecutive patients were randomly assigned to receive sedation for an ERCP with propofol TCI and alfentanil (group A) or with propofol TCI and esketamine (group E). MAIN OUTCOME MEASURES: The primary outcome was effectiveness of the sedation regimen expressed as the total dose of propofol - as a surrogate parameter - necessary to perform ERCP in a satisfactory manner for endoscopist and patients. Secondary outcomes were recovery time, patients' and endoscopists' satisfaction with sedation, side effects (e.g. psychotomimetic effects, nausea and vomiting) and the number of respiratory and cardiovascular adverse events. RESULTS: Data from 162 patients were analysed. The total dose of propofol required was significantly lower in group E (n=83) (8.3 mg kg h) than in group A (n=79) (10.5 mg kg h) (P < 0.001). There were no significant differences in recovery time, patients' and endoscopists' satisfaction, side effects, psychotomimetic effects and the number of sedation-related adverse events. CONCLUSION: Low-dose esketamine reduces the total amount of propofol necessary for sedation during ERCP in American Society of Anesthesiologists I and II patients without affecting recovery time, satisfaction of patients and endoscopists, side effects and respiratory or cardiovascular adverse events, when compared with alfentanil. TRIAL REGISTRATION: The Netherlands Trial Register (NTR5486).

Preterm Physiologically Based Pharmacokinetic Model. Part II: Applications of the Model to Predict Drug Pharmacokinetics in the Preterm Population.

BACKGROUND: Preterm neonates are usually not part of a traditional drug development programme, however they are frequently administered medicines. Developing modelling and simulation tools, such as physiologically based pharmacokinetic (PBPK) models that incorporate developmental physiology and maturation of drug metabolism, can be used to predict drug exposure in this group of patients, and may help to optimize drug dose adjustment. OBJECTIVE: The aim of this study was to assess and verify the predictability of a preterm PBPK model using compounds that undergo diverse renal and/or hepatic clearance based on the knowledge of their disposition in adults. METHODS: A PBPK model was developed in the Simcyp Simulator V17 to predict the pharmacokinetics (PK) of drugs in preterm neonates. Drug parameters for alfentanil, midazolam, caffeine, ibuprofen, gentamicin and vancomycin were collated from the literature. Predicted PK parameters and profiles were compared against the observed data. RESULTS: The preterm PBPK model predicted the PK changes of the six compounds using ontogeny functions for cytochrome P450 (CYP) 1A2, CYP2C9 and CYP3A4 after oral and intravenous administrations. For gentamicin and vancomycin, the maturation of renal function was able to predict the exposure of these two compounds after intravenous administration. All PK parameter predictions were within a twofold error criteria. CONCLUSION: While the developed preterm model for the prediction of PK behaviour in preterm patients is not intended to replace clinical studies, it can potentially help with deciding on first-time dosing in this population and study design in the absence of clinical data.

Evaluation of two different radiotherapy anaesthetic protocols for dogs: a randomized clinical crossover trial.

OBJECTIVES: To describe alfentanil-propofol admixture for induction of anaesthesia for canine radiotherapy and compare it to alfentanil-atropine followed by propofol induction in terms of heart rate (HR), mean arterial pressure (MAP), recovery duration and quality. STUDY DESIGN: Prospective, masked, randomized clinical crossover trial. ANIMALS: A group of 40 client-owned dogs anaesthetized from October 2017 to June 2018. METHODS: Dogs were randomly assigned to be administered one of two protocols. For both protocols, IV preanaesthetic medication was given 30 seconds before rapid IV administration of a set volume of induction agent, with further induction agent administered as needed to permit intubation. For protocol ADMIX, the preanaesthetic medication was 0.04 mL kg-1 0.9% sodium chloride and the induction agent was 0.2 mL kg-1 propofol-alfentanil admixture. For protocol ATRO, the preanaesthetic medication was 10 µg kg-1 alfentanil with 12 µg kg-1 atropine (0.04 mL kg-1 total volume) and the induction agent was 0.2 mL kg-1 propofol. Anaesthesia was maintained with sevoflurane. Cardiorespiratory variables, agitation, hypotension, or inadequate depth of anaesthesia requiring supplemental boluses of propofol or increased vaporizer settings were recorded. Time to extubation, sternal recumbency and walking was noted. Videos were recorded for recovery quality scoring. Owner questionnaires gave feedback about recoveries at home. The other protocol was administered for the next radiotherapy session. RESULTS: The only significantly different variable between protocols was mean HR during anaesthesia, which was lower in ADMIX (p < 0.001). Hypotension was recorded in seven (17.5%) dogs in ATRO and three (7.5%) in ADMIX, with an association (p < 0.005) between ATRO and hypotension. Owners reported animals recovered 'normal' behaviour and appetite by the next morning. CONCLUSIONS AND CLINICAL RELEVANCE: Both protocols were acceptable for dogs undergoing radiotherapy, with minimal differences in anaesthetic quality, recovery duration and quality. Although MAP did not differ overall, the incidence of hypotension was higher in ATRO.

Hemodynamic parameters and reproductive outcome after intracytoplasmic sperm injection and fresh embryo transfer in patients undergoing oocyte retrieval with general anesthesia using fentanyl, remifentanil or alfentanil - A randomized clinical trial.

OBJECTIVE: Anesthesia for assisted reproductive technology is very important to provide less stressful and painful environment for patients, with minimal side effects on oocytes. In the present study, we aimed to evaluate hemodynamic parameters, recovery time and intracytoplasmic sperm injection (ICSI) outcome among patients underwent anesthesia with fentanyl, remifentanil or alfentanil. MATERIAL AND METHODS: This randomized double-blinded clinical trial was conducted in patients undergoing anesthesia for transvaginal ultrasound guided oocyte retrieval (TUGOR). Patients were randomly allocated to alfentanil (A; 15 µg/kg), fentanyl (F; 1.5 µg/kg) or remifentanil (R; 1.5 µg/kg) groups. RESULTS: Three hundred forty patients were assessed for eligibility and randomized for transvaginal oocyte retrieval following general anesthesia and 105 were lost to follow up. No statistically significant differences were noted among groups regarding basic characteristics. Although, time to respond to verbal command was significantly different among groups (A: 1.99 ± 1.64, F: 2.56 ± 1.72, R: 1.78 ± 1.34, P = 0.014). There were no significant differences among groups with respect to the first and second postoperative pain intensity, patient satisfaction, pre-induction and post-induction systolic and diastolic blood pressure (BP). Terminal systolic (A: 101.61 ± 9.15, F: 105.29 ± 12.61, R: 102 ± 12.91, P = 0.01) and diastolic (A: 59.97 ± 9, F: 65.63 ± 9.13, R: 63.69 ± 11.01, P = 0.003) BP was significantly different among groups. The fertilization rate was significantly different among groups (A: 51.6%, F: 54.4%, R: 62.2%, P = 0.018). Implantation rate, biochemical and clinical pregnancy rate was similar among groups. CONCLUSIONS: The results of present study demonstrated that all three opioids have the same efficiency, in regards to patient satisfaction and pregnancy outcome. However, Anesthesia with alfentanil compared with fentanyl and remifentanil, seems to be inferior for TUGOR due to higher effect on fertilization rate and less hemodynamic stability. REGISTRATION NUMBER: IRCT201410258677N4.

Previously published drug interaction models predict loss of response for transoesophageal echocardiography sedation well but not response to oesophageal instrumentation.

Response surface models (RSMs) were used to predict effects of multiple drugs interactions. Our study was aimed to validate accuracy of the previous published volunteer models during transoesophageal echocardiography (TEE). This is a cross-sectional study with 20 patients scheduled for transesophageal echocardiography in Taipei Veterans General Hospital, Taiwan. Effect-site concentration pairs of alfentanil and propofol were recorded and converted to equivalent remifentanil and propofol effect-site concentrations. Observer's Assessment of Alertness/Sedation (OAA/S) scores were assessed every 2 minutes. Using these data, previous published models of loss of response (LOR), intolerable ventilatory depression (IVD), and loss of response to esophageal instrumentation (LREI) were then estimated. Accuracy of prediction is assessed by calculating the difference between the true response and the model-predicted probability. Clinical events such as interruption of TEE were recorded. The average procedure time was 11 minutes. Accuracy for prediction of LOR and LREI is 63.6% and 38.5%, respectively. There were four patients experienced desaturation for less than 1 minute, which were not predicted by IVD model, and one interruption of TEE due to involuntary movement. The previous published drug-interaction RSMs predict LOR well but not LREI for TEE sedation. Further studies using response surface methodology are needed to improve quality for TEE sedation and clinical implementation.

Plasma concentration based response surface model predict better than effect-site concentration based model for wake-up time during gastrointestinal endoscopy sedation.

BACKGROUND: Sedation for esophagogastroduodenoscopy (EGD) and colonoscopy is characterized by rapid patient induction and emergence. The drugs midazolam and alfentanil have long been used for procedural sedation; however, the relationship between plasma or effect-site concentrations (Cp or Ce, respectively) and emergence remains unclear. The aim of this study is to develop patient wake-up prediction models for both Cp and Ce using response surface modeling, a pharmacodynamics tool for assessing patients' responses. METHODS: The Observer's Alertness/Sedation (OAA/S) score was used to monitor sedation depth during the examinations. Concentration pairs of midazolam and alfentanil were calculated for each of Cp and Ce using pharmacokinetic simulation software. Response surface models were developed using the Greco construct. Temporal analysis was done by comparing model-predicted wake-up time with true patient wake-up time. RESULTS: Thirty-three patients with an average body mass index of 21.85 ± 2.3 kg/m2 were pooled for analysis. The average duration of examination were 2.9 ± 1.4 min for EGD and 6.6 ± 2.7 min for colonoscopy. Seventy-five concentration pairs of midazolam and alfentanil were obtained for each Cp and Ce. The Cp-based Greco response surface model showed significant synergy between midazolam and alfentanil and was a better predictor of patient wake-up time, with an average deviation of 1.0 ± 3.9 min, while the Ce model show time deviation greater than 20 min. CONCLUSION: The early phases of drug distribution are unique and complicated by nonsteady-state concentrations, and our study revealed that Ce-based wake-up time prediction is more difficult under these circumstances.

Pupillary Pain Index Changes After a Standardized Bolus of Alfentanil Under Sevoflurane Anesthesia: First Evaluation of a New Pupillometric Index to Assess the Level of Analgesia During General Anesthesia.

BACKGROUND: The pupillary pain index (PPI) is a novel pupillometric index, designed to assess intraoperative analgesia. It is based on the evaluation of the pupillary response to electrical stimuli of increasing intensity. It ranges from 1 (low level of pupillary reactivity, high level of analgesia) to 10 (high level of pupillary reactivity, low level of analgesia). In this first evaluation of the PPI, our objective was to investigate the PPI changes after a bolus of 10 µg·kg(-1) of alfentanil in children under sevoflurane general anesthesia. METHODS: After ethics committee approval and informed consent, 20 healthy children (9 ± 5 years) undergoing elective surgery under general anesthesia were included in this prospective, open, registered pilot study (NCT02646592). Anesthetic induction was standardized with sevoflurane 6% and propofol 1 mg·kg(-1). After tracheal intubation, sevoflurane concentration was maintained at 2% for 10 minutes. A first PPI measurement was performed (PPI-1), and a bolus of 10 µg·kg(-1) was administered. Two minutes after this bolus, a second PPI measurement was performed (PPI-2). Heart rate, blood pressure, and bispectral index were recorded before and after each PPI measurement. Resting pupillary diameter was recorded before each PPI measurement. PPI scores before and after the bolus of alfentanil were compared using a Wilcoxon signed rank test. RESULTS: PPI scores decreased after administration of a bolus of alfentanil (median difference: -3 [95% confidence interval, -4 to -2]). The median (quartiles) of PPI-1 (baseline, before alfentanil) was 6 (4, 7), and the median (quartiles) of PPI-2 (after alfentanil) was 2 (2, 3) (P < .001). No difference was found in resting pupillary diameter before PPI-1 and PPI-2 (2.2 ± 0.2 and 2.2 ± 0.3 mm, respectively; P = .86). There were no significant changes in heart rate or blood pressure after PPI measurements (P = .46 and .49, respectively). Bispectral index was slightly increased after PPI measurements (P = .01; mean bispectral index increase <5%). No withdrawal movements occurred during PPI measurements. CONCLUSIONS: There was a significant decrease in PPI after alfentanil administration. The results of this pilot study suggest that PPI score decreases when the level of analgesia increases. PPI measurement was not associated with a clinical or hemodynamic nociceptive response. This new index might provide useful information to individually adapt opioid administration before nociceptive stimuli under general anesthesia.

Patient response prediction with logistic regression in gastrointestinal endoscopy under midazolam-alfentanil sedation performed as well as response surface model.

BACKGROUND: Researchers have used logistic regression (LR) and non-linear response surface models (RSMs) to predict patient responses to sedation. The reduced Greco and hierarchy RSMs have proven to be more appropriate than other RSMs in gastrointestinal endoscopies using midazolam and alfentanil. In this study, we evaluate the performance of a simpler model, LR, and compared it with that of RSM. METHODS: Thirty-three patients who received esophagogastroduodenoscopy (EGD) and colonoscopy sedation with midazolam and alfentanil were enrolled in the study. LR was performed for the EGD group and validated using the colonoscopy group. The two RSMs were performed using the same process, and performances and receiver operating characteristic (ROC) curves of the models were evaluated. RESULTS: The native EGD LR model had an ROC curve area of 0.94. For external validation, the ROC curves were 0.92, 0.94, and 0.94 for the reduced Greco, hierarchy, and LR models, respectively. Pairwise comparison between models was not significant. CONCLUSION: The LR model performed as well as RSM in generalizing the predicted sedative effect of midazolam and alfentanil during gastrointestinal endoscopies. LR may be used for generalization across patients experiencing procedures with similar stimulus intensities.

Adaptation of non-linear mixed amount with zero amount response surface model for analysis of concentration-dependent synergism and safety with midazolam, alfentanil, and propofol sedation.

BACKGROUND: The non-linear mixed amount with zero amounts response surface model can be used to describe drug interactions and predict loss of response to noxious stimuli and respiratory depression. We aimed to determine whether this response surface model could be used to model sedation with the triple drug combination of midazolam, alfentanil and propofol. METHODS: Sedation was monitored in 56 patients undergoing gastrointestinal endoscopy (modelling group) using modified alertness/sedation scores. A total of 227 combinations of effect-site concentrations were derived from pharmacokinetic models. Accuracy and the area under the receiver operating characteristic curve were calculated. Accuracy was defined as an absolute difference <0.5 between the binary patient responses and the predicted probability of loss of responsiveness. Validation was performed with a separate group (validation group) of 47 patients. RESULTS: Effect-site concentration ranged from 0 to 108 ng ml-1 for midazolam, 0-156 ng ml-1 for alfentanil, and 0-2.6 µg ml-1 for propofol in both groups. Synergy was strongest with midazolam and alfentanil (24.3% decrease in U50, concentration for half maximal drug effect). Adding propofol, a third drug, offered little additional synergy (25.8% decrease in U50). Two patients (3%) experienced respiratory depression. Model accuracy was 83% and 76%, area under the curve was 0.87 and 0.80 for the modelling and validation group, respectively. CONCLUSION: The non-linear mixed amount with zero amounts triple interaction response surface model predicts patient sedation responses during endoscopy with combinations of midazolam, alfentanil, or propofol that fall within clinical use. Our model also suggests a safety margin of alfentanil fraction <0.12 that avoids respiratory depression after loss of responsiveness.

Electroacupuncture-reduced sedative and analgesic requirements for diagnostic EUS: a prospective, randomized, double-blinded, sham-controlled study.

BACKGROUND AND AIMS: The role of electroacupuncture (EA) in reducing sedative and analgesic requirements during EUS is uncertain. The aim of this study was to investigate the efficacy of EA in reducing procedure-related pain and discomfort during EUS. METHODS: This was a double-blinded randomized controlled study conducted between March 2014 and July 2016. Consecutive patients who were scheduled for diagnostic EUS were recruited and randomized to receive EA or sham-electroacupuncture (SA). The primary outcome was the dosage of propofol used. Other outcome measurements included pain scores, anxiety scores, satisfaction scores, patients' willingness to repeat the procedure, total procedure time, and adverse events. RESULTS: A total of 128 patients were recruited to the study. The patients who received EA had significantly fewer requirements for patient-controlled sedation and analgesia (PCA). The median (interquartile range) number of demands for PCA (2 [1-5] vs 16.5 [8.5-33.8]; P < .001), the number of successful demands (2 [1-4] vs 9 [5.3-13]; P < .001), and the total dose of propofol (0.15 [0.08-0.34] vs 0.77 [0.38-1.09]; P < .001) and alfentanil (0.38 [0.20-0.86] vs 1.92 [0.94-2.72]; P < .001) were all significantly less. Patients who received EA also had significantly lower procedural pain scores and anxiety scores (P < .001), and higher satisfaction scores (P < .001), and they were more willing to repeat the procedure (P < .001). Being in the SA group and the procedure time were significant predictors of increased PCA demands (P < .001 and P = .009, respectively). CONCLUSIONS: In conclusion, the use of EA reduced sedative and analgesia demands, improved patient experience, and was associated with a low risk of adverse events during diagnostic EUS. (Clinical trial registration number: NCT02066194.).

A randomized double-blind controlled trial comparing three sedation regimens during flexible bronchoscopy: Dexmedetomidine, alfentanil and lidocaine.

INTRODUCTION: No standardized sedation protocol is available for flexible bronchoscopy (FB). OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of three regimens used for sedation during FB. METHODS: This randomized double-blind controlled trial assessed patients undergoing bronchoscopy and receiving lidocaine alone (C) or combined with dexmedetomidine (D) or alfentanil (A). Tolerance was assessed using the bronchoscopy score, and level of sedation was assessed using the Nursing Instrument for the Communication of Sedation. Safety was evaluated in terms of pulmonary function and vital signs. RESULTS: A total of 162 patients were enrolled. The bronchoscopy score was identical in all groups. Group D subjects were the most sedated (P = .013), whereas group A subjects were the least agitated. Linear regression showed a negative association between bronchoscopy score and age in A (ß = -0.06; P = .001). Positive predictors of bronchoscopy score were female gender (ß = 1.96; P = .003) in D and obesity (ß = 2.41; P = .012), longer procedures (ß = 0.08; P = .009) and female gender (ß = 1.15; P = .038) in C. Longer procedures (ß = -0.12; P = .010) was a negative predictor of bronchoscopy score in D. Desaturation, hypoxia and heart rate changes were most prevalent in group A. Hypotension was mostly observed in D. CONCLUSIONS: No consistent differences were present between the three regimens; however, each was more appropriate in certain patient profiles. We consequently proposed a protocol as a first step towards standardizing sedation practice in FB in a patient-tailored manner. A more comprehensive and detailed protocol including other sedative agents with their corresponding doses should be developed.