Repeated complete atrioventricular block during remifentanil administration in a pediatric patient with brain tumor and acute hydrocephalus: a case report.

BACKGROUND: Remifentanil, an ultra-short-acting µ-opioid receptor agonist, is commonly used for anesthetic management due to excellent adjustability. Remifentanil is known to cause sinus bradycardia, however, because it has a direct negative chronotropic effect on the cardiac conduction system and there is an indirect negative chronotropic effect via the parasympathetic nervous system. CASE PRESENTATION: An 8-year-old Japanese boy was diagnosed with acute hydrocephalus due to a brain tumor in the fourth ventricle and underwent emergency surgery. Imaging examination showed brainstem compression. Endoscopic third ventriculostomy and ventriculoperitoneal shunt surgery were scheduled. Remifentanil was started during induction of general anesthesia, but electrocardiogram showed sinus bradycardia, then Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was immediately discontinued, and we administered atropine sulfate. Complete atrioventricular block was restored to sinus rhythm. When remifentanil was restarted, however, the electrocardiogram again showed sinus bradycardia, Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was again immediately discontinued, we administered adrenaline, and then complete atrioventricular block was restored to sinus rhythm. Fentanyl was used instead of remifentanil with continuous infusion of dopamine. There has since been no further occurrence of complete atrioventricular block. CONCLUSIONS: This is the first known case of complete atrioventricular block in a pediatric patient with increased intracranial pressure seemingly caused by administration of remifentanil.

Remifentanil-induced hyperalgesia: the current state of affairs.

Remifentanil-induced hyperalgesia (RIH) is a part of a general opioid-induced hyperalgesia (OIH) syndrome, seemingly resulting from abrupt cessation of continuous remifentanil infusion at rates equal or exceeding 0.3 mcg/kg/min. The intricate mechanisms of its development are still not completely understood. However, hyperactivation of the N -methyl d -aspartate receptor system, descending spinal facilitation and increased concentration of dynorphin (a κ-opioid ligand) are commonly proposed as possible mechanisms. Several ways of prevention and management have been suggested, such as slow withdrawal of remifentanil infusion, the addition of propofol, pretreatment with or concomitant administration of ketamine, buprenorphine, cyclooxygenase-2 inhibitors (NSAIDs), methadone, dexmedetomidine. In clinical and animal studies, these strategies exhibited varying success, and many are still being investigated.

Serotonin Syndrome After Prolonged Remifentanil and Propofol Infusion for Craniotomy: A Case Report.

Serotonin syndrome (SS) is a life-threatening condition caused by serotonergic medications. We describe a unique case of SS likely caused by prolonged exposure to propofol and remifentanil alone. A young male presented for vestibular schwannoma resection. Several hours into the case, the patient demonstrated hyperthermia and hemodynamic instability, followed by clonus, rigidity, shivering, and tachycardia after emergence. SS was diagnosed using Hunter's criteria and improved with supportive measures. While the patient endorsed a history of methamphetamine use, his urine drug screen was negative. The possibility of SS should be considered when administering propofol and remifentanil, particularly with prolonged infusions.

Hypotension after general anaesthesia induction using remimazolam or propofol in geriatric patients undergoing sevoflurane anaesthesia with remifentanil: a single-centre, double-blind, randomised controlled trial.

BACKGROUND: The occurrence of hypotension after induction of general anaesthesia is common in geriatric patients, and should be prevented to minimise perioperative complications. Compared with propofol, remimazolam potentially has a lower incidence of hypotension. This study aimed to compare the incidence of hypotension after general anaesthesia induction with remimazolam or propofol in geriatric patients. METHODS: This single-centre, double-blind, randomised trial enrolled 90 patients aged ≥80 yr who received general anaesthesia for scheduled surgery. Patients were randomised to receive remimazolam (12 mg kg-1 h-1) or propofol (0.025 mg kg-1 s-1) for anaesthesia induction, with remifentanil and sevoflurane. The presence or absence of hypertension on the ward served as the stratification factor. The incidence of hypotension after the induction of general anaesthesia, defined as a noninvasive mean arterial pressure of <65 mm Hg measured every minute from initiation of drug administration to 3 min after tracheal intubation, was the primary outcome. Subgroup analysis was performed for the primary outcome using preoperative ward hypertension, clinical frailty scale, Charlson Comorbidity Index, and age. RESULTS: Three subjects were excluded before drug administration, and 87 subjects were included in the analysis. The incidence of hypotension was 72.1% (31/43) and 72.7% (32/44) with remimazolam or propofol, respectively. No statistically significant differences (adjusted odds ratio, 0.96; 95% confidence interval, 0.37-2.46; P=0.93) were observed between groups. Subgroup analysis revealed no significant differences between groups. CONCLUSIONS: Compared with propofol, remimazolam did not reduce the incidence of hypotension after general anaesthesia induction in patients aged ≥80 yr. CLINICAL TRIAL REGISTRATION: UMIN000042587.

Puerarin attenuates remifentanil­induced postoperative hyperalgesia via targeting PAX6 to regulate the transcription of TRPV1.

Remifentanil­induced hyperalgesia (RIH) is characterized by the emergence of stimulation­induced pain, including phenomena such as allodynia and thermal hyperalgesia following remifentanil infusion. As a sequence­specific DNA binding transcription factor, PAX6 positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system. It was hypothesized that puerarin could relieve RIH via targeting PAX6 to regulate transcription of transient receptor potential cation channel subfamily V Member 1 (TRPV1). A total of 32 rats were randomly divided into five groups, namely control group, RI group, RI + 10 mg/kg puerarin group (RI + puerarin10), RI + 20 mg/kg puerarin group (RI + puerarin20), and RI + 40 mg/kg puerarin group (RI + puerarin40). Mechanical and thermal hyperalgesia were tested at ­24, 2, 6, 24 and 48 h after remifentanil infusion. Following the sacrifice of rats after the last behavioral test, western blot was used to detect the expression levels of TRPV1 in the tissues; Immunofluorescence staining and western blotting were used to detect the expression of PAX6 in the spinal cord. PharmMapper and JASPAR were used to predict the binding sites of puerarin/PAX6/TRPV1. Chromatin immunoprecipitation­PCR and dual luciferase reporter assay were used to verify the targeting relationship between PAX6 and TRPV1. Immunofluorescence was used to detect the expression levels of TRPV1 and p­NR2B. The results revealed that puerarin (10, 20, 40 mg/kg) dose­dependently reduced thermal and mechanical hyperalgesia from 2 to 48 h after remifentanil infusion. Remifentanil infusion remarkably stimulated the expression of phosphorylated (p­)NR2B. Nevertheless, the increased amount of p­NR2B by RIH was dose­dependently suppressed by puerarin in rats. In conclusion, puerarin was revealed to attenuate postoperative RIH via targeting PAX6 to regulate the transcription of TRPV1.

The Relationship between Pre-Anesthetic Analgesia and Nociception (ANI) and Propofol Injection Pain among Patients Receiving Remifentanil: A Prospective, Randomized, Controlled Study.

Background and Objectives: The analgesia/nociception index (ANI) potentially monitors nociceptive status during anesthesia, but its link to preoperative pain sensitivity is unclear. We investigated the relationship between pre-anesthetic ANI scores and propofol injection pain (PIP) in patients receiving remifentanil. Materials and Methods: This study included 124 male patients aged 19-60 undergoing general anesthesia (ASA class I or II). Patients were randomized to group R (n = 62, remifentanil 4 ng/mL) or group C (n = 62, saline). The primary outcome was the association between PIP and ANI. Secondary outcomes included the incidence and severity of PIP or rocuronium-induced withdrawal movement (RIWM) and their association with ANI. Results: PIP and RIWM incidence and severity were lower in group R than in group C. A weak negative correlation between PIP and ANI at pre-induction (rpb = -0.21, p = 0.02, rpb = -0.37, p < 0.01) and a moderate negative correlation during propofol injection (rpb = -0.48, p = 0.02) were observed. A significant negative correlation was found between RIWM and ANI during rocuronium injection (τb = -0.61, p < 0.01). AUC, cut-off value, specificity, and sensitivity in ANI at pre-induction for predicting PIP were 0.67 (p = 0.02), 59, 76%, and 55%, respectively. AUC, cut-off value, specificity, and sensitivity in ANI during propofol injection for PIP were 0.77 (p < 0.01), 65, 81%, and 67%, respectively. Conclusions: ANI scores demonstrated significant differences between groups, suggesting potential predictive value for PIP despite the low pre-induction AUC value. This study highlights the potential of using ANI scores to predict and manage PIP in patients receiving remifentanil.

Postoperative pain after different doses of remifentanil infusion during anaesthesia: a meta-analysis.

BACKGROUND: This meta-analysis aimed to explore the correlation between the different doses of remifentanil-based anaesthesia and postoperative pain in randomised trials. METHODS: The electronic databases including PubMed, Cochrane, clinical trial registries, and Google Scholar were searched up to November 2022 for randomised controlled trials (RCTs) that assessed the dose dependent efficacy of remifentanil for postoperative pain intensity and hyperalgesia. RESULTS: 31 studies involving 2019 patients were included for analysis. Compared with the high remifentanil dose administration, patients in low doses showed less postoperative pain intensity at 1-2 h (weighted mean differences (WMD): 0.60, 95% CI, 0.05 to 1.15), 3-8 h (WMD: 0.38, 95% CI, 0.00 to 0.75), 24 h (WMD: 0.26, 95% CI, 0.04 to 0.48) and 48 h (WMD: 0.32, 95% CI, 0.09 to 0.55). Remifentanil-free regimen failed to decrease the pain score at 24 h (WMD: 0.10, 95% CI, -0.10 to 0.30) and 48 h (WMD: 0.15, 95% CI, -0.22 to 0.52) in comparison with remifentanil-based anaesthesia. After excluding trials with high heterogeneity, the dose of the remifentanil regimen was closely correlated with the postoperative pain score (P=0.03). In addition, the dose of the remifentanil regimen was not associated with the incidence of postoperative nausea and vomiting (PONV) (P=0.37). CONCLUSIONS: Our meta-analysis reveals that the low dose of remifentanil infusion is recommendable for general anaesthesia maintenance. No evidence suggests that remifentanil-free regimen has superiority in reducing postoperative pain. Moreover, remifentanil doesn't have a dose dependent effect in initiating PONV. TRIAL REGISTRATION: The protocol of present study was registered with PROSPERO (CRD42022378360).

Remifentanil-induced hyperalgesia in healthy volunteers: a systematic review and meta-analysis of randomized controlled trials.

ABSTRACT: Recent literature suggests that the withdrawal of remifentanil (RF) infusion can be associated with hyperalgesia in clinical and nonclinical settings. We performed a systematic review and a meta-analysis of randomized controlled trials with cross-over design, to assess the effect of discontinuing RF infusion on pain intensity and areas of hyperalgesia and allodynia in healthy volunteers. Nine studies were included. The intervention treatment consisted in RF infusion that was compared with placebo (saline solution). The primary outcome was pain intensity assessment at 30 ± 15 minutes after RF or placebo discontinuation, assessed by any pain scale and using any quantitative sensory testing. Moreover, postwithdrawal pain scores were compared with baseline scores in each treatment. Secondary outcomes included the areas (% of basal values) of hyperalgesia and allodynia. Subjects during RF treatment reported higher pain scores after discontinuation than during treatment with placebo [standardized mean difference (SMD): 0.50, 95% confidence interval (CI): 0.03-0.97; P = 0.04, I 2 = 71%]. A significant decrease in pain scores, compared with baseline values, was found in the placebo treatment (SMD: -0.87, 95% CI: -1.61 to -0.13; P = 0.02, I 2 = 87%), but not in the RF treatment (SMD: -0.28, 95% CI: -1.18 to 0.62; P = 0.54, I 2 = 91%). The area of hyperalgesia was larger after RF withdrawal (SMD: 0.55; 95% CI: 0.27-0.84; P = 0.001; I 2 = 0%). The area of allodynia did not vary between treatments. These findings suggest that the withdrawal of RF induces a mild but nonclinically relevant degree of hyperalgesia in HVs, likely linked to a reduced pain threshold.

Remimazolam and Remifentanil Use Induced Severe Respiratory Depression and Laryngeal Spasm During Intravenous Sedation and Analgesia: A Case Report.

INTRODUCTION: Intravenous sedation and analgesia are widely used in minor surgeries. Remifentanil and remimazolam are advantageous in this setting because of their rapid onset of action, and short duration of action leading to a rapid recovery. However, the two drugs combined need to be titrated to avoid airway-related adverse events. CASE PRESENTATION: This article reports a case of severe respiratory depression and severe laryngeal spasm induced by remifentanil and remimazolam when they were used for analgesia and sedation in a patient undergoing oral biopsy. CONCLUSION: We aim to improve awareness about the safety of these drugs among anesthesiologists and increase their ability to manage the risk associated with their use.

SIRT2 overexpression decreases remifentanil-stimulated post-surgical hyperalgesia via microglia.

Remifentanil (Remi)-induced hyperalgesia is a serious but common postoperative clinical problem. Sirtuin 2 (SIRT2) is essential in the pathogenetic mechanisms of several neurological disorders. However, whether SIRT2 contributes to the modulation of Remi-induced postsurgical hyperalgesia (POH) is unknown. Here, we investigated the regulatory potential of SIRT2 in Remi-stimulated POH. A rat Remi-stimulated POH model was built by infusing Remi in the surgical incision. Mechanical allodynia and thermal hyperalgesia were separately assessed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) measurements. SIRT2 and binding adaptor molecule 1 (Iba1) protein expressions and localization in spinal cord samples were detected by western blot and immunofluorescence. The results revealed SIRT2 downregulation in the spinal cord of rats with Remi-stimulated POH. Intrathecal administration of the overexpression plasmid harboring SIRT2 remarkably relieved mechanical allodynia, along with thermal hyperalgesia in the model animals. Iba1 amounts were increased upon intraoperative incision or Remi infusion, and this effect was more pronounced upon combining both treatments. Furthermore, SIRT2 overexpression suppressed microglia activation in the spinal cord of model animals, and starkly relieved incision- and/or Remi-associated pronociceptive processes as well as spinal microglia activation. SIRT2 elevation relieved Remi-associated POH, likely by suppressing spinal microglia activation. Thus, SIRT2 could be a potent target for treating neuropathic pain.

Opioid infusions at different times of the day produce varying degrees of opioid-induced hyperalgesia.

BACKGROUND: Opioids are metabolised by enzymes the activities of which vary with the circadian rhythm. We examined whether opioid infusions administered at different times of the day produce varying degrees of opioid-induced hyperalgesia (OIH) in animal experiments and clinical studies. METHODS: Male Sprague-Dawley rats received remifentanil infusions (1 µg kg-1·min-1 for 1 h) at Zeitgeber times (ZT) 0, 4, 8, 12, 16, or 20 h. Rhythmicity of mechanical hypersensitivity was assayed after the infusion. Mechanical hypersensitivity, drug concentration, and metabolic enzyme activity of Wistar rats that received sufentanil (10 µg kg-1; four consecutive i.p. injections at 15-min intervals) or remifentanil infusion at ZT0 or ZT8 were assayed. Sixty patients who underwent abdominal laparoscopic surgery under general anaesthesia received remifentanil infusion (0.15 µg kg-1 min-1) and sufentanil injection (0.2 µg kg-1) at induction and skin incision, respectively. Postoperative pressure pain sensitivity, pain Numeric Rating Scale (NRS), drug concentrations, and nonspecific esterase activity were assessed. RESULTS: Sprague-Dawley rats that received remifentanil infusion exhibited a robust rhythmic paw withdrawal threshold (JTK_CYCLE: P=0.001, Q=0.001, Phase=26). Wistar rats infused with remifentanil or sufentanil at ZT8 exhibited greater OIH (P<0.001) than those infused at ZT0, with higher blood concentrations (P<0.001) and lower metabolic enzyme activities (P=0.026 and P=0.028, respectively). Patients in the afternoon group exhibited higher pressure pain sensitivity at forearm (P=0.002), higher NRS (P<0.05), higher drug concentrations (sufentanil: P=0.037, remifentanil: P=0.005), and lower nonspecific esterase activity (P=0.024) than the morning group. CONCLUSIONS: Opioid infusions administered at different times of day produced varying degrees of OIH, possibly related to circadian rhythms of metabolic enzyme activities. CLINICAL TRIAL REGISTRATION: NCT05234697.

General purpose models for intravenous anesthetics, the next generation for target-controlled infusion and total intravenous anesthesia?

PURPOSE OF REVIEW: There are various pharmacokinetic-dynamic models available, which describe the time course of drug concentration and effect and which can be incorporated into target-controlled infusion (TCI) systems. For anesthesia and sedation, most of these models are derived from narrow patient populations, which restricts applicability for the overall population, including (small) children, elderly, and obese patients. This forces clinicians to select specific models for specific populations. RECENT FINDINGS: Recently, general purpose models have been developed for propofol and remifentanil using data from multiple studies and broad, diverse patient groups. General-purpose models might reduce the risks associated with extrapolation, incorrect usage, and unfamiliarity with a specific TCI-model, as they offer less restrictive boundaries (i.e., the patient "doesn't fit in the selected model") compared with the earlier, simpler models. Extrapolation of a model can lead to delayed recovery or inadequate anesthesia. If multiple models for the same drug are implemented in the pump, it is possible to select the wrong model for that specific case; this can be overcome with one general purpose model implemented in the pump. SUMMARY: This article examines the usability of these general-purpose models in relation to the more traditional models.

Fetal, Preterm, and Term Neonate Exposure to Remifentanil: A Systematic Review of Efficacy and Safety.

BACKGROUND: Owing to its pharmacodynamic properties, especially the rapid onset and short duration of its action, the use of remifentanil in obstetric anesthesia, as well as in neonatology, might be increasingly used. OBJECTIVE: We conducted a systematic review to assess the efficacy and safety of remifentanil in preterm and term neonates. Outcomes of interest were neonatal adaptation after fetal exposure; neonatal pain, distress, and discomfort control during invasive procedures; and the occurrence of hemodynamic effects or respiratory depression induced by remifentanil infusion. METHODS: Given the different contexts of use, we have organized this work into three parts: (A) use of remifentanil for labor or cesarean section, with exposure of the fetus before birth, (B) brief use for neonatal procedural analgesia, and (C) prolonged use for sedation/analgesia of neonates. The bibliographic search was conducted based on keywords using electronic medical databases (DATABASE, Cochrane Library, PubMed, and EMBASE) from 1 January 2000 until 31 December 2022. RESULTS: Twenty-two articles were included (10 in part A, 5 in part B and 7 in part C). Prospective, controlled, randomized, blinded, and intention-to-treat trials were retained. Neonates were well adapted after exposure to remifentanil in the fetal period. Pain, stress, and discomfort were controlled during a brief or prolonged invasive procedure when remifentanil was used for sedation/analgesia. The physiological parameters were stable and the procedures were straightforward. Chest wall rigidity appeared to be a common side effect, but this can be managed by slow and continuous infusion and by using the minimum effective dose. CONCLUSIONS: Remifentanil appears to be effective and safe in the short term in preterm and full-term neonates. However, its safety is compromised by the risk of chest wall rigidity. It should be used in appropriate neonatal units and in the presence of physicians able to monitor its side effects. Long-term outcomes have not been evaluated, to our knowledge.

Association between intraoperative remifentanil use and postoperative hyperalgesia in adolescent idiopathic scoliosis surgery: a retrospective study.

BACKGROUND: The liberal use of remifentanil in spine surgery has been associated with an increased incidence of postoperative hyperalgesia. Nevertheless, controversies remain as the existing evidence is inconclusive to determine the relationship between remifentanil use and the development of opioid-induced hyperalgesia. We hypothesized that intraoperative infusion of higher dose remifentanil during scoliosis surgery is associated with postoperative hyperalgesia, manifesting clinically as greater postoperative morphine consumption and pain scores. METHODS: Ninety-seven patients with adolescent idiopathic scoliosis (AIS) who underwent posterior spinal fusion surgery at a single tertiary institution from March 2019 until June 2020 were enrolled in this retrospective study. Anesthesia was maintained using a target-controlled infusion of remifentanil combined with volatile anesthetic desflurane in 92 patients, while five patients received it as part of total intravenous anesthesia. Intravenous ketamine, paracetamol, and fentanyl were administered as multimodal analgesia. All patients received patient-controlled analgesia (PCA) morphine postoperatively. Pain scores at rest and on movement, assessed using the numerical rating scale, and the cumulative PCA morphine consumption were collected at a six-hourly interval for up to 48 h. According to the median intraoperative remifentanil dose usage of 0.215 µg/kg/min, patients were divided into two groups: low dose and high dose group. RESULTS: There were no significant differences in the pain score and cumulative PCA morphine consumption between the low and high dose remifentanil group. The mean duration of remifentanil infusion was 134.9 ± 22.0 and 123.4 ± 23.7 min, respectively. CONCLUSION: Intraoperative use of remifentanil as an adjuvant in AIS patients undergoing posterior spinal fusion surgery was not associated with postoperative hyperalgesia.

Effect of Remifentanil vs Neuromuscular Blockers During Rapid Sequence Intubation on Successful Intubation Without Major Complications Among Patients at Risk of Aspiration: A Randomized Clinical Trial.

Importance: It is uncertain whether a rapid-onset opioid is noninferior to a rapid-onset neuromuscular blocker during rapid sequence intubation when used in conjunction with a hypnotic agent. Objective: To determine whether remifentanil is noninferior to rapid-onset neuromuscular blockers for rapid sequence intubation. Design, Setting, and Participants: Multicenter, randomized, open-label, noninferiority trial among 1150 adults at risk of aspiration (fasting for <6 hours, bowel occlusion, recent trauma, or severe gastroesophageal reflux) who underwent tracheal intubation in the operating room at 15 hospitals in France from October 2019 to April 2021. Follow-up was completed on May 15, 2021. Interventions: Patients were randomized to receive neuromuscular blockers (1 mg/kg of succinylcholine or rocuronium; n = 575) or remifentanil (3 to 4 µg/kg; n = 575) immediately after injection of a hypnotic. Main Outcomes and Measures: The primary outcome was assessed in all randomized patients (as-randomized population) and in all eligible patients who received assigned treatment (per-protocol population). The primary outcome was successful tracheal intubation on the first attempt without major complications, defined as lung aspiration of digestive content, oxygen desaturation, major hemodynamic instability, sustained arrhythmia, cardiac arrest, and severe anaphylactic reaction. The prespecified noninferiority margin was 7.0%. Results: Among 1150 randomized patients (mean age, 50.7 [SD, 17.4] years; 573 [50%] women), 1130 (98.3%) completed the trial. In the as-randomized population, tracheal intubation on the first attempt without major complications occurred in 374 of 575 patients (66.1%) in the remifentanil group and 408 of 575 (71.6%) in the neuromuscular blocker group (between-group difference adjusted for randomization strata and center, -6.1%; 95% CI, -11.6% to -0.5%; P = .37 for noninferiority), demonstrating inferiority. In the per-protocol population, 374 of 565 patients (66.2%) in the remifentanil group and 403 of 565 (71.3%) in the neuromuscular blocker group had successful intubation without major complications (adjusted difference, -5.7%; 2-sided 95% CI, -11.3% to -0.1%; P = .32 for noninferiority). An adverse event of hemodynamic instability was recorded in 19 of 575 patients (3.3%) with remifentanil and 3 of 575 (0.5%) with neuromuscular blockers (adjusted difference, 2.8%; 95% CI, 1.2%-4.4%). Conclusions and Relevance: Among adults at risk of aspiration during rapid sequence intubation in the operating room, remifentanil, compared with neuromuscular blockers, did not meet the criterion for noninferiority with regard to successful intubation on first attempt without major complications. Although remifentanil was statistically inferior to neuromuscular blockers, the wide confidence interval around the effect estimate remains compatible with noninferiority and limits conclusions about the clinical relevance of the difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03960801.

Unwanted spontaneous responsiveness and burst suppression in patients undergoing entropy-guided total intravenous anesthesia with target-controlled infusion: An observational prospective trial.

STUDY OBJECTIVE: To estimate the incidence of unwanted spontaneous responsiveness and burst suppression (BSupp) in patients undergoing state entropy (SE) and surgical pleth index (SPI)-guided total intravenous anesthesia (TIVA) with target-controlled infusion (TCI). DESIGN: Observational, prospective, single-center study. SETTINGS: Operating room. PATIENTS: 107 adult (<65 years) and elderly (≥65 years) women undergoing breast surgery. INTERVENTIONS: Propofol-remifentanil TIVA-TCI-guided by SE for depth of anesthesia monitoring (target value 40-60) and SPI for antinociception monitoring (target value 20-50) without neuromuscular blockade. MEASUREMENTS: Age; body mass index; American Society of Anesthesiologists physical status classification; concentration at the effect site of propofol (CeP) and remifentanil (CeR) at loss of responsiveness (LoR), median during anesthesia maintenance (MdM), and at return of responsiveness (RoR); propofol infusion duration; incidence of postoperative delirium (POD) with Confusing Assessment Method for the Intensive Care Unit. MAIN RESULTS: During SE-SPI-guided TIVA-TCI, 13.1% of patients showed unwanted spontaneous responsiveness, whereas 45.8% showed BSupp. Unwanted spontaneous responsiveness was observed mainly in adults (p < 0.05), and higher CeP RoR (p < 0.05) was registered. BSupp was observed mainly in patients showing a lower CeP MdM (p < 0.01) and CeP RoR (p < 0.05). Unwanted spontaneous responsiveness and BSupp were not associated with significant differences in CeRs. An age-related hysteresis effect was observed, resulting in higher CeP LoR than CeP RoR (p < 0.001). 12.2% of patients showed POD. Only preoperative serum albumin was associated with increased likelihood of POD (p = 0.046). CONCLUSIONS: The SE-SPI-guided TIVA-TCI did not prevent unwanted spontaneous responsiveness and BSupp. CeP RoR may be used as a proxy for anesthetic sensitivity.

Opioid-induced hyperalgesia: Are thalamic T-type calcium channels treatment targets?

Opioid-induced hyperalgesia (OIH) is a state of paradoxically enhanced pain transmission, termed nociceptive sensitization, described to occur in both humans and animals after repeated administration of opioid drugs, including rapidly acting remifentanil. However, molecular mechanisms of OIH remain understudied. In this issue of the JCI, Yan Jin and colleagues provided strong evidence that hyperexcitable thalamocortical networks drive remifentanil-induced hyperalgesia in a rodent model of postsurgical pain. Furthermore, the authors specifically identified an important role of the CaV3.1 isoform of low-voltage-activated or T-type calcium channels (T-channels) in this process. Further experiments are needed to determine whether thalamic T channels could serve as targets for the treatment of OIH.

Thalamocortical circuits drive remifentanil-induced postoperative hyperalgesia.

Remifentanil-induced hyperalgesia (RIH) is a severe but common postoperative clinical problem with elusive underlying neural mechanisms. Here, we discovered that glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPLGlu) exhibited significantly elevated burst firing accompanied by upregulation of Cav3.1 T-type calcium channel expression and function in RIH model mice. In addition, we identified a glutamatergic neuronal thalamocortical circuit in the VPL projecting to hindlimb primary somatosensory cortex glutamatergic neurons (S1HLGlu) that mediated RIH. In vivo calcium imaging and multi-tetrode recordings revealed heightened S1HLGlu neuronal activity during RIH. Moreover, preoperative suppression of Cav3.1-dependent burst firing in VPLGlu neurons or chemogenetic inhibition of VPLGlu neuronal terminals in the S1HL abolished the increased S1HLGlu neuronal excitability while alleviating RIH. Our findings suggest that remifentanil induces postoperative hyperalgesia by upregulating T-type calcium channel-dependent burst firing in VPLGlu neurons to activate S1HLGlu neurons, thus revealing an ion channel-mediated neural circuit basis for RIH that can guide analgesic development.

Moderate sedation with dexmedetomidine-remifentanil is safer than deep sedation with propofol-remifentanil for endobronchial ultrasound while providing comparable quality: a randomized double-blind trial.

OBJECTIVE: We compared dexmedetomidine-remifentanil vs. propofol-remifentanil in terms of safety and quality during sedation for Endobronchial ultrasonography (EBUS). METHODS: A randomized, double-blind trial. Outpatients undergoing EBUS randomly received 1 µg/kg/hour dexmedetomidine or a target concentration of 2.5 µg/mL propofol, both combined with remifentanil initially targeted at 1.5 ng/mL and subsequently titrated. Additional sedatives were restricted. The primary outcome was the need for airway rescue interventions to treat oxygen desaturation. RESULTS: Twenty-eight patients received dexmedetomidine-remifentanil and 27 received propofol-remifentanil. Airway rescue interventions were fewer in the dexmedetomidine group vs. the propofol one (23 vs. 76% patients, relative risk 3.21 (95% CI 1.55-6.64, P < 0.002)). Desaturation in the dexmedetomidine group was always resolved by increasing nasal oxygen flow, whereas additional interventions were needed in 60% of patients receiving propofol. Hypotension was more frequent in the propofol group, while hypertension, bradycardia and coughing were similar in both. Bronchoscopists' and patients' satisfaction were similar, although in the dexmedetomidine group two patients needed additional sedatives and two patients would not repeat the sedation technique. CONCLUSION: Moderate sedation with dexmedetomidine-remifentanil for EBUS is safer than deep sedation with propofol-remifentanil but it would occasionally need additional sedatives to ensure patient satisfaction.