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Delta waves (0.1-4 Hz) are a hallmark of unconsciousness in both sleep and general anesthesia (GA). Closed-loop auditory stimulation (CLAS) delivers brief sounds phase-locked to ongoing slow oscillations and can modulate slow-wave activity (SWA) during sleep, but its efficacy and translational relevance under propofol anesthesia, particularly in the presence of nociceptive input, remain unknown. We describe a prospective, within-subject protocol in 30 neurologically healthy adults undergoing elective surgery under propofol GA. Intraoperative high-density electroencephalography (hd-EEG; 128 channels) is recorded while a real-time CLAS algorithm detects -waves at the Fz electrode, and triggers pink-noise bursts in three conditions: (peak-locked), (trough-locked), and . An extended block is then combined with a standardized tetanic nociceptive stimulus (100 Hz, 70 mA, 30 s) to test robustness under an arousal challenge. Depth of hypnosis is monitored with the Bispectral Index (BIS), and nociceptive/autonomic reactivity with the Nociception Level (NOL) index. Primary outcomes quantify -wave morphology and SWA (amplitude, slopes, duration/frequency, transition frequency, density, power spectral density), along with topography, source estimation, and propagation. Secondary outcomes include depth of anesthesia (BIS), nociceptive balance (NOL), functional connectivity (weighted and directed phase-lag indices), graph-theoretical organization (global efficiency, clustering, modularity, small-worldness), and EEG microstates (duration, coverage, transitions). We hypothesize that CLAS will increase amplitude, slope, duration, and density of -waves, and decrease frequency and transition frequency relative to , whereas CLAS will cause a disruption these parameters relative to . Under nociception, CLAS is expected to these parameters preserve -wave integrity, with effects attenuated relative to non-nociceptive conditions. We anticipate BIS values to remain within the surgical range but trend lower during CLAS, alongside reduced nociceptive/autonomic responses. At the network level, we expect CLAS-induced -wave reinforcement to be associated with more locally coherent δ-band activity and reduced frontoparietal integration, consistent with deeper unconsciousness. If confirmed, these findings would position CLAS as a candidate neuromodulation strategy to reinforce anesthetic -wave dynamics and help stabilize anesthesia without necessarily increasing pharmacological dose, while also providing a systems-level test of the role of slow oscillations in sustaining unconsciousness.

The Nociception Level (NOL) index uses a multiparametric approach to measure the balance between sympathetic and parasympathetic systems activity. Recently, a strong correlation between the NOL index response to nociceptive stimuli and the level of opioid analgesia during surgery was reported. Others observed that intraoperative doses of remifentanil and sufentanil were reduced when the NOL index was used. So far, no study has evaluated the impact of NOL-guided fentanyl antinociception in laparoscopic gynecological surgery. The primary hypothesis of this present study was to evaluate whether intraoperative NOL-guided fentanyl administration would reduce intra-operative opioid consumption. Secondary hypotheses were to assess whether this would lead to lower postoperative opioid consumption and pain scores, as well as improved postoperative outcomes. University hospital, operating room. 70 adult patients, ASA 1–3, scheduled for total laparoscopic hysterectomy. Patients were randomized into 2 groups: SOC (standardization of care) and NOL (using the NOL index to guide the administration of fentanyl). The depth of anesthesia was monitored with BIS™. Intraoperative fentanyl boluses were administered based on heart rate and mean arterial pressure variations in the SOC group, and NOL index for the NOL group. Fentanyl total intraoperative dose administered was collected and also averaged per hour. Pain scores and hydromorphone consumption were assessed in the post-anesthesia care unit and up to 24 h. Sixty-six patients completed the study, 33 in each group. Total intraoperative fentanyl administration was not different between the two groups (217 (70) in the NOL group vs 280 (210) in the SOC group (P = 0.11)). Nevertheless, intraoperative fentanyl administration per hour was reduced by 25% in the NOL-guided group compared to the SOC group: 81 (24) vs 108 (66) μg.h−1, respectively (P = 0.03). Hydromorphone consumption and pain scores in the post-anesthesia care unit and at 24 h were not significantly different between the two groups. NOL-guided analgesia allowed for a 22% reduction of the total amount of intraoperative fentanyl which was not significant. Nevertheless, results reported a significant reduction by 25% in the doses of fentanyl averaged per hour of surgery and administered in the NOL-guided group compared with the standardized practice in laparoscopic gynecological surgery. The pain measured postoperatively was similar in the two groups while the average postoperative consumption of opioids to achieve the same level of pain scores in post-anesthesia care unit and at 24 h was not significantly reduced. Further larger multicenter studies centered towards postoperative outcomes are needed. •NOL index is a recently developped index to better assess intraoperative nociception level•NOL-guided intraoperative antinociception allows for rationalized and personalized management of opioids•In hysterectomies it resulted in a significant reduction of intraoperative doses of fentanyl per hour of surgery•No significant difference was seen on postoperative pain scores and analgesics' consumption•Larger studies must be proposed in the future, powered on these postoperative outcomes.

Propofol and sevoflurane are two anesthetic agents widely used to induce and maintain general anesthesia (GA). Their intrinsic antinociceptive properties remain unclear and are still debated. To determine whether propofol presents stronger antinociceptive properties than sevoflurane using intraoperative clinical and experimental noxious stimulations and evaluating postoperative pain outcomes. A prospective randomized monocentric trial. Perioperative care. 60 adult patients with ASA status I to III who underwent elective abdominal laparoscopic surgery under GA were randomized either in propofol or sevoflurane group to induce and maintain GA. We used clinical and experimental noxious stimulations (intubation, tetanic stimulation) to assess the antinociceptive properties of propofol and sevoflurane in patients under GA and monitored using the NOL index, BIS index, heart rate, and mean arterial blood pressure. We measured the difference in the NOL index alterations after intubation and tetanic stimulation during either intravenous anesthesia (propofol) or inhaled anesthesia (sevoflurane). We also intraoperatively measured the NOL index and remifentanil consumption and recorded postoperative pain scores and opioid consumption in the post-anesthesia care unit. Intraoperative management was standardized by targeting similar values of depth of anesthesia (BIS index), hemodynamic (HR and MAP), NOL index values (below the threshold of 20), same multimodal analgesia and type of surgery. We found the antinociceptive properties of propofol and sevoflurane similar. The only minor difference was after tetanic stimulation: the delta NOL was higher in the sevoflurane group (39 ± 13 for the propofol group versus 47 ± 15 for sevoflurane; P = 0.04). Intraoperative and postoperative pain outcomes and opioid consumption were similar between groups. Despite a precise intraoperative experimental and clinical protocol using the NOL index, propofol does not provide a higher level of antinociception during anesthesia or analgesia after surgery when compared to sevoflurane. Anesthesiologists may prefer propofol over sevoflurane to reduce PONV or anesthesia-related pollution, but not for superior antinociceptive properties. •Propofol and sevoflurane's intrinsic antinociceptive properties are not yet clear.•Objective measurement of intraoperative nociception using the multiparametric NOL index helps precisely evaluate noxious stimulations.•Propofol and sevoflurane intraoperative antinociceptive properties were found to be similar.•No difference was observed in postoperative pain scores and consumption of analgesics.

Background Residual neuromuscular blockade (rNMB) after surgery can lead to complications such as respiratory distress, increased length of hospital stay, and higher healthcare costs. Sugammadex, a selective relaxant-binding agent, has shown efficacy in reversing rocuronium-induced neuromuscular blockade more rapidly than neostigmine. This study aimed to evaluate the effectiveness of a low dose of sugammadex (0.5 mg.kg −1 ) compared to standard neostigmine with glycopyrrolate for the reversal of moderate rocuronium-induced neuromuscular blockade. Methods This randomized, double-blind, controlled trial included adult patients undergoing surgery with rocuronium-induced moderate neuromuscular blockade. Participants were randomized to receive either low-dose sugammadex or standard-dose neostigmine with glycopyrrolate at the end of surgery. The primary outcome was the time to achieve a Train-of-Four (TOF) ratio of ≥ 0.9 after administration of the reversal agent. Secondary outcomes included extubation time, incidence of sugammadex rescue therapy for incomplete reversal, and postoperative complications. Statistical analysis used t-tests and Mann–Whitney-Wilcoxon tests for continuous variables and chi-square tests for categorical variables, with significance set at p  < 0.05. Results The median time to reach TOF ratio of ≥ 0.9 was significantly shorter in the sugammadex group (4.3 min, IQR: 3.2–6) compared to the neostigmine group (20.6 min, IQR: 10.1–21.3, p  < 0.001). Extubation times were also reduced with sugammadex, with a median of 11.6 (IQR: 8.6–15.1) minutes versus 25.9 (IQR: 17.7–29.7) minutes in the neostigmine group ( p  < 0.001). Only 4.8% of patients in the sugammadex group required rescue therapy to reverse the neuromuscular block with TOF ratio of ≥ 0.9, compared to 60.6% in the neostigmine group ( p  < 0.001). No significant differences were observed in postoperative respiratory complications or PACU length of stay. Conclusions Low-dose sugammadex provides a faster and more reliable reversal of moderate neuromuscular blockade than standard-dose neostigmine, with implications for improved operating room efficiency and patient safety. Continuous neuromuscular monitoring remains essential, as a small proportion of patients may still require additional intervention. Trial registration Registered retrospectively at ClinicalTrials.gov with registration number NCT05718934 on 2023–02-08.

The number of elderly patients undergoing major surgery is rapidly increasing. They are particularly at risk of developing postoperative neurocognitive disorders (NCD). Earlier studies suggested that processed electroencephalographic (EEG) monitors may reduce the incidence of postoperative NCD. However, none of these studies controlled for intraoperative nociception levels or personalized blood pressure targets. Their results remain unclear if the reduction in the incidence of postoperative NCD relates to avoidance of any electroencephalographic pattern suggesting excessive anesthesia depth. The objective of this trial is to investigate-in patients ≥ 70 years old undergoing major non-cardiac surgery-the effect of EEG-guided anesthesia on postoperative NCD while controlling for intraoperative nociception, personalized blood pressure targets, and using detailed information provided by the EEG monitor (including burst suppression ratio, density spectral array, and raw EEG waveform). This prospective, randomized, controlled trial will be conducted in a single Canadian university hospital. Patients ≥ 70 years old undergoing elective major non-cardiac surgery will be included in the trial. The administration of sevoflurane will be adjusted to maintain a BIS index value between 40 and 60, to keep a Suppression Ratio (SR) at 0%, to keep a direct EEG display without any suppression time and a spectrogram with most of the EEG wave frequency within the alpha, theta, and delta frequencies in the EEG-guided group. In the control group, sevoflurane will be administered to achieve an age-adjusted minimum alveolar concentration of [0.8-1.2]. In both groups, a nociception monitor will guide intraoperative opioid administration, individual blood pressure targets will be used, and cerebral oximetry used to tailor intraoperative hemodynamic management. The primary endpoint will be the incidence of NCD at postoperative day 1, as evaluated by the Montreal Cognitive Assessment (MoCA). Secondary endpoints will include the incidence of postoperative NCD at different time points and the evaluation of cognitive trajectories up to 90 days after surgery among EEG-guided and control groups. NCT04825847 on ClinicalTrials.gov.

Recently, the nociceptive level index (NOL) was shown to more specifically and sensitively detect noxious stimuli during anesthesia, in comparison to previous methods that relied on such parameters as heart rate (HR) and mean blood pressure (MAP). An ongoing study (NCT#03410485) evaluates the intraoperative combination of both NOL and bispectral (BIS) indices to improve quality of recovery after colorectal surgery. Our ethical committee (REB approval #CER15083) initially agreed on an interim analysis of the data from the first 30 patients. More specifically, this present report analyzed all the intravenous phenylephrine (PE) boluses administered during anesthesia as part of our study protocol to see whether they had a significant impact on NOL values as well as other parameters: HR, MAP, BIS index. For this trial, remifentanil and phenylephrine were given in both groups based on a specific algorithm. All study parameters were recorded electronically. Our analysis for the present specific outcome evaluated NOL index for 30 s before the intravenous PE bolus (1 µg kg−1) was given and until 5 min afterwards. The average NOL values after PE bolus, as well as MAP, HR and BIS indices, were recorded and analyzed. A total of 178 events of PE boluses were identified for 28 patients (two were excluded). Median baseline NOL was 3 (1.8–8.3) CI 95% 5.7–8.7; post-PE bolus: 5.3 (2.7–9.9) (95% CI 6.6–8.9; Wilcoxon matched-pairs signed rank test (WMPSRT), P = 0.0003). When analyzing delta NOL (difference between pre- and post-PE bolus in NOL values) for each patient, the median delta NOL was 2.9 (1.2–6.1) (95% CI 3.6–5.5) with 95% of the subjects keeping a delta NOL under 10. MAP and HR values showed expected significant variations after PE bolus: a slight increase and slight decrease, respectively. BIS index values did not change after PE bolus. Our present results demonstrate that intravenous phenylephrine boluses of 1 µg kg−1 had the expected impact on hemodynamic parameters: a significant but very slight increase in MAP and decrease in HR, which might lack clinical relevance. Our report also demonstrates that these same phenylephrine boluses induce a statistically significant increase of the NOL index which does not seem to have much of a clinical relevance for the novel NOL index used to monitor intraoperative nociception as well as for the more classical BIS index for depth of anesthesia. Nevertheless, doses of intravenous PE bolus used in the present study (1 µg kg−1) might be regarded as smaller than more conventional ones (100–200 µg per bolus). Further studies need to be done with the latter doses.

During the perioperative period, nociception control is certainly one of the anesthesiologist's main objectives when assuming care of a patient. There exists some literature demonstrating that the nociceptive stimuli experienced during surgery are responsible for peripheral and central sensitization phenomena, which can in turn lead to persistent postsurgical pain. An individualized approach to the evaluation and treatment of perioperative nociception is beneficial in order to avoid the sensitization phenomena that leads to prolonged postoperative pain and to minimize the consumption of opiates and their adverse effects. In terms of sensitivity, specificity, and positive/negative predictive values when compared to heart rate (HR) and mean arterial pressure (MAP), recent literature has shown that the NOL variation (ΔNOL) is the best index to distinguish noxious from non-noxious stimuli. Chronic treatment with β1-adrenergic antagonists may constitute a limitation to the use of the NOL index. β1-adrenergic antagonists induce a depressive action on the heart rate, which results in a limitation of its variability after a noxious stimulus. Since heart rate and heart rate variability are two parameters integrated into the NOL index, the validity of the NOL index in a population of patients receiving β1-adrenergic antagonists has not yet been determined. Our study sought to explore the NOL index, the BIS, and the heart rate variation in a group of patients under chronic treatment with β1-adrenergic antagonists submitted to standardized noxious stimulus under general anesthesia. We then compared those results to a control group of patients from our previous study (CJA group) that received no β1-adrenergic antagonist chronic treatment. The patients in this study were subjected to a standardized anesthetic protocol from induction up to 3 min after a standardized tetanic stimulus to the ulnar nerve at a frequency of 100 Hz and an amperage of 70 mA, for a duration of 30 s. Data were electronically recorded to obtain NOL, BIS, and heart rate values every 5 s for the duration of the protocol. The NOL maximal mean value reached after noxious stimulation was not different between our two cohorts (CJA: 30(14) versus BETANOL: 36(14) (p = 0.12)). There was no statistically significant difference between our cohorts in regards of the NOL AUC representing the variation of the NOL over a 180 s period (CJA: 595(356) versus BETANOL: 634(301) (p = 0.30)). However, a repeated measurement ANCOVA identified slight statistically significant differences between our cohorts in the peak of variation of the NOL index between 20 and 65 s after noxious stimulation, the NOL index of the cohort of beta-blocked patients being higher than the CJA patients. Moreover, the time to reach the maximum value was not different (CJA: 73(37) versus BETANOL: 63(41) (p = 0.35)). NOL sensitivity and specificity to detect a noxious stimulus under general anesthesia were similar in patients taking beta-blockers or not, and were better than those of heart rate and Bispectral index (AUC NOL 0.97, CI(0.92–1), versus AUC BIS 0.78, CI(0.64–0.89) and AUC HR 0.66, CI(0.5–0.8)). In conclusion, the NOL index is a reliable monitor to assess nociception in a population of patients under chronic beta-blocker therapy. Patients under such therapy achieve similar maximal NOL values over a 180 s period after a standardized noxious stimulus and the NOL variation over time, represented by the AUC is not significantly different from a cohort of non-beta-blocked patients. Whether the patient takes beta-blockers or not, sensitivity of the NOL index is greater than that seen for BIS index or heart rate to detect an experimental noxious stimulus under general anesthesia.

Erythropoietin (Epo) is gaining interest in various neurological insults as a possible neuroprotective agent. We determined the effects of recombinant human Epo (rhEpo, 5000 IU per kg bw) on brain edema induced in rats by traumatic brain injury (TBI; impact-acceleration model; rhEpo administration 30 mins after injury). Magnetic resonance imaging (MRI) and a gravimetric technique were applied. In the MRI experiments, the apparent diffusion coefficient (ADC) and the tissue T1 relaxation time were measured hourly in the neocortex and caudoputamen, during a 6 h time span after TBI. In the gravimetric experiments, brain water content (BWC) was determined in these two regions, 6 h after TBI. Apparent diffusion coefficient measurements showed that rhEpo decreased brain edema early and durably. Gravimetric measurements showed that rhEpo decreased BWC at H6 in the neocortex as well as in the caudoputamen. No significant differences in ADC, in T1, or in BWC were found between rhEpo treated-TBI rats and sham-operated rats. Our findings show that post-traumatic administration of rhEpo can significantly reduce the development of brain edema in a model of diffuse TBI. Further studies should be conducted to identify the biochemical mechanisms involved in these immediate effects and to assess the use of rhEpo as a possible therapy for post-traumatic brain edema.

Background A reliable outcome prognostication tool for patients in coma of various etiologies would facilitate ICU treatment by providing objective information to caregivers and patients' relatives. This study aimed to predict outcome based on supervised machine learning and magnetic resonance diffusion tensor imaging (DTI) metrics. Methods In this multicenter international study, a training set of 531 patients not responding to simple orders at day 5 after coma onset underwent diffusion-weighted MRI between day 5 and 45. A classifier was developed using DTI metrics, patient age, and delay between admission and MRI as features. Unfavorable outcome (UFO) was defined as GOSE 1–4 at one year. Three prognosis areas were defined: a “red” zone (specificity for UFO above 95%), a “green” zone (specificity for favorable outcome, FO, above 90%), and a “no determination zone” (NDZ) for patients classified in neither the red or green zone. The classifier was validated on an external test set of 211 patients. Results The training set included 531 patients (age 48 ± 16 years; MRI at 19 ± 8 days post-injury), with 75.9% GOSE 1–4 and 24.1% GOSE 5–8 at one year. Normalized DTI metrics were FA 0.82 ± 0.12 and MD 1.10 ± 0.13. The external test set (n = 211; age 47 ± 16 years; MRI at 21 ± 12 days) showed similar outcome distribution (75.4% GOSE 1–4, 24.6% GOSE 5–8) and DTI values (FA 0.83 ± 0.09, MD 1.07 ± 0.12). Both sets were comparable in age, sex, initial GCS, and outcome ratios. In the external test set, ROC AUC was 0.89. For UFO classification, specificity was 98.1%, PPV 99.1%, and sensitivity 68.6%. For FO classification, specificity was 95.0%, PPV 77.8%, and NPV 86.3% whereas 30.8% of the patients were in the NDZ. After excluding patients for whom life sustaining therapies were withdrawn (n = 104), specificity was 96.6% and 82.4% for UFO and FO classification, respectively. Conclusion This classifier demonstrates a high specificity to predict coma outcome while patients are still in the ICU, irrespective of coma etiology. These results may assist practitioners in making informed decisions.