Prevention of persistent pain with lidocaine infusions in breast cancer surgery (PLAN): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Persistent pain is a common yet debilitating complication after breast cancer surgery. Given the pervasive effects of this pain disorder on the patient and healthcare system, post-mastectomy pain syndrome (PMPS) is becoming a larger population health problem, especially as the prognosis and survivorship of breast cancer increases. Interventions that prevent persistent pain after breast surgery are needed to improve the quality of life of breast cancer survivors. An intraoperative intravenous lidocaine infusion has emerged as a potential intervention to decrease the incidence of PMPS. We aim to determine the definitive effects of this intervention in patients undergoing breast cancer surgery. METHODS: PLAN will be a multicenter, parallel-group, blinded, 1:1 randomized, placebo-controlled trial of 1,602 patients undergoing breast cancer surgery. Adult patients scheduled for a lumpectomy or mastectomy will be randomized to receive an intravenous 2% lidocaine bolus of 1.5 mg/kg with induction of anesthesia, followed by a 2.0 mg/kg/h infusion until the end of surgery, or placebo solution (normal saline) at the same volume. The primary outcome will be the incidence of persistent pain at 3 months. Secondary outcomes include the incidence of pain and opioid consumption at 1 h, 1-3 days, and 12 months after surgery, as well as emotional, physical, and functional parameters, and cost-effectiveness. DISCUSSION: This trial aims to provide definitive evidence on an intervention that could potentially prevent persistent pain after breast cancer surgery. If this trial is successful, lidocaine infusion would be integrated as standard of care in breast cancer management. This inexpensive, widely available, and easily administered intervention has the potential to reduce pain and suffering in an already afflicted patient population, decrease the substantial costs of chronic pain management, potentially decrease opioid use, and improve the quality of life in patients. TRIAL REGISTRATION: This trial has been registered on clinicaltrials.gov (NCT04874038, Dr. James Khan. Date of registration: May 5, 2021).

Using the nociception level index to compare the intraoperative antinociceptive effect of propofol and sevoflurane during clinical and experimental noxious stimulus in patients under general anesthesia.

STUDY: 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. OBJECTIVE: To determine whether propofol presents stronger antinociceptive properties than sevoflurane using intraoperative clinical and experimental noxious stimulations and evaluating postoperative pain outcomes. DESIGN: A prospective randomized monocentric trial. SETTING: Perioperative care. PATIENTS: 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. INTERVENTIONS: 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. MEASUREMENTS: 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. MAIN RESULTS: 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. CONCLUSIONS: 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.

Prevalence and Risk Factors for Chronic Postsurgical Pain after Cardiac Surgery: A Single-center Prospective Cohort Study.

BACKGROUND: Chronic postsurgical pain is a common complication of surgery. The role of psychologic risk factors like depression and anxiety is substantially understudied in cardiac surgery. This study sought to identify perioperative factors associated with chronic pain at 3, 6, and 12 months after cardiac surgery. The authors hypothesize that baseline psychologic vulnerabilities have a negative influence on chronic postsurgical pain. METHODS: The authors prospectively collected demographic, psychologic, and perioperative factors in a cohort of 1,059 patients undergoing cardiac surgery at the Toronto General Hospital between 2012 and 2020. Patients were followed and completed chronic pain questionnaires at 3, 6, and 12 months after surgery. RESULTS: The study included 767 patients who completed at least one follow-up questionnaire. The incidence of postsurgical pain (more than 0 out of 10) at 3, 6, and 12 months after surgery was 191 of 663 (29%), 118 of 625 (19%), and 89 of 605 (15%), respectively. Notably, among patients reporting any pain, the incidence of pain compatible with a neuropathic phenotype increased from 56 of 166 (34%) at 3 months to 38 of 97 (39%) at 6 months and 43 of 67 (64%) at 12 months. Factors associated with postsurgical pain scores at 3 months include female sex, pre-existing chronic pain, previous cardiac surgery, preoperative depression, baseline pain catastrophizing scores, and moderate-to-severe acute pain (4 or more out of 10) within 5 postoperative days. CONCLUSIONS: Nearly one in three patients undergoing cardiac surgery reported pain at 3 months of follow-up, with approximately 15% reporting persistent pain at 1 yr. Female sex, pre-existing chronic pain, and baseline depression were associated with postsurgical pain scores across all three time periods.

Prediction of acute postoperative pain based on intraoperative nociception level (NOL) index values: the impact of machine learning-based analysis.

The relationship between intraoperative nociception and acute postoperative pain is still not well established. The nociception level (NOL) Index (Medasense, Ramat Gan, Israel) uses a multiparametric approach to provide a 0-100 nociception score. The objective of the ancillary analysis of the NOLGYN study was to evaluate the ability of a machine-learning aglorithm to predict moderate to severe acute postoperative pain based on intraoperative NOL values. Our study uses the data from the NOLGYN study, a randomized controlled trial that evaluated the impact of NOL-guided intraoperative administration of fentanyl on overall fentanyl consumption compared to standard of care. Seventy patients (ASA class I-III, aged 18-75 years) scheduled for gynecological laparoscopic surgery were enrolled. Variables included baseline demographics, NOL reaction to incision or intubation, median NOL during surgery, NOL time-weighted average (TWA) above or under manufacturers' recommended thresholds (10-25), and percentage of surgical time spent with NOL > 25 or < 10. We evaluated different machine learning algorithms to predict postoperative pain. Performance was assessed using cross-validated area under the ROC curve (CV-AUC). Of the 66 patients analyzed, 42 (63.6%) experienced moderate to severe pain. NOL post-intubation (42.8 (31.8-50.6) vs. 34.8 (25.6-41.3), p = 0.05), median NOL during surgery (13 (11-15) vs. 11 (8-13), p = 0.027), percentage of surgical time spent with NOL > 25 (23% (18-18) vs. 20% (15-24), p = 0.036), NOL TWA < 10 (2.54 (2.1-3.0) vs. 2.86 (2.48-3.62), p = 0.044) and percentage of surgical time spent with NOL < 10 (41% (36-47) vs. 47% (40-55), p = 0.022) were associated with moderate to severe PACU pain. Corresponding ROC AUC for the prediction of moderate to severe PACU pain were 0.65 [0.51-0.79], 0.66 [0.52-0.81], 0.66 [0.52-0.79], 0.65 [0.51-0.79] and 0.67 [0.53-0.81]. Penalized logistic regression achieved the best performance with a 0.753 (0.718-0.788) CV-AUC. Our results, even if limited by the small number of patients, suggest that acute postoperative pain is better predicted by a multivariate machine-learning algorithm rather than individual intraoperative nociception variables. Further larger multicentric trials are highly recommended to better understand the relationship between intraoperative nociception and acute postoperative pain.Trial registration Registered on ClinicalTrials.gov in October 2018 (NCT03776838).

Definition and refinement of HYlaDO, a self-hypnosis training program for chronic pain management: A qualitative exploratory study.

One in four Canadians is affected by chronic pain, frequently treated with opioids, which present a risk of addiction and overdose. The development of non-pharmacological interventions is therefore crucial. In a pilot project, a self-hypnosis training program showed encouraging results in improving breast cancer patients' quality of life. Based on this program, we developed a new self-hypnosis program for chronic pain patients: HYlaDO (Hypnosis of pain in French, HYpnose de la DOuleur). To structure the process of adapting an existing program to a new context, we used the ORBIT model (Obesity-Related Behavioral Intervention Trials), which consists of four development phases. This study aimed to collect patients' opinions and recommendations, and to refine HYlaDO (ORBIT Phase Ib). Fifteen participants took part in individual semi-structured interviews about this program. Two analysts coded the verbatims, and a thematic categorization was performed. Six themes emerged: practice training, expected vs. perceived effects, chronic pain management, individual practice, satisfaction, and participants' recommendations. Improvements to be considered in this type of program were finally discussed.

A new machine learning algorithm to predict veno-arterial ECMO implantation after post-cardiotomy low cardiac output syndrome.

BACKGROUND: Post-cardiotomy low cardiac output syndrome (PC-LCOS) is a life-threatening complication after cardiac surgery involving a cardiopulmonary bypass (CPB). Mechanical circulatory support with veno-arterial membrane oxygenation (VA-ECMO) may be necessary in the case of refractory shock. The objective of the study was to develop a machine-learning algorithm to predict the need for VA-ECMO implantation in patients with PC-LCOS. PATIENTS AND METHODS: Patients were included in the study with moderate to severe PC-LCOS (defined by a vasoactive inotropic score (VIS) > 10 with clinical or biological markers of impaired organ perfusion or need for mechanical circulatory support after cardiac surgery) from two university hospitals in Paris, France. The Deep Super Learner, an ensemble machine learning algorithm, was trained to predict VA-ECMO implantation using features readily available at the end of a CPB. Feature importance was estimated using Shapley values. RESULTS: Between January 2016 and December 2019, 285 patients were included in the development dataset and 190 patients in the external validation dataset. The primary outcome, the need for VA-ECMO implantation, occurred respectively, in 16% (n = 46) and 10% (n = 19) in the development and the external validation datasets. The Deep Super Learner algorithm achieved a 0.863 (0.793-0.928) ROC AUC to predict the primary outcome in the external validation dataset. The most important features were the first postoperative arterial lactate value, intraoperative VIS, the absence of angiotensin-converting enzyme treatment, body mass index, and EuroSCORE II. CONCLUSIONS: We developed an explainable ensemble machine learning algorithm that could help clinicians predict the risk of deterioration and the need for VA-ECMO implantation in moderate to severe PC-LCOS patients.

Identification of the intraoperative antinociceptive effect of intravenous fentanyl using the Nociception Level (NOL) index versus clinical parameters in patients undergoing gynecological laparoscopic surgery: A secondary analysis of the NOLGYN study.

BACKGROUND: While we typically assess nociception balance during general anesthesia through clinical parameters such as heart rate (HR) and mean arterial pressure (MAP) variation, these parameters are not specific to nociception. OBJECTIVE: We hypothesized that using the Nociception Level (NOL) index to assess the analgesic effect of a fentanyl bolus would be superior to standard clinical parameters. DESIGN: Ancillary study of the NOLGYN study, a randomized controlled trial comparing intraoperative NOL-guided administration of fentanyl (NOL group) versus standardized care (SC group). SETTING: University hospital in Montréal, Canada between November 2018, and December 2019. PATIENTS: Women undergoing gynecological laparoscopic surgery. INTERVENTION: In our evaluation of intraoperative nociception, we analyzed the analgesic effect of fentanyl using three parameters: MAP, HR, and the Nociception Level (NOL) index. All fentanyl injection events were extracted from the database. MAIN OUTCOME MEASURE: The primary endpoint was the difference between values before and after each injection. RESULTS: The median of the NOL index before fentanyl injection was 30.5 (IQR 19.4 to 40.7) versus 18.9 (IQR 11.5 to 27.4) after (P < 0.001). The median of MAP was 106.4 mmHg (IQR 99.9 to 113.4) before injection versus 103.2 mmHg (IQR 97.5-110.7) after (P < 0.001). The median of HR before injection was 74.2 (IQR 64.2-83.8) versus 72.4 (IQR 63.4-81.3) after (P < 0.001). CONCLUSIONS: The NOL index, HR, and MAP all statistically discriminated the analgesic effect of fentanyl but only the NOL index proved clinically relevant to identify the analgesic effect of one fentanyl injection. TRIAL REGISTRATION: www. CLINICALTRIALS: gov (NCT03776838) registered in October 2018.

Impact of Processed Electroencephalography in Cardiac Surgery: A Retrospective Analysis.

OBJECTIVE: The use of brain function monitoring with processed electroencephalography (pEEG) during cardiac surgery is gaining interest for the optimization of hypnotic agent delivery during the maintenance of anesthesia. The authors sought to determine whether the routine use of pEEG-guided anesthesia is associated with a reduction of hemodynamic instability during cardiopulmonary bypass (CPB) separation and subsequently reduces vasoactive and inotropic requirements in the intensive care unit. DESIGN: This is a retrospective cohort study based on an existing database. SETTING: A single cardiac surgical center. PARTICIPANTS: Three hundred patients undergoing cardiac surgery, under CPB, between December 2013 and March 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred and fifty patients had pEEG-guided anesthesia, and 150 patients did not have a pEEG-guided anesthesia. Multiple logistic regression demonstrated that pEEG-guided anesthesia was not associated with a successful CPB separation (p = 0.12). However, the use of pEEG-guided anesthesia reduced by 57% the odds of being in a higher category for vasoactive inotropic score compared to patients without pEEG (odds ratio = 0.43; 95% confidence interval: 0.26-0.73; p = 0.002). Duration of mechanical ventilation, fluid balance, and blood losses were also reduced in the pEEG anesthesia-guided group (p < 0.003), but there were no differences in organ dysfunction duration and mortality. CONCLUSION: During cardiac surgery, pEEG-guided anesthesia allowed a reduction in the use of inotropic or vasoactive agents at arrival in the intensive care unit. However, it did not facilitate weaning from CPB compared to a group where pEEG was unavailable. A pEEG-guided anesthetic management could promote early vasopressor weaning after cardiac surgery.

Effect of combined intraoperative use of the Nociception Level (NOL) and bispectral (BIS) indexes on desflurane administration.

BACKGROUND: Currently, nociception monitors are not part of standard anaesthesia care. We investigated whether combined intraoperative nociception (NOL index) and anaesthesia (BIS index) monitoring during general anaesthesia would reduce anaesthetics consumption and enhance intraoperative safety and postoperative recovery when compared to standard of care monitoring (SOC). METHODS: In this randomised study, we included 60 patients undergoing colonic surgery under desflurane/remifentanil anaesthesia and epidural analgesia. Patients received either standard monitoring or combined BIS + NOL index monitoring. In the monitored group, remifentanil infusion was titrated to achieve a NOL index below 20. Desflurane was adjusted to BIS values (45-55). In the SOC group, remifentanil and desflurane were titrated on vital signs and MAC. The primary outcome was intraoperative desflurane consumption. RESULTS: Fifty-five patients were analysed. Desflurane administration was reduced in the monitored group from 0.25 ± 0.05 to 0.20 ± 0.06 mL kg-1 h-1 (p < 0.001). The cumulative time with a BIS under 40 was significantly higher in the SOC group with a median time of 12.6 min (95% CI: 0.6-80.0) versus 2.0 min (95% CI: 0.3-5.83) (p = 0.023). Time for extubation was significantly shorter in the monitored group: 4.4 min (95% CI: 2.4-4.9) versus 6.28 min (95% IC: 5.0-8.2) (p = 0.003). We observed no differences in remifentanil or phenylephrine requirements during anaesthesia or in postoperative outcome measures, such as postoperative pain, opioid consumption, neurocognitive recovery. CONCLUSION: Combined intraoperative monitoring of anaesthesia and nociception during colonic surgery resulted in less desflurane consumption and quicker extubation time compared to standard clinical care monitoring.

Intrapandemic regional anesthesia as practice: a historical cohort study in patients undergoing breast cancer surgery.

BACKGROUND: The COVID-19 pandemic has markedly increased delays in oncologic surgeries because of the virus's impact on traditional anesthetic management. Novel protocols, developed to protect patients and medical professionals, have altered the ways and instances in which general anesthesia (GA) can be safely performed. To reduce virus exposure related to aerosol-generating procedures, it is now recommended to avoid GA when feasible and promote regional anesthesia instead. At our institution, we observed faster postoperative recovery in patients who received paravertebral blocks for breast cancer surgery instead of GA. This led us to formally evaluate whether regional anesthesia instead of GA helped improve time to hospital discharge. METHODS: We conducted a historical cohort study to retrospectively analyze two cohorts of patients: prepandemic vs intrapandemic. We obtained approval from our institutional ethics committee to review files of consecutive patients who underwent breast cancer surgery between 30 March 2020 and 30 June 2020 (intrapandemic group; N = 106) and consecutive patients-moving backwards-from 28 February 2020 to 6 December 2019 (prepandemic group; N = 104). The primary outcome was the length of time between the end of surgery to readiness for hospital discharge. Secondary outcomes included the incidence of postoperative nausea and vomiting (PONV), the need for postoperative analgesia, and the duration of stay in the postanesthesia care unit (PACU). RESULTS: The median [interquartile range (IQR)] time to readiness for hospital discharge was significantly lower in patients who received paravertebral blocks for breast cancer surgery compared with GA (intrapandemic group, 119 [99-170] min vs prepandemic group, 191 [164-234] min; P < 0.001) as was the incidence of PONV (3% vs 11%; P = 0.03) and median [IQR] PACU durations of stay (29 [21-39] min vs 46 [37-63] min; P < 0.001). CONCLUSIONS: Patients who received paravertebral blocks for breast cancer surgery in the intrapandemic group were ready for hospital discharge earlier, spent less time in the PACU, and experienced less PONV than those who received GA in the prepandemic group. With growing surgical wait times, concerns related to aerosol-generating procedures, and recommendations to avoid GA when feasible, paravertebral blocks as the principal anesthetic modality for breast cancer surgery offered benefits for patients and medical teams.

RéSUMé: CONTEXTE: La pandémie de COVID-19 a considérablement augmenté les retards dans les chirurgies oncologiques en raison de l'impact du virus sur la prise en charge anesthésique traditionnelle. De nouveaux protocoles, mis au point pour protéger les patients et les professionnels de la santé, ont modifié les façons et les cas dans lesquels une anesthésie générale (AG) peut être réalisée en toute sécurité. Afin de réduire l'exposition au virus liée aux interventions génératrices d'aérosols, il est maintenant recommandé d'éviter l'AG lorsque possible et de privilégier l'anesthésie régionale. Dans notre établissement, nous avons observé une récupération postopératoire plus rapide chez les patientes ayant reçu des blocs paravertébraux pour une chirurgie de cancer du sein au lieu d'une AG. Cela nous a menés à évaluer de façon formelle si l'anesthésie régionale au lieu de l'AG avait contribué à réduire les délais jusqu'au congé de l'hôpital. MéTHODE: Nous avons réalisé une étude de cohorte historique afin d'analyser rétrospectivement deux cohortes de patientes : prépandémie vs intrapandémie. Nous avons obtenu l'approbation de notre comité d'éthique institutionnel pour examiner les dossiers de patientes consécutives ayant bénéficié d'une chirurgie de cancer du sein entre le 30 mars 2020 et le 30 juin 2020 (groupe intrapandémie; n = 106) et des patientes consécutives ­ en reculant ­ du 28 février 2020 au 6 décembre 2019 (groupe prépandémie; n = 104). Le critère d'évaluation principal était le délai entre la fin de la chirurgie et le moment où les patientes étaient prêtes à recevoir leur congé de l'hôpital. Les critères d'évaluation secondaires comprenaient l'incidence de nausées et vomissements postopératoires (NVPO), la nécessité d'une analgésie postopératoire et la durée de séjour en salle de réveil (SDR). RéSULTATS: Le délai médian [écart interquartile (ÉIQ)] jusqu'à la disposition au congé de l'hôpital était significativement plus court chez les patientes ayant reçu des blocs paravertébraux pour une chirurgie de cancer du sein plutôt qu'une AG (groupe intrapandémie, 119 [99-170] min vs groupe prépandémie, 191 [164­234] min; P < 0,001), tout comme l'incidence de NVPO (3 % vs 11 %; P = 0,03) et les durées médianes [ÉIQ] de séjour en salle de réveil (29 [21­39] min vs 46 [37­63] min; P < 0,001). CONCLUSION: Les patientes qui ont reçu des blocs paravertébraux pour une chirurgie de cancer du sein dans le groupe intrapandémie étaient prêtes à quitter l'hôpital plus tôt, ont passé moins de temps en salle de réveil et ont ressenti moins de NVPO que celles qui ont reçu une AG dans le groupe prépandémie. Avec des temps d'attente pour accès à la chirurgie de plus en plus longs, des préoccupations liées aux interventions génératrices d'aérosols et les recommandations d'éviter l'AG lorsque possible, les blocs paravertébraux ont offert des avantages aux patientes et aux équipes médicales en tant que principale modalité anesthésique pour la chirurgie de cancer du sein.

Description of the validity of the Analgesia Nociception Index (ANI) and Nociception Level Index (NOL) for nociception assessment in anesthetized patients undergoing surgery: a systematized review.

Maintaining optimum analgesia in anesthetized patients is challenging due to the inability to self-report pain or exhibit pain-related behaviours. The Analgesia Nociception Index (ANI) (based on heart rate variability [HRV]) and the Nociception Level Index (NOL) (based on HRV, photoplethysmography, skin conductance, and temperature) both include HRV and provide continuous index monitoring for nociception assessment. The research question was: "What are the validation strategies of the NOL and ANI for nociception assessment in anesthetized patients?". The objectives were to describe and analyze the validation strategies and results. A systematized review was conducted using a comprehensive search with keywords under three concepts (nociception/pain, ANI/NOL, and validity) in four databases. A quality assessment using an adapted GRADE approach for measurement tools, and a risk of bias assessment using QUADAS-2 tool were performed by two reviewers. Out of 525 results, 15 validation studies were included. Strategies included hypothesis testing, discriminative, and criterion validation. Significant changes in ANI/NOL values were found in response to nociceptive stimuli at different opioid concentrations (hypothesis testing). Higher ANI/NOL values were observed during nociceptive stimuli (discriminative). AUCs ranging from 0.83 to 0.99 were obtained to detect nociceptive stimuli (criterion). Both technologies performed superiorly in detecting nociceptive stimuli compared to individual monitoring of HR and blood pressure. Although the aforementioned validation strategies are deemed appropriate, in the absence of a gold standard, criterion validation findings should be interpreted with caution. Moreover, reliability could be examined using test-retest with consistent ANI/NOL values during a stable time-interval.

Impact of chronic treatment by ß1-adrenergic antagonists on Nociceptive-Level (NOL) index variation after a standardized noxious stimulus under general anesthesia: a cohort study.

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 ß1-adrenergic antagonists may constitute a limitation to the use of the NOL index. ß1-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 ß1-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 ß1-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 ß1-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.

Exploration of a Multi-Parameter Technology for Pain Assessment in Postoperative Patients After Cardiac Surgery in the Intensive Care Unit: The Nociception Level Index (NOL)TM.

INTRODUCTION: The aim of this study was to explore the use of a multi-parameter technology, the Nociception Level (NOL) index (Medasense Biometrics Ltd, Ramat Gan, Israel), for pain assessment in postoperative awake patients after cardiac surgery during non-nociceptive and nociceptive procedures in the intensive care unit (ICU). MATERIALS AND METHODS: A prospective cohort repeated-measures design was used. Patients were included if they were in the ICU after undergoing cardiac surgery and if they could self-report their pain. A non-invasive probe was placed on the patient's finger for the continuous monitoring of the NOL index. Patients' self-reports of pain and anxiety (0-10 Numeric Rating Scale or NRS), and behavioral scores with the Critical-Care Pain Observation Tool (CPOT) were obtained before and during a non-nociceptive procedure (ie, non-invasive blood pressure [NIBP] using cuff inflation), and before, during and after a nociceptive procedure (ie, chest tube removal [CTR]) for a total of five time points. Non-parametric tests were used to compare scores at different time points, and receiver operating characteristic curve analysis was performed. RESULTS: Fifty-four patients were included in the analysis. The NOL index, pain and anxiety scores were significantly higher during CTR compared to rest and NIBP (p < 0.001). During CTR, the NOL was associated with self-reported pain intensity and unpleasantness but not with anxiety and CPOT scores. The NOL showed a modest performance in detecting pain (NRS ≥1 and ≥5) in this sample with sensitivity and specificity ranging from 61% to 85%. CONCLUSION: The NOL index was able to discriminate between a non-nociceptive and a nociceptive procedure and was associated with self-reported pain. Further validation testing of the NOL is necessary in a heterogeneous sample of ICU patients.

"Impact of Nociception Level (NOL) index intraoperative guidance of fentanyl administration on opioid consumption, postoperative pain scores and recovery in patients undergoing gynecological laparoscopic surgery. A randomized controlled trial".

STUDY OBJECTIVE: 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. SETTING: University hospital, operating room. PATIENTS: 70 adult patients, ASA 1-3, scheduled for total laparoscopic hysterectomy. INTERVENTIONS: 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. MEASUREMENTS: 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. MAIN RESULTS: 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. CONCLUSION: 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.

The impact of bolus versus continuous infusion of intravenous ketamine on bispectral index variations and desflurane administration during major surgery: The KETABIS study.

BACKGROUND: Although ketamine, a NMDA-receptor antagonist, tends to increase the bispectral index (BIS), it remains a widely used analgesic whenever administered in low doses during major surgery. OBJECTIVE: The objective of this study was to compare the impact of intravenous ketamine (given either as a continuous infusion or as a bolus) on BIS and to compare desflurane administration and postoperative outcomes between the groups. DESIGN: Prospective, randomised, parallel-group, open-label study. SETTING: University hospital, operating room. PARTICIPANTS: Fifty patients, scheduled for major abdominal surgery. INTERVENTIONS AND MAIN OUTCOMES MEASURES: Patients were randomised into two groups: ketamine by intravenous continuous infusion - group (KI) and ketamine by i.v. bolus - group (KB). In the KI group, ketamine at a rate of 0.25 mg kg-1 h-1 was commenced at skin incision (T0) and maintained at this rate for the duration of surgery. In group KB, a ketamine bolus of 0.25 mg kg-1was administered at T0 and repeated every hour. The difference in BIS between the groups was compared from T0 onwards. The amount of desflurane administered to keep BIS within the usual recommended range (40-60) was compared, as were the doses of phenylephrine and remifentanil. Postoperative pain and recovery outcomes were also assessed. RESULTS: After T0, the BIS increased significantly from baseline in group KB compared with group KI: the rise in BIS was 20 ±â€Š8 vs. 11 ±â€Š6, respectively (P = 0.0001). The between-group mean difference (95% confidence interval (CI), was 9 (5 to 13). In group KB, desflurane administration significantly increased for the first 15 min after T0: 6.3 ±â€Š1.8 vs. 3.8 ±â€Š1.3 ml (P < 0.0001) with a mean intergroup group difference (95% CI) of 2.4 (1.5 to 3.4) ml. There was no difference in desflurane administration when considering the full hour from T0 to T60 min: 16 ±â€Š9 vs. 15 ±â€Š5 ml (P = 0.63) with a mean intergroup difference (95% CI) of 1 (-3 to 5) ml. After surgery, pain scores, opioid consumption, incidence of nausea and vomiting and recovery scores were similar between groups. CONCLUSION: Compared with a continuous ketamine infusion, a ketamine bolus significantly increased the BIS after T0. In order to keep the BIS below 60, significantly more desflurane was administered from T0 to T15 min in group KB. To prevent such higher desflurane administration and its related atmospheric pollution, our results suggest administering intra-operative intravenous ketamine as an infusion rather than a bolus. TRIAL REGISTRATION: Clinicaltrials.gov registration identifier: NCT03781635.

Effect of electroencephalography-guided anesthesia on neurocognitive disorders in elderly patients undergoing major non-cardiac surgery: A trial protocol The POEGEA trial (POncd Elderly GEneral Anesthesia).

INTRODUCTION: 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. OBJECTIVE: 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). MATERIAL AND METHODS: 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. STUDY REGISTRATION: NCT04825847 on ClinicalTrials.gov.