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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.

Introduction Herpes simplex encephalitis (HSE) is a rare disease with a poor prognosis. No recent evaluation of hospital incidence, acute mortality and morbidity is available. In particular, decompressive craniectomy has rarely been proposed in cases of life-threatening HSE with temporal herniation, in the absence of evidence. This study aimed to assess the hospital incidence and mortality of HSE, and to evaluate the characteristics, management, the potential value of decompressive craniectomy and the outcome of patients with HSE admitted to intensive care units (ICUs). Methods Epidemiological study : we used the hospital medical and administrative discharge database to identify hospital stays, deaths and ICU admissions relating to HSE in 39 hospitals, from 2010 to 2013. Retrospective monocentric cohort : all patients with HSE admitted to the ICU of the university hospital during the study were included. The use of decompressive craniectomy and long-term outcome were analyzed. The initial brain images were analyzed blind to outcome. Results The hospital incidence of HSE was 1.2/100,000 inhabitants per year, 32 % of the patients were admitted to ICUs and 17 % were mechanically ventilated. Hospital mortality was 5.5 % overall, but was as high as 11.9 % in ICUs. In the monocentric cohort, 87 % of the patients were still alive after one year but half of them had moderate to severe disability. Three patients had a high intracranial pressure (ICP) with brain herniation and eventually underwent decompressive hemicraniectomy. The one-year outcome of these patients did not seem to be different from that of the other patients. It was not possible to predict brain herniation reliably from the initial brain images. Conclusions HSE appears to be more frequent than historically reported. The high incidence we observed probably reflects improvements in diagnostic performance (routine use of PCR). Mortality during the acute phase and long-term disability appear to be stable. High ICP and brain herniation are rare, but must be monitored carefully, as initial brain imaging is not useful for identifying high-risk patients. Decompressive craniectomy may be a useful salvage procedure in cases of intractable high ICP.

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.

The poor diffusion of intravenous antibiotics in lung tissue makes nosocomial pneumonia challenging to treat, notably in critical patients under mechanical ventilation. The combination of ultrasound and microbubbles (USMB) is an emerging method for non-invasive and targeted enhancement of uptake of various drugs in several organs. This study aims to evaluate if USMB may increase amikacin concentration in condensed lung tissues in a mechanically ventilated rabbit model. When applied 60 or 160 min after the beginning of an intravenous amikacin infusion, USMB increased amikacin concentration in the condensed lung tissue by 1.33 ( = 0.025) or 1.56-fold ( = 0.028) respectively. When applied 70 min after the beginning of an intravenous amikacin infusion, USMB increased amikacin concentration in the muscle tissue by 2.52 ( = 0.025). In conclusion, this study demonstrates that USMB is a promising method for the targeted delivery of amikacin in mechanically ventilated condensed lung, thus opening new therapeutic fields against lung infections.

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.

Nitrous oxide (N 2 O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls—HC, aged 25–50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N 2 O, as well as potential markers for treatment response with this fast-acting antidepressant.

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).

IntroductionPostoperative pulmonary complications (PPCs) are common after cardiac surgery and are associated with significant morbidity and mortality. Lung-protective ventilation strategies have been proposed to reduce PPCs, but the optimal level of positive end-expiratory pressure (PEEP) and the use of alveolar recruitment manoeuvres (RMs) remain controversial.Methods/analysisIn this investigator-initiated, multicentre, open, randomised, parallel-group, superiority clinical trial, elective cardiac surgery patients at risk of PPCs will be assigned to one of two intraoperative ventilation strategies: (1) an open-lung ventilation strategy with protective ventilation, moderate PEEP and RMs or (2) a standard protective ventilation with low PEEP and no RM. The primary outcome will be a composite of prolonged (>24 hour) postoperative mechanical ventilation, reintubation for any cause or hospital-acquired pneumonia within 7 days of surgery, or death within 28 days of surgery. Data will be analysed on an intention-to-treat basis.Ethics and disseminationThe VACARM (impact of intraoperatiVe moderAte positive end-expiratory pressure with reCruitment mAnoeuvres versus low positive end-expiRatory pressure on major postoperative pulMonary complications and death after on-pump cardiac surgery in high-risk patients) trial has been approved by an independent ethics committee for all study centres. Recruitment began in July 2021. Results will be published in international peer-reviewed medical journals.Trial registration numberClinicalTrials.gov NCT04408495.

Background Sedation/analgesia is a daily challenge faced by intensivists managing patients with brain injury (BI) in intensive care units (ICUs). The optimization of sedation in patients with BI presents particular challenges. A choice must be made between the potential benefit of a rapid clinical evaluation and the potential exacerbation of intracranial hypertension in patients with impaired cerebral compliance. In the ICU, a pragmatic approach to the use of sedation/analgesia, including the optimal titration, management of multiple drugs, and use of any type of brain monitor, is needed. Our research question was as follows: the aim of the study is to identify what is the current daily practice regarding sedation/analgesia in the management of patients with BI in the ICU in France? Methods This study was composed of two parts. The first part was a descriptive survey of sedation practices and characteristics in 30 French ICUs and 27 academic hospitals specializing in care for patients with BI. This first step validates ICU participation in data collection regarding sedation-analgesia practices. The second part was a 1-day prospective cross-sectional snapshot of all characteristics and prescriptions of patients with BI. Results On the study day, among the 246 patients with BI, 106 (43%) had a brain monitoring device and 74 patients (30%) were sedated. Thirty-nine of the sedated patients (53%) suffered from intracranial hypertension, 14 patients (19%) suffered from agitation and delirium, and 7 patients (9%) were sedated because of respiratory failure. Fourteen patients (19%) no longer had a formal indication for sedation. In 60% of the sedated patients, the sedatives were titrated by nurses based on sedation scales. The Richmond Agitation Sedation Scale was used in 80% of the patients, and the Behavioral Pain Scale was used in 92%. The common sedatives and opioids used were midazolam (58.1%), propofol (40.5%), and sufentanil (67.5%). The cerebral monitoring devices available in the participating ICUs were transcranial Doppler ultrasound (100%), intracranial and intraventricular pressure monitoring (93.3%), and brain tissue oxygenation (60%). Cerebral monitoring by one or more monitoring devices was performed in 62% of the sedated patients. This proportion increased to 74% in the subgroup of patients with intracranial hypertension, with multimodal cerebral monitoring in 43.6%. The doses of midazolam and sufentanil were lower in sedated patients managed based on a sedation/analgesia scale. Conclusions Midazolam and sufentanil are frequently used, often in combination, in French ICUs instead of alternative drugs. In our study, cerebral monitoring was performed in more than 60% of the sedated patients, although that proportion is still insufficient. Future efforts should stress the use of multiple monitoring modes and adherence to the indications for sedation to improve care of patients with BI. Our study suggests that the use of sedation and analgesia scales by nurses involved in the management of patients with BI could decrease the dosages of midazolam and sufentanil administered. Updated guidelines are needed for the management of sedation/analgesia in patients with BI.