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).

Nociception Control of Bilateral Single-Shot Erector Spinae Plane Block Compared to No Block in Open Heart Surgery-A Post Hoc Analysis of the NESP Randomized Controlled Clinical Trial.

Background and Objectives: The erector spinae plane block (ESPB) is an analgesic adjunct demonstrated to reduce intraoperative opioid consumption within a Nociception Level (NOL) index-directed anesthetic protocol. We aimed to examine the ESPB effect on the quality of intraoperative nociception control evaluated with the NOL index. Materials and Methods: This is a post hoc analysis of the NESP (Nociception Level Index-Directed Erector Spinae Plane Block in Open Heart Surgery) randomized controlled trial. Eighty-five adult patients undergoing on-pump cardiac surgery were allocated to group 1 (Control, n = 43) and group 2 (ESPB, n = 42). Both groups received general anesthesia. Preoperatively, group 2 received bilateral single-shot ESPB (1.5 mg/kg/side 0.5% ropivacaine mixed with dexamethasone 8 mg/20 mL). Until cardiopulmonary bypass (CPB) was initiated, fentanyl administration was individualized using the NOL index. The NOL index was compared at five time points: pre-incision (T1), post-incision (T2), pre-sternotomy (T3), post-sternotomy (T4), and pre-CPB (T5). On a scale from 0 (no nociception) to 100 (extreme nociception), a NOL index > 25 was considered an inadequate response to noxious stimuli. Results: The average NOL index across the five time points in group 2 to group 1 was 12.78 ± 0.8 vs. 24.18 ± 0.79 (p < 0.001). The NOL index was significantly lower in the ESPB-to-Control group at T2 (12.95 ± 1.49 vs. 35.97 ± 1.47), T3 (13.28 ± 1.49 vs. 24.44 ± 1.47), and T4 (15.52 ± 1.49 vs. 34.39 ± 1.47) (p < 0.001) but not at T1 and T5. Compared to controls, significantly fewer ESPB patients reached a NOL index > 25 at T2 (4.7% vs. 79%), T3 (0% vs. 37.2%), and T4 (7.1% vs. 79%) (p < 0.001). Conclusions: The addition of bilateral single-shot ESPB to general anesthesia during cardiac surgery improved the quality of intraoperative nociception control according to a NOL index-based evaluation.

Pupillary Pain Index Predicts Postoperative Pain but Not the Effect of Peripheral Regional Anaesthesia in Patients Undergoing Total Hip or Total Knee Arthroplasty: An Observational Study.

Background and Objectives: The pupillary pain index (PPI) allows the evaluation of intraoperative nociception by measuring pupillary reaction after a localized electrical stimulus. It was the objective of this observational cohort study to investigate the pupillary pain index (PPI) as a method to evaluate the fascia iliaca block (FIB) or adductor canal block (ACB) sensory areas during general anaesthesia in orthopaedic patients with lower-extremity joint replacement surgery. Materials and Methods: Orthopaedic patients undergoing hip or knee arthroplasty were included. After anaesthesia induction, patients received an ultrasound-guided single-shot FIB or ACB with 30 mL and 20 mL of 0.375% ropivacaine, respectively. Anaesthesia was maintained with isoflurane or propofol/remifentanil. The first PPI measurements were performed after anaesthesia induction and before block insertion, the second at the end of surgery. Pupillometry scores were evaluated in the area of the femoral or saphenous nerve (target) and C3 dermatome (control). Primary outcomes were differences between PPIs before and after peripheral block insertion as well as the relationship between PPIs and postoperative pain scores; secondary outcomes were the relationship between PPIs and opioid requirements after surgery. Results: PPI decreased significantly from the first to the second measurement (4.17 ± 2.7 vs. 1.6 ± 1.2, p < 0.001 for target; 4.46 ± 2.7 vs. 2.17 ± 2.1, p < 0.001 for control). Control and target measurements did not show significant differences. A linear regression analysis showed that early postoperative pain scores could be predicted with intraoperative piritramide with improved prediction after adding PPI scores, PCA opioids and surgery type. Forty-eight-hour pain scores at rest and in movement were correlated with intraoperative piritramide and control PPI after the PNB in movement and with second-postoperative-day opioids and target PPI scores before block insertion, respectively. Conclusions: While the effect of an FIB and ACB could not be shown with PPI postoperative pain scores due to a large effect of opioids, perioperative PPI was shown to be associated with postoperative pain. These results suggest that preoperative PPI may be used to predict postoperative pain.

Foreseeing postoperative pain in neurosurgical patients: pupillometry predicts postoperative pain ratings-an observational study.

Pupillary reflex dilation (PRD) is triggered by noxious stimuli and diminished by opioid administration. In the postoperative period, PRD has been shown to be correlated with pain reporting and a useful tool to guide opioid administration. In this study we assessed whether pupillary measurements taken before extubation were related with the patient's reported pain in the Post-Anesthesia Care Unit (PACU) using the Numerical Rating Scale (NRS). Our objective was to evaluate the correlation of PRD and pupillary variables measured intraoperatively with postoperative pain under the same opioid concentration. This was a prospective observational study of 26 neurosurgical patients undergoing general anesthesia exclusively with propofol and remifentanil. A portable infrared pupillometer was used to provide an objective measure of pupil size and PRD (using the Pupillary Pain Index) before extubation. Pain ratings were obtained from patients after recovery of consciousness, while remifentanil was maintained at 2 ng/mL. A significant correlation was observed between NRS scores and pre-extubation PPI (rS = 0.62; P = 0.002), as well as between NRS scores and pupil diameter before tetanic stimulation PPI (rS = 0.56, P = 0.006). We also found a negative correlation between pupil diameter and age (rS = - 0.42, P = 0.04). The statistically significant correlation between pre-extubation PPI scores and NRS scores, as well as between the pupillary diameter before tetanic stimulation and NRS scores suggest the possibility of titrating analgesia at the end of the intraoperative period based on individual responses. This could allow clinicians to identify the ideal remifentanil concentration for the postoperative period.

Effects of varying remifentanil concentrations on Analgesia Nociception Index® under propofol: an observational study.

Analgesia Nociception Index monitor provides a measurement of the nociception and anti-nociception balance based on heart-rate variability. The aim was to assess the ability of Analgesia Nociception Index (ANI) to detect standard noxious stimulation during anesthesia at different opioid concentrations in comparison to hemodynamic and Bispectral Index parameters. Sixteen patients undergoing general anesthesia with propofol and remifentanil. Standardized tetanic electrical stimulation was applied without any other concurrent stimuli, while different effect site concentrations of remifentanil were increased step-by-step (0.5, 1.5, 3.0, 5 and 7 ng/ml). For each tetanic stimulus, values of the different variables 60 s before and 120 s following the stimulus were analyzed. ANI values decreased significantly 120 s after the stimulus when compared to the mean ANI 60 s before the stimulus (P < 0.01). At lower remifentanil concentrations (0.5 ng/ml), all variables except electromyogram from the Bispectral Index significantly changed after the stimulus but in the higher concentrations (5.0 and 7.0 ng/ml) there was not a significant change. The other variables did not change significantly after the noxious stimulation. ANI was the only variable that positively correlated with the different remifentanil concentrations (R = 0.959, P = 0.01). Our study showed that there was a significant decrease in Analgesia Nociception Index after a tetanic stimulation while hemodynamic and BIS parameters did not change, suggesting that the Analgesia Nociception Index may perform better than traditional hemodynamic parameters at reflecting noxious stimulation. Analgesia Nociception Index significantly changed at lower, but not at higher, remifentanil concentrations.

Does nociception monitor-guided anesthesia affect opioid consumption? A systematic review of randomized controlled trials.

Monitors that estimate nociception during anesthesia may be used to guide opioid and other analgesics administration to optimize anesthesia care and possibly outcome. We reviewed the literature to evaluate current evidence of the effect of nociception-guided management over standard anesthesia practice during surgery. A systematic review of the literature on the effect of nociception monitoring on anesthesia practice was conducted. Reports were eligible if they compared nociception-guided anesthesia to standard practice during surgery. Primary endpoint of this review is intraoperative opioid consumption. Secondary endpoints included hemodynamic control, postoperative pain and pain treatment. We identified 12 randomized controlled trials that compared one of five different nociception monitoring techniques to standard anesthesia care. Most studies were single center studies of small sample size. Six studies reported intraoperative opioid consumption as primary outcome. There was considerable variability with respect to surgical procedure and anesthesia technique. For nociception monitors that were investigated by more than one study, analysis of the pooled data was performed. The surgical plethysmographic index was the only monitor for which an intra operative opioid sparing effect was found. For the other monitors, either no effect was detected, or pooled analysis could not be performed due to paucity of study data. On secondary outcomes, no consistent effect of nociception-guided anesthesia could be established. Although some nociception monitors show promising results, no definitive conclusions regarding the effect of nociception monitoring on intraoperative opioid consumption or other anesthesia related outcome can be drawn.Clinical trial number PROSPERO ID 102913.

Pharmacodynamic modelling of the effect of remifentanil using the Pupillary Pain Index.

Using a targeted controlled infusion of remifentanil during total intravenous anesthesia, we investigated the effect-site concentrations of remifentanil that correlate with different values of the Pupillary Pain Index and which concentrations were necessary for achieving a Pupillary Pain Index ≤ 4 and its usefulness in titrating opioids. The Pupillary Pain Index was measured in 54 patients prior to surgery under different remifentanil effect-site concentrations and subsequently modeled. One hundred and twenty-eight measurements were taken at different remifentanil concentrations while titrating propofol for a similar depth of hypnosis using a BIS monitor. Our modeled Hill equation revealed a remifentanil of 2.96 ng/mL for a PPI of 4, and the probability model a Ce of 3.22 ng/mL for the probability of 50% of patients achieving a PPI score ≤ 4. For the probability of 80% of patients achieving a PPI score ≤ 4 the Ce of remifentanil was 4.39 ng/mL. We conclude that concentrations of remifentanil that have been shown to suppress movement in response to noxious stimulation correspond to a Pupillary Pain Index ≤ 4.

Possibility of Using Surgical Pleth Index in Predicting Postoperative Pain in Patients after Vitrectomy Performed under General Anesthesia.

Adequacy of anesthesia concept (AoA) in the guidance of general anesthesia (GA) is based on entropy, and it also reflects the actual depth of anesthesia and the surgical pleth index (SPI). Therefore, this study aimed to analyze the potential existence of relationships between SPI values at certain stages of the AoA-guided GA for vitreoretinal surgeries (VRS) and the incidence of intolerable postoperative pain perception (IPPP). A total of 175 patients were each assigned to one of five groups. In the first, the VRS procedure was performed under GA without premedication; in the second group, patients received metamizole before GA; in the third, patients received acetaminophen before GA; in the fourth group, patients received Alcaine before GA; and, in the peribulbar block group, the patients received a peribulbar block with a mix of the solutions of lignocaine and bupivacaine. Between the patients declaring mild and statistically significant differences in the IPPP in terms of SPI values before induction (52.3 ± 18.8 vs. 63.9 ± 18.1, p < 0.05) and after emergence from GA (51.1 ± 13 vs. 68.1 ± 8.8; p < 0.001), it was observed that the patients postoperatively correlated with heart rate variations despite the group allocation. The current study proves the feasibility that preoperative SPI values help with predicting IPPP immediately after VRS under AoA guidance and discrimination (between mild diagnoses and IPPP when based on postoperative SPI values) as they correlate with heart rate variations. Specifically, this applies when the countermeasures of IPPP and hemodynamic fluctuations are understood to be of importance in reducing unwelcome adverse events.

[Intraoperative guidance of anesthesia: Analgesie Nociception Index (ANI) vs. standard care for hysterectomy under anesthesia with sevoflurane : A randomized controlled simple blinded study on intraoperative opioid consumption, postoperative pain and patient satisfaction]. / Intraoperative Analgesiesteuerung: Analgesie Nociception Index (ANI) vs. "standard care" bei Hysterektomien unter Sevoflurannarkose : Eine randomisierte kontrollierte Einfachblindstudie zu intraoperativem Opioidverbrauch, postoperativen Schmerzen und Patientenzufriedenheit.

BACKGROUND: General anesthesia leads to different effects depending on the drugs used (hypnosis, analgesia, muscle relaxation). While there are validated methods for clinical monitoring and control of hypnosis and muscle relaxation in routine anesthesia, the assessment of analgesia is still mainly based on the interpretation of clinical vital parameters, such as heart rate, blood pressure, perspiration or intraoperative movements of the patient. The present clinical study investigated whether the use of a so-called nociception monitor to record the intraoperative need for analgesics is superior to the previous analysis of vital parameters. The analgesia nociception index (ANI; MDoloris, Lille, France) was used, which is one of several nociception monitors currently on the market for recording the sympathicovagal balance. In the case of the ANI, the measurement is based on the analysis of the heart rate variability (HRV) as a function of breathing. The index is given in the form of a dimensionless score between 0 and 100, where 0 stands for a lack of parasympathetic activity and 100 for a very strong parasympathetic activity. According to the manufacturer, a value between 50-70 under anesthesia corresponds to sufficient intraoperative analgesia. METHODS: This was a clinical prospective randomized study in which 110 patients who underwent laparoscopic hysterectomy under balanced anesthesia using propofol, fentanyl and atracurium for induction and sevoflurane and fentanyl for anesthesia maintenance, were divided into two groups. In the intervention group (ANI group), during the operation analgesics were administered with the aid of the ANI monitor (bolus of 0.1 mg fentanyl if the ANI was < 50), whereas in the comparison group analgesics were administered according to previous clinical parameters (vital parameters, intraoperative defensive movements). The groups were then compared with respect to intraoperative fentanyl consumption (primary outcome), postoperative pain and opioid-induced side effects (measured by the numeric rating scale [NRS]) as well as patient satisfaction on postoperative day 3 (secondary outcome). RESULTS: The observations showed a higher total intraoperative consumption of fentanyl in the intervention group, due to a significantly higher number of individual doses (0.54 vs. 0.44 mg, p < 0.001). With respect to the other observation points, there were hardly any differences between the groups, neither with respect to the pain score nor the side effects in the recovery room. At most there was a trend towards a slightly lower pain score at the first measurement point in the recovery room (NRS at 15 min). In the patient survey on the postoperative day 3, there was a difference with respect to the subjectively described reduction in vigilance in the ANI group, but not other side effects or overall satisfaction with the pain therapy. CONCLUSION: In this group of patients the additional use of the ANI monitor for intraoperative control of analgesia led to an increased consumption of fentanyl compared to the comparison group, without having an impact on the postoperative pain score, opioid-induced side effects or patient satisfaction. An optimization of pain therapy through intraoperative use of the ANI monitoring in hysterectomy patients under balanced anesthesia with sevoflurane and fentanyl could therefore not be proven. Transferability of the results to a much older and/or sicker patient collective remains questionable.

Intraoperative use of the machine learning-derived nociception level monitor results in less pain in the first 90†min after surgery.

In this pooled analysis of two randomized clinical trials, intraoperative opioid dosing based on the nociception level-index produced less pain compared to standard care with a difference in pain scores in the post-anesthesia care unit of 1.5 (95% CI 0.8-2.2) points on an 11-point scale. The proportion of patients with severe pain was lower by 70%. Severe postoperative pain remains a significant problem and associates with several adverse outcomes. Here, we determined whether the application of a monitor that detects intraoperative nociceptive events, based on machine learning technology, and treatment of such events reduces pain scores in the post-anesthesia care unit (PACU). To that end, we performed a pooled analysis of two trials in adult patients, undergoing elective major abdominal surgery, on the effect of intraoperative nociception level monitor (NOL)-guided fentanyl dosing on PACU pain was performed. Patients received NOL-guided fentanyl dosing or standard care (fentanyl dosing based on hemodynamic parameters). Goal of the intervention was to keep NOL at values that indicated absence of nociception. The primary endpoint of the study was the median pain score obtained in the first 90 min in the PACU. Pain scores were collected at 15 min intervals on an 11-point Likert scale. Data from 125 patients (55 men, 70 women, age range 21-86 years) were analyzed. Sixty-one patients received NOL-guided fentanyl dosing and 64 standard care. Median PACU pain score was 1.5 points (0.8-2.2) lower in the NOL group compared to the standard care; the proportion of patients with severe pain was 70% lower in the NOL group (p = 0.045). The only significant factor associated with increased odds for severe pain was the standard of care compared to NOL treatment (OR 6.0, 95% CI 1.4 -25.9, p = 0.017). The use of a machine learning-based technology to guide opioid dosing during major abdominal surgery resulted in reduced PACU pain scores with less patients in severe pain.

The nociception level index (NOL) response to intubation and incision in patients undergoing video-assisted thoracoscopic surgery (VATS) with and without thoracic epidural analgesia. A pilot study.

Background: The PMD100™ (Medasense Biometrics Ltd., Ramat Yishai, Israel) is a novel non-invasive nociception monitor that integrates physiological parameters to compute a real-time nociception level index (NOL) in the anesthetized patients. Thoracic epidural analgesia provides effective analgesia and improves surgical outcomes. Side effects include sympathectomy, hypotension, changes in skin temperature and a decreased cardiac accelerator fiber tone. The purpose of this pilot study was to evaluate changes in NOL values after incision in patients with and without epidural analgesia.   Methods: Half of the patients scheduled for Video-Assisted Thoracoscopic Surgery (VATS) received a thoracic epidural catheter, placed and tested 2h before surgery and activated prior to incision. The other half of the patients received i.v. fentanyl (1 mcg/kg) five minutes before incision. Anesthesia and analgesia were maintained in a standardized manner. NOL and heart rate (HR) were compared before and after the nociceptive stimuli intubation and skin incision. Results: NOL significantly increased in all patients after intubation by 10.2 points (CI: 4.5-16.0; p=0.002) as well as HR by 9 beats per minute after intubation in all patients (CI: 3.3-15.6; p=0.01). After incision, in patients without epidural analgesia the NOL increased by 13.9 points (CI: 7.4-20.3; p=0.0001), compared to 5.4 points (CI: -6.3-17.1; p=0.29) in patients with epidural analgesia. HR did not significantly vary after incision in both groups. The area under the curve of delta NOL and delta HR variations after incision were significantly different (p<0.05) between groups and delta NOL variations were significantly different from baseline values but not the delta HR variations. Conclusions: This pilot study suggests that the PMD100™ Monitor may be a useful tool to evaluate the efficacy of an intraoperative thoracic epidural analgesia. Clinical Trial Registry Number: ClinicalTrials.gov record ID: NCT01978379 registered 10/25/2014.

Monitoring of nociception, reality or fiction? / Monitorización de la nocicepción, ¿realidad o ficción?

There are currently various projects underway that attempt to monitor the nociceptive responses caused by surgical stress and ensure patients the best analgesic conditions. The systemic response to surgical stress has repercussions in the postoperative period, such as worse pain control, delayed recovery, greater complications, longer stay in resuscitation and hospital units, and increased healthcare costs. However, treatment with higher doses of opioids than necessary may lead to slower awakening, increased drowsiness and adverse effects, as well as situations of postoperative opioid-induced hyperalgesia. There are 2 large groups of nociceptive monitoring according to the origin of the theoretical objective of monitoring response to the stimulus, that may derive from changes in the electroencephalogram or the response of the autonomic nervous system.