Assessing the antinociceptive effect of nitrous oxide to tetanic stimulation in anaesthetised patients with new intra-operative nociception monitors: An observational study.

BACKGROUND: Nitrous oxide (N2O) has been used since the 19th century for its analgesic, antinociceptive and anxiolytic effects during surgical procedures in awake and anaesthetised patients. However, quantification of noxious stimuli that occur under general anaesthesia is a constant challenge for anaesthesiologists, and recently two new indices have been developed to assess intra-operative nociception. OBJECTIVE: The aim of this study was to quantify with new indices as well as with more classical clinical parameters the antinociceptive effect of N2O during general anaesthesia. DESIGN: Prospective, open label, patient-blinded, observational and descriptive trial. SETTING: Single-centre academic hospital. PARTICIPANTS: Forty American Society of Anesthesiologists' physical status 1 to 3 patients undergoing general anaesthesia for elective abdominal surgery via laparotomy were recruited. MAIN OUTCOMES MEASURES: Intra-operative pain was assessed using a standardised electrical stimulation of the forearm (tetanic stimulation at 70 mA, 100 Hz for 30 s), at 0, 25 and 50% inhaled N2O/O2. Heart rate (HR), mean arterial blood pressure, bispectral index, the analgesia nociception index and the nociception level (NOL) index were used to evaluate intra-operative nociception before and after each standardised tetanic stimulation. RESULTS: There was a 16% reduction of the analgesia nociception index reaction, a 31% reduction of the NOL reaction and a 51% reduction of the HR reaction to a standardised electrical tetanic nociceptive stimulation during administration of 50% N2O. Administration of 50 or 25% inhaled N2O produced the same quality of antinociception based on HR and NOL index analyses. HR and the NOL index were the best parameters to identify the antinociceptive effect of intra-operatively administered N2O. CONCLUSION: In anaesthetised patients, our study demonstrated clinically significant antinociceptive properties of N2O. Our results showed that low concentrations of N2O (25%) are as effective as higher concentrations (50%) to achieve a significant antinociceptive effect. These findings may help decrease negative effects of using higher concentrations of N2O, including its side effects and its environmental pollution. TRIAL REGISTRATION: ClinicalTrials.gov registration identifier: NCT02701478.

Validation of the PMD100 and its NOL Index to detect nociception at different infusion regimen of remifentanil in patients under general anesthesia.

BACKGROUND: The NOL index is based on multiparametric analysis of heart rate (HR), skin conductance, wave plethysmography, and their time derivative. The aim of this study was to evaluate the NOL to detect standardized nociceptive stimuli with various remifentanil dosages under general anesthesia. METHODS: A prospective, observational study at a single center (NCT02602379) included 40 ASA I to III patients undergoing laparotomy under remifentanil-desflurane anesthesia with epidural analgesia. A tetanic stimulation was applied (forearm) at remifentanil intravenous (IV) infusion of 0.005, 0.05, 0.1, and 0.15 µg/kg/min. NOL and its variations were compared with other parameters namely heart rate, mean arterial pressure, Bispectral Index, and Analgesia Nociception Index (ANI). Receiver operating characteristic (ROC) curves were plotted to assess the response to both intubation and standardized stimulus under remifentanil infusion of 0.005 µg/kg/min. RESULTS: The post-stimulation NOL values at remifentanil doses of 0.005, 0.05, 0.1 and 0.15 µg/kg/min (39 [23-55], 15 [7-30], 8 [4-14] and 8.5 [4-15]) were significantly higher than pre-stimulation counterparts (P<0.0001). For all other parameters, there was also significant difference between pre- and post-stimulation values at all remifentanil dosages (P<0.0001). Area under the ROC curve (AUC) for the NOL during standardized stimulation was larger than for all other parameters at the exception of ANI (P=0.94). The AUC of NOL for nociception during tracheal intubation was greater (0.93 vs. 0.84 and 0.64 for ANI and HR, respectively). CONCLUSIONS: NOL monitoring is a promising index to assess the level of nociception in patients under general anesthesia.

Evaluation of the analgesia nociception index (ANI) in healthy awake volunteers.

BACKGROUND: Analgesia might be evaluated with simple changes in vital signs, a non-specific and non-sensitive method. Heart rate variability (HRV) correlates with autonomous nervous system activity and can be used to evaluate painful stimuli. Heart rate variability is then transformed into a numeric scale called the analgesia nociception index (ANI), where higher values represent predominant parasympathetic tone, thus low nociception. Under general anesthesia, the ANI decreases following painful stimuli and increases after administration of analgesia, but significant interindividual variability is present. The goal of the present study was to evaluate the ANI as a pain index in healthy awake volunteers. METHODS: Following research ethics board approval, participants were positioned supine in a calm operating room. The participants' vital signs and ANI were monitored. After evaluation of all parameters without any stimulation, 23 volunteers received a 2 Hz electrical stimulus at the wrist with increasing current intensity from 0-30 mA (5 mA increments). The current was kept constant for three minutes at each level, and the volunteers rated their pain on a numeric rating scale (NRS) every minute. The Pearson correlation coefficient and linear regression were used to analyze the relationship between the ANI and the NRS score. The ANI absolute values and the variations from baseline were both analyzed. RESULTS: There was a very weak negative correlation between the NRS score and ANImean (Pearson, -0.089; 95% confidence interval [CI], -0.192 to -0.014; P = 0.045) and between the NRS score and ∆ANImean (Pearson, -0.174; 95% CI, -0.272 to -0.072; P < 0.001; regression slope, -0.586; 95% CI, -0.930 to -0.243; P < 0.001). Heart rate, blood pressure, and respiratory rate did not vary significantly throughout the study. CONCLUSIONS: These findings provide little evidence to support use of the ANI in awake subjects or in awake patients such as those in the emergency room or in the intensive care unit. Nevertheless, based on an important difference between the expected correlation and the real correlation between the ANI and the NRS scores found in our results, the present study might be underpowered. Studies with a larger sample size would be required to enable firm conclusions about the clinical utility of the ANI in this population of awake volunteers as well as in awake patients. This study was registered with ClinicalTrials.gov (NCT02589093).