Nociception Level-guided fentanyl titration: could multimodal anaesthesia and false positives impact results? : Letter to the editor: BJA-2020-02032-HH1290

Nociception Level-guided fentanyl titration: could multimodal anaesthesia have made a difference? And how about the risk of treating false positive measurements? Editor, It was with great interest that we read Meijer et al.’s study1. In their bicenter randomised controlled trial, the authors investigated the capacity of the Nociception Level (NOL) Index (Medasense, Israel) to guide fentanyl administration during laparoscopic/robotic abdominal surgery. They reported that this strategy significantly decreased postoperative pain scores during the first 90 minutes of recovery in the post-operative care unit (PACU). Moreover, the humoral stress response, which was measured through serial analyses of serum cortisol and ACTH levels, was significantly lower in the NOL Index group compared to the control group, which confirms the study of Funcke et al. 2. This study shows a potential advantage of guiding intraoperative opioids towards the NOL Index. Yet, we wonder whether a multimodal analgetic strategy including more non opioid drugs (apart from acetaminophen) could have contributed to the differences in pain perception between groups? Especially, as it is not obvious from fig….whether the observed NOL values differ significantly between groups and the average perioperative opioid use is also not significantly different? We would therefore greatly appreciate if the authors could clarify some of our suspicions as it is not obvious from the presented data that a causal relationship between the NOL monitoring and the outcome is fully confirmed ? The antinociception protocol was (almost) exclusively opioid based, combining fentanyl, with or without the use of remifentanil as an escape for maintaining NOL Index or hemodynamics within targets, and a transition dose of a longer acting opioid (piritramide or morphine) administered at the end of each case. Despite (or because of) these mainly opioid based strategies, rather high pain scores were observed in the CONTROL group and a high incidence of nausea and vomiting was found in both groups. We wonder why the protocol did not include a commonly used multimodal strategy for postoperative analgesia (including non-opioid drugs such as anti-inflammatory drugs (NSAIDS) or dexamethasone as profylaxis for postoperative pain, nausea and vomiting? These additional precautions could have improved the immediate postoperative baseline conditions in both groups. At the other hand, lower initial pain scores, less PONV and the anti-inflammatory effects of a multimodal approach could also have decreased the capacity of the protocol to detect an advantage for the NOL monitored group, in both the pain score as well as the humoral stress response endpoints. Can the authors comment why apart from acetaminophen, no other non-opioid analgetics, neither PONV profylaxis were allowed? Or in case of allowed use in a non-protocolized way, can the authors provide a confirmation that these drugs were used in a similar way in both groups? We were also intrigued by some patients that required remifentanil in addition to fentanyl to control the NOL Index (in the NOL-guided group). We wonder whether this escape treatment did effectively solve the problem or rather whether the NOL remained unresponsive to the treatment with additional opioids? The latter should raise suspicion of a false positive measurement in the NOL? We suspect that factors not related to insufficient opioid effect, could equally have caused these observations? First, an increased end-tidal CO2 (as often seen during laparoscopy, may lead to an increased sympathetic tone which may affect the NOL? 4 Also, different fluid management between groups could affect the plethysmographic variations evoked by ventilation5 and may have affected the NOL Index. Other, non-nociceptive related changes in the NOL Index have been described such as following a bolus of phenylephrine6. Can the authors reassure us that such factors have not contributed to the favourable outcome of the NOL guided group? In conclusion, the study of Meijer et al. showed promising results as even with a statistically non-significant difference in mean cumulative dose of fentanyl, the larger population variability of the cumulative fentanyl dose in the NOL guided group suggest an improved individualization of the dose towards the patients’ needs. (Figure 3) This might be a sufficient reason to explain lower postoperative pain scores in the NOL-guided group, although this mechanism deserves further exploration. Due to the marginal differences found in NOL behavior between groups, we felt obliged to remain critical and propose several potential biases and suspicion for false positive measurements of NOL that might also contribute to a difference in results between groups? We sincerely thank the authors for their outstanding work and for addressing what we consider to be essential considerations . References: 1. Meijer F, Honing M, Roor T, Toet S, Calis P, Olofsen E, et al. 2020. Reduced postoperative pain using Nociception Level-guided fentanyl dosing during sevoflurane anaesthesia: a randomised controlled trial. Br J Anaesth epub ahead 2. Funcke S, Pinnschmidt HO, Wesseler S, Brinkmann C, Beyer B, Jazbutyte V, et al. 2019. Guiding Opioid Administration by 3 Different Analgesia Nociception Monitoring Indices During General Anesthesia Alters Intraoperative Sufentanil Consumption and Stress Hormone Release. Anesth Analg 130: 1264–73 3. De Oliveira GS, Almeida MD, Benzon HT, McCarthy RJ. 2011. Perioperative Single Dose Systemic Dexamethasone for Postoperative Pain. Anesthesiology 115: 575–88 4. Atkinson TM, Giraud GD, Togioka BM, Jones DB, Cigarroa JE. 2017. Cardiovascular and Ventilatory Consequences of Laparoscopic Surgery. Circulation 14: 700–10 5. Cannesson M, Desebbe O, Rosamel P, Delannoy B, Robin J, Bastien O, Lehot JJ. 2008. Pleth variability index to monitor the respiratory variations in the pulse oximeter plethysmographic waveform amplitude and predict fluid responsiveness in the operating theatre. Br J Anaesth 101: 200–2006 6. Raft J, Coulombe MA, Renaud-Roy E, Tanoubi I, Verdonck O, Fortier LP, et al. 2020. Impact of intravenous phenylephrine bolus administration on the nociceptive level index (NOL). J Clin Monit Comput 34: 1079–86