Journal of Clinical Monitoring and Computing (2020) 34:629–641 https://doi.org/10.1007/s10877-019-00362-4

REVIEW PAPER

Does nociception monitor‑guided anesthesia afect opioid consumption? A systematic review of randomized controlled trials

Fleur S. Meijer1 · Marieke Niesters1 · Monique van Velzen1 · Chris H. Martini1 · Erik Olofsen1 · Ruth Edry2 · Daniel I. Sessler3 · Eveline L. A. van Dorp1 · Albert Dahan1 · Martijn Boon1

Received: 25 February 2019 / Accepted: 16 July 2019 / Published online: 20 July 2019 © The Author(s) 2019

Abstract 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 efect of nociception-guided management over standard anesthesia practice during surgery. A systematic review of the literature on the efect 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 identifed 12 randomized controlled trials that compared one of fve diferent 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 surgi- cal plethysmographic index was the only monitor for which an intra operative opioid sparing efect was found. For the other monitors, either no efect was detected, or pooled analysis could not be performed due to paucity of study data. On secondary outcomes, no consistent efect of nociception-guided anesthesia could be established. Although some nociception monitors show promising results, no defnitive conclusions regarding the efect of nociception monitoring on intraoperative opioid consumption or other anesthesia related outcome can be drawn. Clinical trial number PROSPERO ID 102913.

Keywords Nociception monitoring · Opioid consumption · Systematic review

Electronic supplementary material The online version of this article (https​://doi.org/10.1007/s1087​7-019-00362​-4) contains supplementary material, which is available to authorized users.

* Martijn Boon Daniel I. Sessler [email protected] [email protected] Fleur S. Meijer Eveline L. A. van Dorp [email protected] [email protected] Marieke Niesters Albert Dahan [email protected] [email protected] Monique van Velzen 1 Department of Anesthesiology, Leiden University [email protected] Medical Center, Albinusdreef 2 (Postal Zone H5‑Q), Chris H. Martini 2333 ZA Leiden, The Netherlands [email protected] 2 Department of Anesthesiology, Rambam Medical Centre, Erik Olofsen The Ruth and Bruce Rappaport Faculty of Medicine, [email protected] Technion Institute of Technology, Haifa, Israel Ruth Edry 3 Department of Outcomes Research, Anesthesiology Institute, [email protected] Cleveland Clinic, Cleveland, OH, USA

Vol.:(0123456789)1 3 630 Journal of Clinical Monitoring and Computing (2020) 34:629–641

1 Introduction outcomes. To this end, a systematic search was conducted to identify reports that assessed intraoperative nocicep- General anesthesia is intended to produce a state of uncon- tion monitoring versus routine anesthetic management on sciousness combined with suppression of nociception, intraoperative opioid consumption. If possible, analysis of allowing the patient to undergo invasive surgical proce- pooled data was performed to synthesize current evidence. dures without undue harm or awareness. Nociception is defned by the International Association for the Study of Pain as the neural process of encoding noxious stimuli, 2 Materials and methods causing autonomic and/or behavioral responses such as elevation of blood pressure or motor withdrawal refexes; Our goal was to determine whether the use of a monitor noxious stimuli are actually or potentially tissue damag- or algorithm that estimates patients’ nociceptive state dur- ing events that occur during surgery [1]. Nociception is ing general anesthesia alters anesthesia management with generally suppressed by administration of potent opioid respect to the administration of opioids. Secondary aims analgesics. were to evaluate the efect of nociception monitoring on Clinicians usually estimate nociception by evaluating hemodynamic parameters, time related variables (e.g. time hemodynamic responses, along with lacrimation, sweating, to extubation) and postoperative pain score and opioid con- increase in pupil diameter or movement. Recently, nocic- sumption. We searched for trials in which the primary end- eption monitors have been introduced to track nociception point was the amount of opioid analgesic medication given during anesthesia and guide administration of analgesics, during anesthesia. All available nociception monitors were usually opioids. Since inadequate opioid administration is considered, along with indices derived from the electroen- associated with unwanted hemodynamic responses (e.g. cephalogram or evoked potentials. The systematic review hypertension and hypotension), reliable nociception moni- was conducted in accordance with the PRISMA statements. tors may help optimize anesthetic management. Evidence A planned meta-analysis was registered at PROSPERO from preclinical validation studies show that these moni- (www.crd.york.ac.uk/prosp​ero) under Identifer 102913. tors distinguish noxious and non-noxious events far better Since there was so much heterogeneity among the included than hemodynamic responses [2–6]. studies, a valid meta-analysis could not be conducted. Various nociception monitors are already available, Instead, pooled data were analyzed exclusively within and others are being developed. All use algorithms to unique monitors, when available. assess various physiological variables and they produce numerical indexes that give an estimation of the nocic- 2.1 Identifcation of relevant studies eption–antinociception balance (see Table 1). The value of nociception monitors is increasingly assessed in clini- On June 30, 2018 we searched the PubMed electronic data- cal settings, where they are compared to standard anes- base from inception for studies on nociception monitoring. thesia care. We intended to evaluate current evidence of The search strategy is given in Supplemental Document 1; the efect of nociception-guided management on intraop- no language or date restrictions were applied. To reduce erative opioid consumption and other anesthesia related the risk of missing relevant studies, we checked relevant review papers and a previous meta-analysis [7]. The title

Table 1 Individual nociception Monitor Manufacturer Autonomic input variables Index Optimal range/cut of monitor characteristics SPI GE Healthcare Pulse beat interval 0–100 20–50 Pulse wave amplitude ANI MDoloris Heart rate variability 0–100 50 Medical Systems NOL Medasense Heart rate and heart rate variability 0–100 10–25 Pulse wave amplitude Skin conductance CARDEAN Alpha-2 Blood pressure 0–100 60 Heart rate Algiscan ID Med Pupil diameter NA Pupil diameter increase > 30%

SPI surgical plethysmographic index, ANI analgesia nociception index, NOL nociception level index, NA not available

1 3 Journal of Clinical Monitoring and Computing (2020) 34:629–641 631 and abstracts of the retrieved studies were next step-wise random efects models, assuming two sources of variance, evaluated for the following three criteria: (1) study in surgi- within-study error and between-study error. Heterogeneity cal patients, aged 18 years and older, (2) study performed was by measuring the degree of inconsistency in the studies’ during general anesthesia, and (3) randomized trial of noci- results ­(I2). ception monitor-guided administration of opioids versus standard clinical care in which analgesics were administered solely based on blood pressure and heart rate values. All 3 Results papers meeting all criteria were read in full. Three reviewers (FM, AD, and RE) independently performed the selection 3.1 Study selection procedure. The fow chart of the PubMed search is shown in Fig. 1, 2.2 Data extraction which illustrates retrieval of 741 records. After removal of 728 irrelevant studies, 13 trials were carefully examined The identifed reports were searched for the following vari- and assessed for eligibility. Three papers were removed, ables and these were extracted for the review if available: one study using the analgesia nociception index (ANI), the authors, country of origin, year of publication, number of other two the surgical plethysmographic index (SPI, Fig. 1) subjects in each treatment group, type of opioid and anes- [12–14]. Two of these studies were observational (using a thetic used, opioid consumption during surgery, anesthetic historic control group) or case–control studies [13, 14]; the consumption during surgery, duration of anesthesia, hypo- third study did not report data for the complete duration of tension and/or bradycardia events, hypertension and/or tach- the surgical procedure [12]. Finally, two recently published ycardia events, time from end-of-anesthesia or administra- studies were added. The frst is a randomized trial from our tion of reversal agent until extubation or emergence, duration research group that compared nociception level (NOL)- of stay in the post-anesthesia care unit (PACU), average pain guided analgesia with standard clinical care in patients level in the PACU, and opioid consumption in the PACU. undergoing major abdominal surgery [15]. The second study Opioid consumption during surgery was transformed to is a trial that compared SPI guided anesthesia with standard morphine dose (in mg kg−1 h−1) using the following conver- care during laparoscopic cholecystectomy [16]. Our review sion ratios: 1 mg morphine (intravenous) = 0.5 mg oxyco- process therefore resulted in a total of 12 unique studies done = 10 μg fentanyl = 1 μg sufentanil = 10 μg remifenta- eligible for inclusion in the review. nil = 50 μg alfentanil. These conversion rates are arbitrarily based on existing opioid potency data [8]. 3.2 Study characteristics

2.3 Bias assessment Characteristics of the 12 included studies are shown in Table 2 and the main fndings are summarized in Table 3. Study quality was evaluated with the Cochrane Collabora- All publications were in English. A total of 1045 patients tion’s tool for assessing risk of bias in randomized trials were studied, with 520 receiving an intervention compared [9]. This tool considers six domains of bias: (1) selection to 526 treated according to routine clinical care. Care guided bias which includes the presence of random sequence gen- using the SPI was evaluated in six studies [16–21] followed eration and allocation concealment, (2) performance bias by the ANI in three studies [22–24]. The NOL, pupillometry which includes the blinding of participants and personnel, and the beat-to-beat cardiovascular depth of anesthesia index (3) detection bias which includes the blinding of outcome (CARDEAN 2.0) were evaluated in single studies [15, 25, assessment, (4) attrition bias, which includes incomplete 26]. Next, a discussion of the available evidence for each outcome data, (5) reporting bias which includes selective separate monitor is presented. reporting, and (6) other bias. For each study, the presence of bias in each domain was assessed independently by two 3.2.1 Surgical plethysmographic index (SPI) reviewers (FM and MN). Discrepancies in judgment were resolved by consensus and, when required a third reviewer Six reports were identified that compared SPI guided was consulted (AD). anesthesia to standard practice [16–21]. Studies were diverse with regard to the maintenance hypnotic (propo- 2.4 Data analysis fol or sevofurane) and opioids (remifentanil/sufentanil/ fentanyl and oxycodone). The guidance of these agents Analyses of combined data per unique monitor were con- was however uniform: all maintained a bispectral index ducted using the statistical package R (version 3.5.0) with or state entropy value between 40 and 60 and steered their the metafor package [10, 11]. Data were analyzed using SPI values in the intervention group to maintain values

1 3 632 Journal of Clinical Monitoring and Computing (2020) 34:629–641

Fig. 1 Flow diagram of the study selection process follow- ing the PubMed search on June 30, 2018

below 50. Bergman et al. and Chen et al. found that SPI Pooled data analysis shows that the SPI had an overall monitoring reduced remifentanil consumption during ear-, signifcant opioid sparing efect: mean diference in mor- nose- and throat surgery and orthopedic surgery by 23% phine equivalents − 0.06 mg kg−1 h−1 (95% CI − 0.12 to and 25% respectively [17, 18]. Similarly, Won et al. found − 0.00, Z = − 2.0, p = 0.04, ­I2 = 70%), or an 8% reduction in a 30% reduction in oxycodone consumption in SPI guided intra operative opioid consumption. patients for thyroid surgery [21]. However, in absolute val- In conclusion, analysis of the pooled data showed that ues, the reduction in oxycodone from that study equaled to SPI guided management may reduce opioid consumption only 2.8 mg morphine. In contrast with these studies, Jain during surgery, although individual study results varied con- et al. found an increased consumption of fentanyl in SPI siderably. Heterogeneity was substantial due to diferences in guided patients during laparoscopic cholecystectomy [16]. methodology, including type of surgery and choice of opioid This translated to less postoperative pain and a reduced and hypnotic agents. Therefore, no defnitive conclusions need for postoperative adjuvant analgesia. All other stud- can be drawn. ies failed to fnd an efect of SPI guidance on postopera- tive pain or opioid consumption (see Table 2). In general, 3.2.2 Analgesia nociception index (ANI) the efect of SPI guidance on secondary endpoints was limited. No signifcant diferences in mean hemodynamic Three reports were identifed comparing the ANI to stand- values were reported, with the exception of Chen et al., ard of care during lumbar discectomy [24], breast surgery who found that the number of episodes with inadequate [22] and laparoscopic cholecystectomy [23] (see Table 2). anesthesia (a composite endpoint that includes hyper/ All studies used a volatile hypnotic for maintenance (sevo- hypotension and brady/tachycardia) was reduced by 80% furane or desfurane). Fentanyl, remifentanil and morphine under SPI guidance [18]. Recovery times were identical or were used for analgesia. Dundar et al. provided pre-oper- at best 4 min faster with SPI guidance. Finally, the studies ative single shot thoracic paravertebral blockade for 44 of Colombo et al. [19] and Gruenewald et al. [20] found patients receiving breast surgery under general anesthesia no diferences on intraoperative opioid consumption or [22]. This study found a signifcant reduction of intra oper- perioperative secondary outcomes at all. ative remifentanil consumption in the ANI guided group

1 3 Journal of Clinical Monitoring and Computing (2020) 34:629–641 633 specifed. All a patients received - thoracic paraverte block bral There was maxi - was There mum remifentanil No infusion rate. - in post diference pain operative Rescue medica - Rescue tion (thiopental) in case of somatic despite movement - SPI and BIS val ues within target boundaries No diference in diference No pain postoperative Single center study Single Study sites not sites not Study Single center study. center study. Single Single center study Single Single center study. center study. Single Single center study Single Comments Single center study Single Single center study. center study. Single d consumption consumption (mentioned in “ Discussion ”) remifentanil (2) remifentanil consumption. time Recovery (3) - consump tanyl tion oxycodone con - oxycodone sumption unwanted unwanted somatic events modulation episodes with inadequate ­ anesthesia Postoperative NRS Postoperative Total remifentanil remifentanil Total Propofol (1) and Propofol - fen Intraoperative Intraoperative Intraoperative Incidence of Primary outcome Sympathetic Sympathetic Number of Number 18–75 years 18–65 years 18–75 years 18–65 years 20–65 years. 18–65 years 18–50 years 18–70 years ASA 1–2, ASA ASA 1–2, females, 1–2, females, ASA ASA 1–3, ASA ASA 1–2, ASA ASA 1–2, ASA ASA 1–2, ASA Patients (ASA, (ASA, Patients age) ASA 1–2, ASA ASA 1–2, ASA BIS (40–60) BIS (40–60) SE (40–60) BIS (40–60) BIS (40–60) BIS (40–60) Hypnosis monitor Hypnosis monitor all for (target patients) SE (40–60) BIS (40–60) non-opioid analgesia vertebral block vertebral TCI TCI – Sevofurane and – Fentanyl – Rocuronium – Sevofurane – Remifentanil para- – Thoracic – Propofol – Remifentanil – Mivacurium – Sevofurane – Fentanyl – Sevofurane – Oxycodone – Rocuronium – Sevofurane – Sufentanil – Rocuronium - Anesthesia tech nique – Propofol TCI – Propofol – Remifentanil – Cis -atracurium – Propofol TCI – Propofol – Remifentanil – Rocuronium tomy or laminec - tomy tomy in a supine or posi - beach-chair tion ecystectomy or orthopedic surgery chole-cystectomy Lumbar discec - Lumbar Breast surgery Breast Orthopedic surgery - chol Laparoscopic Thyroid resection Thyroid Gynecological Surgery Laparoscopic Laparoscopic ENT surgery 24/26 22/22 76/75 70/70 23/22 42/40 Number of Number - patients (interven tion/control) 30/30 40/40 ) a (20–50) b Δ < 10) ANI (≥ 50) SPI ANI (50–70) SPI (20–50 and SPI (20–50) SPI (20–50) SPI (< 50) SPI (< 50) Nociception Nociception (target monitor intervention for ­ group 2017 2010 2018 2013 2019 2016 2014 2015 Year Properties of thein this included studies review Upton [ 24 ] Upton Chen [ 18 ] Dundar [ 22 ] Bergmann [ 17 ] Bergmann Jain [ 16 ] Won [ 21 ] Won Gruenewald [ 20 ] Gruenewald 2 Table author First Colombo [ 19 ]

1 3 634 Journal of Clinical Monitoring and Computing (2020) 34:629–641 two centers two In case of large In case of large hemodynamic - remifen changes tanil could TCI and/or be changed medica - vasoactive tion or fuids could be given Beat-to-beat blood Beat-to-beat was pressure using measured the Finapress™ using a device cuf. fnger Single center study Single Study performed in Study Comments Single center study. center study. Single Single center study. center study. Single or < 80% of baseline

−1 90 beats min > remifentanil (2) remifentanil consumption. Incidence of anes - inadequate (3) thesia events - postopera frst hour tive sumption - move unwanted ments Propofol (1) and Propofol > 50 mm VAS in Primary outcome Remifentanil con - Remifentanil Reduction in Reduction 18–80 years 18–75 years 18–60 years 20–75 years 60 mmHg; heart rate ASA 1–3, ASA ASA –, ASA Patients (ASA, (ASA, Patients age) ASA 1–2, females, 1–2, females, ASA ASA 1–2, ASA < specifed 80% of baseline or BIS (45–55) BIS depth not BIS depth not Hypnosis monitor Hypnosis monitor all for (target patients) BIS (40–60) BIS (40–60) < - TCI phine and non- opioid analgesia blocker desfurane TCI – Propofol TCI – Propofol – Remifentanil – Rocuronium –Neuromuscular –Neuromuscular – Sevofurane or – Sevofurane mor –Fentanyl, - Anesthesia tech nique – Propofol TCI – Propofol – Remifentanil – Atracurium – Propofol TCI – Propofol – Alfentanil 100 mmHg or mean blood pressure surgery: urology urology surgery: (48%), abdomi - nal surgery (39%), gynecol - ogy (14%) ecystectomy surgery or colonoscopy > Major abdominal Major - chol Laparoscopic Surgery Gynecological Gastroscopy and/ Gastroscopy 120% of baseline or 40/40 59/60 Number of Number - patients (interven tion/control) 25/30 71/75 > 60 and (< c ) a cardiovascular cardiovascular ­ index (10–25) (pupil diameter (pupil diameter 5–30% of base - line) absence of con - signs ventional of nociception) Beat-to-beat Beat-to-beat Nociception level level Nociception ANI (> 50) Pupillometry Nociception Nociception (target monitor intervention for ­ group ; somatic arousal; somatic response ; somatic arousal; 2010 2018 2015 2017 Year −1 (continued) The authors named their monitoring index the surgical stress index which is equivalent to the to SPI is equivalent which index The authors stress named their the monitoring surgical index anesthesia: mean blood pressure Inadequate The target indicates adequate analgesia. A monitor value outside the target range leads to additional opioid administration according to the protocol of the theindividual studies to according protocol additional opioid administration leads to range outside the target value A monitor analgesia. indicates adequate The target and tachycardia in blood pressure algorithm 2.0) is a nociceptive based on changes (CARDEAN depth of anesthesia index cardiovascular The beat-to-beat

Martinez [ 25 ] Meijer [ 15 ] Meijer Szental [ 23 ] surgical plethysmographic index plethysmographic SPI surgical SE state entropy, ENT ear-nose-and-throat, index, BIS bispectral index, nociception ANI analgesia or < 45 beats min 2 Table author First a b c d Sabourdin [ 26 ] Sabourdin

1 3 Journal of Clinical Monitoring and Computing (2020) 34:629–641 635 Other ------90 min of PACU stay stay 90 min of PACU 1.3 on average were pain scores units lower in the ANI group (p = 0.01) ences ences ences ences 7 μg less in SPI was group (p = 0.01) and 0.6 points was VAS in SPI group lower (p = 0.04) ences ences Pain scores in the scores frst Pain No signifcant difer No No signifcant difer No No signifcant difer No No signifcant difer No No signifcant difer No consumption Fentanyl No signifcant difer No Postoperative pain and Postoperative opioid consumption - - - - - ences ences ences ences reduced by 3–4 min by reduced in the SPI group (p < 0.05) ences 9.8 min reduced in SPI 9.8 min reduced group (p = 0.03) shorter with SPI (p = 0.03) No signifcant difer No No signifcant difer No No signifcant difer No No signifcant difer No Recovery times were times were Recovery signifcant difer No Duration of surgery was was of surgery Duration Efciency variables (i.e. Efciency variables extubation) time to Extubation time 3.4 min - - - - - ences (only total ences (only time reported)surgery values or number of values episodes ences pathetic modulation pathetic heart by as measured indices variability rate in the SPI group (p < 0.01) HD variables (apartHD variables intubation: from Δ MAP 9 mmHg, p < 0.005) in mean values with hypertension, or brady hypotension signifcantly cardia reduced (p < 0.01) ences ences No signifcant difer No No diferences in mean diferences No No signifcant difer No There was less sym - was There Hemodynamic variables No diferences in mean diferences No signifcant diference No of episodes Number signifcant difer No No signifcant difer No - −1 −1 h −1 h −1 h −1 −1 ences 0.024 mg kg No signifcant difer No NA 0.3 mg kg 33.5 mg NA Absolute diference in diference Absolute opioid consumption morphine to (converted equivalents) 0.12 mg kg 2.8 mg - - - consumption in theconsumption SPI group (p = 0.017) ences ences - consump remifentanil tion in the SPI group (p < 0.05) - consump remifentanil tion in the ANI group (p = 0.027) ences - consump remifentanil tion in SPI group (p < 0.05) - consump oxycodone tion in the SPI group (p = 0.012) 12% Increase in fentanyl in fentanyl 12% Increase No signifcant difer No No signifcant difer No 23% Reduction in 23% Reduction in 30% Reduction No signifcant difer No Efect on opioid duringconsumption anesthesia 25% Reduction in 25% Reduction 30% Reduction in 30% Reduction SPI ANI SPI SPI ANI SPI Monitor SPI SPI Summary study of outcomes reported each by Jain [ 16 ] Upton [ 24 ] Upton Gruenewald [ 20 ] Gruenewald Chen [ 18 ] Dundar [ 22 ] Colombo [ 19 ] 3 Table Author Bergmann [ 17 ] Bergmann Won [ 21 ] Won

1 3 636 Journal of Clinical Monitoring and Computing (2020) 34:629–641 nociception nociception - move tion in unwanted ments with CARDEAN monitoring at BIS < 60 values (p = 0.001) - remifen between tanil and consumption morphine postoperative requirements - a 50% reduc was There Signifcant correlation Other not available, NOL available, not - - - ) −1 ences consumption 0–12 h consumption (mean diference 0.1 mg kg ences scores ences No signifcant difer No No signifcant difer No morphineReduced No diference in pain diference No No signifcant difer No Postoperative pain and Postoperative opioid consumption - - - ences ences tion time was 2 min tion time was shorter group in NOL (p = 0.03) ences No signifcant difer No No signifcant difer No - extuba to Reversal Efciency variables (i.e. Efciency variables extubation) time to No signifcant difer No - - - if possible ences nicardipine in pupil - nicardipine lometry group (42.3% vs. 0%; p < 0.001) ences ences −1 No signifcant difer No Hemodynamic variables No signifcant difer No patients required More No signifcant difer No h −1 - −1 −1 h h −1 −1 ences 0.42 mg kg NA Absolute diference in diference Absolute opioid consumption morphine to (converted equivalents) 0.18 mg kg No signifcant difer No - - consump remifentanil tion in pupillometry group (p < 0.001) - consump in alfentanil tion (dose corrected for duration) - patients in the CARD EAN group received (83% vs. alfentanil 61%; p = 0.003) - consump remifentanil grouption in the NOL (p < 0.001) ences 48% Reduction in 48% Reduction No signifcant diference signifcant diference No number of Increased Efect on opioid duringconsumption anesthesia 28% Reduction in 28% Reduction No signifcant difer No Pupillometry CARDEAN Monitor NOL ANI (continued) Sabourdin [ 26 ] Sabourdin Martinez [ 25 ] Intraoperative opioid consumption was converted to morphine equivalents in mg kg morphine to equivalents converted was opioid consumption Intraoperative 3 Table Author Meijer [ 15 ] Meijer HD hemodynamic, NA ENT ear-nose-and-throat, depth index, of anesthesia cardiovascular CARDEAN index, BIS bispectral index, nociception ANI analgesia surgical plethysmographic index plethysmographic SPI surgical SE state entropy, level, Szental [ 23 ]

1 3 Journal of Clinical Monitoring and Computing (2020) 34:629–641 637

(30% or 33.5 mg morphine equivalents in total, p = 0.027). 3.2.4 Cardiovascular depth of analgesia (CARDEAN 2.0) This signifcant diference in remifentanil consumption did not translate into faster recovery times or improved pain The systematic search yielded one study that assessed the scores in the PACU. In addition, methodological faws use of the CARDEAN 2.0 monitor versus standard care (for instance, the report fails to detail data collection and during procedural sedation for endoscopic procedures blinding procedures) reduce the quality of evidence of this [27]. Sedation was administered with the use of target- study. The studies of Szental et al. and Upton et al. found controlled infusion propofol, aimed at a BIS of 60. Addi- no diferences in opioid use during anesthesia, however tionally, in the CARDEAN group, alfentanil could be opioid consumption was not the primary outcome of both administered when the monitor value exceeded 60. In the studies and the use of morphine for intraoperative analge- standard care, alfentanil could only be administered if a sia may not have been an ideal choice [23, 24]. Regard- mandatory propofol intervention failed to achieve stability. ing other endpoints, only Upton et al., found lower pain Due to the nature of this protocol, the CARDEAN group scores in ANI guided patients after lumbar discectomy or received more doses of alfentanil, although the normalized laminectomy (mean diference frst 90 min postoperative dose (corrected for procedure time) was not signifcantly 1.3 NRS points, p = 0.01; see Table 2) [24]. However total diferent. The increased use of alfentanil in the CARD- fentanyl dose in the PACU was not signifcantly diferent. EAN group resulted in signifcantly less unwanted move- Pooled data analysis of these studies show that ANI ments during the procedures (50% reduction, p = 0.001), guidance did not result in a significant difference in but also a tendency to increased apnea [27]. intraoperative opioid consumption: mean difference In conclusion, limited evidence from a single center + 0.00 mg kg−1 h−1 morphine (95% CI − 0.018 to 0.024, study shows an increase in opioid administration and a Z = 0.12, p = 0.90, ­I2 = 98%). reduction in unwanted movements when the CARDEAN In conclusion, analysis of the pooled data did not show is used for procedural sedation. The possibility that the a beneft of ANI guidance on intraoperative opioid con- increase in opioid administration is related to the study sumption. Preliminary efects of ANI monitoring con- protocol itself cannot be ruled out. cerning an opioid sparing efect during breast surgery in patients that receive additional neuraxial blockade or on postoperative pain scores after back surgery, need to be 3.2.5 Pupillometry corroborated in future studies. Pupillometry versus standard care was assessed in one study in 55 patients during major gynaecological surgery 3.2.3 Nociception level index (NOL) [26]. In both groups, anaesthesia was maintained with propofol, aimed at a BIS of 40–60. In the pupillometry Our systematic review did not fnd any study that com- group, remifentanil was dosed according to predefned pared NOL guided anesthesia versus standard care on changes in pupil diameter. This study found reduced intraoperative opioid consumption. However, our group remifentanil consumption in pupillometry guided patients recently published a trial in which NOL guided anesthe- (mean diference 0.42 mg kg−1 h−1 morphine equivalents, sia was compared to standard care in 80 patients during p < 0.001). This translated to less morphine requirement major ambulatory laparoscopic and open abdominal sur- in the frst 12 h after surgery. Pain scores did not difer gery without the use of neuraxial blockade [15]. Gen- signifcantly. In addition, persistent pain was less fre- eral anaesthesia was maintained with propofol (bispec- quent after 3 months post-surgery in pupillometry guided tral index target 40–60) and remifentanil (NOL target patients (51% in standard group vs. 13% in pupillometry 10–25 for the intervention group; blinded for standard group, p = 0.004). The reduced intraoperative remifenta- care group). Propofol and remifentanil were administered nil administration in pupillometry group resulted in more using target controlled infusion. This study found a reduc- administration of nicardipine for hypertensive episodes tion in remifentanil consumption of 28% (absolute reduc- (see Table 2) [26]. tion 0.18 mg kg−1 h−1 morphine equivalents; p < 0.001). In conclusion, data from one study indicates that noci- Additionally this study found a trend towards improved ception monitoring by pupillometry may help to reduce hemodynamic stability. Postoperative pain scores or opi- opioid consumption during major gynaecological surgery, oid consumption did not difer signifcantly (see Table 2). with possible secondary benefts on short term (less opioid In conclusion, data from only one study indicates that consumption) and midterm (less persistent pain). Future NOL guided anesthesia may reduce intraoperative remifen- studies are however needed. tanil consumption. Future studies are needed.

1 3 638 Journal of Clinical Monitoring and Computing (2020) 34:629–641

3.3 Risk of bias 4 Discussion

Risk of bias per study is shown in Fig. 2a and summa- Our systematic search on the efect of nociception moni- rized in Fig. 2b. All studies were troubled by the inability toring versus standard care during general anesthesia on to fully blind the investigators due to the nature of the opioid consumption yielded 12 reports. Four did not fnd a intervention, i.e. need to either use or not-use the moni- signifcant diference in opioid consumption, seven found a tor during the surgical procedure. Setting aside this inevi- reduced opioid consumption—with widely varying magni- table performance risk, seven studies had no additional tude and one study found an increased opioid consumption high risk of bias domain according to the defnitions of (see Table 3). We did not conduct a planned meta-analysis the Cochrane Handbook for Systematic Reviews of Inter- because the data were so heterogeneous. However, a meta- ventions [15–17, 20, 21, 23, 24], two studies had one analysis has been published before by Gruenewald et al., additional high risk of bias [18, 19]; and the remaining despite substantial heterogeneity. They found no signifcant three studies had two or three additional high risks of bias efect of nociception monitoring on intraoperative opioid domains [22, 25, 26]. The most common high risk of bias, consumption or other secondary outcomes, apart from a apart from the performance bias, was detection bias (fve reduced rate of unwanted movement [7]. studies) [18, 19, 22, 25, 26] and other bias (three studies) We performed sub-analyses of pooled data from unique [22, 25, 26]. monitors when more than one trial was available which was the case for the SPI and ANI monitors. These analyses

Fig. 2 Evaluation of bias in the selected 12 studies. a Risk of bias per study accord- ing to the domains defned in the Cochrane Handbook for Systematic Reviews of Interven- tions version 5.1.0 (http://handb​ ook-5-1.cochr​ane.org). b Sum- mary of bias per domain

1 3 Journal of Clinical Monitoring and Computing (2020) 34:629–641 639 found no repeatable signifcant efect for the ANI monitor design, study population and surgery and anesthesia type but an opioid sparing efect for the SPI monitor of about (Table 1). The most commonly performed type of surgery 8% or 0.06 mg kg−1 h−1 morphine equivalents. It is debat- was abdominal surgery (fve studies, some of which were able whether this reduction is clinically relevant. Data from laparoscopic) [15, 16, 19, 20, 23, 26]; other procedures single studies concerning the NOL and pupillometry moni- included ear-nose-and-throat surgery [18], breast surgery tors also show a more substantial reduction in intraoperative [22], thyroidectomy [21], lumbar discectomy/laminectomy opioid consumption (0.18 and 0.42 mg kg−1 h−1 morphine [24], and orthopedic surgery (arthroscopy of knee, shoul- equivalents respectively) [15, 26]. However, these results der or ankle) [17]. Anesthesia technique varied consider- require confrmation. On secondary outcomes, no consist- ably among studies: six studies used propofol for mainte- ent benefcial efect of nociception guided management nance of anesthesia [15, 17–19, 25, 26], fve combined with was observed, although admittedly, some individual well remifentanil and one combined with alfentanil. The other conducted trials show promising efects on intraoperative studies used a volatile anesthetic (sevofurane or desfurane) hemodynamic stability [15] or postoperative pain [16, 24, combined with either remifentanil (n = 1), fentanyl (n = 2), 26] (see Table 2). Again, these results need to be confrmed. oxycodone (n = 1) or sufentanil (n = 1) [16, 20–24]. Most Measurement of nociception under general anesthesia is studies used a neuromuscular blocker (n = 9) [15–21, 23, challenging task. In general, noxious stimuli that are per- 24, 26], and one study used a thoracic paravertebral block in ceived by the autonomic nerve system will evoke autonomic both intervention and standard care groups [22]. The ample and behavioral responses. The magnitude of these responses diferences in type of anesthesia and in the intensity of the depends on the intensity of the stimulus and the presence of surgical trauma may profoundly afect the individual study any alleviating agents; i.e. the nociception–anti-nociception results. For instance, noxious stimuli during gastroscopy balance. During anesthesia, autonomic responses are noted under propofol/alfentanil anesthesia will difer signifcantly by their efects on haemodynamic and respiratory control. in intensity from stimuli during discectomy under sevofu- Nociception monitors invariably use one or more of these rane/fentanyl anesthesia or breast surgery under sevofurane/ autonomic variables as input for their algorithm to produce fentanyl surgery with a thoracic paravertebral local anes- an index of nociception (see Table 3). Unfortunately, these thetic block [22, 24]. autonomic variables are not uniquely related to nociception; Also, the comparator arm in most trials (commonly any stressing or alleviating factor may cause a change in defned as standard clinical care) often lacked strict guide- blood pressure or heart rate. In addition, both the choice of lines for opioid administration. Therefore, any efect of maintenance hypnotic and opioid and the type of surgical nociception monitoring on opioid administration could be procedure profoundly afect the nociception–anti-nocicep- confounded by suboptimal clinical practice of the compara- tion balance. All these factors may reduce the specifcity of tor group. Finally, all studies included in our review were nociception monitors when they are tested in the clinical relatively small with fewer than 100 subjects per treatment setting. arm, and most had fewer than 50 per arm. Additionally, all Patients show large inter-individual diferences in their studies had a high risk of performance bias and fve studies response to noxious stimuli and analgesic therapy. Nocicep- had a high risk of detection bias (Fig. 2). tion monitors can be used as an aid to improve individual- ized antinociceptive therapy in daily practice, however they 4.2 Limitations of this review should not be used to maintain nociception index values within a specifc range at all costs. In addition, although Although our search was extensive, it was limited to the some trials showed a reduced opioid consumption in noci- PubMed database and we may have missed some relevant ception guided patients, the use of these monitors can also studies. We therefore performed a secondary search across result in an increased consumption of opioids or other anal- websites of anesthesia societies to detect studies that are gesics for certain procedures [16]. Both ways may improve presented as abstracts. One possible relevant abstract was outcomes for patients, such as reduced postoperative pain. detected. Gruenewald et al. performed a multi-center, single The key utility of these monitors is not reducing opioid con- blinded randomized-controlled trial in 494 patients studying sumption per se, rather to achieve the optimal dosing of any the infuence of SPI and entropy monitoring (i.e. combined analgesic technique for the individual patient that will result analgesia and hypnosis monitoring) versus standard moni- in the best outcome. toring on signs of unwanted anesthesia events [28]. How- ever, in their preliminary report the authors do not mention 4.1 General limitations opioid consumption, which is the endpoint of this review. No other potentially relevant reports were found. Finally, Current data are troubled by the large heterogeneity that we only included studies on adult patients, and we did not was present among studies. Studies difered signifcantly in report on nociception monitoring in children.

1 3 640 Journal of Clinical Monitoring and Computing (2020) 34:629–641

5 Conclusions 7. Gruenewald M, Dempfe A. Analgesia/nociception monitoring for opioid guidance: meta-analysis of randomized clinical trials. Minerva Anestesiol. 2017;83(2):200–13. https://doi.org/10.23736​ ​ Current data are inconclusive about the efect of nociception /s0375​-9393.16.11602​-5. monitoring on intraoperative opioid consumption or anesthe- 8. Knotkova H, Fine PG, Portenoy RK. Opioid rotation: the science sia-related outcome. Future homogeneous (randomized and and the limitations of the equianalgesic dose table. J Pain Symp- tom Manag. 2009;38(3):426–39. https​://doi.org/10.1016/j.jpain​ open) and predefned (to reduce heterogeneity and detection symma​n.2009.06.001. risk) trials are needed to improve current level of evidence. 9. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, Cochrane Bias Methods Group, Cochrane Statistical Methods Group. The Funding This study was supported by institutional and departmental Cochrane Collaboration’s tool for assessing risk of bias in ran- funds. domised trials. BMJ (Clin Res Ed.). 2011;343:d5928. https://doi.​ org/10.1136/bmj.d5928​. 10. R Core Team. R: a language and environment for statistical com- Compliance with ethical standards puting. Vienna: R Foundation for Statistical Computing; 2018. https​://www.R-proje​ct.org/. Accessed 22 July 2018. Conflict of interest AD received Speaker Fee from Medasense Biom- 11. Viechtbauer W. Conducting meta-analyses in R with the metafor etrics Ltd. (Israel); RE and DIS serve on an Advisory Board for Me- package. 2010. https​://www.jstat​soft.org/artic​le/view/. Accessed dasense Biometrics Ltd. and have an Equity Interest in the company. 22 July 2018. Medasense is the Developer of the nociception level index. The other 12. Defresne A, Barvais L, Clement F, Bonhomme V. Standardised authors declare no competing interests. noxious stimulation-guided individual adjustment of remifentanil target-controlled infusion to prevent haemodynamic responses to Open Access This article is distributed under the terms of the Crea- laryngoscopy and surgical incision: a randomised controlled trial. tive Commons Attribution 4.0 International License (http://creat​iveco​ Eur J Anaesthesiol. 2018;35(3):173–83. https​://doi.org/10.1097/ mmons.org/licen​ ses/by/4.0/​ ), which permits unrestricted use, distribu- eja.00000​00000​00074​2. tion, and reproduction in any medium, provided you give appropriate 13. Le Gall L, David A, Carles P, Leuillet S, Chastel B, Fleureau C, credit to the original author(s) and the source, provide a link to the Dewitte A, Ouattara A. Benefts of intraoperative analgesia guided Creative Commons license, and indicate if changes were made. by the Analgesia Nociception Index (ANI) in bariatric surgery: an unmatched case–control study. Anaesth Crit Care Pain Med. 2019;38(1):35–9. https​://doi.org/10.1016/j.accpm​.2017.09.004. 14. Rogobete AF, Sandesc D, Cradigati CA, Sarandan M, Papurica M, References Popovici SE, Vernic C, Bedreag OH. Implications of Entropy and Surgical Pleth Index-guided general anaesthesia on clinical out- 1. Cantineau JP, Porte F, d’Honneur G, Duvaldestin P. Neuro- comes in critically ill polytrauma patients. A prospective observa- muscular efects of rocuronium on the diaphragm and adduc- tional non-randomized single centre study. J Clin Monit Comput. tor pollicis muscles in anesthetized patients. Anesthesiology. 2018;32(4):771–8. https​://doi.org/10.1007/s1087​7-017-0059-2. 1994;81(3):585–90. 15. Meijer F, Martini C, Broens S, Boon M, Niesters M, Aarts L, 2. Edry R, Recea V, Dikust Y, Sessler DI. Preliminary intraoperative Olofsen E, van Velzen M, Dahan A. Nociception-guided versus validation of the nociception level index: a noninvasive nocicep- standard care during remifentanil–propofol anesthesia: a rand- tion monitor. Anesthesiology. 2016;125(1):193–203. https​://doi. omized controlled trial. Anesthesiology 2019;130(5):745–5. https​ org/10.1097/aln.00000​00000​00113​0. ://doi.org/10.1097/ALN.00000​00000​00263​4 3. Funcke S, Sauerlaender S, Pinnschmidt HO, Saugel B, Bremer K, 16. Jain N, Gera A, Sharma B, Sood J, Chugh P. Comparison of Reuter DA, Nitzschke R. Validation of innovative techniques for surgical pleth index guided analgesia using fentanyl versus monitoring nociception during general anesthesia: a clinical study conventional analgesia technique in laparoscopic cholecystec- using tetanic and intracutaneous electrical stimulation. Anesthe- tomy. Minerva Anestesiol. 2019. https​://doi.org/10.23736​/s0375​ siology. 2017;127(2):272–83. https://doi.org/10.1097/aln.00000​ ​ -9393.18.12954​-3. 00000​00167​0. 17. Bergmann I, Gohner A, Crozier TA, Hesjedal B, Wiese CH, Popov 4. Ledowski T, Burke J, Hruby J. Surgical pleth index: prediction AF, Bauer M, Hinz JM. Surgical pleth index-guided remifentanil of postoperative pain and infuence of arousal. Br J Anaesth. administration reduces remifentanil and propofol consumption and 2016;117(3):371–4. https​://doi.org/10.1093/bja/aew22​6. shortens recovery times in outpatient anaesthesia. Br J Anaesth. 5. Stockle PA, Julien M, Issa R, Decary E, Brulotte V, Drolet P, 2013;110(4):622–8. https​://doi.org/10.1093/bja/aes42​6. Henri M, Poirier M, Latulippe JF, Dorais M, Verdonck O, Fortier 18. Chen X, Thee C, Gruenewald M, Wnent J, Illies C, Hoecker J, LP, Richebe P. Validation of the PMD100 and its NOL Index Hanss R, Steinfath M, Bein B. Comparison of surgical stress to detect nociception at diferent infusion regimen of remifen- index-guided analgesia with standard clinical practice dur- tanil in patients under general anesthesia. Minerva Anest- ing routine general anesthesia: a pilot study. Anesthesiology. esiol. 2018;84(10):1160–8. https​://doi.org/10.23736​/s0375​ 2010;112(5):1175–83. https​://doi.org/10.1097/aln.0b013​e3181​ -9393.18.12720​-9. d3d64​1. 6. Martini CH, Boon M, Broens SJ, Hekkelman EF, Oudhof LA, 19. Colombo R, Raimondi F, Rech R, Castelli A, Fossali T, Marchi Buddeke AW, Dahan A. Ability of the nociception level, a mul- A, Borghi B, Corona A, Guzzetti S. Surgical Pleth Index guided tiparameter composite of autonomic signals, to detect noxious analgesia blunts the intraoperative sympathetic response to laparo- stimuli during propofol–remifentanil anesthesia. Anesthesiology. scopic cholecystectomy. Minerva Anestesiol. 2015;81(8):837–45. 2015;123(3):524–34. https​://doi.org/10.1097/aln.00000​00000​ 20. Gruenewald M, Willms S, Broch O, Kott M, Steinfath M, Bein 00075​7. B. Sufentanil administration guided by surgical pleth index vs standard practice during sevofurane anaesthesia: a randomized

1 3 Journal of Clinical Monitoring and Computing (2020) 34:629–641 641

controlled pilot study. Br J Anaesth. 2014;112(5):898–905. https​ assessment of its utility for the reduction of movement during ://doi.org/10.1093/bja/aet48​5. colonoscopy. Anesth Analg. 2010;110(3):765–72. https​://doi. 21. Won YJ, Lim BG, Lee SH, Park S, Kim H, Lee IO, Kong MH. org/10.1213/ane.0b013​e3181​cc9eb​e. Comparison of relative oxycodone consumption in surgical pleth 26. Sabourdin N, Barrois J, Louvet N, Rigouzzo A, Guye ML, Dadure index-guided analgesia versus conventional analgesia during C, Constant I. Pupillometry-guided intraoperative remifentanil sevofurane anesthesia: a randomized controlled trial. Medicine administration versus standard practice infuences opioid use: a (Baltim.). 2016;95(35):e4743. https​://doi.org/10.1097/md.00000​ randomized study. Anesthesiology. 2017;127(2):284–92. https​:// 00000​00474​3. doi.org/10.1097/aln.00000​00000​00170​5. 22. Dundar N, Kus A, Gurkan Y, Toker K, Solak M. Analgesia noci- 27. Rossi M, Cividjian A, Fevre MC, Oddoux ME, Carcey J, Halle ception index (ANI) monitoring in patients with thoracic paraver- C, Frost M, Gardellin M, Payen JF, Quintin L. A beat-by-beat, tebral block: a randomized controlled study. J Clin Monit Comput. on-line, cardiovascular index, CARDEAN, to assess circulatory 2018;32(3):481–6. https​://doi.org/10.1007/s1087​7-017-0036-9. responses to surgery: a randomized clinical trial during spine 23. Szental JA, Webb A, Weeraratne C, Campbell A, Sivakumar H, surgery. J Clin Monit Comput. 2012;26(6):441–9. https​://doi. Leong S. Postoperative pain after laparoscopic cholecystectomy org/10.1007/s1087​7-012-9372-y. is not reduced by intraoperative analgesia guided by analgesia 28. Grüenewald M, Harjuz J, Preckel B, Moinár Z, Yli-Hankalas A, nociception index (ANI(R)) monitoring: a randomized clinical Beins B. Comparison of adequacy of anaesthesia monitoring with trial. Br J Anaesth. 2015;114(4):640–5. https​://doi.org/10.1093/ standard clinical practice during routine general anaesthesia: an bja/aeu41​1. international, multi-centre, single-blinded randomized controlled 24. Upton HD, Ludbrook GL, Wing A, Sleigh JW. Intraoperative trial. In: Abstract 1718. Paper presented at the Euroanaesthesia, “Analgesia Nociception Index”-guided fentanyl administration Copenhagen, 3 June 2018. during sevofurane anesthesia in lumbar discectomy and laminec- tomy: a randomized clinical trial. Anesth Analg. 2017;125(1):81– Publisher’s Note Springer Nature remains neutral with regard to 90. https​://doi.org/10.1213/ane.00000​00000​00198​4. jurisdictional claims in published maps and institutional afliations. 25. Martinez JY, Wey PF, Lions C, Cividjian A, Rabilloud M, Bissery A, Bourdon L, Puidupin M, Escarment J, Quintin L. A beat-by- beat cardiovascular index, CARDEAN: a prospective randomized

1 3