Physiological Signal Processing for Individualized Anti-Nociception Management During General Anesthesia: a Review J

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Physiological Signal Processing for Individualized Anti-nociception Management During General Anesthesia: a Review J. De jonckheere1, V. Bonhomme2, M. Jeanne1,3, E. Boselli4, M. Gruenewald5, R. Logier1,6, P. Richebé7 1 INSERM CIC-IT 1403, Maison Régionale de la Recherche Clinique, CHRU de Lille, France 2 University Department of Anesthesia and ICM, CHR Citadelle, Liege, Belgium 3 Department of Anaesthesiology and Intensive Care, Hopitale Roger Salengro, CHRU de Lille, France 4 Department of Anaesthesiology and Intensive Care, Édouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France 5 Department of Anaesthesiology and Intensive Care, University Hospital Schleswig Holstein Campus Kiel, Kiel, Germany 6 UDSL EA2694, Univeristé Lille Nord de France, Lille, France 7 Department of Anaesthesiology, University of Montreal, Quebec, Canada

Summary Introduction RE, GE Healthcare Helsinki, Finland). The Objective: The aim of this paper is to review existing technol- bispectral index constitutes a combination of General anesthesia combines the use of an- ogies for the nociception / anti-nociception balance evaluation several electroencephalographic parameters during surgery under general anesthesia. algesic, hypnotic and muscle-relaxant drugs computed both in the time domain and in Methods: General anesthesia combines the use of analgesic, hypnotic in order to render patients unconscious, the frequency domain whereas the state and and muscle-relaxant drugs in order to obtain a correct level of patient disconnected from their environment and response entropy indexes are computed in the non-responsiveness during surgery. During the last decade, great unresponsive to stimulation during surgery. frequency domain and represent an evaluation efforts have been deployed in order to find adequate ways to measure During the last decade, great efforts have of the dominated and the total parts of the how anesthetic drugs affect a patient’s response to surgical nocicep- been deployed in order to find adequate spectrum. Both the technologies have proven tion. Nowadays, though some monitoring devices allow obtaining ways to measure how anesthetic drugs affect their ability to evaluate consciousness of the information about hypnosis and muscle relaxation, no gold standard a patient’s response to surgically induced patient under intravenous (propofol) or vola- exists for the nociception / anti-nociception balance evaluation. nociception. Nowadays, the real-time ac- tile agents (sevoflurane) anesthesia but may Articles from the PubMed literature search engine were reviewed. As quisition and analysis of a patient’s physio- not be used under ketamine anesthesia [2]. this paper focused on surgery under general anesthesia, articles about logical parameters provides an efficient way Muscle relaxation monitors have also nociception monitoring on conscious patients, in post-anesthesia care to continuously assess the response of drug been used routinely for many years: They unit or in intensive care unit were not considered. administration in order to suppress nocicep- enable clinicians to precisely adapt muscle Results: In this article, we present a review of existing technol- tion, thus making it possible for clinicians to relaxation to the need of surgeons during the ogies for the nociception / anti-nociception balance evaluation, personalize drug administration. procedure, and to test for residual neuromus- which is based in all cases on the analysis of the autonomous Depth of hypnotic component of anesthe- cular blockade before weaning the patient nervous system activity. Presented systems, based on sensors and sia monitors have now been commercially from ventilatory support. physiological signals processing algorithms, allow studying the available for many years and are used rou- Compared with other components of patients’ reaction regarding anesthesia and surgery. tinely: They record and process simplified anesthesia, no gold standard exists for Conclusion: Some technological solutions for nociception / antinoci- electroencephalographic (EEG) signals and the assessment of nociception / anti-no- ception balance monitoring were described. Though presented devices display the result in real-time, thus enabling ciception (NAN) balance, despite several could constitute efficient solutions for individualized anti-nociception anesthesiologists and nurse anesthetists to management during general anesthesia, this review of current literature existing technical solutions, of which some adjust hypnotic agent administration to reduce emphasizes the fact that the choice to use one or the other mainly relies have been commercialized during the last probability of intraoperative awareness [1] on the clinical context and the general purpose of the monitoring. decade. Inadequate anti-nociception of- or discomfort as well as hypnotic overdose ten results in blood pressure elevation or Keywords which is likely to be involved in postop- tachycardia. The converse, opioid overdose Physiologic monitoring, general anesthesia, nociception, erative delirium or cognitive dysfunction. often results in bradycardia and low blood tranducers, digital signal processing EEG monitors then can calculate indexes pressure episodes, and has been related to related to the patient consciousness such postoperative hyperalgesia [3]. Hence, the Yearb Med Inform 2015;10:95-101 as the bispectral index (BIS®, ASPECT search for the optimal opioid administration http://dx.doi.org/10.15265/IY-2015-004 Medical Systems, Newton, MA) or the is a difficult but important objective of Published online August 13, 2015 state and response entropy index (SE and modern anesthesia.

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In this article, we present a review of an unilateral popliteal sciatic nerve block bed of tissues. The resulting microvascular existing technologies for NAN balance eval- [6]. They tested the PD response to tetanic pulse wave allows the computation of two uation, which is mainly based on the analysis electrical stimulation applied 1) on the parameters: the heart beat interval (HBI) of the Autonomous Nervous System (ANS) blocked leg, 2) on the non-blocked leg. and the PhotoPlethysmoGraphic pulse wave reactions to a changing environment during They found that PD increased by 2% on the Amplitude (PPGA). anesthesia and surgery. blocked leg whereas PD increased by 17 % SPI (previously named the Surgical on the non-blocked leg. The authors con- Stress Index, or SSI) was developed in order cluded that PD allowed the investigation of to provide a simple numerical measure of the efficacy of a peripheral nerve block on the level of surgical stress in an anesthetized Pupillometry blocking nociception. These results could patient [7]. To develop this index, authors Pupillometry is a well-known method to also be considered as a proof of concept studied the influence of a standard surgical study the ANS sympathetic activity. It regarding PD ability to detect inadequate stress on several physiological parameters consists in measuring the pupil diameter anti-nociception. However, PD could be with varying opioid concentrations. Stud- (PD) changes in response to different affected in patients with ocular injury. ied parameters were; the normalized heart painful stimuli. Moreover, such a system does not allow beat interval (HBInorm), the normalized Larson et al. studied the effect of an continuous NAN balance monitoring. PhotoPlethysmoGraphic pulse wave Ampli- electrical noxious stimulus on PD, blood tude (PPGAnorm), the non-invasive systolic pressure (BP) and heart rate (HR) in anes- blood pressure (NIBP), the pulse transit thetized patients [4]. They found that, even time (PTT) and the Response entropy (RE). if stimulation significantly increased HR The Surgical Pleth Index (SPI) The authors defined a total surgical stress and BP, PD response to noxious stimulus The Surgical Pleth Index (SPI) (GE (TSS) index which depends both on stress was much more important. The authors Healthcare, Helsinski, Finland) is an index predefined intensity (PreIntensity) and on concluded that PD was more sensitive to reflecting the ANS sympathetic activity. opioid concentration (Ceremi). noxious stimulation than commonly used This index is computed from the signal is- TSS = PreIntensity- (Ce / 3 ng/ml). hemodynamic variables. sued from a photoplethysmographic sensor remi Constant et al tested PD, BP, HR and BIS positioned on the finger. Such an optical The correlation of each parameter with TSS response to skin incision in children [5]. sensor, composed of a light source and a was measured in order to select the two best They found that PD, BP and HR significantly photodetector (Figure 1), is able to mea- candidate variables regarding correlation, increased after skin incision, whereas BIS sure volume changes in the microvascular continuity and sensitivity to artifacts. After- didn’t vary. Again, PD increase was more important than the increase of BP and HR. Moreover, opioid administration signifi- Fig. 1 Photoplethysmography and photople- cantly reduced PD. The authors concluded tysmographic waveform. An Infrared LED illumi- that PD was more sensitive than commonly nates the skin and the photo-detector measures used variables to assess pain response in changes in light absorption due to blood flow. anesthetized children. A few years ago, a French company, ID- med (IDMed, Marseille, France) developed a medical device based on the pupil response to noxious stimulus; the AlgiScan®. Com- posed of an infrared 67 pictures/s camera, this system allows to monitor changes in PD and to study the pupillary reflex dilatation (PRD in %) in response to a painful stimulus. This system also integrated electrodes and an electric stress generator allowing the performance of tetanic electrical stress in order to measure PRD response. As the system requires a direct access to the eye, its use is limited to an intermittent assessment of the NAN balance. Isnardon et al. used this system to study the PRD response to a noxious stimulus during general anesthesia associated with

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ward, PPGAnorm and HBInorm were selected to on the palmar surface of a patient’s hand, it under general anesthesia [13]. The clinical construct the model and SPI was defined as; allows monitoring electrical conductance stress score was estimated in real time by modulation due to the appearance/removal observing the patient and was based on SPI = 100 – (0.7*PPGA – HBI ). norm norm of sweat related to sympathetic activation/ muscle movement, coughing, eye opening, For clinical use, a SPI value close to 100 in- inhibition. Storm et al. described algorithms sweating on the forehead, tears, face muscle dicates a very high stress level whereas a SPI designed to obtain information on the number reaction and systolic blood pressure (SBP) close to 0 indicates a very low stress level. of SC fluctuation (NSCF) and the amplitude over 130 mmHg. They found that NSCF was Struys et al. studied SPI, HR and RE of SC fluctuation (ASCF) [12] (Med-Storm positively correlated with the clinical stress ability to assess the balance between an- Innovation, Oslo, Norway). To compute score during intubation (r2 = 0.73, p<0.0005) ti-nociception and stress level during general NSCF and ASCF, the system automatically whereas RE showed a less important correla- anesthesia [8]. They observed SPI, HR and detects the valleys and the peaks of the curves tion (r2 = 0.33, p=0.007). NSCF significantly RE response to a standard electrical tetanic by analyzing the derivative of the wave. The increased after tetanic electrical stimulation stimulation under various opioid concentra- amplitude is then computed as the difference (p<0.001) whereas RE didn’t vary. The au- tions, and found that SPI correlates better between the SC value of the peak and the SC thors concluded that NSFC was sensitive to with the opioid concentration than RE and value of the previous valley. If this amplitude noxious stimulation during GA. However, HR. They concluded that SPI could be a is higher than a predefined threshold (0.02 NSFC could be affected by hypothermia. useful measurement of the NAN balance. µS), the peak is taken into account. In their study, Bonhomme et al. investi- In a study aiming at evaluating the gated SPI, HR and BP ability to assess the correlation between skin conductance and NAN balance during GA [9]. Even if the perioperative stress level [12], Storm et Analgesia/Nociception Index (ANI) study design was very close to Struys’ one, al. studied NSCF, ASCF, arterial catechol- The Analgesia/Nociception Index (ANI) they found that, following noxious stim- amines, HR, BIS and BP before, during (Mdoloris Medical Systems, Lille, France) ulation, SPI, HR and BP had comparable and after general anesthesia for elective is a heart rate variability (HRV) based index. performances to predict the opioid concen- laparoscopic cholecystectomy. They found This technology continuously analyzes the tration received. They also found that low that NFSC and ASCF were positively influence of respiratory sinus arrhythmia intravascular volume and a history of treated correlated with BIS, BP, epinephrine level (RSA) on HR, which leads to a measure chronic elevated blood pressure affected SPI, and norepinephrine level. Moreover, during of the relative parasympathetic tone. The HR and BP interpretation. tracheal intubation, NSCF showed the same method consists of detecting each R peak Several studies showed the clinical benefit response as the changes in norepinephrine of an ECG signal in order to construct the of using SPI for personalized anti-nocicep- levels whereas BIS did not vary. The authors RR series (R-R interval evolution over time). tion management during general anesthesia. concluded that NSCF could be a useful The RR series is then normalized and Chen et al. compared SPI-guided anti-no- method to monitor perioperative stress. band pass filtered between 0.15 and 0.4 Hz ciception with standard clinical practice In another study, Gjerstad et al. compared in order to keep parasympathetic related [10]. They found that SPI-guided opioid NSCF, RE and a clinical stress score during variations only, which are mainly influenced administration resulted in lower opioid intubation and tetanic stimulation in patients by the respiration cycle. consumption, better hemodynamic stability and lower incidence of unwanted events. With a similar clinical setting, Bergmann et al. found that SPI-guided opioid administration reduced both opioid and hypnotic drugs consumption, and resulted in faster recovery at the end of the procedure [11]. To conclude, SPI constitutes a non invasive continuous method for NAN monitoring. However, SPI could be affected by artifacts like vasoconstriction, hypovolemia or hypothermia.

Skin Conductance Skin conductance (SC) is a well-known method to study the sympathetic nervous system activity. Through three electrodes positioned Fig. 2 Skin conductance level as a function of time.

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Boselli et al. also hypothesized that ANI could be used to predict postoperative pain felt in the post anesthesia care unit (PACU) [17]. The ANI was evaluated at the end of the surgical procedure, just before tracheal extubation and pain was self-reported by the patients 10 minutes after their arrival in the PACU using a 0-10 Numerical Rating Scale (NRS). A negative linear relationship Fig. 3 ECG signal, R peak detection and R-R interval computation was found between ANI measured before extubation and the NRS measured 10 minutes after the patient’s arrival in PACU (r² = 0,33 ; p<0,01). An ANI threshold of 50 was identified as predictive of acute postoperative pain (NRS>3) with good sensitivity (86%) and specificity (86%). The authors concluded that ANI measured immediately before extubation is predictive of postoperative pain. ANI constitutes a non invasive method for NAN balance continuous monitoring. However, ANI can be affected by several artifacts like arrhythmia, apnea or low respiratory frequency (< 9 cpm).

CARDEAN Fig. 4 Mean centered, normalized and band pass-filtered RR series in 2 different levels of NAN balance: 1) surgical stimulus in the case of The CARdiovascular DEpth of ANalgesia adequate NAN balance (upper panel), 2) surgical stimulus in the case of inadequate anti-nociception (lower panel). (CARDEAN, Alpha-2 Ltd, Lyon, France) index detects the occurrence of a minor elevation in blood pressure followed by Local minima and maxima are then the start of surgery, ANI decreased to 60 minor tachycardia, which reflect the inhi- detected and the resulting envelope is di- and decreased further to 50 after the stress bition of the cardiac baroreflex. This index vided into four subareas A1, A2, A3 and stimulus (pneumoperitoneum inflation), based on the evolution on BP and HR has A4. AUCmin is defined as the minimum of while there were no significant changes in retrospectively been designed in order to the 4 subareas. HR or BP. After completion of surgery, ANI predict unexpected intraoperative movement ANI is then computed as; returned to 90. The authors concluded that in anesthetized and non-paralyzed patients ANI seems more sensitive than HR and BP [18]. According to the authors, in the case ANI = 100×(a×AUCmin+b)/12.8 to moderate noxious stimulation in anesthe- of adequate NAN balance, a minor elevation where a=5.1 and b=1.2 have been deter- tized patients. in blood pressure is followed by a decrease mined on a 200 patients dataset in order to In another study, Jeanne et al. investigated in HR (increase in RR interval, figure 5 A) keep coherence between the visual effect of how ANI could early detect hemodynamic regulated by the cardiac baroreflex. The respiratory influence on RR series and the reactivity defined as an increase in HR or converse, when a minor elevation in blood quantitative measurement of ANI. BP by more than 20% [15]. A ROC curve pressure is followed by minor tachycardia For clinical use, an ANI value close to analysis led to a threshold of 63 for hemody- (decrease in RR interval, figure 5 B), the 0 indicates a very high ANS response to namic reactivity early detection. The authors authors concluded in a cardiac baroreflex stress which is a sign of low anti-nociception conclude that ANI values during general inhibition, which may indicate risk of intra- whereas an ANI close to 100 indicates a very anesthesia are coherent with the evolution of operative movement. low ANS response to stress. the NAN balance and that maintaining ANI CARDEAN is a software that uses ECG Jeanne et al. studied ANI, HR and BP above 63 should decrease the rate of hemod- and non-invasive continuous blood pres- variations during general anesthesia [14] for ynamic episodes, which needs further clinical sure sensors (Finapres medical systems, laparoscopic abdominal surgery. Anesthesia validation. In another study, Boselli et al. also Amsterdam, Netherlands). In case of an induction was followed by a decrease in HR demonstrated ANI ability to predict hemody- increase in SBP between 2 and 5 mmHg, and BP, and an increase in ANI values. After namic reactivity on a larger population [16]. the CARDEAN algorithm analyses the

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under standardized noxious stimulus at different anti-nociception level neither the ability of CARDEAN to predict other sign of inadequate NAN balance. Rossi et al. studied the CARDEAN response to skin incision at varying opioid concentration [20]. They measured the CARDEAN value before and after skin incision in two groups of patients: one group with a low opioid administration (remifentanil concentration of 2 ng/mL) and one group with an important opioid administration (remifentanil concentration of 4 ng/mL). After skin incision, the CARDEAN significantly increased in the first group whereas it did not vary in the second one. The CARDEAN was also predictive of tachycardia and elevated blood pressure (area under the ROC curve = 0.81). The authors concluded that the CARDEAN was related to the adequacy of the NAN balance. However, CARDEAN could be affected by artifacts like vasoconstriction or hypovolemia.

Wavelet Transform Cardiorespiratory Coherence The wavelet transform cardiorespiratory coherence (WTCRC) was developed to estimate the coupling between heart rate and respiration. The WTCRC applies a continuous wavelet transform to the HR time series and to a respiratory wave (for example

expired CO2). Wavelet coefficients derived from the HR time series (WT) and respiratory time series (WR) are then used to compute the power spectrum of the HR time series (WTT), the power spectrum of the respiratory time RR Fig. 5 RR and SPB series at 2 different levels of the NAN balance; A) surgical stimulus in case of adequate anti-nociception (upper panel), B) series (W ) and the cross power spectrum TR surgical stimulus in the case of inadequate anti-nociception (lower panel). (W ). A coherence estimator is defined as: C = (WTR) / (WRR * WTT) SBP and RR area under the curve as well as In a first study, Martinez et al. investigat- WTCRC output vector corresponds to the RR amplitudes in order to obtain an index ed CARDEAN efficacy at reducing the oc- coherence values at the known respiratory related to the cardiac baroreflex activity. currence of movement during surgery [19]. frequency. Thresholds values on SBP and RR area They compared CARDEAN-guided opioid As a proof of concept, Brouse et al. under the curve and RR amplitudes were administration with standard clinical prac- assessed the WTCRC ability to detect determined to obtain the best specificity tice. They concluded that CARDEAN-guid- movements occurring during general anes- and sensibility regarding the occurrence of ed opioid administration significantly thesia [21]. The WTCRC allowed detecting head, limb or finger movements. For clinical decrease the occurrence of intraoperative movements with a sensitivity of 95 % for the use, a CARDEAN higher than 60 is a sign movements (by 51%). However, the authors minimum WTCRC value and 65% with the of cardiac baroreflex inhibition. did not study the variations of CARDEAN mean WTCRC.

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Brouse et al. studied WTCRC, BP and The authors demonstrated that the Ledowski et al. studied the relation-

HR responses to 1) noxious stimulus (den- NoLnon-linear significantly increases after ship between SPI, AFSC and NFSC, and tal dam insertion) and 2) opioid injection minor, moderate and major noxious the stress hormones level [25]. The SPI,

[22]. They found that, even if stimulation stimulation while NoLlinear only increased NFSC, HR and BP were recorded and significantly increased WTCRC, HR and after major and moderate noxious stimulation. blood samples (plasma level of adrenaline, BP, WTCRC response to noxious stimulation The PPGA and HR significantly changed noradrenaline, cortisol...) were withdrawn was much more important than the response after major noxious stimuli whereas HRV-HF, during GA. The authors showed that neither of HR and BP. The authors concluded that SCL and NFSC did not vary. A ROC analysis SPI nor NFSC reflected stress hormones

WTCRC was more sensitive than HR and BP showed that NoLlinear and NoLnon-linear better changes accurately. However, SPI signifi- to assess the balance between nociception discriminate noxious and non-noxious events cantly decreased after opioid administration and anti-nociception. However, WTCRC (area under the curve = 0.97). The NoLlinear whereas NFSC did not vary. could be affected by several artifacts like and NoLnon-linear were positively correlated with The PRD evaluated by the AlgiScan® arrhythmia or apnea. the CISA (r = 0.77 and 0.88 respectively). was compared to the ANI to assess the ef-

The authors concluded that the NoLlinear and fectiveness of regional anesthesia in children NoLnon-linear constituted a better solution than under GA [26]. The pupillary diameter and individual parameters to evaluate the balance the ANI were recorded immediately before Multi-parameter Approach between nociception and anti-nociception. skin incision, and every 30 seconds during Ben-Israel et al. developed the nociception 2 minutes. The authors defined regional level (NoL) indexes that are based on the anesthesia failure by a 10% increase in HR combination of multiple physiological within 2 minutes following the skin incision. parameters [23]. Based on a photoplethys- The PRD and the ANI significantly changed mograpic sensor and skin conductance Discussion after skin incision. Failure of regional anes- electrodes regrouped in single finger In this paper, we presented several existing thesia was predicted by PRD and ANI with probe, the developed the PMD-100TM technologies that allow the evaluation of the reasonable areas under the ROC curves

(Medasense Biometrics Ltd, Ramat Yishai, NAN balance during general anesthesia. (respectively 0.671 and 0.747). The authors Israel) device allows the extraction of Even if these technologies have proven concluded that both ANI and PRD vary with parameters related to pulse-wave and their ability to evaluate the ANS response skin incision and that they could represent skin conductance. The studied parameters to noxious stimulation, the choice to use efficient tools to assess the effectiveness of were the photoplethysmograpic waveform one or the other mainly relies on the clini- regional anesthesia. amplitude (PPGA), HR, the skin conduc- cal context and the general purpose of the Gruenewald et al. studied the ANI, SPI, tance level (SCL) and the number of skin monitoring: intermittent versus continuous, BIS, HR and BP response to painful stimula- conductance fluctuation (NSCF). A high routine versus clinical research, etc. Does tion under various levels of anti-nociception frequency heart rate variability (HRV-HF) the clinician want to limit the opioid admin- [27]. They observed that BIS, HR and BP was also computed as the power spectral istration or the postoperative pain? Does did not change after noxious stimulation density between 0.15 and 0.4 Hz using a he want to limit patient movements and/or whereas SPI and ANI varied after each stim- Lomb-Scargle method. hemodynamic reactivity? ulation: They also noted that higher opioid The authors then defined two indexes re- Moreover, even if some technologies rates resulted in higher ANI and lower HR are already commercially available (SPI, grouping all the studied parameters: NoLlinear and BP values whereas SPI and BIS were which is based on a linear regression and SC, PRD, ANI), others are still under not influenced. The authors concluded that development and therefore not marketed NoLnon-linear which is based on a non-linear both ANI and SPI could detect possible Random Forest regression. (CARDEAN, WTCRC, NoL). inadequate NAN balance. In order to study indexes reactivity re- Several clinical studies have been per- garding the noxious stimuli during surgery formed to compare the different technologies under general anesthesia, the authors de- in various clinical settings. Sabourdin et al. fined non-noxious periods as well as minor, studied the ANI and skin conductance re- moderate and major noxious stimulations. sponse to noxious stimulation under varying Conclusion Besides, the authors defined a combined in- opioid flow rates in a pediatric population More than identifying the “best” monitor dex of stimulus and anti-nociception (CISA) [24]. The ANI decreased significantly after of the NAN balance, this review of current based both on the stimulus intensity (evalu- each noxious stimulation for all opioid flow literature emphasizes the fact that individual ated by clinicians) and the concentration of rates, while skin conductance, HR and BP characteristics of each monitoring device, opioids, defined as follows: were not modified. The authors concluded and hence the physiological understanding it that, in their clinical setting, the ANI might provides, may be of importance when choos- CISA = Stim – *Ce + intensity β opioid γ be a more sensitive tool to evaluate the NAN ing a monitor for anyone’s practice. In our where β = 1/8 and γ = 1.5. balance than HR, BP or skin conductance. view, it is of most importance that the user

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understands how a given monitor is working, of surgical stress during general anaesthesia. Br J 19. Martinez JY, Wey PF, Lions C, Cividjian A, in order to adequately use the information it Anaesth 2007;98:447-55. Rabilloud M, Bissery A, et al. A beat by beat 8. Struys MM, Vanpeteghem C, Huiku M, Uutela cardiovascular index, CARDEAN: A prospective provides and eventually adapt the adminis- K, Blyaert NB, Mortier EP. Changes in a surgical randomized assessment of its utility for the reduc- tration of anesthetic drugs. When looking stress index in response to standardized pain tion of movement during colonoscopy. Anesthes into the clinical designs used for monitoring stimuli during propofol-remifentanil infusion. Br Analg 2010;110:765-72. validation, absolute values seem more or less J Anaesth 2007;99:359-67. 20. Rossi M. Cividjian A, Fevre MC, Oddoux ME, Carcey J, Halle C, et al. A beat by beat, on-line, questionable in all existing devices because 9. 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IMIA Yearbook of Medical Informatics 2015