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Pain

Effect of intravenous lidocaine on pain after head and neck cancer surgery (ELICO trial)

A randomised controlled trial

Wallon, Grégoire; Erbacher, Julien; Omar, Edris; Bauer, Christian; Axiotis, Grégory; Thevenon, Sylvie; Soubirou, Jean-Luc; Aubrun, Frédéric

Author Information
European Journal of Anaesthesiology: September 2022 - Volume 39 - Issue 9 - p 735-742
doi: 10.1097/EJA.0000000000001712
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Abstract

KEY POINTS

  • Intravenous lidocaine has become a part of opioid sparing in multimodal analgesia and early rehabilitation protocols after surgery.
  • No studies have been conducted in major ENT cancer surgery, even though these are procedures with high pain scores and postoperative morphine consumption.
  • In the current study, there was no significant difference in morphine consumption during the first 48 postoperative hours in the lidocaine group compared with the placebo group.
  • Three to six months after surgery, there was no difference in pain scores or analgesic consumption between the lidocaine group and the placebo group.

Introduction

Over the past 10 years, intravenous (i.v.) administration of lidocaine in the peri-operative period during various types of surgery has caught the interest of clinicians.1 The major benefits of i.v. lidocaine are on gastro-intestinal function after surgery; the pain benefits and its effect on opioid consumption are more variable across procedures.2–8 This differential effect could be explained by the specific effect of lidocaine on intestinal smooth muscle. 9 The fact remains, however, that i.v. lidocaine has become a part of opioid sparing in multimodal analgesia and early rehabilitation protocols after surgery (ERAS).10–12

The exact mechanism of action of i.v. lidocaine is still uncertain. The main effect in local anaesthesia is the inhibition of the nociceptive nerve signal by blocking the sodium channels on the neuron membrane and blocking the transmission of the nociceptive signal. However, when lidocaine is administered intravenously, the lidocaine concentration is insufficient to block sodium channels.13 Efficacy of i.v. lidocaine is supposed to rely on its anti-inflammatory (priming of poly-morphonuclear granulocyte) and antihyperalgesic properties acting directly on the central nervous system on various targets (N-methyl-D-aspartate receptors, G-protein-coupled receptors, potassium channels).13

Evaluation of lidocaine in ear, nose and throat (ENT) surgery has been confined to superficial procedures, such as thyroidectomy and septoplasty.14–16 No studies have been conducted so far on major cancer surgery, even though these are the procedures with high pain scores and high postoperative morphine consumption.17,18

Opioid patient-controlled analgesia is the backbone of pain management in this type of surgery.17 Patients are exposed to adverse effects, which can disturb recovery and lead to opioid-induced hyperalgesia, with the risk of chronic postsurgical pain (CPSP).

We thought that this type of surgery was the one which would benefit the most from i.v. lidocaine. It involves extensive resection of cervicofacial soft tissue, which is a richly innervated area. Three to six months after oral cavity surgery, more than 40% of patients express moderate to extreme pain. 19 Blocking the pain cascade would potentially reduce the very high incidence of CPSP. 20,21 We hypothesised that peri-operative i.v. lidocaine would decrease opioid consumption during and after surgery in patients undergoing cancer surgery in the ENT sphere.

Materials and methods

Ethics

Ethical approval (Ethical Committee no. 2016–019-2) was provided by the Ethical Committee CPP Sud-Est II, Groupement Hospitalier Est, Bâtiment Pinel, 59 Boulevard Pinel, 69500 Bron, on 7 July 2016 and the French national drug safety agency (ANSM) (No. 160510A-32, 8 June 2016). The study was conducted according to the guidelines for good clinical practice in clinical trials and was registered under the acronym ELICO for ‘Evaluation de la Lidocaïne par voie Intraveineuse en Chirurgie carcinologique ORL’. The study was registered by the Hospices civils de Lyon (69HCL15_0743) and written informed consent was obtained from all participating in the trial. The trial was registered prior to patient enrolment at European clinical trial database (EUDRACT CT (2015-005799-90) and at clinicaltrials.gov (NCT02894710, principal investigator: Grégoire Wallon, first posted date: 9 September 2016).

Study design and participants

The protocol has been published previously.22 Between December 2016 and December 2019, we conducted a prospective, randomised, placebo-controlled, double-blind phase-3 trial at the Croix-Rousse Hospital (Hospices Civils de Lyon, France), a tertiary hospital and the Centre Léon Bérard (Lyon, France), a cancer care hospital.

Eligible patients were 18 years or older, scheduled for elective major head and neck cancer surgery. The selected procedures were total or partial laryngectomy, oropharyngectomy with or without mandibulotomy, glossectomy, extended floor-of-mouth resection, maxillectomy or intra-oral extended resection. Associated procedures such as pectoralis major flap, free flap, lymph node resection and tracheostomy were recorded. Exclusion criteria were hypersensitivity to amide local anaesthetics, hepatocellular insufficiency (international normalised ratio > 1.6) or cirrhosis, systolic heart failure (left ventricular ejection fraction < 50%), atrioventricular conduction disorders requiring permanent electro-systolic stimulation with pacemaker not yet implemented, treatment with antiarrhythmic or beta-blockers classified by Vaughan Williams, BMI more than 30 kg m−2 pre-operative medication with strong opioids for chronic or neuropathic pain, epilepsy not controlled by treatment, acute porphyria, fluid overload, hypersensitivity to any component of 5% glucose solution, pregnant or breastfeeding women and patients under legal protection measures.

Randomisation and masking

Patients were randomised to either lidocaine or placebo (1 : 1) using a computer-generated list by complete block design, stratified by centre. Participants and investigators were masked to treatment allocation throughout the study. Allocation concealment was provided by enclosure in sealed, opaque, sequentially numbered envelopes. The envelope was opened only upon arrival of the patient in the operating room by a nurse not involved in patient care and who only prepared the allocated treatment in two blinded 50 ml syringes. Medical staff responsible for peri-operative care remained unaware of the patient assignment.

Procedures

Before the skin incision, the lidocaine group received a bolus of 1.5 mg kg−1 of i.v. lidocaine, followed by a continuous infusion at 2 mg kg−1 h−1 until the end of surgery, reducing to 1 mg kg−1 h −1 in the postanaesthesia care unit (PACU). The lidocaine infusion was stopped at the time of discharge from PACU. The placebo group received an infusion with 5% glucose solution at a similar flow. For all patients, a standardised general anaesthetic and postoperative care protocol was followed in each centre. Monitoring was also standardised, and included continuous five-lead electrocardiography, pulse oximetry, blood pressure, capnography and temperature measurements. After pre-oxygenation, anaesthesia was induced with propofol and a target-controlled infusion of remifentanil (Minto model with protocol adapting to arterial pressure and heart rate variations). Neuromuscular blockers were used to facilitate tracheal intubation. Patients were ventilated, and anaesthesia was maintained with sevoflurane. The remifentanil target was adjusted if the heart rate changed by more than 15% from the induction heart rate or if the SBP changed by more than 30% from the preinduction systolic value. Patients were monitored during the drug infusion in the operating room and PACU. Lidocaine-related side effects were defined as dysgeusia, tinnitus, seizures, bradycardia (heart rate below 45 bpm), atrioventricular block and ventricular rhythm disorders (ventricular extrasystoles, ventricular fibrillation). If serious adverse events occurred, the drug infusion was immediately stopped, and appropriate care delivered.

Other analgesics such as ketamine, nitrous oxide, steroid or NSAIDs and local anaesthesia infiltration were not permitted.

Thirty minutes before the end of surgery, 1 g of paracetamol and 0.15 mg kg−1 of i.v. morphine were administered to all patients. After extubation, patients were transferred to the PACU. Morphine was titrated until pain relief was achieved. A numerical rating scale (NRS, 0 to 10) was used for pain assessment at least twice, on arrival and departure from the PACU. A 2 mg i.v. morphine bolus was administered if the NRS exceeded three, and the NRS and morphine administration were repeated every 10 min until an NRS of 3 or less was achieved. Afterwards, the morphine-PCA pump was programmed in an on-demand only mode without a basal rate, allowing a bolus injection of morphine 1mg and droperidol 0.05 mg every 7 min. Patients were discharged from the PACU only when the Aldrete score was 9, and when there was no evidence of pain and/or postoperative nausea and vomiting (PONV). Patients received i.v. analgesia with paracetamol 1 g every 6 h and morphine-PCA during at least the first 48 h after the procedure. Fluid balance, enteral nutrition, antibiotic use and thrombo-embolic prevention were at clinicians’ discretion.

The first follow-up visit was undertaken in the PACU for assessment of morphine consumption, adverse effects and pain evaluation at the start and end of PACU stay. Two other visits were planned at day one and day two of the early postoperative period for assessment of morphine consumption.

Outcomes

The primary endpoint was the cumulative morphine consumption during the first 48 postoperative hours. Secondary end points were intra-operative remifentanil consumption, cumulative morphine consumption during the first 24 postoperative hours and pain score 3 to 6 months after surgery as obtained during a personal interview to assess chronic postsurgical pain with the French version of the McGill Pain questionnaire23 (Short MPQ-QDSA version),24 analgesic consumption and the NRS.

Statistical analysis

The sample size estimation was based on the observed postoperative morphine consumption at 48 h in the Head and Neck Surgery Department of the Hôpital de la Croix-Rousse over a 4 week period: mean ± SD morphine consumption at 48 h was 43 ± 17 mg. The study was powered to detect a 20% reduction of the primary endpoint. With a statistical power of 0.80, 122 patients (61 per group) had to be included in the study to demonstrate such a difference in a Student's 2-sided t-test. To compensate for a possible drop-out of 10% of patients, sample size was augmented to 134 patients (67 per group).

Data were analysed according to the per-protocol principle. Once data collection and cleaning were completed, and after the final freezing of the database, the investigators were no longer blinded. Data were presented as counts and percentages for categorical variables and for continuous variables, median [IQR]. For continuous variables, comparisons between groups were performed by a Student's t-test for normally distributed data with more than 30 in each group and by the nonparametric Mann–Whitney U test otherwise. For between-groups unbalanced factor, the main analysis was checked by a complementary one adjusted on the related factor. Analyses were conducted using SPSS software Version 19.0 (IBM Corp., Armonk, New York, USA) and R software (R Development Core Team, Vienna, Austria), and were based on two-sided P-values, with statistical significance defined by P value less than 0.05.

Results

Between December 2016 and December 2019, 144 patients were included, of whom 71 were assigned to the lidocaine group and 73 to the placebo group. Twenty-six patients were excluded because they did not meet the inclusion criteria or because the planned surgery was cancelled or shortened and 19 were lost to follow up. The per-protocol analysis included 118 patients, 57 in the lidocaine group and 61 in the control group (Fig. 1).

F1
Fig. 1:
Study flow chart. BMI, body mass index; ENT, ear, nose and throat; PCA, patient-controlled analgesia.

Patient and tumour characteristics of the final study groups are summarised in Table 1. The details of the patients in the two groups did not differ significantly, except for the sex distribution, with a higher proportion of men in the lidocaine group. Nearly half of the patients were active smokers, and a quarter of them declared chronic alcohol consumption. Tumour disease progression was equally distributed between the two groups, with no significant difference in tumour location or Tumour Nodes Metastasis score (TNM score).

Table 1 - Patient and tumour characteristics at baseline
Lidocaine (n = 57) Placebo (n = 61) P
Patient data Age (Years) 60 [55 to 66] 61 [53 to 67] 0.59
Male/Female 53 (93) / 4 (7) 47 (77) / 14 (23) 0.016
BMI (kg m-2) 23 [21 to 26] 23 [20 to 25] 0.51
Tobacco smoker 30 (53) 25 (41) 0.28
Alcohol use disorder 13 (23) 15 (25) 0.99
Diabetes mellitus 4 (7) 5 (8) 0.93
Chronic renal insufficiency 1 (2) 1 (2) 0.51
Tumour locationa 0.91
Mouth 16 (28) 19 (31)
Hypopharynx 7 (12) 9 (15)
Larynx 18 (32) 16 (28)
Oropharynx 15 (26) 17 (30)
Others 1 (2) 0 (0)
Tumour stage 0.34
T1 8 (14) 4 (7)
T2 18 (32) 26 (43)
T3 12 (21) 15 (25)
T4 18 (32) 14 (23)
Tx 1 (2) 2 (3)
Nodes stage 0.58
N0 35 (61) 35 (57)
N1 8 (14) 11 (18)
N2 (A/B/C) 2 (4) / 4 (7) / 6 (11) 1 (2) / 9 (15) / 4 (7)
Nx 2 (4) 2 (3)
Metastasis stage 0.28
M0 54 (95) 56 (92)
M1 1 (2) 0 (0)
Mx 2 (4) 5 (8)
Data are given as absolute numbers n (%), and median [IQR] for each group, as appropriate
aTumour lesion could be located on several sites (total >100%).

The main surgical procedure performed, and associated procedures (surgical flaps, lymph node excisions) and median procedure times were similar in both groups (Table 2).

Table 2 - Surgical procedures characteristics
Lidocaine (n = 57) Placebo (n = 61) P
Procedure 0.89
Noninterruptive pelvimandibulectomy 9 (16) 8 (13)
Transmaxillarybuccopharyngectomy 4 (7) 7 (11)
Glossectomy 2 (4) 0 (0)
Partial laryngectomy 11 (19) 9 (15)
Total laryngectomy 12 (21) 14 (23)
Maxillectomy 2 (4) 2 (3)
Oropharyngectomy 6 (10) 8 (13)
Floor of mouth resection 2 (4) 5 (8)
Floor of mouth and tongue resection 6 (10) 5 (8)
Total circular pharyngolaryngectomy 2 (4) 3 (5)
Tracheostomy (modified procedure, secondary excluded) 1 (2) 0 (0)
Duration of surgery (min) 251 [183 to 386] 264 [180 to 383] 0.90
Associated procedures Pectoralis major flap 11 (19) 10 (16) 0.83
Lymph node excision 52 (91) 50 (82) 0.84
Free flap 18 (32) 21 (34) 0.63
Data are given as absolute n (%) and median [IQR] for each group, as appropriate.

With regard to the primary outcome, there was no significant difference in median morphine consumption during the first 48 postoperative hours in the lidocaine group compared with the placebo group with a median [IQR] of 0.60 [0.30 to 1.03] mgkg-1 vs. 0.57 [0.37 to 0.96] mgkg-1; P = 0.92) also expressed in total milligrams: 44 [21 to 73.3] mg vs. 38 [23.3 to 56.5] mg. When looking specifically at morphine consumption by PCA in the first 48 postoperative hours, no significant difference was found between the lidocaine group and the placebo group (Table 3 and Figure s1). The median morphine consumption 48 h after surgery was similar in men and women (0.55 vs. 0.58 mg kg−1; Mann–Whitney U test P = 0.72). As sex distribution was different in both groups, we analysed the possible confounding effect of sex, using a multivariable linear regression analysis of the morphine consumption according to treatment group adjusting for sex, and treatment by sex interaction. The P values were 0.62, 0.51 and 0.78, respectively, suggesting no effect of lidocaine or sex on morphine consumption.

Table 3 - Intra and postoperative morphine and anaesthetic consumption
Lidocaine (n = 57) Placebo (n = 61) P
Intra-operative data Remifentanil dose μg·kg−1 19.9 [14.2 to 28.6] 22.2 [13.8 to 35.6] 0.30
PACU PACU length of stay min 60 [54 to 89] 70 [60 to 90] 0.22
NRS at the PACU entry 0 to 10 scale 0.5 [0 to 5.0] 0 [0 to 4.0] 0.68
NRS at the PACU leave 0 to 10 scale 2 [0 to 3] 2 [0 to 3] 0.72
PACU morphine intake mg 1 [0 to 4.25] 2 [0 to 6] 0.15
PACU morphine intake mg kg−1 0 [0 to 0.05] 0.04 [0 to 0.09] 0.07
Reported adverse effect in OR and PACU N 1a 2b 0.67
Duration of trial solution infusion in PACU min 60 [47 to 83] 70 [54 to 86] 0.30
Postoperative data PCA morphine infusion dose after 24 h mg 17.5 [6.5 to 31] 12.5 [6 to 26] 0.48
PCA morphine infusion dose after 24 h mg kg−1 0.22 [0.06 to 0.43] 0.19 [0.08 to 0.39] 0.97
PCA morphine infusion dose after 48 h mg 35 [12.5 to 69.7] 27 [15 to 48.5] 0.43
PCA morphine infusion dose after 48 h mg kg−1 0.45 [0.11 to 0.94] 0.35 [0.16 to 0.75] 0.71
Morphine total consumption (OR + PACU+ PCA H48) mg 44 [21 to 73.3] 38 [23.3 to 56.5] 0.92
Morphine total consumption (OR + PACU+ PCA H48) mg kg−1 0.60 [0.30 to 1.03] 0.57 [0.37 to 0.96] 0.92
Data are given as absolute number (n) and median [IQR], as appropriateNRS, Numeric Rating Scale; OR, operation room; PACU, postanaesthesia care unit; PCA, patient-controlled analgesia.
aOne bradycardia requiring treatment occurred in the lidocaine group.
bOne premature ventricular complex and one postoperative tremor related to alcohol withdrawal occurred in the placebo group.

With regard to secondary outcomes, there was no significant difference in median cumulative remifentanil dose and 24-h morphine consumption in the lidocaine group compared with the placebo group. Pain on entry and exit from the recovery room, assessed on the NRS, was similar in both groups (Table 3).

There was no difference between the two groups in the occurrence of adverse events. One episode of bradycardia requiring atropine was reported in the lidocaine group. An immediate postoperative episode of ventricular extrasystoles (n = 1) and extremity tremors due to an alcohol withdrawal disorder (n = 1) were reported in the placebo group.

Regarding pain assessment 3 to 6 months after surgery, whether by the Short MPQ-QDSA questionnaire, by the NRS or by a dichotomous NRS at least 4, no significant difference was found between the two groups. Analgesic consumption was not significantly different between the two groups, which was also true when comparing by analgesic levels between the two groups (Table 4).

Table 4 - Pain evaluation 3 to 6 months after surgery
Lidocaine Placebo P
McGill Pain Questionnaire 11 [3 to 16] (n = 50) 12 [3 to 21] (n = 49) 0.25
NRS 3 to 6 months after surgery 0 to 10 scale 3.0 [1.0 to 4.0] (n = 43) 3.0 [1.0 to 5.0] (n = 47) 0.29
NRS ≥ 4; 3 to 6 months after surgery 14 (33) (n = 43) 20 (43) (n = 47) 0.38
Analgesica consumption 3 to 6 months n = 33 n = 32 0.90
step Ia 12 (36) 10 (32) 0.80
step IIa 9 (27) 7 (22) 0.78
step IIIa 11 (33) 13 (41) 0.61
Other (gabapentine, ketamine) 1 (3) 2 (6) 0.61
Data are given as absolute number, n (%) and median [IQR] for each group, as appropriate.NRS, Numeric Rating Scale; OR, operation room; PACU, postanaesthesia care unit; PCA, patient-controlled analgesia.
aAs described in the WHO analgesic ladder.37

Discussion

In our trial, intra-operative lidocaine infusion failed to reduce postoperative morphine consumption in patients undergoing major ENT cancer surgery. To our knowledge, our study is the first one to examine this in major ENT cancer surgery. The results of our study are similar to the findings of subgroup analyses of Weibel's metanalysis, which included 20 ‘other surgery’ trials and found no difference in early pain scores (0 to 4 h, ICU) or postoperative opioid consumption.1

There are three other randomised trials evaluating i.v. lidocaine in ENT surgery. In these studies, the addition of lidocaine was beneficial in acute pain management in two out of three studies. 15,16 In addition, lidocaine appears to reduce CPSP 3 months after robot-assisted thyroidectomy. 14 These studies involved only minor procedures (thyroidectomies or septorhinoplasties), which cannot be compared with major ENT cancer surgery.14–16

With respect to the incidence of CPSP, lidocaine has not yet definitively demonstrated its effect,25 although in major breast surgery and robotic thyroidectomy, the occurrence of CPSP assessed 3 to 6 months after surgery was lower following i.v. lidocaine.14,26 We did not find any benefit in major ENT surgery on chronic pain management or evaluation. The absence of benefit at 3 to 6 months was expected because of the absence of immediate postoperative benefit. This may be due to unknown differences in pathophysiology together with a set of possible confounding factors (associated chemoradiotherapy, population, comorbidities). Our study did not address patients using chronic analgesics before cancer surgery. This choice was made in order not to induce a patient heterogeneity bias in the inclusion criteria. Further studies will have to focus on this subgroup, as the current literature suggests that a benefit may exist. 27

Even if the lidocaine protocols are still debatable, our lidocaine protocol has been based on toxicity studies and meta-analyses studying peri-operative i.v. lidocaine.1,28 Lidocaine toxicity is currently the subject of debate following accidents linked to its neurological and cardiac toxicity. British and Canadian authors have published several warnings concerning the use of i.v. lidocaine in the context of peri-operative analgesia.29,30 For the dose given while following the protocol used in our study, we found one unique episode of bradycardia that could be linked to the use of i.v. lidocaine. The occurrence of lidocaine-related adverse events was not significantly different between the two groups. However, the widespread use of unlicensed i.v. lidocaine infusion in the practice of anaesthesiology should be questioned.

Our study has some limitations that should be acknowledged. First, a negative result has two possible explanations; either there is no effect, that is (i.e. the assumption of a difference was false) or the randomised controlled trial (RCT) was underpowered to observe a difference. Given the very small differences between the groups for the primary and other efficacy outcomes, the first hypothesis seems more likely. However, there were a larger number of nonanalysable patients than expected as shown in the flow-chart diagram. Thus, it was necessary to continue recruitment for an additional year to include 144 patients instead of 134 to reach the necessary power. Despite this, the number of analysable patients was 4 less than the expected number of patients needed. In our study, despite randomisation, the patient characteristics were not similar between the two groups; the proportion of women was lower in the lidocaine group. However, according to the adjusted analysis, sex did not seem to be a confounding factor associated with the postoperative morphine consumption.

Published reports indicate that the sensitivity to pain may be higher in women, but with a more potent analgesic effect of opioids and less postoperative consumption of analgesics especially after minor ENT surgery.31–33

Another confounding factor could be a difference in intra-operative remifentanil consumption, but this was not a problem in our study (Table 3). The use of intra-operative remifentanil was essential in our study because the anaesthetic protocol did not permit a combination of sympathetic system blockers (alpha-2-agonists, beta-blockers) but only sevoflurane with or without lidocaine. Without a strong opioid, haemodynamic stability would not have been achieved. However, i.v. lidocaine seems to produce a deepening of hypnosis during surgical stimulation by an antinociceptive effect. 34–36 The lack of intra-operative remifentanil dose reduction may seem surprising in view of published reports, but this may be due to the fact that we chose to adapt remifentanil to the classical haemodynamic variables. Our choice was not to monitor beyond the analgesia-sedation balance because ENT surgery does not allow the easy use of some monitors (pupillometry, bispectral index) and lidocaine has not been sufficiently evaluated for others (Analgesia- Nociception Index).

We intentionally limited the postoperative analgesia protocol to the combination of paracetamol and morphine. This might suggest we are not in favour of multimodal analgesic management. In head and neck cancer surgery, multimodal analgesia has been shown to reduce morphine consumption.37 This was not the objective of the study. As some patients had contraindications to certain molecules, such as NSAID or nefopam, it would have been necessary to include a larger number of patients to carry out a study of much longer duration with more subgroup analyses; all these elements constitute methodological limitations. This choice in our protocol meant we were unable to describe any potential synergistic effects of lidocaine and co-analgesics.

Finally, other aspects of lidocaine may be useful in this patient group: specifically, the prevention of postextubation cough and postoperative sore throat. 38 As the risk of side effects is very low, it may be interesting to study its benefits in the first hours after surgery.

To conclude, in the absence of other published studies to our knowledge, during major ENT surgery, a bolus of 1.5 mg kg-1 i.v. lidocaine followed by an infusion at 2 mg kg−1 h−1 did not confer any additional analgesic benefit when compared with placebo. Some remaining questions concerning i.v. lidocaine require investigation, such as the use of opioids pre-operatively, whether subgroups of ENT cancer surgery might benefit from it, or a possible synergistic effect of i.v. lidocaine with other co-analgesics.

Acknowledgements relating to this article

Assistance with the study: the authors would like to acknowledge the staff of the Service de Chirurgie ORL et maxillo-faciale, Hôpital de la Croix-Rousse, Lyon and Service de Chirurgie, Centre Léon Bérard, Lyon, and Pierre Pradat for help in statistical analysis.

Financial support and sponsorship: the study was supported by the Fondation Hospices Civils de Lyon (BP 2251 - 3 quai des Célestins, 69229 Lyon Cedex 02, France) and the Fondation APICIL (21, place Bellecour, 69002 Lyon).

Conflict of interest: none.

Presentation: Preliminary data were presented at the GARO congress 2020 and SFAR 2021 congress (presentation number: R135).

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