Osama Abou Arab
email: osama.abouarab@gmail.com.

Marc Olivier Fischer

Alexis Carpentier

Christophe Beyls

Pierre Huette

Abdel Hchikat

Amar Benammar

Beatris Labont

Yazine Mahjoub

Stéphane Bar

Pierre-Grégoire Guinot

Emmanuel Lorne

Dr Osama Abou

Etomidate-induced hypotension: a pathophysiological approach using arterial elastance

Keywords:

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Background

Mean arterial pressure (MAP) is a main determinant of tissue perfusion. A decrease in MAP is associated with adverse postoperative outcomes [START_REF] Mascha | Intraoperative Mean Arterial Pressure Variability and 30-day Mortality in Patients Having Noncardiac Surgery[END_REF]. Several studies have reported associations with postoperative morbidity [START_REF] Abbott | A Prospective International Multicentre Cohort Study of Intraoperative Heart Rate and Systolic Blood Pressure and Myocardial Injury After Noncardiac Surgery: Results of the VISION Study[END_REF]. Pulse pressure less than 53 mmHg increases the risk factor of excess morbidity after major surgery [START_REF] Ackland | Arterial pulse pressure and postoperative morbidity in high-risk surgical patients[END_REF]. It was recently reported better outcomes when MAP was preserved within a 10% variation of the reference value [START_REF] Futier | Effect of Individualized vs Standard Blood Pressure Management Strategies on Postoperative Organ Dysfunction Among High-Risk Patients Undergoing Major Surgery: A Randomized Clinical Trial[END_REF].

Maintaining MAP at a subnormal level remains a main goal to achieve during anaesthesia.

Routine use of etomidate for anaesthesia induction reveals that decrease in MAP is not always observed. Although that variation might be in relation with difference in volume load or sympathetic stimulation between patients, changes in arterial elastance (Ea) could be more accurate to describe MAP variation. Ea is the ratio of end systolic pressure to stroke volume. It reflects the volume-pressure loop work in the left ventricle. To achieve the maximal transfer of energy from the left ventricle to the arterial system, both ventricle elastance and Ea must be similar [START_REF] Chirinos | Ventricular-arterial coupling: Invasive and non-invasive assessment[END_REF]. Ea is a reflection of arterial tone variation. Sunagawa et al obtained multiples Ea values when arterial compliance (C) and peripheral vascular resistance (PVR) were modified whereas left ventricle work is preserved [START_REF] Sunagawa | Optimal arterial resistance for the maximal stroke work studied in isolated canine left ventricle[END_REF] [START_REF] Sunagawa | Left ventricular interaction with arterial load studied in isolated canine ventricle[END_REF]. He estimated that Ea can be approximated from the peripheral vascular resistance and arterial compliance. Thus, by analysis Ea, components of blood pressure can be accurately understood. Ea decreases with PVR decrease and when compliance increases. In cardiovascular disease, Ea is increased mainly due to increase in PVR whereas, in healthy population, exercise practice preserves compliance and Ea at normal value [START_REF] Chirinos | Effective arterial elastance is insensitive to pulsatile arterial load[END_REF] [START_REF] Tanaka | Aging, Habitual Exercise, and Dynamic Arterial Compliance[END_REF].

To avoid hypotension during anaesthesia, Ea could be used as an index reflecting the arterial tone associated to MAP decrease. To our knowledge, Ea variation induced by etomidate was not reported before.

We aimed to assess arterial tone by assessing Ea following etomidate-induced hypotension.

Methods

Ethical approval

The study protocol was approved by the local independent ethics committee (reference 2015-A00765-44) on the 26 th of November 2015. The present report was drafted in line with the STROBE statement for cohort studies [START_REF] Von Elm | The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies[END_REF]. The study complied with the Declaration of Helsinki on ethical principles for medical research involving human subjects. All patients provided written, informed consent prior inclusion to the study.

Study population

A prospective, observational study was performed in Amiens University Hospital's cardiothoracic ICU over a six-month period from November 2016 to February 2017. The main inclusion criteria were patients undergoing elective general anaesthesia with intra-arterial blood pressure monitoring prior to induction. The main exclusion criteria were as follows: age under 18 years, atrial fibrillation, no echo cardiac echogenicity, presence of a pacemaker.

Cardiac index and stroke volume

Transthoracic echocardiography (CX50 Ultrasound System and S5-1 Sector Array Transducer, Philips Medical System, Suresnes, France) was performed by a physician using standards views based in accordance in current guidelines [START_REF] Lang | Recommendations for chamber quantification☆[END_REF]. Left ventricular ejection fraction (LVEF) by the visual method on the 4-chamber view [START_REF] Gudmundsson | Visually estimated left ventricular ejection fraction by echocardiography is closely correlated with formal quantitative methods[END_REF]. Stroke volume (SV) was measured by velocity time integral by pulse Doppler in the left ventricular outflow tract on a 5-chamber view. The velocity time integral was averaged on five measurements. The area of the chamber was calculated from a single diameter of the outflow tract on the parasternal large axis. Cardiac index (l.min -1 .m -2 ) was calculated based on SV and heart rate. The measurements were saved for off line calculation and interpretation by one experimented cardiologist. In our centre, the intra observer variability was 3 ± 1 % [START_REF] Mahjoub | Assessment of an uncalibrated pressure waveform device's ability to track cardiac output changes due to norepinephrine dose adjustments in patients with septic shock: A comparison with Doppler echocardiography[END_REF].

Blood pressure monitoring, peripheral vascular resistance, calculation of arterial elastance

Systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and mean arterial pressure (MAP) and pulse pressure (PP) were measured using an invasive radial arterial line. Heart rate was measured using a continuous 3 lines electrocardiogram. Cardiac length cycle (T) was estimated using the following formula T (seconds)=60/HR. Arterial elastance (Ea) was estimated using the formula Ea (mmHg.ml -1 ) = Pes/SV. Pes is the end systolic pressure in the left ventricle estimated from SAP as Pes (mmHg) =0.9*SAP [START_REF] Kelly | Effective arterial elastance as index of arterial vascular load in humans[END_REF]. Corrected (cEa) is the Ea adjustment to length cycle expressed as following cEa=Ea/T. Corrected peripheral vascular resistance (PVR) to T ratio was calculated using the formula cPVR (mmHg.min.l -1 ) = (MAP/CO)/T. Arterial compliance (C) was expressed as follows C (ml.min -1 .m -2 ) =SV/PP.

To synchronise PP and SV, arterial blood pressure was continuously reported on the echocardiography screen.

Patients with less than 15% MAP variation were allocated to the "preserved MAP" group and patients with greater than 15% MAP variation 2 minutes after induction compared to baseline were allocated to the "etomidate-induced hypotension" group.

Study procedure

On arrival in the operating room, all patients were monitored by continuous three-lead electrocardiogram, pulse oximetry saturation and invasive blood pressure via a radial arterial line. According to our centre's usual practice, patients did not receive any premedication.

Standardised general anaesthesia consisted of intravenous sufentanil 0.3 µg.kg -1 and etomidate 0.4 mg.kg -1 . Titration of hypnotics and opioids was based on the bispectral index (Covidien, Boulder, CO, USA). No neuromuscular block drug was administered before the repeated measurements at 2 minutes following induction. Neither vasopressor nor fluid challenge were administered during the study procedure. Average SV and PP were determined on three measures and Ea was calculated as described above.

Baseline measures were performed before anaesthetic induction during spontaneous breathing without positive pressure ventilation. After pre-oxygenation, anaesthesia induction was initiated and repeated measures were performed under apnoea without intubation or manual ventilation.

Statistics

In the absence of data on compliance, resistance and Ea with etomidate, a convenient sample size of 45 patients was defined. Data area expressed as median [interquartile range] or numbers (percentage). The distribution of variables was assessed using Kolmogorov-Smirnov test. Comparisons were performed by Mann-Whitney test, Chi-square or Fisher's exact test as appropriate. A linear regression model was used to describe the effect of compliance, peripheral vascular resistance and Ea. All statistical analyses were performed with SPSS® software (version 24, IBM® SPSS®). The limit of statistical significance was p<0.05.

Results

Demographic data (Table 1)

Forty-five patients were included: MAP decreased at anaesthesia induction in 21 patients (47%) and did not decrease in 24 (53%) patients.

Demographic data were similar in the two groups, apart from older age in the decreased MAP group (Table 1). LVEF and etomidate dose were similar in the two groups.

Haemodynamic data (Table 2)

HR was similar before induction, but increased in the preserved MAP group compared to the etomidate-induced hypotension group (82 bpm [74-85] vs 67 bpm [61-72], respectively; p=0.004). CI was similar before induction in the preserved MAP and the etomidate-induced hypotension groups (2.2 l.min -1 .m -2 [1.9-2.7] vs 2.3 l.min -1 .m -2 [1.9-3.1], respectively; p=0.777) and did not vary after induction (2.2 ml.min -1 .m -2 [1.9-2.9] and 2.3 ml.min -1 .m -2 [1.8-3.1] for the preserved MAP and the etomidate-induced hypotension groups, respectively; p=0.777). 2 and Figure 1) Ea was similar in the two groups before induction (1.8 mmHg.m -2 .ml -1 [1.5-2.1] and 1.9 mmHg.m -2 .ml -1 [1.3-2.3]; p=0.682), but decreased after induction in the etomidate-induced hypotension group (2.0 mmHg.ml -1 [1.7-2.4] vs 1.4 mmHg.ml -1 [1.0-1.9]; p=0.001). C increased following anaesthesia induction in etomidate-induced hypotension group compared to the preserved MAP group (0.8 [0.6-1.0] vs 0.5 [0.4-0.6], respectively; p<0.0001). cPVR decreased in both groups after induction without any differences between groups (15 mmHg.min.l -1 [START_REF] Gudmundsson | Visually estimated left ventricular ejection fraction by echocardiography is closely correlated with formal quantitative methods[END_REF][START_REF] Mahjoub | Assessment of an uncalibrated pressure waveform device's ability to track cardiac output changes due to norepinephrine dose adjustments in patients with septic shock: A comparison with Doppler echocardiography[END_REF][START_REF] Kelly | Effective arterial elastance as index of arterial vascular load in humans[END_REF][START_REF] Möller Petrun | Bispectral index-guided induction of general anaesthesia in patients undergoing major abdominal surgery using propofol or etomidate: a double-blind, randomized, clinical trial[END_REF][START_REF] Price | Changes in cardiac index and estimated systemic vascular resistance during induction of anaesthesia with thiopentone, methohexitone, propofol and etomidate[END_REF][START_REF] Aggarwal | A comparative study between propofol and etomidate in patients under general anesthesia[END_REF][START_REF] Skovsted | The effects of etomidate on arterial pressure, pulse rate and preganglionic sympathetic activity in cats[END_REF][START_REF] Westerhof | The arterial Windkessel[END_REF] vs 15 mmHg.min.l -1 [START_REF] Lang | Recommendations for chamber quantification☆[END_REF][START_REF] Gudmundsson | Visually estimated left ventricular ejection fraction by echocardiography is closely correlated with formal quantitative methods[END_REF][START_REF] Mahjoub | Assessment of an uncalibrated pressure waveform device's ability to track cardiac output changes due to norepinephrine dose adjustments in patients with septic shock: A comparison with Doppler echocardiography[END_REF][START_REF] Kelly | Effective arterial elastance as index of arterial vascular load in humans[END_REF][START_REF] Möller Petrun | Bispectral index-guided induction of general anaesthesia in patients undergoing major abdominal surgery using propofol or etomidate: a double-blind, randomized, clinical trial[END_REF][START_REF] Price | Changes in cardiac index and estimated systemic vascular resistance during induction of anaesthesia with thiopentone, methohexitone, propofol and etomidate[END_REF][START_REF] Aggarwal | A comparative study between propofol and etomidate in patients under general anesthesia[END_REF][START_REF] Skovsted | The effects of etomidate on arterial pressure, pulse rate and preganglionic sympathetic activity in cats[END_REF][START_REF] Westerhof | The arterial Windkessel[END_REF][START_REF] Stergiopulos | Determinants of Pulse Pressure[END_REF], respectively; p= 0.525).

Comparison of arterial elastance (Ea), peripheral vascular resistance (PVR) and arterial compliance (C) between preserved MAP and etomidate-induced hypotension groups (Table

Ea variation related to arterial compliance (C) and peripheral vascular resistance (cPVR) (figure 2)

Using partial linear regression model, the regression could explain most observed Ea according to cPVR with R 2 =0.697 (p<0.001).

Using partial linear regression model, the regression could explain most observed Ea according to C with R 2 =0.681 (p<0.001).

Discussion

Arterial hypotension occurred in 47% of patients after etomidate induction. Arterial elastance decreased in patients with etomidate-induced hypotension. Resistance decreased in both groups whereas compliance was higher in the etomidate-induced hypotension group only.

To analyse Ea variations in our population, we used the 2 compartments model of Windkessel. This model is based on the principle that pulse pressure is determined by compliance of large arteries and resistance of small arteries. Thus, analysis of Ea therefore provides an assessment of both components. Ea can decrease when compliance increases or when resistance decreases. In the present cohort, compliance increased and resistance decreased in the decreased MAP group, resulting in a decrease in Ea. In the light of these findings, multilinear regression was performed to assess the proportion of C and PVR in effective Ea (figure 2).

The analysis suggests decrease in MAP is in relation with excess arterial compliance.

Studies of the pharmacologic effects of etomidate remain controversial. Etomidate is known to be associated with good haemodynamic stability when used for anaesthesia induction and usually does not induce myocardial depression. In the present cohort, SV and CI were similar in the two groups after induction. In a previous study, etomidate was described to decrease CI and MAP at induction [START_REF] Möller Petrun | Bispectral index-guided induction of general anaesthesia in patients undergoing major abdominal surgery using propofol or etomidate: a double-blind, randomized, clinical trial[END_REF]. Nevertheless, CI was measured by a minimally invasive cardiac output monitoring device whereas we used echocardiography. The displayed values of that device are displayed from a healthy population, which may not be accurate. About HR, it increased in the normal MAP group, suggesting a mechanism of compensation, whereas HR remained in the same range for the decreased MAP group. No difference in terms of medical history or drug use could explain these differences in HR. The BIS level was also similar suggesting the same hypnotic effect. As others, we found that etomidate can induce a decrease in MAP [START_REF] Möller Petrun | Bispectral index-guided induction of general anaesthesia in patients undergoing major abdominal surgery using propofol or etomidate: a double-blind, randomized, clinical trial[END_REF] [START_REF] Price | Changes in cardiac index and estimated systemic vascular resistance during induction of anaesthesia with thiopentone, methohexitone, propofol and etomidate[END_REF]. Aggarwal et al reported a reduction of MAP after etomidate, but to a lesser extent than that observed with propofol [START_REF] Aggarwal | A comparative study between propofol and etomidate in patients under general anesthesia[END_REF]. Skovsted et al showed that etomidate can induce sympathetic tone depression in a rat model [START_REF] Skovsted | The effects of etomidate on arterial pressure, pulse rate and preganglionic sympathetic activity in cats[END_REF]. This finding could explain the decrease in arterial tone. Normally, large artery can store wave energy during systole due to its elastic property and return to smaller vessel during diastole.

In contrast, when vascular tone is inhibited by the sympathetic system, arterial contraction during diastole is decreased, resulting in changes in pulse pressure. These observations are conceptualised in a two-element Windkessel model [START_REF] Westerhof | The arterial Windkessel[END_REF]: the large artery represents compliance and the small artery represents resistance. Stergiopulos et al reported that compliance and resistance both play a role in MAP and pulse pressure [START_REF] Stergiopulos | Determinants of Pulse Pressure[END_REF]. When assessing each parameter alone, a poor regression was observed with MAP. These authors argued that both resistance and compliance are determinants of arterial pressure.

Nevertheless, the respective contributions of each element on arterial pressure can vary depending on clinical situations. On a population of hypertensive patients, the sensitivity of Ea to a change in resistance was 2.5 times more than a similar change in compliance suggesting a more contribution of small artery in Ea [START_REF] Chemla | Contribution of systemic vascular resistance and total arterial compliance to effective arterial elastance in humans[END_REF]. The same findings were found in another hypertensive population [START_REF] Kelly | Effective arterial elastance as index of arterial vascular load in humans[END_REF]. On a population of healthy men, trained athlete's compliance contributes more in Ea than in sedentary men [START_REF] Carrick-Ranson | The effect of lifelong exercise dose on cardiovascular function during exercise[END_REF]. Ea variation is related to decreased resistance in patients with aortic valve stenosis during exercise [START_REF] Laskey | Systemic arterial response to exercise in patients with aortic valve stenosis[END_REF]. In the present cohort, compliance was increased following induction of anaesthesia with etomidate. As mentioned before, we can suppose etomidate induced sympathetic inhibition of arterial tone with a larger increase in compliance than a decrease in resistance. To date, compliance variation with etomidate is only reported on a model of monkey with an increase in compliance [START_REF] Fanton | Cardiovascular responses to propofol and etomidate in long-term instrumented rhesus monkeys (Macaca mulatta)[END_REF].

As Ea describes arterial tone, bedside Ea could be a valuable index in routine practice. Indeed, MAP variation can be induced by cardiac index, volume load or arterial tone variation. Ea could be associated to MAP interpretation to assess arterial tone and to deliver the appropriate therapy management when hypotension occurs. Association between MAP and Ea variations were reported in previous studies to guide norepinephrine weaning.

Following cardiac surgery, Ea monitoring could shorten norepinephrine cumulative dose in vasoplegic syndrome [START_REF] Guinot | Monitoring dynamic arterial elastance as a means of decreasing the duration of norepinephrine treatment in vasoplegic syndrome following cardiac surgery: a prospective, randomized trial[END_REF]. When compared to phenylephrine, norepinephrine preserved better arterial compliance without attenuating the stroke volume [START_REF] Vallée | Norepinephrine reduces arterial compliance less than phenylephrine when treating general anesthesia-induced arterial hypotension[END_REF]. Consequently, norepinephrine might be the most appropriate vasopressor to reverse etomidate-induced hypotension. On contrary, studies on Ea variation following changes in volume load are controversial and requires larger cohorts [27] [28].

Our study presents some limits. The main limit is the difference in HR values between the 2 groups following induction (Table 2). Because calculation of Ea is based on several assumptions that can be influenced by different clinical conditions including HR, we adjusted Ea to cardiac cycle top allow comparisons between groups. We did still have a significant difference between groups. We could not explain the difference in HR between groups. The anaesthetic dose of etomidate and the beta-blocker use was similar (table 1). We can suppose the volume charge prior to induction was different. However anaesthetic protocol was standardised for all patients: no liquid intake from 0:00 am, no administration of diuretic 24 hours before surgery, no fluid challenge before the induction. We could not evaluate the volume load with surrogate markers as pulse pressure variation or stroke volume variation as no mechanical ventilation was applied in the protocol. However, the impact of fasting was assessed in a previous study without effect on the volume load [29].

No nociceptive stimulation was done, especially no laryngoscopy was performed during the 2 minutes of observation. We also hypothesised sympathetic inhibition could differ between groups but the BIS level was similar. We assumed that changes in MAP following induction were exclusively due to the effect of etomidate.

The older patients had also a lower HR and a lower MAP (table 1). It reminds that general anaesthesia for elderly patients remains a challenge in every practice. In a national UK survey assessing the morbidity of major surgery, patients over 70 years had higher complications rate [30]. It also reminds that aging is physiological process with hormonal modifications [31]. Elderly patients with eventual adrenal insufficiency could explain the absence of response to stress induced by general anaesthesia with low HR and low MAP.

Concerning measurement of Ea, stroke volume and pulse pressure were obtained by 2 different devices (echocardiography and invasive arterial monitoring), which could lead to a cycle synchronisation error. However, arterial pressure was gated on cardiac cycle using a cable displaying the cycle on the echocardiography screen.

Conclusion:

Etomidate induced hypotension is associated with a decrease in arterial elastance mainly due to change in arterial compliance rather than in arterial resistance.

[27] Lanchon R, Nouette-Gaulain K, Stecken L, Sesay M, Lefrant J-Y, Biais M. Dynamic arterial elastance obtained using arterial signal does not predict an increase in arterial pressure after a volume expansion in the operating room. Anaesth Crit Care Pain Med 2017 ;36 :377-82. doi: 10.1016/j.accpm.2017.05.001.

[28] Cecconi M, Monge García MI, Gracia Romero M, Mellinghoff J, Caliandro F, Grounds

  RM, et al. The use of pulse pressure variation and stroke volume variation in spontaneously breathing patients to assess dynamic arterial elastance and to predict arterial pressure Muller L, Brière M, Bastide S, Roger C, Zoric L, Seni G, et al. Preoperative fasting does not affect haemodynamic status: a prospective, non-inferiority, echocardiography study. Br J Anaesth 2014; 112:835-41. doi:10.1093/bja/aet478. [30] National Confidential Enquiring into Patient Outcome and Death. Knowing the risk. A

	response	to	fluid	administration.	Anesth	Analg	2015;	120:76-84.
	doi:10.1213/ANE.0000000000000442.
	[29] review	of	the	perioperative	care	of	surgical	patients	n.d.

http://www.ncepod.org.uk/2011report2/downloads/ POC_fullreport.pdf.

[31] Alvis BD, Hughes CG. Physiology Considerations in Geriatric Patients. Anesthesiol Clin 2015 ;33 :447-56. doi: 10.1016/j.anclin.2015.05.003.

Funding

None

Authors contribution

EL and MOF designed the study.

OAA, ABA, AH, AC, CB, PH, SB and EL collected the data and carried out analyses.

OAA, PGG and EL drafted the manuscript.

Acquisition data: OAA, ABA, EL, AC, EB, AB, PH, CB All the authors approved the manuscript.

Disclosure of interest

The authors declare they have no conflict of interests.

Legends to illustrations

Figure 1 Comparisons of peripheral vascular resistance (PVR) (A), arterial compliance (B), and elastance (C) between preserved MAP group and etomidate-induced hypotension

group before and after induction. *: P value <0.0001, **: P value at 0.001 (P value between groups)


M.D. Bettoni Jérémie
email: jeremiebettoni@gmail.com

M.D. Olivetto Matthieu
email: matthieuolivetto@live.fr

M.D Duisit Jérôme
email: duisit.jerome@uclouvain.be

M.D. Caula Alexandre
email: alexandre.caula@gmail.com

M.D. Bitar Ghassan
email: ghassanbitar@hotmail.com

M.D Lengele Benoit
email: benoit.lengele@uclouvain.be

M.D Testelin Sylvie
email: testelin.sylvie@chu-amiens.fr

M.D Dakpé Stéphanie
email: dakpe.stepanie@chu-amiens.fr

M.D Devauchelle Bernard
email: devauchelle.bernard@chu-amiens.fr

Treatment of mandibular osteoradionecrosis by periosteal free flaps

Keywords: osteoradionecrosis, free flap, management, Periosteal free flap, jaw

Mandibular osteoradionecrosis (ORN) is one of the most serious complications of radiotherapy of the head and neck, and is characterised by hypoxia, hypovascularisation, and hypocellularity . Periosteal free flaps have intrinsic osteogenic, and extrinsic neoangiogenic, properties that are related to the periosteum. Our objective was to present our experience with the use of periosteal free flaps in the treatment of ORN (Notani class I or II) that are refractory to conservative management or have a large area of bone (≥ 2 cm) exposed. We organised a single-centre, retrospective study between 2003 and 2013 and describe the management of 11 patients (4 women and 7 men) who were being treated for refractory mandibular ORN. Thirteen periosteal free flaps were used: inner femoral condylar periosteum (n=4), iliac crest (n=1), external brachial with humeral periosteum (n=1), and forearm with radial periosteum (n=7). During follow-up we found three acute complications (haematoma, partial necrosis, and total vascular necrosis) that required immediate construction of a second periosteal free flap. There were also two chronic complications (fistula and post-traumatic fracture). With only one progressive lesion identified, the ORN was stopped in 11/12 patients. Two examples of osteoconduction were identified on postoperative images at six months and two years. Because of its osteoconductive and neoangiogenic capacities, the periosteal free flap seems to offer a real biological dimension to the treatment of ORN, and its efficiency favours its early revascularisation.

Introduction

Mandibular osteoradionecrosis (ORN) is a serious complication of irradiation of the head and neck, which is characterised histologically by hypoxia, hypocellularity, and hypovascularisation. [START_REF] Marx | A new concept in the treatment of osteoradionecrosis[END_REF] Prophylactic measures include identifying any risk factors, [START_REF] Kuhnt | Potential risk factors for jaw osteoradionecrosis after radiotherapy for head and neck cancer[END_REF] controlling traumatic factors, [START_REF] Meyer | Infectious diseases of the jaws[END_REF] and developing prophylactic dentistry and topical treatment with fluoride. [START_REF] Thariat | Compliance with fluoride custom trays in irradiated head and neck cancer patients[END_REF] These measures, together with technical advances such as the development of intensity modulated radiotherapy, have reduced the incidence of ORN from 38% to less than 10% within the last 40 years. [START_REF] Nabil | Risk factors for osteoradionecrosis after head and neck radiation : a systematic review[END_REF] Despite these developments, methods of managing ORN have become increasingly controversial.

In a meta-analysis published in 2015, Rice et al [START_REF] Rice | The management of osteoradionecrosis of the jaws-a review[END_REF] differentiated between ORN lesions with damage to bone above the mandibular canal from those with damage below it, and recommended conservative management for lesions classified as Notani classes I-II (above the inferior alveolar canal), and radical management with immediate reconstruction by free flap for those classified as Notani class III (below the inferior alveolar canal). However, in the case of Notani class I or II lesions with extensive exposure of bone, or those that were refractory to conservative treatment, the lack of consensus remains problematic because of the evolutionary potential of these lesions. Indeed, considering that the more complex the reconstruction, the higher the complication rate, [START_REF] Kroll | Choice of flap and incidence of free flap success[END_REF] in 1997, Beauvillain de Montreuil et al [START_REF] De Montreuil | Limited mandibular osteoradionecrosis.Early conservative surgical treatment[END_REF] were the first to propose early surgical management of ORN. They recommended the use of periosteal free flaps, thereby bringing bony growth factors and progenitor cells that could trigger increased osteogenic [START_REF] Takato | Vascularized periosteal grafts: an experimental study using two different forms of tibial periosteum in rabbits[END_REF] and neoangiogenic 10 responses to the ORN process.

The objective of this study was to report our experience of the use of periosteal flaps for ORN (Notani classes I or II) with a large exposed area of bone or that were refractory to conservative treatment, and to evaluate their therapeutic effectiveness on ORN.

Patients and methods

The records of 11 patients (four women and seven men), mean age 55 (range 34 -69) years, were analysed in a retrospective, single-centre study. They had had revascularisation and reconstruction with periosteal free flaps between January 2003 and December 2013.

For each patient, the data collected were grouped into four distinct categories.

The first included characterisation of the ORN, the time that had elapsed between the end of irradiation and the onset of symptoms, and between the diagnosis of ORN and revascularisation, the mode of occurrence (Wong classification), [START_REF] Wong | Conservative management of osteoradionecrosis[END_REF] the topography of the lesion (Urken classification) [START_REF] Urken | Oromandibular reconstruction using microvascular composite free flaps. Report of 71 cases and new classification scheme for bony, soft-tissue, and neurologic defects[END_REF] , the conservative management before revascularisation, and the depth of the osteolytic injury (Notani classification) [START_REF] Notani | Management of mandibular osteoradionecrosis corresponding to the severity of osteoradionecrosis and the method of radiotherapy[END_REF] (Table 1). The second category concerned the surgical technique, the duration of operation, the choice of recipient vessels and anastomoses, and the type of periosteal free flap. The third category involved the complementary assessments, whether there had been a complete, doubtful, or incomplete resection of bone as evaluated on the postoperative radiograph (dental panoramic radiograph or computed tomographic (CT) scan, or both), and the histopathological confirmation of the lesions. In the fourth and last category we recorded the postoperative radiological and clinical monitoring, the duration of hospital stay, and existing acute (within 30 days) or chronic (30 days or longer) complications.

We then assessed the effectiveness of revascularisation by the absence of either progression or local recurrence of the ORN. Lesions distant from the initial surgical site or recurrence after a period of healing were considered to be new, and independent of the primary lesion.

Results

Characteristics of management of ORN

The mean time between the end of irradiation and the first symptoms of ORN was 48.5 (40) months. Objective analysis of the patients' history showed a triggering factor in eight. Revascularisation had been proposed because conservative management had failed (n=7) or because more than 2 cm of bone were exposed (n=5). The mean (SD) time between the diagnosis of ORN and reconstruction was 7.5 (6.5) months (9.5 (4) months for the group who had initial conservative management, compared with 2.2 (0.9) months for the group who had had immediate revascularisation) (Table 1).

Surgical technique: distribution and types of flaps

We used 13 periosteal free flaps: five were -true‖ periosteal free flaps of internal femoral condyle (n=4) or iliac crest (n=1), and eight were periosteal free flaps with accompanying soft tissue -external brachial free flap with humeral periosteum (n=1) and forearm free flaps with radial periosteum (n=7).

The mean (range) duration of revascularisation was 414 (246 -612) minutes.

We preferred an end-to-end arterial anastomosis in 12 cases: on the facial artery (n=7), the lingual artery (n=1), and the superior thyroid artery (n=4). In one case we did an end-to-side anastomosis on the external carotid artery. For the venous anastomosis, we made one end-to-side anastomosis (on the retromandibular vein), and 12 end-to-end anastomoses: on the thyrolinguofacial trunk (n=8), and the external (n=2) and the internal jugular (n=3) veins. In all patients, the arterial anastomosis was made after permeability had been assured, and an immediate and frank venous return was apparent.

All reconstructions were made after resection (segmental mandibulectomy) of the pathological bone until healthy bleeding bone was reached. No revascularisation was attempted after simple curettage or debridement. The histological examinations of the resected bones showed infiltration into the connective tissue with no osteocytes, osteoclasts, or osteoblasts, and no signs of recurrent tumour in any sample. It did not allow the clinician to judge whether the osteoradionecrotic bone had been completely excised, despite operative bony bleeding.

Postoperative outcome and follow-up

The postoperative period (within seven days of operation) was marked by three acute complications : haematoma, partial necrosis, and ischaemic vascular necrosis that required immediate replacement with a new forearm free flap with radial periosteum.

In two further cases (more than seven days postoperatively), we encountered two chronic complications: a skin fistula caused by intolerance to a vascular clip, and a traumatic mandibular fracture.

Within a mean (range) follow-up time of 83 ( 11.7 -165.5) months we found only one patient whose ORN had progressed as result of exposure of the bone and, despite complete resection, this means that the treatment was effective in only 11/12.

Two patients showed evidence of new bone formation on the follow-up radiographs (Figs. 1 and2).

Dental rehabilitation for all patients was begun six months postoperatively in the absence of recurrence or progression of ORN. Among them, three patients had dental implants inserted without activating any new ORN.

Case Reports

Revascularisation by a forearm free flap with radial periosteum: [START_REF] Yang | Forearm free skin flap transplantation: a report of 56 cases, 1981[END_REF] A 64-year-old patient had a squamous cell carcinoma of the tongue resected, followed by bilateral neck dissection, reconstruction with a forearm free flap, and postoperative radiotherapy (65 Gy). Five years later, he developed ORN of the mandibular symphysis (Wong stage 4) (Fig. 3).

After one year of unsuccessful medical management including three episodes of curettage, long-term antibiotic treatment, and 30 sessions of hyperbaric oxygen, it was decided to revascularise the area with a radial forearm periosteal flap (Fig. 4).

First, we did a marginal mandibulectomy, and then we reconstructed it with a radial forearm free flap with radial periosteum, without separating the vascular pedicle from the radial periosteal membrane. To facilitate the harvest, we find it preferable to dissect the sensitive branches of the radial nerve, and start the periosteal incision from the radial side.

In the second step, we position the flap with sutures from the radial periosteum to the mandibular periosteum, and the skin paddle is sutured to the oral mucosa without tension. Finally, end-to-end vascular anastomoses were made between the radial artery and the right superior thyroid artery, and between the cephalic vein and the thyrolinguofacial venous trunk.

Oral feeding was allowed seven days postoperatively and the patient was discharged on the 13 th postoperative day. At six months' follow-up clinical examination showed complete integration of the flap (Fig. 5), with no recurrence of the ORN on CT.

Revascularisation by a internal femoral condylar periosteal free flap: 15 (Supplemental data, online only) A 55-year-old patient was treated for a squamous cell carcinoma of the base of the tongue. He was initially given radiochemotherapy (three curative doses of cisplatin and 60 Gy radiation). Four years later he developed mandibular ORN after extraction of a molar. After 17 months of ineffective medical management including three episodes of curettage, two surgical debridements, and one episode of the Pentoclo regimen, revascularisation was chosen (Supplemental data 1), using an internal femoral condylar periosteal free flap harvested after marginal mandibulectomy. After careful dissection of the medial genicular artery (Supplemental data 2), a femoral condylar periosteal membrane was harvested (Supplemental data 3). The flap was then positioned in the oral cavity, allowing a tight bony cover and sutured to the mucosa without tension with interrupted absorbable sutures. End-to-end vascular anastomoses were made to the facial vessels.

The postoperative follow-up was uneventful, the patient started oral feeding on the fifth postoperative day and was discharged from hospital on the ninth day (Supplemental data 4).

At the one year follow-up, radiological (Supplemental data 5) and clinical monitoring showed complete integration of the flap, with no recurrence of ORN.

Discussion

With an incidence between 5% and 10%, mandibular ORN is a serious public health problem. [START_REF] Thariat | Compliance with fluoride custom trays in irradiated head and neck cancer patients[END_REF] Recently, the questioning of the effectiveness of the main conservative treatments (hyperbaric oxygen, [START_REF] Annane | Hyperbaric oxygen therapy for radionecrosis of the jaw : a randomized, placebo-controlled, double-blind trial from the ORN96 study group[END_REF] long term antibiotics, [START_REF] Madrid | Osteoradionecrosis : An update[END_REF] and the Pentoclo regimen [START_REF] Martos-Fernandez | Pentoxifylline, tocopherol, and clodronate for the treatment of mandibular osteoradionecrosis: a systematic review[END_REF] ) has made it difficult to establish a consensus about how to manage such lesions. However, it seems to be accepted that pathological fractures or advanced lesions (Notani class III) are dependent on surgical treatment with reconstruction by a microanastomosed free flap. The management of refractory lesions above the mandibular canal (Notani classes I or II) may be problematic. We propose to extend the use of free flaps in the management of ORN, the efficiency of which is from 86% to 100%, [START_REF] Lee | Outcomes of microvascular free flap reconstruction for mandibular osteoradionecrosis: A systematic review[END_REF] to lesions above the mandibular canal that are refractory to conservative management or (according to the conclusion of Delanian et al [START_REF] Delanian | Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifyllinetocopherol-clodronate combination (PENTOCLO): a phase II trial[END_REF] ) with more than 20 mm of exposed bone. In this way we hope to stop the development of ORN by providing periosteal bony vascular supplementation before the bony infrastructure weakens enough to require the use of a free flap of bone, which would increase the risk of complications. [START_REF] Kroll | Choice of flap and incidence of free flap success[END_REF] Indeed, revascularisation for Notani class I or II lesions that are accessible to a "soft-tissue free flap" resection of the pathological bone, and cover of a bleeding bone without tension, seem to stop the ORN.

Our hypothesis is that the supply of healthy vascularised tissue without irradiated cells is a biological response to the hypoxia, hypocellularity, and hypovascularisation of the ORN. [START_REF] Marx | A new concept in the treatment of osteoradionecrosis[END_REF] The reconstruction with restoration of bony tightness alone also avoids the use of inert osteosynthesis material, which in an irradiated area causes 6.5% to 57.7 % of chronic complications [START_REF] Lee | Outcomes of microvascular free flap reconstruction for mandibular osteoradionecrosis: A systematic review[END_REF] and generally requires one or more complementary interventions with the risk of reactivating the ORN.

As far as the choice of soft-tissue free flaps in the treatment of ORN is concerned, we know of no studies that have evaluated the superiority of periosteal composite free flaps compared with fasciocutaneous free flaps in the treatment of early ORN. Nevertheless, the effectiveness of periosteal free flaps in the treatment of degenerative osteoarthritis [START_REF] Trigui | Treatment of congenital pseudarthrosis of the fibula by periosteal flap[END_REF] seems to offer a real biological dimension in the treatment of defects of bony consolidation, which benefits from secondary remodelling of the periosteal flap. In 2007, our team had already decided to use this approach to ORN with a high risk of progression. [START_REF] Trigui | Treatment of congenital pseudarthrosis of the fibula by periosteal flap[END_REF] However, the association of severity factors with risk factors for ORN limits its analysis. [START_REF] D'hauthuille | Mandibular osteoradionecrosis : part I : severity factors[END_REF][START_REF] Goldwaser | Risk factor assessment for the development of osteoradionecrosis[END_REF] Between 1992 and 2002, D'Hauthuille et al [START_REF] D'hauthuille | Part III : free periosteal flaps as a treatment for mandibular osteoradionecrosis[END_REF] reported eight patients with ORN treated by periosteal free flaps that healed completely, including two secondary radiological osteoconductions, and one histological proof of the osteoconductive capacity of the periosteal free flap. In addition to its neoangiogenic capacity and potential for recruiting cells, therefore, the integration of a free flap with periosteal osteoconductivity is an obvious advantage in the physiological therapeutic approach to osteoradionecrotic injuries.

It is remarkable to see how our use of composite periosteal free flaps has increased since 1992 (2/8 patients compared with 8/13 with ORN). [START_REF] D'hauthuille | Part III : free periosteal flaps as a treatment for mandibular osteoradionecrosis[END_REF] This evolution is explained by the many advantages attached to the additional fasciocutaneous interface with the periosteal membrane. Indeed, the skin paddle offers easy monitoring of tissue viability and an additional interface, which optimises bony tightness and facilitates the placement of the periosteal flap (which requires a bony anchor to avoid non-union and exposure of the surgical site). The presence of a skin paddle, in addition to covering ORN, also allows us to correct oral scars, either with surgical flanges or post-radiation retraction. Despite limited complications at the donor site, the periosteal flaps (iliac crest or internal femoral condyle) have short vascular pedicles and these, together with their tendency to retract postoperatively, are their main limitations. Our experience has led us to favour the use of the forearm free flap with a radial periosteal component, mainly because the cutaneous paddle and its long vascular pedicle are so thin. This allows us to adapt to vascular constraints encountered in irradiated or multioperated areas (depleted vessels in the neck or reactive arteriosclerosis). Nevertheless, it is interesting to note that all cases of osteoconduction in our department (four between 1992 and 2013) were secondary to reconstruction by an internal femoral condylar free flap. This suggests that the -true‖ periosteal free flap has an osteoconductive potential superior to that of the composite periosteal free flap.

We are aware that proposing revascularisation for the management of Notani class I or II lesions may seem disproportionate. However, it is important to consider the effectiveness of different treatments and the progression of the lesions. If we consider the conclusions of Delanian et al [START_REF] Delanian | Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifyllinetocopherol-clodronate combination (PENTOCLO): a phase II trial[END_REF] and Rice et al, [START_REF] Rice | The management of osteoradionecrosis of the jaws-a review[END_REF] it is possible to accept that a conservative approach can be proposed in case of ORN located above the mandibular canal and when less than 2 cm of bone are exposed but, in the case of ineffectiveness or aggravation during conservative treatment, the diagnosis of refractory lesion must be considered as reason enough to suggest that potentially the initial strategy should be modified. Under these conditions, the periosteal flap is a reliable and curative alternative for the osteolytic lesions above the mandibular canal, as it allows both control of the ORN and restoration of oral function. Nevertheless, it is necessary to validate this therapeutic approach in a large prospective study with several expert centres to define a common strategy for dealing with ORN of the jaw, because with its high complication rate at any stage (18% -75%) [START_REF] Lee | Outcomes of microvascular free flap reconstruction for mandibular osteoradionecrosis: A systematic review[END_REF] the failure of the initial reconstruction may aggravate the initial lesion. Irradiation and further operations on the neck will only complicate the management further.

Conclusion

The periosteal free flap is an effective way to treat Notani class I or II ORN that is refractory to conservative management or has more than 2 cm of bone exposed.

Because of their neoangiogenic and osteoconductive properties, periosteal free flaps can be considered to be the first step in a cellular approach to the treatment of mandibular ORN. However, our experience needs to be confirmed by a larger prospective study to confirm the importance of reconstruction in the management of ORN, and to identify the limits of medical treatments so that we offer patients the best risk:benefit ratio between efficacy and complications. .

Figure 1 .

 1 Figure 1. Dental panoramic view of case 9 with a Notabi class II ORN of the right

Figure 2 .

 2 Figure 2. Dental panoramic view of case 9 taken one year after revascularisation

Figure 3 .

 3 Figure 3. Three-dimensional reconstruction of the preoperative computed

Figure 4 .

 4 Figure 4. Intraoperative photograph of the forearm free flap with radial periosteum

Figure 5 .

 5 Figure 5. Photograph 14 days postoperatively showing the integration of the flap.

Conflict of Interest

We have no conflicts of interest.

Ethics statement/confirmation of patients' permission

This study adhered to the principles of the Declaration of Helsinki in terms of medical protocols and ethics. Consent for publication was obtained from all patients. Supplemental dataonline only: pages 7 and 8.

QUERIES TO AUTHOR:

Throughout: please do not use the word "average", as it can apply to mean, median, or mode. We have assumed mean.

References: your reference 24 was a duplicate of 2, so has been removed. Trigger factors [START_REF] Marx | A new concept in the treatment of osteoradionecrosis[END_REF] Topograph y of the ORN [START_REF] Kuhnt | Potential risk factors for jaw osteoradionecrosis after radiotherapy for head and neck cancer[END_REF] Depth of osteolytic damage [START_REF] Meyer | Infectious diseases of the jaws[END_REF] Conservative