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PROFESSEURS DES UNIVERSITES-PRATICIENS HOSPITALIERS

Keywords: ionized magnesium, atrial fibrillation, emergency medicine, critical care, cardiology

Background: Magnesium (Mg) is often used to manage de novo atrial fibrillation (AF) in the Emergency Department (ED) and Intensive Care Unit (ICU). Point of care measurement of ionized magnesium (iMg) allows a rapid identification of patients with impaired magnesium status, however, unlike ionized calcium, the interpretation of iMg is not entirely understood. Thus, we evaluated iMg reference values, correlation between iMg and plasmatic magnesium (pMg), and the impact of pH and albumin variations on iMg levels. Secondary objectives were to assess the incidence of hypomagnesemia in de novo AF, and the influence of hypomagnesemia inducing-medication in AF.

Methods: A total of 236 Emergency Department and Intensive Care Unit patients with de novo AF, and 198 control patients were included. Reference values were determined in the control population. Correlation and concordance between iMg and pMg were studied using the calcium (ionized and plasmatic) as control in the whole study population. The impact of albumin and pH was assessed in the discordant iMg and pMg values. Lastly, we assessed incidence of ionized hypomagnesemia among de novo AF.

Results:

The reference range values established in our study for iMg were: 0.48-0.65 mmol/L (the manufacturers were: 0.45-0.60 mmol/L). A strong correlation was observed between pMg and iMg (r=0.85), but, unlike for calcium values, there was no significant impact of pH and albumin in iMg variations. The incidence of hypoMg among de novo AF patients was 8.5% (12.7% using our ranges).

Conclusion:

Our study highlights the need for more accurate reference range values of iMg. Furthermore, our results suggest that blood Mg content is not identical to that of calcium. The incidence of ionized hypomagnesemia among de novo AF patients in our study is only 8.5%.

INTRODUCTION

Magnesium (Mg) is one of the most important cations in the human body [START_REF] Glasdam | Chapter Six -The Importance of Magnesium in the Human Body: A Systematic Literature Review[END_REF]2). It is concentrated in the intracellular compartment, especially in bones -with a strong relationship with calcium (Ca) and phosphate -but also muscles and soft tissues (2)[START_REF] Schuchardt | Intestinal Absorption and Factors Influencing Bioavailability of Magnesium-An Update[END_REF][START_REF] Konrad | Insights into the molecular nature of magnesium homeostasis[END_REF][START_REF] Larsson | Dietary magnesium intake and risk of stroke: a metaanalysis of prospective studies[END_REF]. Plasma magnesium (pMg) represents 2% of the total Mg (6-8), and around 70% of pMg is ionized (iMg) and 30% is bound to albumin [START_REF] Fawcett | Magnesium: physiology and pharmacology[END_REF]. As a divalent cation, Mg content and physiology are often compared to that of calcium (ionized (iCa) and plasmatic (pCa)) but are much less studied (2). For instance, in the interpretation of pMg values, the only indicator of Mg status, the impact of albumin and pH variations is not completely understood (9,10).

The main clinically relevant manifestation of dysregulation of Mg homeostasis is hypomagnesemia (hypoMg), concerning 2% of the general population (2). It is usually defined as pMg under 0.75 mmol/L (7), or iMg under 0.4 mmol/L [START_REF] Greenway | Reference interval for whole blood ionized magnesium in a healthy population and the stability of ionized magnesium under varied laboratory conditions[END_REF]. The symptoms of hypoMg include weakness, nausea, cramps, muscle contractions, seizures, and arrhythmia [START_REF] Badran | L'hypomagnésémie : causes, manifestations et traitement[END_REF]. A

profound Mg depletion also impacts the homeostasis of potassium and calcium and can cause hypokalemia and hypocalcemia (7). Dysregulation of Mg homeostasis symptoms are linked to the key role played by Mg in many physiological functions. As a cofactor, Mg is involved in over 600 enzymatic reactions [START_REF] Caspi | The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases[END_REF], including the functioning of the cardiovascular system via Calcium-ATPases and especially for modulation of cardiac potential action [START_REF] White | Effects of intracellular free magnesium on calcium current in isolated cardiac myocytes[END_REF]. Through phosphorylation, Mg inhibits L-type calcium channels, exerting a protective effect on myocardial cells [START_REF] Gröber | Magnesium in Prevention and Therapy[END_REF]. Furthermore, Na-K ATPase require Mg to modulate action potential duration. Lastly, Mg's effect on cardiomyocytes also depends on its ability to compete with calcium for binding sites in proteins, to act as substrate along with Adenosine Triphosphate for cardiac Calcium-ATPases and to alter the affinity of Natrium-Calcium exchanger (1). One of the most frequent complications of abnormal potential action is atrial fibrillation (AF).

AF is the most common sustained arrhythmia, with an estimated prevalence up to 37.6 million cases worldwide, its prevalence increased by 33% during the last 20 years [START_REF] Kirchhof | ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS[END_REF][START_REF] Cohen | A systematic review of network meta-analyses among patients with nonvalvular atrial fibrillation: A comparison of efficacy and safety following treatment with direct oral anticoagulants[END_REF]. AF is responsible of 600,000 Emergency Department (ED) admissions in the United States every year [START_REF] Bode | Management of Atrial Fibrillation in the Emergency Department[END_REF]. Around a quarter of Intensive Care Unit (ICU) patients have at least one episode of AF [START_REF] Bosch | Atrial Fibrillation in the ICU[END_REF]. The management of AF is based on the reduction of the ventricular rate. Although not perfect, several drugs are recommended for the management of AF including calcium channel blockers, beta-blockers, and Digoxin [START_REF] Taboulet | Prise en charge de la fibrillation atriale en médecine d'urgence. Recommandations de la Société française de médecine d'urgence en partenariat avec la Société française de cardiologie[END_REF]. The administration of Mg in acute atrial tachyarrhythmia has also been proposed as an alternative or in addition to the usual care [START_REF] Moran | Parenteral magnesium sulfate versus amiodarone in the therapy of atrial tachyarrhythmias: a prospective, randomized study[END_REF].

However, the incidence of hypomagnesemia among de novo AF remains unknown.

Point of care measurement of iMg allows a rapid identification of patients with impaired magnesium status, however, unlike iCa, the interpretation of iMg in relation to total magnesemia is not entirely understood. In our study, we evaluated iMg reference values, iMg and pMg correlation, and the impact of pH and albumin variations on iMg levels. Secondary objective was to assess the incidence of hypomagnesemia in AF.

MATERIALS & METHODS

Study Design

We performed a prospective monocentric observational study in the ED, and three different The study population consisted of de novo AF patients, diagnosed by an attending physician using 12-lead electrocardiogram. Exclusion criteria were refusal to participate, medical history of AF, age < 18 years old. Blood samples were collected for each patient on a heparinized syringe for blood gas analysis and measurement of the ionized magnesium concentration.

A control population (n=198) was constituted of 80 ED and 118 ICU patients without AF, for whom blood samples were collected for routine tests. The inclusion criteria were every patient present in the ED on October 30 th or October 31 st , 2021, or in the ICU between November 1 st and November 15 th , 2021, that already had blood sample, and the exclusion criteria were patient with AF. Mg reference range was determined in the 80 ED patients, and compared to the manufacturers', and the prevalence of hypo-iMg was assessed in the whole control population (ED and ICU patients) and compared to that of AF patients.

Data collection

The data collected at admission were age, sex, body mass index (BMI), CHADSVASC score, medical history of dysthyroidisim, hypertension, medications known to induce hypoMg, sepsis, dehydration, and outcome of the AF episode (resolutive vs non-resolutive). Hyperthyroidism was defined by a TSH < 0.358 mUI/L, or if the patient was known for hyperthyroidism on the case report form (CRF). Dehydration was defined by a diastolic blood pressure was < 40 mmHg or systolic blood pressure < 90 mmHg or mean blood pressure < 65 mmHg or plasmatic protein > 80 g/L or if the symptom « hypovolemia » or « dehydration » was validated by the investigator on the CRF. Sepsis was defined if temperature was > 38.5 °C or if diagnosed by the physician and reported on CRF. Hypertension was defined by a systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg or if the patient had a history of high blood pressure or was treated for high blood pressure. Plasma and whole blood results were also collected for iMg, pMg, iCa, pCa, pH, potassium (K) and albumin.

Blood assays

Whole blood iMg, iCa and pH were determined by direct potentiometry using a Stat Profile Ò PRIME Plus analyzer from Nova Biomedical (Les Ulis, France). Regarding iMg, lower detection limit was 0.05 mmol/L and the measuring range extends up to 1.

Statistics

Statistical analyses were performed with Stata Software ® (v15, College Station, StataCorp, Texas, USA). Continuous variables were expressed as mean and standard deviation (SD) or median [p25; p75] and categorical variables were expressed as number (%). The Gaussian distribution for each ionic variable was assessed by a Shapiro-Wilk test.

The first part of this study was performed among our control population, i.e., patients without AF. Secondly, we described our ranges (mean, median, 5%, 95%, p25, p75) of iMg and pMg values, using the control population.

We assessed correlation using Spearman coefficient for iMg, pMg and cMg, interpreted as follow: [0; 0.2] or [-0.2; 0] are considered as very weak; [0.2-0.5] or [-0.5; -0.2] are considered as weak to mild; up to 0.5 [less than -0.5] is considered as strong to very strong. Agreement between iMg, pMg and cMg was assessed by agreement rate and concordance Cohen's kappa coefficient. Values were considered as "concordant" when iMg and pMg were both "hypo", "normal" or "hyper", and "discordant" in all other cases. The results concerning kappa coefficient were interpreted in relation to the recommendations reported in the literature by Altman ( 22): <0.4: no agreement, 0.4-7: poor agreement, >0.7: moderate to strong agreement.

To control our samples, we performed the same analysis with iCa and pCa.

Association between iMg and other etiologies of de novo AF or hypoMg treatments were assessed using Chi 2 for categorical variables and Student t-test or Mann-Whitney test for continuous variables. Lastly, the impact of pH and albumin among discordant Mg, was evaluated with aforementioned statistical tests. Because of frequent comparison between Mg and Ca physiology, we controlled all our data using iCa and pCa [START_REF] Gauci | Pitfalls of Measuring Total Blood Calcium in Patients with CKD[END_REF][START_REF] Payne | Interpretation of serum total calcium: effects of adjustment for albumin concentration on frequency of abnormal values and on detection of change in the individual[END_REF].

All the tests were two-sided, with a Type I error set at 0.05.

RESULTS

Patient Characteristics

Between November 2020 and December 2021, 236 patients with de novo AF were enrolled in the study including 131 from the ED and 105 from the ICUs. Baseline characteristics of de novo AF patients included are presented in Table 1. ED patients were significantly older than ICU patients (76±18.1 versus 71±11.8). 62.7 % of our population was male, with a higher proportion among ICU patients (70.5 % versus 56.5 %). Hypertension was the main etiology of AF in our population (n=140, 66.5%) with a significantly higher proportion in ED patients (p < 0.001).

Other etiologies were hyperthyroidism (n=2, 0.9%), hypokalemia (n=35, 15%), sepsis (n=36, 15.3%) and dehydration (n=29, 12.3%). Hypokalemia, sepsis and dehydration were more present in ICU patients (p=0.006, p<0.001, p=0.034 respectively). Regarding hypomagnesemia-inducing medications, the proportion of proton pump inhibitors intake was higher in the ICU (46.7% vs 9.9%, p<0.001).

Interpretation of iMg

Reference values

The reference range values for iMg were determined in the control population constituted in the ED (80 blood samples collected), median iMg was 0.61 mmol/L (95% Confidence Interval: 0.48-0.65). The reference range was set at 0.48-0.65 mmol/L, while the manufacturer's reference range was 0.45-0.60 mmol/L. A: agreement between iCa and pCa; B: agreement between iCa and cCa; C: agreement between iMg and pMg according to the manufacturer's range; D: agreement between iMg and cMg using the manufacturer's range; E: agreement between iMg and pMg using the determined reference range; F: agreement between iMg and cMg using the determined reference range. Correction formulas used for cCa and cMg are: cCa = pCa + 0.025(40-albumin) and cMg = pMg + 0.005 (40-albumin). iCa= ionized calcium, pCa = plasmatic calcium, cCa = albumin corrected calcium. iMg= ionized magnesium, pMg = plasmatic magnesium, cMg = albumin corrected magnesium

Correlation and agreement between iMg and pMg or cMg

Correlation was assessed for a total of 236 calcium values and 216 magnesium values.

Spearman correlation coefficients were 0.85 between iMg and pMg, 0.85 between iMg and cMg, 0.60 between iCa and pCa, 0.25 between iCa and cCa.

Agreement between the biological interpretation of ionized and total Mg and Ca forms according to the references values used is presented in Figure 1. Agreement between iCa and pCa was 71% with a Κ coefficient at 0.40. It decreased to 63% (Κ=0.14) between iCa and cCa.

Regarding Mg values, using the manufactuter's ranges, the agreement between iMg and pMg was 56% (Κ=0.37), and 58% (Κ=0.39) between iMg and cMg. The agreement increased to 66% (Κ=0.47) between iMg and pMg, and 67% (Κ=0.48) between iMg and cMg using the reference values determined in our study.

A-Impact of albumin

Impact of albumin and pH

The influence of pH and albumin on the concordance/discordance between ionized and total plasmatic values of Mg and Ca is presented in Table2. The manufacturer's reference values for iMg were used for the agreement assessment. A significantly lower albumin median was observed among discordant calcium levels (hypo total plasmatic / normal ionized) compared to concordant calcium levels (normal pCa-normal iCa) (Table 2A, p< 0.001). This result was not observed for Mg (Table 2A, p=0.32).

A significantly higher pH median was observed among discordant calcium levels (normal total plasmatic-hyper ionized) compared to concordant calcium levels (normal pCa-normal iCa) (Table 2B, p=0.026) with a higher proportion of acidosis in discordant group (Table 2B, p=0.019). This result was not observed for Mg (Table 2B, p=0.34 and p=0.37 for pH median and proportion of acidosis respectively). The proportions of hypo-iMg between AF and control groups (Total, ICU, ED) were not significantly different, except for ED patients, when using the ranges determined in our study (p < 0.001).

Resolution of AF

Concerning the outcome of AF patients, 71 (30.1%) AF cases resolved before discharge, 12 (9.2%) in the ED and 59 (56.2%) in the ICU. Patients with hyper-iMg had a higher rate of resolution (p=0.07). The most common treatments administered were Diltiazem, Digoxin, and beta-blockers in the ED, and Amiodarone, fluid loading and magnesium sulfate in the ICUs.

Three (5.6%) patients from the ED received magnesium sulfate, none was regressive. In the ICUs, 55 (52.4%) patients received magnesium sulfate, 34 (58.6%) resolved and 21 (36.2%)

were considered non-resolutives.

DISCUSSION

Ionized Mg is a promising biomarker in emergency medicine considering the importance of its role in cardiac automatism. iMg measurement is available in point of care, and guidelines for sampling, measurement and result reporting have been issued to ensure the quality of the results [START_REF] Rayana | Guidelines for sampling, measuring and reporting ionized magnesium in undiluted serum, plasma or blood: International Federation of Clinical Chemistry and Laboratory Medicine (IFCC): IFCC Scientific Division, Committee on Point of Care Testing[END_REF].

Reference values

The measurement of iMg in our study were carried out on Stat Profile Ò PRIME Plus analyzer from Nova Biomedical. The manufacturers reference values were determined in 1,996 employees across 125 hospitals [START_REF] Dc | Reference interval for whole blood ionized magnesium in a healthy population and the stability of ionized magnesium under varied laboratory conditions[END_REF], and were not studied afterwards. Although Mg is the fourth most present cation in the human body (second in the intracellular compartment), its measurement (ionized form) is still rare, and the literature is poor regarding reference ranges [START_REF] Scarpati | Ionized or Total Magnesium levels, what should we measure in critical ill patients?[END_REF]. In our study, the biological interpretation agreement between iMg and pMg (or cMg) values increased when applying the reference ranges established in our study. Reinforcing the idea that the iMg reference values must be updated.

The initial reference interval (95th percentile) used for total serum Mg concentration was 0.75-0.95 mmol/L, it has been determined in 15,820 "healthy normal individuals" aged 18-74 years in 1974 [START_REF] Lowenstein | Serum magnesium levels in the United States, 1971-1974[END_REF]. There is still a debate about those ranges and daily recommended intakes. Indeed, Mg consumption decreased over the last 30 years due to the increase of fast-food and the decrease of fruits and vegetables consumption [START_REF] Costello | Perspective: The Case for an Evidence-Based Reference Interval for Serum Magnesium: The Time Has Come[END_REF]. A recent study suggests a 0.85 mmol/L threshold for the definition of hypomagnesemia, after collecting 43 serum Mg reference range values from 16 countries [START_REF] Rosanoff | Recommendation on an updated standardization of serum magnesium reference ranges[END_REF].

The lack of reliable data concerning the interpretation of Mg and iMg values may be related to the fact that Mg measurement is rarely prescribed in routine care, since mild hypomagnesemia rarely has clinical implications. Furthermore, the measurement of iMg requires specialized equipment and is even less used. iMg values may also be subject to individual interferences [START_REF] Glasdam | The Importance of Magnesium in the Human Body: A Systematic Literature Review[END_REF].

Lastly, studies have shown that iMg accounts for 60-64% of total pMg [START_REF] Zhan | Circulating Ionized Magnesium as a Measure of Supplement Bioavailability: Results from a Pilot Study for Randomized Clinical Trial[END_REF][START_REF] Rooney | Circulating Ionized Magnesium: Comparisons with Circulating Total Magnesium and the Response to Magnesium Supplementation in a Randomized Controlled Trial[END_REF]. In a study published in 2007, a weak correlation has been described between iMg and pMg, and between iMg and albumin. In the same study, authors set iMg reference range values to 0.48-0.63 mmoL/L [START_REF] Johansson | Weak relationship between ionized and total magnesium in serum of patients requiring magnesium status[END_REF]. These values are similar to the ones described in our study (0.48-0.65 mmol/L).

A large observational study using different measuring instruments would be of value for the harmonization of reference range values allowing an appropriate evaluation of Mg status.

Influencing variables

The impact of pH and albumin variations on calcium levels have been widely studied [START_REF] Payne | Interpretation of serum total calcium: effects of adjustment for albumin concentration on frequency of abnormal values and on detection of change in the individual[END_REF][START_REF] Bushinsky | Effects of pH on bone calcium and proton fluxes in vitro[END_REF].

Patients with severe hypoalbuminemia present low total calcium levels without clinical relevance, since the ionized concentration remains normal [START_REF] Payne | Interpretation of serum total calcium: effects of adjustment for albumin concentration on frequency of abnormal values and on detection of change in the individual[END_REF]. Furthermore, patients with severe acidosis present normal total calcium levels while the ionized (active) form is increased [START_REF] Gauci | Pitfalls of Measuring Total Blood Calcium in Patients with CKD[END_REF]. Since Mg content and physiology are considered as analog to that of calcium, pMg and iMg levels are assumed to be similarly affected by pH and albumin variations (9,10) Our results are in accordance with these observations concerning calcium levels, constituting an external validation criteria. However, we did not find such results for Mg.

A strong correlation has been observed between iMg and pMg (r=0.85), reinforcing the idea of a limited impact of pH and albumin on iMg levels. Furthermore, the albumin correction of Mg values did not improve the correlation coefficient (r=0.85 between iMg and cMg). This strong correlation observed in our study is inconsistent with the findings of a study in a smaller cohort of 48 ICU and ED patients, where a weak correlation was observed between iMg and pMg (r=0.59) [START_REF] Johansson | Weak relationship between ionized and total magnesium in serum of patients requiring magnesium status[END_REF].

Incidence of hypomagnesemia during de novo AF

To our knowledge, we performed the first study on the incidence of hypomagnesemia in the setting of de novo AF in ED and ICU patients. We found that 8.5% of patients (10.5% of ICU patients and 6.9% of ED patients) with de novo AF had hypo-iMg. This incidence seems independent from AF in ICU patients since we observed a similar proportion of hypo-iMg for ICU patients without AF. However, hypo-iMg is significantly higher in ED patients with AF.

We did not find any data in the literature to compare our results. However, it has been described that serum Mg is inversely associated with the risk to develop AF in type 2 diabetes patients during a six-year follow-up study [START_REF] Oost | Serum Magnesium Is Inversely Associated With Heart Failure, Atrial Fibrillation, and Microvascular Complications in Type 2 Diabetes[END_REF]. Among 162 patients, 22 (1.4%) developed AF over a median follow-up of 25.3 months, suggesting an association between mild and moderate hypomagnesemia and incident AF without a temporal relationship between hypomagnesemia and the early occurrence of AF [START_REF] Markovits | Database evaluation of the association between serum magnesium levels and the risk of atrial fibrillation in the community[END_REF]. Lastly, the Framingham study showed that individuals in the lowest quartile of serum magnesium were 50% more likely to develop AF compared to those in the upper quartiles [START_REF] Khan | Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study[END_REF]. iMg during AF was more studied during peri-operative period.

For example, the iMg level immediately before admission to ICU may be associated with the development of post-operative AF after surgery for esophageal cancer. Among 151 patients, 23% developed AF, which is far more than our results [START_REF] Hizuka | Ionized Hypomagnesemia Is Associated With Increased Incidence of Postoperative Atrial Fibrillation After Esophageal Resection: A Retrospective Study[END_REF]. Lastly, among 30 patients that had benefited of a bypass surgery, 73% had at least one episode of hypo-iMg. However, some patients had both hypo and hyper-iMg during ICU's stage [START_REF] Aziz | Blood ionized magnesium concentrations during cardiopulmonary bypass and their correlation with other circulating cations[END_REF]. Among ED patients, the 6.9% incidence of hypo-iMg is lower than in literature. An Australian study showed a 10% of abnormal (hypo and hyper) serum Mg level [START_REF] Taylor | Risk variables associated with abnormal calcium, magnesium and phosphate levels among emergency department patients[END_REF] and a recent study based on 1,008 patients found a 17.2% rate of hypomagnesemia [START_REF] Lapointe | Identification of Predictors of Abnormal Calcium, Magnesium and Phosphorus Blood Levels in the Emergency Department: A Retrospective Cohort Study[END_REF].

Magnesium supplementation as AF therapy

The use of magnesium sulfate as an alternative or additional therapy to usual care has previously been investigated on small samples with controversial results and non-consistent Mg posology [START_REF] Moran | Parenteral magnesium sulfate versus amiodarone in the therapy of atrial tachyarrhythmias: a prospective, randomized study[END_REF][START_REF] Piotrowski | Magnesium for the treatment and prevention of atrial tachyarrhythmias[END_REF][START_REF] Hornestam | Adding magnesium sulfate to usual care may improve rate and rhythm control for people with rapid atrial fibrillation[END_REF][START_REF] Ganga | Magnesium Adjunctive Therapy in Atrial Arrhythmias[END_REF][START_REF] Bouida | Low-dose Magnesium Sulfate Versus High Dose in the Early Management of Rapid Atrial Fibrillation: Randomized Controlled Double-blind Study (LOMAGHI Study)[END_REF]. In our study, magnesium sulfate indication and posology were decided by the physician in charge of the patient regardless of the iMg status. There was no significant difference in the AF reduction between patients that received magnesium sulfate and those that did not received it. Furthermore, patients with hypo-iMg and AF that received magnesium sulfate did not have a higher chance to reduce their AF. Further studies are needed to specifically establish the therapeutic effect of magnesium in AF.

Limitations

Our study has some limitations. Firstly, our monocentric design and the relatively low number of patients included may affect the interpretation of our results. However, the sample size was sufficient for the primary objective evaluating concordance/correlation. The study could be considered underpowered for secondary objectives, i.e. to determine the factors associated to the observed discrepancies. A multicentric design using different types of analyzers would increase the power and the generalization of our result.

CONCLUSION

Our study highlights the need for more accurate reference range values for iMg. Furthermore, albumin and pH did not impact iMg and pMg interpretation, suggesting that blood Mg content is not identical to that of calcium. Furthermore, the incidence of hypoiMg among de novo AF patients is 8.5% in our ICU and ED population, and a Mg supplementation does not appear to be correlated with resolution of de novo AF in ICU and ED patients.

Conclusion

Notre étude souligne la nécessité de disposer de valeurs de référence plus précises pour le

A l'équipe

  du bloc opératoire de Vichy : Merci à tous les chefs pour vos connaissances et votre confiance. Merci à Tim pour ces presque 6 mois (#têtefémoraledanslehutlehuc) dans la bonne humeur et le rire. A l'équipe de CCV : merci de m'avoir réconcilié avec la réanimation. Merci à l'équipe para-médicale et l'équipe médicale pour tout. Et merci a Arthur, Timothée et Luc pour avoir ajouté du piment d'Espelette et l'avoir rendu si exceptionnel. Merci à Ahn et Huy pour ces délicieux repas vietnamiens et pour ces soirées. A l'équipe de vasculaire : Mes co-internes Vianney et Clarisse, à l'équipe médicale et chirurgicale de choc (hémorragique surtout).A l'équipe de réa-neuro : Wouaw, quel stage ! Le plus intense et le meilleur. Merci à tous les chefs pour m'avoir appris la rigueur et dans la bonne ambiance en plus ! Cette ambiance elle est également due à une équipe de para med de folie, à Joyceline qui a su rendre nos comptes rendus lisibles, mais surtout à des co-internes incroyables.Oussama, la force tranquille, Céline la fausse tranquille (alias le grain de café), Julien le trop tranquille (alias si on allait au ciné), Alex le jamais à l'heure mais toujours de bonne humeur, Clémence élue miss potin ex aequo avec Lulu qui ont apporté autant de nouvelles infos que de fous rires. Et à Benjamin, mon co-pilote de galère de planning. Qu'est-ce qu'on a ri pour ne pas pleurer ! Merci pour ces moments.A l'équipe d'année recherche : Merci au Professeur Bazin et au Docteur Godet pour l'aide précieuse que vous m'avez apporté. Merci au Docteur Vernis, à Ridvan et Randy pour ces séances de simulation.

  Informed consent: Patients were informed of their right to express their disagreement regarding the use of their clinical information for research purposes. Ethical approval: This research complied with the tenets of the Helsinki Declaration (as revised in 2013) and has received approval by the French Patient Protection Committee (CPP Sud-Est VI) (Reference 2020/CE65). Author contributions: JBBM, LK and FV analyzed and interpreted the data. JBBM and SK wrote the initial version of the manuscript. DB and EF designed the study and assisted with interpretation of the data and writing of the manuscript. LM, RE, MJ and FM supervised the trial and data collection. VS, JD, SK and DB carried out assays. BP provided statistical advice for the study design and analyzed the data. All the authors contributed to revision of the manuscript before submission.

  ICUs (general, trauma, and cardiac) of the University Hospital of Clermont-Ferrand, France, between November 30 th , 2020, and December 11 th , 2021. The study was approved by the Ethics Committee South-East VI as number 2020/CE65. Patients were informed of their right to express their disagreement regarding the use of their clinical information for research purposes.

  5 mmol/L. Typical within-assay precision was below 2%. The iMg manufacturer's reference ranges are 0.45-0.60 mmol/L (11). The reference range values for iCa are 1.09-1.3 mmol/L, and 7.35-7.45 for pH. pMg, pCa, K and albumin measurements were performed using a Vista® analyzer (Siemens, Munich, Germany) following the manufacturer's recommendations. Correction formulas were used for Ca and Mg: cCa (albumin corrected calcium) = pCa + 0.025*(40-albumin) (21) and cMg (albumin corrected magnesium) = pMg + 0.005*(40-albumin) (9).

Figure 1 :

 1 Figure 1: Agreement between the biological interpretation of ionized and total Mg and Ca forms according to the references values used.A: agreement between iCa and pCa; B: agreement between iCa and cCa; C: agreement between iMg and pMg according to the manufacturer's range; D: agreement between iMg and cMg using the manufacturer's range; E: agreement between iMg and pMg using the determined reference range; F: agreement between iMg and cMg using the determined reference range. Correction formulas used for cCa and cMg are: cCa = pCa + 0.025(40-albumin) and cMg = pMg + 0.005(40-albumin). iCa= ionized calcium, pCa = plasmatic calcium, cCa = albumin corrected calcium. iMg= ionized magnesium, pMg = plasmatic magnesium, cMg = albumin corrected magnesium

  magnésium ionisé. De plus, l'albumine et le pH n'expliquent pas les discordances entre le magnésium ionisé et le plasmatique. Cela suggère que la teneur en Mg du sang n'est pas identique à celle du calcium. Par ailleurs, l'incidence de l'hypomagnésémie ionisée chez les patients souffrant de fibrillation auriculaire de novo est de 8,5 % dans notre population de soins intensifs et d'urgences. Une supplémentation en Mg ne semble pas être corrélée à la résolution de la FA de novo dans cette population. Doyen Directeur de la faculté de médecine, Président du jury,

chère et tendre famille Merci à mes parents

  pour votre amour inconditionnel et votre éducation. Merci pour nous avoir élevés dans cette double culture qui est notre force et notre fierté.Papa, toi et moi on s'aimera pour toute la vie et bien plus encore. Si j'en suis là aujourd'hui c'est en partie grâce à Samy, mon confident, mon modèle, mon binôme. Merci pour notre enfance remplie de joie et de rires. Merci d'avoir été le grand frère idéal. Tu m'as toujours soutenu et épaulé. Je suis fière de l'homme que tu es devenu et d'être le témoin de votre amour avec Marion. Sara, ma petite soeur chérie que j'adore tant. Quand je vois la femme épanouie et pleine de projets que tu es devenue, je suis si fière d'être ta grande soeur. Je serai toujours à tes côtés.

	Mme GOUMY Carole Mme AUBEL Corinne Plus qu'un prof de sport, tu m'as appris un code moral, le sens de l'honneur, le respect, la combativité, et la Cytologie et Histologie, Cytogénétique Oncologie Moléculaire
	M. MARCEAU Geoffroy Mme MINET-QUINARD Régine Mme GUILLET Christelle M. BIDET Yannick compétitivité. Tous mes échecs m'ont rendu plus forte grâce à cet état d'esprit. Biochimie Biologie Moléculaire Biochimie Biologie Moléculaire Nutrition Humaine Oncogénétique
	PROFESSEURS DES UNIVERSITES DE MEDECINE GENERALE M. ROBIN Frédéric Bactériologie M. DALMASSO Guillaume Bactériologie
	Mme VERONESE Lauren M. PIZON Frank A mes amis du PEV : Je vous aime	Cytologie et Histologie, Cytogénétique Santé Publique
	UNIVERSITE CLERMONT AUVERGNE M. DELMAS Julien Bactériologie Mme MIRAND Audrey Bactériologie Virologie M. SOLER Cédric Biochimie Biologie Moléculaire M. GIRAUDET Fabrice Biophysique et Traitement de l'Image A Camille : tu es inspirante, merci d'être une source de motivation constante toi.
	___________________ Biostatistiques, Informatique Médicale Neurosciences -Neuropharmacologie Maman, tu es mon modèle et ma source d'énergie. Merci d'être ce que tu es, tout simplement la meilleure des M. OUCHCHANE Lemlih M. LOLIGNIER Stéphane A Kelian : merci pour ta bonne humeur et ton état d'esprit à la martiniquaise 1ère CLASSE et Technologies de Communication Mme MARTEIL Gaëlle Biologie de la Reproduction mamans. A Alex pour tes danses mémorables et inimitables
	PRESIDENTS HONORAIRES M. VORILHON Philippe M. LIBERT Frédéric Mme COSTE Karen M. PINEL Alexandre A mon frangin et ma petite soeur, que j'aime plus que tout A Léo, pour connaitre toutes les paroles de chanson de la terre entière Médecine Générale Pharmacologie Médicale Pédiatrie Nutrition Humaine : JOYON Louis UNIVERSITE D'AUVERGNE Mme LAPORTE Catherine Médecine Générale Mme AUMERAN Claire Hygiène Hospitalière A Vincent, le sosie de Freddy Mercury : DOLY Michel Mme NOURRISSON Céline Parasitologie -Mycologie A Victaz, you are giant, merci pour ta choré : TURPIN Dominique : VEYRE Annie : DULBECCO Philippe Mme PONS Hanaë Biologie et Médecine du Développement et de la Reproduction MAITRES DE CONFERENCES ASSOCIES DES UNIVERSITES A Aude, la fraicheur de l'été qui éclate tout le monde au karting.
	: ESCHALIER Alain A Anne So, pour ta douceur et ton calme. Et ta capacité à rester à toutes les soirées jusqu'à 6h du mat, respect. 2ème CLASSE
	PRESIDENTS HONORAIRES PROFESSEURS DES UNIVERSITES Mme ESCHALIER Bénédicte A Brice : le petit brie qui apporte la petite touche sympa à tous les repas (nouveau slogan pas de copyright svp) Médecine Générale : CABANES Pierre UNIVERSITE BLAISE PASCAL : FONTAINE Jacques : BOUTIN Christian : MONTEIL Jean-Marc : ODOUARD Albert : LAVIGNOTTE Nadine 2ème CLASSE M. COLL Guillaume Mme RICHARD Amélie Médecine Générale Neurochirurgie M. GODET Thomas Anesthésiologie-Réanimation et M. TESSIERES Frédéric Médecine Générale Mme ROUGE Laure A mes amis de Moulins : Merci pour ces soirées dans la cave, ces repas devant top chef et Koh Lanta. Médecine Générale Médecine Péri-Opératoire M. LACHAL Jonathan Mme BERTRAND-JARROUSSE Véronique Médecine Générale A Clémence la diva au coeur tendre Pédopsychiatrie M. MOUSTAFA Farès Médecine d'Urgence Mme VICARD-OLAGNE Mathilde Médecine Générale A Maxime toujours motivé, la fast life parfois un peu trop fast (#retraitdepermis)
	Mme MALPUECH-BRUGERE Corinne M. CHENAF Chouki A Raphaël pour ces séances de sport (tu as toujours les anneaux ?) Nutrition Humaine Pharmacologie Clinique
	PRESIDENT DE L'UNIVERSITE A Charles et ton amour pour les chats (Licorno <3)	: BERNARD Mathias
	PREMIERE VICE-PRESIDENTE CHARGEE DU PILOTAGE ET DES MOYENS A Chlount, tes escapades en skate et tes escalades en soirée	: FOGLI Anne
	VICE PRESIDENTE CHARGEE DE LA FORMATION A Clothilde, notre mère à tous	: PEYRARD Françoise
	VICE-PRESIDENTE CHARGEE DE LA RECHERCHE DIRECTEUR GENERAL DES SERVICES PROFESSEURS ASSOCIES DES UNIVERSITES : PREVOT Vanessa MAITRES DE CONFERENCES DES UNIVERSITES A Yoann et nos soirées futsal : PAQUIS François DE MEDECINE GENERALE A Steven pour ta piscine éphémère (BTP4ever)
	Mme BOTTET-MAULOUBIER Anne	Médecine Générale
	²²²²² Médecine Générale A Fanny. De cette rencontre fortuite en garde est née une amitié. Merci de nous faire sortir de notre zone de M. CAMBON Benoît
	M. TANGUY Gilles M. BERNARD Pierre confort, le	Médecine Générale Médecine Générale 1ère CLASSE
	UFR DE MEDECINE Mme VAILLANT-ROUSSEL Hélène Médecine Générale
	ET DES PROFESSIONS PARAMEDICALES en créant des hologrammes, ou tout simplement au
	DOYENS HONORAIRES lycée et en vadrouille, tous les moments avec chacun de vous sont des moments de bonheur simple que je regarde MAITRES DE CONFERENCES DES UNIVERSITES -: DETEIX Patrice : CHAZAL Jean PRATICIENS HOSPITALIERS MAITRES DE CONFERENCES DES UNIVERSITES avec nostalgie.
	DOYEN RESPONSABLE ADMINISTRATIVE Au Harem Merci d'avoir rendu mes années d'externat si plaisantes et mémorables. HORS CLASSE HORS CLASSE Lisa la souriante, Lucie la docteur Quinn qui est venue soigner mon petit coeur au prix de feu la twingo, Lolo : CLAVELOU Pierre : ROBERT Gaëlle
	Mme CHAMBON Martine l'aventurière en mer ou sur ses skis, Victoria toujours belle et apprêtée, Salomé et sa folie, Céline toujours prête à Bactériologie Virologie Mme BOUTELOUP Corinne Nutrition Mme FOGLI Anne Mme GOUAS Laetitia Cytologie et Histologie, Cytogénétique Mme VAURS-BARRIERE Catherine Biochimie Biologie Moléculaire Biochimie Biologie Moléculaire M. BLANCHON Loïc Biochimie Biologie Moléculaire M. MARCHAND Fabien Pharmacologie Médicale s'ambiancer, Alix la compliante et Pierre le beau couz
	A l'AMPc, que de moments mémorables !
	1ère CLASSE CLASSE NORMALE Merci Ssssophie pour ces années d'externat, plus belles et ensoleillées à tes côtés
	A mon professeur de Judo, Christian.
	M. MORVAN Daniel M. BAILLY Jean-Luc	Biophysique et Traitement de l'Image Bactériologie Virologie

A Monsieur le Professeur Emmanuel FUTIER, de me faire l'honneur de présider mon jury de thèse. Je vous remercie d'avoir partagé vos connaissances pratiques et théoriques ainsi que votre passion pour ce métier. A Monsieur le Professeur Damien BOUVIER, de me faire l'honneur d'être le directeur de cette thèse. Je vous remercie pour m'avoir accordé votre confiance et votre temps. Merci de m'avoir accompagné sur ce sujet de recherche. A Monsieur le Professeur Matthieu JABAUDON, merci pour ta bienveillance, ton accessibilité et le partage de tes connaissances. A Monsieur le Professeur Romain ESCHALIER, de me faire l'honneur de participer au jury de cette thèse. Merci de votre regard de cardiologue pour ce sujet de recherche. A Monsieur le Docteur Jean-Baptiste BOUILLON-MINOIS pour ta disponibilité, ton aide, tes conseils avisés et ta bonne humeur. A Madame Julie Durif pour ton travail rigoureux et appliqué. A Monsieur Bruno PERREIRA pour votre professionnalisme, votre accessibilité et votre gentillesse. A Madame Florence VITTE, c'est une immense joie de partager ce travail avec toi. Cette thèse nous a permis de faire plus ample connaissance et de fonder des bases solides de confiance lorsque l'on sera collègues de travail. A ma Marion et Lucas, merci de faire partie de nos vies et de rendre heureux ma soeur et mon frère, qui sont la prunelle de mes yeux. A toute ma famille en Algérie, merci de votre amour, je suis fière et heureuse d'apporter un nouveau Dr Khaled dans la famille. One, two, three, viva l'Algérie ! A ma famille Buisson, Najar et Contardo, qui représente toute la beauté et la force d'une famille soudée. Merci à mes grands-parents pour votre amour et votre soutien, à mes cousins Manon, Alix et Lucas que je vois grandir et murir un peu plus à chaque fois et aux jeunes et heureux mariés tonton et Sandrine. A mes amis d'enfance, notre amitié ne s'est érodée ni avec le temps ni avec la distance. A Gaëlle, ma partenaire de toujours, la vie sans toi serait comme un hot dog sans saucisse. A Manon, ma chère Manon, c'est avec beaucoup d'émotion et d'amour que je me rappelle nos premiers pas ensemble en maternelle et que je ne vous vois aujourd'hui, épanouies A Annabel, mon pilier. Même le destin n'arrive pas à nous séparer (50m porte à porte). Merci de faire partie de ma vie. A Charlotte, que de rire et de folie à tes côtés !!! A Arnaud, JB, Laure, Thibault, Juliette et PJ : Au Théâtre,

voyage au Sahara est ancré dans mon esprit. Hâte de la suite des aventures. A mes amis clermontois moldus

	A Adrien et Clément, les journées passées à vos côtés sont si sympas et enrichissantes. La vie est plus fun (et plus
	verte) à vos côtés.
	A toute l'équipe de CMF, pour m'avoir formé alors que je n'étais qu'un foetus anesthésiste. Merci à Julien,
	Emeline, Sophie, Mme Beaujard et aux IADEs pour m'avoir inculqué des bases solides. Merci à Maman Florine
	pour m'avoir pris sous ton aile et à Tata Lucie pour avoir pris la relève au départ de ma mère.
	A toute l'équipe de digestif : mes co-internes Gauthier, Nadia et Marion. A Johan et Adnan pour avoir partagé
	votre passion.

Au service de réanimation du Puy en Velay mais

	Aux IDE de réanimation, merci pour tous ces fous rires ! Et surtout merci à Géraud et Fifou d'être devenus de
	véritables amis.
	A l'
	surtout au service d'anesthésie, qui m'a chaleureusement
	accueilli.
	A Julien, un co-interne en or, que dis-je, un ami en or. Merci de ton soutien, des rares sourires que tu m'as accordés,
	et merci de m'avoir supporté. Ce stage n'aurait pas été si bien acceptable sans toi.

équipe du bloc opératoire de Moulins :

  Merci pour m'avoir formé en ces temps difficiles de pandémie. A Chachou, ma co-interne qui a une vie plus tumultueuse que toutes les saisons de grey's anatomy et desperate housewife réunies. Merci pour ta gentillesse et ta sincérité. C'est un honneur d'avoir assisté à tes premiers pas en tant qu'interne.

Table des matières

 des Liste des tableaux et figures…………..………………………………………..13 Liste des abréviations…..……………………………..………………………..14

	Résumé……………..…………………………………………………………..15
	Article scientifique…………..……………………………………..…………..16
	ABSTRACT……………………………………………………………………….…………….18
	INTRODUCTION………………………………………..…………………………………….19
	MATERIALS & METHODS……………………………..………………………….………..21
	RESULTS……………………………………………………………………………………….24
	DISCUSSION………………………………………………………………………………….28

REFERENCES…………………………………………………………………………………32

Conclusion……………………………………………………………………...36 Serment d'Hippocrate…………………………………………………………..37

Liste des tableaux et figures

Table 1 : Characteristics of the study population (de novo AF patients).Table 2 : Impact of albumin and pH on the interpretation of total plasmatic concentration of 2 divalent cations: Ca and Mg.Table 3 : Repartition of hypo, normo and hyper iMg among 236 patients with de novo AF and controls. Figure 1: Agreement between the biological interpretation of ionized and total Mg and Ca forms according to the references values used. Liste des abréviations

 123

	iMg n'est

AF : Atrial Fibrillation Ca : Calcium ED : Emergency Department K : Potassium cCa : Corrected calcium by albumin cMg : Corrected magnesium by albumin ICU : Intensive Care Unit iCa : Ionized calcium iMg : Ionized magnesium Mg : Magnesium Résumé Contexte : Le magnésium (Mg) est souvent utilisé pour traiter la fibrillation auriculaire (FA) de novo dans les services d'urgence et les unités de soins intensifs (USI). La mesure délocalisée du magnésium ionisé (iMg) permet d'identifier rapidement les patients dont le statut en magnésium est altéré. Cependant, contrairement au calcium ionisé, l'interprétation de l'l'hypomagnésémie dans la FA de novo, et l'influence des traitements induisant une hypomagnésémie dans la FA. Méthodes : Un total de 236 patients du service des urgences et de l'unité de soins intensifs présentant une FA de novo, et 198 patients témoins ont été inclus. Les valeurs de référence ont été déterminées dans la population témoin. La corrélation et la concordance entre iMg et pMg ont été étudiées en utilisant le calcium (ionisé et plasmatique) comme contrôle dans l'ensemble de la population étudiée. L'impact de l'albumine et du pH ont été évalué dans les valeurs discordantes d'iMg et de pMg. Enfin, nous avons évalué l'incidence de l'hypomagnésémie ionisée parmi les FA de novo.

Résultats : Les valeurs seuils établies dans notre étude pour l'iMg étaient : 0,48-0,65 mmol/L (celles des fabricants étaient : 0,45-0,60 mmol/L). Une forte corrélation a été observée entre pMg et iMg (r=0.85), mais, contrairement aux valeurs de calcium, il n'y avait pas d'impact significatif du pH et de l'albumine dans les variations d'iMg. L'incidence de l'hypoMg ionisée chez les patients atteints de FA de novo était de 8,5 % (12,7 % selon nos valeurs seuils).

Conclusion : Notre étude souligne la nécessité d'avoir des valeurs de référence plus précises pour l'iMg. De plus, nos résultats suggèrent que la teneur en Mg du sang n'est pas identique à celle du calcium. L'incidence de l'hypomagnésémie ionisée chez les patients atteints de FA de novo dans notre étude est de 8,5 %.

Table 1 : Characteristics of the study population (de novo AF patients

 1

	Total (n=236)	ED (n=131) ICU (n=105)	p

). ED: Emergency Department, ICU: Intensive Care Unit, SD: Standard Deviation, BMI: Body Mass Index, kg: kilogram, m 2 : square meters, CHADSVASC: anticoagulation score.

Table 2 : Impact of albumin and pH on the interpretation of total plasmatic concentration of 2 divalent cations: Ca and

 2

			Concordant:
				Discordant: normal
			normal ionized
	Agreement between ionized and total values		ionized and hypo	p
			and total
				total plasmatic
			plasmatic
		n	131	39	/
	Calcium
		Albumin, g/L, median [p25; p75]	36.8 [30.3; 41.4]	28.2 [22.9; 33.3]	<0.001
		n	73	7	/
	Magnesium
		Albumin, g/L, median [p25; p75]	35.1 [30.5; 40.8]	32.7 [21.7; 37.9]	0.32
	B-Impact of pH
			Concordant:
				Discordant: hyper
			normal ionized
	Agreement between ionized and total values		ionized and normal	p
			and total
				total plasmatic
			plasmatic
		n	131	21	/
	Calcium	pH, median [p25; p75]	7.43 [7.39; 7.46]	7.40 [7.38; 7.42]	0.026
		Acidosis -pH<7.32, n (%)	2 (1.5)	3 (14.3)	0.019
		n	73	86	/
	Magnesium	Median [p25; p75]	7.43 [7.39; 7.46]	7.42 [7.39; 7.47]	0.34
		Acidosis -pH<7.32 n (%)	7 (9.6)	5 (5.8)	0.37

Mg. SD=Standard Deviation. g/L=grams per liter. mmol/L= millimole per liter.

Table 3 : Repartition of hypo, normo and hyper iMg among 236 patients with de novo AF and controls.

 3 Values are expressed as number of patients (percentages) for all patients, ED patients and ICU patients using manufacturer's range values in the upper part and our ranges in the lower part. ED = Emergency Department, ICU = Intensive Care unit; AF=Atrial Fibrillation. iMg values are expressed in mmol/L. p value is considered as significant if < 0.05.The repartition of hypo -normo and hyper iMg is presented in Table3. Using the manufacturer's ranges, 20 (8.5%) of the 236 AF patients were classified in the hypoiMg group,

			TOTAL n (%)		ICU n (%)			ED n (%)
			AF group (n = 236)	Control group (n = 198)	p	AF group (n = 105)	Control group (n = 118)	p	AF group (n = 131)	Control (n = 80) group	p
	Manufacturer's	< 0.45	20 (8.5)	15 (7.6)		11 (10.5)	14 (11.9)		9 (6.9)	1 (1.3)
	range of iMg	0.45 to 0.60 89 (37.7)	77 (38.9)	0.93	32 (30.5)	34 (28.8)	0.93	57 (43.5)	43 (53.8)	0.09
	(mmol/L)	> 0.60	127 (53.8) 106 (53.5)		62 (59.0)	70 (59.3)		65 (49.6)	36 (45.0)
	IMAF's range	< 0.48	30 (12.7)	21 (10.6)		18 (17.1)	17 (14.4)		12 (9.2)	4 (5.0)
	of iMg	0.48 to 0.65 115 (48.7) 124 (62.6)	0.01	37 (35.2)	52 (44.1)	0.40	78 (59.5)	72 (90.0)	<0.001
	(mmol/L)	> 0.65	91 (38.6)	53 (26.8)		50 (47.6)	49 (41.5)		41 (31.3)	4 (5.0)

Remerciements

Serment d'Hippocrate

Mon premier souci sera de rétablir, de préserver ou de promouvoir la santé dans tous ses éléments, physiques et mentaux, individuels et sociaux.

Je respecterai toutes les personnes, leur autonomie et leur volonté, sans aucune discrimination selon leur état ou leurs convictions. J'interviendrai pour les protéger si elles sont affaiblies, vulnérables ou menacées dans leur intégrité ou leur dignité. Même sous la contrainte, je ne ferai pas usage de mes connaissances contre les lois de l'humanité. J'informerai les patients des décisions envisagées, de leurs raisons et de leurs conséquences.

Je ne tromperai jamais leur confiance et n'exploiterai pas le pouvoir hérité des circonstances pour forcer les consciences.

Je donnerai mes soins à l'indigent et à quiconque me les demandera. Je ne me laisserai pas influencer par la soif du gain ou la recherche de la gloire.

Admis(e) dans l'intimité des personnes, je tairai les secrets qui me seront confiés.

Reçu(e) à l'intérieur des maisons, je respecterai les secrets des foyers et ma conduite ne servira pas à corrompre les moeurs.

Je ferai tout pour soulager les souffrances. Je ne prolongerai pas abusivement les agonies. Je ne provoquerai jamais la mort délibérément.

SERMENT D'HIPPOCRATE

En présence des Maîtres de cette FACULTE et de mes chers CONDISCIPLES, je promets et je jure d'être fidèle aux lois de l'Honneur et de la Probité dans l'exercice de la Médecine.

Je donnerai mes soins gratuits à l'indigent et je n'exigerai jamais un salaire au-dessus de mon travail. Admis dans l'intérieur des maisons, mes yeux ne verront pas ce qui s'y passe, ma langue taira les secrets qui me seront confiés et mon état ne servira pas à corrompre les moeurs ni à favoriser le crime.

Respectueux et reconnaissant envers mes MAÎTRES, je rendrai à leurs enfants l'instruction que j'ai reçue de leurs pères.

Que les HOMMES m'accordent leur estime si je suis fidèle à mes promesses. Que je sois couvert d'OPPROBRE et méprisé de mes confrères si j'y manque.

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