Clément Sigalas

Jean-Louis Bory

The Second World War Seen From the Balcony. Representations of the Spectacle of War in the French Post-War Novel

Clostermann's Le Grand Cirque (1948), one of the four best-selling books in France in 1961. 1 Their authors, all members of the French Resistance, found themselves in the heart of the war and then wrote what can be called the epic of the French Resistance, celebrating courage and brotherhood.

On the other hand, "narratives of Vision" give an account of a war experienced indirectly rather than in harsh reality. In these, one is able to gaze at the war or to hear it without being directly struck by it. These narratives, mainly novels, emphasise the distance separating the spectator from the spectacle and highlight the mediating function of the act of looking. Between the subject and the real there are always harmless intermediaries -at least, less violent than gun fire -that tend to have a "derealising" effect: resistance graffiti or posters, maps, newspapers, radio, windows or balconies.

The balcony then, which gives its name to one of the best French novels about war, Un balcon en forêt, turns out to be the metaphor of a peculiar way of apprehending this conflict: perceiving it at a distance, converting violence into a spectacle -in keeping with the theatrical specialist sense of the word 'balcony'. I would like to examine and question this mediated representation of war in order to outline its political implications.

1 "Les best sellers du siècle", Bulletin du livre, 65 (October 1961), 32-34.

The corpus of the "indirect war" is quite extensive. 2 Consequently I will have to restrict my study to six novels I consider representative of the whole. Four of them were awarded the

forms of the war ("symptoms") and representations of the war (pictures, maps, radio…) have to be distinguished.

In novels portraying life under the Occupation, war appears mostly in softer forms: neither weapons nor blood, but words (posters, graffiti),5 symbols (little coffins that Resistance fighters send to the collaborators as a threat) 6 and looks. These in particular play an important role in Mon village à l'heure allemande and Les Forêts de la nuit, two quite similar7 depictions of everyday life in the occupied zone, staging the destiny of various characters and their contrasted behaviours toward the enemy. The Goncourt Prize they were awarded and their public success may indicate that the indirect war they described looked familiar to many readers. In both novels, looks are substitutes for weapons. The protagonist of this peculiar war -or "phoney war", if one considers that it did not end with the defeat in June 1940 -in Mon village à l'heure allemande is the old maid Miss Vrin, who is asked by the pro-German priest to observe the villagers' behaviour from her skylight. This elevated position is like a pacific and parodic version of the height from which, in battle paintings, the general takes in the whole battlefield. Hence the martial terminology: "La position est bonne. Une position stratégique." (49) "This is the correct position : a strategic position "; "Mademoiselle Vrin, dit-il, il faut continuer votre faction. Vous viendrez au rapport au moment de l'angélus" (71) "Miss Vrin, he said, you must remain on duty. You are to report at angelus time". This example shows how slight the difference is between war and the parochial quarrels inherited from the French Third Republic, embodied here in the rivalries between the priest and the pro-Resistance primary school teacher. At this point, war seems to be a continuation of the past rather than a disruption, even though this war "by looks" will eventually have serious consequences.

Les Forêts de la nuit stages a similar balance between fairly peaceful appearances and a tragic outcome. In the first chapter, young Francis, one of the few authentic heroes in the novel, helps a Resistance fighter cross the Demarcation Line. Chapter four opens with a look which will have considerable repercussions on the plot: "Mme Costellot, une cigarette aux doigts, regardait à travers la vitre, dans la rue calme et grise. -Tiens, remarqua-t-elle, le petit Balansun a dû passer la ligne une fois de plus" (33) "Mme Costellot, smoking a cigarette, was watching the quiet gray street through the windowpane. 'There,' she said, 'the Balansun boy must have crossed the line again" (Forests of the Night 23). The spatial organisation is typical of many novels about the Occupation: outside is the war (in this case, an action defying German laws); inside are peaceful signs (a conversation, an armchair, a cigarette); in the middle stands the window, with its ambivalent place and function. The window simultaneously gives Mme Costellot the power to see and know -it gives her power in itself -and allows her an indirect, even peaceful relation to war. On the one hand, she uses it as a spy or soldier would use a weapon -hence the same military metaphors as in Mon village à l'heure allemande. 8 On the other hand, the window acts as a screen, shields the one who looks through it, and leaves no stain either on the hands or on the conscience: the Gestapo, not Mme Costellot, will murder Francis.9

Just as fever is part of sickness, looks are part of war, but they are still "symptoms": apparently innocuous signs hardly referring to a reality which is both tragic and faraway. The second type of signs Ducrot and Todorov evoke, which they consider signs in the strictest sense, are totally cut off from their referent, that is to say, from the reality they are supposed to refer to. In these novels, they are pictorial, photographic and radio representations. The definition the two linguists give is very helpful to this study: "Le signe est à la fois marque et manque: originellement double" (133); "The sign is both a mark and an absence: therefore intrinsically dual". 10 In fact, novels about the Occupation and the Phoney War are based on this duality. Their characters watch the war, listen to it, but do not feel it; neither are they affected by it.

The treatment of the radio illustrates this ambiguity. Everyone knows about the important role the radio played in the Allied victory, from the appeal of 18 June 1940, to the famous poem by Verlaine giving the signal for the Normandy landing. However, in such novels as Mon village à l'heure allemande, the radio mostly reveals the absence of war rather than its mark. Far from being an instrument of war, the news broadcast is the only indication of fights occurring somewhere in the world -but not here, to be sure. Only in May 1944 does the war news begin to pose a significant threat to the villagers, when a presenter mentions the village of Jumainville: Dans presque toutes mes cuisines, on a fait: hein! oh! ah! non? On a regardé le poste avec un effroi incrédule; brusquement, il prenait une réalité menaçante parce qu'il parlait pour la première fois de quelque chose que l'on connaissait bien. Tant que cette boîte nommait Stalingrad, Tunis ou Cassino, la T.S.F. n'était qu'une belle invention, et le village était loin de la guerre, et Londres était à plusieurs centaines de kilomètres.

Mais voilà qu'à Londres on parlait de Jumainville! 11 (202-203) In almost all my kitchens, people went "what! oh! no! They watched the radio with fright and incredulity; suddenly, it took on a threatening reality because for the first time it was talking of something familiar. As long as that box mentioned Stalingrad, Tunis or Cassino, the wireless was nothing but a nice invention, and the village was a long way from the war, and London was miles away. But now, in London, they were talking about Jumainville.

Up to the eve of the Normandy landing, the radio has referred to nothing "real" nor warlike: it was "a nice invention", a means of entertainment allowing the villagers to keep the war away.

Even soldiers of the Phoney War can hardly face the reality of war. In Un balcon en forêt, the garrison listens to "the Stuttgart Traitor", a famous French presenter working for the enemy and broadcasting propaganda against France: "Après un long grésillement, toute l'irréalité de la guerre fusait à travers le brouillage avec cette voix mince et acide, qui prenait les temps de ses répliques comme un troisième couteau" (37). "After a long sputtering, all the war's unreality melted through the static into this thin, piercing voice, which lingered over its words, hissing like the villain of a melodrama" (28). Since a "troisième couteau" refers to a (ham) actor and "réplique" means both "reply" and "line" in the theatrical sense, the war sounds as unreal as a bad play. Moreover, insisting on the "long sputtering", the novel stresses what separates the listener from the enemy, thus from the battle.

Similarly, the Phoney War seems unreal to the protagonist of La Grande Éclipse, by Alain Bosquet. On 10 May 1944, while the German troops are launching their attack in the 11 Emphasis added. The village is speaking, like a human being.

Ardennes, André Bénévent is in the Alps, at a considerable distance from the fighting: "Le soir, c'était La Pétanque, les dés, le pernod, parfois les cartes, parfois les liqueurs, le tout interrompu de nouvelles à la radio: l'ennemi avançait." (42) "In the evening, at La Pétanque, there were dice games, pernod, sometimes card games, sometimes liqueurs, with occasional interruption by radio news: the enemy was advancing." The novel focuses on a peaceful place, the café "La Pétanque", very similar to the aptly-named "Café de la Paix" in Mon village à l'heure allemande. As long as the characters listen to the radio, they need not be scared of the fighting. What they learn from the radio is not so much how far the Germans have advanced as how far the war still is from them.

In Un balcon en forêt, the radio is but one of the many intermediaries between the war and the character. Others include maps:

Il allait parfois jeter un coup d'oeil sur la carte de Belgique épinglée à la tête de son litun supplément gratuit en couleurs du "Petit Ardennais" entouré de sa frange de drapeaux français, allemands et belges, à découper, le moment venu, pour usage, suivant le pointillé. ( 127)

He would glance at the map of Belgium tacked over his bed -compliments of the Petit Ardennais -printed in three colors and surrounded by a fringe of French, German and Belgian flags with perforated outlines, to be used at the appropriate moment for marking the fronts. ( 104)

The map should help lieutenant Grange have a global view of the operating forces. Instead, the light is shed not on the referent, but on the signs, on the materiality of the medium; in other words, not on the real, but on an abstract representation of it. The war seems to be a puzzle for children to solve -only children can discover with such pleasure that the supplement is free and in colour… The upcoming tragedy has turned into a play activity.

Besides maps, Grange looks at photos of German blockhouses: L'ensemble, fait de feuilles libres sur papier glacé, encartées dans une couverture, avec les mensurations des ouvrages et des numéros de référence, évoquait la présentation soignée des collections de printemps que vous propose un tailleur. (47)

The whole thing, consisting of loose-leaf sheets of glossy paper in a ringed notebook, with measurements of the structures and reference numbers, reminded him of the careful presentation of spring collections at a tailor's shop. (36)

The verb "paraissaient" operates several transfers. Firstly, from pragmatic to aesthetic considerations: signs of the war do not arouse fear, but a certain pleasure experienced while contemplating beauty. Secondly, from masculinity to femininity: while the army is traditionally considered to be a man's world, fashion vocabulary and terms like "measurement" connote femininity, suggesting sartorial rather than military preoccupations… Lastly, from reality to its artistic representation: once again, the emphasis is put not on the real, but on the medium (sheets, paper). Described elsewhere as "baroque" and "theatrical", war has become a spectacle.

The Spectacle of War

All these novels show a spatial organisation that is characteristic of any spectacle: on the one hand, a spectator whose position at a distance is emphasized; on the other hand, events turning into a spectacle and seeming unreal to their witnesses. What we will see now is that such a spatial organisation makes the spectacle either enigmatic or pleasant, but by no means traumatic.

As many critics have commented, viewpoints play a crucial role in Julien Gracq's works. In this respect, there is, however, a striking discrepancy between Un balcon en forêt and Le Rivage des Syrtes. In the latter, the setting is a desert plain, marked by the absence of any visible sign, which, according to Michel Collot, stimulates the characters' imagination (112). On the contrary, Gracq's next novel, as its title implies, is set in the forest. The screen of trees, a widely used metaphor in the novel, abounds in signs. That is why Grange spends his time on the watch. In Un balcon en forêt, the paradigmatic sequence is a two-step process: firstly, identifying the viewpoint; then, describing the spectacle. By foregrounding the viewpoint, this type of sequence emphasizes the distance between the spectator and the spectacle, between the warrior-in-waiting and the war. Now, what can Grange see from his balcony -"balcony" serving as a generic term for any viewpoint -? One night, through a wide-open skylight, he can observe "un clin d'oeil sec et isolé" (195) ("a quick, isolated flash", 164) and "un point de feu minuscule et très clair" (196) ("a tiny, very distinct point of light", 164). The day after, he is watching through "a gun sight": "Un mince tiret tremblé, dessiné par une cursive agile, enjamba la laie blanche, se perdit dans la marge d'herbe: une martre." (230) "A thin hyphen drawn by an agile, cursive hand, crossed the white road and disappeared into the grass: a marten" (195). In brief, Grange can never see warlike signs (bombings, planes…), but telegraphic and graphic ones (flashes, points, hyphens, handwriting, and the metaphor of the "margin" in the French version). For the observers, war is but an indecipherable text.

Cette scène demeura pour moi ineffaçable et incompréhensible. (42)

A German soldier was running toward a little group of his fellows. Some distance behind him ran a young civilian, going even faster. He caught up with the soldier and the two ran on, side by side, in a sort of frenzy, until they had reached the others.

Immediately, and with the speed and the precision of robots, the soldier who had been running and another soldier began to rain down blows with their fists upon the head and face of the civilian. He collapsed. Still with a speed and co-ordination that seemed a delusion, two other soldiers picked him up. Each gesture was that of an expert. Holding the adolescent by his armpits, they carried him in a vertical position without his feet touching the ground. His head hung down on his chest. I wondered if he was dead. The group of soldiers marched off, in step. This scene remained, for me, unforgettable and incomprehensible. ( 35)

The spectator -she refers to a "scene" -seems to have witnessed the event as if in a dream state. The description combines precise elements (the participants and their coordinated movements as a well-oiled machine) with very vague ones ("some distance behind"). It lacks explicit spatial and temporal markers, especially because this passage, like the four previous ones, is surrounded with blanks. This raises the question of where and when this event occurred, even whether it really occurred that way. As in dreams, logic and will no longer prevail: the unit the first warrior and the civilian seemed to form suddenly breaks, for no apparent reason, and all the characters act as automatons. As in Gracq's novel, the spectator, because of her position at a distance, cannot understand the signs and remains excluded from the experience of war.

When not incomprehensible, the war can turn into a pleasant spectacle. It would be no exaggeration to say that all these novels propose a new reading of Lucretius' "Suave mari magno", the first two verses of which read as follows: "How lovely it is, when the winds lash the great sea into huge waves that beset sailors, to gaze out from dry land at the tribulations of others." (Lucretius 48). Originally, this was an allegory for the opposition between the philosopher's serenity -thanks to his taste for reason and moderation -and the distress of those troubled by passion. Applied to World War Two, it means something very different. The spectator's calm gaze at the troubled waters indicates either that he is not able to experience the war as such or that he is trying to protect himself by casting doubt on its reality. The spectacle transforms violence into pleasure, as manifested by the depiction of a bombing, in the opening of La Grande Éclipse:

Le bruit procura une grande joie au jeune homme, qui s'accouda à la fenêtre, se demandant si une deuxième bombe allait suivre la première. Un avion s'abattit tout à coup. Cette masse qui tourbillonnait dans l'air et lâchait une fumée épaisse donnait à Bénévent la sensation d'assister à un spectacle grandiose. (9-10)

The noise filled the young man with a great joy. He leaned on the window, wondering if a second bomb would follow the first. Suddenly a plane crashed. This swirling mass filling the air with thick smoke gave Bénévent the impression that he was attending a gorgeous spectacle.

This passage contains all the characteristics found in Lucretius' poem: a viewpoint (the window), a disaster turned into a spectacle due to the distance, and the happiness one experiences when seeing danger and yet escaping it. Exactly the same features appear in Léon Morin, prêtre when the narrator observes from her balcony "comets, bloody bouquets, fiery roses, whips, snakes of lightning, flaming horns of plenty, paroxysms of light". 12 (34) From the balcony, overlooking the mountains instead of the forest, bombings metamorphose into "fireworks", and fear into elation. Metaphors and comparisons relating to flowers ("bouquets") and animals ("snakes") mitigate violence. Another widely used metaphor in the novels is that of white flakes, referring to antiaircraft both in Mon village à l'heure allemande ("white flakes of vapour as soft as wads of cottonwool" 13 ) and Un balcon en forêt ("A languid trail of globular puffs followed behind [the German plane] at some distance, blooming in its wake with a cottony "plop.", 107) 14 Both descriptions use metaphors defined by rhetoric as in absentia, which substitute the comparing term (soft material in this case) for the compared idea (the "real" fires, which are totally absent from the text). Again, the view from the window transforms exploding shells into blooming flowers, the war into a "spectacle": "Le spectacle ne parut à Grange nullement guerrier, plutôt ornemental et gracieux". (Gracq 129); "The spectacle seemed not in the least warlike to Grange, but rather ornamental, graceful".

(107) Such an aestheticization of violence leads to its fictionalization. In a study about accounts of shipwrecks in the 16 th century, Frank Lestringant considers, as I do, this fictionalisation to be closely linked to the position of the spectator: 12 See also in the opening of the book: "Une nuit, je fus éveillée par une canonnade proche. Transportée de joie, je volai à la fenêtre" (10) "One night I was awakened by the noise of nearby shooting. Joyfully I flew to the window" (4). 13 "Un flocon de vapeur blanche aussi moelleux qu'un tampon d'ouate." (Bory 289) 14 "Une traînée languide de flocons globuleux suivait [l'avion allemand] à bonne distance, qui venaient éclore l'un après l'autre dans son sillage avec un 'plop' cotonneux et mou." (Gracq 129) La tragédie et le naufrage contemplé depuis la rive ont en commun la place du spectateur, regardant à distance et à l'abri du danger. L'éloignement et le confort du témoin tendent à déréaliser le malheur, et à faire du triste tableau de l'humaine condition une fiction fascinante. ( 120)

Tragedy and shipwreck viewed from the shore share the characteristic of a spectator watching them at a safe distance from danger. The witness's remote and comfortable position tends to divest tragedy of its reality and to transform the sad picture of the human condition into a fascinating fiction. 15 Though not relating to World War II, these words apply very well to the novels studied here, with one difference. The spectator of a tragedy does not belong to the fictional world: according to Aristotle's theories, fiction acts on him as a catharsis, thus has a therapeutic value. Instead, in novels about war, spectators are part of the story world: they experience reality as a fiction from which they seem unable to emerge. They are cut off from the action as much as from the actors of History. That is why the spectacle of the war must be analysed in political terms.

The Spectator's Feelings: From Strangeness to Guilt

By "political", I refer neither to any left-right division nor to the question of "commitment". Rather, I mean that the position of the spectator in relation to the spectacle of war may be linked to a certain position toward the City ("polis"), that is to say, toward the French community. In this respect, in the immediate post-war years, the most widely spread image of France was that of a whole country supporting the Resistance groups and fighting (with weapons or not) against the enemy.16 In other words, those years imposed the image not only of a people involved in action, but also of a united one, while the novels I study show both passive and individualistic protagonists. 17 In Un balcon en forêt, for example, Grange keeps away from the war as much as he does from his fellow soldiers: "Il ne participait pasd'instinct, chaque fois qu'il le pouvait, il gardait son quant à soi et prenait du recul. ( 14) ("He did not participate -instinctively, whenever possible, he kept his reserve and a certain distance", 5). The French term "quant à soi" also applies to his two friends, Hervouët and Gourcuff, whose behaviour is similar. 18 Grange particularly hates meeting on Sunday with all the officers, guardians of the "esprit de corps", 19 one of whom writes some "petits sonnets patriotiques dans l'Écho du front, le journal de corps que diffusait l'armée". (43) ("He published occasional patriotic verses in L'Echo du Front, the corps paper circulated by the Army", 33) Standing back from the corps, Grange embodies the feeling of separateness from the community.

So does André Bénévent throughout La Grande Éclipse. When he sets foot on a Normandy beach three months after the Allied landing, "il était, comme toujours, comme partout, un étranger et un témoin un peu à l'écart" (167) "He was as always, no matter where, a stranger and a witness standing slightly apart." Ironically called a "rearguard soldier" (48), he successively occupies three positions from which war remains quite a harmless amusement. First, he is mobilised during the phoney war and joins a pioneer company of the Alpine light infantry, whose famous uniform he feels proud to wear: Il se compara tantôt à Cyrano de Bergerac, tantôt à Aramis, et se dit que cette guerre prenait des allures chevaleresques et primesautières. […] Comme à regret on lui enseignait le rôle de pionnier alpin, ses instructeurs sachant mieux que quiconque qu'une fois le rôle bien appris, il serait trop tard pour le jouer. (41) He sometimes compared himself to Cyrano de Bergerac, sometimes to Aramis, and felt that this war was taking on a chivalrous and impulsive character […] He was trained for an Alpine pioneer company, albeit reluctantly it seemed, presumably because his instructors knew better than anyone that, once he had fully learnt his part, it would be too late to play it. War for André is but an entertaining fiction, since his models are literary ones (the heroic comedy Cyrano de Bergerac, by Edmond Rostand, Les Trois Mousquetaires, by Alexandre 18 "Tous deux plaisaient à Grange […] par leur quant à soi" ( 27) "He was pleased by their discretion and reserve" (20). 19 "Il était clair que les dimanches du capitaine Varin […] avaient quelque chose à voir avec le maintien de l'esprit de corps" (42). "It was evident that Captain Varin's Sundays […] had something to do with the maintenance of esprit de corps" (33).

Dumas, and the medieval literature of chivalry). These are all books André would, like other children, have read at school, and the heroic roles would never have to be played out in real life. The theatrical vocabulary suits this soldier who shoots at the enemy only once and does not even know whether he aimed accurately.

In the second part of the novel, André emigrates to the United States, where he is offered the chance to "go to school and learn his part as a future member of occupation forces" 20 . Again he finds himself behaving as a child and playing roles. This time, André participates in war simulations set up by Stanford University, "plays the part of a lieutenantcolonel heading a battalion", "attack[s] a fake hill and take[s] pretend prisoners". 21 Lastly, André is sent to London early in 1944. For once, he may be considered as playing a real role in the struggle, since he works for the intelligence service. However, his war remains a game, even a circus, as suggested by the fact that his office is not only situated in an Oxford Circus store, but in what used to be the toy department. 22 As a consequence, André, who is in charge of mapping the German fortifications on the French coast, can see nothing but signs of the war devoid of any reality: "Sur cette carte au 1/50.000, vous verrez des symboles: batteries, nids de mitrailleuses, champs de mines, points d'appuis." (159) "On this Ordnance Survey map, you'll see symbols: batteries, machine gun nests, minefields, operational bases." The map only shows symbols, and when André is shown photos from the front, human losses are only mentioned in passing. André tries to neutralise violence by representing it in abstract forms and by talking about the media (maps, pictures) rather than the real, even in aesthetic terms ("Nice work", he says 23 ). Though really involved in the Allied air bombings, he remains a stranger to the war, which induces a feeling of guilt.

The third and last section of La Grande Éclipse is entitled "La victoire des autres" ("The victory of others"). André, who never fought with weapons during the war, finds himself an impostor when he lands in France in 1944: "Il avait fui comme un lâche; maintenant, il revenait en vainqueur: il y avait dans son destin une telle tricherie!" (168) "He had run away like a coward and was now returning victorious: his fate was riddled with deception!" In some ways, this individual deception is an image of the official one, embodied 20 "Aller à l'école et apprendre son rôle de futur occupant" (139). 21 "Tout à l'heure, il jouerait le rôle d'un lieutenant-colonel à la tête d'un bataillon. Il donnerait l'assaut à une colline postiche et s'emparerait de prisonniers théoriques". ( 141) 22 The reference to the toys confirms, if necessary, that "Circus" is used in both senses of the term. 23 "Joli travail" (158).

by General de Gaulle's speech at the Hôtel de Ville of Paris on 25 August 1944, asserting that France has freed herself from the German Occupier. While there is no denying that many people in France actively participated in the Allies' victory, the discourse attributing this heroic attitude to the whole country needs demythologizing. André's fictional war may be considered as an image of a collective mystification, and symbolises the bad conscience of a country which, although included among the winners, had not behaved unambiguously.

More broadly, the diverse forms adopted by the literary representation of the spectacle of war may convey the feeling, experienced by some people, of having 'missed' the war, of not having sufficiently shared in the action and hardships common to most representations of it. In Léon Morin, prêtre for example, it seems that war does not strike hard enough, so that everything looks like a play: the narrator, in the first pages, mistakes the Italian occupiers in Grenoble for "traveling actors" ("comédiens routiers", 7), then compares a Resistance group's assault to a theatrical performance. 24 War has been replaced by its parody, an idea also expressed in Un balcon en forêt. Gracq twice uses the French verb "singer" (to ape): firstly when depicting the Officers' Mess on Sundays (44); secondly, when Grange, having been wounded by the Germans, orders his subordinate Gourcuff to run away and not to wait for him:

C'est un ordre, ajouta Grange, d'un ton qu'il sentit malgré lui vaguement parodique. De nouveau, le sentiment le traversa que cette guerre, jusque dans le détail, singeait quelque chose, sans qu'on pût au juste savoir quoi. (242) That's an order, Grange added, and felt that in spite of himself his tone was vaguely burlesque. Again he had the sense that this war, in its least detail, was imitating something without being able to decide what it was. (205) There are two questions being raised here, the answers to which differ: in the first case, the demobilised warriors of the phoney war seem to feign peaceful life, Sunday lunches and family meals, so as to forget that, sooner or later, fighting will break out. In the second case, I would suggest that Grange like his comrades cannot help copying -and above all, betraying -the heroic representational model for all French men in 1940: that of the "Poilus" of the Great War, who fought so bravely. The theme of the spectacle thus has to be considered a consequence of the gap the characters bitterly observe between the epic of World War I and the defeat of 1940, followed by a certain passivity during the Occupation. Spectators of the war feel somewhat guilty not only towards those who were involved in action -whether it be the Resistance fighters, the Allies, or their glorious forebears -, but also towards those who were badly hurt by the conflict. It is not a coincidence that the novel which most insists on guilt, La Grande Éclipse, was written by a man who, in 1945, was one of the first to enter the Buchenwald extermination camp. This episode does not appear in La Grande Éclipse, but in an autobiography Bosquet published years later, entitled Les Fêtes cruelles. In the following excerpt, Bosquet asks an American officer: "-Qu'ai-je fait pour mériter ce supplice: être le témoin? -Nous avons libéré le camp; vous, vous êtes de passage. Nous sommes dans l'irréel, et vous un spectateur." (254) "'What have I done to deserve this torture: being a witness?' 'We have freed the camp; you are but passing through. We are in the midst of the unreal, you are a spectator.'" 25 The position of a spectator turns out to be that of one who simply witnessed the drama, without being hurt in person.

The same applies to Le Temps des morts, by Pierre Gascar. The novel, based on the author's own experience, recounts the captivity of French prisoners of war sent to a camp on the borders with Ukraine. However, this is a peculiar form of captivity, since the prisoners, gravediggers in charge of taking care of the graveyard, do not suffer excessively. Again, the distant view plays a key role: from the graveyard, situated on the top of a knoll, the prisoners can see and hear the "death trains" carrying the Jewish populations to the extermination camps. They can also observe from the window of their huts the Jews going to the station and being hit by the German guards, but the action is set too far from the spectators to allow them to perceive it in all its brutality: "C'était des coups un peu bas, maladroits et silencieux, plus semblables à de sournois méfaits qu'à des violences." (221); "Silent, clumsy blows, aimed low, more like stealthy misdeeds than like acts of violence." (207) What follows in the book stresses the role of the window and will serve as a general conclusion:

On me disait: "Il y en a un qui est tombé. Les gardiens lui tapent dessus… Ça y est: il repart…" On me disait: "Tiens, regarde celle-là qui court pour rattraper le groupe!", commentaires inlassables où passaient des accents de pitié mais qui révélaient une sorte de détachement, car la passion consiste justement à ne pas aller jusqu'au bout de l'événement et ceux-là le parcouraient tout entier avec l'avidité triste des témoins. (221-222) Somebody said: "One of them has fallen. The guards are hitting him… Now he's up, he's starting off again…" Somebody said: "Oh, look at that woman running to catch up with the group!" The untiring commentaries, despite transient notes of pity, disclosed a sort of detachment, for passionate feeling will not allow you to see things through to the end, whereas these men followed the whole business with the mournful eagerness of witnesses. ( 207)

Here is the viewpoint of the "witnesses" or "commentators", not of the victims; the spectators feel detached from the events, not overwhelmed by them. Since they did not participate in the epic of World War II or did not much suffer, they came out of the war unharmed, but consumed with guilt.

  Similarly, in Béatrix Beck's novel Léon Morin, prêtre, watching the war does in no way lead to a global comprehension of it. The end of Chapter Two is a good illustration of this. It consists of five strange "scenes" which are five visions recounted by the narrator from the position of a spectator. The last one looks like a hallucination: Un soldat allemand courait vers une petite troupe de ses compagnons. À une certaine distance en arrière, un jeune civil courait plus vite encore. Il rejoignit le soldat et tous deux, côte à côte, à une allure de forcenés, atteignirent la troupe. Aussitôt, avec une rapidité et une précision d'automates, le soldat qui arrivait, et un autre, martelèrent de coups de poing redoublés le visage et la tête du civil. Il s'écroula. Toujours avec une célérité et une coordination de mouvements hallucinantes, deux autres soldats le relevèrent. Ils semblaient spécialisés dans chacun de leurs gestes. Tenant l'adolescent sous les aisselles, ils le portèrent verticalement, sans que ces pieds touchassent terre. Sa tête pendait sur sa poitrine. Je me demandai s'il était mort. Le peloton s'éloigna au pas cadencé.

Bory 22, 46, 201, 202, 273; Curtis 171.

Bory 226; Curtis 357.

They are similar in their viewpoint: both novels are set in a typical French village or town and intend to give an image of France as a whole during the war. Nevertheless, Curtis's novel is far more pessimistic and darker than Bory's.

For example, the keyhole through which Mme Costellot's servant Berthe spies on her employer is called a "poste d'observation" (261) ("observation post", 188).

In the plot, she informs the Germans about Francis, yet without knowing this will lead to his death.

My translation.

Translation by Catherine Hoffmann.

The historian Henry Rousso called this image a "myth", or the "mythologie résistancialiste", underlining its exaggerations and complacency (20).

On this subject, seeMargaret Atack, Literature and the French Résistance: Cultural Politics and Narrative Forms, 1940-1950. Manchester: Manchester University Press, 1989.

"La scène se déroulait comme une représentation théâtrale d'une mise au point très poussée, où chaque acteur aurait possédé son rôle à la perfection, mais joué sans naturel" (19) "The scene resembled a stage play, elaborately produced, in which all the actors knew their parts perfectly but failed to give a convincing performance" (13).

Translation by Catherine Hoffmann. As far as I know, Les Fêtes cruelles has never been translated into English.


D Garrigue

A Godier

A Glacet

J Labreuche

E Kipnis

C Paris

A Duham El

E Resch

A Bauters

F Machuron

P Renom

P Goldstein

B Tavernier

A S Ailliol

S Susen

French lyophilized plasma versus fresh frozen plasma for the initial management of trauma-induced coagulopathy: a randomized open-label trial

Keywords:

French lyophilized plasma versus fresh frozen plasma for the initial management of trauma-induced coagulopathy:

a randomized open-label trial

Introduction

Traumatic injury is the leading cause of death worldwide among persons under the age of 45 years [START_REF]Injuries and Violence: the facts[END_REF] . Currently, it accounts for 10% of all deaths and the three leading causes of death from injuries (motor vehicle collisions, homicide and suicide) are all predicted to rise compared with other causes of death [START_REF]Injuries and Violence: the facts[END_REF] . Thus, trauma continues to represent a global public health problem [START_REF] Gbd | Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study[END_REF] and recent terrorist attacks have brought to attention the issue of managing mass casualties. In both trauma and mass casualties, severe hemorrhage remains a major cause of potentially preventable deaths [START_REF] Rossaint | The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition[END_REF] . Death from traumatic exsanguination usually occurs rapidly, typically within the first 6 h, and trauma-induced coagulopathy (TIC) increases both the risk and severity of bleeding. Trauma-induced coagulopathy appears immediately following trauma, at the scene and before resuscitation [START_REF] Floccard | Early coagulopathy in trauma patients: an on-scene and hospital admission study[END_REF] . This coagulopathy is characterized by hyperfibrinolysis, hypofibrinogenemia, activated systemic anticoagulation and endothelial dysfunction [START_REF] Gruen | Haemorrhage control in severely injured patients[END_REF] and is associated with poor clinical outcome [START_REF] Rossaint | The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition[END_REF] . Accordingly, trauma management has evolved towards hemostatic resuscitation as early as possible. Current guidelines recommend that monitoring and measures to support coagulation be initiated immediately upon hospital admission [START_REF] Rossaint | The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition[END_REF] . They also recommend transfusing plasma at a plasma:red blood cell (RBC) ratio of at least 1 : 2 in the initial management of patients with expected massive hemorrhage; that is, the period between arrival in the emergency department and availability of results from coagulation monitoring [START_REF] Rossaint | The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition[END_REF] . The immediate delivery of plasma creates serious logistical challenges. Indeed, fresh frozen plasma (FFP) requires time-consuming preparation, including controlled thawing. Lyophilized plasma is an alternative to solve this logistical issue and allows immediate plasma transfusion [START_REF] Pusateri | Dried plasma: state of the science and recent developments[END_REF] . The French Military Blood Institute (Centre de Transfusion Sanguine des Armées) manufactures French lyophilized plasma (FLyP) to support overseas operations of the French armed forces [START_REF] Martinaud | In vitro hemostatic properties of French lyophilized plasma[END_REF] . FLyP is a universal therapeutic viro-inactivated plasma, compatible with all blood types, which can be reconstituted in less than 6 min at the point-of-care. Thus, FLyP is an attractive, logistically superior alternative to FFP that allows quick delivery of plasma and immediate application of high plasma:RBC ratios in the trauma setting. In this context, the Transfusion for Trauma-induced Coagulopathy and Fibrinogen Concentration (TRAUCC) trial was designed to address a simple question: in trauma patients requiring immediate delivery of plasma at a high ratio, is lyophilized plasma more effective than FFP for the initial management of trauma-induced coagulopathy? To answer this question, we performed a prospective randomized controlled trial including trauma patients requiring immediate transfusion with high ratios. In these patients, we assessed whether initial FLyP transfusion would increase fibrinogen concentration compared with FFP transfusion.

Methods Study design and participants

The TRAUCC trial was a monocentric phase 3, randomized, open-label, active-controlled, single-center clinical trial designed to determine the efficacy of early transfusion of FLyP vs. FFP for the initial management of trauma-induced coagulopathy. Severely injured adult trauma patients admitted directly to the trauma center from the injury scene were eligible for the trial if the attending doctor decided on an immediate transfusion of an 'emergency pack' of 4 red blood cell units associated with 4 plasma units in a 1 : 1 ratio within 6 h of injury. Patients were ineligible if they met at least one of the following criteria: transfusion of any blood product or coagulation factor concentrate prior to randomization, admission from another healthcare facility, devastating injuries and expected imminent death, recent history of anticoagulant therapy, known pregnancy, age under 18 years, or lack of mental capacity per national legal standards prior to trauma. Consent procedures were established by the local regulatory instances and the institutional ethics committee. Informed consent was obtained from trauma patients if physical and mental capacity allowed. If patients could not provide consent, proxy consent was obtained from a relative or representative. If a proxy was unavailable, then consent was deferred or waived. When consent was deferred or provided by a proxy, the patient was informed about the trial as soon as possible and consent sought for use of the data collected. The trial was approved by the institutional review board (Comité de Protection des Personnes Nord-ouest IV, approval number: CPP12/18), as per French regulations. The trial was monitored by the Clinical Research Unit of the Lille University Hospital in France. This study was registered at ClinicalTrials.gov, number NCT02750150.

Randomization and blinding

Participants were randomly assigned in a 1 : 1 ratio to receive either FLyP or FFP. The allocation sequence was provided by a statistician, who did not take part in assessing the patients at any point of the study. The sequence was based on a computer-generated list of random numbers that was used to assign the patients to either the FLyP or FFP group, in blocks of four participants (2:2 per block). Allocation was concealed using a sealed opaque envelope and occurred as soon as inclusion was determined. The patient was declared randomized when the envelope seal was broken.

The trial was open-label: clinicians, study staff and trial participants could not be blinded to treatment allocation because of the inherent characteristics of the studied products. However, allocation was concealed to the hemostasis department assessing biological parameters. Procedures Patients were randomly allocated to receive 4 units of FLyP or 4 units of FFP in association with 4 packed RBC units; blood products were electronically ordered and the 4 units of allocated plasma were prepared accordingly. The 4 units of FLyP were immediately reconstituted at the bedside in the trauma center and were immediately transfused into the patient. The 4 units of FFP were issued by the blood bank after thawing following the order, delivered after thawing to the trauma center by a pneumatic system, and transfused into the patient upon receipt. Blood samples were drawn at different time-points: at randomization (baseline sample), and 45 min, 6, 12 and 24 h after randomization. With the exception of the first four plasma units, medical management was identical in both groups throughout the entire follow-up period. All participants received standard care according to contemporary European and national trauma guidelines [START_REF] Rossaint | The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition[END_REF] . The follow-up period for safety events and mortality was up to day 30.

Outcomes

The primary endpoint was the fibrinogen concentration (STA Liquid Fib, Diagnostica Stago, Asnières sur Seine, France) at 45 min after randomization. Secondary endpoints included: (i) the rate of patients with a fibrinogen concentration above the recommended 1.5 g L -1 threshold at 45 min, (ii) changes from randomization in hemostatic parameters measured at different time-points (45 min, 6, 12 and 24 h after randomization), including fibrinogen concentration, prothrombin time (PT) ratio (STA Neoplastin R15, Diagnostica Stago), activated partial thromboplastin time (APTT) ratio (Triniclot aptt HS, Diagnostica Stago), coagulation factors II and V (Plasma deficient FII, FV, Diagnostica Stago), fibrin monomer (Liatest FM, Diagnostica Stago), base excess and serum lactate (ABL800 FLEX, Radiometer, Copenhagen,Denmark); (iii) time to transfusion, including interval between randomization and transfusion of the first plasma unit and interval between randomization to end of transfusion of the fourth plasma unit, (iv) fibrinogen concentrate and blood product requirements over the first 24 h after randomization, and (v) all-cause hospital death within 30 days of injury.

Statistical analysis

We calculated that a sample of 42 patients would provide 90% power to detect a mean difference between treatment groups of 0.5 g L -1 in fibrinogen concentration at 45 min after randomization, with a two-sided type I error of 0.05, assuming a standard deviation of 0.5 [START_REF] Rourke | Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes[END_REF] . Because the sample size calculation did not take into account that the analysis of covariance adjusted for baseline values was planned to be used to compare the primary endpoint, the power was expected to be greater than 90%. All analyses were performed on all randomized patients in their original group of randomization (intention-to-treat analysis). A per-protocol sensitivity analysis was performed for the primary endpoint after excluding patients who did not meet all the enrolment criteria (administration of coagulation factor concentrate before randomization, and patients who discontinued intervention or did not receive red blood cell transfusion). Categorical variables were expressed as frequencies and percentages. Quantitative variables were expressed as mean (standard deviation) or median (interquartile range, IQR). Normality of distribution was assessed graphically and using the Shapiro-Wilk test. Comparison of fibrinogen concentrations at 45 min after randomization between the two treatment groups was performed using analysis of covariance (ANCOVA) adjusted for baseline fibrinogen concentration. We derived the adjusted mean difference (FLyP vs. FFP) and its 95% confidence intervals (CIs) from the ANCOVA model as treatment effect size. To compare changes in hemostatic parameters between the two treatment groups, a constrained longitudinal data analysis (cLDA) model was used 9., 10.. In this model, both the baseline and post-baseline values are modeled as dependent variables using a linear mixed model, and the true baseline means are constrained to be the same for the two treatment groups to adjust for observed baseline difference. The between-group differences in changes from randomization to the time of interest (45 min, 6, 12 and 24 h after) were estimated by the time-by-treatment group interaction. We visually inspected the normality of model residuals and detected no deviations from normality assumption for all hemostatic parameters. Regarding other endpoints, we used Mann-Whitney U-tests to compare the transfusion intervals and the cumulative levels of fibrinogen concentrate and blood product at 24 h after randomization, and we used the Fisher's exact test to compare the 30-day hospital mortality rates. All statistical tests were two-sided and P < 0.05 was considered statistically significant. No adjustment for multiple testing was applied for all secondary objectives considered as exploratory. Data were analyzed using the SAS software package, release 9.4 (SAS Institute, Cary, NC, USA).

Role of the funding source

The funders had no role in the design, collection, analysis or interpretation of the data, in the writing of the report, or in the decision to submit the article for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

From July 2013 to March 2016, a total of 48 patients were randomized and enrolled in the TRAUCC trial, with 24 patients assigned to receive 4 units of FLyP (FLyP group) and 24 assigned to receive 4 units of FFP (FFP group). Among them, one patient from the FLyP group was subsequently found to have a history of long-term anticoagulant treatment. As soon as this information was available the study was discontinued for this patient. Discontinuation occurred before assessment of the primary endpoint (fibrinogen concentration measurement); thus, this patient was excluded from the primary efficacy analysis (Fig. 1). As shown in Table 1, baseline characteristics were well balanced across the two treatment groups.

Primary endpoint

After adjustment for baseline differences in fibrinogen concentration, the mean fibrinogen concentration 45 min after randomization was significantly higher in the FlyP group than in the FFP group (Table 2). Compared with FFP, the use of FLyP was associated with a mean difference in fibrinogen at 45 min, adjusted on baseline values, of 0.29 g L -1 (95% CI, 0.08 to 0.49; P = 0.006). As a result, 48% (n = 11) of patients in the FLyP group and 25% (n = 6) in the FFP group had fibrinogen concentrations at 45 min above the recommended 1.5 g L -1 threshold (P = 0.10). A similar mean difference in fibrinogen concentration at 45 min between FLyP and FFP was found in the per-protocol sensitivity analysis (Table 2).

Secondary Endpoints

Hemostatic parameters

The changes in coagulation parameters within 45 minutes of randomization differed significantly between the two treatment groups, except for APTT ratio and fibrin monomers (Table 3). FlyP transfusion was associated with an improvement in all coagulation parameters (PT ratio, factor II and factor V) within 45 min, whereas these parameters worsened or remained unchanged in the FFP group. The beneficial effect of FLyP on fibrinogen concentration remained significant 6 h after randomization (Fig. 2). At 6 h, the estimated mean change from randomization was 1.18 g L -1 (95% CI, 0.87-1.49) in the FlyP group and 0.68 g L -1 (95% CI, 0.37 to 0.98) in the FPP group (mean between-treatment difference, 0.51 g L -1 ; 95% CI, 0.14 to 0.88; P = 0.008). Moreover, similarly to 45 min after randomization, changes 6 h after randomization in PT ratio, factor II and factor V also remained greater in the FLyP group. After 6 h, the beneficial effects of FLyP on coagulation parameters diminished progressively and changes from baseline were no longer different between the two groups. Mean changes (and their 95% confidence interval) from randomization were estimated using a constrained longitudinal data analysis model to adjust on baseline values (T0). P-values for comparison of mean changes at each time-point were reported. After adjustment for baseline values, the estimated mean change (95% CI) at 45 min after randomization was 0.17 g L -1 (95% CI, 0.02 to 0.31) in the FlyP group and -0.12 g L -1 (95% CI, -0.27 to 0.02) in the FPP group (mean betweentreatment group difference, 0.29 g L -1 ; 95% CI, 0.09 to 0.48; P = 0.006). APPT, activated partial thromboplastin time; FFP, fresh frozen plasma; FLyP, French lyophilised plasma; PT, prothrombin time; T0, randomization. We found no difference in changes in base excess and serum lactate at any time-point. In both study groups, base excess increased over time, whereas serum lactate decreased. Blood product and fluid requirements and all-cause mortality The need for fibrinogen concentrates was reduced in the FLyP group compared with the FFP group over the first 24 h after randomization, albeit at the threshold for statistical significance (P = 0.052). No difference was observed regarding RBC transfusion requirements or fluid therapy using either crystalloid or colloid solutions (Table 4). 0.27 IQR, interquartile range; FFP, fresh frozen plasma; FLyP, French lyophilised plasma. All-cause in-hospital mortality within 30 days after randomization occurred in 12 (26%) patients overall without difference between the two treatment groups; five (22%) deaths occurred in the FlyP group and seven (29%) in the FFP group (P = 0.56). All deaths occurred after completion of the randomized treatment and all except one in each group occurred after the first 24 h. Discussion Our randomized trial shows that FLyP allows a more rapid, pronounced and extended increase in fibrinogen concentration than FFP, and is more effective in achieving one major endpoint of the initial management of trauma-induced coagulopathy. To our knowledge, the TRAUCC trial is the first randomized trial of lyophilized plasma in severe trauma patients, and its successful outcome conveys several important messages. First, the TRAUCC trial confirms, in a civilian 'real-life' clinical setting, that lyophilized plasma is superior to frozen plasma for the rapid delivery of plasma. This is crucial, because (i) hemorrhage remains the leading cause of preventable death in trauma patients, (ii) most early deaths due to hemorrhage occur within 2-3 h 11., 12., and (iii) TIC development increases mortality [START_REF] Frith | Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations[END_REF] . As a result, plasma transfusion should begin immediately to prevent and treat TIC and improve survival. However, immediate plasma transfusion faces logistical challenges. Fresh frozen plasma must be thawed, making it difficult to transfuse the first plasma concomitantly with the first packed RBC. In our trial, median time to first FFP transfusion was 77 [64-90] min, which was close to times previously reported in both US and English trauma centers 14., 15. A prospective study including trauma patients with activation of the massive hemorrhage protocol in 22 English trauma centers reported that the median time to first FFP transfusion was 87 (43-229) min after arrival [START_REF] Stanworth | Mortality from trauma haemorrhage and opportunities for improvement in transfusion practice[END_REF] . As a result, less than 15% of patients reached an FFP:RBC ratio of 1 : 2 or higher within the first hour of admission, demonstrating that FFP is not suitable for initial hemostatic resuscitation. To deal with this issue, several centers use thawed plasma prepared from FFP that can be maintained at 1-6 °C for up to 5 days. This extended-thawed FFP was used in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial, which demonstrated that early administration, within minutes of arrival, of plasma, platelets and red blood cells in a 1 : 1: 1 ratio decreased the rate of death from exsanguination [START_REF] Holcomb | Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma[END_REF] . This immediately available plasma allowed 11 of the 12 centers of the trial to meet the goal of delivering a first pack of 6 plasma units 10 min after they were ordered [START_REF] Novak | Making thawed universal donor plasma available rapidly for massively bleeding trauma patients: experience from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios[END_REF] . However, the use of extended-thawed FFP is a suboptimal workaround because it exposes to a potential reduction in potency as coagulation factor activity and a theoretical risk of bacterial contamination and increased levels of phthalate exposure [START_REF] Cardigan | Thawed and liquid plasma: what do we know?[END_REF] . Finally, the increasing use of extended-thawed plasma has two logistical drawbacks: potential excessive wastage if plasma is routinely thawed in advance but not always transfused, especially in small centers where demand is unpredictable, and above all, immediate delivery of extended-thawed FFP before the patient's blood group can be determined leads to AB plasma overuse while AB blood donors are scarce, further decreasing AB plasma availability. In this context, FLyP has several advantages. FLyP is stored at room temperature and is reconstituted in approximately 6 min in 200 mL of sterile water [START_REF] Sailliol | The evolving role of lyophilized plasma in remote damage control resuscitation in the French Armed Forces[END_REF] . Moreover, FLyP has universal ABO compatibility and lyophilization induces little change in coagulation factors [START_REF] Martinaud | In vitro hemostatic properties of French lyophilized plasma[END_REF] . Safety is provided by pathogen inactivation based on an amotosalen-ultraviolet illumination process. The French hemovigilance system has recorded more than 2700 transfusions of French lyophilized plasma with no report of any significant adverse effect 19 . FLyP is used routinely by the French military but is also available to the US military under an agreement between the US and French Governments. Second, the TRAUCC trial shows that an early 1 : 1 plasma:RBC ratio transfusion strategy with FLyP is more effective than with FFP for correcting TIC, as improvements of fibrinogen concentration but also PT ratio, factors II and factor V were greater in the FLyP group. Observational studies previously reported a benefit of high plasma:RBC ratios when achieved early, within the first 6 h of admission 11., 20.. Especially, De Biasi and colleagues showed that plasma deficit was associated with mortality in the first hour of resuscitation of trauma patients requiring urgent transfusion; afterwards this relationship diminished and disappeared [START_REF] Biasi | Blood product use in trauma resuscitation: plasma deficit versus plasma ratio as predictors of mortality in trauma[END_REF] . Interestingly, although therapeutic management of FLyP and FFP groups only differed for the administration of the four first plasma products, the beneficial effect of FLyP was sustained up to 6 h after randomization (i.e. at least 4 h after the 4 plasma units were transfused in both groups). These data illustrate that the 'golden hour' management impacts the course of TIC. Third, our data show that FLyP represents a substantial fibrinogen supply. Although plasma is usually not considered as an ideal source of fibrinogen repletion, the plasma transfusion strategy based on FLyP was associated with a reduction in fibrinogen administration [START_REF] Martinaud | In vitro hemostatic properties of French lyophilized plasma[END_REF] . Moreover, early administration of FLyP might not only correct the fibrinogen deficit itself but also partly reverse TIC and the mechanisms involved in fibrinogen deficit, including consumption, fibrinogenolysis, fibrinogen breakdown due to acidosis and decreased fibrinogen synthesis due to hypothermia [START_REF] Aubron | Efficacy and safety of fibrinogen concentrate in trauma patients-a systematic review[END_REF] . This hypothesis is supported by the significant improvement in fibrin monomers observed with FLyP, 12 h after randomization. These effects may result from plasma's ability to globally promote systemic vascular stability, which mitigates the endotheliopathy of trauma; however, our study was not planned to explore plasma mechanisms of action. Our study has several limitations. The sample size is small, calculated according to our biological endpoint and not powered to assess mortality. We used biological endpoints as surrogate markers because hemostatic resuscitation is considered as an interim standard-of-care in trauma management [START_REF] Rossaint | The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition[END_REF] . As the potential benefit of FLyP is related to the reduction of time to administration of the product, we have planned to investigate the fibrinogen concentration as early as possible at a fixed time-point (i.e. 45 min), allowing theoretically transfusion of either FLyP (reconstituted in less than 6 min) or FFP (thawed in 20 min). However, given the observed median time to administration of FFP in our study, we must acknowledge that fibrinogen concentration at 45 min after randomization does not really reflect superiority of FLyP over FFP as FFP was not transfused yet in the FFP group. Nevertheless, the beneficial effect on fibrinogen levels persisted after 6 hours. As none of the patients died before the assessment of the primary endpoint, the results were not exposed to the immortal time bias. Despite randomization, we observed a baseline imbalance between groups in the primary outcome of fibrinogen concentration, probably due to the small sample size. However, this difference was taken into account in the primary endpoint (fibrinogen at 45 min after randomization) comparison using an analysis of covariance adjusted for baseline fibrinogen concentrations. Another limitation inherent to the study design was the open label use of the studied products. This was unavoidable because point-of-care preparation of FLyP vs. the blood bank thawing and delivering FFP contributed to the studied inherent advantages and disadvantages of each. In conclusion, these data show that FLyP is superior to FFP for faster plasma transfusion. FLyP induces a faster and greater fibrinogen increase and TIC improvement. FLyP is an attractive option for trauma management, especially when facing logistical issues such as combat casualties or civilian mass casualties related to terrorism or natural disasters. Addendum D. Garrigue and A. Godier obtained funding for the trial, co-coordinated the trial, and drafted the manuscript. A. Glacet obtained funding for the trial, collected the data, and supervised the inclusions. P. Goldstein supervised the collection of the data, critically reviewed the endpoints, and was consulted for interpretation of clinical data. A. Sailliol, E. Resch, C. Paris, and P. Renom coordinated the availability of the products and were consulted for the interpretation of all the transfusion-related data. A. Bauters supervised all the biological analysis and critically reviewed the manuscript. E. Kipnis and B. Tavernier were involved in the design of the trial and critically reviewed the study protocol and the manuscript. F. Machuron performed all the statistical analyses supervised by J. Labreuche and A. Duhamel. A. Sailliol was involved in the design of the trial and critically reviewed the manuscript. A. Godier and S. Susen designed the trial. S. Susen supervised the trial, obtained funding, and critically reviewed the manuscript. Disclosure of Conflict of Interests E. Kipnis reports non-financial support from Laboratoire Francais du Biomédicament (LFB), outside the submitted work. S. Susen reports research grants from Laboratoire Français du Biomédicament (LFB) and from Stago, outside the submitted work. The other authors state that they have no conflict of interest.

Figure 1 .

 1 Figure 1. Study flow chart.

Figure 2 .

 2 Figure2. Change from randomization (T0) to 45 min, 6, 12 and 24 h in coagulation parameters in fibrinogen concentration. Mean changes (and their 95% confidence interval) from randomization were estimated using a constrained longitudinal data analysis model to adjust on baseline values (T0). P-values for comparison of mean changes at each time-point were reported. After adjustment for baseline values, the estimated mean change (95% CI) at 45 min after randomization was 0.17 g L -1 (95% CI, 0.02 to 0.31) in the FlyP group and -0.12 g L -1 (95% CI, -0.27 to 0.02) in the FPP group (mean betweentreatment group difference, 0.29 g L -1 ; 95% CI, 0.09 to 0.48; P = 0.006). APPT, activated partial thromboplastin time; FFP, fresh frozen plasma; FLyP, French lyophilised plasma; PT, prothrombin time; T0, randomization. We found no difference in changes in base excess and serum lactate at any time-point. In both study groups, base excess increased over time, whereas serum lactate decreased.Transfusion intervalsIn comparison to FFP, the use of FLyP reduced the transfusion intervals. From randomization, the median [IQR] time to transfusion of the first plasma unit was shorter in the FLyP group (14[5-30] min) than the FFP group (77 [64-90] min, P < 0.0001). As a result, the interval between randomization and end of transfusion of the 4 units was also reduced with FLyP compared with FFP (median [IQR], 45 [45-70] vs. 112 [91-125]; P < 0.0001). Blood product and fluid requirements and all-cause mortality The need for fibrinogen concentrates was reduced in the FLyP group compared with the FFP group over the first 24 h after randomization, albeit at the threshold for statistical significance

  Figure2. Change from randomization (T0) to 45 min, 6, 12 and 24 h in coagulation parameters in fibrinogen concentration. Mean changes (and their 95% confidence interval) from randomization were estimated using a constrained longitudinal data analysis model to adjust on baseline values (T0). P-values for comparison of mean changes at each time-point were reported. After adjustment for baseline values, the estimated mean change (95% CI) at 45 min after randomization was 0.17 g L -1 (95% CI, 0.02 to 0.31) in the FlyP group and -0.12 g L -1 (95% CI, -0.27 to 0.02) in the FPP group (mean betweentreatment group difference, 0.29 g L -1 ; 95% CI, 0.09 to 0.48; P = 0.006). APPT, activated partial thromboplastin time; FFP, fresh frozen plasma; FLyP, French lyophilised plasma; PT, prothrombin time; T0, randomization. We found no difference in changes in base excess and serum lactate at any time-point. In both study groups, base excess increased over time, whereas serum lactate decreased.Transfusion intervalsIn comparison to FFP, the use of FLyP reduced the transfusion intervals. From randomization, the median [IQR] time to transfusion of the first plasma unit was shorter in the FLyP group (14[5-30] min) than the FFP group (77 [64-90] min, P < 0.0001). As a result, the interval between randomization and end of transfusion of the 4 units was also reduced with FLyP compared with FFP (median [IQR], 45 [45-70] vs. 112 [91-125]; P < 0.0001). Blood product and fluid requirements and all-cause mortality The need for fibrinogen concentrates was reduced in the FLyP group compared with the FFP group over the first 24 h after randomization, albeit at the threshold for statistical significance

Table 1 .

 1 Baseline characteristics

	Empty Cell

Table 2 .

 2 Primary outcome: fibrinogen level (g L -1 ) at 45 min after randomization FFP, fresh frozen plasma; FLyP, French lyophilised plasma; ITT, intention to treat; PP, per protocol; SD, standard deviation. T0 indicates fibrinogen level at randomization (baseline) and T45 fibrinogen level 45 minutes after randomization.

	Empty Cell	FlyP No. Mean ± SD No. Mean ± SD FFP	Difference in fibrinogen at T45 adjusted on baseline value, mean (95% CI)*	P-value*
	ITT analysis
	T0	23 1.44 ± 0.90 24 1.14 ± 0.51
	T45	23 1.57 ± 0.78 24 1.05 ± 0.51 0.29 (0.08 to 0.49)	0.006
	PP analysis
	T0	21 1.41 ± 0.94 21 1.12 ± 0.49
	T45	21 1.56 ± 0.81 21 0.93 ± 0.40 0.40 (0.23 to 0.57)	<0.001
	CI, confidence interval;

* Calculated using analysis of covariance adjusted for baseline value.

Table 3 .

 3 Hemostatic parameters from randomization to 24 h according to treatment group

	Hemostatic parameter	FlyP group No. Mean ± SD No. Mean ± SD FFP group	Difference in change from baseline, mean (95% CI)*	P-value*
	Fibrinogen
	T0	23 1.44 ± 0.9 24 1.14 ± 0.5 -	-
	45 min	23 1.57 ± 0.8 24 1.05 ± 0.5 0.29 (0.09 to 0.48)	0.006
	6 h	22 2.50 ± 0.6 23 1.93 ± 0.6 0.51 (0.14 to 0.88)	0.008
	12 h	22 2.69 ± 0.7 23 2.44 ± 0.4 0.20 (-0.17 to 0.57)	0.29
	24 h	20 3.61 ± 0.7 17 3.45 ± 0.6 0.16 (-0.26 to 0.58)	0.45

Table 4 .

 4 Median cumulative requirement of fibrinogen concentrates, transfusion and fluid therapy at 24 h after randomization

	Empty Cell	FLyP No. Median [IQR] No. Median [IQR] FFP	P-value
	Fibrinogen concentrates, 1.5-g doses	23 2 [0-3]	24 3 [2-4]	0.052
	Crystalloids, 500-mL doses	21 3 [2-4]	22 4 [3-5]	0.28
	Colloids, 500-mL doses	22 1.5 [1-2]	23 2 [1-4]	0.12
	Platelet concentrate, units	23 0 [0-1]	24 1 [0-2]	0.14
	Red blood cell, units	23 6 [4-10]	24 7 [6-11.5]	0.12
	Plasma, units	23 4 [4-8]	24 5.5 [4-9]


Fabien Picard

Julien Adjedj

Jean-Philippe Collet

Eric Van Belle

Jacques Monsegu

Bernard Karsenty

Patrick Dupouy

Marine Quillot

Guillaume Bonnet

Alexandre Gautier

Guillaum E Bonnet

Guillaume Cayla

Hakim Benamer

Pharmacological coronary spasm provocative testing in clinical practice: A French Coronary Atheroma and Interventional Cardiology Group (GACI) position paper

Keywords:

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

Introduction

More than 60 years ago, Prinzmetal first described a variant of angina occurring at rest associated with electrocardiogram modifications. This condition, called vasospastic angina (VSA), is a heterogeneous phenomenon that can occur in patients with or without coronary atherosclerosis, can be focal or diffuse and can affect epicardial or microvasculature coronary arteries. VSA is caused by an intrinsic anomaly of coronary vasomotricity, which may be responsible for resting chest pain with concomitant electrocardiogram changes, such as transient ST-segment elevation; it can classically result in angina or myocardial infarction with no obstructive coronary arteries [START_REF] Amsterdam | AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Circulation[END_REF], [START_REF]JCS Joint Working Group Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina)[END_REF], [3]. Many centres have been unwilling to perform routine provocative testing for multiple reasons, including longer procedural time, the lack of definitive provocative spasm protocol and reported deaths related to provocative testing [4]. Initially performed at the bedside, with intermittent electrocardiogram monitoring and administration of nitrates, catheterization laboratory-based provocative testing, in which short half-life provocative drugs are administered, has become the standard of care. Nevertheless, the drugs and protocols available for coronary spasm diagnosis are heterogenous [5], and VSA is still a frequently overlooked diagnosis. Timely diagnosis of VSA is mandatory to prevent further lifethreatening events [6], [7]. This position paper from the French Coronary Atheroma and Interventional Cardiology Group (GACI) aims to review the indications for provocative tests, the testing conditions, drug protocols and positivity criteria.

Coronary vasospasm pathophysiology

Coronary spasm most often affects 50-year-old smokers, but its physiopathology is multifactorial, including extrinsic (smoking) and intrinsic (genetic) factors. Several studies have highlighted the role of coronary endothelial dysfunction, coronary smooth muscle hypercontractility with Rho-kinase as a key player and neurohormonal abnormalities as triggering factors [5]. The incidence of coronary spasm varies greatly depending on screening policies at each centre. Approximately 10% of patients presenting with symptoms at rest and with no evidence of obstructive coronary artery disease display evidence of coronary artery spasm when systematic screening is implemented [START_REF]JCS Joint Working Group Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina)[END_REF], [8]. Identification of VSA is important, as it may lead to acute coronary syndromes, ventricular arrhythmias, conduction disorders and sudden death [9], [10]. Guidelines from Europe, the USA and Japan emphasize that coronary spasm provocative testing should be applied in routine practice in patients with angina or myocardial infarction with no obstructive coronary arteries [START_REF] Amsterdam | AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Circulation[END_REF], [START_REF]JCS Joint Working Group Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina)[END_REF], [3].

Indications for provocative testing

Patients with VSA have a higher risk of major adverse cardiovascular events (MACE) compared with the general population. Identification of VSA is of utmost importance given that smoking cessation, calcium channel blockers and long-acting nitrates have been demonstrated to drastically reduce symptoms and the occurrence of subsequent cardiac events [11]. If a definitive diagnosis can be made in a typical case of spontaneous episodes of nitrateresponsive angina with either transient ischaemic electrocardiogram changes or coronary artery spasm, defined as transient total or subtotal coronary artery occlusion (> 90% vasoconstriction), this situation is deemed very rare, and provocative testing is necessary to rule in/out suspected VSA. In addition, provocative testing should be undertaken after cardiac life-threatening events without evident underlying cause (Table 1). No symptoms suggestive of VSA ANOCA: angina with no obstructive coronary arteries; MINOCA: myocardial infarction with no obstructive coronary arteries; VSA: vasospastic angina. Few contraindications exist, such as the acute phase of resuscitated cardiac arrest or acute coronary syndrome, because induction of coronary vasospasm could induce severe ventricular arrythmia or provoke ischaemia, which can be life-threatening at the acute phase. For the same reasons and because the VSA diagnosis might not be retained, provocative tests should not be performed in case of severe multivessel coronary artery disease or left main coronary artery stenosis, as well as when the patient presents with severe myocardial dysfunction, unless this dysfunction might be a consequence of coronary spasm (controversial). Last, patients without symptoms suggestive of VSA should not undergo systematic provocative testing, as its performance and safety to diagnose asymptomatic patients has not been evaluated. In case of acute coronary syndrome or resuscitated cardiac arrest with no obstructive coronary artery disease or alternative cause, delayed provocative spasm testing should be performed after the decrease of cardiac troponin peak, although no specific data are available. Specific triggers of coronary artery vasospasm should be known, such as illicit drug abuse (mainly cocaine and amphetamines), medications (including sumatriptan and derivatives, pseudoephedrine and leukotriene modifiers for asthma), systemic inflammatory conditions, physical and mental stress, cold pressor via sympathetic activation, hyperventilation syndrome, hormonal fluctuations (e.g. variations during menstrual cycle or menopause), alcohol withdrawal, Kounis syndrome (where an allergic or hypersensitivity reaction triggers a coronary artery spasm) and hypereosinophilia (Table 2). Table 2. Specific triggers of coronary vasospasm.

Hyperventilation syndrome (alkalosis)

Valsalva manoeuvre

Physical and mental stress

Smoking

Alcohol consumption or withdrawal

Illicit drug abuse (cocaine, amphetamines)

Medications (triptans and derivatives, pseudoephedrine, leukotriene modifiers, sympathomimetic agents [adrenaline, noradrenaline], beta-blockers, parasympathomimetic agents [acetylcholine, pilocarpine], ergot alkaloid [ergonovine, ergotamine], 5-fluorouracil)

Sympathetic activation (cold pressor)

Kounis syndrome (allergic or hypersensitivity reaction) Hypereosinophilia

Provocative testing methods

Although consensus papers on the diagnostic criteria for microvascular angina and VSA during provocative test have been published by the Coronary Vasomotor Disorders International Study (COVADIS) working group [12], consensus on a standardized provocative protocol remains to be established. Although a large variety of provocative test protocols exists, they are used routinely in only a few specialized centres [START_REF] Feenstra | Principles and pitfalls in coronary vasomotor function testing[END_REF]. This lack of consensus on a uniform functional testing protocol hampers widespread adoption in clinical practice. Provocative methods and agents are summarized in Table 3. Table 3. Proposed provocative coronary artery spasm testing protocols.

Coronary spasm provocative test conditions Continuous electrocardiogram monitoring

Radial A Diluted in 20 mL of saline solution. B In the event of an ischaemic change on the electrocardiogram or chest symptom, perform angiography at the time of its onset.

Provocative testing conditions

Electrocardiogram monitoring is mandatory. Radial or femoral routes can be used, and vasodilator administration is allowed to prevent radial spasm [START_REF] Lee | Feasibility and safety of the transradial approach for the intracoronary spasm provocation test[END_REF], [START_REF] Sueda | Kohno Acetylcholine spasm provocation test by trans-radial artery and brachial vein approach[END_REF]. After angiography of the left coronary artery (LCA) and right coronary artery (RCA) with either a diagnostic or guiding catheter without wires, acetylcholine, ergonovine or methylergonovine is given. The intracoronary route is used for acetylcholine, whereas the intracoronary or intravenous route can be used for ergonovine and methylergonovine (Table 3). Control angiography should be performed immediately when chest pain with ST-segment elevation or depression occurs or within 3-5 minutes after the last dose of provocative agent. Sublingual, intravenous or intracoronary nitrates should be then administered, irrespective of the presence of an induced spasm. A final angiogram of the LCA and RCA is mandatory. Ergonovine and acetylcholine provocation tests can be undertaken in an ambulatory setting [START_REF] Lee | Feasibility and safety of the transradial approach for the intracoronary spasm provocation test[END_REF], [START_REF] Saito | Feasibility and safety of outpatient cardiac catheterization with intracoronary acetylcholine provocation test[END_REF]. Right ventricle temporary pacing is not required.

Ergonovine and methylergonovine

Ergonovine and its analogue methylergonovine are synthetic ergot alkaloids, which act on smooth muscle, mainly by the activation of serotoninergic receptors (5-HT 2A ), to produce vasoconstriction [START_REF] Schiff | Ergot and its alkaloids[END_REF], [START_REF] Suyama | Mechanisms of the ergonovine-induced vasoconstriction in the rabbit main coronary artery[END_REF]. Adverse reactions to ergot alkaloids are diverse, and include coronary vasospasm, arrhythmia, nausea, allergic reaction and ergotism. Various testing protocols using intracoronary and intravenous administration of ergonovine and methylergonovine have been described. For intravenous ergonovine/methylergonovine, we propose the use of the most commonly described protocol, consisting of a direct bolus injection of 400 μg of ergonovine/methylergonovine. For intracoronary ergonovine/methylergonovine, we propose the slow injection (over 3 minutes) of 100 μg sequentially into the LCA and RCA.

Although no randomized controlled studies have compared intravenous versus intracoronary testing, one small-scale observational retrospective study showed that the intracoronary route may lead to a higher rate of positive testing [START_REF] Benamer | Vasospastic angina: An under-diagnosed pathology[END_REF]. In addition, European Society of Cardiology (ESC) and Japanese Circulation Society guidelines recommend intracoronary over intravenous ergonovine testing for safety reasons (i.e. to avoid delayed coronary vasospasm) [START_REF]JCS Joint Working Group Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina)[END_REF]. In case of a positive ergonovine/methylergonovine test, long-term oral calcium channel inhibitors should be given.

Acetylcholine

Acetylcholine is a parasympathetic nervous system transmitter that binds to both nicotinic and muscarinic receptors, playing a central role in vascular tone regulation. In the case of a healthy vascular system, a predominant role of the endothelium over smooth muscle cells is responsible for endothelial-dependent vasodilation, whereas, in the case of vascular dysfunction, the cell-mediated vasoconstriction of smooth muscle overcomes vasodilation [3]. Intracoronary administration of acetylcholine is the most common method for assessing vascular reactivity, although safety concerns persist, limiting its widespread use. Its use as provocative agent for coronary spasm is still off-label in several western countries, including France. Acetylcholine has to be administered via the intracoronary route, as summarized in Table 3; this route is not specified in the drug instructions, leading to a discouraging situation for many catheterization laboratories. For testing with acetylcholine we propose the following protocol: slowly (over > 20 seconds) administer 50 μg diluted in 20 mL of saline solution into the RCA, wait for 3 minutes and control the angiography; if no spasm occurs, then administer 100 μg diluted in 20 mL of saline solution into the RCA, wait for 3 minutes and control the angiography. Thereafter, administer 100 μg of acetylcholine diluted in 20 mL of saline solution into the LCA, wait for 3 minutes and control the angiography; if no spasm occurs, administer 200 μg of acetylcholine diluted in 20 mL of saline solution into the LCA, with a final control at 3 minutes. After performing the acetylcholine test, always administer intracoronary nitrates and perform a final angiogram. In case of a positive acetylcholine test, long-term oral calcium channel inhibitors should be given.

Provocative testing protocol choice

For France, as acetylcholine coronary use is still off-label, we recommend the use of intracoronary over intravenous methylergonovine in order to reduce the risk of delayed vasospasm. Nevertheless, intravenous methylergonovine according to local protocol, experience and follow-up can also be given, as no clear data exist on the increased risk and performance of intravenous over intracoronary administration. In case of negative methylergonovine provocative testing and high suspicion of VSA, an offlabel acetylcholine provocative test might be undertaken in order to increase provocative test performance.

Positivity criteria

The diagnosis of coronary artery spasm is made, according to the COVADIS [12] and ESC recommandations [3], if all of the following criteria are obtained in response to the provocative stimulus: reproduction of the usual chest pain; transient ischaemic electrocardiogram changes; and transient total or subtotal (≥ 90%) coronary vasoconstriction on angiography. The test result is considered equivocal if the provocative stimulus does not induce all three components (Fig. 1). Catheter-induced spasms, frequent on the proximal segment of the RCA, should not be classified as positive provocative tests. Focal spasm is defined as a focal transient vessel narrowing of ≥ 90% compared with the proximal segment of one isolated coronary artery, whereas diffuse spasm is defined as a diffuse transient vessel narrowing of ≥ 90% compared with basal angiography, and which extends into at least two adjacent coronary segments in one of the three major coronary arteries and branches (Fig. 1).

Combined testing

Acetylcholine and ergonovine/methylergonovine interact with muscarinic cholinergic and serotogenic receptors, respectively, and may have different coronary responses. Some patients may be responsive to only acetylcholine or only ergonovine, inducing potential false negative responses [START_REF] Sueda | Differential incidence and morphology of provoked spasm between intracoronary acetylcholine and ergonovine testing: recommendation of supplementary use[END_REF]. Acetylcholine provokes spasm more distally and diffusely, whereas ergonovine provokes spasm more proximally and focally. Ergonovine testing after a negative acetylcholine test documented spasm in approximately 9% of cases. Another investigation with a limited sample size demonstrated the potential utility of adding acetylcholine to ergonovine in patients with a negative provocative test [START_REF] Goto | Evaluation of adjunctive intracoronary administration of acetylcholine following intravenous infusion of ergonovine to provoke coronary artery spasm[END_REF].

Provocative testing risks

Serious major complications, including acute myocardial infarction, sustained ventricular tachycardia or fibrillation and death have been described when non-invasive administration of provocative agents was performed. When provocative tests are performed during coronary angiography, reported major complication rates are low, ranging from 0.2% to 4.7% with intravenous ergonovine, 0.4% to 0.8% with intracoronary ergonovine and 0% to 4.9% with intracoronary acetylcholine, with a mean complication rate of 0.62% [START_REF] Sueda | Overview of complications during pharmacological spasm provocation tests[END_REF]. As serious major complications, such as death, were reported only with intravenous administration of ergonovine [4], whereas no deaths were reported with intracoronary administration of ergonovine, a selective intracoronary ergonovine provocative test is perceived as safer. Isogai et al. [START_REF] Isogai | Serious cardiac complications in coronary spasm provocation tests using acetylcholine or ergonovine: analysis of 21 512 patients from the diagnosis procedure combination database in[END_REF] reported in 21,512 participants that an acetylcholine provocative test was associated with a higher rate of serious cardiac complications (defined as the composite of cardiac complications requiring urgent procedures or death) than ergonovine (0.9% vs 0.4%; P = 0.003 after propensity score matching). Contemporary reports suggest that provocative testing is a safe procedure that should be performed in a catheterization laboratory with dedicated protocols and trained personnel.

Outpatient approach and postprocedural observation after provocative testing

In 1981, intravenous ergonovine provocative testing was reported in 61 ambulatory participants, 10% of whom had a positive test without reported complications [START_REF] Ginsburg | Harrison Application and safety of outpatient ergonovine testing in accurately detecting coronary spasm in patients with possible variant angina[END_REF]. The radial approach for intracoronary ergonovine testing was more recently reported in 174 patients, 45% of whom were ambulatory, with same-day discharge in 76 out of 78, without major complications [START_REF] Lee | Feasibility and safety of the transradial approach for the intracoronary spasm provocation test[END_REF]. An intracoronary acetylcholine provocative test was also performed in a cohort of 323 patients, 38% of whom were in an outpatient group [START_REF] Saito | Feasibility and safety of outpatient cardiac catheterization with intracoronary acetylcholine provocation test[END_REF]. The study protocol mandated observation for 4 hours without monitoring in a dedicated outpatient unit. Coronary angiography was performed mostly through the radial approach using a 4F sheath. There were two cases of cardiac complications in the hospitalization group and one in the outpatient group, which led to unexpected hospitalization. Although there is no clear consensus on such an approach, given the lack of robust data, outpatient management with a minimum of 4 hours of uneventful observation seems reasonable. Continuous monitoring after provocative testing is not mandatory, and an electrocardiogram should be performed before discharge.

Provocative test under medical therapy

Provocative tests can be repeated to assess the efficacy of preventive pharmacological therapy and adjust the subsequent treatment strategy. If chest pain continues while provocative testing is negative, the patient may be reassured. In contrast, if patients still exhibit vasospasticity, dose escalation and refinement of vasoactive drugs should be performed and adjusted according to testing, to alleviate symptoms and prevent future ischaemic events [5]; this is especially relevant after sudden cardiac death, to determine the need for an implantable cardioverter-defibrillator [7], [START_REF] Sueda | Sequential spasm provocation tests under medications are indispensable in patients with aborted sudden cardiac death due to coronary spasm[END_REF]. Therefore, this strategy could help to identify high-risk individuals who may require closer monitoring, more aggressive treatment strategies or consideration for invasive interventions.

Microvascular spasm diagnosis

Abnormal vasomotion can also affect the coronary microvasculature, which cannot be directly visualized because of the limitation of the spatial resolution of coronary angiography. Diagnosis of microvascular spasm is therefore based on the reproduction of symptoms associated with electrocardiogram changes in the absence of epicardial spasm during a provocative test. Both acetylcholine and ergonovine/methylergonovine can be used, although acetylcholine is the drug most studied. The same protocols apply for microvascular and epicardial spasm detection. Microvascular spasm may also lead to an increase in microvascular resistances, inducing decreased blood velocity, assessed invasively by thermodilution or the index of microvascular resistance (defined as the ratio of distal coronary pressure [P d ] and the thermodilution-derived mean transit time during maximal hyperaemia, measured with a pressure/temperature wire) [START_REF] Adjedj | Coronary microcirculation in acute myocardial ischaemia: From non-invasive to invasive absolute flow assessment[END_REF]. This index is specific for the coronary microcirculation, with some degree of variability as a result of the manual injection of an intracoronary bolus of saline at room temperature [START_REF] Picard | Adjedj In vitro test-retest repeatability of invasive physiological indices to assess coronary flow[END_REF]. The need for the administration of a hyperaemic agent concomitant with a spasm-provoking agent complicates the evaluation of this method. More recently, the use of maximal absolute coronary flow (L/min) and minimal resistances (Woods units) has been introduced as a novel method to diagnose microvascular spasm without the need for a hyperaemic agent. This technique uses an infusion microcatheter (RayFlow; Hexacath, Rueil-Malmaison, France) placed in the proximal part of the vessel, with a pressure/temperature wire that is advanced distally. A saline solution at room temperature is infused at a fixed flow rate (called Qi) through the catheter side holes, creating haemolysis and release of adenosine diphosphate, producing hyperaemia. The mixture between blood and saline reaches a steady state (called T) in a few seconds. Thereafter, the pressure/temperature wire is pulled back at the side-hole level to measure the temperature of saline at the exit of the infusion catheter (called Ti). Coronary flow (called Q) is simply calculated as the ratio between Ti and T multiplied by Qi and a constant of blood of 1.08. The pressure/temperature wire gives pressure and temperature simultaneously. As pressure equals the flow multiplied by the resistances, microvascular resistances can be calculated as the ratio between P d and Q [START_REF] Adjedj | Coronary microcirculation in acute myocardial ischaemia: From non-invasive to invasive absolute flow assessment[END_REF], [START_REF] Adjedj | Accurate assessment of coronary blood flow by continuous thermodilution technique: Validation in a swine model[END_REF] before and after the provocative test in case of high suspicion of microvascular spasm. Microvascular spasm can be assessed by other methods; it can cause angiographic slow-flow phenomenon associated with reduced Thrombolysis in Myocardial Infarction (TIMI) flow assessed by TIMI frame count [START_REF] Adjedj | Coronary microcirculation in acute myocardial ischaemia: From non-invasive to invasive absolute flow assessment[END_REF], [START_REF] Fragasso | Coronary slow-flow causing transient myocardial hypoperfusion in patients with cardiac syndrome X: long-term clinical and functional prognosis[END_REF], [START_REF] Martinez Pereyra | Coronary microvascular spasm as the underlying cause of the angiographic slow flow phenomenon[END_REF]. Additionally, lactate concentration in the coronary sinus, myocardial lactate extraction ratio or desaturation of coronary sinus blood can be used to diagnose microvascular spasm in equivocal provocative tests, such as reproduction of symptoms without ischaemic electrocardiogram changes and vice versa [START_REF] Takahashi | Measurement of myocardial lactate production for diagnosis of coronary microvascular spasm[END_REF]. However, this diagnostic method requires selective catheterization of the coronary sinus, which limits broad and routine utilization. In practice, lactate levels are sampled simultaneously in the LCA and the coronary sinus during spasm provocation testing, and the net production of lactate across the coronary circulation is then calculated as coronary sinus concentration minus LCA concentration divided by LCA concentration. A positive value favours pathological production or release, whereas a negative value favours physiological uptake of lactate in the coronary circulation. The diagnostic algorithm for microvascular coronary spasm is shown in Fig. 1, and VSA phenotypes are described in Table 4

Fig. 1 .

 1 Fig. 1. Spasm provocative test diagnosis algorithm. If only two of the three components of diagnosis are provoked, the test is considered equivocal, except if microvascular spasm is diagnosed. ACh: acetylcholine; ECG: electrocardiogram; ER: ergonovine maleate; M-ER: methylergonovine.7. Combined testingAcetylcholine and ergonovine/methylergonovine interact with muscarinic cholinergic and serotogenic receptors, respectively, and may have different coronary responses. Some patients may be responsive to only acetylcholine or only ergonovine, inducing potential false negative responses[START_REF] Sueda | Differential incidence and morphology of provoked spasm between intracoronary acetylcholine and ergonovine testing: recommendation of supplementary use[END_REF]. Acetylcholine provokes spasm more distally and diffusely, whereas ergonovine provokes spasm more proximally and focally. Ergonovine testing after a negative acetylcholine test documented spasm in approximately 9% of cases. Another investigation with a limited sample size demonstrated the potential utility of adding acetylcholine to ergonovine in patients with a negative provocative test[START_REF] Goto | Evaluation of adjunctive intracoronary administration of acetylcholine following intravenous infusion of ergonovine to provoke coronary artery spasm[END_REF].8. Provocative testing risksSerious major complications, including acute myocardial infarction, sustained ventricular tachycardia or fibrillation and death have been described when non-invasive administration of provocative agents was performed. When provocative tests are performed during coronary angiography, reported major complication rates are low, ranging from 0.2% to 4.7% with intravenous ergonovine, 0.4% to 0.8% with intracoronary ergonovine and 0% to 4.9% with intracoronary acetylcholine, with a mean complication rate of 0.62%[START_REF] Sueda | Overview of complications during pharmacological spasm provocation tests[END_REF]. As serious major complications, such as death, were reported only with intravenous administration of ergonovine [4], whereas no deaths were reported with intracoronary administration of ergonovine, a selective intracoronary ergonovine provocative test is perceived as safer. Isogai et al.[START_REF] Isogai | Serious cardiac complications in coronary spasm provocation tests using acetylcholine or ergonovine: analysis of 21 512 patients from the diagnosis procedure combination database in[END_REF] reported in 21,512 participants that an acetylcholine provocative test was associated with a higher rate of serious cardiac complications (defined as the composite of cardiac complications requiring urgent procedures or death) than ergonovine (0.9% vs 0.4%; P = 0.003 after propensity score matching). Contemporary reports suggest that provocative testing is a safe procedure that should be performed in a catheterization laboratory with dedicated protocols and trained personnel.

  Central illustration. Spasm provocative testing in France. ANOCA: angina with no obstructive coronary arteries; ECG: electrocardiogram; IC: intracoronary; IV: intravenous; LCA: left coronary artery; MT: medical therapy; MINOCA: myocardial infarction with no obstructive coronary arteries; PCI: percutaneous coronary intervention; RCA: right coronary artery; SL: sublingual; VSA: vasospastic angina; # Diluted in 20 mL of saline solution.

Table 1 .

 1 Indications for provocative coronary artery spasm testing.

	Strong indications	ANOCA, especially if:
		-resting angina
		-nitrate responsive
		-important diurnal variation in symptoms and exercise
		tolerance (more pronounced at night and early morning)
		-MINOCA in the absence of a culprit lesion

Table 4 .

 4 . Vasospastic angina phenotypes according to clinical, electrocardiographic and angiographic results. Spasm provocative testing remains underperformed, resulting in an underestimation of VSA. Simple and user-friendly acetylcholine and ergonovine/methylergonovine protocols with clear testing conditions and diagnostic criteria should increase spasm provocative testing in France, resulting in a higher proportion of symptomatic patients with an accurate diagnosis and appropriate treatment (Central illustration).

	Empty Cell	Reproducible symptoms	Ischaemic electrocardiogram changes	Coronary diameter reduction > 90%	Microvascular dysfunction
	Epicardial spasm	+	+	+	-
	Microvascular spasm	+	+	-	±
	Negative spasm -	-	-	±
	Equivocal	±	±	-	±
	Mixed angina +	+	+	+
	12. Conclusions