Jérôme Moutet Ibode
email: moutet.j@chu-toulouse.fr

Dochead dossier Sous-dochead Le temps au bloc opératoire Surtitre informatisation L'optimisation du programme opératoire en quelques clics

Keywords: informatisation, parcours patient, programme opératoire, qualité des soins, régulation, traçabilité

De la programmation chirurgicale à la traçabilité peropératoire, jusqu'à l'analyse des données, l'organisation des blocs opératoires a été restructurée autour de projets. Les exigences de la certification et l'émergence de nouvelles techniques chirurgicales a rendu l'informatisation des grands plateaux techniques primordiale pour améliorer la performance des blocs opératoires et garantir la qualité des soins apportés au patient.

présent vers l'extérieur. Au-delà des évolutions des techniques opératoires (robotique, réalité augmentée…), l'informatisation du bloc opératoire se révèle nécessaire au quotidien pour une prise en charge globale du patient.

T1 Le "live", un module à succès TEG1 Suivre en direct l'avancement du programme opératoire est devenu indispensable pour tous les acteurs de soins. Les plateaux techniques s'étendant géographiquement, ce module avait, et a toujours aujourd'hui, la fonction d'écran de contrôle qui permet aux cadres de bloc de réguler l'activité en suivant l'avancement des différentes interventions à distance. Ce moniteur "live", installé à l'origine uniquement sur de grands écrans au sein des salles de régulation, s'est étendu petit à petit à tous les ordinateurs des blocs opératoires, pour finir par être utilisé partout dans l'établissement de santé (figure 1).

TEG1 Comme des aiguilleurs du ciel dans une tour de contrôle, les régulateurs des blocs, suivent à distance l'avancement du programme opératoire (figure 2), et peuvent ainsi décider en temps réel des actions à mener : • transférer un patient dans une salle différente si le lieu initial est occupé ;

• reporter des interventions si le programme a pris trop de retard. TEG1 Grâce à ce moniteur "live, également installé dans chaque salle d'opération, les membres de l'équipe peuvent connaître l'état d'avancement du programme opératoire, et savoir si le patient suivant est arrivé.

TEG1 Restreint aux blocs opératoires à ses débuts, ce module s'avère également très utile dans les autres services de l'établissement. Installés dans les unités d'hospitalisation, les moniteurs permettent aux personnels de santé des services de suivre en direct l'évolution du programme opératoire et ainsi d'ajuster les actions prévues. En parallèle, ils renseignent de manière autonome les accompagnants des personnes opérées sans importuner le personnel des blocs. TEG1 D'après les cadres de bloc, l'installation de ce module dans les unités de soins a permis de réduire de manière significative les coups de téléphone pour savoir où en était l'intervention de la personne opérée. À un degré moindre, les opérateurs peuvent suivre en direct l'évolution de la préparation de la personne qu'ils vont opérer et ainsi anticiper le moment où ils doivent intervenir en salle, sans que le personnel du bloc opératoire ait besoin de les appeler.

T1 Optimisation de la programmation opératoire TEG1 La construction de ce moniteur "live" ne se fait pas approximativement. Avant d'arriver à une complète fonctionnalité, intégrant l'évolution de la traçabilité du parcours patient, de nombreux paramétrages sont nécessaires, notamment ceux des salles d'interventions et des vacations chirurgicales.

TEG1 Afin d'avoir une programmation de qualité, il faut au préalable déterminer des durées d'ouverture de salle, les paramétrées puis leur attribuer des vacations chirurgicales. En bornant des créneaux chirurgicaux de base, il est ainsi possible de visualiser bien à l'avance les plages dédiées et d'éviter la sur-ou la sous-programmation.

Lorsque des débordements sont à craindre, les cadres de bloc peuvent réajuster le tableau opératoire de façon anticipée et éviter au patient d'être déprogrammé à la dernière minute.

TEG1 Si tous les acteurs de la programmation chirurgicale du patient, comprennent l'intérêt de l'outil et son principe, une programmation opératoire au plus près de la réalité est obtenue. Les chirurgiens peuvent proposer rapidement des créneaux opératoires à leur patient sans se soucier des différentes contraintes, si celles-ci sont au préalable correctement paramétrées. En effet si les vacations, les ressources critiques, les fermetures de salles, les places d'hospitalisations sont configurées, le chirurgien n'a plus à se préoccuper des créneaux disponibles, l'outil lui proposera plusieurs choix qui s'insèreront dans son programme opératoire sans risque de sur-programmation ou de matériel indisponible.

TEG1 En fonction de la date déterminée par le logiciel, le chirurgien aura la possibilité de visualiser le programme déjà inscrit le jour donné afin d'avoir une vue globale de son planning, ce qui lui permet de confirmer ou d'infirmer la proposition.

TEG1 Un des aspects intéressants pour le chirurgien est de pouvoir renseigner ses absences et de proposer ces plages opératoires à ses collègues. De ce fait, en renommant sa vacation au nom de son équipe chirurgicale, tous ses collègues pourront avoir accès à cette plage comme une des leurs et la proposer à leurs patients si le créneau leur convient. Cette option présente deux avantages :

• permettre aux patients de bénéficier de délais d'attente moins longs avant l'intervention chirurgicale, puisque le chirurgien récupère des vacations auxquelles il n'avait pas accès avant ou difficilement identifiables ;

• éviter les plages vides qui entraînent une sous-exploitation de la salle d'intervention.

TEG1 Ce système de programmation permet également de confier la planification des patients aux IDE de coordination en secteur de consultations. Le logiciel, qui calcule les durées opératoires par chirurgien (automatiquement mises à jour tous les jours en fonction des temps référencés au bloc opératoire) et affiche les vacations chirurgicales ainsi que les ressources critiques, permet à l'IDE d'être autonome et d'organiser l'hospitalisation du patient à partir de la date proposée par le logiciel. Si un élément ne correspond pas, l'IDE peut facilement trouver une autre proposition de date en respectant le programme opératoire préétabli.

T1 Le Jour J TEG1 Avant l'arrivée du premier patient au bloc opératoire, l'Ibode vérifie la présence et la fonctionnalité des différents éléments de la salle d'intervention, ceci à l'aide d'une liste de vérification paramétrée dans le logiciel en fonction des spécificités de chaque spécialité. Cette check-list est construite de manière concertée par les Ibode et adaptée à leur spécialité. La salle et le matériel nécessaire à l'intervention étant prêts, toutes les identifications des patients (dites étiquettes) sont alignées sur le moniteur de contrôle pour la journée à venir.

TEG1 La première étape étant validée, le "live" se met en action. Le patient de la salle 3 est prêt dans l'unité de chirurgie ambulatoire, son étiquette devient rose, le brancardier est appelé pour le patient de la salle 1, son identification passe en jaune. Les patients des salles 2 et 5 attendent dans le sas d'accueil, leur étiquette est violette (figure 3). Au fur et à mesure que les patients arrivent au bloc opératoire, les check-lists de la Haute Autorité de santé (HAS) "Sécurité du patient au bloc opératoire" peuvent être débutées avec les patients dans les sas d'accueil sur des terminaux dédiés puis être poursuivies sur les ordinateurs en salle.

TEG1 Les patients une fois transférés dans les salles, toute la traçabilité se fait via le logiciel : les différents temps opératoires, le personnel présent, toutes les actions réalisées. Si la check-list de la HAS n'est pas renseignée au moment du clic horaire de l'incision chirurgicale, des verrous informatiques bloquent la traçabilité, ce qui alerte l'Ibode en cas d'oubli.

TEG1 La traçabilité des dispositifs médicaux utilisés est renseignée à l'aide d'un scanner (figure 4), ce qui la rend plus rapide et plus sûre, et permet ainsi d'alléger les tâches administratives pour se consacrer plus de temps au patient. L'informatisation de la traçabilité des dispositifs médicaux réutilisables (DMR), outre la facilité de la traçabilité pour le patient, permet de rationaliser leur utilisation, car l'Ibode peut connaître en direct l'état des stocks des containers et des paniers d'instrumentation dans les arsenaux.

De plus, les informations sur les instruments défectueux ou manquants peuvent être communiquées par les Ibode via le logiciel aux agents de l'unité de stérilisation qui recomposeront la boîte d'instrumentation ultérieurement.

•

  visualiser la position du patient au fil de son parcours au sein du bloc (sas d'accueil, sas d'anesthésie, salle d'intervention, salle de surveillance post-interventionnelle [SSPI]…) ; • anticiper la venue des patients suivants en limitant le temps d'attente dans le sas d'accueil et en évitant les retards d'enchaînement du programme opératoire ;

TEG1Figure 1 .Figure 2 .Figure 3 .

 123 Figures

Figure 4 .

 4 Figure 4. La traçabilité des dispositifs médicaux utilisés est renseignée à l'aide d'un scanner, ce qui la rend rapide et sûre, tout en libérant plus de temps à consacrer au patient.


Justine Cristante

Olivier Chabre

Unilateral adrenalectomy in primary bilateral macronodular hyperplasia

Purpose of review

To analyze the benefits and potential drawbacks of unilateral adrenalectomy (UA) for the treatment of patients with Primary bilateral macronodular adrenal hyperplasia (PBMAH) and hypercortisolism with either overt or subclinical Cushing's syndrome (CS).

Recent findings. Unilateral adrenalectomy has progressively emerged as an interesting

treatment for PBMAH as it offers a high rate of remission of CS, even in patients with free urinary cortisol well above 2 times the upper limit of normal. UA carries a risk for secondary adrenal insufficiency, which cannot be properly identified by the cosyntropin test, but is both limited and transient. This makes it an attractive alternative to bilateral adrenalectomy (BA), which condemns the patient to total and definitive primary adrenal insufficiency and a risk for adrenal crisis. Recently however the issue has been raised of a potential risk of mortality in UA patients, linked to persistent dysregulated secretion of cortisol or recurrence.

Summary Further studies are necessary to better compare the long term risks of dysregulated secretion of cortisol with UA vs adrenal insufficiency in BA. Up to now the clinician has to remember that UA can be transformed in BA, while the opposite is impossible.

Introduction

Primary bilateral macronodular hyperplasia (PBMAH) is a disease of the adrenal cortex that affects both adrenal glands, leading to a progressive enlargement of the adrenals and an increase in their secretion of cortisol, which is independent of pituitary ACTH.

The clinical impact of PBMAH is the consequence of chronic dysregulated secretion of cortisol, which first results in subclinical Cushing's syndrome (SCS), that can develop in overt Cushing's syndrome (OCS) generally after the 4 th decade. Although elegant, the pharmacological therapeutic strategy based on antagonizing activation of abnormally expressed receptors [START_REF] Lacroix | Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome[END_REF] is rarely effective and tolerated on long term, and there are few reports on prolonged pharmacological inhibition of either cortisol synthesis or action, so that therapeutic choices are mainly between bilateral adrenalectomy (BA), unilateral adrenalectomy (UA), or observation. Bilateral adrenalectomy (BA) terminates cortisol hyper secretion but exposes the patient to the morbi-mortality of total and definitive primary adrenal insufficiency. In this review we will focus on the benefits and potential drawbacks of UA.

physiopathology of secretion and proliferation of PBMAH cells.

Primary bilateral macronodular hyperplasia (PBMAH) has a likely genetic origin, that has already been established in 25-50% of the cases, related to germinal mutations in ARMC5 [START_REF] Assie | ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome[END_REF].

The adrenals of patients with PBMAH show two major differences with normal adrenals: a progressive enlargement, with the development of hyperplasia and multiple nodules over time, and a capacity to secrete cortisol in the absence of pituitary ACTH. In patients with ARMC5 mutations adrenal enlargement is at least partially explained by an anti apoptotic effect of the mutated ARMC5 gene, which behaves as a tumor suppressor gene: the inherited germinal mutation is believed to be responsible for hyperplasia whereas the somatic mutations would be reponsible for nodule development, both generating ultimately sufficient cell mass for hypersecretion [START_REF] Assie | ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome[END_REF]. Pituitary independent cortisol secretion by PBMAH cells is dependent on activation of abnormally expressed receptors [START_REF] Lacroix | Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome[END_REF], and intra adrenal secretion of ACTH [START_REF] Louiset | Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia[END_REF]. Interestingly, and counter intuitively, adrenocortical cells of PBMAH patients have a much lower cortisol synthesis activity than normal adrenocortical cells [START_REF] Assie | Systematic analysis of G protein-coupled receptor gene expression in adrenocorticotropin-independent macronodular adrenocortical hyperplasia identifies novel targets for pharmacological control of adrenal Cushing's syndrome[END_REF]. Accordingly pathogenic mutations of ARMC5 in PBMAH decrease, rather than increase, the secretion of cortisol [START_REF] Assie | ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome[END_REF], which might appear paradoxical in a disease responsible for hypersecretion of cortisol. However it can be understood by considering that the number of adrenocortical cells progressively increases in PBMAH so with time the added secretions of a high number of low producing cortisol cells eventually exceeds the secretion of a normal adrenal, which suppresses pituitary ACTH production. As PBMAH cells can continue to secrete cortisol despite suppression of pituitary ACTH, hypercortisolism develops. It is important to note that, at the time when hypercortisolism appears, the size of PBMAH adrenals exceeds by far the size of normal adrenals, with each PBMAH adrenals usually much larger than 2 normal adrenals.

Finally one has to note that, although cortisol secretion of PBMAH cells is independant of pituitary ACTH in the sense that it can continue despite suppression of pituitary ACTH, it is actually quite sensitive to stimulation by ACTH. This is shown by the good response of PBMAH patients to the cosyntropin test (4), even if this response remains low for cell mass, which is explained by low expression of MC2R and steroidogenic enzymes [START_REF] Antonini | Expression of ACTH receptor pathway genes in glucose-dependent insulinotrophic peptide (GIP)-dependent Cushing's syndrome[END_REF].

Secretion of the remaining PBMAH gland after Unilateral adrenalectomy (Figure 1)

These characteristics of PBMAH cells help understand the unique situation of a PBMAH patient with overt Cushing's syndrome right after unilateral adrenalectomy: the patient is left with a large adrenal, but, due to previous long-standing suppression by hypercortisolism his pituitary ACTH secretion is suppressed, so this large adrenal can only secrete its dysregulated, pituitary ACTH independant, cortisol secretion. This secretion might be insufficient at morning or during stress conditions, resulting in secondary adrenal insufficiency , although it might at the same time exceed normal values during evening and the first part of the night. The patient is then expected to progressly recover pituitary ACTH secretion, resulting in normal cortisol values at morning and during stress conditions and remission of adrenal insufficiency but he is not likely to recover a normal circadian rythm and he may keep inappropriate levels of cortisol during evening and night, similar to what is encountered in patients with subclinical Cushing's syndrome (SCS) or in any kind of Cushing's syndrome treated by drugs that inhibit cortisol secretion. Finally, the patients' remaining adrenal might enlarge with time, carrying the prospect for recurrence of Cushing's syndrome.

In PBMAH patients without overt Cushing's syndrome who present with dysregulated cortisol secretion or "subclinal Cushing's syndrome" UA is also suppose to reduce cortisol secretion by at least 50%. If ACTH secretion is suppressed before UA the frequency of post operative AI is expected to be higher than in overt Cushing's syndrome as the remaining adrenal secretion is expected to be lower, but one might expect a more rapid recovery of pituitary ACTH secretion.

With this complex physiopathology in mind the rationale of UA for the treatment of overt hypercortisolism linked to PBMAH is the following: removing one of the 2 adrenals should diminish global cortisol production enough to eliminate the clinical consequences of hypercortisolism, while keeping a cortisol production sufficient to prevent adrenal insufficiency. Finally the remaining adrenal should not progress so that there is no recurrence of hypercortisolism.

In this review we will analyze the results of UA in PBMAH with the aim to compare them to the results of the main alternative therapy, bilateral adrenalectomy (BA). The results of BA are easier to describe: total and definitive primary adrenal insufficiency, a condition which imposes life long substitution and has its own morbidity and mortality [START_REF] Bergthorsdottir | Premature mortality in patients with Addison's disease: a population-based study[END_REF], even in educated patients [START_REF] Hahner | High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study[END_REF] and even in 2018 [START_REF] Hahner | Acute adrenal crisis and mortality in adrenal insufficiency: Still a concern in 2018![END_REF] .

Unilateral Adrenalectomy for treatment of overt hypercortisolism (Table 1)

The rationale of UA for the treatment of overt hypercortisolism linked to PBMAH is based on the assumption that removal of one of the 2 adrenals will diminish global cortisol production enough to bring it back to normal levels and this would induce clinical remission of Cushing's syndrome. Ideally cortisol production by the remaining adrenal would be sufficient to prevent adrenal insufficiency, and finally the remaining adrenal would not progress so that there is no recurrence of hypercortisolism.

We will thus analyze the published reports on UA in PBMAH with overt Cushing's syndrome with 3 questions in mind 1) is removal of one adrenal sufficient to normalize cortisol production? (primary efficacy of UA)

2) is the remaining adrenal sufficient to prevent AI? (short term morbidity of UA)

3) can the remaining adrenal be responsible for recurrence of Cushing's syndrome or at least subclinical Cushing's syndrome (long term morbidity of UA)? UA has been reported since 1996 in several studies, including case reports and small size series, which are listed in Table 1 [START_REF] Li | Diagnosis and treatment of adrenocorticotrophic hormoneindependent macronodular adrenocortical hyperplasia: A report of 23 cases in a single center[END_REF][START_REF] Tanaka | Retention of aberrant cortisol secretion in a patient with bilateral macronodular adrenal hyperplasia after unilateral adrenalectomy[END_REF] [START_REF] Osswald | Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia After Unilateral Adrenalectomy[END_REF] and on which we will base our analysis.

Primary efficacy of UA

The primary efficacy of UA is rather satisfying: overall normalization of urinary free cortisol (UFC) has been reported in 91% of the cases, and disappearance or at least significant improvement of CS in 81% of the case. Such good results are often surprising to many clinicians who have a tendency to believe that in PBMAH patients UA would only normalize UFC if UFC is below 2 times the normal range. Our analysis clearly shows that this "2 times the normal limit" rule is not true : although we did not have access to all the individual data of the patients described in these studies, we do list in Table 1 all the UFC values that are available in the articles and it is clear that most patients with a UFC over 2 ULN were controlled. If we consider the 36 patients controlled by UA who had available individual pre-operative UFC data reported, 21 patients (58%) have a UFC above 2ULN. We believe that the explanation for the efficacy of UA even in patients with a UFC above 2ULN is firstly that UA of the larger adrenal removes more than 50% of the production of cortisol and secondly that even if UA was removing only 50% of cortisol production in patients with 2 adrenals of similar size, a 50% reduction of cortisol production is expected to reduce UFC by more than 50%, as UFC is not linear to cortisol production, as discussed in [START_REF] Debillon | Unilateral Adrenalectomy as a First-Line Treatment of Cushing's Syndrome in Patients With Primary Bilateral Macronodular Adrenal Hyperplasia[END_REF].

Short term morbidity of Unilateral Adrenalectomy: adrenal insufficiency

The frequency of AI after UA is significant: 37%, which further demonstrates that despite being much larger than a normal adrenal, the remaining large hyperplastic adrenal in a PBMAH patient treated by UA may not be able to secrete as much cortisol as a normal adrenal. It should be noted that unlike AI after BA AI after UA is a secondary adrenal insufficiency, due to previous suppression of pituitary ACTH by hypercortisolism, and it does not last long : the median of recovery is 3 months in the Munich study [START_REF] Osswald | Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia After Unilateral Adrenalectomy[END_REF], where it is elegantly demonstrated that recovery of AI after UA for PBMAH is much faster than in UA for a unilateral cortisol producing adenoma (CPA) (18 months) . This fast recovery of AI after UA for PBMAH is very likely due to the recovery of ACTH secretion, acting on an adrenal which is not hypotrophic, unlike the controlateral adenoma of a a patient operated by UA for a CPA.

The other important difference of AI in UA vs BA in PBMAH is that with BA the AI is not only definitive, but also total, with both cortisol and aldosterone deficiency whereas with UA AI is only a secondary cortisol deficiency.

In conclusion UA in PBMAH can be complicated by post operative AI, but this is a secondary, incomplete and transient AI. It still needs to be diagnosed and treated in the immediate post operative period and regarding diagnosis there is an important point : the cosyntromin test does not appear to be appropriate for diagnosis of AI after UA for PBMAH patient, as the remaining adrenal might be both insufficient but still sensitive to ACTH, allowing a "normal" cortisol response to this test although the pituitary ACTH deficient patient will not be able to stimulate his adrenal (see the case report in ( 21)).

So AI diagnosis should be based either on a low 8 am cortisol levels or on the response to a test that explores pituitary fonction such as insulin-induced hypoglycemia test.

Long term morbidity of Unilateral Adrenalectomy: sub clinical Cushing's, recurrence and mortality

Although UA appears to have a good primary efficiency with a limited incidence of partial and transient post operative AI there is some concern regarding the long term outcome of patients. First there is a risk for recurrence, which is not surprising as the remaining adrenal is still a pathological adrenal, which might be expected to continue to increase both in size and in cortisol secretion. Although increase in size is rarely reported, increase in cortisol secretion leading to recurrency of CS have been reported, with widely difference in frequency, as high as 71% in the Italian Padua study (22), as low as 13% in the multicenter French study [START_REF] Debillon | Unilateral Adrenalectomy as a First-Line Treatment of Cushing's Syndrome in Patients With Primary Bilateral Macronodular Adrenal Hyperplasia[END_REF] whereas in the Munich study [START_REF] Osswald | Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia After Unilateral Adrenalectomy[END_REF], only 12% of the patients needed a controlateral adrenalectomy for either recurrence or persistance but 33% of the patients treated by UA experienced on long term recurrence in hypercortisolism defined by an elevation of UFC. This underlines a major question for the follow-up of these patients, who have a remaining adrenal that does not have a proper circadian rythm, a little similar to what has been described in patients with pituitary ACTH independant cortisol secretion by a unilateral cortisol secreting adrenal adenoma, diagnosed mostly as an incidentaloma, in whom the question of increased mortality has been raised by several retrospective studies, including 2 major studies [START_REF] Debono | Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas[END_REF][START_REF] Dalmazi | Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome: a 15-year retrospective study[END_REF]. In this light the recent results of the Munich study are worrysome [START_REF] Osswald | Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia After Unilateral Adrenalectomy[END_REF], as they report 3 deaths in the follow up of 25 PBMAH patients treated by UA vs no death in 9 PBMAH patients treated by BA. Of note this article does not provide the stasticial analysis to compare these 2 groups as they curiously provide instead a statistical analysis on the comparison of the 25 PBMAH patients treated by UA to a composite group including not only the 9 PBMAH patients treated by BA, but also 39 patients with an other adrenal disease: CPA. So that we learn that CPA patients treated by UA have a better outcome than PBMAH patients treated by UA but this is not the issue when you have to decide how to treat a PBMAH patient, who cannot be transformed in a CPA patient. It should also be noted that the 3 deaths reported in the Munich study were all in patients with biological hypercortisolism, but it is not clear whether these were patients with a recurrence or patients not in remission after UA. Finally it must also be noted that in the Munich study 38% of the PBMAH patients treated by BA had an adrenal crisis per year, whereas as expected no adrenal crisis occured in the patients treated by UA.

Unilateral Adrenalectomy for treatment of subclinical hypercortisolism (Table

2)

We decided to analyze separately the reports on treatment by UA of PBMAH patients with no overt Cushing's syndrome. Some of these patients are present in the studies already mentionned ( 15), ( 12),( 22) while some studies specifically target PBMAH patients with no overt Cushing's syndrome [START_REF] Ogura | Unilateral adrenalectomy improves insulin resistance and diabetes mellitus in a patient with ACTH-independent macronodular adrenal hyperplasia[END_REF][START_REF] Vezzosi | Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors[END_REF], the largest series being greek [START_REF] Perogamvros | Biochemical and Clinical Benefits of Unilateral Adrenalectomy in Patients with Subclinical Hypercortisolism and Bilateral Adrenal Incidentalomas[END_REF] .

Efficacy of UA in PBMAH patients with no overt Cushing's syndrome can be evaluated by analyzing the evolution of comorbidities usually associated with subclinical Cushing's / autonomous cortisol secretion (31): hypertension, glucose intolerance and diabetes, dyslipidemia, obesity, osteoporosis. Table 2, which relies mostly on the greek study [START_REF] Perogamvros | Biochemical and Clinical Benefits of Unilateral Adrenalectomy in Patients with Subclinical Hypercortisolism and Bilateral Adrenal Incidentalomas[END_REF] shows that after UA for PBMAH there is some normalization of cortisol secretion abnormalities and some improvement in these comorbidities, with a relatively high rate of adrenal insufficiency (50%).

How to choose which adrenal should be removed

For patients with either overt or subclinical Cushing's syndrome if UA is decided it seems logical to try to remove the adrenal that secretes the most, in order to maximize the chance of remission, even if it might increase the chance of post operative AI. The explorations available to evaluate pre operatively which adrenal secretes the most includes the size of the adrenals at CT scan, the intensity of fixation at iodine 131noriodocholesterol, while some also advocate bilateral adrenal veinous sampling (AVS) [START_REF] Ueland | Adrenal Venous Sampling for Assessment of Autonomous Cortisol Secretion[END_REF]. The criteria for choosing the side of adrenalectomy are not always detailed in all the studies who often combine different procedures, as in [START_REF] Osswald | Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia After Unilateral Adrenalectomy[END_REF]. In [START_REF] Lamas | Is unilateral adrenalectomy an alternative treatment for ACTH-independent macronodular adrenal hyperplasia?: Long-term follow-up of four cases[END_REF][START_REF] Iacobone | Adrenal Cushing's syndrome due to bilateral macronodular adrenal hyperplasia: prediction of the efficacy of beta-blockade therapy and interest of unilateral adrenalectomy[END_REF][START_REF] Ogura | Unilateral adrenalectomy improves insulin resistance and diabetes mellitus in a patient with ACTH-independent macronodular adrenal hyperplasia[END_REF][START_REF] Perogamvros | Biochemical and Clinical Benefits of Unilateral Adrenalectomy in Patients with Subclinical Hypercortisolism and Bilateral Adrenal Incidentalomas[END_REF] the choice was always to remove the larger gland on CT. In the french multicenter study the choice of the adrenal removed was always the larger on CT and primary efficacy of UA was 100% in 15 patients [START_REF] Debillon | Unilateral Adrenalectomy as a First-Line Treatment of Cushing's Syndrome in Patients With Primary Bilateral Macronodular Adrenal Hyperplasia[END_REF]. In this study 8 patients were also explored by iodine 131noriodocholesterol scintigraphy and in all 8 patients the adrenal with the maximum uptake of 131 iodo cholesterol was always the larger on CT scan. In (22) the choice was also based on the larger gland on CT but when the sizes of the 2 adrenals were equal it was based on the gland with the higher iodine 131-noriodocholesterol uptake. In the study by Ueland AVS is supposed to be the gold standard, however 5 patients with no lateralization of cortisol secretion at AVS were treated by UA with removal of the larger gland at CT, and from the data presented in this study one can conclude that at least 4 were in remission post operatively [START_REF] Ueland | Adrenal Venous Sampling for Assessment of Autonomous Cortisol Secretion[END_REF]. So in conclusion it appears that in most cases the adrenal removed was the larger on CT scan.

Conclusion

The clinician in charge of a patient with PBMAH faces a difficult choice, as he may choose two different solutions which have their own benefits and drawbacks (Figure 3 and4) .

If the patient has overt Cushing's syndrome he can either choose UA, which has a rate of primary success around 85%, even in patients with UFC above 2 ULN, with a 37% risk of transient and incomplete (secondary) AI which means the patient has a high chance of clinical improvement, with either no medical treatment or only substitutive therapy for some months. However this patient may be at risk for recurrence and long term complications of dysregulated cortisol secretion, so it is essential that the patient agrees with a long term follow-up, which can result in a decision of controlateral adrenalectomy. If the the clinican rather chooses BA the primary sucess is 100% and the risk for recurrence virtually inexisent (there was one case of recurring nodule after BA in ( 25)) but the patient will need life time substitutive therapy and he will be exposed to the risk of adrenal crisis, which can result in mortality. One can also add that even in BA patients there might be some long term cardiovascular morbi-mortality if substitutive therapy brings too much glucocorticoids.

As long as there is no prospective randomized trial comparing not only the short but also the long term outcomes of UA and BA in PBMAH the clinician will have to discuss with the patient the benefits and drawbacks of both strategies and he will need to be sensitive to the patients preferences. It is wise to note that UA can always be transformed in BA while the opposite is obviously impossible.

In PBMAH patients with no overt Cushing's syndrome but only autonomous cortisol secretion/SCS it seems to us that the drawbacks of BA, life long substitutive therapy and risk for adrenal crisis, would outweigh its benefits and we would favor UA, although in patients with no metabolic or cardiovascular comorbidities there can be a case for observation as UA will carry a relativey high risk of post operative AI . Title and Legends of the Figure The effect of UA can be compared to a travel back to the time when the patient had the same adrenal mass with 2 adrenals than with one adrenal after UA, except that he will keep a suppressed ACTH, which can be responsible for post operative secondary adrenal insufficiency.

Figure 1

 1 Figure 1 Schematic representation of the development of hypercortisolism in PBMAH and the effects of UA in patients with overt Cushing's syndrome.

Figure 2

 2 Figure 2 Schematic representation of the development of hypercortisolism in PBMAH and the effects of UA in patients with subclinical Cushing's syndrome.

Figure 3 Figure 4

 34 Figure 3 Pros and cons of UA in PBMAH patients with overt Cushing's syndrome Figure 4 Pros and cons of UA in PBMAH patients with subclinical Cushing's syndrome

Table 1

 1 Studies on PBMAH patients with overt hypercortisolism treated by Unilateral

	Adrenalectomy
	Study	n Norm	pre operative	pre operative	Post	Improve	recurrenc	Death	follow-up
			alisat	UFC	of	UFC of non	opera	ment CS	e of CS		(yrs)
			ion	normalized		normalized	tive		requiring
			UFC	patients		patients	Adren		reinterve
			or AI	(ULN)			al		ntion
							insuffi
							ciency
	(9)	1 1	4,0		-	0	1	0	0	10 yrs
	(10)	1 1	NR		-	ND	1	0	0	ND
	(11)	1 1	NR		-	1	1	0	0	2,25
	(12)	4 4	1.1;1.1; 2.4;	-	2	4	0	0	6,6
				3.0
	(13)	1 1	2.8		-	1	ND	0	0	0,7
	(14)	1 1	14.6		-	1	1	0	0	1,7
	(15)	7 6	1.2;1.4		6.6	3	6	0	0	4,4
				3.8;5.6;
				7.6;14.2
				(average
				5.6)
	(16)	1 1	5.7		-	0	1	0	0	7
	(18)	1 1	NR		-	0	1	0	0	2yrs
	(19)	1	12	4.7 (average	NR	2	12	0	0	5,75
		3		13 patients)
	(20)	1 1	NR		-	0	1	1 (3 yrs) 0	3 yrs
	(21)	1	15	1.4;1.5;1.6;	-	6	15	2	0	5
		5		1.7;1.7;1.9;				(7yrs,8y
				2.0;2.2;2.3;				rs)
				2.3;2.3;3.2;
				3.5;4.0;6.7
				(average
				2.5)
	(22)	8 7	1.5;1.5;2.1;	1.16	2	7	5(4,5yrs	0	7,9
				2.8;4.0;8.2;				)
				9.6
				(average

Table 2

 2 Studies on PBMAH patients with subclinical hypercortisolism treated by

	Unilateral Adrenalectomy
	Study n	Normali	Normalisation	Normalisatio	Improvement	Adrenal	recurrence death	Foll
			sation	1mg Dex	n ACTH levels	of metabolic parameters	insufficiency			ow
			of							up
			cortisol
			Circadia
			n rythm
	(28)	1	NR	1	1	HOMA	0	0	0	0.8
						HbA1c
	(29)	1	1	1	0		1	0	0	0.6
	(17)	1	NR	NR	0	HbA1c	0	1	0	5
	(30)	14	13/14	10/14	13/14	Hypertension	7/14		0	4.5
						4/7		0
						IGT 3/3
						Diabetes 1/1
						Dyslipidemia
						1/1
						Osteoporosis
						2/3
	(22)	3	NR	NR	NR	NR	NR	2/6	0	4.6


MD Thibaut Girardot

MD Antoine Schneider

MD Thomas Rimmelé
email: thomas.rimmele@chu-lyon.fr

Blood purification techniques for sepsis and septic AKI

Keywords: Acute Kidney Injury, Adsorption, Blood purification, Hemoperfusion, Renal Replacement Therapy, Sepsis

Sepsis is the primary cause of AKI in critically ill patients. During the last decades, several extracorporeal blood purification techniques have been developed for sepsis and sepsis-induced AKI management. These therapies could act on both the infectious agent itself and the host immune response. In this manuscript, we review the available literature discussing the different extracorporeal blood purification techniques, including high volume hemofiltration, cascade hemofiltration, hemoperfusion, coupled plasma filtration adsorption, plasma exchange and specific optimized renal replacement therapy membranes.

Introduction

Septic shock represents approximatively 15% of ICU admissions and its incidence is increasing [START_REF] Quenot | The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study[END_REF]. It is the leading cause of death in the ICU [START_REF] Bossi | Diagnosis of sepsis, severe sepsis and septic shock][END_REF]. Despite recent advances in intensive care and the release of international recommendations, mortality related to sepsis is still very high, reaching 40% at day 28 in case of septic shock [START_REF] Quenot | The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study[END_REF][START_REF] Rhodes | Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016[END_REF].

Septic shock management combines symptomatic support of organ dysfunctions, early and adapted antimicrobial therapy, and source control whenever possible. Severe inflammatory conditionssuch as septic shockare characterized by marked immune alterations. The host systemic inflammatory response to sepsis, although necessary, can become deleterious if excessive or unbalanced. The new definition of sepsis, a dysregulated host response to an infectious process, is in line with this concept [START_REF] Singer | The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[END_REF]. Intense anti-inflammatory cytokinesnamely IL-10production [START_REF] Kasten | Neutrophils are significant producers of IL-10 during sepsis[END_REF], endotoxin tolerance, i.e. incapacity to produce TNF-α after a new exposure to endotoxin [START_REF] Astiz | Monocyte response to bacterial toxins, expression of cell surface receptors, and release of anti-inflammatory cytokines during sepsis[END_REF], and finally immunoparalysis due to prolonged release of inflammatory mediators, are some examples of these immune alterations [START_REF] Hotchkiss | Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy[END_REF]. Most sepsis-induced deaths occur during this secondary phase of immune incompetence, mainly due to healthcare-associated infections or viral reactivations [START_REF] Venet | Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies[END_REF].

Adjuvant therapies have been developed in order to modulate the complex immunoinflammatory process triggered by sepsis. Hydrocortisone effect on survival to septic shock is still debated [START_REF] Venkatesh | Adjunctive Glucocorticoid Therapy in Patients with Septic Shock[END_REF][START_REF] Annane | Hydrocortisone plus Fludrocortisone for Adults with Septic Shock[END_REF]. The most promising molecules to date seem to be rhIL-7 and GM-CSF [START_REF] Venet | Management of Sepsis-Induced Immunosuppression[END_REF][START_REF] Shindo | Interleukin 7 immunotherapy improves host immunity and survival in a two-hit model of Pseudomonas aeruginosa pneumonia[END_REF][START_REF] Francois | Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial[END_REF][START_REF] Shindo | Interleukin-7 and antiprogrammed cell death 1 antibody have differing effects to reverse sepsis-induced immunosuppression[END_REF]. These therapies could limit sepsis-induced immunoparalysis, thus avoiding secondary infectious complications, which are responsible for an important part of sepsis-associated mortality [START_REF] Venet | Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies[END_REF][START_REF] Hotchkiss | Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach[END_REF]. Thanks to technological advances on membranes and extracorporeal circuits, some therapies have also been developed to induce a non-specific modulation of the uncontrolled immuno-inflammatory process observed during septic shock. Some have been well studied yet, others are currently under investigation. These techniques rely on the concept of "blood purification" [START_REF] Rimmelé | Clinical review: blood purification for sepsis[END_REF]. They could interfere with pro and anti-inflammatory mediators, with the infectious agent itself or with its components, or both [START_REF] Lukaszewicz | Purification methods: a way to treat severe acute inflammation related to sepsis?[END_REF][START_REF] Ronco | Endotoxin removal: history of a mission[END_REF]. The aim of this review is to present the pathophysiological theories underlying the blood purification concept and to discuss the available literature assessing these therapies.

Extracorporeal blood purification techniques: rationale

Several theories have been proposed to explain the potential positive effects of blood purification techniques. First, Ronco et al. proposed the "cytokine peak hypothesis": blood purification lowers pro-and anti-inflammatory molecules' plasmatic concentrations during early sepsis, avoiding a "toxic threshold" and thus limiting organ dysfunctions (19) (Figure 1). Blood purification could also involve the pathogen agent itself, or one of its components such as the endotoxin [START_REF] Ronco | Endotoxin removal: history of a mission[END_REF]. Indeed, infusion of ultrafiltrate obtained from infected animals to healthy ones led to death, suggesting the transmission of either the infectious agent itself or some cytokines that induced fatal organ dysfunctions [START_REF] Lee | Continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine[END_REF]. Later, Honoré et al. suggested that cytokine removal from the blood compartment would mobilize cytokines from the tissues via concentrations equalization. Cytokine removal from tissues could limit their local deleterious effects. This theory was named the "threshold immunomodulation hypothesis" [START_REF] Honoré | Extracorporeal removal for sepsis: Acting at the tissue level--the beginning of a new era for this treatment modality in septic shock[END_REF]. More recently, the "cytokinetic model" proposes that lowering cytokines blood concentration would restore an appropriate cytokine gradient between blood and infected tissues, thus promoting leucocyte chemotaxis (16) (Figure 2). Lastly, a "cellular" theory suggested that complex interactions could occur between the adsorbing material or the hemofilter and immune cells. For example, expression of surface molecules, involved in leukocyte adhesion and migration, antigen presentation, and apoptosis, may be modulated by various blood purification techniques [START_REF] Peng | Blood purification in sepsis: a new paradigm[END_REF][START_REF] Rimmelé | Leukocyte capture and modulation of cell-mediated immunity during human sepsis: an ex vivo study[END_REF][START_REF] Srisawat | The effect of polymyxin B hemoperfusion on modulation of human leukocyte antigen DR in severe sepsis patients[END_REF]. Some immune cells (namely monocytes and neutrophils) can also be adsorbed on the blood purification device, thus participating in the immune modulation [START_REF] Ma | Granulocyte and monocyte adsorptive apheresis ameliorates sepsis in rats[END_REF].

Hence, blood purification mechanisms of action are not completely understood yet, justifying further experimental research. Moreover, optimal initiation timing and duration of extracorporeal blood purification for septic shock are not determined to date. Recent advances in ICU patients' immune monitoring will probably help to answer those questions within the next decade. The best biomarker(s) to describe sepsis-associated immune alterations, to choose a therapeutic strategy and monitor its efficacy are still unknown [START_REF] Rouget | Biological markers of injury-induced immunosuppression[END_REF]. Our team recently conducted the REALISM study with the goal to help answering these questions, not only during sepsis but also in case of other severe inflammatory states such as severe trauma, burns, and major surgeries [START_REF] Rol | REALISM study group. The REAnimation Low Immune Status Markers (REALISM) project: a protocol for broad characterisation and follow-up of injury-induced immunosuppression in intensive care unit (ICU) critically ill patients[END_REF]. Results will be available in the upcoming years.

Available extracorporeal blood purification techniques

High volume hemofiltration

High volume hemofiltration (HVHF) is a modification of continuous renal replacement therapy (RRT), in hemofiltration mode. In HVHF, ultrafiltration flow is set to a much higher value (i.e. > 50 mL.kg -1 .h -1 ) than that recommended for standard renal support for AKI [START_REF] Rimmelé | High-volume hemofiltration in the intensive care unit: a blood purification therapy[END_REF]. High ultrafiltration flow enhances middle molecular weight (500 Da to 60 kDa) hydrophilic molecules clearance [START_REF] Kellum | Diffusive vs. convective therapy: effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome[END_REF].

The first encouraging results were obtained in the 1990's when studying cardiac function of septic pigs [START_REF] Grootendorst | High volume hemofiltration improves right ventricular function in endotoxin-induced shock in the pig[END_REF]. Later, in an experimental porcine model of acute pancreatitis complicated with sepsis, HVHF improved hemodynamic parameters, 60-hour survival, and immunoparalysis.

The magnitude of these beneficial effects correlated with higher ultrafiltration flows and frequent hemofilter changes [START_REF] Yekebas | Attenuation of sepsis-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis[END_REF][START_REF] Wang | Amelioration of hemodynamics and oxygen metabolism by continuous venovenous hemofiltration in experimental porcine pancreatitis[END_REF].

In humans, numerous studies have demonstrated hemodynamic [START_REF] Cole | High-volume haemofiltration in human septic shock[END_REF][START_REF] Boussekey | A pilot randomized study comparing high and low volume hemofiltration on vasopressor use in septic shock[END_REF] and respiratory [START_REF] Tapia | Effectiveness of short-term 6-hour high-volume hemofiltration during refractory severe septic shock[END_REF] improvement, as well as a lower than expected mortality [START_REF] Tapia | Effectiveness of short-term 6-hour high-volume hemofiltration during refractory severe septic shock[END_REF][START_REF] Honore | Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock[END_REF][START_REF] Rapaport | Impact of high volume hemofiltration on hemodynamic disturbance and outcome during septic shock[END_REF][START_REF] Ratanarat | Pulse highvolume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival[END_REF]. However, the IVOIRE trial ("hIgh VOlume in Intensive care"), a randomized controlled trial, comparing ultrafiltration flow rates of 35 and 70 mL.kg -1 .h -1 during a 96-hour period in 140 early septic shock patients with AKI, did not show any difference on mortality at day 28, 60, or 90. HVHF also failed to improve secondary outcomes (ventilator-, RRT-, and vasopressors-free days, length of stay, hemodynamic and standard biologic parameters, severity scores evolution) [START_REF] Honoré | High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial[END_REF]. A recent metaanalysis did not report any 28-day survival benefit of HVHF compared with conventional CVVH (continuous veno-venous hemofiltration) in septic AKI [START_REF] Clark | High-volume hemofiltration for septic acute kidney injury: a systematic review and meta-analysis[END_REF]. The Cochrane collaboration metaanalysis on this subject was recently updated. It did not conclude in any beneficial effect of HVHF during sepsis, compared to usual renal support techniques [START_REF] Borthwick | Highvolume haemofiltration for sepsis in adults[END_REF].

It is also worth noting important HVHF drawbacks. Of those, removal of little molecular weight molecules must be taken into account (nutrients, vitamins, trace elements, medications like antibiotics). Treatment cost and nursing workload are increased, due to the frequent change of substitution fluid containers [START_REF] Srisawat | Cost of acute renal replacement therapy in the intensive care unit: results from The Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) study[END_REF].

Cascade hemofiltration

Cascade hemofiltration has been proposed to avoid these limitations while conserving theoretical HVHF advantagesnamely high clearance of middle weight molecules [START_REF] Rimmelé | Hemofiltration with the Cascade system in an experimental porcine model of septic shock[END_REF]. The primary idea is to selectively remove middle molecules, while retaining little ones (trace elements, vitamins, medications) by combining two hemofilters with distinct cut-offs. The first hemofilter, with a relatively high cut-off, generates a first ultrafiltrate containing low and middle weight molecules and directs it towards a second filter. This latter is characterized by a much lower cut-off. Only middle molecules will then be cleared in the final effluent, while little ones will be re-injected as a pre-dilution before the first hemofilter, to be finally infused back to the patient. Infused volumes are much lower than those required for HVHF [START_REF] Rimmelé | Cascade hemofiltration: principle, first experimental data[END_REF].

Cascade hemofiltration lowered epinephrine requirements in a porcine septic shock model [START_REF] Rimmelé | Cascade hemofiltration: principle, first experimental data[END_REF]. In humans however, a recent study comparing adjunction of cascade HVHF to standard care in 60 septic shock patients did not show any beneficial effect, neither inflammatory mediators nor on clinical endpoints, except the number of RRT-free days [START_REF] Quenot | Very high volume hemofiltration with the Cascade system in septic shock patients[END_REF].

Hemoperfusion

Hemoperfusion is a technique in which patient's blood is in contact with adsorbing materials. Some molecules can therefore adhere to such materials, thanks to van der Waals, electrostatic, and/or hydrophobic interactions [START_REF] Winchester | Sorbents in acute renal failure and the systemic inflammatory response syndrome[END_REF]. Removal of high molecular weight molecules is then allowed, with no particular cut-off consideration. Biocompatibility issues with these adsorbing materials have been resolved. Importantly, hemoperfusion is notbut can be added to a renal replacement therapy technique.

Polymyxin B

Polymyxin B (Toraymyxin ® , Toray industries, Tokyo, Japan) is the most commonly used adsorbing material worldwide, particularly in Japan where it is routinely provided to patients with Gram negative bacilli (GNB)-induced severe septic conditions. Indeed, this therapy targets bacterial endotoxin, which largely triggers inflammation in septic shock. Interestingly, blood purification techniques' beneficial effects, suggested by a recent meta-analysis, were primarily due to results from Japanese cohorts assessing polymyxin B hemoperfusion [START_REF] Zhou | Blood purification and mortality in sepsis: a metaanalysis of randomized trials[END_REF]. Several retrospective Japanese cohorts triggered conflicting results on mortality [START_REF] Iwagami | Postoperative polymyxin B hemoperfusion and mortality in patients with abdominal septic shock: a propensity-matched analysis[END_REF][START_REF] Lee | Behalf of the NTUH Center of Microcirculation Medical Research (NCMMR). Effects of polymyxin B hemoperfusion on hemodynamics and prognosis in septic shock patients[END_REF][START_REF] Saito | Efficacy of polymyxin Bimmobilized fiber hemoperfusion for patients with septic shock caused by Gram-negative bacillus infection[END_REF]. Two other propensity-matched cohorts were recently published. The first one, conducted on nearly 2000 septic shock patients requiring renal replacement therapy, concluded in a 6% absolute mortality lowering [START_REF] Iwagami | Potential Survival Benefit of Polymyxin B Hemoperfusion in Septic Shock Patients on Continuous Renal Replacement Therapy: A Propensity-Matched Analysis[END_REF]. The second one confirmed this positive result, with an 8% absolute hospital mortality decrease among 500 septic shock Japanese patients [START_REF] Nakamura | Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study group. Potential survival benefit of polymyxin B hemoperfusion in patients with septic shock: a propensity-matched cohort study[END_REF]. The analysis of a registry recording data from septic shock patients treated with polymyxin B hemoadsorption in Asia (n=60) and in Europe (n=297) showed an improvement in SOFA score after polymyxin B hemoperfusion, although there was no control group in this cohort [START_REF] Cutuli | Polymyxin-B hemoperfusion in septic patients: analysis of a multicenter registry[END_REF].

Considering randomized controlled trials, the EUPHAS ("Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis") study, enrolling patients with abdominal severe sepsis or septic shock, showed hemodynamic and respiratory enhancement. A positive effect on 28-day survival was also observed, although it was not the primary outcome [START_REF] Cruz | Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial[END_REF]. Polymyxin B hemoperfusion was also evaluated in peritonitis-induced early septic shock in the ABDOMIX trial ("effects of hemoperfusion with a polymyxin B membrane in peritonitis with septic shock").

Approximatively 140 patients were randomized to receive either standard care or standard care plus two hemoperfusion sessions (> 90 minutes with a 24-hour interval between sessions). The intervention was not associated with different SOFA score evolution. However, it was associated with a trend towards higher mortality (34 vs. 24%, p=0.11) [START_REF] Payen | Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial[END_REF]. Cytokines plasmatic concentrations were not different between groups after the second hemoperfusion session, even when restricting analysis to patients with GNB-proven peritonitis [START_REF] Coudroy | Modulation by Polymyxin-B Hemoperfusion of Inflammatory Response Related to Severe Peritonitis[END_REF]. Finally, the EUPHRATES ("safety and efficacy of polymyxin B hemoperfusion for septic shock") trial was a double blinded (sham circuit in the control group) randomized controlled trial, conducted in North America. It this study, 450 septic shock patients with a demonstrated elevated plasma endotoxin level (EAA>0.6) were randomized to either standard of care or standard of care plus hemoperfusion (two sessions of 90 to 120 minutes within 24 hours). In this trial, day 28 mortality was not different between groups, including in a per-protocol analysis of the subgroup of patients with a high organ dysfunction score and who did effectively receive the two polymyxin hemoperfusion sessions (n=244) [START_REF] Dellinger | Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial[END_REF]. However, an exploratory post-hoc analysis suggested a beneficial effect on hemodynamic parameters, ventilator-free days, and survival, in the subgroup of patients with an EAA between 0.6 and 0.9 (n=194) [START_REF] Klein | Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial[END_REF].

To sum up with polymyxin B hemoperfusion, it seems that its potential beneficial effect on survival can be observed only when the control group mortality is higher than 30-40% [START_REF] Chang | Effects of Polymyxin B Hemoperfusion on Mortality in Patients With Severe Sepsis and Septic Shock: A Systemic Review, Meta-Analysis Update, and Disease Severity Subgroup Meta-Analysis[END_REF].

However the level of evidence for the effect of polymyxin B hemoperfusion on mortality remains quite low. Future research should focus on patients with very high expected mortality and/or EAA between 0.6-0.9. Lastly, considering the numerous positive results obtained in Japan, one could also hypothesize that patient's genetic and enzymatic profile could play a role in patient's response to this therapy.

CytoSorb

®

Other adsorbing materials are available such as divinylbenzene (CytoSorb ®, CytoSorbents Corp., Monmouth Junction, NJ, USA). CytoSorb ® is designed and marketed to remove pro-and anti-inflammatory cytokines from the blood. An ex vivo study demonstrated that this adsorbing cartridge can remove activated leucocytes and monocytes from blood and modulate cytokine (TNF-α, IL-8) expression [START_REF] Rimmelé | Leukocyte capture and modulation of cell-mediated immunity during human sepsis: an ex vivo study[END_REF]. This cartridge also lowers plasma concentrations of several DAMPs and PAMPs (Damage or Pathogen Associated Molecular Patterns), as well as mycotoxins, in an in vitro model of bovine blood added with inflammatory mediators [START_REF] Gruda | Broad adsorption of sepsis-related PAMP and DAMP molecules, mycotoxins, and cytokines from whole blood using CytoSorb® sorbent porous polymer beads[END_REF]. In another in vitro study with human blood, CytoSorb ® efficiently removed numerous pro and antiinflammatory cytokines, complement factors, serine protease, and growth factors, with removal rates higher than 90-95% for almost all these molecules at 120 minutes. Importantly, endotoxin is not removed by CytoSorb ® (61).

In a murine septic shock model, treatment with CytoSorb ® lowered IL-6 and IL-10 but also mortality [START_REF] Peng | Effects of hemoadsorption on cytokine removal and shortterm survival in septic rats[END_REF]. In humans, evidence is scarce. Almost all publications are case reports or case series [START_REF] Houschyar | Continuous hemoadsorption with a cytokine adsorber during sepsis -a review of the literature[END_REF]. A prospective case-control trial took place recently in Hungary, but results are not available yet (NCT 02288975). In a randomized controlled trial comparing standard care and adjunction of hemoperfusion with CytoSorb ® (6-hour sessions during 7 consecutive days) in septic shock patients with respiratory failure, hemoperfusion with Cytosorb ® was not associated with a decrease in IL-6 plasma levels (primary endpoint). The intervention was associated with a modest cross-adsorber IL-6 clearance [START_REF] Schädler | The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: A randomized controlled trial[END_REF]. Intermittent and short sessions of hemoperfusion were used, and IL-6 levels were quite low for septic shock patients, potentially explaining these results.

To date, the level of evidence supporting the use of CytoSorb ® in septic shock remains low.

However, further studies are required to establish its safety and efficacy in patients with very high inflammatory response. Indeed, CytoSorb ® can also be used in other conditions generating inflammation, such as severe burns or cardio-pulmonary bypass. It also removes many drugs and medications, and myoglobin, bilirubin, and bile acids [START_REF] Poli | Hemoadsorption with CytoSorb®[END_REF].

Plasma exchange

Techniques derived from plasmapheresis have also been evaluated in septic shock. Only a limited number of studies are available, with interesting results especially in GNB-induced sepsis. Early initiation seems to be associated with better efficacy [START_REF] Hjorth | Plasmapheresis as part of the treatment for septic shock[END_REF]. A randomized trial first suggested a decrease in early sepsis inflammatory markers and a trend towards less organ dysfunctions in plasmapheresis-treated patients [START_REF] Reeves | Continuous plasmafiltration in sepsis syndrome. Plasmafiltration in Sepsis Study Group[END_REF]. Another trial involving 100 severe sepsis or septic shock patients even suggested a survival benefit when plasma exchange was added to conventional care [START_REF] Busund | Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial[END_REF]. This study however presents several limitations. Groups were not strictly comparable before treatment, with patients older and more likely to have respiratory failure in the control group. Moreover, this positive result was mainly driven by the subgroup of patients with intra-abdominal sepsis. In other types of infection, plasmapheresis did not appear to confer any advantage over standard care. In children, another study, although underpowered, did not show any beneficial effect of plasma filtration [START_REF] Long | A randomised controlled trial of plasma filtration in severe paediatric sepsis[END_REF]. A meta-analysis focusing on adult septic shock patients concluded that plasma exchange could be beneficial on survival, but the methodological quality of included studiesconducted 20 years agois questionable [START_REF] Rimmer | The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis[END_REF]. A recent pilot (n=20) non randomized trial demonstrated a rapid reduction of vasopressors requirements and plasmatic cytokine lowering, along with reduction of endothelial hyperpermeability, after plasma exchange during early septic shock [START_REF] Knaup | Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers[END_REF]. However, the level of evidence of such trials cannot support the routine use of this technique to date in sepsis.

Coupled plasma filtration and adsorption (CPFA)

CPFA is an extracorporeal therapy in which plasma is separated from blood at the beginning of the extracorporeal circuit, then runs slowly through an adsorbing cartridge. The slow plasma flow enables a prolonged contact time with the adsorbing material, thus optimizing molecules adhesion. "Purified" plasma is then returned to the main circuit. Blood then undergoes conventional hemofiltration, allowing for kidney support in addition to blood purification for sepsis (Figure 3). CPFA has shown similar positive results than HVHF on hemodynamics [START_REF] Ronco | A pilot study of coupled plasma filtration with adsorption in septic shock[END_REF][START_REF] Formica | Hemodynamic response to coupled plasmafiltration-adsorption in human septic shock[END_REF] and immune function modulation, reflected for instance by monocyte HLA-DR expression [START_REF] Mao | Effects of coupled plasma filtration adsorption on immune function of patients with multiple organ dysfunction syndrome[END_REF]. In the COMPACT-1 randomized trial, patients who received the highest "dose" of CPFA seemed to benefit from this therapy on the mortality criterion, compared to controls [START_REF] Livigni | Gruppo Italiano per la Valutazione degli Interventi in Terapia Intensiva (Italian Group for the Evaluation of Interventions in Intensive Care Medicine) is an independent collaboration network of Italian Intensive Care units. Efficacy of coupled plasma filtration adsorption (CPFA) in patients with septic shock: A multicenter randomised controlled clinical trial[END_REF]. Therefore, the COMPACT-2 trial (NCT 01639664) evaluated the effect of high doses of CPFA in septic shock.

This study was stopped prematurely, as CPFA was associated with an increase in early mortality compared to the control group. Before publication of the final results, the manufacturer released a safety report recommending not to use CPFA in septic shock. Definitive results should be available soon.

Hemofiltration with highly adsorbing membranes

The potential synergistic effect of the various blood purification techniques may represent an interesting strategy [START_REF] Honore | Are the synergistic effects of high-volume haemofiltration and enhanced adsorption the missing key in sepsis modulation?[END_REF]. Several associations have been tested ex vivo or in animal models [START_REF] Uchino | Super high flux hemofiltration: a new technique for cytokine removal[END_REF]. For example, a standard polyacrilonytrile hemofiltration membrane was modified with the adjunction of a positively-charged polyethyleneimine polymer (oXiris ® ), to enhance its endotoxin and cytokines adsorption capacities (Figure 4). The oXiris ® membrane was compared to a standard hemofiltration membrane in a porcine model of septic shock. After 6 hours of HVHF, volume of fluids infused was reduced, as well as hyperlactatemic acidosis, in the oXiris ® group [START_REF] Rimmelé | High-volume haemofiltration with a new haemofiltration membrane having enhanced adsorption properties in septic pigs[END_REF]. An industry-sponsored in vitro study showed that the oXiris ® membrane present similar endotoxin adsorption properties than polymyxin B, while CytoSorb ® does not adsorb endotoxin.

Regarding pro and anti-inflammatory cytokines, removal rates were similar with oXiris ® and CytoSorb ® (> 90% at 120 min for most cytokines studied), while polymyxin B was less efficient [START_REF] Malard | In vitro comparison of the adsorption of inflammatory mediators by blood purification devices[END_REF]. Moreover, oXiris ® is a continuous renal replacement therapy membrane, while neither CytoSorb ® nor polymyxin B are. However, clinical evidence remains scarce and often limited to case series. One of them compared 6 patients with sepsis-induced AKI treated with oXiris ® to 24 historical severity-matched controls, and concluded that the SOFA score was reduced after 48h in the oXiris ® group [START_REF] Shum | Application of endotoxin and cytokine adsorption haemofilter in septic acute kidney injury due to Gram-negative bacterial infection[END_REF]. We recently launched the multicenter randomized controlled trial ECRO (Endotoxin and Cytokines Removal during continuous hemofiltration with oXiris ® ), comparing a standard membrane and the oXiris ® filter in peritonitis-induced septic shock with indication for renal replacement therapy (NCT 03426943). A comparable Swedish study was recently completed in GNB-documented or suspected septic shock, but results have not been published yet (NCT 02600312). Other highly adsorbing membranes are commercialized, for example AN69 ST ® [START_REF] Shiga | Continuous hemodiafiltration with a cytokine-adsorbing hemofilter in patients with septic shock: a preliminary report[END_REF] or polymethylmetacrylate membranes [START_REF] Honore | Newly designed CRRT membranes for sepsis and SIRS--a pragmatic approach for bedside intensivists summarizing the more recent advances: a systematic structured review[END_REF], for which thrombogenicity issues seem to be solved [START_REF] Oshihara | A New Poly(Methyl Methacrylate) Membrane Dialyzer, NF, with Adsorptive and Antithrombotic Properties[END_REF].

High cut-off membranes

To enlarge the spectrum of middle molecular weight molecules removal, the membrane cut-off can be increased. These filters, first used with hemofiltration techniques, were associated with hemodynamic improvement in experimental [START_REF] Lee | Continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine[END_REF] and human sepsis [START_REF] Morgera | Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure[END_REF]. The major drawback was the massive albumin leakage into the effluent, which could rise up to 15 g in 4 hours [START_REF] Morgera | Intermittent high permeability hemofiltration in septic patients with acute renal failure[END_REF].

Nevertheless, when used with diffusive rather than convective modalities, albumin loss is clearly and logically reduced [START_REF] Haase | Hemodialysis membrane with a high-molecular-weight cutoff and cytokine levels in sepsis complicated by acute renal failure: a phase 1 randomized trial[END_REF]. Cut-off and other membrane parameters optimization (for example surface or pore size homogeneity) represent another solution to such difficulties [START_REF] Honore | Newly designed CRRT membranes for sepsis and SIRS--a pragmatic approach for bedside intensivists summarizing the more recent advances: a systematic structured review[END_REF].

Such "modified HCO membranes" display similar properties, but their slightly lower cut-off limits albumin loss while still removing inflammatory mediators [START_REF] Haase | Hemodialysis membrane with a high-molecular-weight cutoff and cytokine levels in sepsis complicated by acute renal failure: a phase 1 randomized trial[END_REF][START_REF] Naka | Super high-flux" or "high cut-off" hemofiltration and hemodialysis[END_REF].

HCO membranes have shown promising properties on inflammation mediators removal, although the level of evidence is still low. When assessing the single-pass effect and compared to standard-CVVH, HCO-CVVH resulted in lowering one of the apoptosis indices in a pilot study of AKI patients [START_REF] Atan | High cut-off hemofiltration versus standard hemofiltration: a pilot assessment of effects on indices of apoptosis[END_REF]. On the opposite, it did not modify nucleosome concentration of levels of TLR2 and TLR4 expression [START_REF] Atan | Nucleosome levels and toll-like receptor expression during high cut-off haemofiltration: a pilot assessment[END_REF]. Sieving coefficients of many cytokines were higher with HCO-CVVH than with standard-CVVH, but this did not result in lower plasma cytokine concentration [START_REF] Atan | High cut-off hemofiltration versus standard hemofiltration: effect on plasma cytokines[END_REF]. In a retrospective analysis of 28 septic shock patients treated with HCO-CVVHD (with no control group), effective removal of IFN-α, IL-1β, IL-2, IL-6, IL-10 and IL-12 was observed [START_REF] Kade | Effectiveness of High Cut-Off Hemofilters in the Removal of Selected Cytokines in Patients During Septic Shock Accompanied by Acute Kidney Injury-Preliminary Study[END_REF]. In a prospective observational cohort of 38 patients with septic shock-associated AKI treated with HCO-CVVHD, a significant reduction in circulating IL-6 and TNF-α levels was observed [START_REF] Villa | Organ dysfunction during continuous veno-venous high cut-off hemodialysis in patients with septic acute kidney injury: A prospective observational study[END_REF]. One retrospective study focused on clinical outcome. HCO-CVVHD was compared to high flux-CVVHDF in 16 vs 8 septic patients with AKI. In the HCO group, ICU length of stay and mortality were reduced, but hospital-mortality was not different between groups (92).

Conclusion

Will extracorporeal blood purification be someday part of standard sepsis management? Data published so far from animal and human studies are too conflicting to firmly answer this question (Table 1). Although hemodynamic and respiratory improvements, along with inflammation mediators removal, have been observed when using such techniques, a clear clinical positive effect on patient survival has not been proven yet. While some blood purification techniques did not show any clear benefit in randomized controlled trials, membrane optimization (highly adsorptive, high cut-off) seems to be a promising field for future development and research. Patients' selection based on biomarkers like endotoxin levels could also allow to identify those patients who will benefit from such therapies.

Figure 1 :

 1 Figure 1: Cytokine peaks model hypothesis

Figure 2 :Figure 3 :

 23 Figure 2: Cytokinetic model hypothesis

Figure 4 :

 4 Figure 4: oXiris ® membrane layers

Table 1 .

 1 Major publications for each blood purification technique.

	Technique	Animal studies	Human non-RCTs	Human RCTs
	HVHF	Yekebas et al., Crit Care Med	Tapia et al., J Trauma Acute Care	Joannes-Boyau et al., Intensive
		2001	Surg 2012	Care Med 2013, "IVOIRE"
		 mortality,	Respiratory improvement, mortality	No difference on mortality
		 immunosuppression	lower than expected	No difference on ventilator-, RRT-,
				and vasopressors-free days, length
				of stay, hemodynamic and standard
				biologic parameters, severity
				scores evolution
	Cascade	Rimmelé et al., Ann Fr Anesth	NA	Quenot et al., Intensive Care
		Réanim 2009		Med 2015
		 epinephrine requirements		No difference on mortality
				No difference on vasopressors-or
				ventilator-free days
				More RRT-free days
	Hemoperfusion	Iba et al., J Surg Res 2011
	with polymyxin B	 organ damage,  pro-
		inflammatory cytokines, 
		mortality

Mitaka et al., J Surg Res 2016 Hemodynamic

  and acid-base balance maintained,  lactate,  creatinine,  IL-6 and IL-10

Iwagami et al., Blood Purif 2016  6% absolute mortality Nakamura et al., Crit Care 2017  8% absolute hospital mortality Payen et al., Intensive Care Med 2015, "ABDO-MIX"

	No difference on mortality
	No difference on SOFA evolution
	or cytokines concentration
	Dellinger et al., JAMA 2018,
	"EUPHRATES"
	No difference on mortality
	Post-hoc analysis : 
	hemodynamic parameters,
	ventilator-free days, and 
	survival, in patients with EAA 0.6-
	0.9
	Hemoperfusion
	with CytoSorb ®

Gruda et al., PloSOne 2018  DAMPs and PAMPs Malard et al., Intensive Care Med Exp 2018 Schädler et al., PloSOne 2017

  No decrease in plasmatic IL-6 level

			Removal rates > 90-95% for	Modest cross-adsorber IL-6
		Peng et al., Crit Care Med 2008	numerous pro and anti-inflammatory	clearance
		 IL-6 and IL-10	cytokines, complement factors, serine
		 mortality	protease, and growth factors
	Plasma exchange	Toft et al., Blood Purif 2008	Hjorth & Stenlund, Scand J Infect	Reeves et al., Crit Care Med
		Temporary  activated cell-	Dis 2000	1999
		mediated immunity	Mortality < expected by APACHE	 early sepsis inflammatory
				markers, trend towards less organ
		Natanson et al., Transfusion	Knaup et al., Crit Care 2018	dysfunctions
		1993	 vasopressors requirement, 
		 survival, worsened	plasma cytokines,  endothelial
		hemodynamics	permeability
				"COMPACT-2" (not published
				yet)
				 early mortality (72 hours)
	Highly-adsorptive	Rimmelé et al., Nephrol Dial
	membranes	Tranplant 2009
		 fluids requirements,
		 hyperlactatemic acidosis

Busund et al., Intensive Care Med 2002  mortality (result very discussed CPFA Tetta et al., Crit Care Med 2000  mortality Sykora et al., Shock 2009 No beneficial effect Ronco et al., Crit Care Med 2002  vasopressors requirements  immunosuppression markers Livigni et al., BMJ Open 2014, "COMPACT-1"  mortality in patients receiving the higher "dose" of CPFA ?

Shum et al., Hong Kong Med J 2013  SOFA score NA High cut-off membranes Lee et al., Crit Care Med 1993 Hemodynamic improvement Villa et al., PloSOne 2017

   IL-6 and TNF-α

Chelazzi et al., Blood Purif 2016

   ICU length of stay,  ICU mortality NA

interest for this work. TR has received speaker and consulting honoraria from Fresenius Medical Care, Baxter Healthcare Corp, Biomérieux, Medtronic, Nikkiso and B. Braun. He is the principal investigator of the ECRO trial, comparing the effects of the oXiris ® membrane to a standard membrane on endotoxins and cytokines levels during peritonitis-induced septic shock (NCT 03426943). AS has received a grant from the Leenaards Foundation, speaker honoraria from Fresenius Medical Care, Baxter Healthcare Corp and consulting honoraria from B. Braun Melsungen AG. He is the principal investigator of the CCCC trial, a pilot trial evaluating the impact of CytoSorb ® during cardiac surgery (NCT02775123).