MD Alida Ainouche
email: alida.ainouche@gmail.com

Dr Carole Durot
email: cdurot@chu-reims.fr

Philippe Soyer
email: philippe.soyer@aphp.fr

Dr Sébastien Mulé
email: sebastien.mule@gmail.com

Christine Hoeffel

Unusual Intestinal and Extra Intestinal Findings in Crohn's Disease Seen on Abdominal Computed Tomography and Magnetic Resonance Enterography Pictorial Essay

Keywords: Crohn's disease, extra intestinal manifestations, intestinal manifestations, extra enteric complications

The magnetic resonance (MR) enterography technique has improved over the past few years to provide an excellent means of evaluating the gastrointestinal tract for suspected Crohn's disease. Although the prevalent intestinal manifestations of Crohn's disease have been extensively discussed in the radiology literature, some of its rare complications, especially extra intestinal, have received less attention. Uncommon findings that may be seen on MR enterography and abdominal CT examinations performed in patients with Crohn's disease include hepatic sinusoidal dilatation, primary sclerosing cholangitis, fistulas in unusual locations, hepatic and splenic abscesses, and spondylarthritis. Radiologists should be aware of these potentially rare manifestations. They should be kept in mind during clinical examinations and should be routinely searched for and reported if present.

BODY TEXT INTRODUCTION

Computed tomography (CT) and magnetic resonance enterography (MRE) are currently routinely performed in patients with suspected or known Crohn's disease (CD). Imaging features of the intestinal manifestations and usual complications of CD have been extensively described throughout the literature [START_REF] Bernstein | The Prevalence of Extraintestinal Diseases in Inflammatory Bowel Disease: A Population-Based Study[END_REF]. However, less frequent findings may be missed by the radiologist confronted with CT or MRE in a context of CD assessment. They include rare sites of involvement of the disease, unusual patterns of common complications, and extra intestinal findings. These manifestations have to be kept in mind and should be routinely searched for and reported if present. To this aim, we review and illustrate the unusual findings that may be seen on abdominopelvic CT or MR enterography (MRE) performed for the evaluation of patients with CD. These include unusual locations of the disease, manifestations of the disease, complications, associated extra intestinal findings, and potential incidental findings.

UNUSUAL SITES OF INVOLVEMENT

Although the ileum is the most common site of involvement in CD, other less common sites have been described, such as the stomach [START_REF] Zhi | Gastric Crohn's Disease: A Rare Cause of Intermittent Abdominal Pain and Vomiting[END_REF], duodenum (Fig. 1), the proximal small bowel, Meckel's diverticulum, and the appendix. Of note, in a recent study involving 1329 patients, 16.7% showed involvement of the proximal small bowel (3). The appendix is frequently involved with ileocolonic CD, with similar findings to those found in the small bowel. However, it rarely is the first presentation of CD. Appendiceal involvement may also be caused by contact inflammation in the setting of ileitis (Fig. 2). Interestingly, in a study of 76 patients with CD studied with CT enteroclysis (4), hyperenhancement of the appendiceal wall had a specificity of 100% for active CD versus inactive CD.

UNUSUAL TYPES OF COMPLICATIONS 1. ENTERIC COMPLICATIONS 1.1 Fistulas

Fistulas developing anywhere around the gastrointestinal tract may be diagnosed on CT or MR images. Some locations are particularly rare such as enterocutaneous, sigmoïdovaginal and enterovesicular fistulas. As stated in recent consensus recommendations for the utilization of CT and MRE in patients with CD, imaging of the entire anus should be obtained for every CT and MRE examination in order to evaluate the presence or absence of perianal disease. If perianal disease is present, or if clinically indicated, then a dedicated MR of the pelvis may be performed for more detail and precision by a dedicated MR pelvic examination.

Moreover, fistulas connecting bowel inflammatory segments to some part of the skeletal system may cause spondylodiscitis, osteomyelitis, and abscesses. Bone must be examined by bone windowing to find focal sclerosis along the femoral head. These fistulas may be indistinct and difficult to detect. They most frequently involve the sacrum and the ilium because of the proximity of these structures to the ileum (Fig. 3,4). Muscles may also be a site of involvement, more likely those of the anterior abdominal wall.

Cancer

Patients with longstanding CD have an increased risk of developing small bowel and anal adenocarcinoma [START_REF] Barral | Gastrointestinal cancers in inflammatory bowel disease: An update with emphasis on imaging findings[END_REF]. They present a diagnostic challenge, as the tumor is often indiscernible from the underlying inflammatory bowel disease (IBD). Loss of stratification of the bowel wall and asymmetric marked focal mural thickening are findings suggestive of malignancy in these patients. Small bowel adenocarcinomas most often occur in a specific region of chronic inflammation such as a fistula tract or in strictured segments (Fig. 5) [START_REF] Barral | Gastrointestinal cancers in inflammatory bowel disease: An update with emphasis on imaging findings[END_REF][START_REF] Cañete | Mucinous adenocarcinoma over an anorectal fistula in a patient with Crohn's diseases[END_REF]. Likewise, cancers may develop in longstanding anoperineal fistulas. They consist of either squamous cell carcinomas or mucinous adenocarcinomas. Longstanding fistulas thus have to be carefully assessed for any changes in size or shape. In cases of mucinous adenocarcinomas, the MRI findings are those of a hypersignal T2-weighted lobulated lesion with peripheral enhancement on gadolinium-enhanced fat suppressed T1-weighted MR images (6) (Fig. 6).

EXTRA ENTERIC COMPLICATIONS

Hepatobiliary

Most of the extra intestinal complications are hepatic, including drug-induced hepatitis, gallstones in part due to vitamin B12 deficiency, hepatic abscesses, and sepsis-related hepatic sinusoidal dilatation (Fig. 7). Fatty liver is the most common hepatobiliary complication of CD [START_REF] Restellini | Hepatic Manifestations of Inflammatory Bowel Diseases[END_REF], resulting from chronic malnutrition, protein loss, and corticosteroid therapy. Liver abscess is a rare but serious complication of CD (Fig. 8). Several risk factors for liver abscess and related conditions have been reported, such as intra abdominal abscesses or fistulas, steroid or metronidazole therapy, and cholangitis. Abscesses are mostly of bacterial origin, Streptococcus milleri being the most frequent [START_REF] Mir-Madjlessi | Liver Abscess in Crohn's Disease. Report of Four Cases and Review of the Literature[END_REF]. However, they may rarely be aseptic with negative microbiologic investigations and failure of antibiotic therapy. It has been suggested that aseptic abscesses could result from an immunoinflammatory process associated with CD due to the aberrant homing of gut T memory/effector lymphocytes in the liver. This hypothesis is supported by the effectiveness of immunosuppressive therapy [START_REF] Sakharpe | A Case and Review of Aseptic Liver Abscess in Crohn's Disease[END_REF]. Hepatic sinusoidal dilatation may be observed in CD as in any other acute extrahepatic disease associated with a marked systemic inflammatory syndrome (Fig. 7). CT and MRI then show a reticulated enhancement pattern of the liver, reversible with the resolution of the initial disease. This pattern is usually visible at both arterial and portal phases and disappears during the delayed phase [START_REF] Ronot | Acute Extrahepatic Infectious or Inflammatory Diseases Are a Cause of Transient Mosaic Pattern on CT and MR Imaging Related to Sinusoidal Dilatation of the Liver[END_REF]. The areas showing a fern-like pattern are hypoattenuated on unenhanced CT, hypointense on T1-weighted, and hyperintense on T2-weighted images. The associated clinical findings may include right upper quadrant abdominal pain, hepatomegaly, and minimal elevation of liver function tests. The main pathological finding is enlargement of the sinusoid lumen by more than one hepatic plate in width.

Drug-induced hepatitis may result from iatrogenic hepatotoxic effects of thiopurines, methotrexate, sulfasalazine, cyclosporine, infliximab, adalimumab, and certolizumab used for treatment of CD. Generally, non-specific imaging features of hepatitis can be found, such as hepatomegaly, peri-portal edema, hepatic steatosis, and gallbladder wall thickening. The association of these findings with elevated results of liver function tests should raise concern in CD patients. Iatrogenic complications such as nodular regenerative hyperplasia (NRH) have been described. Cases of NRH are mainly reported in patients receiving thiopurines for CD [START_REF] Seksik | Incidence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Azathioprine[END_REF]. Cholangiocarcinoma has been described as a CD-related primary sclerosing cholangitis (PSC) complication with a poor prognosis. [START_REF] Magro | Extra-Intestinal Malignancies in Inflammatory Bowel Disease: Results of the 3rd ECCO Pathogenesis Scientific Workshop (III)[END_REF][START_REF] Walker | Diagnosing Cholangiocarcinoma in Primary Sclerosing Cholangitis: An "Evidence Based Radiology[END_REF]. Imaging findings of PSC and cholangiocarcinoma may overlap, usually leading to delayed diagnosis of cholangiocarcinoma at an inoperable stage. However, persisting or progressing bile duct stricture, large nodular defects, capsular retraction, portal vein invasion, and mass-forming lesions with delayed enhancement may raise concern about malignant transformation of PSC.

Musculoskeletal

Rare musculoskeletal complications include drug-related avascular necrosis of the femoral head and chronic non-bacterial osteomyelitis, which may partly be explained by potential CD-related mutations in CARD 15, encoding the NOD2 protein [START_REF] Morbach | Association of Chronic Non-Bacterial Osteomyelitis with Crohn's Disease but Not with CARD15 Gene Variants[END_REF].

Urinary

The incidenceof urinary complications in patients with Crohn's disease has been reported to be 4%-23%, ranging from the most common simple cystitis to rarer advanced urinary sepsis [START_REF] Ben-Ami | Diagnosis and Treatment of Urinary Tract Complications in Crohn's Disease: An Experience over 15 Years[END_REF]. The most commonly encountered urinary disorders are urolithiasis and pyelonephritis. Renal stone formation may be partly explained by hypocitraturia and hypomagnesiuria, influencing crystal nucleation [START_REF] Viana | Crohn's disease and kidney stones: much more than coincidence?[END_REF]. Urolithiasis and pyelonephritis incidence ranges from 4% to 23% with a risk 10-100 times greater than the risk for the general population [START_REF] Gaspar | Urolithiasis and Crohn'sDisease[END_REF]. Hydronephrosis may result from nephrolithiasis as a manifestation of CD, as the two disorders are associated in up to 12% of cases. The composition of kidney stones is usually based on calcium oxalate (resulting from hyperabsorption of oxalate) or uric acid (due to increased bicarbonate losses). It may also result from acalculous ureteral inflammatory entrapment, compression or fibrosis as a complication of penetrating CD, preferably in longstanding diseases (18) (Fig. 9). Classic Crohn's disease granulomas may also very rarely develop in the kidney, causing granulomatous interstitial nephritis and mimicking hypervascular renal tumors in imaging [START_REF] Semjén | Renal Involvement in Crohn's Disease: Granulomatous Inflammation in the Form of Mass Lesion[END_REF].

Genital

Genital involvement mainly results as a complication of penetrating CD, either from anoperineal fistulizing disease or from colonic or enteric involvement. For instance, tuboovarian abscesses may occur and may be depicted on CT. To allow adequate analysis of genital complications, subsequent high-resolution perianal MRI with T2-weighted sequences and intravenous contrast is needed. [START_REF] Dwarkasing | Anovaginal Fistulas: Evaluation with Endoanal MR Imaging[END_REF].

Vascular

Patients with CD have an increased risk of thromboembolic events, particularly venous embolism. These thromboembolic complications may be explained by many factors, such as common histories of abdominal surgery, corticosteroid use, and increased concentration of clotting factors in severe disease [START_REF] Rothfuss | Extraintestinal Manifestations and Complications in Inflammatory Bowel Diseases[END_REF][START_REF] Violi | Prevalence and Clinical Importance of Mesenteric Venous Thrombosis in the Swiss Inflammatory Bowel Disease Cohort[END_REF]. The portal vein and its branches are the veins which are most affected by thrombosis. However, the superior or inferior mesenteric veins and the inferior vena cava may also be involved and detected on abdominopelvic CT or MRE (Fig. 10). Pulmonary embolism, which is a major cause of mortality in these patients, also has to be suspected. Thrombi in the mesenteric veins generally resolve without anticoagulation, but peripheral mesenteric venous thrombi frequently evolve into chronic peripheral mesenteric venous occlusion seen on follow-up imaging, with development of collateral pathways or small bowel varices [START_REF] Bruining | Consensus Recommendations for Evaluation, Interpretation, and Utilization of Computed Tomography and Magnetic Resonance Enterography in Patients With Small Bowel Crohn's Disease[END_REF].

Peritoneal inclusion cysts

In patients with Crohn's disease, women, almost exclusively premenopausal, may present with peritoneal inclusion cysts. These cyst develop as a result of adhesions and/or dysfunction of the peritoneum related to prior episodes of inflammation of prior surgeries

The fluid thus accumulates in the locules formed by the potential adhesions inside the peritoneum. Loculated fluid in the pelvis surrounding normal ovaries will be observed both by CT and MRE and should not be mistaken for pelvic cystic lesions, as it conforms to the peritoneal space.

UNUSUAL FINDINGS AND ASSOCIATED DISEASES

1. Hepatobiliary CD patients have an increased incidence of hepatobiliary findings, including PSC and its complications [START_REF] Olpin | Beyond the Bowel: Extraintestinal Manifestations of Inflammatory Bowel Disease[END_REF],granulomatous Crohns' hepatitis, and PSC-autoimmune hepatitis overlap syndrome. PSC is the most common hepatobiliary Crohn's-associated disease, characterized by progressive inflammation, obliterative fibrosis, and destruction of the bile ducts. PSC may be recognized on abdominopelvic CT or MRE when some segments of the biliary tree are dilated, but diagnosis is far easier when PSC is more advanced or even complicated with cirrhosis. PSC will be, of course, best evaluated using further complementary hepatic MRI and MR cholangiography which can show evidence of alternating stenoses and dilatations on the biliary intra or extrahepatic ducts. (Fig. 11). In IBD patients, the use of MRI increases the detection of PSC3-foldcompared to detection based on symptoms alone [START_REF] Lunder | Prevalence of Sclerosing Cholangitis Detected by Magnetic Resonance Cholangiography in Patients With Long-Term Inflammatory Bowel Disease[END_REF]. Indeed, only 10%-15% of patients exhibit symptoms at the time of diagnosis [START_REF] Tischendorf | Characterization, Outcome, and Prognosis in 273 Patients with Primary Sclerosing Cholangitis: A Single Center Study[END_REF].

When CT or MRI show features of PSC and autoimmune hepatitis in the same patient, the diagnosis of autoimmune hepatitis overlap syndrome can be suspected. The definitive diagnosis is based on the International Autoimmune Hepatitis Group Criteria, which includes histologic, demographic and biomarkers [START_REF] Rojas-Feria | Hepatobiliary Manifestations in Inflammatory Bowel Disease: The Gut, the Drugs and the Liver[END_REF]. Granulomatous Crohn's hepatitis is also a challenging unusual diagnosis in CD patients, often caused by medications (sulfasalazine), malignancies, infections, or CD metastasis (28).

Musculoskeletal

Pancreatitis

In CD patients, acute pancreatitis is usually idiopathic, with granulomatous inflammation of the pancreas being a hypothesis [START_REF] Antonini | Pancreatic Disorders in Inflammatory Bowel Disease[END_REF]. CD-associated pancreatitis frequently remains clinically silent and hyperamylasemia or exocrine pancreatic insufficiency may be the only manifestation of the disease. CT and MR imaging features of acute pancreatitis are non specific. In autoimmune pancreatitis, a "sausage-like" appearance of the pancreas and a low attenuation halo may be seen. The role of antibodies against exocrine pancreatic tissue (PABs) in the pathogenesis of autoimmune pancreatitis is still under discussion [START_REF] Barral | Gastrointestinal cancers in inflammatory bowel disease: An update with emphasis on imaging findings[END_REF]. Three other main causes of pancreatitis in CD are duodenal involvement as well as biliary and iatrogenic etiologies such as the use of azathioprine. However, pancreatitis is often overdiagnosed in these patients because of non specific elevation of serum lipase and recurrent abdominal pain [START_REF] Pitchumoni | Pancreatitis in Inflammatory Bowel Diseases[END_REF]. CD patients may also develop chronic pancreatitis. Intrapancreatic duct changes in patients with CD may partly explain the development of chronic pancreatitis, whose pathogenesis remains unclear [START_REF] Mendoza | Extraintestinal manifestations in inflammatory bowel disease: differences between Crohn's disease and ulcerative colitis][END_REF]. Classic signs of chronic pancreatitis may be seen on either CT or MRE images.

Miscellaneous disorders

Hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a recurrent inflammatory disease of the pilosebaceous follicle consisting of inflamed lesions of apocrine glands, usually of the anogenital, axillary, and inguinal regions (Fig. 12). HS is an unusual Crohn's-associated disease [START_REF] Principi | Hydradenitis Suppurativa and Inflammatory Bowel Disease: An Unusual, but Existing Association[END_REF]. HS-related anoperineal abnormalities may also be a differential diagnosis of CD-related anoperineal disorders. Indeed, when the disease is primarily perianal, the differential diagnosis can be challenging since the presentations may overlap. However, perianal disease in HS is characterized by the fact that the lesions are not predominant in the perianal area, unlike those observed in perineal involvement in CD. They are rather located in the anterior/inguinal and/or sacral/gluteal regions. HS-related anoperineal involvement is also characterized by bilaterality of the features. Moreover, the rectal wall is rarely thickened. [START_REF] Monnier | Anoperineal Disease in Hidradenitis Suppurativa : MR Imaging Distinction from Perianal Crohn's Disease[END_REF].

INCIDENTAL FINDINGS NOT RELATED TO CD

The prevalence of ankylosing spondylitis (AS) in CD (1%-6%) is higher than in the general population (0.25%-1%) [START_REF] Sheth | Management of Musculoskeletal Manifestations in Inflammatory Bowel Disease[END_REF]. Axial manifestations of AS frequently precede the diagnosis of CD by several years. Sacroileitis is the most obvious finding that may be depicted on CT or MRE, more often as an incidental finding showing long standing disease than acute inflammation (Fig. 12). CT features initially include joint space irregularity, followed by classic erosion, sclerosis, and eventually ankyloses. MRI allows early diagnosis of osteitis in acute sacroiliitis, seen as subchondral bone marrow edema on short tau inversion recovery (STIR)-weighted images. Subchondral sclerosis, periarticular erosions, synovitis, capsulitis, and enthesitis may also be described in CDassociated sacroiliitis. Some patients may present imaging features of sacroiliitis without AS criteria, called isolated sacroiliitis. Its reported prevalence is between 16% and 46% [START_REF] Olpin | Beyond the Bowel: Extraintestinal Manifestations of Inflammatory Bowel Disease[END_REF]. Spondylitis may also be seen on MRE, including Romanus lesions, bone marrow edema called shiny corners, and post inflammatory fatty bone marrow degeneration in a chronic phase. Other musculoskeletal manifestations have been reported in the literature, such as inflammatory bowel disease-related arthropathy, osteoporosis, osteomalacia, hypertrophic osteoarthropathy, and osteonecrosis [START_REF] Olpin | Beyond the Bowel: Extraintestinal Manifestations of Inflammatory Bowel Disease[END_REF].

The radiologist must not forget to look for incidental findings. However, the most common fortuitous findings discovered on MRE are simple liver or renal cysts [START_REF] Jensen | Incidental Findings at MRI-Enterography in Patients with Suspected or Known Crohn's Disease[END_REF]. Jensen et al. reported a 20% incidence of incidental extra enteric findings on MRE images, but only 6% had substantial or incompletely characterized findings warranting additional examinations such as CT [START_REF] Radhamma | MRI Enterography: What Is the Clinical Impact of Unsuspected Extra-Enteric Findings?[END_REF].

CONCLUSION

Radiologists should be aware of these potentially rare findings and complications that can be seen on MR enterography and pelvic MRI in order to provide referring clinicians with the means to make the appropriate diagnosis warranting additional imaging examinations.

Figure 1 Coronal balanced fast field echo MRE (True FISP)-weighted MR image in a 39-year-old male with longstanding Crohn's disease involving the ileum, jejunum, and duodenum and displaying a short fibrous stenosis of the third duodenum responsible for a marked dilatation of the upstream second duodenum and stomach (arrow). The patient was undergoing immunosuppressive and antitumor necrosis factor treatment. This stenosis was confirmed with an upper GI endoscopy and biopsy.

Figures 2 a andb Coronal single shot fast spin echo (HASTE) T2-weighted (a) and axial gadolinium-enhanced fatsuppressed T1-weighted (b) MRE images showing an enlarged appendix with a thick markedly enhanced wall (arrows, a and b). The 25-year-old male patient had an acute flare up of Crohn's colitis and underwent surgery. A histological analysis of the appendix confirmed its involvement. Coronal single shot fast spin echo (HASTE) T2-weighted MRE image performed at follow-up of a 71-year-old female patient with longstanding ileal Crohn's disease showing an irregular heterogeneous mass (arrows) developed at the ileocaecal junction. Note the distal ileum, which is involved in her Crohn's disease (arrowhead). Surgery was performed and the pathological examination confirmed a mucinous adenocarcinoma developed at the ileocaecal junction over underlying CD.

Figures 6 a, b, andc Axial contrast-enhanced abdominopelvic CT image (a) in a 50-year-old male with a longstanding complex anoperineal fistula showing a large hypodense lesion surrounding the anal canal (arrow,a). Pelvic MRI was performed and coronal single shot fast spin echo (HASTE) T2 (b) and sagittal gadolinium-enhanced fat-suppressed T1-weighted MR images (c) display a large lobulated heterogeneous lesion superimposed on the bed of the former fistula with peripheral enhancement, consistent with mucinous adenocarcinoma which was confirmed by pathological examination (arrows, b and c).

Figures 7 a, b, andc. Coronal gadolinium-enhanced fat-suppressed T1-weighted image at the arterial phase (a) and portal phase (b). MRE images show fern-like abnormalities of the liver, predominantly in the arterial phase and at the periphery of the liver (arrows, a and b) consistent with sinusoidal dilatation. Coronal single shot fast spin echo (HASTE) T2-weighted MRE images (c) show discrete hypersignal intensity areas (arrow, c) at the periphery of the liver in this 29-year-old male presenting at our emergency department with anemia, considerable weight loss for the last year, asthenia, and psoitis. A large abscess in the psoas was diagnosed (black arrow, c) related to a fistula from severe adjacent ileal Crohn's disease. Findings were confirmed at surgery. Nine months later, MRE showed complete resolution of the liver abnormalities and abscess (not shown). Coronal CT scanner image (c) performed one year after the acute episode of the fistula and inflammatory mass shows a dilated right ureter related to the fibrous sequelae of the fistula (arrowhead, c).

Figures 10 a, b, andc Coronal fat-suppressed gadolinium-enhanced T1-weighted MRE image (a) showing a thrombus in the right iliac vein extending upwards to the inferior vena cava (arrow) in a 25-year-old patient with a flare up of colonic Crohn's disease. In the same patient, a coronal single shot fast spin echo (HASTE)T2-weighted MR image (b) and coronal abdominopelvic CT (c) shows irregularity along the articular margins of the sacroiliac joint with subchondral sclerosis and edema, consistent with ankylosing spondylitis (arrows).

FIGURES HIGHLIGHTS  Unusual sites of involvment

o Although the ileum is the most common site of involvement in CD, other less common sites have been described, such as the stomach, the duodenum, the proximal small bowel, Meckel's diverticulum, and the appendix. o Extra enteric Unusual extra enteric complications include sepsis-related hepatic sinusoidal dilatation, avascular necrosis of the femoral head, non-bacterial osteomyelitis, acalculous ureteral inflammatory entrapment, thromboembolic events, peritoneal inclusion cysts.

 Unusual associated diseases o Unusual associated disease include PSC and its complications, granulomatous Crohns' hepatitis, PSC-autoimmune hepatitis overlap syndrome, ankylosing spondylitis, osteomalacia, hypertrophic osteoarthropathy, pancreatitis, hidradenitis suppurativa

 Incidental findings

Figures 3 a

 3 Figures 3 a and b Axial fat-suppressed T1-weighted gadolinium-enhanced MR images (a,b) showing an inflammatory mass and fistula (arrow,a) extending to the right sacral root (arrow, b) in a 38-yearold male with Crohn's disease presenting with right sciatica.

Figure 4

 4 Figure 4 a and b Coronal HASTE T2 (a) and axial fat-suppressed gadolinium-enhanced T1-weighted (b) MRE images showing a sacral abscess (arrows,a and b) related to an entero-osseous fistula (arrowhead,b) in a 17-year-old male with active Crohn's disease

Figure 8

 8 Figure 8 Coronal abdominopelvic CT scanner image showing a hepatic (white arrow) and subhepatic abscess (black arrow), with a fistula to the right psoas (arrowhead) complicating active CD.

Figures 11

 11 Figures 11 a and bAxial single shot fast spin echo (HASTE) T2-weighted MRE image (a) showing a somewhat irregular discrete dilatation of the intrahepatic bile ducts in a 21-year-old male patient with Crohn's disease (arrow). Further cholangic MRI (b) depicts findings consistent with primary sclerosing cholangitis that was subsequently confirmed, including alternate small stenoses and dilatations of the intrahepatic bile duct (arrows, b) as well as a narrow benign stenosis of the common bile duct (arrowhead).

Figure 12

 12 Figure 12Axial fat-suppressed gadolinium-enhanced MR image showing multiple abscesses and marked granuloma enhancement in the setting of hidradenitis associated with Crohn's disease (arrow). The bilaterality of features and the anterior and posterior involvement of the inferior part of the perineum point to hidradenitis.

Figures 11

 11 Figures 11 a and bAxial single shot fast spin echo (HASTE) T2-weighted MRE image (a) showing a somewhat irregular discrete dilatation of the intrahepatic bile ducts in a 21-year-old male patient with Crohn's disease (arrow). Further cholangic MRI (b) depicts findings consistent with primary sclerosing cholangitis that was subsequently confirmed, including alternate small stenoses and dilatations of the intrahepatic bile duct (arrows, b) as well as a narrow benign stenosis of the common bile duct (arrowhead).

Figure 12

 12 Figure 12Axial fat-suppressed gadolinium-enhanced MR image showing multiple abscesses and marked granuloma enhancement in the setting of hidradenitis associated with Crohn's disease (arrow). The bilaterality of features and the anterior and posterior involvement of the inferior part of the perineum point to hidradenitis.



  Unusual types of complications o EntericRare fistulas may occur such as enterocutaneous, sigmoïdovaginal and enterovesicular fistulas. Patients with longstanding Crohn disease have an increased risk of developing small bowel and anal adenocarcinoma, including mucinous adenocarcinoma.

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Sophie Provenchère
email: sophie.provenchere@aphp.fr

Jean Guglielminotti

Aurélie Gouel-Chéron

Edouard Bresson
email: edouardbresson@gmail.com

Laetitia Desplanque
email: laetitia.desplanque@gmail.com

Claire Bouleti
email: claire.bouleti@aphp.fr

Bernard Iung
email: bernard.iung@aphp.fr

Philippe Montravers
email: philippe.montravers@aphp.fr

Monique Dehoux
email: monique.dehoux@aphp.fr

Dan Longrois
email: dan.longrois@aphp.fr

; Edouard Bresson

; Bernard Iung

Postoperative Cardiac Troponin I Thresholds Associated With 1-Year Cardiac Mortality After Adult Cardiac Surgery: An Attempt to Link Risk Stratification With Management Stratification in an Observational Study

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

Introduction

Cardiac troponin I or T (cTnI/T) isoforms are sensitive and specific biomarkers of myocardial damage, independently of the causative injury [START_REF] Committee | Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery[END_REF][START_REF] Haaf | High-sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac noncoronary artery disease[END_REF][START_REF] Study | Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery[END_REF][START_REF] Mccarthy | Type 2 Myocardial Infarction-Diagnosis, Prognosis, and Treatment[END_REF]. Previous research in adult cardiac surgery patients [START_REF] Lasocki | Cardiac troponin I is an independent predictor of in-hospital death after adult cardiac surgery[END_REF][START_REF] Fellahi | Short-and long-term prognostic value of postoperative cardiac troponin I concentration in patients undergoing coronary artery bypass grafting[END_REF][START_REF] Provenchere | Plasma brain natriuretic peptide and cardiac troponin I concentrations after adult cardiac surgery: association with postoperative cardiac dysfunction and 1-year mortality[END_REF][START_REF] Van Geene | Cardiac troponin I levels after cardiac surgery as predictor for in-hospital mortality[END_REF][START_REF] Vikenes | Long-term prognostic value of cardiac troponin I and T versus creatine kinase-MB mass after cardiac surgery in low-risk patients with stable symptoms[END_REF][START_REF] Buse | The prognostic value of troponin release after adult cardiac surgery -a meta-analysis[END_REF][START_REF] Buse | Troponin T and B-type natriuretic peptide after on-pump cardiac surgery: prognostic impact on 12-month mortality and major cardiac events after adjustment for postoperative complications[END_REF][START_REF] Mauermann | Postoperative High-Sensitivity Troponin and Its Association With 30-Day and 12-Month, All-Cause Mortality in Patients Undergoing On-Pump Cardiac Surgery[END_REF], including meta-analyses [START_REF] Domanski | Association of myocardial enzyme elevation and survival following coronary artery bypass graft surgery[END_REF][START_REF] Buse | The prognostic value of troponin release after adult cardiac surgery -a meta-analysis[END_REF] have reported an association between increased postoperative cTnI/T concentrations and short-or intermediate-term allcause mortality. Many, but not all, cardiac surgery centers routinely measure postoperative cTnI/T concentrations as part of postoperative risk stratification [START_REF] Shahian | Biomarkers and risk models in cardiac surgery[END_REF].

However, no study has specifically examined whether the information "increased postoperative cTnI/T concentration" may help clinicians to decide interventions (e.g., changes in diagnostic/monitoring or therapeutic strategies) that could result in improved patient outcome. This approach is sometimes referred as management reasoning (i.e., the process of making decisions about patient management) as opposed to diagnosis reasoning and relies on specific tools [START_REF] Cook | Management Reasoning: Beyond the Diagnosis[END_REF]. There is a clear lack of management reasoning and stratification as compared to diagnosis reasoning and risk stratification concerning the use of troponin measurements following cardiac surgery. Several explanations may account for this absence of management stratification triggered by an increased postoperative cTnI/T concentration.

The first one is the absence of a universally accepted cTnI/T threshold associated with an increased risk of adverse postoperative outcome. The definition of such a threshold is complex because it depends on: (i) patients populations [START_REF] Collinson | Influence of population selection on the 99th percentile reference value for cardiac troponin assays[END_REF]; (ii) type of cardiac surgical procedures (coronary artery bypass grafting (CABG) procedures versus non-CABG procedures with myotomy) [START_REF] Fellahi | Determination of the threshold of cardiac troponin I associated with an adverse postoperative outcome after cardiac surgery: a comparative study between coronary artery bypass graft, valve surgery, and combined cardiac surgery[END_REF]; (iii) timing of postoperative measurements [START_REF] Fellahi | Kinetic analysis of cardiac troponin I release is no more accurate than a single 24-h measurement in predicting in-hospital outcome after cardiac surgery[END_REF]; (iv) definitions of the outcomes; (v) and the troponin assays used [START_REF] Apple | Biomarkers ITFoCAoC: Analytical characteristics of highsensitivity cardiac troponin assays[END_REF].The second one is that studies that defined cTnI/T thresholds associated with an increased risk of postoperative mortality were based on a statistical approach that maximized statistical metrics such as the Youden index (i.e. that maximizes both sensitivity and specificity) [START_REF] Ray | Statistical evaluation of a biomarker[END_REF]. However, this approach attributes the same weight to a false positive and a false negative result. Maximizing both sensitivity and specificity makes sense only if consequences for the patient of an intervention based on a false positive result or of a non-intervention based on a false negative result are equal, which is a rare situation in medicine [START_REF] Vickers | Decision curve analysis: a novel method for evaluating prediction models[END_REF]. A clinical-based approach for defining a threshold value of "increased postoperative cTnI/T" and the subsequent decisionmaking process is probably more appropriate. When interventions do not exist, or their efficacy is not documented or are associated with potential adverse effects, it is desirable to choose a threshold value associated with lower sensitivity and higher specificity. Finally, the third possible explanation for the lack of stratification management based on increased cTnI/T values (whatever the threshold value) after cardiac surgery is that the outcome used in previous studies is all-cause mortality, including cardiac and non-cardiac causes [START_REF] Lasocki | Cardiac troponin I is an independent predictor of in-hospital death after adult cardiac surgery[END_REF][START_REF] Provenchere | Plasma brain natriuretic peptide and cardiac troponin I concentrations after adult cardiac surgery: association with postoperative cardiac dysfunction and 1-year mortality[END_REF][START_REF] Buse | Troponin T and B-type natriuretic peptide after on-pump cardiac surgery: prognostic impact on 12-month mortality and major cardiac events after adjustment for postoperative complications[END_REF][START_REF] Mauermann | Postoperative High-Sensitivity Troponin and Its Association With 30-Day and 12-Month, All-Cause Mortality in Patients Undergoing On-Pump Cardiac Surgery[END_REF].

Because interventions to prevent cardiac and non-cardiac mortality triggered by an increase in

postoperative cTnI/T values may not be the same, preventing all-cause mortality is challenging if not impossible [START_REF] Ausset | Cardiac troponin I release after hip surgery correlates with poor long-term cardiac outcome[END_REF][START_REF] Foucrier | The long-term impact of early cardiovascular therapy intensification for postoperative troponin elevation after major vascular surgery[END_REF][START_REF] Ausset | Quality of postoperative care after major orthopedic surgery is correlated with both longterm cardiovascular outcome and troponin Ic elevation[END_REF]. On the contrary, prevention of cardiac mortality is a credible challenge and examples of such interventions have been recently published in noncardiac surgery [START_REF] Ausset | Cardiac troponin I release after hip surgery correlates with poor long-term cardiac outcome[END_REF][START_REF] Foucrier | The long-term impact of early cardiovascular therapy intensification for postoperative troponin elevation after major vascular surgery[END_REF][START_REF] Ausset | Quality of postoperative care after major orthopedic surgery is correlated with both longterm cardiovascular outcome and troponin Ic elevation[END_REF][START_REF] Van Waes | Cardiac Health After Surgery I: One-Year Mortality, Causes of Death, and Cardiac Interventions in Patients with Postoperative Myocardial Injury[END_REF].

The goal of this study was to calculate cTnI thresholds for one-year cardiac mortality with specificity greater than 80% in CABG and non-CABG procedures. From these threshold cTnI values we conducted an a posteriori exploratory analysis to identify potential interventions (e.g., changes in monitoring duration/intensity and or changes in drugs/therapeutic regimens) that could have been undertaken in deceased patients (separated into cardiac and non-cardiac deaths) with cTnI greater than this threshold. To the best of our knowledge, this study is the first attempt, in cardiac surgery patients, to shift from statistical associations between increased postoperative cTn values and mortality (risk stratification) to proposals for management stratification.

Material and Methods

TRIPOD and STROBE statements for reporting were followed.

Source of data/Participant

Bichat-Claude Bernard Hospital is a 900-bed teaching hospital performing 1200 annual cardiac surgical procedures with cardiopulmonary bypass (CPB). Patients and surgery characteristics as well as outcomes are entered into an institutional database by trained research personnel since 2005. It allows calculation of the EuroSCORE II [START_REF] Nashef | EuroSCORE II[END_REF]. Death during the hospital stay and up to one year after surgery is also collected in this database that is interfaced with the hospital information system where deaths are systematically recorded.

Data from consecutive patients who underwent cardiac surgery between January 1, 2009 and December 31, 2012 were first selected. This time period corresponds to the same cTnI measurement assay. Then patients with the following criteria were excluded: 1) emergent cardiac surgery (within 24 hours after hospital admission); 2) complex or unusual procedures (e.g., aortic arch surgery with circulatory arrest and deep hypothermia, congenital heart disease such as atrial septal defect); 3) death on the day of surgery or death more than 365 days after the procedure; and 4) missing postoperative cTn values (Fig 1).

For the purpose of the study, procedures were defined as isolated CABG (CABG group) or non-isolated CABG. The latter group included isolated valve procedures, valve procedures combined with CABG, and ascending aorta procedures.

Plasma cTnI concentrations were measured on the 20 th postoperative hour with a sensitive assay on the Dimension Vista 1500 analyser (Siemens Healthcare Diagnostics, Saint Denis, France). The limit of detection, the limit of quantification (coefficient of variation <10 %), and the 99th percentile value provided by the manufacturer were 15 ng/L, 40 ng/L and 45 ng/L, respectively. They were confirmed by our laboratory [START_REF] Bruneel | External evaluation of the Dimension Vista 1500(R) intelligent lab system[END_REF].

Aims of the study

The primary aim of the study was to calculate the postoperative cTn I concentration associated with specificity greater than 80% for one-year cardiac mortality. The secondary aim was to identify potential interventions (as part of an attempt to evolve from risk stratification to management stratification) that could be implemented in patients with cTnI values higher than the defined threshold.

Medical records of non-survivors were assessed by two senior cardiac anesthesiologists (SP, DL) to determine the causes of death and identify the potential interventions that could have been proposed to prevent death. The reviewers were blinded to cTnI concentrations. Causes of death were a priori categorized, based on the literature [START_REF] Hicks | ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards)[END_REF] as cardiac and non-cardiac. These definitions are presented in Table 1. Each of the two reviewers reviewed the medical files independently. Possible discordance was solved by consensus with a third senior anesthesiologist (EB). Potential interventions were categorized as hemodynamic optimization, enhanced diagnosis/monitoring/therapeutics or none. This approach is similar to that published for non-cardiac surgery patients [START_REF] Ausset | Cardiac troponin I release after hip surgery correlates with poor long-term cardiac outcome[END_REF][START_REF] Foucrier | The long-term impact of early cardiovascular therapy intensification for postoperative troponin elevation after major vascular surgery[END_REF][START_REF] Ausset | Quality of postoperative care after major orthopedic surgery is correlated with both longterm cardiovascular outcome and troponin Ic elevation[END_REF][START_REF] Van Waes | Cardiac Health After Surgery I: One-Year Mortality, Causes of Death, and Cardiac Interventions in Patients with Postoperative Myocardial Injury[END_REF].

Predictors

A multivariable logistic regression model was developed to identify risk factors for cardiac deaths. The candidate variables were selected a priori based on clinical relevance and included: (i) preoperative factors that are consolidates in the EuroSCORE II values (all preoperative data with few modifiable parameters); (ii) the duration of aortic cross-clamping (that reflects the ischemic burden); (iii) type of surgery (CABG or non-CABG),and (iv) cTnI values greater than the threshold with an 80% specificity.

A priori and a posteriori power of the study

The required sample size was calculated to observe an odds ratio ≥ 1.5 for the risk of death associated with cTnI values greater than the threshold with an 80% specificity and the following hypotheses: in-hospital mortality 5%, alpha 5%, power 90%, and a two-tailed test.

At least 1300 patients had to be included. The power calculated a posteriori was 99%

Missing data analysis

One hundred and seventy patients with missing cTn value were excluded from the statistical analysis (Fig 1). They were subsequently compared with patients without missing postoperative cardiac troponin I (cTnI) values (Supplemental Table 1).

Statistical analyses

The statistical analyses were performed with R version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). Results are expressed as median (interquartile range) or count (percentages). Comparisons of continuous variables used unpaired Wilcoxon tests and comparisons of discrete variables Chi-square or Fisher exact tests. For comparisons of continuous variables among three groups, Kruskall-Wallis tests were used followed by unpaired Wilcoxon tests. The P-value for statistical significance was 0.05. The Bonferroni correction was applied when necessary.

The ability of postoperative cTnI concentration to discriminate 1-year survivors from non-survivors used the area under the receiver operator characteristic curve (AUCROC).

Comparisons of 2 AUCROCs used the DeLong method. Confidence intervals for the difference between 2 AUCROCs were calculated with bootstrap resampling (B=2000) with replacement and the percentiles method.

Sensitivity and specificity were calculated with standard formulas: true positive / (true positive + false negative) and true negative / (false positive + true negative), respectively. The cTnI threshold value associated with a specificity ≥ 80, 85, and 90% was the lowest value with a specificity ≥ 80, 85, and 90%, respectively. Confidence intervals for the threshold value were calculated with bootstrap resampling (B=2000) with replacement and the percentiles method.

A multivariable logistic regression model with backward selection was developed to identify risk factors for cardiac deaths. The candidate variables were selected a priori based on clinical relevance and included: cTnI greater than the threshold with an 80% specificity for cardiac mortality, type of surgery (CABG or non-CABG), EuroSCORE II values, and duration of aortic cross-clamping. The final regression model was used to calculate the adjusted odds ratio for the risk of cardiac death associated with a cTnI>threshold.

The value of adding the cTnI>threshold to the EuroSCORE II to estimate the risk of cardiac death was estimated by comparing 2 logistic regression models with cardiac death as the dependent variable. The first model included the EuroSCORE II as the only independent variable and the second model included the EuroSCORE II and the cTnI>threshold as the 2 independent variables. The 2 models were compared using the C-index, the Hosmer-Lemeshow test, and the additive and absolute net reclassification index (NRI) [START_REF] Pencina | Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond[END_REF][START_REF] Alba | Discrimination and Calibration of Clinical Prediction Models: Users' Guides to the Medical Literature[END_REF]. The additive NRI quantifies the extent to which a biomarker correctly reclassifies individuals to a higher or lower category of risk. The absolute NRI indicates the proportion of patients correctly or incorrectly reclassified. Three groups of risk were considered: low-, intermediate-, and high-risk based on a risk of death as calculated by the EuroSCORE II less than 4%, between 4 and 8, and greater than 8 [START_REF] Nishimura | AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines[END_REF]. No internal validation was performed (e.g., splitting the dataset into a training and a validation sets) because of the relatively low number of cardiac deaths and the controversy surrounding this approach [START_REF] Altman | Prognosis and prognostic research: validating a prognostic model[END_REF].

Perioperative management

Perioperative management and the anesthesia/intensive care and surgical teams were unchanged during the study period. On the morning of surgery, all the patients received hydroxyzine and those on chronic beta-blocker therapy received their usual dose. Anesthesia was induced and maintained with effect-site target-controlled infusions of propofol [START_REF] Levitt | Human physiologically based pharmacokinetic model for propofol[END_REF] and sufentanil [START_REF] Gepts | Linearity of pharmacokinetics and model estimation of sufentanil[END_REF] without use of inhaled anesthetics that could have confounded the interpretation of post-operative troponin values [START_REF] Bignami | Volatile anaesthetics added to cardiopulmonary bypass are associated with reduced cardiac troponin[END_REF]. Muscular relaxation was provided by atracurium. Patients were monitored with invasive radial artery blood pressure, 5-lead electrocardiogram (EKG), pulse oximetry, and bispectral index (BIS Vista®, Medtronic, USA). Trans esophageal echocardiography was used selectively. Pulmonary artery catheter monitoring was limited to patients with severe left ventricular dysfunction, i.e. left ventricular ejection fraction (LVEF) < 40% or pulmonary arterial hypertension. An autologous blood recovery system was used for every patient. In the absence of contraindications (e.g., idiopathic thromboembolic disease; glomerular filtration rate < 30 ml/min/m 2 ), all patients received a 20 mg/kg tranexamic acid intravenous bolus followed by a continuous infusion of 2 mg/kg/h. In case of arterial hypotension [START_REF] Forestier | Propofol and sufentanil titration with the bispectral index to provide anesthesia for coronary artery surgery[END_REF] boluses of phenylephrine were given to maintain mean arterial blood pressure between 50 and 80 mm Hg.

Cardiopulmonary bypass (CPB) was conducted under normothermia (central temperature > 35.5°C). An initial dose of 300 UI/kg of unfractionated heparin (UFH) was administrated, before the initiation of CPB. Efficacy of UFH was checked with the activated coagulation time (ACT, Hemochron®, Gamida, Eaubonne, France) with the goal of ACT > achieved by intermittent anterograde or retrograde warm blood cardioplegia. Patients who underwent CABG had mainly anterograde cardioplegia whereas patients who underwent complex surgery had anterograde and/or retrograde cardioplegia according to surgical constraints. Management of CPB was targeted both saturation of the venous line > 80 % and mean arterial pressure (MAP) values > 60-80 mmHg according to the preoperative MAP values. After aortic unclamping, if necessary, internal cardioversion (given at 20 J, increased to 30 J after the second shock) was used. Inotropic support following aortic unclamping was mainly based on norepinephrine and/or dobutamine infusion to maintain a stable hemodynamic state. As soon as patients were weaned from CPB, protamine was administered (1:1 ratio for the total UFH dose). When required, blood products were administrated according to the international recommendations [START_REF] Menkis | Drug, devices, technologies, and techniques for blood management in minimally invasive and conventional cardiothoracic surgery: a consensus statement from the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS)[END_REF][START_REF] Yaffee | Management of blood transfusion in aortic valve surgery: impact of a blood conservation strategy[END_REF] and adapted to the results of the coagulation tests performed after protamine infusion.

Postoperative care in the ICU was provided by cardiac anesthesiologists who were also intensivists, and in the telemetry unit and on the ward by cardiologists who routinely and exclusively take care of cardiac surgery patients. EKGs were performed upon arrival in the ICU and daily until discharge. Postoperative echocardiography was performed in the ICU in case of hemodynamic instability, EKG changes or major bleeding, or later on the ward by the cardiologists. Routine biologic testing, arterial blood gases and chest radiographs were obtained upon arrival in the ICU, and then daily and when indicated thereafter. Patients were weaned from mechanical ventilation 6-8 hours after admission to the ICU, except in cases of hemodynamic, respiratory or of bleeding complications. Standard postoperative care included blood glucose control, intravenous heparin (100U/Kg) beginning no sooner than 6 h after surgery in the absence of significant bleeding followed by the application of the institutional anticoagulation protocols. In chronically treated patients, beta-blocking agents, statins and oral antiplatelet agents were resumed as soon as possible postoperatively (mainly following day 1 after surgery).

Results

The selection of the study sample is presented in Figure 1 and characteristics of patients excluded for missing cTnI values are summarized in Supplemental Table 1. During the study period, 3,228 procedures were analyzed, including 1,247 CABG (39%).

Characteristics of the CABG and non-CABG groups are presented in Table 2. Compared with patients in the CABG group, patients in the non-CABG group had higher postoperative cTnI concentrations: 4.8 (2.7-9.4) versus 2.2 (1.4-3.6) µg/l, respectively (P <0.0001). In the non-CABG group postoperative cTnI concentrations did not differ across the 3 types of procedures (Supplemental Table 2).

During the study period, 129 deaths (4.0%) were recorded in the institutional database that undergoes regular quality controls during the first year following surgery. There were 83 cardiac deaths (64.4%), including 48 deaths (57.8%) with initially obvious/severe cardiac dysfunction and 35 deaths (42.2%) with initially absent/mild cardiac dysfunction (Table 3).

Postoperative cTnI concentrations did not differ between cardiac deaths with initially obvious/severe cardiac dysfunction and cardiac deaths with initially absent/mild cardiac dysfunction (13.7 versus 12.3 µg/l, respectively; P=0.10) but were higher than in non-cardiacdeaths (4.0 µg/l). EuroSCORE II values and type of surgery did not differ across the causes of death (Table 3). Interestingly, the time to deaths was significantly different between the 48 deaths with initially obvious/severe cardiac dysfunction versus the 35 deaths with initially absent/mild cardiac dysfunction (see Table 3).

Postoperative cTnI concentrations and one-year all-cause mortality:

Postoperative cTnI concentrations were higher in non-survivors (all-cause mortality) than in survivors both in the CABG and in the non-CABG groups: 5.2 (3.1-11.5) versus 2.1

(1.4-3.6) µg/l in the CABG group (P<0.0001) and 15.1 (7.1-38.4) versus 4.7 (2.6-8.9) µg/l in the non-CABG group (P<0.0001). The ability of cTnI concentration to discriminate survivors from non-survivors (all-cause mortality) assessed with the AUCROC curve was 0.80 (95% CI: 0.71 to 0.89) for the CABG group and 0.76 (95% CI: 0.69 to 0.84) for the non-CABG group (P=0.53 for comparison between the two AUCROCs; difference between the 2 AUCROCs: 0.04; 95% CI: -0.08 to 0.14).

Postoperative cTnI concentrations and one-year cardiac mortality

In the CABG group, cTnI threshold values with an 80% specificity for one-year cardiac mortality was 4.2 (95% CI: 3.9 to 4.5) µg/l (Table 4). In the non-CABG group, the threshold value was 10.7 (95% CI: 10.0 to 11.3) µg/l.

Risk factors for cardiac mortality

In the final multivariable logistic regression model of risk factors for cardiac mortality, two factors were identified: EuroSCORE II (adjusted OR 1.09 per 1-unit increase; 95% CI, 1.06 to 1.12) and cTnI>threshold (adjusted OR 5.6; (95% CI: 3.4 to 9.4) (Supplemental Table 3).

Added value of the cTnI concentration:

Compared with a logistic model including only the EuroSCORE II, adding cTnI concentration increased the C-index of the logistic model from 0.801 (95% CI, 0.754 to 0.848) to 0.825 (95% CI, 0.778 to 0.872) and the Hosmer-Lemeshow test P-value from 0.001 to 0.006 (Table 5 and Supplemental Figure 1). The additive NRI was 0.288 and the absolute NRI 14.1% (Table 5 and Supplemental Table 4).

Potential interventions and cTnI thresholds values

In the 129 deceased patients, an intervention was estimated possible in 71 (55%) (Table 6). It could have been enhanced postoperative monitoring in 22 (31%) and hemodynamic (drugs) optimization in 49 (69%) patients. When limiting the analysis to the 66 deceased patients with a cTnI value greater than the defined threshold (51%), a potential intervention was estimated possible in 47 (71%). It could have been enhanced postoperative monitoring in 12 (25%) and hemodynamic (drugs) optimization in 35 (75%). For the 13 noncardiac deaths with a cTnI greater than the threshold, no intervention was deemed possible.

Of notice, in survivors, 607 out of 3,099 (20%) had a cTnI value greater than this threshold.

When examining the cause of death, 53 out of the 83 cardiac deaths (64%) had a cTnI value greater than the cTnI threshold and an intervention was considered possible in 47 out of these 53 cases (89%).

Discussion

Main findings and clinical context

The main findings of this manuscript is that by defining cTnI thresholds associated with a specificity of > 80 % for cardiac mortality we identified a subgroup of patients that could mostly benefit from potential interventions: patients with absent/ mild postoperative cardiovascular dysfunction.

Clinicians that routinely prescribe cTnI/T measurements after cardiac surgery for risk stratification would like that this be followed by at least a change in medical practice (management stratification) if not improved patient outcome. The transition from risk stratification to management stratification in medical practice faces several challenges: the availability of a validated threshold to define "increased cTnI/T" and the proposal followed by validation of potential interventions (management stratification) for patients with cTnI/T values above this threshold [START_REF] Cook | Management Reasoning: Beyond the Diagnosis[END_REF]. The conceptual difficulties of the transition from risk stratification to management stratification have been described in the Introduction section and are mainly related to the issues of:(i) all-cause mortality versus cardiac mortality; (ii) the clinical "value" or implications of false positive/false negative results.

When comparing our results with previous articles, it is obvious that the strategy to define threshold values for increased postoperative cTnI in this study is different from previous research [START_REF] Fellahi | Determination of the threshold of cardiac troponin I associated with an adverse postoperative outcome after cardiac surgery: a comparative study between coronary artery bypass graft, valve surgery, and combined cardiac surgery[END_REF]. First, previous research used a statistical approach for cTnI/T thresholds that maximized sensitivity and specificity but attributed the same clinical value to a false positive and a false negative result. When interventions do not exist, or are associated with potential adverse effects or when their efficacy is not documented, it is desirable to choose a threshold value associated with higher specificity even at the price of lower sensitivity. This is the reason why we calculated thresholds with a specificity greater than 80 %. Second, because interventions that could address all-cause mortality especially noncardiac mortality are difficult to imagine, we calculated cTnI threshold values for cardiac deaths defined from the analysis of individual medical records and the published definitions of cardiac/non cardiac deaths [START_REF] Hicks | ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards)[END_REF]. This analysis was performed without knowledge of the cTnI value.

Threshold values for cTnI in this study were similar to those reported by Fellahi et al. [START_REF] Fellahi | Determination of the threshold of cardiac troponin I associated with an adverse postoperative outcome after cardiac surgery: a comparative study between coronary artery bypass graft, valve surgery, and combined cardiac surgery[END_REF] for the composite outcome of severe cardiac events and/or cardiac deaths based on maximization of the Youden index: 5.2 µg/l for CABG (versus 4.2 µg/l in our study) and 11.0 µg/l for non-CABG (versus 10.7 µg/l in our study). We chose to combine all non-CABG procedures into a single group because we did not observe significant differences in cTnI concentration across valve, combined valve and CABG, or ascending aorta procedures.

Higher cTnI values and thresholds in non-CABG procedures are probably related to the myotomy performed during these procedures and the longer duration of aortic cross-clamping [START_REF] Fellahi | Determination of the threshold of cardiac troponin I associated with an adverse postoperative outcome after cardiac surgery: a comparative study between coronary artery bypass graft, valve surgery, and combined cardiac surgery[END_REF]. If a threshold value for increased cTnI has to be defined and used for clinical decision making, our results clearly highlight that this must take into consideration the type of surgical procedure. In our study, the proportion of deceased patients with a cTnI greater than these thresholds was 51% overall (all-cause mortality) and 64% for cardiac deaths. In survivors, this proportion was 20%. Similar proportions were reported by Fellahi et al. with 69% of patients with severe cardiac events or deaths having cTnI concentration greater than the threshold and 27% of patients without such events having cTnI concentration greater than the threshold.

We also confirmed the independent statistical association between cTnI and one-year cardiac mortality with an adjusted odds ratio of 5.6 for cardiac deaths in patients with cTnI concentration greater than the defined thresholds (Supplemental Table 3). Importantly, in the multivariable model, the duration of aortic cross-clamping was not statistically associated with an increased risk of death thus rendering the information "postoperative cTnI values > threshold" even more important. The cTnI value > threshold probably reflects individual susceptibility to ischemia/reperfusion and in this context, and adds independent prognostic value thus justifying its measurement. Indeed, the NRI is 0.288 for a model combining cTnI and EuroSCORE II compared with EuroSCORE II alone. This additive NRI value is in the high range of overall published NRI [START_REF] Leening | Net reclassification improvement: computation, interpretation, and controversies: a literature review and clinician's guide[END_REF]. As a specific example concerning the use of cTn to improve risk prediction, one article reported an NRI was only 0.04 [START_REF] Defilippi | Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults[END_REF]. More importantly, for deceased patients, 42 % of the patients were reclassified to a higher risk by the cTnI values > threshold. This is a strong argument to support the clinical utility of measuring cTnI after cardiac surgery (risk stratification) provided that interventions are implemented (shift to management stratification). with initially absent/mild cardiac dysfunction the median time to deaths was 17 days, suggesting that enough time would be available for interventions to be implemented. These numbers of deceased patients that could have benefited from an intervention if their cTnI values had been above the threshold must be compared to the 20% (N=629) of the survivors who had a cTnI above the threshold. Although one can argue that "all efforts are performed for all patients at any time", we consider that this may not reflect routine clinical practice. In this context, a patient without an alarming clinical context would benefit from cTnI measurements early (20 th ) after surgery thus allowing an optimization of care.

We acknowledge several limitations of our study. Some are technical: first, 5% of cTnI values were missing which may have biased our results. However, only slight differences were observed between patients with and without missing cTnI values. Second, the medical records of the 3,099 survivors were not analyzed and possible interventions in survivors were not explored. This prevents us from conducting a definitive cost-consequence analysis to estimate the benefit of routine cTnI measurement in all postoperative patients to decide an intervention. Third, we did not analyze cardiac morbidity because most of previous research has focused on mortality. We cannot exclude that results would have been different for cTnI if morbidity had been taken into consideration. Fourth, we used a single-biomarker approach and inclusion of multiple markers such as BNP in the decision making process may lead to different results [START_REF] Provenchere | Plasma brain natriuretic peptide and cardiac troponin I concentrations after adult cardiac surgery: association with postoperative cardiac dysfunction and 1-year mortality[END_REF][START_REF] Buse | Troponin T and B-type natriuretic peptide after on-pump cardiac surgery: prognostic impact on 12-month mortality and major cardiac events after adjustment for postoperative complications[END_REF][START_REF] Mauermann | Absolute Postoperative B-Type Natriuretic Peptide Concentrations, but Not Their General Trend, Are Associated With 12-Month, All-Cause Mortality After On-Pump Cardiac Surgery[END_REF][START_REF] Brynildsen | The predictive value of NT-proBNP and hs-TnT for risk of death in cardiac surgical patients[END_REF]. In addition we used a single time-point measurement of cTnI (at the 20 th postoperative hour) based on the fact that: (i) we wanted an early information thus allowing potential subsequent interventions and (ii) it was demonstrate that a single time-point value had similar prognostic values as multiple time-point [START_REF] Fellahi | Kinetic analysis of cardiac troponin I release is no more accurate than a single 24-h measurement in predicting in-hospital outcome after cardiac surgery[END_REF]. Fifth, our proposals for interventions are speculative but we consider that they are the first step in the transition from risk stratification to risk management [START_REF] Cook | Management Reasoning: Beyond the Diagnosis[END_REF]. A similar analysis was recently performed for patients with increased cTn values after non cardiac surgery [START_REF] Van Waes | Cardiac Health After Surgery I: One-Year Mortality, Causes of Death, and Cardiac Interventions in Patients with Postoperative Myocardial Injury[END_REF]. In that article the authors enumerated the implemented interventions targeted at treating the triggering events (tachycardia, anemia, hypertension, hypotension, inflammation and sepsis, hypovolemia, fluid overload). Similar "basic" interventions should be implemented for all patients after cardiac surgery. They could be complemented by more "specific" interventions such as measurements of natriuretic peptides concentrations to titrate therapy or prescription of addition cardiovascular medication/monitoring. A study published in 2014 used afterload reduction as goal-directed therapy in cardiac failure patients with optimized drug therapy: this is an example of intervention that could be targeted on well-defined patients [START_REF] Borlaug | A randomized pilot study of aortic waveform guided therapy in chronic heart failure[END_REF].

Conclusion

Our results, based on a novel approach of defining thresholds of postoperative cTnI (prediction of cardiac deaths with a specificity > 80 %) is a first step in the transition from risk stratification to management stratification. To the best of our knowledge this is the first attempt to explore potential interventions following the availability of the information "cTnI values above the threshold". Our exploratory analyses suggest that the sub-population of patients that could benefit from interventions is defined by mild alteration of cardiac function.

2-Non-cardiac death

No myocardial dysfunction or mild myocardial dysfunction that did not contribute to death or death that could be unequivocally attributed to another postoperative event (e.g., mediastinitis, severe bleeding with massive transfusion without myocardial dysfunction documented by echocardiography).

  The study was approved by Bichat Hospital Institutional Review Board (IRB 00006477-of HUPNVS, Paris 7 University, AP-HP), Pr. Michel LEJOYEUX, Chair of the Institutional Review Board on March 19, 2015 ("Comité d'Evaluation des Projets de Recherche Biomédicale Paris Nord"). It waived need for patient's informed consent because cTn measurements after cardiac surgery are part of routine care in our Institution.

  This would allow time for both enhanced monitoring and/or improved pharmacological interventions. We hypothesize that any prospective study of potential interventions based on the information "cTnI values above the threshold" should in priority focus on this type of patients.List of abbreviation:cTn: cardiac troponin, CABG: coronary artery bypass grafting; CPB: cardiopulmonary bypass, LVEF: left ventricular ejection fraction; UFH: unfractionated heparin, ACT: activated coagulation time; ICU: intensive care unit; AUCROC: area under the receiver operator characteristic curve; NRI: net reclassification index

Figure 1 :Table 1 :-

 11 Figure 1: Selection of the study sample.

Potential interventions 1 -

 1 Haemodynamic optimization: any enhanced/optimized cardiac support such as inotropes, vasodilators, or mechanical cardio-circulatory support 2-Optimized basic interventions: correction of perioperative triggers of myocardial oxygen imbalance such as anemia, tachycardia, hypo/hypertension, inflammation/sepsis, fluid overload, hypoxemia (24). 3-Optimization of drugs therapy: β-blockers, antiplatelet agents, statins, angiotensin-converting enzyme inhibitors, diuretics, vasodilators and others new drugs (41) 2-Enhanced or prolonged cardiac diagnosis/ monitoring Repeated/ more frequent echocardiographic examination; postoperative natriuretic peptides measurements, prolonged stay in ICU or in telemetry unit, out-of-hospital follow-up for titration of cardiovascular medication on specific hemodynamic goals (42) 3-None

Table 2 :

 2 Characteristics of the two groups of surgical procedures

	CABG	Non-CABG
		P-value
	(N=1,247)	(N=1,981)

(*) Creatinine clearance was calculated with the Modification of Diet in Renal Disease formula

Table 3 :

 3 Postoperative cTnI values, time to death, EuroSCORE II values, and type of surgery according to causes of death Results are expressed as median (interquartile range) or number (%). The P-values are from of a Chi-square test or a Kruskal-Wallis test followed by Wilcoxon tests (ns indicate not statistically significant with Bonferroni corrections for the 3 comparisons)

		Cardiac	Cardiac	Non	P-	1	1	2
		deaths with	deaths with	cardiac-	value	versus	versus	versus
		initially	initially	deaths		2	3	3
		obvious/severe	absent/mild	(3)
		cardiac	cardiac
		dysfunction	dysfunction	N=46
		(1)	(2)
		N=48	N=35
	cTnI
		13.7	12.3	4.0		0.10		0.053
	concentration				0.0004		<0.0001
		(5.3-65.9)	(3.6-18.9)	(2.2-16.6)		(ns)		(ns)
	(µg/l)
	Time to		17	45
					<0.0001	0.019	<0.0001 0.0006
	death (days)	(3-24)	(10-45)	(26-97)
	EuroSCORE	8.0	7.1	6.8	0.42	--	--	--
	II	(4.7-14.2)	(4.7-11.6)	(3.6-10.9)
	Type of				0.88
	surgery
	-CABG	13 (27%)	10 (29%)	11 (24%)		--	--	--
	-Non-CABG	35 (73%)	25 (71%)	35 (76%)		--	--	--
	Footnote:

Abbreviations: CABG: coronary artery bypass grafting; cTnI: cardiac troponin I; N: number.

Table 4 :

 4 Postoperative cardiac troponin I thresholds for 3 selected specificity values for oneyear cardiac mortality according to the type of surgery

		Specificity≥	Specificity≥	Specificity≥
		80%	85%	90%
	CABG procedures
	(N=1,224 survivors and 23 non-
	survivors)
	cTnI threshold (µg/l) (95% CI)	4.2 (3.9 to 4.5)	5.0 (4.6 to 5.4)	6.8 to 7.4)
	Sensitivity	60.9%	56.6%	39.1%
	Non-CABG procedures
	(N=1,921 survivors and 60 non-
	survivors)
		10.7	13.0	17.1
	cTnI threshold (µg/l) (95% CI)
		(10 to 11.3)	(12.0 to 14.1)	(15.6 to 18.4)
	Sensitivity	65.0%	63.3%	45.0%
	Footnote: Results are expressed as median (interquartile range) or number
	Abbreviations: CABG: coronary artery bypass grafting; CI: confidence interval; cTnI: cardiac
	troponin I; N: number.

Table 5 :

 5 Logistic regression models used to compute the net reclassification index The threshold value is 4.2 µg/l for CABG patients and 10.7 µg/l for non-CABG patients

	Model 1		Model 2
	Variables in the model	OR (95% CI)	Variables in the model OR (95% CI)
	EuroSCORE II (per unit)	1.12 (1.09-1.14)	EuroSCORE II	1.09 (1.06-1.12)
			cTnI>threshold (*)	5.46 (3.40-8.77)
	Model performance
		0.80		0.82
	C-index (95% CI)
		(0.75-0.84)		(0.77-0.87)
	Hosmer-Lemeshow test P-value	0.001		0.006
	Additive net reclassification index			0.288
	Absolute net reclassification index			14.1%

Abbreviations: CI: confidence interval; OR: odds ratio (*)

Table 6 :

 6 Potential interventions according to the causes of death and type of surgery and proportion of non-survivors and survivors with a cTnI concentration greater than the threshold with 80% specificity for one-year cardiac mortality

			Non-survivors			Survivors
		Cardiac deaths	Cardiac deaths	Non-	P-value
		with initially	with initially	cardiac-
		obvious/severe	absent/mild	deaths (3)
		cardiac	cardiac
		dysfunction (1)	dysfunction (2)
	CABG and non-CABG	N=48	N=35	N=46		N=3,099
	-Potential interventions	45 (94%)	25 (71%)	1 (2%)	<0.0001	--
	-cTnI>threshold (*)	31 (65%)	22 (63%)	13 (28%)	0.0005	607
						(20%)
	-Potential interventions	30/31 (97%)	17/22 (77%)	0/13 (0%)	<0.0001	--
	when cTnI>threshold
	CABG	N=13	N=10	N=11		N=1,213
	-Potential intervention	13 (100%)	8 (80%)	1 (9%)	<0.0001	--
	-cTnI>threshold (*)	9 (69%)	5 (50%)	0 (0%)	0.002	237
						(20%)
	-Potential intervention	9/9 (100%)	5/5 (100%)	0/0 (0%)	--	--
	when cTnI>threshold
	Non-CABG	N=35	N=25	N=35		N=1,886
	-Potential intervention	32 (91%)	17 (68%)	0 (0%)	<0.0001	--
	-cTnI>threshold (*)	22 (63%)	17 (68%)	13 (37%)	0.03	370
						(20%)
	-Potential intervention	21/22 (95%)	12/17 (71%)	0/13 (0%)	<0.0001	--
	when cTnI> threshold

Acknowledgements relating to this article:

The authors thank INSERM CIC 1425, for monitoring and data management of the study.

Funding Sources:

Support was provided by the Department of Anaesthesiology, Bichat Hospital, Paris, France Jean Guglielminotti is supported by an R03 from the Agency for Healthcare Research and Quality (1 R03 HS025787-01).

Availability of data and materials:

All data generated or analyzed during the study are included in this published article and its supplementary information files.

Declarations:

Trial registration: ClinicalTrials.gov ID: NCT03393169

Ethics approval:

The study was approved by Bichat hospital Institutional Review Board ("Comité d'Evaluation des Projets de Recherche Biomédicale Paris Nord"; IRB 00006477). It waived need for patient's informed consent.

Consent to participate: not applicable

Conflict of Interest:

None declared

Authors' contributions:

SP initiated and conducted the study, performed data acquisition, analyzed and interpreted the data and wrote the first manuscript draft. JG performed the statistical analysis, analyzed and interpreted the data and helped with drafting and revising the manuscript. AGC, EB, LD, CB were involved in data acquisition and helped with drafting the manuscript. BI, PM, MD, were involved in revising the manuscript. DL was involved in study design, in statistical analysis, analyzed and interpreted the data, and drafting and revising the manuscript. The statistical analysis was performed and interpreted by JG (PhD and postdoc in Clinical Epidemiology), SP and DL. All authors read and approved the final manuscript.

Strengths and limitations of this study: an attempt to evolve from risk stratification to management stratification

There is an obvious contradiction of this study since it makes proposals for a transition from risk stratification to management stratification. The proposals are by definition not validated but they open the way for future validation studies. In this respect, these proposals targeted on a specific type of patients (see below) can be considered a strength. Forty-seven of the 53 patients (89 %) with cardiac deaths and cTnI values > threshold could have benefited from an intervention. For example, for patients with initially obvious/severe cardiac dysfunction (e.g. cardiogenic shock, massive myocardial infarction), an intervention was actually implemented (several catecholamines, extracorporeal circulatory support) in 97% of patients with a cTnI greater than the thresholds (Table 6). It is obvious that these interventions would not have required cTnI results to be decided. For non-cardiac deaths, for none of the patients with cTnI was greater than the thresholds an intervention was estimated as possible because of the diverse clinical contexts (e.g. delayed infection or abdominal complications) (Table 6). Our results suggest that if a decision to implement an intervention based on cTnI values above the threshold could have been taken, it could have been most relevant for patients with initially absent/mild cardiac dysfunction (Table 6). For those patients, the immediate postoperative period was characterized by mild cardiac dysfunction that could have been overlooked if the information "increased cTnI values" had not existed. If the practice of cTnI measurements after cardiac surgery is maintained, we suggest that a cTnI greater than the threshold value without an alarming clinical context (e.g. severe cardiac dysfunction) could be a warning sign to further assess cardiac function (e.g. repeated echocardiography) and decide interventions such as optimized monitoring (e.g. repeated measurements of cTn or natriuretic peptides) or optimized pharmacological support (e.g. vasodilators, angiotensin converting enzyme inhibitors) [START_REF] Ekeloef | Troponin elevations after non-cardiac, non-vascular surgery are predictive of major adverse cardiac events and mortality: a systematic review and meta-analysis[END_REF][START_REF] Gordin | New medications for heart failure[END_REF]. Interestingly, in patients

Supplemental

Supplemental Figure 1: ROC curves for the 2 logistic regression models examining cardiac mortality.

Supplemental