MD Jean Chastre
email: jean.chastre@aphp.fr

MD Charles-Edouard Luyt

Does this patient have VAP?

Introduction

Ventilator-associated pneumonia (VAP) is the most frequent intensive care unit (ICU)-acquired infection among patients on mechanical ventilation (MV). Because VAP leads to substantial antibiotic use and is associated with increased morbidity, prolonged MV and higher mortality rates, its diagnosis is of paramount importance, with two major objectives [START_REF] Chastre | Ventilator-associated pneumonia[END_REF][START_REF] Timsit | De-escalation as a potential way of reducing antibiotic use and antimicrobial resistance in ICU[END_REF]. First, immediately recognize patients with true VAP versus an extrapulmonary bacterial infection, in order to start effective antibiotics against the causative microorganisms as soon as possible.

Second, avoid overusing antibiotics in patients with only proximal airways colonization and no ongoing bacterial infection. Epidemiological results have clearly demonstrated that indiscriminate antimicrobial use in ICU patients can have immediate and long-term consequences, which contribute to the emergence of multiresistant pathogens and increase the risk of serious superinfections [START_REF] Bretonniere | Strategies to reduce curative antibiotic therapy in intensive care units (adult and paediatric)[END_REF][START_REF] Luyt | Antibiotic stewardship in the intensive care unit[END_REF][START_REF] Holmes | Understanding the mechanisms and drivers of antimicrobial resistance[END_REF].

Theoretically, VAP diagnosis requires documenting an intense infiltration of neutrophils, fibrinous exudates and cellular debris into the intraalveolar spaces, particularly around terminal bronchioles, caused by infectious agents not present or incubating at MV onset [START_REF] Chastre | Ventilator-associated pneumonia[END_REF][START_REF] Tejerina | Accuracy of clinical definitions of ventilator-associated pneumonia: comparison with autopsy findings[END_REF]. However, establishing which criteria are really pertinent to diagnosing VAP when histopathological findings are out of reach, as is most often the case in clinical practice, is hampered by the extreme difficulty of confirming or excluding the reality of the lung parenchyma invasion by bacterial pathogensi.e., to distinguish between patients with a true pneumonia and those merely colonized or with only some form of tracheobronchitis.

VAP is typically identified at the bedside by combining imaging, clinical and laboratory findings that include three criteria: 1) new or progressive persistent radiographic infiltrates; 2) clinical observations suggesting infection, e.g., the new onset of fever, purulent sputum, leukocytosis, increased minute ventilation, arterial oxygenation decline and/or the need for increased vasopressor infusion to maintain blood pressure; and 3) "positive" microbiological culture results for a potentially pathogenic microorganism isolated from endotracheal aspirates (ETAs), bronchoalveolar lavage fluid (BALF), pleural fluid and/or blood [START_REF] Horan | CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting[END_REF]. However, this VAP-case definition is complex, frequently inaccurate and leaves room for subjective interpretation as to whether or not a new or worsening pulmonary infiltrate is presentindeed, the latter remains a prerequisite for VAP diagnosis according to the Centers for Disease Control and Prevention (CDC) criteria since it is the only criterion confirming the involvement of the intraalveolar spaces by the infectious processand/or for deciding which threshold should be applied to define a "positive" culture when using semi-quantitative or quantitative ETA or BALF cultures, especially for specimens obtained after starting new antibiotics (see Table 1) [START_REF] Chastre | Ventilator-associated pneumonia[END_REF]. Thus, the absence of undisputable "reference standards" continues to fuel controversy about the adequacy and relevance of many studies in this field and have led investigators to describe either other types of lower respiratory tract infection, e.g. ventilator-associated tracheobronchitis (VAT), or even to abandon the concept of VAP and replace it by a new construct that comprises different levels of "ventilator-associated events", including infection-related ventilator-associated condition (IVAC) [START_REF] Magill | Developing a new, national approach to surveillance for ventilator-associated events*[END_REF]. The following case scenario exemplifies some of the difficulties encountered in diagnosing real VAP.

Case Scenario

A 69-year-old man was admitted to the ICU for postoperative cardiogenic shock and multiorgan failure after cardiac surgery requiring high-dose catecholamine IV infusion, venoarterial-extracorporeal membrane oxygenation, continuous renal replacement therapy and MV. He slowly recovered thereafter but still required MV over the following 10 days, when he became febrile (38.3°C), with an elevated white blood cell count (14,000 per mm 3 , 83% neutrophils). His endotracheal secretions were somewhat purulent and a slight (<50 mmHg) PaO 2 /FIO 2 blood-gas deterioration occurred-not requiring any major ventilator modifications for the PEEP level or FIO 2 . Serum procalcitonin (PCT) concentrations measured the day infection was suspected and 2 days earlier were 4.5 and 0.6 µg/L, respectively (normal value, <0.5 µg/L). A portable chest radiograph showed bilateral infiltrates in the lower lobes that were confirmed on a CT scan obtained the same day (see Figure 1 in the supplementary appendix). However, no clear-cut progression of the radiographic abnormalities could be discerned upon comparison of chest films obtained during the preceding 5 days and that obtained the day pneumonia was suspected (see Fig. 2 in the supplementary appendix).

Before starting any new antibiotics, fiberoptic bronchoscopy with BAL was performed to obtain distal respiratory secretions from a left lower lobe segment visualized during bronchoscopy that had purulent secretions and endobronchial inflammatory lesions. Direct microscopic examination of cytocentrifuged BALF stained with modified Wright-Giemsa stain (Diff-Quik) demonstrated neutrophilic alveolitis with numerous bacilli (see Figure 3 in the supplementary appendix). Two days later, BALF quantitative cultures yielded 10 6 Serratia marcescens CFU/mL and antimicrobial therapy was adjusted based on the antibiogram.

VAP versus VAT

Because a new or progressive radiographic infiltrate could not be documented with certainty, this patient does not entirely satisfy the current CDC definition of VAP used by many infection-control practitioners. Nonetheless, the likelihood that he has developed true pneumonia is very high based on the clinical and laboratory findings, including increased PCT and BAL results that strongly point to pathogen invasion of the deep lung compartment. Clinical experience and many studies have confirmed that BAL is an accurate sampling technique for assessing the cellular and acellular components of distal bronchioles and gas-exchange units, enabling characterization of the lesion types present in the lung parenchyma and the presence or absence of bacteria [START_REF] Chastre | Ventilator-associated pneumonia[END_REF][START_REF] Meyer | An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease[END_REF]. Most probably, the infection occurred in preexisting atelectatic/injured lung areas, thereby explaining why no further radiographic abnormalities could be detected. Evidently, immediately after fiberoptic bronchoscopy, such a patient should receive antimicrobial therapy targeting Gram-negative bacilli chosen based on local epidemiology and previously received, if any, antibiotics. Several studies on patients with acute respiratory distress syndrome (ARDS), pulmonary edema and/or atelectasis demonstrated that most VAPs develop in previously injured lung territories, rendering irrelevant a criterion requiring progression of the previously seen radiological abnormalities to diagnose it in this context [START_REF] Wunderink | Radiologic diagnosis of ventilator-associated pneumonia[END_REF][START_REF] Dudeck | National Healthcare Safety Network report, data summary for 2011, device-associated module[END_REF]. Although CT scans as well as lung ultrasonography can confirm the presence of lung infiltrates and whether or not an air bronchogram is present in such patients, they cannot prove the invasion of the lung parenchyma by bacteria, except perhaps in the few cases in which clinical and microbiological observations strongly suggest infection and serial exams are available, documenting the progression of the lung infiltrates to new territories [START_REF] Berlet | Sonographic patterns of lung consolidation in mechanically ventilated patients with and without ventilator-associated pneumonia: a prospective cohort study[END_REF].

Yet, some investigators will reject a VAP diagnosis for this patient and classify him as having only VAT, arguing that microorganism invasion of the lung parenchyma was not documented in the absence of visualized progression of radiological abnormalities (see table 1). This rejection is highly problematic for several reasons. First, as indicated above, it is highly unlikely that this patient's infectious process was confined to the proximal airways and did not involve the airspaces. Thus, diagnosing VAT in that setting is inherently wrong and might lead to inappropriate management if doctors at the bedside were to be falsely reassured by the absence of visible pneumonia. Indeed, the results of a recent prospective, multicenter, observational study conducted in 114 ICUs in eight countries showed that patients with no visible radiographic progression on chest radiographs but who met the other diagnostic criteria for VAT, including positive microbiological isolation from ETAs (≥10 5 CFU/mL) or BALFs (≥10 4 CFU/mL)i.e., like our case-scenario patienthad longer MV durations and ICU lengths of stay, compared to patients with no ventilator-associated lower respiratory tract infection, confirming that VAT, as defined in that study, overlaps substantially with VAP and affects patients' outcomes [START_REF] Martin-Loeches | Incidence and prognosis of ventilator-associated tracheobronchitis (TAVeM): a multicentre, prospective, observational study[END_REF].

Second, not classifying this patient and others fulfilling the same criteria as VAP will impact the ICU infection-surveillance program: artificially decreasing the visibility and severity of ventilator-associated infections by avoiding VAP diagnosis, while continuing to heavily treat patients with antibiotics. Several investigators have demonstrated that relying too much on the interpretation of chest films, usually retrospectively, consistently underestimated the VAP incidence compared with clinical criteria combined with quantitative cultures, hence underreporting the acquired-pneumonia rate during MV [START_REF] Skrupky | A comparison of ventilator-associated pneumonia rates as identified according to the National Healthcare Safety Network and American College of Chest Physicians criteria[END_REF]. Even though 25% of American ICUs are now reporting a zero VAP rate, those very low rates have never been associated with corresponding reports of decreased antibiotic use or mortality. Third, no consensual VAT definition exists. Some physicians, as indicated above, require a very high bacterial burden in the airways to retain the VAT diagnosis, applying the same cutoffs as those used to define VAP (≥10 5 CFU/mL for ETAs and ≥10 4 CFU/mL for BALFs), while others accept any culture positivity, even low or very low bacterial counts. Indeed, the definition applied runs the risk of opening Pandora's box of antibiotic overuse: when the VAT cutoff is high, VAP and VAT patients will overlap considerably because of the non-specificity of radiographic findings and their interpretation, and, when that threshold is low or not used, VAT and only proximal airways-colonization diagnoses could be blurred [START_REF] Price | Control of infection due to Klebsiella aerogenes in a neurosurgical unit by withdrawal of all antibiotics[END_REF].

VAP versus IVAC

In September 2011, the CDC proposed abandoning the conventional VAP definition and creating new constructs VAC and IVAC, using routine objective clinical data, readily amenable to electronic data capture [START_REF] Magill | Developing a new, national approach to surveillance for ventilator-associated events*[END_REF]. The aim was to identify patients with strongly deteriorating respiratory status after a period of stability or improvement and eliminate some non-specific prerequisites, such as abnormal chest radiographs, that are likely to exclude many patients with pneumonia. Specifically, VAC diagnosis requires an increase of the daily minimum PEEP of ≥3 cm of H 2 O and/or the daily minimum FiO 2 of ≥20 points sustained for ≥2 days. IVAC requires in addition that some evidence of infection be present, e.g. abnormal temperature or white blood cell count, and that patients be prescribed a new antibiotic for ≥4 days (Table 1). No specific microbiological specimens are needed to qualify for IVAC, completely disconnecting the infection diagnosis from the bacterial burden present in the tracheobronchial tree. As found in several investigations, IVAC is clearly associated with higher mortality and longer MV durations than for patients without it [START_REF] Kollef | Ventilator-associated Complications, Including Infection-related Complications: The Way Forward[END_REF][START_REF] Muscedere | The clinical impact and preventability of ventilator-associated conditions in critically ill patients who are mechanically ventilated[END_REF]. However, surveillance for IVAC missed a substantial number of microbiologically documented VAP episodes, particularly when the infection was not sufficiently severe to deteriorate gas exchanges markedly, and, moreover, these symptoms may be observed in many non-VAP diseases, like pulmonary edema, ARDS and/or atelectasis. A growing body of evidence is clearly showing that IVAC and VAP definitions are not interchangeable, targeting different morbid conditions, with different incidences, and attributable morbidities and mortalities. Clearly, when the objective is to decide whether or not an ICU patient should be given antibiotics, the VAC construct cannot replace the usual VAP definition. This situation was once again highlighted in our case scenario, in which worsening oxygenation was insufficient to qualify for VAC and, thus, IVAC.

Conclusion

No consensus has yet been reached on appropriate diagnostic strategies for VAP. However, although the plain (usually portable) chest film is still an important component in the evaluation of ventilated patients with suspected pneumonia, its interpretation remains speculative for many patients and the source of divergent notifications. Our proposal would be to delete the requirement to demonstrate a "new" or "progressive" persistent infiltrate on serial chest radiographs from the VAP definition, arguing that many pneumonia acquired during MV occur in a territory already injured and do not immediately progress to new ones. Because BAL harvests cells and secretions from a large area of the lung (~1 million alveoli) and specimens can be microscopically examined immediately after the procedure to verify the presence or absence of intracellular or extracellular bacteria in the lower respiratory tract, it is particularly well-suited to provide rapid identification of an infection that has reached the intraalveolar spaces and the distal bronchioles. If fiberoptic bronchoscopy with BAL is not available, results of ETA quantitative cultures can be used as an acceptable substitute, provided that a sufficiently high threshold (i.e., ≥10 5 CFU/mL) is applied to avoid overusing antibiotics in patients with only proximal airway colonization. Whether lung ultrasonography and/or new methods for quantifying the bacterial burden present in the LRT can improve our ability to diagnose VAP or LRT infection requiring antimicrobial therapy in addition to BAL remain elusive and warrant being the focus of future investigations.

Table :

 : Diagnostic criteria requested for VAP, VAT and IVAC.

			from endotracheal aspirate
			specimen (e.g., ETA >10 5 CFU
		VAP ->5% BAL-obtained cells per mL) contain intracellular bacteria on	VAT (using a strict definition as defined by	VAT (as defined by CDC)	IVAC
			direct microscopic exam	Martin-Loeches et al. (see
		-Histopathologic exam shows	ref. 13)
	New or progressive persistent infiltrate on	-	Present one of the following: Abscess formation or foci of consolidation with intense PMN	Must NOT be present	Must NOT be present	Not applicable
	chest radiograph Clinical observation	accumulation in bronchioles and At least two of the alveoli -Positive quantitative culture of lung	At least two of the	At least two of the	Both of the following two
	suggesting infection Limitations and drawbacks	following: -New onset of fever parenchyma -A new or progressive -Purulent endotracheal aspirate -Leukocytosis or leucopenia -Increased minute ventilation -Arterial oxygenation decline -Need for increased vasopressor infusion to maintain blood persistent pulmonary infiltrate is impossible to demonstrate in many patients with VAP, even using serial chest	following: -Body temperature >38.5°C or -Such a definition uses <36.5°C -Leucocyte count >12 000 cells per μL or <4000 cells per μL, -Purulent endotracheal aspirate essentially the same microbiological criteria as those used for defining VAP, and only differs by the	following: -Body temperature >38.0°C or -Accepting any ETA <36.0°C culture positivity or -Cough using a low threshold for -Rhonchi, wheezing -Leucocyte count >12 000 defining a positive result renders difficult to cells per μL or <4000 cells per μL, distinguish VAT from	criteria within 2 days -VAP episodes not before or after the onset of sufficiently severe to worsening oxygenation (PEEP increase of ≥3 cm deteriorate gas exchange for qualifying for VAC of H 2 O and/or FiO 2 increase of ≥20 points are missed, disqualifying sustained for ≥2 days): such a definition when
			pressure radiographs.	interpretation made for	-New or increased purulent proximal airways	-Body temperature >38°C or the objective is for
		-Which threshold should be applied to define a "positive" culture when using semi-quantitative or quantitative ETA or	the chest radiographs. -It is highly unlikely that the infectious process in these cases be confined to the proximal airways	endotracheal aspirate colonization. (moderate-heavy WBC on Gram stain) -Using such a definition considerably increases the risk of overusing antibiotics.	<36°C, or leucocyte deciding whether or not count≥12 000 cells per μL or an ICU patient should <4000 cells per μL, receive antibiotics. -AND a new antimicrobial -The symptoms agent(s) is started and continued for ≥4 calendar qualifying for IVAC
			BALF cultures, is	and do not involve the		days may be observed in
	Microbiological	At least one of the controversial, especially	At least one of the airspaces.	"Positive" respiratory	Positive respiratory tract many non-VAP diseases,
	culture results	following: for specimens obtained	following: -Not classifying patients	culture (obtained by deep	Gram stain and/or culture like pulmonary edema,
		-Positive blood culture not after starting new	-Positive quantitative culture fulfilling these criteria as	tracheal aspirate or	(depending whether ARDS and/or atelectasis.
		related to another infection -Positive pleural fluid culture -Positive quantitative culture from minimally contaminated antibiotics.	from minimally contaminated VAP is inherently wrong LRT specimen (e.g., BAL in most cases and might >10⁴ CFU per mL) -Positive quantitative culture lead to inappropriate	bronchoscopy) . No thresholds required	qualitative or quantitative cultures were done and their results, the episode is
			LRT specimen (e.g., BAL >10⁴	from endotracheal aspirate management.		classified as probable or
			CFU per mL)	specimen (e.g., ETA >10 5		possible VAP)
		-Positive quantitative culture	CFU per mL)


MD Magalie Lefrancois

MD, PhD Jérémie H Lefevre

MD Najim Chafai

MD Sophie Pitel

MD Laure Kerger

MD Julie Agostini

MD Guillaume Canard

MD). Emmanuel Tiret

Dr Jeremie H Lefevre
email: jeremie.lefevre@sat.aphp.fr

Management of acute appendicitis in ambulatory surgery. Is it possible? How to select patients?

Keywords: Appendicitis, laparoscopic surgery, outpatient, early discharge, ambulatory surgery

INTRODUCTION

Appendectomy for acute appendicitis (AA) is a common surgical procedure.

Actually, it requires in most cases at least a one-night hospitalization. While several studies have shown that cholecystectomy can be safely performed as an outpatient procedure [START_REF] Gurusamy | Meta-analysis of randomized controlled trials on the safety and effectiveness of day-case laparoscopic cholecystectomy[END_REF] , only few studies have reported their experience of outpatient appendectomies [START_REF] Alvarez | The road to ambulatory laparoscopic management of perforated appendicitis[END_REF][START_REF] Gilliam | Day case emergency laparoscopic appendectomy[END_REF][START_REF] Brosseuk | Day-care laparoscopic appendectomies[END_REF][START_REF] Schreiber | Results of outpatient laparoscopic appendectomy in women[END_REF][START_REF] Jain | Outpatient laparoscopic appendectomy[END_REF][START_REF] Cross | Laparoscopic appendectomy for acute appendicitis: a safe same-day surgery procedure?[END_REF][START_REF] Sabbagh | The feasibility of short-stay laparoscopic appendectomy for acute appendicitis: a prospective cohort study[END_REF][START_REF] Dubois | Impact of an outpatient appendectomy protocol on clinical outcomes and cost: a case-control study[END_REF][START_REF] Cash | A prospective treatment protocol for outpatient laparoscopic appendectomy for acute appendicitis[END_REF][START_REF] Alkhoury | A prospective study of safety and satisfaction with same-day discharge after laparoscopic appendectomy for acute appendicitis[END_REF] . This may seems paradoxical because this procedure is most often performed in young and healthy people, with an operating time inferior to one hour and with mastered risks. Therefore ambulatory's conditions are met. Yet, appendectomy still continues to be carried out during a conventional hospitalization. Ambulatory surgery (AmbSurg) is defined as an hospital stay inferior to 12 hours without overnight hospitalization. Ambulatory appendectomy is not yet performed routinely because it requires most of the time the deferral of surgery to the next morning. The main obstacle for this type of care is the fear of missing a complicated appendicitis or meeting unexpected operating difficulties. However, we believe that, in selected patients, emergency laparoscopic appendectomy (LA) may be feasible in ambulatory surgery.

Unfortunately, data on clinical, biological and radiological preoperative criteria that could predict the success of this type of care are missing.

The aims of this study were to determine preoperative criteria associated with discharge at day-1, to validate them on a prospective series and apply them to select patients for ambulatory surgery.

MATERIALS AND METHODS

Retrospective study and creation of the score

All records of patients who underwent appendectomy between January 1, 2010, and December 31, 2012 were reviewed retrospectively. We included patients who underwent emergency LA after diagnosis of AA based on CT-or US-findings. Patients who underwent interval appendectomy after medical emergency treatment (antibiotic treatment of appendicular plastron or radiological drainage of appendicular abscess), those who had appendectomy by laparotomy and those with stump appendicitis were excluded.

Univariate and multivariate analysis of preoperative variables were performed to create the score.

Prospective study, validation of the score and ambulatory care.

Patients and surgical management

Between January 1 and December 15, 2013, all patients with a diagnosis of AA were prospectively included. Diagnosis was always supported by CT-scan or ultrasound (appendicular thickening greater than 6 mm and periappendicular fat stranding). The calculated score was used before admission.

For a score superior or equal to 4, AmbSurg was considered. If ambulatory operating room was available and in the absence of exclusion criteria (history of pelvic surgery, pregnancy, severe comorbidities, severe sepsis, excessive pain, no accompanying person, home located over one hour transport, insufficient understanding), LA in AmbSurg was proposed to the patient. If accepted, the day of surgery depended on the time of diagnosis.

Between 7:00 and 13:00 AM, the patient was directly admitted in AmbSurg unit. After 13:00 AM, the operation was delayed until the next morning. If the operation was postponed to the next day, the patient returned home with oral antibiotics (amoxicillin plus clavulanic acid, 3 g per day) and analgesics. In case of refusal, LA was performed in a conventional surgery (ConvSurg) unit.

For a score inferior to 4, patients were systematically admitted in a ConvSurg ward. In case of uncomplicated AA on CT or US-scan, the time until surgery depended on the hour of admission and the choice of each surgeon. If appendectomy was postponed to the next day, patients received intravenous antibiotics during the waiting period. Patients with clinical or radiological evidences of abscess or peritonitis were immediately operated.

Operative technique

The surgical technique did not differ according to the type of support. Since January 1, 2013, except if patients had a history of laparotomy, appendectomy was systematically performed by laparoscopy. A standard laparoscopic operative technique was used. A 10 mm optic trocar was introduced at the umbilicus, by an open technique, and was used for insufflation of pneumoperitoneum. If possible, low-pressure pneumoperitoneum (9-mmHg) was used. Then a 5 mm suprapubic port and a 5 mm left iliac fossa port were placed under direct vision. A bipolar plier was used to coagulate the mesoappendix. If healthy, the appendical base was tied with a preformed suture loop. The appendix was then placed in a bag and retrieved through the optical port. Intraperitoneal abcess were simply aspirated. Peritoneal lavage was used only in cases of peritonitis. No drainage was routinely placed. Each trocar was systematically infiltrated with 5 mL of Ropivacain 7.5%. Patients with mild appendicitis just received a single intraoperative dose of antibiotics (2 g of amoxicillin plus clavulanic acid).

Postoperative management

Patients undergoing ConvSurg were monitored for few hours in the recovery room and then returned to the surgical ward. Patients without severe comorbidity were routinely discharged from hospital at day-1, i.e. the morning following appendectomy, if they tolerated feeding, had pain controlled by usual analgesics and no fever. In case of vomiting, fever, excessive pain, hospitalization was prolonged.

Patients who underwent LA in AmbSurg unit were monitored in the recovery room until full awakening and a light meal was given. In the absence of fever, pain, nausea or vomiting, the patient was discharged directly from the recovery room.

The follow-up evaluation was performed 30 days after surgery for all patients.

Data collection

For both retrospective and prospective studies, clinical data collected were: age, gender, ASA score, Body Mass Index (BMI), delay of pain before consultation, temperature.

Biological data collected were: C-reactive protein (CRP) and white cell count (WCC).

Radiological findings collected were: appendix diameter, presence of an appendicolith, signs of perforation (defined by the presence of collection, free peritoneal fluid, pneumoperitoneum or ileus). Operative data collected were: time between admission and surgery, severity of appendicitis, operative time, conversion. Postoperative data were: length of the postoperative stay, morbidity (defined as any complication within 30 days of operation), mortality, rehospitalization, reoperation, pathological report.

Statistical analysis

Descriptive analyses are presented as median (range) or mean +/-standard deviation for quantitative data and as number of patients (percentage of patients) for categorical data.

The correlation between the early discharge and the variables of interest was studied by univariate analysis (Chi-square). All tests were two-sided, and a p-value <0.05 was considered to be significant. The multivariate analysis was performed using a backward stepwise logistic regression model that included all variables with a p-value <0.1 in univariate analysis. Results of this multivariate analysis are shown as odds ratio (OR); [95 percent confidence interval]. All analyses were performed using JMP9 (SAS Institute Inc, Cary, NC, USA).

RESULTS

Retrospective study and creation of the score

Patients

Between 2010 and 1012, 560 emergency appendectomies were performed in our hospital.

Ninety-two patients (16%) were excluded for: open approach (n=85), stump appendicitis (n=4) or missing files (n=3). Finally, 468 (84%) patients were included in the study.

Details about the overall study population are given in table 1.

Predictive factor analysis of early discharge

One hundred eighty-one patients were discharged at day-1 (39%). In univariate analysis (table 2), 7 factors associated with early discharge were: BMI<28 kg/m 2 (p=0.0016), ASA score<2 (p=0.0223), duration of pain<2 days (p=0.0001), WCC<15.0 per μL (p=0.0369), CRP<30 mg/L (p<0.0001), no radiological signs of perforation (p<0.0001) and appendix diameter≤10 mm (p<0.0001). In multivariate analysis, 5 independent factors were identified: BMI<28 kg/m 2 , WCC<15.0 per μL, CRP<30 mg/L, no radiological signs of perforation and appendix diameter≤10 mm (Table 2).

Saint-Antoine's score

The 5 factors associated with the patients' conditions were used in a score ranging from 0 to 5, according to the presence of these criteria (Table 3). The rates of discharge at day-1 ranged from 0% to 72% for a score of 0 or 5, respectively (p<0.0001). The rates of complicated AA was also significantly influenced by the score from 0% to 100% for a score of 5 or 0 (p<0.0001)(figure 1).

Prospective study, validation of the score, ambulatory appendectomy Patients

During the study period, 191 AA were diagnosed (84% by a CT-scan) and 7 patients (0.4%) were excluded because they had medical treatment or laparotomy (Figure 2) leaving 184 patients included. Clinical, operative and postoperative data for the prospective study population are listed in table 1. Among them, 103 (56%) had a score superior or equal to 4. After appendectomy, pathological confirmation was observed in 181 specimens (98%).

Conventional surgery and validation of the score.

Finally 146 patients underwent LA in ConvSurg and 58% were discharged at day-1. The rate of discharge at day-1 was significantly associated with the score ranging from 0% to 92% for a score of 0 or 5, respectively (table 3). The St-Antoine's score was therefore validated on this prospective series (p<0.0001). As for the retrospective group, the rate of complicated appendicitis was associated with the score (p<0.0001) (Figure 1).

Ambulatory surgery group

Thirty-eight patients underwent ambulatory LA. Among them, 22 (58%) were directly admitted to AmbSurg unit, with a mean time between diagnosis and surgery of 2.9h ± 2.1. For the remaining 16 patients (42%), LA was postponed to the next day. The mean time between diagnosis and surgery was 15.5h ± 3.8 for this group of patients. All patients were directly discharged from recovery room, except one patient (2.6%) who had to be admitted for the night in ConvSurg unit due to insufficient awakening. The mean time between surgery and discharge was 4.5h ± 6.6 and the mean hospital length of stay was 8.4h ± 6.9h.

The AmbSurg group (n=37) was compared with the 65 patients with a score≥4 hospitalized in ConvSurg unit (table 4). One patient operated in AS was excluded because he had a score of 3 points due a wrong estimation of the appendicular size (11 mm). The 2 groups were comparable regarding age, sex ratio, score distribution, surgical postponing, time between diagnosis and surgery and operative data (except operative time significatively shorter in the AS group). Time between surgery and discharge and length of hospital stay were significantly longer in ConvSurg group (p<0.0001). The rates of unplanned consultation, rehospitalization and surgical morbidity were similar in the 2 groups.

DISCUSSION

The laparoscopic approach is now widely used for appendectomy. Indeed, several studies have shown its benefit over conventional appendectomy in reducing postoperative pain and enabling faster return to normal activities, with a lower incidence of wound infection, even if it has been identified a higher incidence of pelvic abscess. Moreover, it has been shown that the laparoscopic approach reduces the length of hospital stay [START_REF] Sauerland | Laparoscopic versus open surgery for suspected appendicitis[END_REF] . That's why we routinely use it in the management of AA in our department.

While outpatient procedure has become the standard of care for elective cholecystectomy [START_REF] Gurusamy | Meta-analysis of randomized controlled trials on the safety and effectiveness of day-case laparoscopic cholecystectomy[END_REF] , only few studies have reported their experience of outpatient appendectomies [START_REF] Alvarez | The road to ambulatory laparoscopic management of perforated appendicitis[END_REF][START_REF] Gilliam | Day case emergency laparoscopic appendectomy[END_REF][START_REF] Brosseuk | Day-care laparoscopic appendectomies[END_REF][START_REF] Schreiber | Results of outpatient laparoscopic appendectomy in women[END_REF][START_REF] Jain | Outpatient laparoscopic appendectomy[END_REF][START_REF] Cross | Laparoscopic appendectomy for acute appendicitis: a safe same-day surgery procedure?[END_REF][START_REF] Sabbagh | The feasibility of short-stay laparoscopic appendectomy for acute appendicitis: a prospective cohort study[END_REF][START_REF] Dubois | Impact of an outpatient appendectomy protocol on clinical outcomes and cost: a case-control study[END_REF][START_REF] Cash | A prospective treatment protocol for outpatient laparoscopic appendectomy for acute appendicitis[END_REF][START_REF] Alkhoury | A prospective study of safety and satisfaction with same-day discharge after laparoscopic appendectomy for acute appendicitis[END_REF] . Some retrospective studies have shown the feasibility of LA for AA during an hospitalization inferior to 24 hours [START_REF] Alvarez | The road to ambulatory laparoscopic management of perforated appendicitis[END_REF][START_REF] Gilliam | Day case emergency laparoscopic appendectomy[END_REF][START_REF] Brosseuk | Day-care laparoscopic appendectomies[END_REF][START_REF] Schreiber | Results of outpatient laparoscopic appendectomy in women[END_REF][START_REF] Jain | Outpatient laparoscopic appendectomy[END_REF][START_REF] Cross | Laparoscopic appendectomy for acute appendicitis: a safe same-day surgery procedure?[END_REF] . They reported an overall success rate ranging from 57 to 75%, a very low morbidity ranging from 0 to 6.4 % and no mortality. Sabbagh et al.

showed in a prospective study that 52% of laparoscopic appendectomies can be achieved during a hospital length of stay inferior to 24 hours [START_REF] Sabbagh | The feasibility of short-stay laparoscopic appendectomy for acute appendicitis: a prospective cohort study[END_REF] . This percentage rises to 73% after exclusion of patients with medical or social contraindications to outpatient procedure and complicated appendicitis.

To our knowledge, only 3 prospective series are dealing with same-day discharge after LA [START_REF] Dubois | Impact of an outpatient appendectomy protocol on clinical outcomes and cost: a case-control study[END_REF][START_REF] Cash | A prospective treatment protocol for outpatient laparoscopic appendectomy for acute appendicitis[END_REF][START_REF] Alkhoury | A prospective study of safety and satisfaction with same-day discharge after laparoscopic appendectomy for acute appendicitis[END_REF] . In these different studies, definitive inclusion of patients was made during surgery, after exclusion of complicated AA. Dubois et al. found, in a prospective study of 161 patients, that same-day discharge was feasible in 45% of cases. This percentage rises to 66% considering only uncomplicated AA [START_REF] Dubois | Impact of an outpatient appendectomy protocol on clinical outcomes and cost: a case-control study[END_REF] . In matched comparison, there was no significant difference in complications or reoperation rates between the study cohort and the historical cohort. Cash and colleagues were able to raise the success rate of same-day discharge for uncomplicated AA from 35 to 85% due to the implementation of a protocol, without increasing morbidity (8.4 vs. 5.2%) [START_REF] Cash | A prospective treatment protocol for outpatient laparoscopic appendectomy for acute appendicitis[END_REF] . In a prospective study of 158 children (mean age 12 years), Alkhoury et al. reported a success rate of 80% and a satisfaction rate of 87% of same-day discharge following LA [START_REF] Alkhoury | A prospective study of safety and satisfaction with same-day discharge after laparoscopic appendectomy for acute appendicitis[END_REF] . These three studies reported a median postoperative length of stay ranging from 2.8 hours to 4.8 hours. The length of hospital stay was not reported in any of these studies. In the study of Cash [START_REF] Cash | A prospective treatment protocol for outpatient laparoscopic appendectomy for acute appendicitis[END_REF] , some patients underwent LA during the night, while in the study of Alkhoury 11 , children diagnosed with appendicitis during the night were admitted to the inpatient surgical ward and underwent LA the following morning. These studies show that it is possible to shorten the postoperative monitoring after appendectomy without increasing morbidity. However, a classic hospitalization is still needed while we are living in a time of cost-cutting budgets and reduction of the number of available beds in surgical wards. Moreover, these study do not meet the strict definition of AmbSurg. Indeed, AmbSurg is defined by a hospital length of stay of less than 12 hours without overnight hospitalization. This implies that LA must be performed during the daytime, so that surgery must often be postponed to the next day and that the patient has to return home for the night. Moreover, in our department, as it is often the case, the ambulatory operating theatres are different from the classical theatre and patients are discharged directly from recovery room. So, the choice of an ambulatory surgery needs to be taken prior to admission. Surgical hazards (complicated AA, conversion) must be anticipated to decrease the risk of unexpected overnight admission. That's why we thought that selection of patients must be based on preoperative criteria only and not on peroperative findings. That's because predictive factors of success for this type of support are lacking, that we analyzed in a preliminary retrospective study which preoperative criteria were associated with discharge at day-1, assuming that patient discharged at day-1 could have been discharged at the same day of surgery. It allowed us to establish predictive score of early discharge, based on five preoperative criteria. The prospective study confirmed that this score was safe and valid. Moreover, if the score was applied to AmbSurg, it allowed us to reach a success rate of 97%. We also showed that AL performed in AmbSurg did not increase morbidity, even if 42% were postponed to the next day. Of note, the mean time between diagnosis and surgery was 15.5 hours if patients were reconvened to the next day. Studies are contradictory regarding the impact of delaying appendectomy on the rate of perforated appendicitis in adults [START_REF] Ingraham | Effect of delay to operation on outcomes in adults with acute appendicitis[END_REF][START_REF] Abou-Nukta | Effects of delaying appendectomy for acute appendicitis for 12 to 24 hours[END_REF][START_REF] Busch | In-hospital delay increases the risk of perforation in adults with appendicitis[END_REF][START_REF] Kearney | Influence of delays on perforation risk in adults with acute appendicitis[END_REF][START_REF] Ditillo | Is it safe to delay appendectomy in adults with acute appendicitis?[END_REF] . In the largest study based on the American College of Surgeons National Surgical Quality Improvement Program database, including 32,782 patients [START_REF] Ingraham | Effect of delay to operation on outcomes in adults with acute appendicitis[END_REF] , Ingraham et al. found that delay of appendectomy after admission does not adversely affect postoperative outcome. In a retrospective study of 389 patients, Abou-Nukta et al. showed no statistically significant differences in the length of stay, rate of advanced appendicitis or complications between patients who underwent appendectomy 12 and 24 hours after presenting to the emergency department compared with less than 12 hours [START_REF] Abou-Nukta | Effects of delaying appendectomy for acute appendicitis for 12 to 24 hours[END_REF] . Others have demonstrated a negative impact on outcomes associated with a delay in appendectomy. Busch et al, in a prospective study of 1675 patients, found that the rate of perforations at the time of surgery was statistically associated with a delay of more than 12 hours after admission (29.7 % vs. 22.7%; p=0.01) [START_REF] Busch | In-hospital delay increases the risk of perforation in adults with appendicitis[END_REF] . Kearney et al. showed that overall duration of symptoms prior to operation was independently associated with the risk of perforation [START_REF] Kearney | Influence of delays on perforation risk in adults with acute appendicitis[END_REF] . In-hospital waiting time was not a predictor for perforation. This is in accordance with the findings of Ditillo et al. who suggests that prehospital delay in presentation contributes more significantly to worsening pathology compared with in-hospital delay [START_REF] Ditillo | Is it safe to delay appendectomy in adults with acute appendicitis?[END_REF] . So it appears that it is possible, especially in patients selected according to the five criteria above, to postpone appendectomy to the next morning without increasing morbidity. Indeed, the score was also associated with the rate of complicated AA. On a small number of patients, we did not find complicated AA, even if delay before surgery was extended.

One could ask whether CT-scan is not sufficient to select patients. In a retrospective series of 244 patients, Bixby et al. showed that the presence of ileus, extraluminal gas or abscess were highly specific of perforation [START_REF] Bixby | Perforated versus nonperforated acute appendicitis: accuracy of multidetector CT detection[END_REF] . On the other hand, the sensitivities of these findings were disappointing, ranging from 34 to 53%. They concluded that, unless abcess or extraluminal gas is present, multidetector CT cannot enable the diagnosis of perforation. Our score, by adding clinical and biological criteria to radiological criteria allowed us to obtain a probability of ignoring complicated AA of only 8 and 3% for scores of respectively 4 and 5.

Different prospective randomized trials comparing antibiotics and surgery to treat uncomplicated AA found comparable treatment efficacy [START_REF] Styrud | Appendectomy versus antibiotic treatment in acute appendicitis. a prospective multicenter randomized controlled trial[END_REF][START_REF] Hansson | Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients[END_REF][START_REF] Vons | Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial[END_REF] . In our study, most of patients with a score≥4 would probably have been treated successfully with antibiotics alone. Medical treatment could further reduce the costs of care provided that patients are not hospitalized. In the first two studies [START_REF] Styrud | Appendectomy versus antibiotic treatment in acute appendicitis. a prospective multicenter randomized controlled trial[END_REF][START_REF] Hansson | Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients[END_REF] , among patients who initially improved without surgery, 15% had recurrent appendicitis at a median of 1 year. In the study of Vons 21 , this percentage raises to 29%. This difference is probably due to a low rate of lost to follow-up but also to the fact that diagnosis was always supported by a CT-scan, in contrast to other two studies. It's because of this high rate of recurrence that emergency appendectomy for AA remains the standard of care in our institution.

One criticism that could also be done is that this score is too restrictive. It is true that only about one half of patients met criteria for ambulatory care but our very low unexpected overnight admission rate was achieved through a strict selection of patients. Finally, 21% of the overall LA could have been performed in AmbSurg. This low rate was mainly due to logistical problems. The main obstacle identified was the difficulty to dispose of available operating room in AmbSurg unit. Indeed, in our institution, the AmbSurg unit is open only eleven hours per day and is closed on Saturday and Sunday, which reduces the possibility of support for surgical emergencies. So efforts should be made in the future to facilitate the management of gastrointestinal surgical emergencies in AS, especially AA which concern 80,000 patients per year in France.

CONCLUSION

We identified five preoperative criteria associated with discharge at day-1 after LA. It allowed us to establish a simple predictive score of early discharge which was validated on a prospective cohort. When applied to ambulatory surgery, it allowed us to select patients eligible for this type of care with a success rate of 97%. We didn't note increasing morbidity after LA performed in AmbSurg even if it was postponed to the next day. Our study is the first one to report the experience of ambulatory care in the management of AA. This type of care needs to be validated on a largest cohort. St-Antoine's Score Rate of complicated appendicitis

Figure 1 .

 1 Figure 1. Rate of complicated appendicitis according to the score for both studies.

Figure 2 .

 2 Figure 2. Flow of patients included in the prospective study.

Figure

  Figure

Figure 2 .

 2 Figure 2. Flow of patients included in the prospective study.

Figure

  Figure

Table 1 .

 1 Clinical, operative and postoperative data for patients included. Rate of complicated appendicitis according to the score for both studies.

	Variables	Retrospective study n=468	Prospective study n=184
	Women	227 (48.5%)	85 (46.2%)
	Age (years)	34 ± 14 (16-89)	37 ± 15 (15-82)
	ASA 1 score	404 (86%)	156 (84.8%)
	Time between diagnosis and surgery (h)	7.7 ± 8.3 (0.3-113)	7.0 ± 6.8 (0.3-35.5)
	Operative time (min)	69 ± 34 (15-355)	56 ± 29 (14-180)
	Complicated appendicitis	107 (22.8%)	56 (30.4%)
	Conversion	25 (5.3%)	13 (7.1%)
	Time between surgery and discharge (h)	47.1 ± 55.4 (6.7-902)	41.8 ± 59.0 (3.4-354)
	Hospital length of stay (h)	54.8 ± 56.6 (11.0-923)	49.3 ± 59.4 (5.0-357)
	Surgical morbidity	34 (7.3%)	24 (13.0%)
	Surgical site infection	24 (5.1%)	11 (9.2%)
	Rehospitalization	25 (5.3%)	16 (8.7%)

Table Figure 1.