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A prospective non-randomized controlled, multicenter trial comparing Appendectomy and Conservative Treatment for Patients with Uncomplicated Acute Appendicitis (the ACTUAA study)

  • Clinical Study Protocol
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Abstract

Purpose

Acute appendicitis (AA) is among the most common causes of lower abdominal pain and admissions to the emergency department. Over the past 20 years, there has been a renewed interest in the conservative management of uncomplicated AA, and several studies demonstrated that an antibiotic-first strategy is a viable treatment option for uncomplicated AA. The aim of this prospective non-randomized controlled, multicenter trial is to compare antibiotic therapy and emergency appendectomy as treatment for patients with uncomplicated AA confirmed by US and/or CT or MRI scan.

Methods

All adult patients in the age range 18 to 65 years with suspected AA, consecutively admitted to the Surgical Department of the 13 participating Italian Hospitals, will be invited to take part in the study. A multicenter prospective collected registry developed by surgeons, radiologists, and pathologists with expertise in the diagnosis and treatment of uncomplicated acute appendicitis represents the best research method to assess the long-term role of antibiotics in the management of the disease. Comparison will be made between surgical and antibiotic-first approaches to uncomplicated AA through the analysis of the primary outcome measure of complication-free treatment success rate based on 1-year follow-up. Quality of life, length of hospital stay, pain evaluation, and time to return to normal activity will be evaluated as secondary outcome measures.

Trial registration

Clinicaltrials.gov ID: NCT03080103

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Abbreviations

AA:

Acute Appendicitis

CT:

Computed Tomography

MRI:

Magnetic Resonance Imaging

US:

Ultrasound Scan

AIR:

Appendicitis Inflammatory Response

VAS:

Visual Analogue Scale

IBD:

Inflammatory Bowel Disease

SF-12:

Short Form-12

WBC:

White Blood Cell

CRP:

C-Reactive Protein

CDC:

Center for Disease Control (Atlanta)

SSI:

Surgical Site Infection

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Acknowledgements

The authors would like to thank and express gratitude to Professor Silvio Garattini and Doctor Vittorio Bertele’ (Mario Negri Institute for Pharmacological Research, Milan, Italy) for the intellectual review of the ACOI Study Project on Acute Appendicitis and Ms. Lydia O’Sullivan (Department of General Surgery, King’s College Hospital, London) for the English language editing process. The study has been possible mainly thanks to all the colleagues of the ACOI study group on Acute Appendicitis and the Italian Surgical Units involved, which have taken the time to give their unique contribution.

The ACTUAA Study Collaborative Working Group: Francesco Balestra, Roberto Ottonello, Antonio Lai, Silverio Piro, Giulio Argenio, Sergio Gemini, Miriam Pala, Mario Piras, Enrico Erdas, Angelo Nicolosi, Luca Gordini, Francesco Podda, Adolfo Pisanu, Jenny Atzeni, Gaetano Poillucci, Carlo De Nisco, Luigi Casciu, Maurizio Piano, Salvatore Labate, Luca Saba, Simona Aresu, Antonio Azzinnaro, Giovanna Ioia, Luciano Turri, Fabio Pulighe, Marco Anania, Alfonso Canfora, Vincenzo Bottino, Diego Piazza, Gianluigi Luridiana, Piergiorgio Serra, Alessandra Saba, Antonio Tuveri, Giovanni Pinna, Antonella Piredda, Francesco Madeddu, Patrizia Dalla Caneva, Daniele Delogu, Antonella Saliu, Gianfranco Cogoni, Antonello Deserra, Renata Pau, Sergio Cossu, Luisa Canu, Gianni Marcias, Franco Garau, Salvatore Loi, Giulia Bellisano, Luigi Presenti, Antonio Maccioni, Giorgio Norcia, Emanuele Piras, Stefania Fiume, Antonella Pitzalis, Paola Bianco, Mariangela Cappai, Flavio Nicola Cadeddu, Alessandra Manca, Giovanni Occhioni, Arianna Magoni Rossi, Salvatore Rizzo, Maurizio Centonze, Vincenzo Portolano, Mattia Barbareschi, Elena Barrasi, Martina Martorana, Franca Ferro, Claudia Casarini, Giorgio Stella, Paola Generoso, Sabina Rossi, Fabrizio Abelli, Laura Casula, Chiara Gerardi, Vittorio Bertele’.

Author information

Authors and Affiliations

  1. General, Minimally Invasive and Robotic Surgery Unit, San Francesco Hospital, Via Mannironi 1, 08100, Nuoro, Italy

    Mauro Podda

  2. General Surgery Unit, Civil Hospital, Alghero, Italy

    Fernando Serventi

  3. Surgical Science Department, Cagliari University Hospital, Cagliari, Italy

    Lorenzo Mortola

  4. Radiology Department, Santissima Trinità Hospital, Cagliari, Italy

    Stefano Marini

  5. Radiology Department, Brotzu Hospital, Cagliari, Italy

    Danilo Sirigu

  6. Pathology Department, Santissima Trinità Hospital, Cagliari, Italy

    Michela Piga

  7. General and Emergency Surgery, San Marcellino Hospital, Muravera, Italy

    Marcello Pisano

  8. General and Emergency Surgery, Nostra Signora della Mercede Hospital, Lanusei, Italy

    Massimiliano Coppola

  9. General and Emergency Surgery, Adria Civil Hospital, Adria, Italy

    Ferdinando Agresta

  10. Department of General Surgery, King’s College Hospital, NHS Foundation Trust, London, UK

    Francesco Virdis

  11. Emergency and Trauma Surgical Unit, Maggiore Hospital, Bologna, Italy

    Salomone Di Saverio

  12. General Surgery Unit, Santissima Trinità Hospital, Cagliari, Italy

    Nicola Cillara

Authors
  1. Mauro Podda
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  2. Fernando Serventi
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  3. Lorenzo Mortola
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  4. Stefano Marini
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  5. Danilo Sirigu
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  6. Michela Piga
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  7. Marcello Pisano
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  8. Massimiliano Coppola
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  9. Ferdinando Agresta
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  10. Francesco Virdis
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  11. Salomone Di Saverio
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  12. Nicola Cillara
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Consortia

The ACTUAA Study Collaborative Working Group

  • Francesco Balestra
  • , Roberto Ottonello
  • , Antonio Lai
  • , Silverio Piro
  • , Giulio Argenio
  • , Sergio Gemini
  • , Miriam Pala
  • , Mario Piras
  • , Enrico Erdas
  • , Angelo Nicolosi
  • , Luca Gordini
  • , Francesco Podda
  • , Adolfo Pisanu
  • , Jenny Atzeni
  • , Gaetano Poillucci
  • , Carlo De Nisco
  • , Luigi Casciu
  • , Maurizio Piano
  • , Salvatore Labate
  • , Luca Saba
  • , Simona Aresu
  • , Antonio Azzinnaro
  • , Giovanna Ioia
  • , Luciano Turri
  • , Fabio Pulighe
  • , Marco Anania
  • , Alfonso Canfora
  • , Vincenzo Bottino
  • , Diego Piazza
  • , Gianluigi Luridiana
  • , Piergiorgio Serra
  • , Alessandra Saba
  • , Antonio Tuveri
  • , Giovanni Pinna
  • , Antonella Piredda
  • , Francesco Madeddu
  • , Patrizia Dalla Caneva
  • , Daniele Delogu
  • , Antonella Saliu
  • , Gianfranco Cogoni
  • , Antonello Deserra
  • , Renata Pau
  • , Sergio Cossu
  • , Luisa Canu
  • , Gianni Marcias
  • , Franco Garau
  • , Salvatore Loi
  • , Giulia Bellisano
  • , Luigi Presenti
  • , Antonio Maccioni
  • , Giorgio Norcia
  • , Emanuele Piras
  • , Stefania Fiume
  • , Antonella Pitzalis
  • , Paola Bianco
  • , Mariangela Cappai
  • , Flavio Nicola Cadeddu
  • , Alessandra Manca
  • , Giovanni Occhioni
  • , Arianna Magoni Rossi
  • , Salvatore Rizzo
  • , Maurizio Centonze
  • , Vincenzo Portolano
  • , Mattia Barbareschi
  • , Elena Barrasi
  • , Martina Martorana
  • , Franca Ferro
  • , Claudia Casarini
  • , Giorgio Stella
  • , Paola Generoso
  • , Sabina Rossi
  • , Fabrizio Abelli
  • , Laura Casula
  • , Chiara Gerardi
  •  & Vittorio Bertele’

Contributions

Mauro Podda: Co-principal investigator. Ideated and designed the study, performed the literature search, drafted and critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Fernando Serventi: Ideated and designed the study, critically revised the article for important intellectual content, and edited and approved the English version of the manuscript.

Lorenzo Mortola: Designed the electronic registration form and database, critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Stefano Marini: Ideated and designed the study, critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Danilo Sirigu: Ideated and designed the study, critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Michela Piga: Ideated and designed the study, critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Marcello Pisano: Ideated and designed the study, critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Massimiliano Coppola: Ideated and designed the study, critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Ferdinando Agresta: Ideated and designed the study, critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Francesco Virdis: Critically revised the article for important intellectual content and edited and approved the final version of the manuscript.

Salomone Di Saverio: Ideated and designed the study, critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Nicola Cillara: Principal investigator. Ideated and designed the study, critically revised the article for important intellectual content, and edited and approved the final version of the manuscript.

Guarantor: Mauro Podda, M.D.

Corresponding author

Correspondence to Mauro Podda.

Ethics declarations

All the investigators agree to conduct the study in accordance with the principles of the Declaration of Helsinki and its later amendments and “good clinical practice” guidelines. A written informed consent will be obtained from all patients included in the study prior to the data collection and evaluation.

Ethics and dissemination

The study has been approved by the Medical Ethical Committee of the University of Cagliari (Acceptance Code PG/2017/8426, May 29, 2017).

Ethical approval

Independent Ethical Committee of the University of Cagliari Acceptance Code PG/2017/8426, May 29, 2017. ClinicalTrials.gov ID NCT03080103.

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Additional information

Strengths and limitations of this study

1. Over the past 20 years, there has been a renewed interest in the conservative management of uncomplicated acute appendicitis. However, despite all the improvements in the diagnostic process, the crucial decision of whether to operate or not remains challenging.

2. The aims of the study are to investigate the efficacy, safety, and feasibility of the antibiotic-first approach and to perform a comparative analysis of the quality of life of the patients following either surgery or antibiotic therapy. Furthermore, the study aims to investigate which patient-specific variables are related to antibiotic therapy failure, if any.

3. In order to overcome the limitations reported by previous studies, we developed this prospective non-randomized controlled, multicenter trial comparing appendectomy and conservative treatment for patients with uncomplicated acute appendicitis.

4. In order to overcome possible selection bias due to the non-randomized design of the study and reduce both the rate of negative appendectomy and that of complicated appendicitis, this study protocol provides clear inclusion criteria and standardized CT and US scan templates for the diagnosis of uncomplicated acute appendicitis.

On behalf of the Italian Society of Hospital Surgeons-ACOI Study Group on Acute Appendicitis.

Sponsor: The publication of this study protocol was endorsed by the Italian Society of Hospital Surgeons ACOI—Via C. Morin 45–00195, Rome (Italy).

Study Contacts

Principal Investigator: Dr. Nicola Cillara, M.D.

Co-Principal Investigator: Dr. Mauro Podda, M.D.

Coordinating Ethics: Medical Ethical Committee of the University of Cagliari, Italy.

Study Coordination and Data Management: The ACTUAA Study Collaborative Working Group.

Informatic Support: Dr. Lorenzo Mortola, M.D. Department of Surgical Science, University of Cagliari, Italy., Dr. Laura Casula, M.Sci.Stat.D., Department of Medicine and Public Health, University of Cagliari, Italy.

Local Monitoring: The ACTUAA Study Collaborative Working Group.

Appendix

Appendix

A. Definitions and classifications adopted

Intraoperative complications

Any adverse event in the course of the surgical procedure will be recorded and described by each of the participating surgeons in the operation notes. Particularly, the rate of the following events will be detected and analyzed:

  • Injury of visceral organs.

  • Bleeding (intra-abdominal and/or from the trocar site).

  • Vascular lesions.

  • Anesthesia complications.

  • Adverse drug reactions due to antibiotic administration will be recorded and described by each of the participating surgeons in the clinical notes.

Postoperative complications

Any adverse event leading to a deviation from the normal postoperative course during a patient’s hospitalization will be detected, recorded, described, and classified using the Dindo-Clavien scale [41].

Moreover, early and late complications after discharge will be detected from the medical records and analyzed:

  • Postoperative bleeding (documented by clinical signs and symptoms or the need for transfusion, blood samples revealing acute anemia, reports of radiological investigations, reports of surgical procedures).

  • Wound infection (superficial or deep surgical site infections, reported in medical records, according to the CDC classification) [23].

  • Intra-abdominal abscess or fluid collection (confirmed by US or CT and reported in medical records).

  • Small bowel obstruction and ileus due to adhesions (documented by clinical examination and signs of intestinal dilatation on abdominal X-ray and/or CT scan and reported in medical records).

  • Incisional hernia (either from laparotomy or trocar sites, documented by clinical examination and eventually US and/or CT scan, and reported in medical records).

  • Pulmonary embolism, cardiovascular complications, complications due to anesthesia.

Antibiotic treatment complications

Any antibiotic side effect (defined as an unwanted reaction occurring in addition to the desirable therapeutic action of the antibiotic), pulmonary embolism, and cardiovascular complications will be detected and recorded in the medical reports.

B. Ultrasound scan protocol

A collaborative group for the quality improvement in radiology, focalized on the diagnosis of AA, met on the September 15, 2015 in Oristano (Italy) to discuss a standardized ultrasound reporting template for appendicitis. The current literature was reviewed to design a template with high sensitivity and specificity [31, 39, 40, 42,43,44,45,46,47].

As result of the meeting, the following US diagnostic criteria were chosen to carry out the diagnosis of uncomplicated AA. Criteria have been divided into direct (primary) and indirect (secondary).

Primary criteria

  • An outer diameter of the appendix of greater than 6 mm.

  • An appendiceal wall thickness of greater than 3 mm with graded compression.

  • The finding of peri-appendiceal abnormalities (hyperechogenic periappendiceal and or omental fat, augmented wall thickness of the cecum, augmented wall thickness of the ileal bowel loops in the right inferior fossa).

  • The loss of compressibility of the appendix.

  • The positivity of the US Blumberg sign (under direct ultrasound visualization of the appendix).

  • The absence of gas into the appendiceal lumen.

  • The presence of hypoechoic fluid-filled lumen.

  • The presence of hypoechoic mucosa/submucosa.

  • The presence of hypoechoic muscularis layer.

  • The presence of hypervascularization of the appendiceal wall.

Secondary criteria

  • Free fluid surrounding the appendix, not extended beyond the right iliac fossa and the Douglas pouch.

  • Increased echogenicity of local mesenteric fat.

  • Enlarged local mesenteric lymph nodes.

On the other hand, the following criteria were adopted by the experts to define the diagnosis of complicated acute appendicitis.

Primary criteria

  • The loss of the submucosal layer.

  • The finding of free peritoneal fluid extended beyond the right iliac fossa and the Douglas pouch, associated with the presence of the radiologic signs of acute appendicitis.

  • The finding of a peri-appendiceal fluid collection consistent with an appendicular abscesses.

  • Hypovascularity to avascularity in abscess and necrosis.

  • The finding of a hypoechoic appendiceal mass.

Secondary criteria

  • The finding of local dilatation and hypoperistalsis of the bowel consistent with focal peritonitis.

  • Signs of secondary small bowel obstruction.

  • Thickening of the peritoneum.

At least three of the abovementioned criteria are required for a compliant US report. Non-diagnostic exams are defined as US reports for which the description was insufficient to carry out or exclude the diagnosis of uncomplicated AA. Experts stated that US is read as negative only if a normal appendix is seen.

C. CT scan protocol

A collaborative group for the quality improvement in radiology, focalized on the diagnosis of AA, met on September 15, 2015 in Oristano (Italy) to discuss a standardized CT scan high resolution protocol for the diagnosis of appendicitis. The current literature was reviewed to design a template with high sensitivity and specificity [29,30,31, 39, 48,49,50,51].

Experts stated that all abdominal CT scans must be performed from the diaphragm to the pubic symphysis. A study series without contrast must be performed. Only if this study will be non-diagnostic, a study series with contrast will be performed during the porto-venous phase (70-s delay from the end of injection). Slice thickness and reconstruction interval values must be of 1.2 mm, collimation of 2 × 128 × 0.6 mm3, and rotation time of 0.28 s. The intravenous contrast medium (80–100 ml of iodinated contrast agent at 400 mg/ml concentration) is injected at 4 ml/s, followed by 20 ml of saline injected at 3 ml/s, in order to enhance the bowel walls and solid organs.

The following criteria were chosen to define the diagnosis of uncomplicated acute appendicitis at the CT scan:

  • An outer diameter of the appendix of greater than 6 mm.

  • An appendiceal wall thickness of greater than 3 mm.

  • Thickening and contrast enhancement of the appendiceal wall.

  • Inflammatory edema.

  • Minor fluid collection around the appendix.

  • “Dirty fat” sign (the adipose tissue surrounding the appendix is increased in density).

The final CT diagnosis of uncomplicated acute appendicitis requires a clear visualization of the appendix presenting with the above-listed characteristics and the absence of the following CT scan findings which make a shift in diagnosis from uncomplicated to complicated disease:

  • Focal poor enhancement of the appendiceal wall.

  • Destruction of the appendiceal wall.

  • Periappendiceal abscess.

  • Extraluminal gas closer to the appendix.

  • Extraluminal free air.

  • Free peritoneal fluid.

  • Tumor of the appendix.

  • Extraluminal faecalith.

At least three of the abovementioned criteria are required for a compliant CT scan report.

D. List of the involved surgical centers

  1. 1.

    Cagliari (General and Oncologic Surgical Unit, Santissima Trinità Hospital)

  2. 2.

    Nuoro (General, Emergency and Minimally Invasive Surgical Unit, San Francesco Hospital)

  3. 3.

    Lanusei (General Surgery Unit, Nostra Signora delle Mercede Hospital)

  4. 4.

    Cagliari (General and Endocrine Surgical Unit, University Hospital)

  5. 5.

    Cagliari (General and Emergency Surgery, University Hospital)

  6. 6.

    Voghera (General Surgery Unit, Civil Hospital)

  7. 7.

    Cavalese (General Surgery Unit, Civil Hospital)

  8. 8.

    Muravera (General Surgery Unit, San Marcellino Hospital)

  9. 9.

    Iglesias (General Surgery Unit, CTO Hospital)

  10. 10.

    Carbonia (General Surgery Unit, Sirai Hospital)

  11. 11.

    Napoli (Emergency Surgery Unit, Villa Betania Evangelic Hospital)

  12. 12.

    Cagliari (Emergency Surgery Unit, Brotzu Hospital)

  13. 13.

    Alghero (General Surgery Unit, Civil Hospital).

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Podda, M., Serventi, F., Mortola, L. et al. A prospective non-randomized controlled, multicenter trial comparing Appendectomy and Conservative Treatment for Patients with Uncomplicated Acute Appendicitis (the ACTUAA study). Int J Colorectal Dis 32, 1649–1660 (2017). https://doi.org/10.1007/s00384-017-2878-5

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  • DOI: https://doi.org/10.1007/s00384-017-2878-5

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