Brief Title
RISK FACTORS FOR NECROTIC CHOLECYSTITIS DURING COVID-19 PANDEMIC: THE ChoCO WSES PROSPECTIVE MULTICENTER OBSERVATIONAL STUDY
Official Title
RISK FACTORS FOR NECROTIC CHOLECYSTITIS DURING COVID-19 PANDEMIC: THE ChoCO WSES PROSPECTIVE MULTICENTER OBSERVATIONAL STUDY
Brief Summary
The ChoCO (Cholecystitis under COVID-19 pandemic) STUDY PROTOCOL Gangrenous cholecystitis is
the most common complication of acute cholecystitis, affecting around 15% (range 2-30%) of
patients and it occurs as a result of ischemia with necrosis of the gallbladder wall.
Preliminary data showed that COVID-19 patients have a high risk to present necrotic
cholecystitis.
Our aim is to investigate risk factors related to develop necrotic cholecystitis in COVID-19
negative and positive patients carrying out a multicentric prospective observational study.
Detailed Description
Background Gangrenous cholecystitis (GC) is the most common complication of acute
cholecystitis (AC), affecting around 15% (range 2-30%) of patients and it occurs as a result
of ischemia with necrosis of the gallbladder wall [1].
It is related to increased mortality rate (mortality rate ranging between 15 and 50%)
compared with non-necrotic AC [2].
Retrospective studies that investigated risk and predictive factors related to GC showed that
males, older patients with diabetes, coronary artery disease, and other comorbidities are at
risk to have GC. [1-3] Another study identified longer delay time prior to hospital admission
and low white blood cell count as independent risk factors affecting mortality and indicated
the presence of diabetes mellitus, higher blood levels of aspartate aminotransferase, alanine
aminotransferase, alkaline phosphatase and total bilirubin, pericholecystic fluid in
abdominal ultrasonography, and conversion from laparoscopic surgery to open surgery as risk
factors increasing mortality [2] In any case, the treatment of GC is similar to that of
patients with AC but in presence of GC, cholecystectomy can be difficult because of
adhesions, insufficient anatomic explorability, complications like bleeding, and injury to
bile ducts.
There is high variability in the reported conversion rate to be 30% to 50% [4], down to 8.7%
[5]. These results are probably due to a careful preoperative selection of patients for
laparoscopic cholecystectomy and early surgery [6].
Hunt et al [7] reported decreased morbidity and mortality rates with the implementation of
laparoscopic cholecystectomy for GC.
Onder et al [2] showed that mortality was higher in cases in which conversion to open surgery
occurred.
Recently, many authors reported necrotic and perforated cholecystitis as the most common
complication of COVID-19 pneumonia [8-9-10].
A recent multisocietary position paper suggested to consider percutaneous drainage of the
gallbladder after the failure of conservative therapy with antibiotics but highlighted that
advanced age, or other factors of higher COVID-19 risk, cannot be regarded as sufficient to
indicate this alternative treatment except in real conditions of the impracticability of
cholecystectomy [11].
In the lack of evidence and guidelines about the management of a patient with acute
cholecystitis during COVID-19 pandemic, laparoscopic cholecystectomy, at most preceded by
percutaneous trans-gall bladder drainage (PTGBD) in high surgical risk patients, remains the
gold standard for the treatment of acute cholecystitis on COVID-19 patients, with high
morbidity rate and length of hospital stay that increases the risk of spreading the virus
among health care staff and negative COVID-19 patients.
Our aim is to study all patients, Covid-19 (+) and Covid-19 (-) presenting cholecystitis,
including those having GC, to improve their management.
Rationale for the trial:
To evaluate the management of acute (complicated) cholecystitis focuzing on the treatments
and the outcomes of operative or non-operative management in COVID (+) and COVID (-) patients
with the aim to improve the results, reducing morbidity and mortality rates related to
emergency setting and high-risk patients.
Objectives:
1. Evaluate the prevalence of cholecystitis, in female and male patients during COVID-19
pandemic.
2. Evaluate the risk factors for necrosis or gangrenous cholecystitis in COVID-19 patients.
3. Evaluate the clinical outcomes of early (<72h from the onset of symptoms) versus delayed
(>72h from the onset of symptoms) cholecystectomy, and of cholecystostomy in terms of
mortality and morbidity.
Primary objective Our hypothesis is that COVID-19 patients should not be treated
conservatively (antibiotics only/ percutaneous drainage of the gallbladder for the high
risk of progressing to necrotic and then perforated cholecystitis.
It was reported that COVID-19 disease predisposes to both venous and arterial
thromboembolism, explained by excessive inflammation, hypoxia, immobilization and
diffuse intravascular coagulation. In particular, critically ill patients with
SARS-CoV-2 showed a high risk to present thromboembolic events.
Secondary objective Our aim is to investigate the risk factors for necrotic
cholecystitis in the general population.
Study Design:
Prospective Multicenter Observational Study.
Study population:
All patients admitted to the surgical department with clinical and histologic diagnosis
of acute cholecystitis (with and without gangrenous cholecystitis).
Inclusion criteria Patients of all ages and sex admitted in the emergency department for
acute cholecystitis, aged >=18 yo.
Exclusion criteria Patients aged< 18 yo. Period: 2020/10/01 to 2021/04/31 Data
collection: all the epidemiological, clinical, and surgical data will be collected by a
google form sheet that will be sent by mail to the participating centers.
Statistical analysis:
Prevalence study and univariate and multivariate analysis of each scheduled parameter.
In the statistical analysis, we will differentiate the data also by gender.
Prevalence study and univariate and multivariate analysis of each scheduled parameter.
In the statistical analysis we will differentiate the data also by gender. It is very
important to study all patients having cholecystitis including those having gangrenous
cholecystitis. Previous World Society of Emergency Surgery prospective studies on sepsis
(Sartelli et al, WJES, 2019; 14: 34; Sartelli et al, 2015; 10: 61) show that this is
feasible and our aim is getting exactly the numbers of these two studies. We expect that
the COVID-19 patients will be less for two reasons 1) the incidence 2) Trial to treat
them conservatively outside the hospitals. Nevertheless, even if the numbers are very
small, we can use non-parametric methods which work even if the groups are less than 20
and analyzes the ranks and not the crude numbers.
Ethical Aspects: This an observational study. It will not attempt to change or modify
the clinical practice of the participating physicians. All surgeons involved in the
patient's recruitment will be included in the research authorship.
Methods and assessments:
Anonimous questionnaire by Google form, sent by mail the surgical departments of
participant clinical centers identified by a number assigned by the principal
investigators before starting to enter data.
The following data will be investigated/recorded/obtained:
City of the medical institution:
Country of the medical institution:
Number assigned:
Patient Characteristics:
Gender
- Female
- Male
- Unknown Age (years as numbers)
Risk factors Malignancy -Yes
- No COVID-19 PCR test
- Yes
- Not performed COVID-19 PCR test
- Positive
- Negative
- Uncertain Immunosuppression (Chronic treatment with glucocorticoids, with
immunosuppressive agents or chemotherapy, and patients with lymphatic diseases or
with virus-related immunosuppression such as HIV)
- Yes
- No Severe cardiovascular disease (Clinical history of ischemic heart disease,
history of heart failure, severe valvular disease according to ACC/AHA 2007
Guidelines on Perioperative Cardiovascular Evaluation and Care for Non cardiac
Surgery)
- Yes
- No Diabetes mellitus
- Clinical history of diabetes
- No diabetes
- Pre-diabetic (= blood sugar level is higher than it should be but not high enough
to diagnose diabetes type 2).
- Diabetes without organ dysfunction
- Diabetes with organ dysfunction
Severe Chronic kidney disease in preparation for or permanent renal replacement therapy:
- Yes
- No
Severe chronic pulmonary disease (clinical history of severe chronic pulmonary disease,
different from COVID-19 pneumonia):
- Yes
- No
Acute Respiratory Distress Syndrome (ARDS):
-Yes
-No
Mechanical Ventilation:
- Yes
- No
If yes how many days (numbers)?:
....
Parenteral Nutrition:
- Yes
- No
If yes, how many days (as numbers)?:
…
Septic shock (Septic shock is defined by persisting hypotension requiring vasopressors
to maintain a mean arterial pressure of 65 mm Hg or higher and a serum lactate level
greater than 2 mmol/L (18 mg/dL) despite adequate volume resuscitation):
- Yes
- No qSOFA score:
PIPAS severity score:
…. Physiologic indicators at admission
Temperature (C):
…. Systolic blood pressure (mmHg)
….. Heart rate (bpm)
…. Respiratory rate (number of breaths/min)
...
Blood oxygen saturation level (SpO2%):
...
Laboratory parameters at admission WBC (cells/mm³)
….. NOT PERFORMED Platelets (cells/mm³) *
….. NOT PERFORMED CRP (mg/L) *
…. NOT PERFORMED ALT (Value = …………….. /units per liter) GGT (Value =………………./units per
liter) ASAT (Value =………………./units per liter) Procalcitonin (ng/mL)
….. NOT PERFORMED Lactate (mmol/L) *
…. Fibrinogen (g/L)
.... NOT PERFORMED D-dimer (nmol/L)
.... NOT PERFORMED Prothrombin time (PT; sec)
.... NOT PERFORMED Activated partial thromboplastin (aPT; sec)
.... NOT PERFORMED INR
.... NOT PERFORMED
Interleukine 6 (ng/dL):
…. NOT PERFORMED
Tromboelastography:
Normal Increased Maximum Amplitude (MA) Decreased Maximum Amplitude (MA) Increased Lysis
Index at 30 minutes after MA (LY30) Decreased LY30 Other:….. NOT PERFORMED Diagnosis
Radiological diagnosis
- Ultrasound
- Computed Tomography
- No radiological diagnosis Abdominal findings
Localized abdominal pain:
Yes/No
Localized abdominal rigidity:
Yes/No
Diffuse abdominal pain (more than one abdominal quadrant):
Yes/No
Diffuse abdominal rigidity (more than one abdominal quadrant):
Yes/No
Delay in ED visit (Number of days from onset of symptoms from ED visit):
….
Murphy Ultrasonography Sign:
- Yes
- No Pre-operative diagnosis
- Lithiasic Cholecystitis
- Alithiasic Cholecystitis
- Others:…. Gallbladder wall thickness
- 3-4 mm
- 4-5 mm
- 5-6 mm
->6 mm Source of infection Peritonitis diffusion
- Localized peritonitis/abscess
- Diffuse peritonitis Setting of acquisition
- Community-acquired
- Hospital-acquired
Treatment:
- Laparoscopic intervention in an urgent setting
- Laparoscopic intervention in urgent setting+antibiotics
- Open cholecystectomy in an urgent setting
- Open cholecystectomy in urgent setting+antibiotics
- Percutaneous drainage of the gallbladder+antibiotics
- Conservative approach (antibiotics alone)
- Other:…. Type of intervention:* Total Cholecystectomy in laparoscopy Partial
Cholecystectomy in laparoscopy Total Cholecystectomy in open technique Total
cholecystectomy in open technique after conversion Partial cholecystectomy in open
technique after conversion
Delay in the surgical/radiology intervention (number of hours):
- No Adequate source control
- Yes
- No Adequate empirical antimicrobial therapy
- Yes
- No Culture of bile or gallbladder specimen including fungus*
- Yes
- No (If yes, what the result, main bacteria or yeast…………………………………………..) Detection of
SARS-CoV-2 in bile
- Yes
- No
If yes, it was:
- Negative
- Positive for SARS-CoV-2
Detection of SARS-CoV-2 in peri-hepatic fluid:
- Yes
- No
If yes, it was:
- Negative
- Positive Post-operative course (In-hospital) mortality * Yes No Hospital stay
(days)
Immediate post-operative complications (By 72 hours)
- Localized biliary peritonitis
- Diffuse biliary peritonitis
- Biliary fistula
- Common bile duct injuries
- Hollow viscus iatrogenic injury
- Bleeding
- Postoperative collection
Early post-operative complications:
- Incisional surgical site infection
- Eventration
- Post-operative peritonitis
- Post-operative abdominal abscess
- Chest infection NO COMPLICATIONS
Other:
Reoperation *
- Yes
- No
Reoperation strategy (If reoperation was performed):
- Laparoscopy
- on demand laparotomy
- Planned laparotomy
- Radiological intervention Timing of re-operation (If re-operation was performed)
<24 hours > 24 hours <72 hours Histopathologic findings
- Acute cholecistitis
- Cholecistitis with necrosis Other diagnosis:…. Safety Considerations There are not
safety issues
Informed consent Every patients included in this study will be asked to sign a written
consent to authorise anonymous treatment of personal data.
Data Management and Statistical Analysis Every participant investigators is responsible
for entering data on one Google sheet for every patients included in the study.
Expected Outcomes of the Study To demonstrate the correlation between necrotic
cholecystitis and predisposition to thromboembolism in COVID-19 patients.
Dissemination of Results and Publication Policy The outcomes of this study will be
analysed and published on a The World Journal of Emergency Surgery in 2021.
Duration of the Project 1 year
Ethics This is an observational study: no need for Ethics Committee approval.
Budget No budget study
Financing and Insurance Not applicable
References Bourikian, Seda et al.Risk factors for acute gangrenous cholecystitis in
emergency general surgery patients. The American Journal of Surgery, Volume 210, Issue
4, 730 - 733
Akın Önder, Murat Kapan, Burak Veli Ülger, Abdullah Oğuz, Ahmet Türkoğlu, and Ömer
Uslukaya (2015) Gangrenous Cholecystitis: Mortality and Risk Factors. Int Surg: February
2015, Vol. 100, No. 2, pp. 254-260.
Gomes CA, Soares C, Di Saverio S, Sartelli M, de Souza Silva PG, Orlandi AS, Heringer
TL, Gomes FC, Catena F. Gangrenous cholecystitis in male patients: A study of prevalence
and predictive risk factors. Ann Hepatobiliary Pancreat Surg. 2019 Feb;23(1):34-40. doi:
10.14701/ahbps.2019.23.1.34.
Contini S, Corradi D, Busi N, Alessandri L, Pezzarossa A, Scarpicnato A. Can gangrenous
cholecystitis be prevented? A plea against a "wait and see" attitude. J Clin
Gastroenterol 2004;38(8):710-716
Eldar S, Eitan A, Bickel A, Sabo E, Cohen A, Abrahamson J et al. The impact of patient
delay and physician delay on the outcome of laparoscopic cholecystectomy for acute
cholecystitis. Am J Surg 1999;178(4):303-307
Pisano M et al.2017 WSES and SICG guidelines on acute calcolous cholecystitis in elderly
population.World J Emerg Surg. 2019 Mar 4;14:10. doi: 10.1186/s13017-019-0224-7.
eCollection 2019. Review.
Hunt DRH, Chu CK. Gangrenous cholecystitis in the laparoscopic era. Aust N Z J Surg
2000;70(6):428-430
Edoardo Mattone, Maria Sofia, Elena Schembari et al. Acute acalculous cholecystitis on a
COVID-19 patient: a case report, 15 July 2020, PREPRINT (Version 1) available at
Research Square [+https://doi.org/10.21203/rs.3.rs-42230/v1+]
Ying, M., Lu, B., Pan, J. et al. COVID-19 with acute cholecystitis: a case report. BMC
Infect Dis 20, 437 (2020). https://doi.org/10.1186/s12879-020-05164-7
Bruni, A., Garofalo, E., Zuccalà, V. et al. Histopathological findings in a COVID-19
patient affected by ischemic gangrenous cholecystitis. World J Emerg Surg 15, 43 (2020).
https://doi.org/10.1186/s13017-020-00320-5
Campanile, F.C., Podda, M., Arezzo, A. et al. Acute cholecystitis during COVID-19
pandemic: a multisocietary position statement. World J Emerg Surg 15, 38 (2020).
https://doi.org/10.1186/s13017-020-00317-0
Study Type
Observational [Patient Registry]
Primary Outcome
Risk factors for necrotic cholecystitis in COVID-19 patients
Condition
Cholecystitis, Acute
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Estimated Enrollment
800
Start Date
October 2020
Completion Date
September 2021
Primary Completion Date
May 2021
Eligibility Criteria
Inclusion Criteria:
All patients presenting acute cholecystitis during COVID 19 pandemic, aged >=18 yo
Exclusion Criteria:
Patients presenting with acute cholecystitis aged <18 yo
Gender
All
Ages
18 Years - 100 Years
Accepts Healthy Volunteers
No
Contacts
, ,
Location Countries
France
Location Countries
France
Administrative Informations
NCT ID
NCT04542512
Organization ID
06012020
Responsible Party
Principal Investigator
Study Sponsor
Poissy-Saint Germain Hospital
Study Sponsor
, ,
Verification Date
September 2020