Operative vs Non-Operative Management of Acute Appendicitis and Acute Cholecystitis in COVID-19 Positive Patients
Phase: NA
Conditions: Covid19, Appendicitis, Cholecystitis, Acute, Cholecystitis; Gallstone, Cholecystitis
Sponsor: The Cleveland Clinic

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Pilot Study: Operative vs Non-Operative Management of Uncomplicated Acute 
Appendicitis and Acute Cholecystitis in COVID-19 Positive Patients  
PI: Clayton Petro, MD  
  
 
 

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INTRODUCTION  
 
As the novel coronavirus disease 2019 (COVID-19) disseminates across the United 
States, more routine preoperative testing is going to expose the 81% of infected patients with no 
or mild pneumonia symptoms.(1) Surgeons are going to face challenging decisions regarding 
whether or not to operate for non-elective cases requiring general anesthesia when non-operative 
treatment options exist.   
Currently, little is known regarding the true consequences of general anesthesia in 
COVID-positive (COVID+) patients.  A series of 34 COVID+ patients from Wuhan who 
underwent elective surgery found that all patients developed postoperative pneumonia with 
abnormal findings on CT, 15 (44%) required a postoperative ICU-admission, and 7 (21%) died. 
That said, “low-risk” surgical procedures – as defined by the National Health Commission of 
China – carried a low ICU-admission rate (1/12, 8%) and no mortalities. (2) Another series of 3 
patients from Iran who underwent elective operations describes concerning postoperative 
pulmonary complications culminating in 2 (66%) deaths.(3) While the decision to delay elective 
surgery is practical in COVID+ patients, those presenting with urgent operative indications can 
present more difficult scenarios.  
Specifically, COVID+ patients with uncomplicated acute appendicitis could be treated 
non-operatively with antibiotics.(4) Likewise, COVID+ patients with acute cholecystitis could be 
treated with antibiotics or a percutaneous cholecystostomy tube.(5, 6) Either approach could 
obviate or delay the need for an operation with general anesthesia until the patient has recovered 
from their viral illness.  However, patients managed without a definitive operation may 
alternatively result in more resource utilization, PPE consumption, interactions with hospital 
personnel, and treatment failures that could exacerbate their concomitant viral illness.  Therefore, 
we hypothesize that COVID+ patients with uncomplicated acute appendicitis or acute 
cholecystitis amendable to a laparoscopic procedure can have safe operative outcomes compared 
to those managed non-operatively.  Given the paucity of literature on this topic, we will enroll 
patients in a pilot study and monitor for safety primarily as defined by: a) pulmonary 
complications.  Secondary outcomes will include b) post-intervention ICU admission, c) 
mortality, d) overall complications measured by the Clavien-Dindo classification and 
comprehensive complication index, e) hospital length of stay, f) emergency room 
visits/readmission, and g) failure rates of non-operative management. 
STUDY DESIGN 
This will be a prospective, non-blinded, pilot randomized controlled trial with a 1:1 
allocation ratio. No important changes to the methods are anticipated. This will be a multi-center 
study coordinated at the Main Campus of Cleveland Clinic Foundation (CCF) in Cleveland, Ohio 
with enrollments performed at Main Campus, Fairview, Hillcrest, Marymount, Lutheran, South 
Pointe, and Akron General Hospitals. Data will be collected in a secure CCF REDCap. 
Investigator training will occur through one or more virtual meetings in which the study PI will 

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review procedures for screening and randomization, inclusion and exclusion criteria, and details 
of management of both study arms with each enrolling surgeon. Enrolling surgeons will be 
provided slides containing this information for reference as well. 
 
Specific inclusion criteria are: 
 ≥18 years old  
 COVID-19 confirmed positive by a microbiologic test within 14 days of a COVID 
diagnosis 
 Mild COVID-19 – no or mild pneumonia ultimately.  Diagnosis at the discretion of the 
attending surgeon (see exclusion criteria).(1) 
 EITHER 
o Uncomplicated acute appendicitis without a fecalith  
 
OR 
o Acute cholecystitis – by TG18/TG13 diagnostic criteria(7) 
 A. Local signs of inflammation etc. 
 (1) Murphy's sign, (2) RUQ mass/pain/tenderness 
 B. Systemic signs of inflammation etc. 
 (1) Fever, (2) elevated CRP, (3) elevated WBC count 
 C. Imaging findings 
 Imaging findings characteristic of acute cholecystitis 
 Definite diagnosis: one item in A + one item in B + C 
 
Specific exclusion criteria are: 
 Active pregnancy 
 Positive COVID test more than 14 days prior to surgical consultation. 
 COVID-19 severe disease that would be a contraindication to operative intervention at 
the discretion of the attending surgeon supported by the following, none of which are 
individually required or are a strict exclusion criterion as some of these could be 
attributed or exacerbated by the underlying surgical problem: 
o Persistent dyspnea 
o Persistent respiratory frequency >30/min 
o Persistent blood oxygen saturation <93% 
o Partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300 
o Lung infiltrates >50%  
 COVID-19 critical disease – respiratory failure, shock, or multiorgan dysfunction  
 The surgeon expects increased operative complexity – high risk of conversion to open or 
prolonged procedure 
 Unable or unwilling to consent or fulfill study procedures – need to complete 90 day 
follow-up by telephone 
 

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The study will consist of two treatment arms, assigned in a 1:1 fashion. (1) Non-operative 
management, and (2) operative management.  
1. Non-operative management – Patients will be treated with 2-3 days of intravenous 
antibiotics followed by 7 days of oral antibiotics, as described below: 
 
Non-penicillin allergic patients –  
 piperacillin/tazobactam 3.375g IV every 6 hours for 2-3 days 
 amoxicillin/clavulanate 875/125mg by mouth every 12 hours for 7 days 
 
Penicillin allergic patients –  
 ertapenem 1g IV every 24 hours for 2-3 days 
 ciprofloxacin 500mg every 12 hours AND metronidazole 500mg every 8 
hours for 7 days 
 
Patients may be considered to have failed non-operative management (e.g. treatment 
failure) if they experience absence of clinical improvement, worsening abdominal pain and/or 
localized/diffuse peritonitis in the judgment of the treating surgeon at any point within the study 
window. If this occurs, then surgeons may proceed with rescue appendectomy or percutaneous 
drainage in the setting of appendicitis, or with placement of a percutaneous cholecystostomy tube 
in the setting of acute cholecystitis. 
 
2. Operative management – Patients will undergo surgical removal of the affected organ. 
The initial approach will be in a minimally invasive, laparoscopic fashion. If necessary, 
conversion to an open operation may be performed, and these patients will be included in 
analysis in an intent-to-treat fashion. These patients will be treated preoperatively and 
postoperatively with similar antibiotic regimens, however the duration of IV and PO 
antibiotic therapies will be dependent on factors such as intraoperative findings, 
resolution of laboratory abnormalities, and tolerance of PO medications.  
 
A computer-generated randomization scheme will be built by a CCF. Randomization will 
take place on the Research Electronic Data Capture (REDCap®) database program. Patients will 
be randomized to operative management or non-operative management immediately after 
signing consent, within 36 hours of surgical consultation at the treating hospital. They will be 
informed regarding the management that they will receive. The staff surgeon will document their 
planned treatment using a standardized dot-phrase.   
OUTCOMES TO BE INVESTIGATED  
PRIMARY OUTCOME MEASURES 
1. Pulmonary complications – Including pneumonia, acute respiratory distress syndrome 
(ARDS) or unexpected postoperative ventilation. Time Frame: initial hospital admission and 
within 90 days of randomization.  

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a. For operative cases – any episode of non-invasive ventilation, invasive ventilation, or 
extracorporeal membrane oxygenation after initial extubation after surgery, or patient 
cannot be extubated as planned after surgery. 
b. For non-operative cases – any intubation. 
 
SECONDARY OUTCOME MEASURES 
2.  Post-intervention ICU admission – Time Frame: initial hospital admission and within 90 days 
of randomization 
3.  Mortality – Time Frame: initial hospital admission and within 90 days of randomization 
4.  All complications as measured by the Clavien-Dindo classification – Time Frame: within 90 
days of enrollment.   
5.  Hospital length of stay 
6.  Emergency room visits/readmission – Time Frame: within 90 days of enrollment.   
7.  Treatment failure for non-operative management. – Time Frame: initial hospital admission 
and within 90 days of randomization 
Specific Aim #1: To determine if patients with mild COVID-19 and appendicitis or cholecystitis 
managed operatively have greater rates of pulmonary complications compared to similar 
patients managed nonoperatively 
The primary outcome is pulmonary complications after randomization. These outcomes 
will be recorded for the initial hospital stay, as well as for the 90-day follow-up period.  
Specific Aim #2: To determine if patients with mild COVID-19 and appendicitis or cholecystitis 
managed operatively have different rates of ICU admission after randomization compared to 
patients managed non-operatively.   
For all cases, this will be considered to be any ICU admission occuring after 
randomization. ICU admission will be recorded as a categorical outcome, and for patients who 
are admitted to the ICU, the duration of ICU admission in hours will be recorded as well. These 
outcomes will be recorded for the initial hospital stay, as well as for the 90-day follow-up period.  
Specific Aim #3: To determine if patients with mild COVID-19 and appendicitis or cholecystitis 
managed operatively have different rates of mortality compared to patients managed non-
operatively.  
Mortality at the index hospital admission and within 90-day follow-up period will be 
recorded as a categorical outcome. Date and cause of mortality will also be recorded.  
Specific Aim #4: To determine if patients with mild COVID-19 and appendicitis or cholecystitis 
managed operatively have greater rates and/or severity of complications, as measured by 
Clavien-Dindo scale, compared to patients managed non-operatively. 

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Complications after randomization will be recorded prospectively using Clavien-Dindo 
scale and Comprehensive Complication Index. Rates and severity of complications will be 
compared between groups. 
Specific Aim #5: To determine if patients with mild COVID-19 and appendicitis or cholecystitis 
managed operatively have shorter length of hospital stay compared to patients managed non-
operatively. 
 
Length of stay will be recorded from time of randomization to time of index hospital 
discharge. Additionally, length of any hospital readmissions will also be recorded. 
Specific Aim #6: To determine if patients with mild COVID-19 and appendicitis or cholecystitis 
managed operatively have decreased rates of hospital readmission or ED visits in the 90 days 
after initial randomization compared to patients managed non-operatively. 
 
Patients will be contacted at 90 days after hospital discharge and will be asked whether 
they have had any additional visits to the ED or hospital readmissions. If patients are unable to 
be reached, available data within the electronic medical record will be used. If available, number 
of ED visits/readmissions and length of hospital readmissions will also be recorded. 
Specific Aim #7: To determine the rate and timing of failure of nonoperative management for 
patients with mild COVID-19 and appendicitis or cholecystitis managed nonoperatively. 
 
Patients may be considered to have failed non-operative management (e.g. treatment 
failure) if they experience absence of clinical improvement, worsening abdominal pain and/or 
localized/diffuse peritonitis. If this occurs, then surgeons may proceed with rescue 
appendectomy or percutaneous drainage in the setting of appendicitis, or with placement of a 
percutaneous cholecystostomy tube in the setting of acute cholecystitis. If this occurs, the date of 
failure of nonoperative management will be recorded, and these patients will remain considered 
in the group to which they were originally assigned (e.g. intent-to-treat analysis). 
ANTICIPATED TIME FRAME 
 
Estimated patient accrual time is six months with data collection to occur over 90 days 
from the last enrolled patient. Data analysis and manuscript production will occur within one 
month of completion of data collection.  
 
PATIENT RISKS AND DISCOMFORTS 
 
The effect of mild COVID-19 on outcomes after lower-complexity surgery for non-
elective surgical conditions is unknown. Therefore, the major risk associated with the study is 
that we simply cannot predict what the outcomes are going to be. As detailed later, a Data Safety 
Monitoring Board will be convened to monitor outcomes routinely to ensure that patients are not 
being placed at undue risk. Beyond this, both operative and non-operative management strategies 

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of acute cholecystitis and acute appendicitis are used regularly and both represent relatively low 
risk.  
PATIENT BENEFITS 
 
There are no direct benefits to subjects for participation in this study. Study participation 
will, however, help physicians and hospital administrators better understand outcomes of patients 
with mild COVID-19 presenting for management of non-elective surgical conditions. 
COSTS TO THE SUBJECTS 
 
There are no extra costs to the subjects associated with this research endeavor. 
Procedures related to preoperative evaluation, any surgery or intervention, and other hospital and 
post-hospital care are considered standard of care and will be billed to the subject or the subject’s 
insurance company. 
ALTERNATIVES TO PARTICIPATION 
 
Patients are under no obligation to participate in this study.  The investigators will discuss 
all available surgical options with patients.  It will be emphasized that refusal to participate in 
this study will not impact any patient’s ability to receive care at participating sites. 
PAYMENTS TO SUBJECTS 
 
There will be no direct payments or financial benefit to the subjects. Participation will be 
voluntary. 
PLAN FOR OBTAINING INFORMED CONSENT 
 
For each subject, written informed consent will be obtained prior to any protocol-related 
activities. As part of the informed consent procedure, the principal investigator, surgeon co-
investigator, or one of the approved study coordinators will explain verbally and in writing the 
nature, duration, and purpose of the study in such a manner that the subject is aware of potential 
risks, inconveniences, or adverse effects that may occur. Subjects will be informed that they may 
withdraw from the study at any time and will receive all information required by federal 
regulations. 
 
  Following identification of a potential study participant, the investigator or co-
investigator will be responsible for instituting the informed consent process in a face-to-face 
manner. Before starting any study procedures, the investigator will discuss the proposed research 
study in detail with the potential subject to discuss treatment options. The subject will be allowed 
ample time to read and review the informed consent document and to ask questions. The 
informed consent document will be reviewed with the subject in depth by the participating 
investigator or by a designated member of the research team to ensure that the potential 
participant has a thorough understanding of the study protocol and understands the potential risks 
and benefits of study participation and his or her rights as a study participant. After 

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consideration, the subject may ask additional questions before signing the informed consent 
document to participate in this study. Patients may ask for additional time to consider study 
participation, however the decision to participate should occur within 36 hours of surgical 
consultation at the presenting hospital so as not to delay treatment for these non-elective 
conditions. 
 
Patients will be provided with the information sheet on COVID-19 clinical trials at the 
Cleveland Clinic. If a patient is in quarantine and cannot provide informed consent process in the 
face-to-face manner described above, the following COVID consent process measures will be 
taken: 
1. A copy of the consent will be provided to the subject by a health care worker who has 
entered the room.  
2. The informed consent will be conducted over the phone by an investigator or research 
nurse knowledgeable about the research and an uninvolved witness.  
3. The consent will be taken to our research office by the health care worker who entered 
the room and placed in a secure/locked cabinet. 
4. Documentation of the consent will be placed in EPIC per IRB policy.  
5. If the consent document is not able to be collected, one of two options will be performed:  
a. Attestations by the witness who participated in the call and by the investigator or 
research nurse that the patient confirmed that they agreed to participate in the 
study. 
b. A photograph of the informed consent document with attestation by the person 
entering the photograph in the study record that states how the photograph was 
obtained and that it is a photograph of the informed consent signed by the patient.  
 
PROVISIONS FOR SUBJECTS FROM VULNERABLE POPULATIONS 
 
The population to be studied includes adults of at least 18 years of age. Children, 
cognitively-impaired persons, pregnant women, students and house staff under the direct 
supervision of the investigator are considered vulnerable populations and will, therefore, be 
excluded from participation. If a staff member or employee of the participating institutions is a 
potential candidate for the study, the subject will be informed during the consent process that 
his/her participation or refusal to participate will not influence grades, employment, or 
subsequent recommendations. 
 
 
If a subject cannot read a consent form due to illiteracy or blindness, a member of the 
research study staff will read and explain the consent form to the participant or to the 
participant’s legally-authorized representative. A witness who will sign and date the consent 
form must be present during this encounter. 
SUBJECT PRIVACY AND DATA CONFIDENTIALITY 

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    Subject anonymity and data confidentiality will be maintained throughout this study.  
Every effort will be made to maintain the confidentiality of documents that identify the subject 
by name (e.g., signed informed consent documents, clinic charts), except to the extent necessary 
to allow monitoring by the Offices of Research Compliance at the participating institutions or by 
other regulatory authorities. 
 
All of the information collected, such as name or medical record number, will be stored 
in REDCap®, or in an Excel file stored in a secure network folder to which only the 
investigators at each site have access. Randomization will occur with the use of a customized 
REDCap® database program housed at CCF, a secure network/firewall-protected electronic 
database for which only the investigator and the designated members of the study team will have 
access using an individually-assigned login and password. Only approved study members listed 
on the IRB protocol will have access to a separately-stored master list. Only the Principal 
Investigator, Lead Research Coordinators, and Biostatisticians will be granted access to retrieve 
patient data for data quality assessment and data analysis. All electronic records pertaining to the 
clinical study will be password-protected and only approved study members listed on the IRB 
protocol will have password access. 
SAMPLE SIZE / POWER CALCULATION 
A total of 50 patients are planned to be enrolled in this trial, with approximately 25 
patients enrolled in each arm. A power calculation was not performed as the goal of this study is 
to act as a pilot study to evaluate the safety of both management strategies for patients with mild 
COVID-19 and to provide surgeons with high-quality, useful data to engage in shared decision-
making with patients while future larger studies are pending. Because acute cholecystitis and 
acute appendicitis have similar expected operative times and postoperative lengths of stay and 
similar postoperative complication rates, we do not intend to stratify by disease process. 
Additionally, the primary outcome of pulmonary complications should not be greatly influenced 
by which presenting disease process a participant has, as it is rare for a patient to remain 
intubated after either cholecystectomy or appendectomy. 
STATISTICAL ANALYSIS 
Descriptive statistics, including means, standard deviations, and/or percentages, will be 
calculated for demographic and baseline variables. Categorical variables will be reported using 
proportions. Continuous variables will be reported using either means and standard deviations 
for normally distributed data or median and interquartile range for non-normally distributed data. 
Appropriate statistical tests including Chi square and/or Fisher’s exact tests for comparisons of 
proportions and t-tests and/or Mann-Whitney U-tests for comparison of continuous variables will 
be used. R software will be used for all analyses. A two-tailed p-value <0.05 will be considered 
statistically significant. Analysis will be performed in an intent-to-treat fashion. 
DATA SAFETY MONITORING BOARD 

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As mentioned previously, the major risk associated with the study is that we cannot 
predict what the outcomes are going to be for these patients as there is little high-quality 
literature surrounding COVID-19 in surgical contexts. A Data Safety Monitoring Board will be 
convened to monitor outcomes routinely to ensure that patients are not being placed at undue 
risk. We will plan to review outcomes after 20 and after 40 patients enrolled in the study. 
The progress of the study including safety events will also be reviewed through weekly 
communication among study investigators. Safety events that will be reviewed will include any 
instances of intraoperative adverse events, pulmonary complications, ICU admission, and 
hospital readmission. Collection of this safety information will be ongoing, and review of this 
information will occur on a weekly basis. Additionally, a monthly phone and/or virtual 
conference call between site PIs and research coordinators and fellows will be held to address 
study progress and ensure that there is an opportunity to resolve any outstanding issues.  
CLINICAL SIGNIFICANCE/INNOVATION 
COVID-19 presents a substantial dilemma to surgeons in the context of non-elective 
surgical problems. Determining whether proceeding with definitive surgical management of 
common acute disease processes in the context of mild COVID-19 is safe compared to 
nonoperative management will be a major step forward in our understanding of how to manage 
such patients with common surgical conditions in the months and years to come. 
REFERENCES 
1. 
Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus 
Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the 
Chinese Center for Disease Control and Prevention. Jama. 2020 Feb 24. 
2. 
Lei S, Jiang F, Su W, et al. Clinical characteristics and outcomes of patients undergoing 
surgeries during the incubation period of COVID-19 infection. EClinicalMedicine. 2020 Apr 
5:100331. 
3. 
Aminian A, Safari S, Razeghian-Jahromi A, Ghorbani M, Delaney CP. COVID-19 
Outbreak and Surgical Practice: Unexpected Fatality in Perioperative Period. Annals of surgery. 
2020 Mar 26. 
4. 
Podda M, Gerardi C, Cillara N, et al. Antibiotic Treatment and Appendectomy for 
Uncomplicated Acute Appendicitis in Adults and Children: A Systematic Review and Meta-
analysis. Annals of surgery. 2019 Dec;270(6):1028-40. 
5. 
Gomi H, Solomkin JS, Schlossberg D, et al. Tokyo Guidelines 2018: antimicrobial 
therapy for acute cholangitis and cholecystitis. Journal of hepato-biliary-pancreatic sciences. 
2018 Jan;25(1):3-16. 

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6. 
Davis CA, Landercasper J, Gundersen LH, Lambert PJ. Effective use of percutaneous 
cholecystostomy in high-risk surgical patients: techniques, tube management, and results. 
Archives of surgery. 1999 Jul;134(7):727-31; discussion 31-2. 
7. 
Yokoe M, Hata J, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and 
severity grading of acute cholecystitis (with videos). Journal of hepato-biliary-pancreatic 
sciences. 2018 Jan;25(1):41-54.