Open Access Protocol

Protocol for extended antibiotic therapy

after laparoscopic cholecystectomy for
acute calculous cholecystitis
(Cholecystectomy Antibiotic
Randomised Trial, CHART)
Pablo Pellegrini,1 Juan Pablo Campana,1 Agustn Dietrich,1 Jeremas Goransky,1
Juan Glinka,1 Diego Giunta,2 Laura Barcan,3 Fernando Alvarez,1 Oscar Mazza,1
Rodrigo Snchez Claria,1 Martin Palavecino,1 Guillermo Arbues,1 Victoria Ardiles,1
Eduardo de Santibaes,1 Juan Pekolj,1 Martin de Santibaes1

To cite: Pellegrini P, ABSTRACT common complications of cholelithiasis,

Campana JP, Dietrich A, et al. Introduction: Acute calculous cholecystitis represents which can be found in 20% of symptomatic
Protocol for extended one of the most common complications of
antibiotic therapy after
patients. It is known that the initial event in
cholelithiasis. While laparoscopic cholecystectomy is ACC is the obstruction of the gallbladders
laparoscopic cholecystectomy
the standard treatment in mild and moderate forms, drainage due to an impacted gallstone in the
for acute calculous
cholecystitis the need for antibiotic therapy after surgery remains
Hartmanns pouch or the cystic duct.
(Cholecystectomy Antibiotic undefined. The aim of the randomised controlled
Cholecystectomy Antibiotic Randomised Trial (CHART)
Intraluminal pressure increases, reducing
Randomised Trial, CHART).
BMJ Open 2015;5:e009502. is therefore to assess if there are benefits in the use of blood irrigation and lymphatic drainage,
doi:10.1136/bmjopen-2015- postoperative antibiotics in patients with mild or which nally produces gallbladder inam-
009502 moderate acute cholecystitis in whom a laparoscopic mation. It is assumed that this inamma-
cholecystectomy is performed. tion is initially sterile. However, if the
Prepublication history for Methods and analysis: A single-centre, double-blind, obstruction persists, infection can develop,
this paper is available online. randomised trial. After screening for eligibility and commonly with bacteria of the family of
To view these files please informed consent, 300 patients admitted for acute Enterobacteriacea, Enteroccocus spp and
visit the journal online calculus cholecystitis will be randomised into two groups anaerobes.24
(http://dx.doi.org/10.1136/ of treatment, either receiving amoxicillin/clavulanic acid
bmjopen-2015-009502). The diagnostic criteria and severity assess-
or placebo for 5 consecutive days. Postoperative ment of acute cholecystitis have been well
Received 22 July 2015
evaluation will take place during the first 30 days.
established in the 2007 Tokyo Guidelines,
Revised 28 September 2015 Postoperative infectious complications are the primary
end point. Secondary end points are length of hospital
updated in 2013. According to these guide-
Accepted 20 October 2015
stay, readmissions, need of reintervention (percutaneous lines, ACC is classied as mild (grade I),
or surgical reinterventions) and overall mortality. The moderate (grade II) and severe (grade III).
results of this trial will provide strong evidence to either Severe acute cholecystitis is associated with
support or abandon the use of antibiotics after surgery, at least one organ dysfunction. Moderate
impacting directly in the incidence of adverse events acute cholecystitis is associated with any of
associated with the use of antibiotics, the emergence of the following conditions: elevated white cell
bacterial resistance and treatment costs. count (WCC) (18 000/mm3); palpable
Ethics and dissemination: This study and informed tender mass in the right upper abdominal
consent sheets have been approved by the Research quadrant; duration of symptoms for more
Projects Evaluating Committee (CEPI) of Hospital Italiano than 72 h; marked local inammation (gan-
de Buenos Aires (protocol N 2111).
grenous cholecystitis, pericholecystic
Results: The results of the trial will be reported in a abscess, hepatic abscess, biliary peritonitis,
peer-reviewed publication.
emphysematous cholecystitis). Mild acute
For numbered affiliations see Trial registration number: NCT02057679.
end of article.
cholecystitis does not meet the criteria of
any of the former conditions. It can also be
INTRODUCTION dened as an acute cholecystitis in a
Correspondence to
Martin de Santibaes;
More than 90% of the cases of acute calculus healthy patient with no organ dysfunction
martin.desantibanes@ cholecystitis (ACC) are associated with gall- with only mild inammatory changes in the
hospitalitaliano.org.ar stones.1 2 ACC represents one of the most gallbladder.5

Pellegrini P, et al. BMJ Open 2015;5:e009502. doi:10.1136/bmjopen-2015-009502 1

Open Access

While laparoscopic cholecystectomy (LC) is the gold patients will not be eligible for randomisation and will
standard treatment of mild and moderate forms of ACC, be dismissed from the statistical analysis. Nevertheless,
the need for antibiotic therapy after surgery continues this group will be considered in the nal ow chart.
to be a matter of debate. There is a lack of evidence After screening for eligibility and informed consent is
regarding duration and type of antimicrobial therapy obtained, patients will be randomised in a 1:1 ratio into
after surgery.26 The updated Tokyo Guidelines propose one of the following study groups (gure 1):
to administer antibiotics only up to 24 h after surgery Antibiotic treatment
for mild ACC and 47 days in moderate or severe cases.4 Placebo
It has been suggested that a -lactam monoscheme (ie,
amoxicillin/clavulanic acid (AMC)) would be adequate In summary, patients are recruited prior to surgery
in patients with mild and moderate cholecystitis without but are randomised only after surgery, once the investi-
intraoperative complications such as bile peritonitis, gators conrm that no exclusion criteria are present
cholangitis, gallbladder perforation or abscesses.47 intraoperatively.
However, the real benets of its use in these situations Patients will be randomised using the online randomi-
have not been well studied. Antibiotics are associated ser provided by the Hospital Italiano Statistics
with common adverse effects such as allergic reactions Department (http://protocolos.hospitalitaliano.org.ar).
and digestive intolerance (nausea, vomits and diar- This randomiser provides a list with a sequence of
rhoea). Nowadays, there is a clear tendency towards the numbers from 1 to 300, each one randomly assigned to
rational use of antibiotics in order to prevent bacterial one of the study groups. Patients will be assigned to
resistance. Amoxicillin has been associated with a 78% each number in order according to the moment they
incidence of toxicodermia, 1% of allergy reactions and a enter the protocol. Neither the researchers nor the
very low incidence of anaphylactic shock (0.010.04% patients will have knowledge of the assigned treatment
with the use of penicillin).8 Hence, we decided to until the end of the study. Each Treatment Pack (TP)
conduct a randomised controlled trial (RCT) in patients will have a code to retrospectively help identify which
undergoing LC for mild and moderate ACC, randomis- group of treatment modalities the patient was assigned
ing patients to receive AMC or placebo after surgery. to. Each TP contains capsules for a 5-day treatment to
The primary objective of the present trial is to assess be administered three times per day. The capsules will
whether antibiotic treatment after LC in mild or moder- be provided by the HIBA Central Pharmacy according to
ate ACC reduces the incidence of postoperative infec- the randomisation list. The antibiotic and placebo cap-
tious complications. The hypothesis is that postoperative sules will be packaged and labelled identically. These
antibiotics have no positive impact on patients outcome capsules will be made of insipid gelatine material and
and therefore should not be indicated in this subset of will have the same colour.
patients.

Trial organisation
METHODS AND ANALYSIS Trial population and patient recruitment
Trial design, setting and randomisation All consecutive patients with the new diagnosis of mild
The Cholecystectomy Antibiotic Randomised Trial or moderate ACC according to the Revised Tokyo
(CHART) is a randomised, controlled and blind to Guidelines5 admitted to the HIBA will be screened for
patient, investigator and data analysts study, which com- eligibility to be enrolled in the CHART.
pares antibiotic treatment after LC due to mild and Patients will be approached for randomised inclusion
moderate ACC versus no antibiotic treatment. From if they meet each of the following inclusion criteria:
February 2014, surgeons initiated this study ( protocol diagnosis of mild or moderate ACC; willingness to par-
V.1.0) at Hospital Italiano de Buenos Aires (HIBA). This ticipate in the study; ability to understand the nature of
is a teaching hospital afliated to the University of the study and what will be required of them; men and
Buenos Aires Medical School and the HIBA University non-pregnant, non-lactating women between 18 and 85
Medical School. years of age who undergo early LC (before 3 days after
All patients admitted with acute calculous cholecystitis the onset of the symptoms).
will receive parenteral hydration, gastric protection with Exclusion criteria are rejection to participate in the
proton pump inhibitors, analgesics and intravenous trial or the process of informed consent; hypersensitivity
treatment with AMC. This treatment is continued until to AMC or lactose (used in placebo); severe ACC; mod-
the operation. Surgery will be performed within the rst erate ACC associated with liver and/or gallbladder
5 days after admission. Those patients who worsen abscesses, cholangitis or bile peritonitis; intraoperative
during the waiting time will be explored as soon as pos- ndings such as liver cancer, liver metastases, common
sible. Potential complications (such as bile peritonitis, bile duct stones or gallbladder carcinoma; conversion to
cholangitis, gallbladder perforation or abscesses) or evi- laparotomy; previous treatment with antibiotics for more
dence of greater severity of cholecystitis may occur and than 5 days; active oncological diseases; AIDS trans-
this can only be diagnosed during surgery. These planted patients.

2 Pellegrini P, et al. BMJ Open 2015;5:e009502. doi:10.1136/bmjopen-2015-009502

 Open Access

Figure 1 Trial design chart

(ACC, acute calculous
cholecystitis; AMC, amoxicillin/
clavulanic acid; EV, endovenous;
LC, laparoscopic
cholecystectomy).

Trial interventions moderate ACC reduces the incidence of postoperative

All patients admitted to HIBA from February 2014 with infectious complications.
mild or moderate ACC were invited to participate in the
study. Surgeons from the hepatobliopancreatic section
of the HIBA will recruit participants. Patients will receive Primary end point
parenteral hydration, gastric protection with proton The primary efcacy end point is postoperative
pump inhibitors, analgesics and treatment with 1000 mg infectious complications, dened as any infection
of AMC intravenously every 8 h until surgery, which has occurring within the rst 30 postoperative days, classi-
to be performed within 5 days after admission. No extra ed according to the Clavien-Dindo Classication.9
dose of AMC will be administered during surgery. After randomisation, patients will be followed up for
If there are no intraoperative criteria for exclusion, 30 days.
patients will be randomly assigned to either group of
intervention: Secondary end points
Experimental group: antibiotic treatment after surgery: Length of hospital stay: number of days from admis-
Patients in the experimental group will receive sion to hospital discharge.
1000 mg of AMC orally every 8 h for 5 days, immediately Readmission: need of readmission due to post-
after the surgery. operative complications that require hospital care
Control groupplacebo treatment after surgery: (hydration, intravenous antibiotics, percutaneous
Patients in the control group will receive placebo drainage, surgical treatment).
orally every 8 h for 5 days, immediately after the surgery. Reintervention: need of surgical treatment under
general anaesthesia or percutaneous procedure in
Study objectives and end points complicated patients.
The primary objective of the present trial is to assess Overall mortality: deaths occurring during the rst
whether antibiotic treatment after LC in mild or postoperative month.

Pellegrini P, et al. BMJ Open 2015;5:e009502. doi:10.1136/bmjopen-2015-009502 3

Open Access

Trial implementation Clinical management and abandonment

Inclusion, evaluation and follow-up Patients included are warned not to take medications
Patients will be screened according to the eligibility cri- from other doctors outside the study. In case a patient
teria and asked for written informed consent. requires antibiotics for some reason, the blind will be
Afterwards, they will be allocated randomly to each of revealed to ensure the proper treatment for this patient.
both study groups. This event will be registered and the patient will be con-
sidered in the statistical analysis.
Each patient is informed to be free to abandon the
Study schedule treatment at any time by informing the researchers. If
The evaluation schedule for all patients will be as the medical team or researchers consider that the
follows: patient is at risk due to the study, the patient will be
Stage 1: Every patient included in the protocol will be removed and the doctors will provide feedback to the
registered in a sheet containing personal information patient.
and data on the primary and secondary end points.
TP will be administered during the ve postoperative Damage and complications
days. Each patient will receive a medicament control If the patient presents any infectious complication
sheet where they will register every dose. On days 7 and
during the postoperative stage or any sign of persistent
30, patients will be monitored in the outpatients ofce. infection such as leukocytosis (dened as a WCC of
Patients will be given contact telephone numbers in case 10 000/mm3 or more), fever over 38C (100.4F), hepa-
they have any concern or need to report any event
togram alterations, cholangitis or hepatic abscesses, the
during follow-up. All data collected will be registered in medical team will proceed to stop the administration of
the follow-up sheet. TP and decide which medical actions need to be taken
Stage 2: During this stage, researchers will carry out a
according to each particular case. Any adverse event
statistical analysis of the analysed variables and their detected during outpatient monitoring will be registered
relations. and classied according to its severity into mild, moder-
ate and severe.
Sample size 1. Mild: Transitory events that do not require special
We hypothesised that the absence of postoperative anti- treatment. These events do not affect a patients daily
biotic treatment would not be inferior to receiving anti- life.
biotics after surgery for the development of surgical site 2. Moderate: Events that interfere in the patients daily
and distant infections after cholecystectomy. Our sample routine that require minimal, local or non-invasive
size calculation was based on published data1013 and on intervention.
an expected postoperative infection rate in the antibiotic 3. Severe: Medically signicant, disabling or immediately
group of 3%. Assuming a non-inferiority margin of 5%, life-threatening events that require hospitalisation
a one-tailed error of 5% and a power of 80% to reject and/or urgent intervention.
this null hypothesis, we estimated that the required
sample size would be 150 cases in each group. ETHICS AND DISSEMINATION
Ethics approval
The CHART is conducted in line with the current
Monitoring
All data will be registered in follow-up sheets by the national and international regulations: World Medical
investigators. These sheets will be exported weekly to Association Declaration of Helsinki, Regulation 5330/07
ANMAT, the Standards of Good Practices ICH E6 and
Microsoft Access (V.2013, Microsoft Corporation). The
Research Projects Evaluating Committee (CEPI) of the laws and regulations of the country, providing the
HIBA will audit this trial every 6 months. An interim greatest protection to the patient. The CHART has been
registered at Clinicaltrial.gov database (ClinicalTrials.gov,
analysis will be performed once 150 patients are
recruited. identier: NCT02057679).

Informed consent and confidentiality

Statistical analysis In all cases, the participation in the study is voluntary
Confirmatory analysis and certied by the process of informed consent. The
A non-inferiority design was chosen. The results will be right to refuse to participate in the study will be
analysed on an intention-to-treat basis. The association respected at all times without any implications in the
between outcome and the assigned treatment will be treatment of the patient disease. The antibiotics pro-
evaluated using the 2 TEST in discrete variables and posed correspond to the empirical initial scheme that is
analysis of variance for continuous variables. All data in use in our institution for patients with inammatory/
analysis will be performed using the SPSS software infectious hepatobiliary affections acquired in the com-
package V.17.0 (SPSS, Chicago, Illinois, USA). munity. All data collected will be treated with

4 Pellegrini P, et al. BMJ Open 2015;5:e009502. doi:10.1136/bmjopen-2015-009502

 Open Access

condentiality and anonymously. Authorised personnel cholecystectomies and a 10% conversion rate). It has
can only access the records of the study in compliance been widely demonstrated that one of the advantages
with the current legal regulation: National Law of of the laparoscopic approach is that it is associated with
Personal Information Protection No. 25.326 (Habeas the less surgical side infections rate.16 Thus, both
Data Law). approaches should be studied separately. Another limi-
All patients will be informed of the aims of the study, tation of this study is that it does not include a placebo
the possible adverse events, the procedures and possible group, which may lead placebo effect bias.
hazards to which they will be exposed, and the mechan- The trial proposed here is an original study in which,
ism of treatment allocation. Furthermore, it is the for the rst time, antibiotics are compared with placebo
responsibility of the investigator to explain to the after LC in cases of ACC. The CHART is a double-blind
patients their duties within the trial. They will be RCT designed to evaluate the need for and safety of
informed about the strict condentiality of their per- antibiotic treatment after LC for mild or moderate ACC.
sonal data, but that their medical records may be The results of this trial will provide strong evidence for
reviewed for trial purposes by authorised individuals decision-making in this matter. This could avoid the
other than their treating physician. Trial ndings will be unnecessary use of antibiotics after surgery, decreasing
stored in accordance with local data protection law/ICH the incidence of associated adverse events, as well as the
GCP-Guidelines and will be handled in the strictest con- emergence of bacterial resistance and treatment costs.
dence. For protection of these data, organisational pro-
cedures are implemented to prevent distribution of data Author affiliations
1
to unauthorised people. Department of General Surgery, Hospital Italiano de Buenos Aires, Buenos
Aires, Argentina
2
Department of Internal Medicine and Statistics, Hospital Italiano de Buenos
Dissemination Aires, Buenos Aires, Argentina
3
Anonymised results of the study will be published in a Department of Internal Medicine and Infectology, Hospital Italiano de Buenos
peer-reviewed journal, and will be presented at academic Aires, Buenos Aires, Argentina
meetings and scientic conferences. Only the registered
Acknowledgements The authors would like to thank the Central Pharmacy
investigators will have access to the individual patient staff of the HIBA. The CHART is funded exclusively by the institutional/
data. departmental sources.
Contributors The concept of the study was derived from MdS. This study
was designed by PP, JGo, AD and MdS. The article was written by PP, JPC
DISCUSSION and MdS. DG performed the sample size calculation and planned the
Although ACC is one of the most common diseases in statistical analyses. PP, AD, JGo, JGl, JPC, DG, LB, OM, FA, RSC, MP, GA,VA,
general surgery, few trials have assessed the role of anti- EdS, RSC, JP and MdS were involved in trial implementation and critically
biotic therapy after LC. Most publications on the subject revised the manuscript. All authors have read and approved the manuscript.
analyse the use of antibiotics after conventional proce- Competing interests None declared.
dures, or mix in the same design open and laparoscopic Patient consent Obtained.
procedures.
Ethics approval Research Projects Evaluating Committee (CEPI) of Hospital
In the late 1980s, Lau et al randomised 203 patients Italiano de Buenos Aires ( protocol N 2111).
and compared a short course of two doses versus a long
Provenance and peer review Not commissioned; externally peer reviewed.
course of 7 days of cefamandole after early open chole-
cystectomy. They found that the short course was as Open Access This is an Open Access article distributed in accordance with
effective as the long one in reducing postoperative infec- the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
tious complications with the additional advantages of commercially, and license their derivative works on different terms, provided
lower costs, risks of adverse events and length of hospital the original work is properly cited and the use is non-commercial. See: http://
stay.14 This was the rst study to suggest that a reduction creativecommons.org/licenses/by-nc/4.0/
in the use of postoperative antibiotics may be possible.
However, this study is outdated given the many changes
in bacterial resistance over time and the modern surgi-
cal therapies. In addition to these ndings, Mazeh et al3 REFERENCES
conducted a RCT in which they demonstrated that the 1. Yusoff IF, Barkun JS, Barkun AN. Diagnosis and management of
cholecystitis and cholangitis. Gastroenterol Clin North Am
addition of intravenous antibiotic treatment to support- 2003;32:114568.
ive care has limited, if any, effect in patients with mild 2. Strasberg SM. Clinical practice. Acute calculous cholecystitis. N Engl
J Med 2008;358:280411.
ACC. 3. Mazeh H, Mizrahi I, Dior U, et al. Role of antibiotic therapy in mild
Recently, Regimbeau et al15 published a multicentre acute calculus cholecystitis: a prospective randomized controlled
RCT in which patients admitted with mild and moder- trial. World J Surg 2012;36:17509.
4. Yoshida M, Takada T, Kawarada Y et al. Antimicrobial therapy for
ate ACC were randomised to antibiotics or no treat- acute cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg
ment after surgery. In the authors opinion, the main 2007;14:8390.
5. Yokoe M, Takada T, Strasberg SM, et al. TG13 diagnostic criteria
limitation of this study is that it includes both conven- and severity grading of acute cholecystitis (with videos).
tional and laparoscopic approaches (15% open J Hepatobiliary Pancreat Sci 2013;20:3546.

Pellegrini P, et al. BMJ Open 2015;5:e009502. doi:10.1136/bmjopen-2015-009502 5

 Open Access
6. Kanafani ZA, Khalif N, Kanj SS, et al. Antibiotic use in acute 12. Jatzko GR, Lisborg PH, Pertl AM, et al. Multivariate comparison of
cholecystitis: practice patterns in the absence of evidence-based complications after laparoscopic cholecystectomy and open
guidelines. J Infect 2005;51:12834. cholecystectomy. Ann Surg 1995;221:3816.
7. Fuks D, Coss C, Rgimbeau JM. Antibiotic therapy in acute 13. Lujan JA, Parrilla P, Robles R, et al. Laparoscopic cholecystectomy
calculous cholecystitis. J Visc Surg 2013;150:38. . vs open cholecystectomy in the treatment of acute
8. Johannes CB, Ziyadeh N, Seeger JD, et al. Incidence of allergic cholecystitis: a prospective study. Arch Surg 1998;
reactions associated with antibacterial use in a large, managed care 133:1735.
organisation. Drug Saf 2007;30:70513. 14. Lau WY, Yuen WK, Chu KW, et al. Systemic antibiotic regimens for
9. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo acute cholecystitis treated by early cholecystectomy. Aust N Z J
classification of surgical complications: five-year experience. Ann Surg 1990;60:53943.
Surg 2009;250:18796. 15. Regimbeau JM, Fuks D, Pautrat K, et al. Effect of postoperative
10. Yildiz B, Abbasoglu O, Tirnaksiz B, et al. Determinants of antibiotic administration on postoperative infection following
postoperative infection after laparoscopic cholecystectomy. cholecystectomy for acute calculous cholecystitis: a randomized
Hepatogastroenterology 2009;56:58992. clinical trial. JAMA 2014;312:14554.
11. Agabiti N, Stafoggia M, Davoli M, et al. Thirty-day complications after 16. Coccolini F, Catena F, Pisano M, et al. Open versus laparoscopic
laparoscopic or open cholecystectomy: a population-based cohort cholecystectomy in acute cholecystitis. Systematic review and
study in Italy. BMJ Open 2013;3:pii: e001943. meta-analysis. Int J Surg 2015;18:196204.

6 Pellegrini P, et al. BMJ Open 2015;5:e009502. doi:10.1136/bmjopen-2015-009502