Abstract

Background

Acute calculous cholecystitis is a frequently encountered disease in surgical practice that generally mandates emergency cholecystectomy. Although this is considered to be a low-risk procedure, the complication rate is not negligible. The most common complication is a postoperative infection, either at the surgical site or a distant site, occurring in approximately 17% of patients [1]. As such, many patients receive antibiotic prophylaxis before cholecystectomy, often to be continued for several postoperative days, in order to reduce postoperative infectious complications.

The Working Party on Antibiotic Policy in the Netherlands (Stichting Werkgroep Antibioticabeleid) issued guidelines for perioperative antibiotic prophylaxis in Dutch hospitals [2]. According to these guidelines, perioperative antibiotic prophylaxis is recommended for surgical procedures with a moderate or high risk of postoperative infections, including biliary surgery. Prophylaxis given within 2 h before incision appears to be most effective [2]. Recommended is single-dose prophylaxis, not only because it has proven to be as effective as multiple-dose prophylaxis but also for reasons of cost-effectiveness and prevention of bacterial resistance. The Surgical Infection Society and the Infectious Diseases Society of America, as well as the Tokyo Guidelines, also recommend antimicrobial prophylaxis for patients undergoing cholecystectomy for acute cholecystitis [3, 4]. These recommendations, however, are based on low-quality evidence, and therefore the actual effect of perioperative antibiotic prophylaxis remains unclear. Consequently, the use of antibiotic prophylaxis in the treatment of acute cholecystitis is highly variable among surgeons and hospitals.

In patients undergoing elective cholecystectomy for uncomplicated cholelithiasis, high-level evidence is available demonstrating that prophylactic antibiotics do not reduce the incidence of postoperative infections [5–9]. For this indication, the use of perioperative antibiotic prophylaxis is discouraged. According to a recent randomized controlled trial, also in emergency cholecystectomy the continuation of antibiotic prophylaxis after surgery is disputable [1]. This study demonstrated that postoperative antibiotic prophylaxis (in addition to a single prophylactic dose prior to surgery) in patients with mild and moderate acute cholecystitis did not reduce the risk of infectious complications. Antibiotic prophylaxis after cholecystectomy for acute cholecystitis may therefore be omitted. The remaining question is whether a single preoperative dose of antibiotic prophylaxis is beneficial in patients undergoing emergency cholecystectomy for acute cholecystitis. This has never been studied.

If the present study demonstrates that omitting antibiotic prophylaxis does not increase the postoperative infection rate, the use of antibiotics for this indication can be dropped as a whole. If so, the role of antibiotic prophylaxis in surgery of the entire upper gastrointestinal tract will become questionable. A decrease of antibiotic use on such a scale may result in a large reduction of needless medical activities, costs, and bacterial resistance. The latter is a growing issue in contemporary medicine and has emerged as one of the eminent public health concerns nowadays [10].

The Perioperative Antibiotic Use in the Treatment of Acute Inflammation of the Gallbladder (PEANUTS II) trial is designed to assess whether preoperative antibiotic prophylaxis is indicated to prevent postoperative infectious complications in patients undergoing emergency cholecystectomy for acute calculous cholecystitis. The hypothesis is that the absence of antibiotic prophylaxis does not lead to an increase in infectious complications.

Methods

Design

The PEANUTS II trial is a randomized, controlled, multicenter, open-label noninferiority trial. Patients will be randomly allocated to receive either no antibiotics or a single dose of antibiotic prophylaxis before emergency cholecystectomy (Fig. 1).

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Fig. 1

Flowchart of study outline of included patients. * According to the severity assessment criteria of the Tokyo Guidelines [11]

Study population

All patients presenting with acute calculous cholecystitis to one of the participating hospitals will be assessed for eligibility. Patients are eligible if diagnosed with mild or moderate acute calculous cholecystitis as defined according the Tokyo Guidelines [11] (Table 1). The inclusion and exclusion criteria are presented in Table 2.

Table 1

Diagnostic criteria for acute cholecystitis according to the Tokyo Guidelines [11]

Severity grade	Criteria
Mild (grade I)	Does not meet the criteria of “severe” or “moderate” acute cholecystitis. Can also be defined as acute cholecystitis in a healthy patient with no organ dysfunction and mild inflammatory changes in the gallbladder.
Moderate (grade II)	Associated with any one of the following conditions: 1. Elevated white blood cell count (>18,000/mm3) 2. Palpable tender mass in the right upper abdominal quadrant 3. Duration of complaints>72 h 4. Marked local inflammation (gangrenous cholecystitis, pericholecystic abscess, hepatic abscess, biliary peritonitis, emphysematous cholecystitis)
Severe (grade III)	Associated with dysfunction of any of the following organs/systems: 1. Cardiovascular dysfunction (hypotension requiring treatment with dopamine>5 μg/kg/minute or any dose of norepinephrine) 2. Neurological dysfunction (decreased level of consciousness) 3. Respiratory dysfunction (PaO2/FiO2 ratio<300) 4. Renal dysfunction (oliguria, creatinine>2.0 mg/dl) 5. Hepatic dysfunction (PT-INR>1.5) 6. Hematological dysfunction (platelet count<100,000/mm3)

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Abbreviations: PaO ₂ /FiO ₂ Ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, PT-INR Prothrombin time-international normalized ratio

Table 2

Inclusion and exclusion criteria

Inclusion criteria

Exclusion criteria

● Acute calculous cholecystitis, graded as mild or moderatea according to Tokyo Guidelines [11] A. Local signs of inflammation and so forth: 1. Murphy’s sign 2. RUQ mass/pain/tenderness B. Systemic signs of inflammation and so forth: 1. Fever 2. Elevated CRP 3. Elevated WBC count C. Imaging findings suspect for acute cholecystitis Definite diagnosis: one positive item in A and one positive item in B ● Patient will undergo cholecystectomy

●<18 years of age ● Acalculous cholecystitis ● Acute calculous cholecystitis graded as severe according to Tokyo Guidelines [11] ● Already receiving or needing antibiotics for a concomitant infection ● Proven allergy to cefazolin ● Pregnancy ● Indication for ERCP on admission

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Abbreviations: CRP C-reactive protein, ERCP Endoscopic retrograde pancreaticocholangiography, RUQ Right upper quadrant, WBC White blood cell

^aThe diagnostic criteria for mild and moderate acute cholecystitis are shown in Table 1

Data collection and follow-up

Each patient will receive an anonymous study number that will be used for the study record forms and the database. On admission, baseline characteristics, including age, sex, body mass index, comorbidity, American Society of Anesthesiologists physical status score, clinical data (i.e., temperature on admission, white blood cell count, C-reactive protein, and duration of symptoms), will be collected and documented by the admitting physician or (local) study coordinator (Fig. 2). Data regarding the surgical procedure, including conversion, bile culture, empyema, bile spill, and the severity of cholecystitis, will be documented by the performing surgeon immediately after the procedure. On the day of discharge, a case record form will be completed with information on the occurrence of infectious complications and, if so, the way the infection was objectified and treated. One week after discharge, the patients will be called by phone by the study coordinator, and 1 month after discharge, the patient will be seen in the outpatient clinic by a surgeon who will complete a questionnaire on the patient’s clinical condition and the development of infectious complications. Every 3 months, all entered data will be checked for completion by the study coordinator, and missing data will be collected from the participating centers.

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Fig. 2

Content for schedule of enrollment, interventions, and assessments according to the Standard Protocol Items: Recommendations for Interventional Trials statement [13]

Discussion

Whether antibiotic prophylaxis has any additional value in preventing infectious complications after emergency cholecystectomy is a much-debated subject in the surgical community. Evidence-based guidelines are lacking, and, as a result, the use of antibiotic prophylaxis varies greatly among surgeons and hospitals. Recently, high-level evidence became available demonstrating that postoperative antibiotic prophylaxis (in addition to a single preoperative dose) does not reduce the risk of infectious complications [1]. Preoperative antibiotic prophylaxis in relation to the risk of infectious complications, however, has never been studied. We therefore designed the PEANUTS II trial with the aim of determining the utility of preoperative antibiotic prophylaxis in patients undergoing emergency cholecystectomy for acute calculous cholecystitis.

The PEANUTS II trial has a noninferiority design. The hypothesis is that the absence of antibiotic prophylaxis will not lead to an increase of postoperative infectious complications. In the nontreatment group, either an increase of the infectious complication rate or no effect will be seen. Because it is very improbable that the absence of antibiotic prophylaxis will lead to a decrease of infectious complications, and thus deviation is possible in only one direction, a noninferiority design is best suited to answering this primary question.

The best design for a therapeutic trial is a placebo-controlled, double-blind trial, but because treatment of acute cholecystitis is often performed in an acute setting outside regular working hours, such a design is difficult to organize. Therefore, an open comparative design was chosen. We believe that blinding and placebo are not of absolute importance, because the primary outcome of the study is an objective criterion with a clearly defined (internationally accepted) definition. In addition, all potential endpoints will be assessed individually by the members of the adjudication committee, who are blinded to the treatment allocation. Only after reaching consensus on each individual endpoint for each patient will final analysis be performed by an unblinded independent statistician.

Patients with grade III (severe) acute cholecystitis are septic and require antibiotic treatment in addition to appropriate organ support [11, 15]. This is the rationale for exclusively including patients with grade I (mild) and grade II (moderate) acute cholecystitis.

If this study demonstrates that omitting antibiotic prophylaxis does not increase the postoperative infection rate in patients with acute cholecystitis, the role of antibiotic prophylaxis in surgery of the entire upper gastrointestinal tract will become questionable. A decrease in the use of antibiotics may result in a large reduction of bacterial resistance, the latter being an increasingly serious threat to global public health [10].

Acknowledgements

Abbreviations

Authors’ contributions

CSL and DB drafted the manuscript. AAWvG, GAPN, BV, JCK, CAJK, PRdR, MHGB, and HCvS coauthored the manuscript. CSL, BV, JCK, CAJK, HCvS, and DB participated in the design of the study. CSL, JCK, and DB performed the sample size calculations. CSL is currently performing the coordination and follow-up of the trial. All authors edited the manuscript, and all authors read and approved the final manuscript.

Notes

Footnotes

Contributor Information

Charlotte S. Loozen, Phone: 0031(0)643443077, Email: [email protected].

Hjalmar C. van Santvoort, Email: [email protected].

Antoinette A. W. van Geloven, Email: ln.ioogret@nevolegnava.

Grard A. P. Nieuwenhuijzen, Email: [email protected].

Philip R. de Reuver, Email: [email protected].

Mark H. G. Besselink, Email: [email protected].

Bart Vlaminckx, Email: [email protected].

Johannes C. Kelder, Email: ln.siuhnekeizsuinotna@10dlek.

Catherijne A. J. Knibbe, Email: [email protected].

Djamila Boerma, Email: [email protected].

References