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Figure. Patient flowchart showing the enrollment and randomization of 292 patients for a prospective, randomized, double-blind, placebo-controlled trial to determine whether extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery with tube thoracostomy reduces the risk of infectious complications compared with preoperative prophylaxis only. GFR indicates glomerular filtration rate.

Figure. Patient flowchart showing the enrollment and randomization of 292 patients for a prospective, randomized, double-blind, placebo-controlled trial to determine whether extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery with tube thoracostomy reduces the risk of infectious complications compared with preoperative prophylaxis only. GFR indicates glomerular filtration rate.

Table 1. Definitions of Infectious End Points
Table 1. Definitions of Infectious End Points
Table 2. Baseline Characteristics of Intention-to-Treat Population
Table 2. Baseline Characteristics of Intention-to-Treat Population
Table 3. Postrandomization Findings in Intention-to-Treat Population
Table 3. Postrandomization Findings in Intention-to-Treat Population
Table 4. Primary Study End Point Results
Table 4. Primary Study End Point Results
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Original Article
May 2013

Postoperative Antibacterial Prophylaxis for the Prevention of Infectious Complications Associated With Tube Thoracostomy in Patients Undergoing Elective General Thoracic SurgeryA Double-blind, Placebo-Controlled, Randomized Trial

Author Affiliations

Author Affiliations: Divisions of Infectious Diseases (Drs Oxman, Issa, Marty, Licona, and Baden) and Thoracic Surgery (Drs Mentzer, Jaklitsch, Bueno, Colson, Swanson, and Sugarbaker, Ms Panizales, and Mr Johnson), Departments of Pharmacy (Dr Patel) and Anesthesiology (Drs McKenna and Frendl), Brigham and Women's Hospital, Boston, Massachusetts; and Division of Pulmonary and Critical Care, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (Dr Oxman).

JAMA Surg. 2013;148(5):440-446. doi:10.1001/jamasurg.2013.1372
Abstract

Objective To determine whether extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery with tube thoracostomy reduces the risk of infectious complications compared with preoperative prophylaxis only.

Design Prospective, randomized, double-blind, placebo-controlled trial.

Setting Brigham and Women's Hospital, an 800-bed tertiary care teaching hospital in Boston, Massachusetts.

Participants A total of 251 adult patients undergoing elective thoracic surgery requiring tube thoracostomy between April 2008 and April 2011.

Interventions Patients received preoperative antibacterial prophylaxis with cefazolin sodium (or other drug if the patient was allergic to cefazolin). Postoperatively, patients were randomly assigned (at a 1:1 ratio) using a computer-generated randomization sequence to receive extended antibacterial prophylaxis (n = 125) or placebo (n = 126) for 48 hours or until all thoracostomy tubes were removed, whichever came first.

Main Outcome Measures The combined occurrence of surgical site infection, empyema, pneumonia, and Clostridium difficile colitis by postoperative day 28.

Results A total of 245 patients were included in the modified intention-to-treat analysis (121 in the intervention group and 124 in the placebo group). Thirteen patients (10.7%) in the intervention group and 8 patients (6.5%) in the placebo group had a primary end point (risk difference, −4.3% [95% CI, −11.3% to 2.7%]; P = .26). Six patients (5.0%) in the intervention group and 5 patients (4.0%) in the placebo group developed surgical site infections (risk difference, −0.93% [95% CI, −6.1% to 4.3%]; P = .77). Seven patients (5.8%) in the intervention group and 3 patients (2.4%) in the placebo group developed pneumonia (risk difference, −3.4% [95% CI, −8.3% to 1.6%]; P = .21). One patient in the intervention group developed empyema. No patients experienced C difficile colitis.

Conclusions Extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery requiring tube thoracostomy did not reduce the number of infectious complications compared with preoperative prophylaxis only.

Trial Registration clinicaltrials.gov Identifier: NCT00818766

There is currently no clear standard for the duration of use of prophylactic antibacterials in patients undergoing elective thoracic surgery requiring a tube thoracostomy (chest tube) placement. Currently, the approach to postoperative antibacterial prophylaxis for these patients varies widely among clinicians.1,2Quiz Ref IDPostoperative prophylactic antibacterials are routinely given for 24 or 48 hours after the placement of the chest tube and often for even longer.35 Reducing postsurgical infectious complications is an important goal,6 but the unnecessary use of antibacterials is costly, may be associated with increased antimicrobial resistance and toxicity, and could be complicated by drug-resistant bacterial infections including Clostridium difficile colitis, which could be deadly.7,8 Preoperative surgical prophylaxis using first-generation cephalosporins administered within 30 minutes before the incision time is currently recommended to prevent surgical site infections in clean or clean-contaminated operations.6 Additional intraoperative antibacterials could also be administered for lengthy surgical procedures.9 To assess whether additional antibacterials administered postoperatively to patients undergoing elective thoracic surgery with thoracostomy tube placement leads to a reduced rate of infectious complications, we compared 2 approaches for the prevention of surgical site infections. The first approach consists of administering standard preoperative antibacterial prophylaxis only, with no additional antibacterial therapy given postoperatively. The second approach also uses standard preoperative antibacterial prophylaxis, but with additional antibacterial therapy given for 48 hours postoperatively or until all thoracostomy tubes are removed, whichever comes first.

METHODS
STUDY DESIGN AND PARTICIPANTS

We conducted this randomized, double-blind, placebo-controlled study at Brigham and Women's Hospital, an 800-bed tertiary care teaching hospital in Boston, Massachusetts. Our study was approved by the hospital's institutional review board. Patients 18 years or older presenting for elective lung surgery who were expected to require tube thoracostomy were approached for participation in our study at the time of preoperative evaluation. Patients gave informed written consent prior to enrollment. Patients were ineligible to participate if any of the following procedures were planned: pneumonectomy, decortication, pleurodesis or pleurectomy, lung volume reduction, esophagectomy, or lung transplantation. Patients with known active infections prior to surgery, with cystic fibrosis, or with a history of antimicrobial use within 1 week of the surgery were excluded. Patients with an estimated glomerular filtration rate of less than 60 mL/min or with an allergic reaction to both β-lactam antibiotics and vancomycin hydrochloride were also excluded.

RANDOMIZATION AND MASKING

Eligible patients were randomly assigned (at a 1:1 ratio) to receive either normal saline (placebo arm) or additional antibacterial treatment (cefazolin or vancomycin for cephalosporin-allergic patients) immediately following surgery. These patients were randomly assigned in blocks of 4 via a randomization table that was prepared for our study, and patients were assigned to study arms sequentially by the members of the hospital's Investigational Drug Service, who were unaware of patient characteristics. Study drug doses were prepared by the Investigational Drug Service and administered in intravenous bags identical in appearance to those used in clinical practice. Nurses, clinicians, study investigators, and patients were masked to assigned study group throughout the study and were unaware of the block randomization strategy.

STUDY PROCEDURES AND OUTCOMES

All of the patients who enrolled in our study received the standard skin preparation (povidone-iodine) and the standard recommended doses of preoperative antibacterial therapy to prevent surgical site infection according to institutional guidelines. The patients with a prolonged operative time received additional antibacterial doses intraoperatively. Immediately after surgery, patients were randomly assigned to either additional postoperative antibacterials (intervention group) or placebo.Quiz Ref IDPostoperatively, patients received either additional antibacterials or placebo for 48 hours or until all chest tubes were removed, whichever occurred first. Patients with no history of an allergic reaction to cephalosporins received cefazolin (1 g for patients weighing ≤80 kg and 2 g for patients weighing >80 kg) or placebo every 8 hours. Patients with a history of an allergic reaction to β-lactams received 1 g of vancomycin or placebo every 12 hours. Chest tube management was done by the surgical team as per routine postprocedure care.

The primary study end point was the combined incidence of the following postoperative infectious complications: surgical site infection, empyema, pneumonia, and the occurrence of C difficile colitis within 28 days of surgery. Definitions of the infectious end points are based on criteria from the Centers for Disease Control and Prevention and are listed in Table 1. The protocol's prespecified secondary end points were the length of hospital stay, the time to removal of the chest tubes, the need for a reoperation, the administration of additional antibacterials for any reason within 28 days after surgery, any allergic reactions, and 28-day all-cause mortality. Surveillance for study end points was performed daily while the patient was hospitalized, at the patient's 2-week postoperative clinic appointment (at which time all patients received routine chest radiography and evaluation by their surgeon), and by a telephone call at the end of 28 days.

Each potential infectious complication was adjudicated by 2 study investigators. If there was disagreement between the 2 study investigators on the outcome classification, a third investigator decided the final outcome after reviewing the data and following the preset end-point definitions. All end points and postrandomization data were verified and adjudicated before unblinding.

STATISTICAL ANALYSIS

The reported occurrences of surgical site infection, empyema, and postprocedure pneumonia following elective thoracic surgery range from 7% to 14%.3,4,1225 We estimated that we would need to enroll 352 patients with a power of 80% and a 1-sided α level of .05 to exclude more than 3% absolute difference between the treatment groups. The projected accrual period was 3 years, and no interim analysis was planned. The study accrual was stopped at 3 years owing in part to planned changes in preoperative methicillin-resistant Staphylococcus aureus screening and owing to funding constraints. Data were analyzed using SAS 9.2 software (SAS Institute). The Fisher exact test and the Wilcoxon rank sum test were used to compare binary variables and continuous variables, respectively. Logistic regression analysis was used to adjust for potential confounding factors.

RESULTS

Between April 4, 2008, and April 4, 2011, a total of 292 patients consented to participate in our study and were assessed for eligibility. Forty-one patients were excluded (Figure). Of those who were excluded, the most common reasons for exclusion were cancellation of surgery (14 patients [34.1%]), receipt of antibacterials other than preoperative prophylactic antibiotics (7 patients [17.1%]), and a procedure not meeting inclusion criteria (6 patients [15.0%]).

A total of 251 patients were randomly assigned postoperatively to receive either extended antimicrobial prophylaxis (intervention group; n = 125) or no additional antibacterial prophylaxis (placebo group; n = 126). Of the 125 patients allocated to receive extended prophylaxis, 3 did not receive the allocated intervention: one withdrew consent, one was found to have an infection during surgery, and one erroneously received a nonstudy open-label antibacterial after surgery. All patients allocated to receive placebo received the allocated intervention. Three patients (1 in the intervention group and 2 in the placebo group) were enrolled twice in our study at separate occasions. Only data from their first enrollment in our study were analyzed. All patients completed the 2-week visit. We were unable to contact 21 patients (11 in the intervention group and 10 in the placebo group) for the day 28 follow-up telephone call. One patient in the intervention group died of complications of atrial fibrillation and cerebrovascular accident before day 28.

A total of 245 patients were included in the final analysis (121 in the intervention group and 124 in the placebo group). Sixteen patients had protocol violations after being randomly assigned (7 in the intervention group and 9 in the placebo group): 6 patients received additional doses of the study drug after removal of the chest tube (3 in each arm), 4 patients missed 1 study drug dose (3 in placebo group and 1 in intervention group), 3 patients had a study drug dose delayed by 2 hours or more (2 in the placebo group and 1 in the intervention group), 2 patients inadvertently received 1 dose of wrongly assigned study drug (1 in each arm), and 1 patient in the intervention group received 1 lower dose of cefazolin.

The patients' baseline characteristics are summarized in Table 2. The median age and body mass index and the proportions of patients with regard to sex and race were similar in both arms. The median duration of operation, the type of surgery, the type of antibacterial prophylaxis used, the median time to antibacterial administration prior to incision, and the number of additional intraoperative doses of antibacterials administered were all similar in both groups. The type of surgical approach (video-assisted thoracoscopic surgery [VATS] vs open thoracotomy) was similar in both groups. Quiz Ref IDWedge resection was the most commonly performed surgical intervention (146 of 245 patients [60.0%]), followed by lobectomy (76 of 245 patients [31.0%]). Cefazolin was used for preoperative prophylaxis in 227 of the 245 patients (93.0%).

Postoperatively, the most common pathologic finding was malignancy (76.0%) (86 in the intervention group vs 100 in the placebo group). The number of postoperative chest tubes placed and the median time to removal of all chest tubes were similar in both arms (Table 3). The number of postoperative doses of study drug administered was similar in both arms (median, 5 doses [range, 0-6 doses]; P = .70).

Thirteen patients had at least 1 or more events as part of the primary study end point in the intervention group compared with 8 patients in the placebo group (risk difference [RD], −4.3% [95% CI, −11.3% to 2.7%]; P = .26) (Table 4). Quiz Ref IDSix patients had surgical site infections in the intervention group compared with 5 patients in the placebo group (RD, −0.9% [95% CI, −6.1% to 4.3%]; P = .77). Seven patients were diagnosed with pneumonia in the intervention group compared with 3 patients in the placebo group (RD, −3.4% [95% CI, −8.3% to 1.6%]; P = .21). One patient in the intervention group had an empyema. This patient also had a surgical site infection. No patient in either group developed C difficile colitis or an allergic reaction to a drug.

Of the 245 patients included in the final analysis, 63 (26.0%) received additional antibacterials postoperatively during the study period (32 in the intervention group compared with 31 in the placebo group). Of these 63 patients, 21 (33.3%) received additional antimicrobials because they had one of the study outcomes (surgical site infection, pneumonia, or empyema). The most common indications for additional antimicrobials during the study period, excluding patients with study end points, were urinary tract infection (15 patients [6.1%]), upper respiratory tract infection (13 patients [5.3%]), and additional surgical interventions (9 patients [3.7%]) (Table 3). The median time to use of additional antibacterials after surgery for patients without a study end point were 12 days (range, 1-28 days) in the intervention group and 5 days (range, 1-30 days) in the placebo group (P = .31). Fifteen patients (6.1%) required a reoperation: 5 in the intervention group and 10 in the placebo group (P = .29). Among the 15 patients who required a reoperation, only 1 procedure (decortication) was performed for a patient in the intervention group who had empyema. The other 14 reoperations were performed for the following reasons: vocal cord paralysis (n = 3), percutaneous gastric tube placement (n = 2), air leak (n = 2), tracheostomy (n = 1), hemothorax (n = 1), chest wall hematoma (n = 1), chest wall necrosis without infection (n = 1), adhesiolysis (n = 1), nasal septal deviation (n = 1), and skin lesion excision (n = 1). The median length of stay (3 days) was no different between the 2 arms. Nine patients (7.3%) in the placebo arm had upper respiratory tract infection compared with 4 patients (3.3%) in the intervention arm. Although these patients did not meet definition criteria for pneumonia, we explored the effect of additional postoperative antimicrobial treatment on an expanded composite end point that included any respiratory tract infection for which patients received additional antibacterial treatment. When any respiratory tract infection for which additional antibacterials were prescribed were included in the composite outcome, there were no differences in the number of outcomes in either group (17 events in each arm; RD, −0.34% [95% CI, −9.0% to 8.3%]; P = .99). The number of events was similar in both groups (6 in the intervention group and 5 in the placebo group) when pneumonia was excluded from the composite end point (RD, −0.93% [95% CI, −6.12% to 4.26%]; P = .77).

COMMENT

To establish evidence-based standards for surgical prophylaxis for patients undergoing elective general thoracic surgical procedures requiring the placement of a chest tube, we examined whether additional postsurgical antibacterial prophylaxis for 48 hours or until all chest tubes were removed, whichever occurred first, decreased further the rate of infectious complications compared with standard preoperative prophylaxis only. We also examined the possible deleterious effects that could potentially be associated with the use of extended antibacterial prophylaxis (ie, allergic reaction and C difficile colitis).

The major finding in our study is that extended postsurgical prophylaxis did not offer any additional benefits in terms of reducing the overall rate of postoperative infectious complications when compared with placebo. In fact, more composite end points occurred in the intervention arm compared with the placebo arm (10.7% vs 6.5%; P = .26).

We explored several important variables that could have skewed the results of our study. All variables were evenly distributed in both arms of the study. The baseline characteristics in the intervention arm and the placebo arm were all well balanced, including age, weight, body mass index, procedure type, and duration of surgery. The majority of patients received their preoperative prophylactic antimicrobials within 60 minutes of the incision time (Table 2), as recommended by the Centers for Disease Control and Prevention and the Society of Thoracic Surgeons practice guidelines.6,26

The estimated occurrence of surgical site infection, empyema, and postoperative pneumonia in patients undergoing elective thoracic surgery varies widely among studies depending on the criteria employed to define infectious end points, the type of surgery performed (VATS vs open thoracotomy), and the preoperative antimicrobial prophylactic regimen used. In most studies,3,4,1217,1925 the estimated occurrences of surgical site infection, pneumonia, and empyema after elective thoracic surgical procedures range from 7% to 14%.

In our study, the overall rate of infectious complications and the rates of surgical site infection, pneumonia, and empyema were all within those observed in similar studies involving elective thoracic surgery (8.6%). Of the 245 patients, 132 (54.0%) underwent a VATS; this procedure has a relatively lower rate of perioperative complications compared with an open thoracotomy.16,18,19,25,2731 In our study, the number of patients who underwent an open thoracotomy and the number of patients who underwent a VATS were similar in both arms of our study (P = .89) (Table 2). More infectious outcomes were noted in the open thoracotomy group (11.5%) compared with the VATS group (6.1%), which is consistent with previously published studies.16,18,19,25,27,28,30,31

Several studies32,33 have documented that an important proportion of postoperative infectious complications develop after the patient has been discharged from the hospital. This makes it challenging to correctly classify and capture study end points after hospital discharge. In our study, the compliance rate of patients at 2 weeks after surgery was 100%. Patients were physically seen and examined by the operating surgeon, underwent chest radiography, and were assessed for the occurrence of any of the study end point. In addition, we were able to contact the majority of patients at postoperative day 28. We were unable to reach 22 patients (9%) by phone at day 28; however, we were able to assess for occurrence of any study end point by reviewing the documented follow-up visits for all patients.

Although our study was closed to enrollment before reaching its target accrual, the findings demonstrate the lack of benefit of extended antibacterial prophylaxis for patients who undergo elective thoracic surgical procedures that require chest tube placement. More end points occurred in the intervention arm (10.7%) than in the placebo arm (6.5%) (RD, −4.3% [95% CI, −11.3% to 2.7%]). The 95% CI of the RD on the composite end point between treatment arms excluded our protocol's prespecified 3% RD in favor of extended antimicrobial prophylaxis. It is unlikely that increasing the number of patients enrolled would have resulted in a clinically meaningful difference that would make the findings in our study less applicable. In addition, the numbers of patients who received additional antimicrobials during the follow-up period were similar in both arms. When any respiratory tract infection for which additional antibacterials were prescribed were included in the composite outcome, there were no differences in the number of outcomes in either group (17 events in each arm; RD, −0.34% [95% CI, −9.0% to 8.3%]).

Quiz Ref IDThe findings in our study might not be applicable to all types of thoracic surgical procedures. Patients undergoing more complex procedures such as pneumonectomy, lung volume reduction, and esophagectomy were not eligible for enrollment in our study. Patients requiring these types of procedures often have coexisting morbidities that inherently carry an increased risk of infectious complications, including fistulization, dead space infection, and the prolonged placement of drains. Our findings, however, may be applicable to the vast majority of elective clean or clean-contaminated thoracic surgical procedures requiring tube thoracostomy placement. These findings could also be extrapolated to other types of surgery in which a tube or a drain is inserted in sterile fashion in a sterile compartment for a short period of time.

In summary, extending postoperative surgical prophylaxis for patients undergoing elective general thoracic surgery with chest tube placement does not seem to offer any additional benefits in terms of reducing infectious complications compared with standard preoperative surgical prophylaxis. Although not demonstrated in our study, extending nonbeneficial antibacterial prophylaxis to the postsurgery period could potentially be associated with adverse effects such as the selection of more drug-resistant organisms, allergic reactions, drug toxicities, C difficile colitis, and higher costs.

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Article Information

Correspondence: Nicolas C. Issa, MD, Division of Infectious Diseases, Brigham and Women's Hospital, 75 Francis St, PBB A-4, Boston, MA 02115 (nissa@partners.org).

Accepted for Publication: October 5, 2012.

Published Online: January 16, 2013. doi:10.1001/jamasurg.2013.1372

Author Contributions: Drs Oxman and Issa contributed equally to this work. Dr Issa had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Oxman, Marty, Panizales, McKenna, Frendl, Bueno, Sugarbaker, and Baden. Acquisition of data: Oxman, Issa, Patel, Panizales, Johnson, Licona, Frendl, Mentzer, Jaklitsch, Swanson, Sugarbaker, and Baden. Analysis and interpretation of data: Oxman, Issa, Marty, Panizales, Licona, Frendl, Colson, and Baden. Drafting of the manuscript: Oxman, Issa, Panizales, Frendl, Sugarbaker, and Baden. Critical revision of the manuscript for important intellectual content: Oxman, Issa, Marty, Patel, Johnson, Licona, McKenna, Frendl, Mentzer, Jaklitsch, Bueno, Colson, Swanson, Sugarbaker, and Baden. Statistical analysis: Issa, Marty, and Panizales. Obtained funding: Frendl and Baden. Administrative, technical, and material support: Marty, Patel, Panizales, Johnson, Licona, McKenna, Frendl, Bueno, Sugarbaker, and Baden. Study supervision: Oxman, Issa, Marty, Frendl, and Baden.

Conflicts of Interest Disclosures: None reported.

Funding/Support: Funding for the study was provided by the Division of Infectious Diseases and the Surgical Intensive Care Unit Translational Research Center, Brigham and Women's Hospital, Boston, Massachusetts.

Role of the Sponsors: The Division of Infectious Diseases and the Surgical Intensive Care Unit Translational Research Center did not participate in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank Belisa B. Guzman-Suarez, MD, and Kimberly Cheng, BA, for their assistance in the data collection and analysis and the Brigham and Women's Hospital Investigational Drug Service team.

REFERENCES
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