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Ann Thorac Surg 2005;79:153-161
© 2005 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, Örebro, Sweden
b Department of Clinical Microbiology, and Infectious Diseases, Örebro University Hospital, Örebro, Sweden
c Department of Cardiothoracic Surgery, Linköping University Hospital, Linköping Sweden
d Sweden
Accepted for publication June 11, 2004.
* Address reprint requests to Dr Friberg, Department of Cardiothoracic Surgery, Örebro University Hospital, SE-701 85 Örebro, Sweden (E-mail: orjan.friberg{at}orebroll.se).
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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METHODS: Two thousand cardiac surgery patients were randomized to routine prophylaxis with intravenous isoxazolyl-penicillin alone (control group) or to this prophylaxis combined with application of collagen-gentamicin (260 mg gentamicin) sponges within the sternotomy before wound closure. Endpoint was any sternal wound infection within 2 months postoperatively. Evaluations were double-blind and made on an intention-to-treat basis.
RESULTS: Evaluation was possible in 967 and 983 patients in the control and treatment groups, respectively. The incidence of sternal wound infection was 4.3% in the treatment group and 9.0% in the control group (relative risk 0.47; 95% confidence interval 0.33–0.68; p < 0.001). Early reoperation for bleeding was more common in the treatment group (4.0% vs 2.3%, p = 0.03). No difference in postoperative renal function was noted.
CONCLUSIONS: Local collagen-gentamicin reduced the risk for postoperative sternal wound infections. Further studies are warranted to confirm these results, particularly with regard to deep infections.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Prophylaxis with intravenous (IV) ß-lactam antibiotics (cephalosporins or in Sweden most commonly isoxazolyl-penicillins), during surgery and with continuation for up to 48 hours postoperatively, is routinely practiced [8, 9]. However, most CoNS are methicillin resistant, and are thus resistant to all ß-lactam antibiotics due to the presence of the mecA gene [10]. Therefore, vancomycin is often the only effective antibiotic available for treatment of sternal infections caused by CoNS, but its use for routine prophylaxis is strongly discouraged because of the risk of selection of resistant bacteria with consequent ecological and therapeutic consequences [11]. Also, vancomycin is intrinsically a less active antistaphylococcal agent than are ß-lactam antibiotics [10]. Hence, alternative approaches to prevent postoperative sternal infections need to be explored.
With local application of gentamicin, bound to bovine collagen in padlike sponges (Collatamp-G; Schering-Plough, Stockholm, Sweden), there is evidence that the concentration of gentamicin in the mediastinal fluid reaches levels high enough to be effective against bacteria that are normally considered resistant (including most CoNS) [12]. The aim of this study was to determine whether locally administered gentamicin in addition to routine IV prophylaxis with isoxazolyl-penicillin could reduce the total incidence of SWI after cardiac surgery.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Eligible for inclusion in the study were all patients undergoing cardiac surgery through median sternotomy, including operations on the ascending aorta. Exclusion criteria were: known allergy to gentamicin; pregnancy or breastfeeding; treatment with aminoglycosides during the last 2 weeks before surgery; and expected difficulty in fulfilling the follow-up requirements, for linguistic or other reasons.
The trial was approved by the ethics committees at both participating centers, and written informed consent was obtained from all patients. In accordance with the ethics committees' approval, emergency patients were included and informed immediately after surgery. If they did not agree to participate they were excluded from further evaluation.
Design and Treatment
The study was randomized, prospective, and double-blind (ie, the patients and those physicians and nurses who collected all the postoperative data and classified the infections were blinded regarding what treatment the patients had received).
An external statistician who was not involved in the enrolment or assessment of the patients performed the randomization. The allocation sequence was computer-generated with a variable block size of 8, 12, or 16 patients and was stratified for center. Assignments were concealed in sealed envelopes. At the end of the operation, immediately before sternal closure, the envelope was opened and the patient was allocated to a treatment group (routine IV prophylaxis combined with sternal application of collagen-gentamicin; see below) or a control group (IV prophylaxis alone). No documentation concerning the group to which the patient had been randomized was left in the patient's file.
Collatamp-G consists of a flat absorbable bovine collagen sponge with gentamicin sulfate. A 10 x 10 x 0.5-cm sponge contains 280 mg collagen and 130 mg gentamicin (200 mg gentamicin sulfate). The treatment group received two such sponges in the wound immediately before closure. The sponges were cut into appropriate sizes and put between the sternal halves. More than two layers of Collatamp-G were avoided so as not to compromise sternal healing and stability, and any left-over sponge were put behind the sternum at the proximal or distal end.
In the control group the wound was closed in a conventional way. The primary end-point was any SWI within 2 months postoperatively.
Surgical Technique
A policy of strict hygiene routines to prevent infections has been adopted at both centers including avoidance of unnecessary personnel rotation in the operating rooms. One center had laminar air flow ventilation in the operating rooms, the other had upward displacement ventilation. Most, but not all, surgeons used double gloving. The operations were performed with a standard technique. Cardiopulmonary bypass (CPB) was used in all patients except in 9% of the coronary bypass (CABG) operations, which were carried out off pump (Table 1). Internal mammary arteries were harvested with a pedicle (not skeletonized). The sternum was sutured with 6 to 8 sternal wires, and the fascia, subcutis and skin were closed with running, monofilament, absorbable sutures. The surgeon who performed the heart operation, usually a senior surgeon, also closed the wound. Antibiotic prophylaxis was given IV, in accordance with the protocol of each center, starting immediately before the skin incision and then with 1 to 2 repetitions during surgery, with cloxacillin at one center and dicloxacillin at the other, at the doses 2 g and 1 g, respectively. This was continued every 8th hour for 24 to 48 hours postoperatively, depending on whether the drainage tubes had been removed. Patients with penicillin intolerance received clindamycin 600 mg at similar intervals. Preoperative topical nasal antibiotics were not used. Preoperative oral mouthwash twice, the night and the morning before surgery, with chlorhexidine solution was implied at one of the centers (Örebro).
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Follow-Up and Data Collection
During the postoperative stay in the surgical department, all reoperations and SWIs were recorded. Serum creatinine was measured preoperatively, on postoperative days 1 and 3, and then on clinical indications. All major complications during the postoperative stay were recorded.
After discharge the patients were contacted by telephone 2 months postoperatively and were asked to answer a structured list of standardized questions. Those who could not be reached by phone were sent a letter with a questionnaire containing the same questions. Any reported symptom of impaired wound healing or possible wound infection resulted in a check of medical records from all postoperative contacts with medical services. Data on clinical status, bacterial cultures, laboratory findings, and surgical or antibiotic treatment were recorded.
Four infections diagnosed after more than 2 months were discovered (60 to 73 days). These were also included in the analysis because the randomization had not been broken. Mortality data were double-checked against the national Swedish population register.
Classification of Infections
All classifications were made by the same person, a senior surgeon (Ö.F.), before the randomization code was broken. A second opinion was obtained from another surgeon or from a specialist in infectious diseases in doubtful cases.
Criteria for definition and classification of surgical site infections according to Centers of Disease Control and Prevention [11] were used with minor modifications (Table 2). Depths 1 and 2 were considered as superficial infections, and depths 3 and 4 were considered as deep infections.
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Five samples for bacterial culture, of which at least two were tissue samples, were taken intraoperatively at reoperations for deep infection. To be classified as definite mediastinitis or sternitis (depth 4), two of these five cultures had to be positive with the same bacterial isolate. In infected patients handled at referring hospitals, cultures were taken on clinical indications alone.
Statistical Analysis
The sample size was chosen so as to detect an approximate 50% reduction in the incidence of any SWI, and the incidence in the control group was assumed to be at least 4%. One thousand eighteen patients in each group provide a power of 80% for distinguishing between infection rates of 4% and 1.9% in the two groups (two-sided type I error of 5%). Therefore the 1000 patients in each group were considered to be appropriate because the incidence of 4% in the control group was assumed to be somewhat underestimated.
Subgroup analyses with regard to bacterial etiology, depth of infection and established preoperative risk groups (diabetes and high body mass index [BMI]) [13–20] were conducted. The sample size calculations did not account for these subgroup analyses but since the true incidence proved higher than assumed the analyses were considered justifiable.
All analyses were made on an intention-to-treat basis, ie, patients who died and those reoperated on for bleeding or other reasons during the follow-up period were included in the analysis. An interim analysis was performed by an external statistician after completion of follow-up of 1000 patients.
For categorical variables the relative risk with 95% confidence intervals was calculated and two-sided P values were calculated with Pearson's X2 test or, if expected frequencies fell below 5, Fisher's exact test. For continuous variables the Mann-Whitney rank sum test was used. For the statistical analyses, Statistica 6.1 (StatSoft Inc, Tulsa, OK), SPSS 11.5 (SPSS Inc, Chicago, IL) software, and Microsoft Excel (Microsoft, Redmond, WA) were used.
Role of the Funding Source
The sponsors had no role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Outcome
The total incidence of SWI (primary end-point) was 9.0% in the control group and 4.3% in the treatment group (p < 0.001). There was a reduction in all major microbiological types of infections (Table 3, Fig 2). Significantly fewer patients in the treatment group received antibiotics or needed surgical revision of the sternal wound during the follow-up.
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All patients, except one (belonging to the control group), with symptoms of sternal dehiscense that required refixation were classified as having a SWI.
General Outcome
There were no significant differences in mortality, postoperative rise in creatinine or need for dialysis between the groups (Table 3). The total 60-day mortality of the 129 patients with SWI was 1.5% (2 patients with deep SWI, both in the treatment group).
There were significantly more reoperations for bleeding in the treatment group (4.0% vs 2.3%). Data retrieved from the clinical databases of the centers showed that 3.5% of the 792 patients not included in the study had had reoperations for bleeding. Four of 39 patients reoperated on for bleeding in the treatment group and 1 of 22 such patients in the control group had postoperative SWI.
The reduction of infections was similar when excluding patients who were reoperated for bleeding (n = 61), reoperated for other reasons (n = 7), or who died within 2 months (n = 36) from the analysis (leaving 1850 patients, 927 and 923 in the control and treatment groups, respectively). In this group there were 62 (6.7%) versus 25 (2.7%) superficial infections (p < 0.001), and 31 (3.3%) versus 19 (2.1%) deep infections (p = 0.088) in the control and treatment groups, respectively.
The mean lengths of postoperative stay until discharge were 6.7 and 7.1 days in the treatment and control groups, respectively, with a median of 6 days in both groups.
Adverse Reactions
No case of verified or suspected allergic or other adverse reaction to gentamicin or bovine collagen was identified.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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A limitation of our study is the absence of a placebo arm with collagen without gentamicin. However, the patients and those assessing the outcome were blinded regarding treatment. Since the proposed hemostatic effect of collagen did not reduce reoperation rate for bleeding, it is conceivable that the reduction in SWI was due to the gentamicin component.
Definition and classification of surgical site infections are, despite classification systems, occasionally subjective. In this study infections were therefore classified as definite or probable. However, the risk reductions in these two classes were almost equal and – scientifically most important – there were significant reductions in the definite infections, in staphylococcal (including CoNS) infections, in surgical revisions and in antibiotic treatment.
The reported incidences of postoperative SWI varies considerably, not only because of differences in definitions and classification of infections but also because of variations in follow-up between centers and notably because most published series are retrospective [5, 13, 16, 19, 21–23]. The 9.0% infection rate in our control group is certainly higher than many surgeons would anticipate. However, it should be emphasized that the majority of the infections detected in the present study were not deep infections, as shown in Table 3. Furthermore, in this study, 4 of 5 infections were diagnosed after discharge. This underlines the importance of thorough follow-up. In a recent study with complete 90-day follow-up, the total incidence of SWI was 9.0% [24], which is similar to that found in our control group. In two earlier studies with complete 2-months follow-up, assessing the ASEPSIS wound score [25, 26], the incidence of any sternal wound infection was 8.0% and 7.3%, respectively.
The clinical characteristics of CoNS infections also deserve consideration. They have led to more insidious infections that have required extensive antibiotic treatment and not uncommonly delayed extensive surgical revision, consuming substantial healthcare resources [1]. Hence, over the last decade a policy of active surveillance and early aggressive surgical revision was developed at both centers, which has resulted in earlier detection, less complicated revisionary surgery, and reduced length of antibiotic treatment [27]. We suggest that the mortality of only 1.5% during 60 days of follow-up in patients with SWI in the present study is in accordance with this policy.
We applied the criteria for definition and classification of Surgical Site Infections according to Centers of Disease Control and prevention [11]. This is a systematic and frequently used classification, made for applying on any surgical site infection. It is focused on the depth, but not on the clinical severity, of the infection. An evaluated clinical wound score system, such as the ASEPSIS score [25], would have given additional information, but to apply this to almost 2000 patients was beyond our resources.
Randomized studies of prophylaxis with local collagen-gentamicin have reported a reduction of surgical site infections in "dirty" abdominal surgery [28–31] and in prosthetic repair of groin hernias [32]. There is one report of successful use of collagen-gentamicin for treatment of mediastinitis [33].
Intravenous aminoglycosides have been used for prophylaxis in cardiac surgery, usually combined with ß-lactam antibiotics [9]. However, no significant additional effect of the IV combination, compared to cephalosporins alone, has been reported [34–36].
In a recent meta-analysis IV ß-lactam antibiotics were superior to glycopeptides, such as vancomycin, for prevention of SWI after cardiac surgery, although glycopeptides were superior for prevention of infections caused by methicillin-resistant gram-positive bacteria [37]. Topical vancomycin has been shown to reduce the incidence of sternal infection in one randomized study [38].
Local application of gentamicin produces high local antibiotic concentrations that may have an effect on bacteria that are normally considered to be resistant [12]. Although gentamicin is generally used for gram-negative infections, it does have a spectrum of bactericidal activity for many gram-positive organisms, including staphylococci [39]. Synergism between aminoglycosides and ß-lactam antibiotics has also been shown [40]. Further detailed analyses of the bacteriological findings, including antibiotic susceptibility patterns, are required.
The gentamicin-collagen sponges were placed between the sternal halves. We hypothesized that this is where it is most important to achieve high antibiotic concentrations in order to prevent osteomyelitis. A lower incidence of SWI was found in the treatment group in all four depths but the study was not powered to detect significant differences in subgroups. Even so, the reduction in superficial infections was significant and patients with established risk factors for infection (diabetes or increased BMI) revealed a significant reduction in deep infections. Further studies are warranted to confirm these results. From a clinical perspective, the significant difference in the incidence of infections that required surgical treatment is important.
Bovine collagen is rapidly absorbed and is theoretically an attractive vehicle for antibiotics. The product is considered safe regarding BSE and is approved for commercial use in, for example, the countries within the European Union. We found no evidence of allergic reactions or adverse local effects on sternal healing. On the other hand, we found a higher incidence of early reoperation for bleeding in the treatment group. The medical records from the reoperation of the patients in the treatment group provided no obvious explanation, nor was any obvious, repeated or unusual source of the bleeding reported. Notably, the incidence of reoperation for bleeding in the treatment group was close to that seen in our routine practice and among the patients not included in the study. Thus, although this issue needs to be monitored in the future, available data, rather than pointing at any untoward effect, seem to suggest a lower than expected reoperation rate in the control group. Nevertheless, patients reoperated on for bleeding did not become infected to an extent that significantly influenced the overall result in an untoward direction.
A potential drawback of the local gentamicin treatment is the risk of selecting gentamicin-resistant bacterial clones over time. However, aminoglycosides have already been used extensively for many years. The pharmacokinetics of local gentamicin, with an early, high peak in the local gentamicin concentration, low serum concentrations and then rapid disappearance of the drug reduces the selection of resistant bacteria and may, in this respect, even be favorable compared to normal IV use [12].
Given the unique role of vancomycin for antibiotic treatment of overt sternal wound infections and the inadvisability of using it for routine prophylaxis in consideration of the ecological drawbacks, local gentamicin provides the potential advantage of reducing the total exposure of the environment to vancomycin.
Strict blood glucose control has in recent years been identified as a means of reducing SWI [41]. This was not yet fully in clinical practice during the study period and further studies are required to establish if local gentamicin may provide additional benefit in practices employing such strategies.
In conclusion, our study indicates a significant risk reduction in postoperative SWI in cardiac surgery. Further studies are warranted to confirm this result particularly with regard to deep infections. Such studies should also address the question whether routine use may be justified or whether high-risk groups that may have particular benefit from this approach should be identified.[14, 15, 17, 18, 20
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Acknowledgments |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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= control; 
= treatment. (SWI = sternal wound infections; CoNS = coagulase negative Staphylococci.)