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BY
T HE J OURNAL
OF
B ONE
AND J OINT
S URGERY, I NCORPORATED
Delayed Wound Closure Increases Deep-Infection Rate Associated with Lower-Grade Open Fractures A Propensity-Matched Cohort Study Richard J. Jenkinson, MD, MSc, FRCS(C), Alexander Kiss, PhD, Samuel Johnson, MD, David J.G. Stephen, MD, FRCS(C), and Hans J. Kreder, MD, MPH, FRCS(C) Investigation performed at the Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
Background: Primary closure of skin wounds after debridement of open fractures is controversial. The purpose of the present study was to determine whether primary skin closure for grade-IIIA or lower-grade open extremity fractures is associated with a lower deep-infection rate. Methods: We identified 349 Gustilo-Anderson grade-I, II, or IIIA fractures treated at our level-I academic trauma center from 2003 to 2007. Eighty-seven injuries were treated with delayed primary closure, and 262 were treated with immediate closure after surgical debridement. After application of a propensity score-matching algorithm to balance prognostic factors, 146 open fractures (seventy-three matched pairs) were analyzed. Results: After application of a propensity score-matching algorithm with adjustment for age, sex, time to debridement, American Society of Anesthesiologists (ASA) class, fracture grade, evidence of gross contamination, and a tibial fracture rather than a fracture at another anatomic site, the two treatment groups were compared with respect to the prevalence of infection. Deep infection developed at the sites of three of the seventy-three fractures treated with immediate closure (infection rate, 4.1%; 95% confidence interval [CI], 0.86 to 11.5) compared with thirteen in the matched group of seventythree fractures treated with delayed primary closure (infection rate, 17.8%; 95% CI, 9.8 to 28.5) (McNemar test, p = 0.0001). Conclusions: Immediate closure of carefully selected wounds by experienced surgeons treating grade-I, II, and IIIA open fractures is safe and is associated with a lower infection rate compared with delayed primary closure. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewed by an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.
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reatment standards for open fractures require timely irrigation and adequate debridement1. Traumatic openfracture wounds traditionally have been left open after the initial debridement in order to minimize the risk of later deep infection, especially with Clostridium2. This treatment strategy is traced to the experience of trauma surgeons from the pre-antibiotic era, especially during World War I and World War II3,4. Delayed wound closure until a few days post-injury is currently advocated by many surgeons to allow drainage of any collecting infectious material and to allow for a universal secondlook debridement2,5. However, with advances in stabilization
methods, antibiotics, and wound management, the strict avoidance of immediate wound closure has been challenged, with several investigators reporting low infection rates6-8. Immediate wound closure after initial debridement has the advantage of providing immediate soft-tissue cover to the traumatized limb as well as some protection against nosocomial pathogens9. Also, subsequent visits to the operating room for second-look debridements may be avoided if immediate closure is chosen, thereby simplifying and streamlining management of the traumatized patient. There are no clear guidelines for determining the time frame for safe closure of traumatic open fracture wounds, and
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
J Bone Joint Surg Am. 2014;96:380-6
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http://dx.doi.org/10.2106/JBJS.L.00545
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Materials and Methods TABLE I Baseline Characteristics
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Variable Average age (yr)
40.7
Male sex*
240 (68.8%)
ASA class >2*
66 (18.9%)
ISS >25 points*
155 (44.4%)
Gunshot mechanism*
28 (8.0%)
Average injury to debridement time (hr)
11.27
Average injury to first antibiotic time (hr)
2.53
Tibial fracture*
148 (42.4%)
Gross contamination*
140 (40.1%)
Fracture grade* Grade I Grade II Grade IIIA
53 (15.2%) 141 (40.4%) 155 (44.4%)
Primary closure*
262 (75.0%)
Deep infection*
25 (7.2%)
*Values are given as the number of patients, with the percentage in parentheses.
this determination is left to the judgment and experience of the treating orthopaedic surgeon. Higher-risk open fractures would be expected to have higher rates of more conservative wound management. We compared the rate of subsequent deep infection between patients in whom an open fracture had been treated with immediate primary closure after debridement and those in whom the fracture had been treated with delayed primary closure. Bias was reduced with use of a matched-pairs design. We hypothesized that early wound closure would reduce the rate of subsequent deep infection.
onsecutive patients treated for an open extremity fracture from January 1, 2003, to January 1, 2007, at our level-I trauma center were identified with use of our trauma database. Open hand and pelvic fractures were excluded. We supplemented case identification with the billing database of the central orthopaedic department with use of specific coding identifiers for open fractures (E556 modifier). Medical records were abstracted by two orthopaedic surgeons (R.J.J. and S.J.). We identified 417 patients who had a total of 459 fractures. The inclusion and exclusion criteria are shown in Figure 1. Gustilo-Anderson gradeIIIB fractures usually are not amenable to primary closure and were excluded. Gustilo-Anderson grade-IIIC fractures also were excluded because these injuries often are treated simultaneously with fasciotomies, for which skin closure is contraindicated. This left 345 patients with a total of 415 fractures. Thirteen patients died from their traumatic injuries during the index hospital stay and were excluded, which left 332 patients available for follow-up. Complete follow-up was defined as twelve months, which was not achieved for thirtyeight patients (rate of complete follow-up = 89%). Our final cohort consisted of 294 patients with a total of 349 Gustilo-Anderson grade-I, II, or IIIA fractures. The collected patient demographic characteristics included age, sex, and American Society of Anesthesiologists (ASA) class. The collected injury variables included the injury severity score (ISS), evidence of gross contamination of the fracture, the anatomic fracture location, and the time delay to surgery (defined as from ambulance call time to surgical start time). A Gustilo-Anderson 1,10 grade was assigned to the fracture on the basis of the surgical description of the injury after debridement. Gross contamination was documented if dirt or foreign material was present. None of the wounds had fecal or farmyard contamination or contamination with grass. The primary outcome measure for the present study was deep infection, defined as infection of the injured bone and deep tissue necessitating an unplanned operative irrigation and debridement at more than two weeks after the injury. We chose a two-week cutoff in order to address the concern of whether an early debridement was planned or unplanned. Planned repeat debridements and superficial infections not requiring surgery were not considered to be deep infections. All deep infections were treated with one or more surgical debridements, possible implant removal, and/or skeletal stabilization. Initial characteristics of the injuries are shown in Table I. The standard treatment protocol at our institution included intravenous antibiotics immediately administered on arrival in the emergency department and continued during hospitalization until at least twenty-four hours after definitive wound closure. Intravenous cefazolin was administered, although clindamycin was used when a severe penicillin allergy was known. Gentamicin was added for grade-III open fractures. Debridements were performed urgently,
Fig. 1
Patients included and excluded from the study.
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TABLE II Characteristics of Wound Closure Treatment Groups Prior to Matching Variable Average age (yr)
Primary Closure (N = 262) 41.3
Male sex ASA class >2*
Delayed Closure (N = 87) 39.7
66.7%
74.7%
58 (22.1%)
8 (9.2%)
P Value 0.24 0.17 0.0016
Average injury to debridement time (hr)
12.06
8.90
0.0016
Average injury to first antibiotic time (hr)
2.44
2.81
0.47
Tibial fracture*
104 (39.7%)
44 (50.6%)
0.0056
84 (32.1%)
56 (64.4%)
0.0001
Fracture grade* Grade I Grade II Grade IIIA
49 (18.7%) 112 (42.7%) 101 (38.5%)
4 (4.6%) 29 (33.3%) 54 (62.1%)
0.0001 0.127 0.0001
Deep infection*
9 (3.4%)
16 (18.4%)
0.0008
Gross contamination*
*Values are given as the number of patients, with the percentage in parentheses.
on the basis of availability of the operating room. Normal saline solution was used for irrigation, with gravity or pulse lavage used at the discretion of the treating surgeon. Wound culture specimens were not routinely taken at the time of initial debridement. Antibiotic choice, fixation method, and wound closure were also at the discretion of the treating physicians. Vacuum-assisted closure dressings were not used for any of these fractures. Second-look debridement after approximately forty-eight hours was performed routinely when delayed closure was chosen and was performed in patients who had undergone primary closure when chosen by the treating surgeon on the basis of the impression of the adequacy of the debridement. All statistical analyses were performed with use of SAS version 9.2 (SAS Institute, Cary, North Carolina) with input from a statistician (A.K.). To adjust 11 12,13 for confounding by indication , a propensity-score matched-cohort study was developed from the original data set (Table I). Injury characteristics were used in a logistic regression model to predict the likelihood of the need for
treatment with delayed wound closure. As eighty-seven patients were managed with delayed wound closure, up to eight degrees of freedom could be specified 14 in the propensity score . Dichotomous and continuous variables used one degree of freedom each, whereas the three-level variable used two degrees of freedom. The factors considered to be the most important confounders also contributing to deep-infection risk were chosen for the propensity-score algorithm. These factors included patient age, sex, time delay to debridement, fracture grade (Gustilo-Anderson grade I, II, or IIIA), evidence of gross contamination, tibial compared with nontibial site, and ASA class (1 or 2 compared with 3 or higher). These factors were chosen, based on consensus among the investigators, as the factors most important for predicting later infection but also as those most divergent between the immediate and delayed-closure groups 15 (Table II). A one-to-one matching algorithm was used to pair injuries with a similar propensity for delayed wound closure. This algorithm searches for the most exact match available to eight decimal places and then works back to one
TABLE III Characteristics of Wound Closure Treatment Groups After Matching Variable Average age (yr) Male sex ASA class >2*
Primary Closure (N = 73) 38.6
Delayed Closure (N = 73) 37.8
P Value 0.78
76.7%
73.9%
0.70
7 (9.6%)
8 (11.0%)
0.78
Average injury to debridement time (hr)
9.75
8.8
0.30
Average injury to first antibiotic time (hr)
1.92
2.75
0.09
Tibial fracture*
30 (41.1%)
33 (45.2%)
0.6191
Gross contamination*
44 (60.3%)
43 (58.9%)
0.8672
Fracture grade* Grade I Grade II Grade IIIA
4 (5.5%) 22 (30.1%) 47 (64.4%)
4 (5.5%) 27 (37.0%) 42 (57.5%)
1.0 0.38 0.40
Deep infection*
3 (4.1%)
13 (17.8%)
0.0001
*Values are given as the number of patients, with the percentage in parentheses.
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Fig. 2
Comparison of major fracture characteristics between different closure treatment groups prior to matching.
decimal place. The maximum difference between propensity probabilities for matching was set at 0.1. Seventy-three matched pairs of patients were identified. Fourteen open fractures from the delayed-closure group were not paired because of a lack of a suitable similar injury from the immediate primary-closure group with which to match them. These unpaired injuries were more severe, with higher open-fracture grades and more contamination. This process generated matched pairs with similar injury characteristics for analysis of the infection outcome. The results were analyzed with standard descriptive statistics for the baseline unpaired data. Infection rates were compared between the paired cohorts with use of the McNemar test and conditional logistic regression.
Source of Funding No external funding was received for this study.
Results able II shows the fracture characteristics of the cohort of patients prior to matching. As expected, patients managed with delayed wound closure had fractures with more negative prognostic factors, including a higher proportion of grade-IIIA fractures (p = 0.0001), tibial fractures (p = 0.0056), and gross contamination (p = 0.0001) (Fig. 2). The patients managed with delayed wound closure also had a higher proportion of deep infection before matching (18.4% compared with 3.4%, p = 0.0008), but this is an invalid comparison because of the selection bias that results in more severe injuries being preferentially treated with delayed wound closure.
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Fig. 3
Comparison of major fracture characteristics between different closure groups after matching.
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TABLE IV Infecting Organisms by Closure Group* Primary Closure
Delayed Closure
Enterococcus faecalis
MRSA
MRSA
MRSA
MRSA
Staphylococcus aureus Staphylococcus aureus Staphylococcus aureus Coagulase-negative Staphylococcus Pseudomonas aeruginosa Pseudomonas aeruginosa Enterococcus faecalis Enterococcus faecalis Escherichia coli Gram-negative bacilli Mixed aerobic organisms Hafnia alvei Candida Negative culture in one patient
*MRSA = methicillin-resistant Staphylococcus aureus.
After the propensity score-matching algorithm was applied, there were seventy-three matched pairs of patients and fractures available for comparison (Table III). The two matched treatment groups showed similar characteristics among all of the elements of the propensity score, including fracture grade (p = 0.4), gross contamination (p = 0.87), and tibial fractures (p = 0.62) (Fig. 3). Patients with delayed closure had routine second-look debridements, whereas planned second-look debridements were carried out in fourteen (19%) of the seventy-three patients who had undergone a primary closure. Deep infection developed at the sites of three of the seventythree open fractures treated with primary closure (infection rate, 4.1%; 95% confidence interval [CI], 0.86 to 11.5) compared with thirteen of the seventy-three fractures treated with delayed closure (infection rate, 17.8%; 95% CI, 9.8 to 28.5) (McNemar test, p = 0.0001) (see Appendix). This finding suggests an absolute risk reduction of 13.7% for development of deep infection for the primary-closure group. This value corresponds to a number needed to treat of 7.3 patients. Conditional logistic regression was also used to confirm the significance of this finding while accounting for paired data. This yielded an odds ratio of 11.0 (95% CI, 1.42 to 85.2) times more likely to develop deep infection if delayed rather than primary closure was performed. No patient had a Clostridium infection. The infecting organisms in each patient group are shown in Table IV. Discussion urrent orthopaedic literature does not provide clear direction to guide the choice between immediate wound closure and the more traditional delayed techniques. A small random-
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ized trial6 showed no increase in the rate of infection with primary closure. Primary closure has also been advocated by DeLong et al.8, who reviewed 119 open fractures treated with either primary closure or delayed methods. They found infection rates to be independent of closure technique and suggested that primary closure after thorough debridement is a viable option when carried out by an experienced surgeon. The deferral to surgical judgment is a common theme in the literature regarding this subject. Most orthopaedic surgeons would not suggest that primary closure be performed for patients with persistent wound contamination with dirt, feces, and nonviable tissue. Definitive closure of a wound without an adequate debridement increases reoperation and infection rates. However, objective characterization of what makes a wound ‘‘clean enough’’ for primary closure is not available. Because more severe open fractures will be considered ‘‘not clean enough’’ for primary closure, a selection bias will occur in retrospective studies on this topic, including the current study prior to matching. There is confounding by indication when the treatment method is chosen at least partially on the basis of the external prognostic factors that are associated with the injury11. In our study, higher-grade tibial fractures with a degree of gross contamination were more likely to be selected for delayed-closure treatment. Because these more severe injuries carry a higher risk for deep infection, we cannot conclude that treatment with delayed closure leads to a higher likelihood of infection without accounting for this confounding. Traditional matching for each individual variable is often too restrictive and does not allow enough pairs to be created because of the constraints of finding an exact match for each variable. The benefit of a propensity score is that it allows matching for many different factors by creating a composite probability of receiving a particular treatment—in the present study, either primary or delayed closure. Propensity-score matching is a method of balancing treatment groups based on known confounding variables and is particularly suited to account for confounding by indication12. In the current study, the patients managed with delayed closure were matched with patients who had a similar severity of injury. After matching, similar groups of patients and injuries were available for comparison. This creates a pseudo-randomized or quasi-randomized study12 in which the two treatment groups can be effectively matched according to the known prognostic factors that inform the propensity score. However, this method can control only for known factors that are included in the algorithm. Propensity score-matching techniques are referred to as pseudo-randomized because matching of treatment groups for all nontreatment variables is possible in only a prospective, truly randomized study. A higher infection rate was found among the fractures treated with delayed closure, even after we accounted for important prognostic factors, including contamination, fracture grade, and anatomic location. This finding suggests that primary closure is safe and actually may be preferable to delayed closure for selected lower-grade open fractures. Infection rates may be decreased when primary closure is employed for these carefully chosen injuries. The elimination of
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an automatic second-look debridement for all open fractures has the potential for streamlining patient care and for large cost-savings. The present study should be interpreted with its limitations in mind. A propensity score is a valuable tool to use to balance groups on the basis of known confounding variables. A limitation of this technique is that unknown or nonmeasurable variables cannot be accounted for. An experienced trauma surgeon will use many different injury and patient characteristics—often unconsciously and intuitively—to make an informed decision about wound management. A randomized trial remains the gold standard, as it allows balanced treatment groups that are based on both known and unknown confounding variables. Additionally, the data used in the present study were collected retrospectively. Complete initial and follow-up data were available for 89% of the possible patients who could have been examined. Efforts were made to define the injury and outcome variables as objectively as possible in order to minimize classification errors; however, some inaccuracy is inevitable in a retrospective study. Not all medical data were easily obtained via chart review; for example, smoking status was inconsistently recorded and thus was not a useful variable for data analysis. The ASA grade was used as an indicator of medical frailty but does not provide a complete picture of the patient’s medical status. Time to first antibiotic dose was similar between treatment groups (Table II). We did not include this variable in the propensity-score algorithm because we had to select the most important variables that indicated a difference between treatment groups. Time to debridement was included in the propensity-score algorithm because it was a major factor that differed between treatment groups. This suggests that, for the surgeons at this institution, delay to surgery likely was a consideration for choosing delayed rather than primary closure. However, the data presented in this paper do not directly support or refute delay to surgery as an important factor in the development of infection after open fracture. Defining a superficial infection is difficult with these retrospective data, especially because many patients are given oral antibiotics for various indications. Early antibiotic treatment alone may suppress and delay but will not usually eliminate a deep infection. This is why deep infection was chosen as our primary outcome of interest. All deep infections were treated with surgical debridement(s), possible implant removal, and/ or skeletal stabilization. Some infections that were excluded as being superficial actually may have been deeper infections that resolved without surgical debridement. The Gustilo-Anderson classification scheme has limitations in terms of interobserver variability16; however, it is the most frequently used classification scheme in current practice. Although newer schemes are in development17, the GustiloAnderson classification remains the most useful tool currently available to characterize open-fracture severity. The chart abstractors in our study both were experienced orthopaedic surgeons (an orthopaedic trauma fellowship-trained surgeon [R.J.J.] and a trauma fellow with more than five years of community experience [S.J.]), which helped to improve the interpretation of the clinical variables. Treatment was not standardized, and
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individual surgeons made choices regarding primary closure and many other treatment variables. Also, the follow-up time to determine whether an infection was present was one year. Posttraumatic infections can be relatively quiescent and may not present for longer times. We acknowledge that a longer duration of follow-up may result in more infections presenting at a later follow-up interval. The patients were all treated at a level-I academic trauma center. All participating clinicians had an interest in orthopaedic trauma and would be expected to have had sufficient clinical experience to perform adequate initial debridements. This may help to explain why few deep infections were found among patients managed with primary closure without second-look debridement. Surgeons with less experience in open fracture management may be more likely to perform insufficient debridements, possibly leading to complications from immediate closure. Also, the more severe (grade-IIIB and grade-IIIC) injuries were excluded from the current study. Generalization of the study findings to more severe injuries and those not treated with adequate initial debridement is not warranted. It should also be stated that patients with fasciotomies or those who are at high risk for developing compartment syndrome should not undergo primary wound closure. Primary closure was chosen for several patients even when a second-look debridement was planned, which may have restored some degree of skin barrier to nosocomial contamination (Table IV). Negative-pressure wound therapy and bead pouch techniques were not employed in this cohort. Future work in this area should consist of prospective studies—preferably large, randomized trials. Sample-size calculations for potential randomized trials must be based on previous findings so that potential effects can be estimated, and the present study provides some such findings. Additional work is required in order to identify the particular injury factors that allow for safe primary closure. Surgeon judgment regarding the adequacy of debridement and wound closure is still paramount in the treatment of open fractures; however, primary closure may be preferable for carefully selected low-grade injuries. Patients must be monitored closely, regardless of closure type, in order to assess for a surgicalsite infection and to institute timely treatment. Appendix A figure comparing the infection rates between the matched treatment groups is available with the online version of this article as a data supplement at jbjs.org. n
Richard J. Jenkinson, MD, MSc, FRCS(C) Alexander Kiss, PhD Samuel Johnson, MD David J.G. Stephen, MD, FRCS(C) Hans J. Kreder, MD, MPH, FRCS(C) Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Suite MG-321, Toronto, ON M4N 3M5, Canada. E-mail address for R.J. Jenkinson: [email protected]
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References 1. Gustilo RB, Anderson JT. Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones: retrospective and prospective analyses. J Bone Joint Surg Am. 1976 Jun;58(4):453-8. 2. Hampton OP Jr. Basic principles in management of open fractures. J Am Med Assoc. 1955 Oct 1;159(5):417-9. 3. Trueta J. ‘‘Closed’’ treatment of war fractures. Lancet. 1939;233(6043):1452-5. 4. Trueta J. Reflections on the past and present treatment of war wounds and fractures. Mil Med. 1976 Apr;141(4):255-8. 5. Okike K, Bhattacharyya T. Trends in the management of open fractures. A critical analysis. J Bone Joint Surg Am. 2006 Dec;88(12):2739-48. 6. Benson DR, Riggins RS, Lawrence RM, Hoeprich PD, Huston AC, Harrison JA. Treatment of open fractures: a prospective study. J Trauma. 1983 Jan;23(1):25-30. 7. Cullen MC, Roy DR, Crawford AH, Assenmacher J, Levy MS, Wen D. Open fracture of the tibia in children. J Bone Joint Surg Am. 1996 Jul;78(7):1039-47. 8. DeLong WG Jr, Born CT, Wei SY, Petrik ME, Ponzio R, Schwab CW. Aggressive treatment of 119 open fracture wounds. J Trauma. 1999 Jun;46(6):1049-54. 9. Carsenti-Etesse H, Doyon F, Desplaces N, Gagey O, Tancr`ede C, Pradier C, Dunais B, Dellamonica P. Epidemiology of bacterial infection during management of open leg fractures. Eur J Clin Microbiol Infect Dis. 1999 May;18(5):315-23. 10. Gustilo RB, Mendoza RM, Williams DN. Problems in the management of type III (severe) open fractures: a new classification of type III open fractures. J Trauma. 1984 Aug;24(8):742-6.
11. Salas M, Hofman A, Stricker BH. Confounding by indication: an example of variation in the use of epidemiologic terminology. Am J Epidemiol. 1999 Jun 1;149(11):981-3. 12. D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998 Oct 15;17(19):2265-81. 13. Austin PC. Primer on statistical interpretation or methods report card on propensity-score matching in the cardiology literature from 2004 to 2006: a systematic review. Circ Cardiovasc Qual Outcomes. 2008 Sep;1(1):62-7. 14. Peduzzi PN, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996 Dec;49(12):1373-9. 15. Parsons LS. Performing a 1:N Case-Control Match on Propensity Score. In: Proceedings of the 29th SAS Users Group International 2004; 2004 May 9-12; Montreal, Canada. Paper no. 165–29. http://www2.sas.com/proceedings/ sugi29/165-29.pdf. 16. Brumback RJ, Jones AL. Interobserver agreement in the classification of open fractures of the tibia. The results of a survey of two hundred and forty-five orthopaedic surgeons. J Bone Joint Surg Am. 1994 Aug;76(8): 1162-6. 17. Orthopaedic Trauma Association: Open Fracture Study Group. A new classification scheme for open fractures. J Orthop Trauma. 2010 Aug;24(8):457-64.
BY
T HE J OURNAL
OF
B ONE
AND J OINT
S URGERY, I NCORPORATED
Delayed Wound Closure Increases Deep-Infection Rate Associated with Lower-Grade Open Fractures A Propensity-Matched Cohort Study Richard J. Jenkinson, MD, MSc, FRCS(C), Alexander Kiss, PhD, Samuel Johnson, MD, David J.G. Stephen, MD, FRCS(C), and Hans J. Kreder, MD, MPH, FRCS(C) Investigation performed at the Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
Background: Primary closure of skin wounds after debridement of open fractures is controversial. The purpose of the present study was to determine whether primary skin closure for grade-IIIA or lower-grade open extremity fractures is associated with a lower deep-infection rate. Methods: We identified 349 Gustilo-Anderson grade-I, II, or IIIA fractures treated at our level-I academic trauma center from 2003 to 2007. Eighty-seven injuries were treated with delayed primary closure, and 262 were treated with immediate closure after surgical debridement. After application of a propensity score-matching algorithm to balance prognostic factors, 146 open fractures (seventy-three matched pairs) were analyzed. Results: After application of a propensity score-matching algorithm with adjustment for age, sex, time to debridement, American Society of Anesthesiologists (ASA) class, fracture grade, evidence of gross contamination, and a tibial fracture rather than a fracture at another anatomic site, the two treatment groups were compared with respect to the prevalence of infection. Deep infection developed at the sites of three of the seventy-three fractures treated with immediate closure (infection rate, 4.1%; 95% confidence interval [CI], 0.86 to 11.5) compared with thirteen in the matched group of seventythree fractures treated with delayed primary closure (infection rate, 17.8%; 95% CI, 9.8 to 28.5) (McNemar test, p = 0.0001). Conclusions: Immediate closure of carefully selected wounds by experienced surgeons treating grade-I, II, and IIIA open fractures is safe and is associated with a lower infection rate compared with delayed primary closure. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewed by an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.
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reatment standards for open fractures require timely irrigation and adequate debridement1. Traumatic openfracture wounds traditionally have been left open after the initial debridement in order to minimize the risk of later deep infection, especially with Clostridium2. This treatment strategy is traced to the experience of trauma surgeons from the pre-antibiotic era, especially during World War I and World War II3,4. Delayed wound closure until a few days post-injury is currently advocated by many surgeons to allow drainage of any collecting infectious material and to allow for a universal secondlook debridement2,5. However, with advances in stabilization
methods, antibiotics, and wound management, the strict avoidance of immediate wound closure has been challenged, with several investigators reporting low infection rates6-8. Immediate wound closure after initial debridement has the advantage of providing immediate soft-tissue cover to the traumatized limb as well as some protection against nosocomial pathogens9. Also, subsequent visits to the operating room for second-look debridements may be avoided if immediate closure is chosen, thereby simplifying and streamlining management of the traumatized patient. There are no clear guidelines for determining the time frame for safe closure of traumatic open fracture wounds, and
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
J Bone Joint Surg Am. 2014;96:380-6
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http://dx.doi.org/10.2106/JBJS.L.00545
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Materials and Methods TABLE I Baseline Characteristics
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Variable Average age (yr)
40.7
Male sex*
240 (68.8%)
ASA class >2*
66 (18.9%)
ISS >25 points*
155 (44.4%)
Gunshot mechanism*
28 (8.0%)
Average injury to debridement time (hr)
11.27
Average injury to first antibiotic time (hr)
2.53
Tibial fracture*
148 (42.4%)
Gross contamination*
140 (40.1%)
Fracture grade* Grade I Grade II Grade IIIA
53 (15.2%) 141 (40.4%) 155 (44.4%)
Primary closure*
262 (75.0%)
Deep infection*
25 (7.2%)
*Values are given as the number of patients, with the percentage in parentheses.
this determination is left to the judgment and experience of the treating orthopaedic surgeon. Higher-risk open fractures would be expected to have higher rates of more conservative wound management. We compared the rate of subsequent deep infection between patients in whom an open fracture had been treated with immediate primary closure after debridement and those in whom the fracture had been treated with delayed primary closure. Bias was reduced with use of a matched-pairs design. We hypothesized that early wound closure would reduce the rate of subsequent deep infection.
onsecutive patients treated for an open extremity fracture from January 1, 2003, to January 1, 2007, at our level-I trauma center were identified with use of our trauma database. Open hand and pelvic fractures were excluded. We supplemented case identification with the billing database of the central orthopaedic department with use of specific coding identifiers for open fractures (E556 modifier). Medical records were abstracted by two orthopaedic surgeons (R.J.J. and S.J.). We identified 417 patients who had a total of 459 fractures. The inclusion and exclusion criteria are shown in Figure 1. Gustilo-Anderson gradeIIIB fractures usually are not amenable to primary closure and were excluded. Gustilo-Anderson grade-IIIC fractures also were excluded because these injuries often are treated simultaneously with fasciotomies, for which skin closure is contraindicated. This left 345 patients with a total of 415 fractures. Thirteen patients died from their traumatic injuries during the index hospital stay and were excluded, which left 332 patients available for follow-up. Complete follow-up was defined as twelve months, which was not achieved for thirtyeight patients (rate of complete follow-up = 89%). Our final cohort consisted of 294 patients with a total of 349 Gustilo-Anderson grade-I, II, or IIIA fractures. The collected patient demographic characteristics included age, sex, and American Society of Anesthesiologists (ASA) class. The collected injury variables included the injury severity score (ISS), evidence of gross contamination of the fracture, the anatomic fracture location, and the time delay to surgery (defined as from ambulance call time to surgical start time). A Gustilo-Anderson 1,10 grade was assigned to the fracture on the basis of the surgical description of the injury after debridement. Gross contamination was documented if dirt or foreign material was present. None of the wounds had fecal or farmyard contamination or contamination with grass. The primary outcome measure for the present study was deep infection, defined as infection of the injured bone and deep tissue necessitating an unplanned operative irrigation and debridement at more than two weeks after the injury. We chose a two-week cutoff in order to address the concern of whether an early debridement was planned or unplanned. Planned repeat debridements and superficial infections not requiring surgery were not considered to be deep infections. All deep infections were treated with one or more surgical debridements, possible implant removal, and/or skeletal stabilization. Initial characteristics of the injuries are shown in Table I. The standard treatment protocol at our institution included intravenous antibiotics immediately administered on arrival in the emergency department and continued during hospitalization until at least twenty-four hours after definitive wound closure. Intravenous cefazolin was administered, although clindamycin was used when a severe penicillin allergy was known. Gentamicin was added for grade-III open fractures. Debridements were performed urgently,
Fig. 1
Patients included and excluded from the study.
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TABLE II Characteristics of Wound Closure Treatment Groups Prior to Matching Variable Average age (yr)
Primary Closure (N = 262) 41.3
Male sex ASA class >2*
Delayed Closure (N = 87) 39.7
66.7%
74.7%
58 (22.1%)
8 (9.2%)
P Value 0.24 0.17 0.0016
Average injury to debridement time (hr)
12.06
8.90
0.0016
Average injury to first antibiotic time (hr)
2.44
2.81
0.47
Tibial fracture*
104 (39.7%)
44 (50.6%)
0.0056
84 (32.1%)
56 (64.4%)
0.0001
Fracture grade* Grade I Grade II Grade IIIA
49 (18.7%) 112 (42.7%) 101 (38.5%)
4 (4.6%) 29 (33.3%) 54 (62.1%)
0.0001 0.127 0.0001
Deep infection*
9 (3.4%)
16 (18.4%)
0.0008
Gross contamination*
*Values are given as the number of patients, with the percentage in parentheses.
on the basis of availability of the operating room. Normal saline solution was used for irrigation, with gravity or pulse lavage used at the discretion of the treating surgeon. Wound culture specimens were not routinely taken at the time of initial debridement. Antibiotic choice, fixation method, and wound closure were also at the discretion of the treating physicians. Vacuum-assisted closure dressings were not used for any of these fractures. Second-look debridement after approximately forty-eight hours was performed routinely when delayed closure was chosen and was performed in patients who had undergone primary closure when chosen by the treating surgeon on the basis of the impression of the adequacy of the debridement. All statistical analyses were performed with use of SAS version 9.2 (SAS Institute, Cary, North Carolina) with input from a statistician (A.K.). To adjust 11 12,13 for confounding by indication , a propensity-score matched-cohort study was developed from the original data set (Table I). Injury characteristics were used in a logistic regression model to predict the likelihood of the need for
treatment with delayed wound closure. As eighty-seven patients were managed with delayed wound closure, up to eight degrees of freedom could be specified 14 in the propensity score . Dichotomous and continuous variables used one degree of freedom each, whereas the three-level variable used two degrees of freedom. The factors considered to be the most important confounders also contributing to deep-infection risk were chosen for the propensity-score algorithm. These factors included patient age, sex, time delay to debridement, fracture grade (Gustilo-Anderson grade I, II, or IIIA), evidence of gross contamination, tibial compared with nontibial site, and ASA class (1 or 2 compared with 3 or higher). These factors were chosen, based on consensus among the investigators, as the factors most important for predicting later infection but also as those most divergent between the immediate and delayed-closure groups 15 (Table II). A one-to-one matching algorithm was used to pair injuries with a similar propensity for delayed wound closure. This algorithm searches for the most exact match available to eight decimal places and then works back to one
TABLE III Characteristics of Wound Closure Treatment Groups After Matching Variable Average age (yr) Male sex ASA class >2*
Primary Closure (N = 73) 38.6
Delayed Closure (N = 73) 37.8
P Value 0.78
76.7%
73.9%
0.70
7 (9.6%)
8 (11.0%)
0.78
Average injury to debridement time (hr)
9.75
8.8
0.30
Average injury to first antibiotic time (hr)
1.92
2.75
0.09
Tibial fracture*
30 (41.1%)
33 (45.2%)
0.6191
Gross contamination*
44 (60.3%)
43 (58.9%)
0.8672
Fracture grade* Grade I Grade II Grade IIIA
4 (5.5%) 22 (30.1%) 47 (64.4%)
4 (5.5%) 27 (37.0%) 42 (57.5%)
1.0 0.38 0.40
Deep infection*
3 (4.1%)
13 (17.8%)
0.0001
*Values are given as the number of patients, with the percentage in parentheses.
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Fig. 2
Comparison of major fracture characteristics between different closure treatment groups prior to matching.
decimal place. The maximum difference between propensity probabilities for matching was set at 0.1. Seventy-three matched pairs of patients were identified. Fourteen open fractures from the delayed-closure group were not paired because of a lack of a suitable similar injury from the immediate primary-closure group with which to match them. These unpaired injuries were more severe, with higher open-fracture grades and more contamination. This process generated matched pairs with similar injury characteristics for analysis of the infection outcome. The results were analyzed with standard descriptive statistics for the baseline unpaired data. Infection rates were compared between the paired cohorts with use of the McNemar test and conditional logistic regression.
Source of Funding No external funding was received for this study.
Results able II shows the fracture characteristics of the cohort of patients prior to matching. As expected, patients managed with delayed wound closure had fractures with more negative prognostic factors, including a higher proportion of grade-IIIA fractures (p = 0.0001), tibial fractures (p = 0.0056), and gross contamination (p = 0.0001) (Fig. 2). The patients managed with delayed wound closure also had a higher proportion of deep infection before matching (18.4% compared with 3.4%, p = 0.0008), but this is an invalid comparison because of the selection bias that results in more severe injuries being preferentially treated with delayed wound closure.
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Fig. 3
Comparison of major fracture characteristics between different closure groups after matching.
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TABLE IV Infecting Organisms by Closure Group* Primary Closure
Delayed Closure
Enterococcus faecalis
MRSA
MRSA
MRSA
MRSA
Staphylococcus aureus Staphylococcus aureus Staphylococcus aureus Coagulase-negative Staphylococcus Pseudomonas aeruginosa Pseudomonas aeruginosa Enterococcus faecalis Enterococcus faecalis Escherichia coli Gram-negative bacilli Mixed aerobic organisms Hafnia alvei Candida Negative culture in one patient
*MRSA = methicillin-resistant Staphylococcus aureus.
After the propensity score-matching algorithm was applied, there were seventy-three matched pairs of patients and fractures available for comparison (Table III). The two matched treatment groups showed similar characteristics among all of the elements of the propensity score, including fracture grade (p = 0.4), gross contamination (p = 0.87), and tibial fractures (p = 0.62) (Fig. 3). Patients with delayed closure had routine second-look debridements, whereas planned second-look debridements were carried out in fourteen (19%) of the seventy-three patients who had undergone a primary closure. Deep infection developed at the sites of three of the seventythree open fractures treated with primary closure (infection rate, 4.1%; 95% confidence interval [CI], 0.86 to 11.5) compared with thirteen of the seventy-three fractures treated with delayed closure (infection rate, 17.8%; 95% CI, 9.8 to 28.5) (McNemar test, p = 0.0001) (see Appendix). This finding suggests an absolute risk reduction of 13.7% for development of deep infection for the primary-closure group. This value corresponds to a number needed to treat of 7.3 patients. Conditional logistic regression was also used to confirm the significance of this finding while accounting for paired data. This yielded an odds ratio of 11.0 (95% CI, 1.42 to 85.2) times more likely to develop deep infection if delayed rather than primary closure was performed. No patient had a Clostridium infection. The infecting organisms in each patient group are shown in Table IV. Discussion urrent orthopaedic literature does not provide clear direction to guide the choice between immediate wound closure and the more traditional delayed techniques. A small random-
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ized trial6 showed no increase in the rate of infection with primary closure. Primary closure has also been advocated by DeLong et al.8, who reviewed 119 open fractures treated with either primary closure or delayed methods. They found infection rates to be independent of closure technique and suggested that primary closure after thorough debridement is a viable option when carried out by an experienced surgeon. The deferral to surgical judgment is a common theme in the literature regarding this subject. Most orthopaedic surgeons would not suggest that primary closure be performed for patients with persistent wound contamination with dirt, feces, and nonviable tissue. Definitive closure of a wound without an adequate debridement increases reoperation and infection rates. However, objective characterization of what makes a wound ‘‘clean enough’’ for primary closure is not available. Because more severe open fractures will be considered ‘‘not clean enough’’ for primary closure, a selection bias will occur in retrospective studies on this topic, including the current study prior to matching. There is confounding by indication when the treatment method is chosen at least partially on the basis of the external prognostic factors that are associated with the injury11. In our study, higher-grade tibial fractures with a degree of gross contamination were more likely to be selected for delayed-closure treatment. Because these more severe injuries carry a higher risk for deep infection, we cannot conclude that treatment with delayed closure leads to a higher likelihood of infection without accounting for this confounding. Traditional matching for each individual variable is often too restrictive and does not allow enough pairs to be created because of the constraints of finding an exact match for each variable. The benefit of a propensity score is that it allows matching for many different factors by creating a composite probability of receiving a particular treatment—in the present study, either primary or delayed closure. Propensity-score matching is a method of balancing treatment groups based on known confounding variables and is particularly suited to account for confounding by indication12. In the current study, the patients managed with delayed closure were matched with patients who had a similar severity of injury. After matching, similar groups of patients and injuries were available for comparison. This creates a pseudo-randomized or quasi-randomized study12 in which the two treatment groups can be effectively matched according to the known prognostic factors that inform the propensity score. However, this method can control only for known factors that are included in the algorithm. Propensity score-matching techniques are referred to as pseudo-randomized because matching of treatment groups for all nontreatment variables is possible in only a prospective, truly randomized study. A higher infection rate was found among the fractures treated with delayed closure, even after we accounted for important prognostic factors, including contamination, fracture grade, and anatomic location. This finding suggests that primary closure is safe and actually may be preferable to delayed closure for selected lower-grade open fractures. Infection rates may be decreased when primary closure is employed for these carefully chosen injuries. The elimination of
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an automatic second-look debridement for all open fractures has the potential for streamlining patient care and for large cost-savings. The present study should be interpreted with its limitations in mind. A propensity score is a valuable tool to use to balance groups on the basis of known confounding variables. A limitation of this technique is that unknown or nonmeasurable variables cannot be accounted for. An experienced trauma surgeon will use many different injury and patient characteristics—often unconsciously and intuitively—to make an informed decision about wound management. A randomized trial remains the gold standard, as it allows balanced treatment groups that are based on both known and unknown confounding variables. Additionally, the data used in the present study were collected retrospectively. Complete initial and follow-up data were available for 89% of the possible patients who could have been examined. Efforts were made to define the injury and outcome variables as objectively as possible in order to minimize classification errors; however, some inaccuracy is inevitable in a retrospective study. Not all medical data were easily obtained via chart review; for example, smoking status was inconsistently recorded and thus was not a useful variable for data analysis. The ASA grade was used as an indicator of medical frailty but does not provide a complete picture of the patient’s medical status. Time to first antibiotic dose was similar between treatment groups (Table II). We did not include this variable in the propensity-score algorithm because we had to select the most important variables that indicated a difference between treatment groups. Time to debridement was included in the propensity-score algorithm because it was a major factor that differed between treatment groups. This suggests that, for the surgeons at this institution, delay to surgery likely was a consideration for choosing delayed rather than primary closure. However, the data presented in this paper do not directly support or refute delay to surgery as an important factor in the development of infection after open fracture. Defining a superficial infection is difficult with these retrospective data, especially because many patients are given oral antibiotics for various indications. Early antibiotic treatment alone may suppress and delay but will not usually eliminate a deep infection. This is why deep infection was chosen as our primary outcome of interest. All deep infections were treated with surgical debridement(s), possible implant removal, and/ or skeletal stabilization. Some infections that were excluded as being superficial actually may have been deeper infections that resolved without surgical debridement. The Gustilo-Anderson classification scheme has limitations in terms of interobserver variability16; however, it is the most frequently used classification scheme in current practice. Although newer schemes are in development17, the GustiloAnderson classification remains the most useful tool currently available to characterize open-fracture severity. The chart abstractors in our study both were experienced orthopaedic surgeons (an orthopaedic trauma fellowship-trained surgeon [R.J.J.] and a trauma fellow with more than five years of community experience [S.J.]), which helped to improve the interpretation of the clinical variables. Treatment was not standardized, and
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individual surgeons made choices regarding primary closure and many other treatment variables. Also, the follow-up time to determine whether an infection was present was one year. Posttraumatic infections can be relatively quiescent and may not present for longer times. We acknowledge that a longer duration of follow-up may result in more infections presenting at a later follow-up interval. The patients were all treated at a level-I academic trauma center. All participating clinicians had an interest in orthopaedic trauma and would be expected to have had sufficient clinical experience to perform adequate initial debridements. This may help to explain why few deep infections were found among patients managed with primary closure without second-look debridement. Surgeons with less experience in open fracture management may be more likely to perform insufficient debridements, possibly leading to complications from immediate closure. Also, the more severe (grade-IIIB and grade-IIIC) injuries were excluded from the current study. Generalization of the study findings to more severe injuries and those not treated with adequate initial debridement is not warranted. It should also be stated that patients with fasciotomies or those who are at high risk for developing compartment syndrome should not undergo primary wound closure. Primary closure was chosen for several patients even when a second-look debridement was planned, which may have restored some degree of skin barrier to nosocomial contamination (Table IV). Negative-pressure wound therapy and bead pouch techniques were not employed in this cohort. Future work in this area should consist of prospective studies—preferably large, randomized trials. Sample-size calculations for potential randomized trials must be based on previous findings so that potential effects can be estimated, and the present study provides some such findings. Additional work is required in order to identify the particular injury factors that allow for safe primary closure. Surgeon judgment regarding the adequacy of debridement and wound closure is still paramount in the treatment of open fractures; however, primary closure may be preferable for carefully selected low-grade injuries. Patients must be monitored closely, regardless of closure type, in order to assess for a surgicalsite infection and to institute timely treatment. Appendix A figure comparing the infection rates between the matched treatment groups is available with the online version of this article as a data supplement at jbjs.org. n
Richard J. Jenkinson, MD, MSc, FRCS(C) Alexander Kiss, PhD Samuel Johnson, MD David J.G. Stephen, MD, FRCS(C) Hans J. Kreder, MD, MPH, FRCS(C) Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Suite MG-321, Toronto, ON M4N 3M5, Canada. E-mail address for R.J. Jenkinson: [email protected]
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References 1. Gustilo RB, Anderson JT. Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones: retrospective and prospective analyses. J Bone Joint Surg Am. 1976 Jun;58(4):453-8. 2. Hampton OP Jr. Basic principles in management of open fractures. J Am Med Assoc. 1955 Oct 1;159(5):417-9. 3. Trueta J. ‘‘Closed’’ treatment of war fractures. Lancet. 1939;233(6043):1452-5. 4. Trueta J. Reflections on the past and present treatment of war wounds and fractures. Mil Med. 1976 Apr;141(4):255-8. 5. Okike K, Bhattacharyya T. Trends in the management of open fractures. A critical analysis. J Bone Joint Surg Am. 2006 Dec;88(12):2739-48. 6. Benson DR, Riggins RS, Lawrence RM, Hoeprich PD, Huston AC, Harrison JA. Treatment of open fractures: a prospective study. J Trauma. 1983 Jan;23(1):25-30. 7. Cullen MC, Roy DR, Crawford AH, Assenmacher J, Levy MS, Wen D. Open fracture of the tibia in children. J Bone Joint Surg Am. 1996 Jul;78(7):1039-47. 8. DeLong WG Jr, Born CT, Wei SY, Petrik ME, Ponzio R, Schwab CW. Aggressive treatment of 119 open fracture wounds. J Trauma. 1999 Jun;46(6):1049-54. 9. Carsenti-Etesse H, Doyon F, Desplaces N, Gagey O, Tancr`ede C, Pradier C, Dunais B, Dellamonica P. Epidemiology of bacterial infection during management of open leg fractures. Eur J Clin Microbiol Infect Dis. 1999 May;18(5):315-23. 10. Gustilo RB, Mendoza RM, Williams DN. Problems in the management of type III (severe) open fractures: a new classification of type III open fractures. J Trauma. 1984 Aug;24(8):742-6.
11. Salas M, Hofman A, Stricker BH. Confounding by indication: an example of variation in the use of epidemiologic terminology. Am J Epidemiol. 1999 Jun 1;149(11):981-3. 12. D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998 Oct 15;17(19):2265-81. 13. Austin PC. Primer on statistical interpretation or methods report card on propensity-score matching in the cardiology literature from 2004 to 2006: a systematic review. Circ Cardiovasc Qual Outcomes. 2008 Sep;1(1):62-7. 14. Peduzzi PN, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996 Dec;49(12):1373-9. 15. Parsons LS. Performing a 1:N Case-Control Match on Propensity Score. In: Proceedings of the 29th SAS Users Group International 2004; 2004 May 9-12; Montreal, Canada. Paper no. 165–29. http://www2.sas.com/proceedings/ sugi29/165-29.pdf. 16. Brumback RJ, Jones AL. Interobserver agreement in the classification of open fractures of the tibia. The results of a survey of two hundred and forty-five orthopaedic surgeons. J Bone Joint Surg Am. 1994 Aug;76(8): 1162-6. 17. Orthopaedic Trauma Association: Open Fracture Study Group. A new classification scheme for open fractures. J Orthop Trauma. 2010 Aug;24(8):457-64.
