Femur fractures are common among trauma patients and are typically seen in patients with multiple injuries resulting from high-energy mechanisms.1 Internal fixation with intramedullary nailing is the ideal method of treatment. However, the optimal timing for internal fixation remains controversial.2–4 Proponents of early stabilization point to more desirable outcomes, such as fewer complications, shorter hospital stays, and lower costs of care.5–12 Opponents suggest that early definitive stabilization may not be safe for the most severely injured patients or those with associated head, chest, or serious abdominal injuries due to increased blood loss, surgical stress, and pulmonary complications and that these and other factors may lead to increased mortality.13–17 Several other researchers have suggested a lack of benefit to early stabilization.18–25
In 2001, an Eastern Association for the Surgery of Trauma (EAST) practice management guideline (PMG) promoted early stabilization of long bone fractures, including the femur, in polytrauma patients.6 EAST recently adopted the methodology of the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) for PMGs.26,27 The purpose of the current review was to update EAST’s femur fracture stabilization guidelines using GRADE methodology and systematic review. We critically evaluated the literature regarding the benefit of early (<24 hours) versus late (>24 hours) open reduction and internal fixation of open or closed femur fractures in trauma patients.
The GRADE methodology addresses many of the perceived shortcomings of existing models of evidence evaluation. Crucially, when using GRADE, the evidence is rated not by each study individually but across studies for specific clinical outcomes and evaluation of alternative management strategies. Evaluating clinical outcomes makes the guideline a useful and relevant tool for clinicians and, more importantly, for patients.28
The objective of this guideline was to evaluate the comparative effectiveness of early (<24 hours) versus late (>24 hours) open reduction and internal fixation of an open or closed femur fracture in trauma patients, particularly in preventing mortality, infection, nonunion/malunion, amputation, and venous thromboembolism (VTE). Our PICO [Population, Intervention, Comparator, and Outcome] question is defined as follows:
- Population: trauma patients with an open or closed femur fracture
- Intervention: open reduction and internal fixation within 24 hours of injury
- Comparator: open reduction and internal fixation greater than 24 hours after injury
- Outcomes: mortality, infection, nonunion/malunion, amputation, VTE
INCLUSION CRITERIA FOR THIS REVIEW
For the purpose of making recommendations, studies included randomized controlled trials (RCTs), prospective observational or retrospective studies, and case-control studies. Only studies pertaining to open reduction and internal fixation of open or closed femur fractures were included.
We included studies with adult patients, any sex, and with no restriction on inclusion of ethnicities or patients with comorbidities. Meta-analyses, case reports, letters, and reviews containing no original data or comments were excluded.
We included studies comparing open reduction and internal fixation performed within 24 hours from the time of injury to stabilization performed greater than 24 hours after injury.
Outcome Measure Types
An initial list of all relevant outcomes (infection, nonunion/malunion, compartment syndrome, VTE, fat embolism syndrome, regional pain, neurologic impairment, arthritis, hardware failure, impaired function, mortality, or amputation) was generated and distributed to panelists. Eight panelists independently rated the relative importance of each outcome on a 9-point scale ranging from 1 (less important) to 9 (critically important for decision making). The five highest rated outcomes were selected as follows: mortality, infection, VTE, nonunion/malunion, and amputation. A systematic review of the literature was then conducted to identify relevant articles. Each article was evaluated independently by three members of the committee to extract pertinent data. We did not find any articles with data regarding the outcomes of nonunion/malunion and amputation, so these outcomes were excluded from the analysis.
Other outcomes considered were respiratory complications of fixation such as adult respiratory distress syndrome, fat embolism, pneumonia, and other pulmonary dysfunction. However, these outcomes were not included in this review.
We conducted our literature search and appraisal based on guidelines for systematic reviews. A MEDLINE and Cochrane search was conducted to identify English language human subjects prospective RCTs, non-RCTs, existing systematic reviews, guidelines, case-control, and observational studies published before November 2013. Search terms included (1) femoral fractures, (2) long bone stabilization, (3) timing fixation, (4) delayed fixation, (5) early fixation, (6) immediate fixation, (7) fracture fixation, (8) timing fracture, and (9) timing osteosynthesis, alone or in combination. In addition to the electronic search, the bibliographies of relevant articles and systematic reviews were hand searched to find additional potentially appropriate publications to be included in this review.
A single panelist conducted the literature search and assessed the titles and abstracts to identify relevant publications, applying inclusion criteria. We excluded case reports and review articles. The resulting studies then underwent full-text review by three independent reviewers to determine appropriateness for inclusion.
Data Extraction and Management
Data were extracted by a single reviewer, confirmed by two other reviewers, and entered into Review Manager X.6 (RevMan). Information included authorship, publication year, methodology of the study, population, intervention, and relevant outcome measures.
Methodological Quality Assessment
The articles were evaluated using the GRADE system.27–40 The quality of evidence was classified as high, moderate, low, or insufficient for each outcome. The quality of evidence is reflected as the extent to which one can be confident that an estimate of effect is correct and includes an explicit consideration of the following domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias.31–36 Recommendations were developed based on the results of the meta-analysis as well as the quality of evidence, and per the GRADE approach, they were classified as either “strong” or “weak”.41 A strong recommendation, prefaced by the statement “we strongly recommend,” indicates that the panel is certain the desirable consequences of a course of action outweigh the undesirable effects in most patients. A weak recommendation, prefaced by the statement “we conditionally recommend,” indicates that the panel concludes the desirable effects of adherence to a recommendation probably outweighed the undesirable effects but it was not as confident. These recommendations were based on the quality of evidence and the risk-versus-benefit ratio.
Measures of Treatment Effect
We created a detailed set of evidence tables containing all abstracted information. Clinical outcomes, including mortality, infection, and VTE reported in each included study, were individually pooled for meta-analysis. The relative risk (RR) and 95% confidence interval (CI) were calculated for each study using a random-effects model.42 A p < 0.05 was considered significant for all analyses. STATA 12.1 (College Station, TX) statistical analysis software was used for all statistical analyses.43 There were not enough data to undertake meta-analysis for the other two outcomes (nonunion/malunion and amputations).
Assessment of Heterogeneity
Potential heterogeneity existed because of population differences, different types of surgery, and how patients were defined. We examined these differences across studies to assess clinical and methodological heterogeneity. For the meta-analysis, we used RevMan to calculate the I2 statistic to determine the proportion of variation between studies attributable to heterogeneity, and variation was categorized as “low” (I2 = 25–49%), “moderate” (I2 = 50–74%), or “high” (I2 = 74–100%).
We retrieved 9,091 articles during the first phase of the literature search, of which 9,032 were excluded by duplicate removal and title review (Fig. 1). Fifty-nine articles addressing optimal timing of long bone fracture stabilization underwent a full review to identify 11 studies comparing early (<24 hours) versus late (>24 hours) open reduction and internal fixation of femur fractures in trauma patients (Table 1). Of the 11 studies, 1 was a prospective randomized study5 and 10 were retrospective cohort studies.11,15,19,21–23,44–47 Across all studies, 7,189 patients were included, with 5,064 receiving early stabilization and 2,125 receiving late stabilization.
The range of the mean ages in the studies reviewed was 18 years to 43 years. Most of the patients were men (61–78%). The mean Injury Severity Score (ISS) for patients receiving early stabilization ranged from 12 to 27, while patients receiving late stabilization ranged from 12 to 34 (Table 1).
RESULTS BY OUTCOME
Eight studies reported the incidence of mortality,5,11,19,21–23,44,45one of which was a prospective randomized study (Fig. 2).5 These studies included 6,930 patients (sample size range, 22–3,069). A meta-analysis of these eight studies showed no difference in mortality among patients with early stabilization compared with those undergoing late stabilization (RR, 0.74; 95% CI, 0.50–1.08; p = 0.313). Of note, the I2 statistic was 15%, falling into the “low” heterogeneity category, indicating that the studies were comparable. In the only RCT, early internal fixation, there were only three total deaths (two in the early and one in the late cohort), which was not statistically significantly different.5
We included three studies reporting on infection and included 667 patients (sample size range, 68–492) (Fig. 3).11,15,46 A meta-analysis of these three studies showed no difference in infection between patients undergoing early surgery compared with those undergoing late surgery (RR, 0.40; 95% CI, 0.10–1.60; p = 0.888). The I2 statistic was “low” at 0%, although this is likely caused by the wide CIs of each study rather than a true homogeneity between the studies.
We included six studies reporting on VTE and included 1967 patients (sample size range, 67–1,081),5,11,15,19,22,46 including the previously mentioned prospective randomized study (Fig. 4).5 A meta-analysis of these six studies showed no difference in VTE between patients undergoing early surgery compared with those undergoing late surgery (RR, 0.63; 95% CI, 0.37–1.07; p = 0.896). The I2 statistic was “low” at 0%, although this is likely caused by the wide CIs of each study rather than a true homogeneity between the studies.
Only one study reported nonunion/malunion outcomes, resulting in insufficient evidence to perform a meta-analysis for this outcome.47 This study compared patients treated within 24 hours of their injury at their hospital with patients from another hospital who were treated greater than 24 hours after injury. They found delayed fixation resulted in more callus and more frequent secondary bone healing. In both patient groups, however, there were no nonunions or malunions reported.
Only one study reported amputation outcomes, resulting in insufficient evidence to perform a meta-analysis for this outcome.15 This study retrospectively reviewed outcomes for multiple trauma patients with femoral shaft fractures based on the presence of additional severe thoracic injuries. Only two patients in each stabilization group (early vs. late) required amputation (early, 3.4%; late, 4.1%).
Grading the Evidence
With the use of the GRADE framework for assessing all relevant outcomes, no serious risk of inconsistency or indirectness was found. However, moderate imprecision was noted since the studies were small and CIs were large. We rated the prospective randomized study as having a moderate risk of bias, primarily based on study design.5 Among the retrospective studies, we rated only one study as having a moderate risk of bias23 and the remainder as having a high risk of bias. Starting from observational studies (which are considered low quality), we did not rate up for the quality of evidence.
We rated the strength of evidence as low to support a reduction in mortality, infection, and VTE in trauma patients treated with early stabilization relative to late stabilization (Table 2). We rated the strength of evidence as insufficient to support any increase or decrease in nonunion/malunion or amputation in trauma patients treated with early stabilization relative to late stabilization (Table 3).
The findings of this study indicate that internal fixation of femur fractures in less than 24 hours after injury may be associated with a reduction in mortality, infection, and VTE. There was insufficient evidence to comment on the outcomes of amputation or nonunion/malunion. The studies reviewed did not separate outcomes of open from closed fractures. Hence, this recommendation applies to all femur fractures. Unlike the previous EAST PMG on long bone fractures, all other long bones, including tibia, were excluded from this analysis.
A major implication of this study is that early fracture fixation should be considered in all patients with femur fractures. In the absence of a clear contraindication to surgery or anesthesia, the recommendation of this review, although conditional, should prompt early fixation. However, the surgical decision must be individualized to each patient’s needs. Delayed treatment has been associated with improved survival rates among patients with serious abdominal injuries and a reduction in adverse outcomes in patients with multiple injuries.13 In addition, delayed stabilization (24–48 hours) may be safer than stabilization within 12 hours for severely injured patients.48
Of the large number of articles reviewed, there was only one prospective randomized trial addressing the issue of early versus late fixation of femur fractures.5 The total number of patients in this study (83) was relatively small. The only outcomes of interest with respect to this PMG were mortality and VTE. Among the other outcomes reported in this study, the early fixation arm had significantly shorter stay in the intensive care unit and in the hospital. As a result of the lower length of stay, the average hospital cost was also decreased in the early fixation arm.
The rest of the other articles reviewed were retrospective reviews. Hence, patients were not matched in early versus delayed fixation groups. Another issue was inconsistent timing of fracture fixation. In many articles, the time of fixation was less than 48 hours and not further specified. These were not included in the analysis. One article reported fixation less than 12 hours or greater than 48 hours.49 Another article excluded all patients who had fixation after 48 hours. In addition, there were variations in the fracture type. We specifically excluded studies with intertrochanteric fracture fixation.50 One article was excluded because patients with femur fractures were not separated from pelvis and spine fractures.51 Other articles were excluded as they compared the type of fixation, instead of the timing of fixation. Pediatric studies were also excluded. Finally, all case series with four or fewer cases were excluded.
Some of the articles reported damage-control orthopedics compared with definitive fixation. These articles had external fixation performed early, followed by definitive internal fixation later on. These articles were also excluded because their patients did not have internal fixation within 24 hours. Another major common reason for exclusion was that the outcomes reported were not relevant to this review, namely, mortality, infection, VTE, nonunion/malunion, and amputation. One of the items not considered was economics. However, it seems early fixation did lead to an efficient use of operating room and other resources compared with delayed fixation.5,46
This PMG has several limitations primarily related to the study design resulting in a high risk of bias in all but two studies, resulting in a conditional recommendation. In addition, we were unable to separate open from closed femoral fractures. The findings are also limited to the five outcomes included in the literature review. No inference should be made about other outcomes such as fat embolism, compartment syndromes, and functional outcomes.
In trauma patients with open or closed femur fractures, we suggest early (<24 hours) open reduction and internal fracture fixation. This recommendation is conditional because the strength of the evidence is low. Early stabilization of femur fractures shows a trend (statistically insignificant) toward lower risk of infection, mortality, and VTE. Therefore, the panel concludes that the desirable effects of early femur fracture stabilization probably outweigh the undesirable effects in most patients. Additional well-designed observational or prospective cohort studies may be informative. Although the overall quality of evidence was low, the other factors GRADE allows the writing committee to consider helped to guide our recommendation. The potential patient benefit of early femur fixation likely outweighs the harm in most patients.
RECOMMENDATION: In trauma patients with open or closed femur fractures, we suggest early (<24 hours) open reduction and internal fracture fixation. This recommendation is conditional, and the strength of the evidence is low. Early stabilization of femur fractures shows a trend (statistically insignificant) toward lower risk of infection, mortality, and VTE. Therefore, the panel concludes that the desirable effects of early femur fracture stabilization probably outweigh the undesirable effects in most patients. Conditional recommendation (low quality of evidence).
USING THESE GUIDELINES IN CLINICAL PRACTICE
This guideline represents a very detailed summary of the literature regarding open reduction and internal fixation of femur fractures and surgical timing and is meant to inform the decision-making process, not replace clinical judgment. The optimal timing for internal fixation remains controversial.2–4 The literature available for review thus far support the course of earlier open reduction and internal fixation in polytrauma patients with open or closed femur fractures.
In conclusion, we conditionally recommend internal fixation of femur fractures in less than 24 hours from the time of injury to reduce mortality, infection, and VTE. Further research in a well-designed fashion with adequate sample size is needed to determine the benefits of early fixation of femur fractures.
R.R.G., S.S. and E.R.H. conceived the study. R.R.G. built the PICO questions. J.K.L., D.A., J.W., T.R., E.H., F.B.R., S.S., and R.R.G. voted regarding the outcomes of interest for the PICO questions. R.R.G., S.S., and T.L.O. evaluated the articles independently for outcomes and relevance. T.L.O. performed the entire literature search, read all the abstracts, and selected the articles for review. R.R.G., S.S., and T.L.O. reviewed and summarized those articles selected. T.L.O. extracted the data from those articles. E.R.H. and B.L. placed the extracted data in the RevMan and GRADEpro programs and evaluated the results for recommendations. R.R.G., S.S., and T.L.O. also evaluated the results for the recommendation. R.R.G., S.S., and T.L.O. wrote the manuscript. E.R.H. and B.L. contributed to the writing of the methods and results. All authors participated in the critical review of this article.
We thank the Eastern Association for the Surgery of Trauma (EAST) and the EAST foundation for the opportunity to write this article, the specialized training provided to the writers regarding the GRADE method, and the detail-oriented peer review of multiple versions of this article by the guidelines committee.
E.R.H. is the primary investigator and supported by a contract (CE-12-11-4489) from the Patient-Centered Outcomes Research Institute (PCORI) entitled “Preventing Venous Thromboembolism: Empowering Patients and Enabling Patient-Centered Care Via Health Information Technology.” E.R.H. receives royalties from Lippincott, Williams, & Wilkins for a book, “Avoiding Common ICU Errors” and has given expert witness testimony in various medical malpractice cases. E.R.H. is a member of the EAST Board of Directors and Chairs the EAST Guidelines Committee. R.R.J. is a speaker for Lifecell. E.H. is supported by grants from Synthes and Smith and Nephew and is a consultant for Synthes. E.H. is also a speaker for AO North America Faculty. B.L. is the co–principal investigator of a contract (CE-12-11-4489) with the Patient-Centered Outcomes Research Institute (PCORI) entitled “Preventing Venous Thromboembolism: Empowering Patients and Enabling Patient-Centered Care Via Health Information Technology.” H.A.V. is a member of the board for the Orthopaedic Trauma Association and Center for Orthopaedic Trauma Advancement. H.A.V. receives support for the METRC research consortium funded by the Department of Defense, the FAITH research study funded by the National Institute of Health, and the sacrum research study funded by the Orthopaedic Trauma Association. J.W. is supported by a grant to study acupuncture in the ICU by the Medical Research Foundation and receives travel expenses for PROPPR trial meetings. S.S., F.B.R., T.R., D.A., J.K.L., and T.L.O. have nothing to disclose.
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