Abstract
Background
The systemic inflammatory response syndrome (SIRS) is a clinical reaction that can occur due to a variety of stimuli. Reamed intramedullary femoral nailing is a common orthopedic surgery that has been shown to induce SIRS. To date, no nationwide analyses have been performed to evaluate the incidence, risk factors, and economic burdens of SIRS following intramedullary femoral nailing for femoral shaft fractures. The objective of this study is to investigate the independent predictors, incidence, post-operative, and economic burden of SIRS among patients treated with intramedullary nailing for femoral shaft fractures.
Methods
We utilized the 2016–2019 National Inpatient Sample (NIS) to identify patients who underwent intramedullary femoral nailing and were diagnosed with non-infectious SIRS (NI-SIRS) based on ICD-10-CM coding. Identified patients who underwent intramedullary femoral nailing were dichotomized into SIRS and Non-SIRS groups to assess independent predictors of SIRS development, and to compare post-operative complications and costs.
Results
A total of 65,240 patients with femur shaft fractures underwent IMFN, of which 665 (1.0 %) developed NI-SIRS. Patients with NI-SIRS had a higher incidence of laparotomy (OR = 13.97, p < 0.001), initial treatment with external fixation (OR = 1.845, p < 0.001), and late application of external fixation (OR = 4.884, p = 0.005). Routine discharge (OR = 0.491, p < 0.001) was less likely in patients with NI-SIRS. Length of stay (12.38 days vs 7.16 days, p < 0.001) and total charges ($278, 590 vs $145,118, p < 0.001) were both increased in patients with NI-SIRS.
Conclusion
NI-SIRS is associated with increasing injury severity and post-operative complications. Those that developed NI-SIRS experienced higher healthcare resource utilization. Risk factors associated with development of NI-SIRS warrant further investigation.
Keywords: Trauma, Systemic inflammatory response syndrome, Femur, Reamed intramedullary nailing
1. Background
The systemic inflammatory response syndrome (SIRS) is a potentially devastating, amplified inflammatory response to infection, trauma, ischemia, or a combination of several factors.1 Surgery is also a known precipitator of the systemic inflammatory response. Trauma patients with femoral shaft fractures are often diagnosed with SIRS.1, 2, 3, 4, 5, 6 Conventional treatments towards femoral fractures involve an initial external fixation (ExFix) followed by a conversion to an intramedullary femoral nail (IMFN).5,7 Reamed intramedullary femoral nailing is a common orthopedic procedure that has been shown to induce SIRS.1, 2, 3, 4, 5, 6
The advantage of reamed intramedullary femoral nailing is that it allows for the insertion of a larger nail which provides more stability.8 The outcomes of reamed nailing surgeries have been associated with improved union rates of fractures, faster healing time, and decreased incidence of delayed union.8,9 Despite these positive outcomes, the surgical operation remains a risk factor for SIRS. Past studies that examined the SIRS response following IMFN for femur fracture management suggested that a variety of patient related-factors may increase the likelihood of SIRS development, including severe shock, concomitant head or thoracic injuries, and the presence of pulmonary contusions on initial presentation.10, 11, 12 A few studies highlighted that there was a significant association between preceding chest trauma and lung injury and the further development of SIRS and acute respiratory distress syndrome following IMFN.11,12 Damage control orthopedics (DCO) is a method for providing care to initially stabilize trauma patients before definitive surgery to prevent subsequent injury that follows reconstructive surgery.2 Postoperative findings have demonstrated that in comparison to initial early IMFN fixation, DCO procedures have been associated with reduced operative time, and reduced severity and duration of subsequent systemic inflammation.2,5 Past studies have demonstrated that postoperative SIRS scores have been found to be significantly lower with DCO procedures than after early stabilization with IMFN.2,3 Additionally, IL-6, which is commonly used to quantify the level of an inflammatory response in trauma patients, has also been found at lower quantities after DCO than after IMFN.13
Past research on this area has focused on uncovering the mechanism of SIRS following reamed IMFN procedure but fails to provide a nationwide analysis that evaluates the risk factors, incidence, and economic burdens of SIRS following intramedullary femoral nailing for femoral shaft fractures. The objective of this study is to investigate the incidence, economic burden, and potential independent predictors of SIRS among patients treated with intramedullary nailing for femoral shaft fractures.
2. Methods
This retrospective analysis utilized the National Inpatient Sample (NIS) database discharge data for the years 2016–2019. The data is a part of the Healthcare Cost and Utilization Project (HCUP) Agency for Healthcare Research and Quality.14 The institutional review board at New York Medical College considered the current study exempt.
2.1. Patient selection
International Classification of Disease, 10th revision procedure codes were used to extract patients who underwent intramedullary femoral nailing of femur shaft fractures. The development of SIRS in patients who underwent intramedullary femoral nailing was quantified using the non-infectious SIRS ICD-10-CM code. Only patients with the ICD-10 code designations for femoral shaft fractures, intramedullary femoral nailing, and SIRS diagnosis were included in the analysis, and further patient and treatment characteristics were collected from this sample, as discussed below. Please see Supplementary Tables for the ICD-10 codes used for both patient selection (Supplementary Table 1) and patient variables analyzed (Supplementary Table 2).
2.2. Data variables
Baseline demographics such as age, sex, and insurance status were extracted for each patient. Medical comorbidities of obesity, smoking, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), diabetes mellitus (DM), hypertension (HTN), obstructive sleep apnea (OSA), depression, alcohol abuse, and substance abuse were recorded. The Elixhauser Comorbidity Index was defined for each case and calculated.15 An injury severity scale was developed based on the cumulative ICD-10 diagnostic codes consistent with traumatic injury. Complications of hospital stay including following procedure, osteomyelitis, sepsis, deep venous thrombosis (DVT), acute kidney injury (AKI), pulmonary embolism (PE), myocardial infarction (MI), aspiration pneumonitis, acute respiratory distress syndrome (ARDS), pneumonia (PNA), pulmonary contusion, infection post procedure, blood transfusion were defined. Total healthcare charges, discharge disposition, and inpatient death were also recorded. Routine discharge was defined as patients who were discharged to home or self-care. Application of external fixation on admission and after 48 h of hospitalization was also recorded using the respective ICD-10 codes.
2.3. Statistical analysis
Categorical baseline and hospital course variables were evaluated using Pearson's Chi Squared test. The distribution of continuous variables in the analysis were evaluated using the Kolmogorov-Smirnov test. The Mann-Whitney U test was used to compare the averages of non-normally distributed continuous variables. Multivariate binary logistic regression was utilized to identify independent predictors of NI-SIRS. Statistical analysis was performed using SPSS (IBM Corp. Released 2021. IBM SPSS statistics for Windows, Version 28.0, Armonk, NY: IBM Corp).
3. Results
3.1. Baseline characteristics
A total of 65,240 patients with femur shaft fractures underwent IMFN, of which 665 (1.0 %) developed NI-SIRS. Patients with a history of CHF (OR = 2.789, p < 0.001), alcohol (OR = 1.705, p < 0.001) and substance (OR = 3.066, p = 0.002) abuse were associated with NI-SIRS development. A decreased incidence of NI-SIRS was associated with female (OR = 0.684, p < 0.001) sex and obesity (OR = 0.447, p = 0.001). The Elixhauser comorbidity index (1.7669 vs 1.4780, p < 0.001) and injury severity scale (7.0902 vs 4.1954, p < 0.001) were higher in patients with NI-SIRS; there was no difference in age (p = 0.510) (Table 1).
Table 1.
NI-SIRS vs Non-SIRS Baseline Demographics and Comorbidities of Femur Shaft Fracture Patients Undergoing Intramedullary Femoral Nailing.
| Variables | All (65,240) | Non-SIRS (64,575, 99.0 %) | NI-SIRS (665, 1.0 %) | NI-SIRS |
|
|---|---|---|---|---|---|
| OR (CI 95 %) | P value | ||||
| Female | 26230 (40.2 %) | 26020 (40.3 %) | 210 (31.6 %) | 0.684 (0.58–0.806) | <.001 |
| Obesity | 3960 (6.1 %) | 3940 (6.1 %) | 20 (3 %) | 0.477 (0.305–0.746) | 0.001 |
| Smoker Status | 13385 (20.5 %) | 13240 (20.5 %) | 145 (21.8 %) | 1.081 (0.899–1.301) | 0.412 |
| Chronic Obstructive Pulmonary Disease | 2970 (4.6 %) | 2940 (4.6 %) | 30 (4.5 %) | 0.99 (0.685–1.431) | 1 |
| Congestive Heart Failure | 730 (1.1 %) | 710 (1.1 %) | 20 (3 %) | 2.789 (1.776–4.379) | <.001 |
| Diabetes Mellitus | 6415 (9.8 %) | 6355 (9.8 %) | 60 (9 %) | 0.909 (0.696–1.186) | 0.513 |
| Hypertension | 13585 (20.8 %) | 13460 (20.8 %) | 125 (18.8 %) | 0.879 (0.723–1.069) | 0.212 |
| Obstructive Sleep Apnea | 2285 (3.5 %) | 2265 (3.5 %) | 20 (3 %) | 0.853 (0.546–1.334) | 0.527 |
| Depression | 4540 (7 %) | 4505 (7 %) | 35 (5.3 %) | 0.741 (0.526–1.043) | 0.091 |
| Alcohol Abuse | 5195 (8 %) | 5110 (7.9 %) | 85 (12.8 %) | 1.705 (1.356–2.145) | <.001 |
| Substance Abuse | 330 (0.5 %) | 320 (0.5 %) | 10 (1.5 %) | 3.066 (1.626–5.78) | 0.002 |
| Variables | Non-SIRS Mean (St. Dv.) | NI-SIRS Mean (St. Dv.) | P value | ||
|---|---|---|---|---|---|
| Age | 40.95 (±24.313) | 40.33 (±21.965) | 0.510 | ||
| Elixhauser Comorbidity Index | 1.4780 (±1.80632) | 1.7669 (±1.83214) | <.001 | ||
| ISS | 4.1954 (±4.35091) | 7.0902 (±5.19566) | <.001 |
3.2. Hospital course
Patients with NI-SIRS had a higher incidence of complications following procedures (OR = 3.392, p < 0.001), DVT OR = 2.108, p < 0.001), AKI (OR = 2.867, p < 0.001), MI (OR = 2.723, p = 0.005), ARDS (OR = 5.314, p < 0.001), PNA (OR = 2.029, p = 0.001), pulmonary contusion (OR = 2.147, p < 0.001), and blood transfusion (OR = 1.405, p < 0.001). Patients with NI-SIRS had a higher incidence of laparotomy (OR = 13.97, p < 0.001), initial treatment with external fixation (OR = 1.845, p < 0.001), and late application of external fixation (OR = 4.884, p = 0.005). Routine discharge (OR = 0.491, p < 0.001) was less likely in patients with NI-SIRS. Length of stay (12.38 days vs 7.16 days, p < 0.001) and total charges ($278, 590 vs $145,118, p < 0.001) were both increased in patients with NI-SIRS (Table 2).
Table 2.
NI-SIRS vs Non-SIRS Hospital Course of Femur Shaft Fracture Patients Undergoing Intramedullary Femoral Nailing.
| Variables | All (65,240) | Non-SIRS (64,575, 99.0 %) | NI-SIRS (665, 1.0 %) | NI-SIRS |
|
|---|---|---|---|---|---|
| OR (CI 95 %) | P value | ||||
| Complication Following Procedure* | 605 (0.9 %) | 585 (0.9 %) | 20 (3 %) | 3.392 (2.158–5.332) | <.001 |
| Osteomyelitis | 30 (0 %) | 30 (0 %) | 0 (0 %) | 1 (0.999–1) | 1 |
| Sepsis | 715 (1.1 %) | 705 (1.1 %) | 10 (1.5 %) | 1.383 (0.737–2.594) | 0.343 |
| Deep Vein Thrombosis | 1200 (1.8 %) | 1175 (1.8 %) | 25 (3.8 %) | 2.108 (1.408–3.156) | <.001 |
| Acute Kidney Injury | 4725 (7.2 %) | 4605 (7.1 %) | 120 (18 %) | 2.867 (2.348–3.502) | <.001 |
| Pulmonary Embolism | 930 (1.4 %) | 920 (1.4 %) | 10 (1.5 %) | 1.056 (0.564–1.979) | 0.868 |
| Myocardial Infarction | 370 (0.6 %) | 360 (0.6 %) | 10 (1.5 %) | 2.723 (1.446–5.129) | 0.005 |
| Aspiration Pneumonitis | 865 (1.3 %) | 860 (1.3 %) | 5 (0.8 %) | 0.561 (0.232–1.356) | 0.233 |
| Acute Respiratory Distress Syndrome | 195 (0.3 %) | 185 (0.3 %) | 10 (1.5 %) | 5.314 (2.799–10.087) | <.001 |
| Pneumonia | 2015 (3.1 %) | 1975 (3.1 %) | 40 (6 %) | 2.029 (1.469–2.801) | <.001 |
| Pulmonary Contusion | 6695 (10.3 %) | 6565 (10.2 %) | 130 (19.5 %) | 2.147 (1.77–2.605) | <.001 |
| Infection Post Procedure | 265 (0.4 %) | 260 (0.4 %) | 5 (0.8 %) | 1.874 (0.771–4.555) | 0.202 |
| Blood Transfusion | 10440 (16 %) | 10300 (16 %) | 140 (21.1 %) | 1.405 (1.165–1.695) | <.001 |
| Laparotomy | 40 (0.1 %) | 35 (0.1 %) | 5 (0.8 %) | 13.97 (5.456–35.768) | <.001 |
| Initial ExFix | 2205 (3.4 %) | 2165 (3.4 %) | 40 (6 %) | 1.845 (1.336–2.547) | <.001 |
| Late Exfix (After 48 h) | 105 (0.2 %) | 100 (0.2 %) | 5 (0.8 %) | 4.884 (1.983–12.031) | 0.005 |
| Inpatient Death | 530 (0.8 %) | 520 (0.8 %) | 10 (1.5 %) | 1.881 (1.001–3.533) | 0.052 |
| Routine Discharge | 30360 (46.5 %) | 30160 (46.7 %) | 200 (30.1 %) | 0.491 (0.416–0.58) | <.001 |
| Variables | Non-SIRS Mean (St. Dv.) | NI-SIRS Mean (St. Dv.) | P value | ||
|---|---|---|---|---|---|
| Length of Stay | 7.16 (±9.548) | 12.38 (±11.339) | <.001 | ||
| Total Charges | $145,118.69 (±$190,180.171) | $278,590.03 (±$282,236.037) | <.001 |
*Complications of surgical and medical care, not elsewhere classified.
3.3. Predictors of NI-SIRS
Increasing age (OR = 1.005, p = 0.011), ARDS (OR = 2.902, p = 0.001), increasing ISS (OR = 1.113, p < 0.001), and laparotomy (OR = 6.914, p < 0.001) were independently associated with development of NI-SIRS in patients undergoing intramedullary femoral nailing for femur shaft fracture (Table 3).
Table 3.
Predictors of non-infectious SIRS among femur shaft fracture patients undergoing intramedullary femoral nailing.
| Variablesa | Non-Infectious SIRS |
|
|---|---|---|
| OR (CI 95 %) | P value | |
| Increasing Age | 1.005 (1.001–1.008) | 0.011 |
| Acute Respiratory Distress Syndrome | 2.902 (1.513–5.564) | 0.001 |
| Increasing Injury Severity Score | 1.113 (1.096–1.13) | <.001 |
| Initial Exfix | 0.823 (0.576–1.176) | 0.285 |
| Late ExFix (After 48 h) | 2.633 (0.988–7.02) | 0.053 |
| Laparotomy | 6.914 (2.636–18.137) | <.001 |
| Pulmonary Contusion | 0.994 (0.793–1.247) | 0.961 |
Multivariate logistic regression controlling for age, acute respiratory distress syndrome, injury severity score, initial external fixation, late external fixation (after 48 h), laparotomy, and pulmonary contusion.
4. Discussion
Femoral shaft fractures are a common serious injury in trauma patients and the injury is known to be associated with SIRS.1, 2, 3, 4, 5, 6,16 Previous studies have described the complex mechanism of the inflammatory response following femoral nailing.1,4,6 Intramedullary femoral nailing commonly serves as the “second-hit” in the well described “two-hit hypothesis,” in which a traumatic injury primes the immune system for a subsequent stimulus to produce an exaggerated inflammatory response, which can result in increased morbidity and mortality.17 Our study is the first to analyze a nationwide patient sample to evaluate the incidence, post-operative, and economic burden of the systemic inflammatory response syndrome among patients treated with intramedullary nailing.
Damage control orthopedics depicts the notion of temporary stabilization using an external fixator followed by secondary definitive stabilization of major fractures in patients at high risk of developing a profound systemic inflammatory response and postoperative complications.2,18 In our study, damage control surgery describes patients who underwent initial stabilization with an external fixator with later conversion to an intramedullary femoral nail. Patients managed with external fixation both on admission and 48 h after presentation prior to conversion to an intramedullary femoral nail had a significantly higher incidence of NI-SIRS, however, neither variable was found to be an independent predictor of NI-SIRS development, and there was no difference in association of NI-SIRS in patients treated with initial external fixation versus external fixation after 48 h. This finding may support the use damage control surgery to minimize the effect of surgery on the inflammatory reaction. Further, the patients who developed NI-SIRS also had significantly higher ISS, which likely supports the hypothesis that the severity of the trauma is a more influential determinant for SIRS development than the surgical strategy; it is possible that SIRS will develop in higher ISS cases regardless of the timing of intervention, given the severity of the trauma.
While surgery is a known cause of SIRS, the response is guided by both patient and surgical factors.6,19, 20, 21 Patient factors include the patient's age, health, nutritional status, genetic predisposition, and severity of injury of the trauma, while surgical factors include the technique, duration, and magnitude of the procedure.19, 20, 21 Although several factors help determine the post-operative course of polytrauma patients, it is possible that the severity of injury is the most important factor in the development of SIRS, as opposed to the surgery associated with it, presumably due to the extent of the initial inflammatory reaction. A well-described phenomenon contributing to inflammatory responses trauma patients is the priming of leukocytes following the initial injury.22 Past studies have reported that this activation of leukocytes is associated with an increase in the IL-6 concentrations.22 Several clinical studies have also demonstrated this increase in IL-6 levels during reamed intramedullary nailing of the femur.1,3,4,6,13,17
Our study results demonstrate that there was a decreased incidence of NI-SIRS associated with female and obese patients. With regards to gender, to our knowledge, no study has evaluated the difference in SIRS development between males and females. Morley et al. included gender and ISS breakdowns in examining SIRS following IMFN, but no comparison was made between the two cohorts with regards incidence of SIRS.8 Although no past studies have shown this association, a few experimental studies have reported that estrogens have a protective effect of the immune response following major trauma.23 This same concept is similar to our finding with a decreased incidence in obese patients, as past research has elucidated that patients with a higher BMI may be protected from inflammatory reactions following polytrauma and have better outcomes, although there are conflicting reports.24,25 The authors postulate that the increased adiposity mass in obese patients results in higher estrogen levels, which may limit the levels of inflammatory markers and clinical reaction, which may also explain our study's findings in these two categories.24
Although there is evidence that suggests femoral nailing primes the immune system, patients likely have an overstimulated baseline immune system which elicits the reaction to the surgery.4 This phenomenon could explain the SIRS following intramedullary nailing in trauma patients, as the initial trauma severity resulted in a heightened baseline immune response. Although there is no definitive conclusion, this concept has been raised in past studies.8,16,26,27 In a study that analyzed the second-hit phenomena of femoral nailing in 32 patients, the authors reported one patient with an ISS of 9 was found to have a hyper-stimulated immune response both before and after femoral nailing.4 This suggests the prominence of an excessive inflammatory reaction in the development of these serious injuries.
Hypoperfusion and ischemia are potential stimuli of the SIRS development. It is recommended that patients be properly resuscitated before the placement of a reamed IMFN, which further worsens blood loss and the hypo-perfused state.1,17 If the degree of initial hypoperfusion is an indicator of the development of SIRS following surgery, it would make sense that more severe injuries are associated with higher rates of SIRS following surgery; this would be consistent with our findings as the NI-SIRS cases had higher injury severity scores. The importance of proper preoperative resuscitation is supported by a study by O'Toole et al.28 which showed a significant lower ARDS rate in patients who responded to resuscitation before IMFN.28 An explanation for the discrepancy in the literature might be due to differences in preoperative resuscitation or medical care provided to manage shock.28 Physician awareness of patients at risk of developing SIRS and a further understanding of which patients will respond to certain treatment regimens is crucial in reducing post-operative complications of trauma patients. As our results demonstrate that patients that developed NI-SIRS had higher hospital charges, longer length of stays, and less routine hospital discharges, it is important to efficiently manage these cases to limit the economic and healthcare burden. Additional research should further investigate subgroups of trauma patients to determine predictors of the development of SIRS.
This study has several limitations. First, due to its retrospective design, this study is at risk for selection bias in patient extraction from the database. Also, there may be missing data that is unable to be extracted from the dataset that limits our analysis. Second, while using the NIS database we were able to identify femoral fracture patients who were diagnosed with non-infectious SIRS, we are unable to determine the temporality of their diagnosis in relation to their treatments with ExFix or IMFN, as well as the development of complications. Additionally, as our paper did not dichotomize closed versus open fractures, future studies should assess for the effect of open femoral shaft fractures and determine if there is a difference in SIRS incidence as compared to closed injuries.
5. Conclusion
In conclusion, the nationwide analysis demonstrates that 1 % of patients with femoral fracture patients treated with IMFN developed NI-SIRS. These patients had a higher incidence of complications, hospital length of stay, and total charges. Increasing age, increasing ISS, laparotomy, and ARDS were found to be independent predictors of NI-SIRS development. While NI-SIRS patients had a higher incidence of initial treatment with external fixation and late application of external fixation, neither was found to be an independent predictor NI-SIRS development. SIRS in trauma patients is associated with a significant healthcare cost burden and complications. Given the literature and detailed proven response of SIRS following IMFN, we recommend that the treatment for polytrauma patients with femoral shaft fractures should be individualized with consideration of the patient's stability and resuscitation efforts; many polytrauma patients may benefit from DCO to avoid additional inflammatory injuries and overall health burden. The optimal prevention and management strategies of SIRS warrants further investigation.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jor.2023.10.030.
Appendix A. Supplementary data
The following are the Supplementary data to this article.
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