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. 2018 Feb 13;476(3):453–462. doi: 10.1007/s11999.0000000000000099

How Common—and How Serious— Is Clostridium difficile Colitis After Geriatric Hip Fracture? Findings from the NSQIP Dataset

Patawut Bovonratwet 1,2, Daniel D Bohl 1,2, Glenn S Russo 1,2, Nathaniel T Ondeck 1,2, Denis Nam 1,2, Craig J Della Valle 1,2, Jonathan N Grauer 1,2,✉
PMCID: PMC6260047  PMID: 29443839

Abstract

Background

Patients with geriatric hip fractures may be at increased risk for postoperative Clostridium difficile colitis, which can cause severe morbidity and can influence hospital quality metrics. However, to our knowledge, no large database study has calculated the incidence of, factors associated with, and effect of C. difficile colitis on geriatric patients undergoing hip fracture surgery.

Questions/Purposes

To use a large national database with in-hospital and postdischarge data (National Surgical Quality Improvement Program® [NSQIP®]) to (1) determine the incidence and timing of C. difficile colitis in geriatric patients who underwent surgery for hip fracture, (2) identify preoperative and postoperative factors associated with the development of C. difficile colitis in these patients, and (3) test for an association between C. difficile colitis and postoperative length of stay, 30-day readmission, and 30-day mortality.

Patients and Methods

This is a retrospective study. Patients who were 65 years or older who underwent hip fracture surgery were identified in the 2015 NSQIP database. The primary outcome was a diagnosis of C. difficile colitis during the 30-day postoperative period. Preoperative and procedural factors were tested for association with the development of C. difficile colitis through a backward stepwise multivariate model. Perioperative antibiotic type and duration were not included in the model, as this information was not recorded in the NSQIP. The association between C. difficile colitis and postoperative length of stay, 30-day readmission, and 30-day mortality were tested through multivariate regressions, which adjusted for preoperative and procedural characteristics such as age, comorbidities, and surgical procedure. A total of 6928 patients who were 65 years or older and underwent hip fracture surgery were identified.

Results

The incidence of postoperative C. difficile colitis was 1.05% (95% CI, 0.81%-1.29%; 73 of 6928 patients). Of patients who had C. difficile colitis develop, 64% (47 of 73 patients) were diagnosed postdischarge and 79% (58 of 73 patients) did not have a preceding infectious diagnosis. Preoperative factors identifiable before surgery that were associated with the development of C. difficile colitis included admission from any type of chronic care facility (versus admitted from home; relative risk [RR] = 1.98; 95% CI, 1.11-3.55; p = 0.027), current smoker within 1 year (RR = 1.95; 95% CI, 1.03-3.69; p = 0.041), and preoperative anemia (RR = 1.76; 95% CI, 1.07-2.92; p = 0.027). Patients who had pneumonia (RR = 2.58; 95% CI, 1.20-5.53; p = 0.015), sepsis (RR = 4.20; 95% CI, 1.27-13.82; p = 0.018), or “any infection” (RR = 2.26; 95% CI, 1.26-4.03; p = 0.006) develop after hip fracture were more likely to have C. difficile colitis develop. Development of C. difficile colitis was associated with greater postoperative length of stay (22 versus 5 days; p < 0.001), 30-day readmission (RR = 3.41; 95% CI, 2.17-5.36; p < 0.001), and 30-day mortality (15% [11 of 73 patients] versus 6% [439 of 6855 patients]; RR = 2.16; 95% CI, 1.22-3.80; p = 0.008).

Conclusions

C. difficile colitis is a serious infection after hip fracture surgery in geriatric patients that is associated with 15% mortality. Patients at high risk, such as those admitted from any type of chronic care facility, those who had preoperative anemia, and current smokers within 1 year, should be targeted with preventative measures. From previous studies, these measures include enforcing strict hand hygiene with soap and water (not alcohol sanitizers) if a provider is caring for patients at high risk and those who are C. difficile-positive. Further, other studies have shown that certain antibiotics, such as fluoroquinolones and cephalosporins, can predispose patients to C. difficile colitis. These medications perhaps should be avoided when prescribing prophylactic antibiotics or managing infections in patients at high risk. Future prospective studies should aim to determine the best prophylactic antibiotic regimens, probiotic formula, and discharge timing that minimize postoperative C. difficile colitis in patients with hip fractures.

Level of Evidence

Level III, therapeutic study.

Introduction

Clostridium difficile is a serious infection that can evolve into a life-threatening process such as pseudomembranous colitis or toxic megacolon [37]. C. difficile colitis is implicated as the cause of severe morbidity and is used as a measure of hospital quality [24]. In 2009, 336,600 hospitalizations that involved C. difficile colitis were documented and this number accounted for nearly 1% of all hospital stays in the United States [25]. Previous studies have shown C. difficile colitis to be associated with advanced age, previous surgery, increased hospital length of stay, and the use of antibiotics [18, 20, 22, 28, 40]. Based on these studies, the hip fracture population is inherently at risk. These patients usually are older than 65 years, have multiple comorbidities, and are given broad-spectrum antibiotics, such as cephalosporins, as prophylaxis [39, 40]. Owing to the aging of the population, there are more than 300,000 hip fractures annually in the United States population, with total treatment costs estimated at more than USD 12 billion [42].

However, to our knowledge, only single-institution studies from the United Kingdom have investigated C. difficile colitis in patients with hip fractures [18, 36, 40]. Owing to their small sample sizes, these studies were not able to determine independent risk factors for development of C. difficile colitis. Further, these studies did not define the timing of diagnosis or effect of C. difficile colitis on hospital readmission, a pertinent outcome in the present healthcare climate [8, 32]. The use of national databases can circumvent these limitations by providing large patient numbers and rigorously tracked outcome measures that can generate enough statistical power to synthesize clinically meaningful results.

The purpose of our study was to use a large national database with in-hospital and postdischarge data (National Surgical Quality Improvement Program [NSQIP]) to (1) determine the incidence and timing of C. difficile colitis in geriatric patients who underwent surgery for hip fracture, (2) identify preoperative and postoperative factors associated with the development of C. difficile colitis in these patients, and (3) test for an association between C. difficile colitis and postoperative length of stay, 30-day readmission, and 30-day mortality.

Patients and Methods

Database

A retrospective study was performed using data from the 2015 NSQIP database. The NSQIP database uses trained surgical reviewers to collect more than 100 perioperative variables from more than 500 institutions in the United States [2, 16]. Methods of data collection include medical chart abstraction, operative reports, and patient interviews [11]. In addition, patient data is recorded through the 30th postoperative day, regardless of hospital discharge status [21, 30]. The use of the NSQIP database in orthopaedic research has become increasingly frequent and accepted [12, 13, 35]. The first and only year currently available from the NSQIP to include postoperative C. difficile colitis as an outcome variable is 2015. This is because the NSQIP only started to collect this variable in 2015. Our institutional review board granted an exemption for studies using this dataset because all data are deidentified and anonymous.

Patient Selection and Baseline and Procedural Characteristics

Patients were considered to have met inclusion criteria if they (1) were 65 years or older, (2) underwent hip fracture surgery, and (3) had the outcome variable of C. difficile colitis available for analysis. Of the 15,703 patients who were identified based on Criterion 1 and Criterion 2, 8005 patients met Criterion 3. Of these 8005 patients, 99% (7958 patients) were admitted during the third and fourth quarters of 2015. Therefore, it was thought that the reason for the approximately 50% missing postoperative C. difficile colitis variable in the initially identified patient population, based on Criterion 1 and Criterion 2, was because most of the NSQIP participating institutions began to collect data on postoperative C. difficile colitis in the second half of 2015. Concern for selection bias was minimal as missing C. difficile colitis data were not targeted toward a certain patient group. Patients were considered to have undergone hip fracture surgery if the following criteria were met. First, patients must have had one of the ICD-9 revision codes or one of the ICD-10 revision codes indicative of hip fracture (see Appendix, Supplemental Digital Content). Second, patients must have had a Current Procedural Terminology (CPT) code signifying hip fracture surgery (27245 [intramedullary fixation], 27244 [plate/screw fixation], 27125/27236 [hemiarthroplasty], or 27130 [total hip arthroplasty]). For the current study, the CPT code 27236 was categorized as a hemiarthroplasty procedure, following a previous study [4].

Perioperative antibiotic type and duration were not included in the current study, as this information was not recorded in the NSQIP database. Although these two important data points could not be analyzed, several other important variables, such as patient comorbidities, patient preoperative laboratory values, facility transfer status, and delay to surgery, could be examined. In addition, the current study was able to investigate the association between postoperative C. difficile colitis and hospital length of stay, 30-day readmission, and 30-day mortality. These associations may not have been identifiable without the use of a national database that could provide a large enough patient population.

Following the inclusion criteria, 1077 patients (approximately 10%) in the current study had missing data for preoperative and procedural characteristics. These variables included height, weight, American Society of Anesthesiologists (ASA) class, functional status before surgery, preoperative hematocrit, transfer status, operative time, and length of stay. Patients missing any of these data points were excluded from the study. Concern for selection and transfer bias here was minimal as datasets with small proportions of missing data (approximately 10%) are less susceptible to bias when the dataset is manipulated with complete-case analysis [6]. Preoperative serum albumin was the only variable in the current study with missing data for greater than approximately 10% of patients (missing for 37%). Owing to the high percentage of missing data, patients with missing preoperative serum albumin were not excluded to prevent bias [6]. These patients were treated using the missing-indicator method instead [17]. Briefly, this method creates a separate group for patients with missing data and adjusts for it during multivariate analysis. This approach was supported over alternative methods [17] by a study on missing data in the NSQIP database [19]. Since the missing-indicator method does not exclude patients with missing data, concern for selection bias was minimal but there still may be the possibility of a transfer bias. However, of all variables included in the current study, only preoperative albumin had a high degree of missing data.

Patients were categorized regarding sex, age, functional status before surgery, BMI, ASA classification, preoperative anemia, smoking status (current smoker within 1 year), preoperative hypoalbuminemia, diabetes mellitus, hypertension, chronic steroid use, operative time, dyspnea on exertion, transfer status (admission from home, admission from outside hospital, admission from a nursing home, a chronic care facility, or an intermediate care facility), chronic obstructive pulmonary disease, days from hospital admission to operation (0 days, 1 day, ≥ 2 days), and surgical procedure. BMI was defined as kg/m2 and stratified into ranges of 18–24.9 (healthy), 25–29.9 (overweight), 30–34.9 (obese), and ≥ 35 (morbidly obese). Preoperative anemia was defined as preoperative hematocrit less than 36% for women or 39% for men [7]. Preoperative hypoalbuminemia was defined as preoperative serum albumin levels less than 3.5 g/dL [5]. Diabetes mellitus was stratified as no diabetes, noninsulin-dependent diabetes mellitus, and insulin-dependent diabetes mellitus [43].

Perioperative Complications and 30-day Readmission

Patients in the 2015 NSQIP database were tracked for the development of postoperative C. difficile colitis and other individual complications through the 30th postoperative day. NSQIP surgical reviewers use rigorous criteria to diagnose C. difficile colitis (see Appendix, Supplemental Digital Content). In addition, NSQIP documents the number of days after a surgical procedure that each complication was diagnosed for each patient. These data were used to establish which infections preceded a diagnosis of C. difficile colitis, which diagnosis occurred before or after discharge, and which diagnoses occurred after a hospital readmission. All patients who had postoperative C. difficile colitis had postoperative day of diagnosis recorded. In addition, no patient had missing data regarding occurrence and timing of other postoperative complications (urinary traction infection, pneumonia, wound infection, sepsis, readmission, mortality) included in the current study.

Statistical Analysis

All statistical analyses were performed using Stata® Version 13.1 (StataCorp LP, College Station, TX, USA). The level of significance was set at a two-sided level of 0.05 (p < 0 .05). Multivariate Poisson regression with robust error variance [45] was used to test for association between preoperative and procedural characteristics and occurrence of C. difficile colitis. The final multivariate model was selected using a backward stepwise method, where all preoperative and procedural factors (Table 1) were initially included in the model and variables with the highest p values were eliminated one by one until only variables with a probability less than 0.05 remained. Variables that remained in the model represented independent preoperative associations with the occurrence of C. difficile colitis.

Table 1.

Patient population

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Next, multivariate Poisson regression with robust error variance [45] was used to test for association between each postoperative infection (urinary tract infection, pneumonia, wound infection, sepsis, and “any infection”) and occurrence of C. difficile colitis. All preoperative and procedural characteristics (Table 1) were controlled for in each of these regressions. Patients who had one of these postoperative infections develop before the development of C. difficile colitis or without later development of C. difficile colitis were characterized as having a potentially contributory infection develop. Patients who had one of these postoperative infections develop after development of C. difficile colitis or did not have any of these postoperative infections develop were characterized as not having a potentially contributory infection develop.

Multivariate linear regression was used to compare postoperative length of stay between patients who had C. difficile colitis develop during index hospitalization and patients who did not. All preoperative and procedural characteristics (Table 1) were controlled for in this regression.

Finally, 30-day readmissions and 30-day mortality were examined. Multivariate Poisson regression with robust error variance [45] was used to test for association between 30-day readmission and development of C. difficile colitis after hospital discharge. For this analysis, patients who had C. difficile colitis develop after hospital readmission were categorized as not being readmitted owing to C. difficile colitis. Multivariate Poisson regression with robust error variance [45] also was used to test for association between mortality and development of C. difficile colitis any time during the 30-day postoperative period. All preoperative and procedural characteristics (Table 1) were controlled for in both of these regressions.

Study Population

A total of 8005 patients met the previously described inclusion criteria. Of these, 1077 were excluded for missing data, leaving 6928 patients (87%) for analysis. Of these patients, 774 (11%) underwent plate and screw fixation, 2714 (39%) had intramedullary fixation, 3132 (45%) underwent hemiarthroplasty, and 308 (5%) had THA (Table 1). The mean age of the patients was 82 ± 8 years, mean BMI was 25 ± 5 kg/m2, and 71% of the patients were female.

Results

Incidence and Timing of C. difficile Colitis

A total of 73 patients had C. difficile colitis develop, generating an incidence of 1.05% (95% CI, 0.81%-1.29%; 73 of 6928 patients). Only 36% (26 of 73) of patients with C. difficile infections were diagnosed before discharge, with the majority (64%; 47 of 73) being diagnosed after hospital discharge.

Factors Associated with C. difficile Colitis

After controlling for potentially confounding variables such as age, comorbidities, and surgical procedure, the only preoperative factors associated with postoperative C. difficile colitis included admission from a nursing home, a chronic care facility, or an intermediate care facility (versus admitted from home; relative risk [RR] = 1.98; 95% CI, 1.11-3.55; p = 0.027), current smoker within 1 year (versus nonsmoker or prior smoker; RR = 1.95; 95% CI, 1.03-3.69; p = 0.041), and preoperative anemia (versus patients without anemia; RR = 1.76; 95% CI, 1.07-2.92; p = 0.027) (Table 2).

Table 2.

Independent preoperative or procedural factors associated with development of Clostridium Difficile colitis

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After adjusting for preoperative and procedural characteristics, postoperative infectious factors associated with the development of postoperative C. difficile colitis included pneumonia (RR = 2.58; 95% CI, 1.20-5.53; p = 0.015), sepsis (RR = 4.20; 95% CI, 1.27-13.82; p = 0.018), or “any infection” (RR = 2.26; 95% CI, 1.26-4.03; p = 0.006) (Table 3). However, the development of C. difficile colitis was not associated with postoperative urinary tract infection or wound infection.

Table 3.

Postoperative factors associated with development of C. Difficile colitis

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Interestingly, only 15 [21%] patients diagnosed with C. difficile colitis had a preceding infection; three had a preceding urinary tract infection, seven had pneumonia, one had pneumonia and a urinary tract infection, one had wound infection, and three had urinary tract infections associated with systemic sepsis.

Clinical Implications of C. difficile Colitis

After adjusting for preoperative and procedural characteristics, patients who had C. difficile colitis develop during index hospitalization had a greater postoperative length of stay compared with patients who did not (22 versus 5 days; adjusted difference = 16days; 95% CI, 15–18 days; p < 0.001). Likewise, patients who had C. difficile colitis develop after discharge had a higher risk for 30-day readmission compared with patients who did not (30% [14 of 47 patients] versus 9% [591 of 6881 patients]; RR = 3.41; 95% CI, 2.17–5.36; p < 0.001). Finally, patients who had C. difficile colitis develop anytime during the 30-day postoperative period had a higher risk for 30-day mortality compared with patients who did not (15% [11 of 73 patients] versus 6% [439 of 6855 patients]; RR = 2.16; 95% CI, 1.22–3.80; p = 0.008).

Discussion

C. difficile infections are associated with severe morbidity and mortality [3]. Further, these infections are factored into hospital quality metrics and reimbursement because of their primarily nosocomial nature. Therefore, a thorough understanding of factors associated with, and clinical implications of, C. difficile colitis after common surgical procedures is crucial. We used a large national database with postdischarge data to study the development of C. difficile colitis after hip fracture surgery in geriatric patients. The rate of C. difficile colitis after surgery was approximately one in 100 patients. Preoperative factors associated with postoperative C. difficile colitis were admission from a nursing home or care facility, current smoking within 1 year, and preoperative anemia. While pneumonia, sepsis, or “any infection” were postoperative infectious factors associated with the development of C. difficile colitis, the majority of patients, 79% (58 of 73 patients), had C. difficile colitis develop in the absence of postoperative infections that would have prompted postoperative antibiotic use.

The main limitation of the current study is the absence of data regarding perioperative antibiotic type and duration, which are known risk factors for developing C. difficile colitis [31, 38]. To try to account for the degree of postoperative antibiotic use, we used surrogate measures. For instance, postoperative pneumonia, sepsis, and "any infection" likely were closely tied to longer and more intensive use of antibiotics after surgery. However, the current study could not provide any insight into prophylactic antibiotic use. Future studies should investigate this important issue by performing interrupted time series analyses to assess the effects of different prophylactic antibiotic regimens (type, duration, and dose) on incidence of postoperative C. difficile colitis. The second limitation of the current study pertains to the study design, which may introduce certain biases. First, because some patients had missing data regarding postoperative C. difficile colitis, there is some concern for selection bias. However, the reason for these missing data was most likely because NSQIP participating institutions only started collecting these data for patients admitted during the third or fourth quarter of 2015. Therefore, selection bias here was thought to be minimal as missing data were not targeted toward a certain patient group. Second, because some patients had missing preoperative and procedural data, there is some concern for transfer bias. However, most variables had a low degree of missing data and concern for transfer bias was minimal. The only variable with a high degree of missing data was preoperative albumin levels. Although, the current study did not identify preoperative albumin as being associated with postoperative C. difficile colitis, readers should interpret this result cautiously owing to the high degree of missing data for this variable. Finally, as with any database study, there is concern for assessment bias attributable to coding errors. However, the NSQIP database undergoes routine auditing, with reported interrater disagreement rates less than 2% for all variables assessed [2, 12]. Additional limitations of the current study are those of the NSQIP database. These include followup data for only 30 days, the lack of clinical outcomes, the lack of quality outcome measures, and the lack of details regarding providers from whom each patient may have received care.

The incidences of C. difficile colitis after other orthopaedic surgical procedures range from 0.07% to 17% [10, 18, 26, 36, 37]. However, after hip fracture surgery, the rate of C. difficile colitis has been reported to be as much as 7.1% [18, 36]. We found an overall 30-day postoperative incidence of approximately 1% (73 of 6928 patients), which is lower than those reported in previous hip fracture studies [18, 36] but higher than those reported after other orthopaedic procedures [18, 26, 36, 37]. This difference from the previously reported higher number might be related to the strict definition of C. difficile colitis used by NSQIP (see Appendix, Supplemental Digital Content), the followup being limited to 30 postoperative days, or the different patient population in previous studies, which included only patients from the United Kingdom. In addition, we found that only 36% (26 of 73) of patients with C. difficile colitis are diagnosed during the index hospitalization. This result is in line with findings from a recent nationwide surveillance study in the United States, which showed that the majority of healthcare-associated C. difficile infections occurred after hospital discharge [23]. Based on these findings, orthopaedic surgeons should be vigilant for the occurrence of C. difficile colitis in patients at high risk through the entire postoperative period.

Patients at high risk identified in the current study include those who were admitted from any type of chronic care facility, who were current smokers within 1 year, or who had preoperative anemia. Transfer from a nursing home and current smoker status have been linked to development of C. difficile infection in other patient populations [33, 34]. The association between preoperative anemia and C. difficile colitis has been studied less but has been described in case reports [14]. These findings may help clinicians establish a high-risk subcohort. In addition to identifying preoperative factors, the current study also established postoperative infections as factors associated with development of C. difficile colitis. These infections included pneumonia, sepsis, or the aggregated infection variable “any infection”. Postoperative infections are thought to lead to later C. difficile colitis through the use of antibiotics to manage the initial infection, which can cause an environment for C. difficile overgrowth [27]. Particular antibiotic classes, such as fluoroquinolones and cephalosporins, are associated with a marked increased risk for development of C. difficile colitis [31, 38]. When treating patients who were shown in the current study to be at high risk for C. difficile colitis, surgeons should strive to avoid the use of antibiotics known to predispose to development of C. difficile colitis to avoid compounding the risk.

Geriatric patients who had C. difficile colitis develop after hip fracture surgery had an increased length of hospital stay, higher rate of 30-day readmission, and higher rate of 30-day mortality. The link between increased length of stay and C. difficile infections has been extensively investigated [1, 15, 44]. However, the causality in the relationship between length of stay and C. difficile infection must be interpreted carefully, as the increased length of stay can be a risk factor for and a consequence of C. difficile infection. The associations with length of stay, readmission, and mortality have important implications in the current environment of bundled payments, quality improvement, and hospital metric comparisons [8, 32].

C. difficile colitis occurs in one of 100 geriatric patients undergoing surgery for hip fracture. Intriguingly, 64% (47 of 73 patients) of C. difficile colitis diagnoses occurred after discharge from the hospital and 79% (58 of 73 patients) occurred in patients without any prior infectious diagnosis. The preoperative factors associated with the development of C. difficile colitis include admission from any type of chronic care facility, current smoker within 1 year, and preoperative anemia. Associated postoperative infectious factors include pneumonia, sepsis, or “any infection”. Given the severe morbidity and mortality associated with these infections, patients at high risk should be targeted with preventative measures. From previous studies, these measures include implementing early case finding methodologies and rapid initiation of appropriate therapy, preventing placement of patients at high risk in the same room as patients who are C. difficile-positive, and enforcing strict hand hygiene with soap and water (not alcohol sanitizers) if caring for patients at high risk and those who are C. difficile-positive [9, 29, 41]. Further, other studies have shown that certain antibiotics, such as fluoroquinolones and cephalosporins, can predispose patients to C. difficile colitis [31, 38]. These medications perhaps should be avoided when prescribing prophylactic antibiotics or managing infections in patients at high risk. Future prospective studies should aim to determine the best prophylactic antibiotic regimens, probiotic formula, and discharge timing that minimize postoperative C. difficile colitis in patients with hip fractures.

Footnotes

One of the authors certifies that he (DDB), or a member of his immediate family, has or may receive payments or benefits, during the study period: an amount of less than USD 10,000 from Mid-America Orthopaedic Association (Rochester, MN, USA) and an amount of less than USD 10,000 from Cervical Spine Research Society (Rosemont, IL, USA), all outside the submitted work.

One of the authors certifies that he (JNG), or a member of his immediate family, has or may receive payments or benefits, during the study period an amount of less than $10,000 from Andante Medical Services (White Plains, NY, USA), an amount of USD 10,000 to USD100,000 from ISTO Technologies (St Louis, MO, USA), an amount of less than USD 10,000 from Vertex (Boston, MA, USA), an amount of less than USD 10,000 from Medtronic (Minneapolis, MN, USA), an amount of USD 10,000 to USD 100,000 from Bioventus (Durham, NC, USA), and an amount of USD 10,000 to USD 100,000 from Stryker (Kalamazoo, MI, USA), and an amount of less than USD 10,000 from the Orthopaedic Trauma Association(Rosemont, IL, USA), all outside the submitted work.

One of the authors certifies that he (DN), or a member of his immediate family, has or may receive payments or benefits, during the study period an amount of less than USD 10,000 from Acelity Inc (San Antonio, TX, USA), an amount of less than USD 10,000 from Zimmer-Biomet Inc (Warsaw, IN, USA), an amount of less than USD 10,000 from Heron Therapeutics (Redwood City, CA, USA), and an amount of less than USD 10,000 from Stryker (Kalamazoo, MI, USA), all outside the submitted work.

One of the authors certifies that he (CJD), or a member of his immediate family, has or may receive payments or benefits, during the study period an amount of USD 10,000 to USD 100,000 from Depuy Orthopaedics Inc (Raynham, MA, USA), an amount USD 10,000 to USD 100,000 from Smith & Nephew (Jericho, NY, USA), an amount USD 10,000 to USD 100,000 from Zimmer-Biomet (Warsaw, IN, USA), an amount USD 10,000 to USD 100,000 from CD Diagnostics (Claymont, DE , USA), an amount of less than USD 10,000 from SLACK Inc (Thorofare, NJ, USA), and an amount of less than USD 10,000 from Wolters Kluwer (Alphen aan den Rijn, Netherlands), all outside the submitted work.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Each author certifies that his institution waived approval for the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.

This work was performed at the Yale School of Medicine (New Haven, CT, USA) and Rush University Medical Center (Chicago, IL, USA).

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