Surgical Site Infection, Unplanned Fracture-Related Reoperation, Open Appendicular Fracture, Closed Lower Extremity Fracture, Pelvic Fracture
Conditions
Keywords
Surgical Site Infection, Open Fracture, Lower Extremity Fracture, Pelvis; Fracture, DuraPrep, ChloraPrep, Peri-operative Preparation Solutions
Brief summary
The prevention of infection is an important goal influencing peri-operative care of extremity fracture patients. Standard practice in the operative management of extremity fractures includes sterile technique and pre-operative skin preparation with an antiseptic solution. The available solutions kill bacteria and decrease the quantity of native skin flora, thereby decreasing surgical site infection (SSI). While there is extensive guidance on specific procedures for prophylactic antibiotic use and standards for sterile technique, the evidence regarding the choice of antiseptic skin preparation solution is very limited for extremity fracture surgery.
Detailed description
More than one million Americans suffer an extremity fracture (broken bone in the arm, leg, or pelvis) that requires surgery each year. Approximately 5% (or 50,000) of surgical fracture patients develop a surgical site infection (SSI), which is twice the rate among most surgical patients and nearly five times the rate among patients undergoing elective orthopaedic surgeries (e.g. joint replacement). Patients who develop a SSI after their fracture fixation surgery experience a long and difficult treatment pathway. Researchers have identified that when a fracture patient experiences a SSI, they typically undergo at least two additional surgeries to control the infection, spend a median of 14 additional days in the hospital, and have significantly lower health related quality of life (HRQL). Similarly, results from the recently completed Fluid Lavage of Open Wounds (FLOW) trial confirmed that patients who had a SSI, or another complication, that required an additional surgery reported significantly lower physical and mental HRQL in the 12 months following their fracture compared to patients who did not experience a SSI. In the most severe cases, when a SSI cannot be controlled, a limb amputation becomes necessary. Open fractures, closed lower extremity fractures, and pelvic fractures represent some of the most severe musculoskeletal injuries. Due to their high-energy mechanisms, these fractures are often accompanied by soft-tissue injuries that contribute to unacceptably poor outcomes. The FLOW trial of 2,447 open fracture patients reported a 13.2% incidence of open fracture-related reoperations; Closed fractures of the lower extremity are also at high risk of complications, particularly when compared to closed upper extremity fractures. For example, the rate of SSI in closed tibial plateau and plafond fractures range from 5.6 - 11.9%, although some cohort studies have reported infection rates as high as 25.0%. This is contrast with SSI rates of \<5% for common upper extremity fractures like humeral shaft, forearm, or distal radius fractures. This is further illustrated in a series of 214 deep orthopaedic fracture infections, in which 58% occurred in the tibia and ankle, and only 10% occurred anywhere in the upper extremity. Finally, pelvic fractures are associated with some of the most challenging SSIs to treat among closed fractures because of their propensity to gram negative organisms and limitations in reconstruction options post-infection. Ultimately, infectious complications in these fracture populations lead to prolonged morbidity, loss of function, and potential limb loss.
Interventions
DRUGDuraPrep
The iodine-based treatment intervention is an antiseptic solution comprised of iodine povacrylex (0.7% free iodine) in 74% isopropyl alcohol. 3M™ DuraPrep™ \[3M Health Care, St Paul, MN\], will be the commercial product used.
DRUGChloraPrep
The CHG intervention is an antiseptic solution comprised of 2% CHG in 70% isopropyl alcohol. ChloraPrep® \[CareFusion Inc., Leawood, KS, USA\] will be the product used.
Sponsors
McMaster University
Patient-Centered Outcomes Research Institute
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The orthopaedic team (including the study coordinators) cannot be blinded to the treatment allocation as the antiseptic solutions are visually distinguishable and these individuals need to lead the implementation of the cluster-crossover protocol at their clinical site. The Adjudication Committee Members and data analysts will be blinded to the study treatment. All interpretation of study results will initially be done in a blinded manner by developing two interpretations of the results. One interpretation will assume treatment A is iodine povacrylex, the other interpretation will assume it is CHG. Once the data interpretations for each assumption are finalized, the data will be unblinded and the correct interpretation will be accepted.
Intervention model description
Treatment allocation will be determined using a cluster-randomized crossover trial design. The open and closed fracture populations will be treated with the same allocated solution at all times during the trial. The order of treatment allocation for each orthopaedic practice will be randomly assigned using a computer-generated randomization table. Each site will start with the initially allocated study solution and eventually crossover to the other solution for their second recruitment period. This process of alternating treatments will repeat approximately every 2 months as dictated by the initial randomization.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The open fracture inclusion criteria are: 1. Patients 18 years of age or older. 2. Open fracture of the appendicular skeleton. 3. Received or will receive definitive fracture treatment with a surgical implant(s) (i.e., internal fixation, external fixation, joint prosthesis, etc.). 4. Open fracture wound management that includes formal surgical debridement within 72 hours of their injury. 5. Will have all planned fracture care surgeries performed by a participating surgeon or delegate. 6. Informed consent obtained. 7. Patient enrolled within 3 weeks of their fracture. The open fracture
Exclusion criteria
are: 1. Fracture of the hand (distal to radial carpal joint). 2. Patients who did not or will not receive the allocated pre-operative surgical preparation solution due to a medical contraindication. 3. Received previous surgical debridement or management of their fracture at a nonparticipating hospital or clinic (as applicable). 4. Open fracture managed outside of the participating orthopaedic service (e.g., foot fracture managed by podiatrist). 5. Chronic or acute infection at or near the fracture site at the time of initial fracture surgery. 6. Burns at the fracture site. 7. Incarceration. 8. Expected injury survival of less than 90 days. 9. Terminal illness with expected survival less than 90 days. 10. Currently enrolled in a study that does not permit co-enrollment. 11. Unable to obtain informed consent due to language barriers. 12. Likely problems, in the judgment of study personnel, with maintaining follow-up with the patient. 13. Prior or current enrollment in a PREP-IT trial. 14. Enrolled in the PREPARE closed cohort. 15. Excluded due to sampling strategy. The closed fracture inclusion criteria are: 1. Patients 18 years of age or older. 2. Closed fracture of the lower extremity or pelvis. 3. Received or will receive definitive fracture treatment with a surgical implant(s) (i.e., internal fixation, external fixation, joint prosthesis, etc.). 4. Fracture management requires a surgical incision (i.e., for fracture reduction or implant insertion). 5. Will have all planned fracture care surgeries performed by a participating surgeon or delegate. 6. Informed consent obtained. 7. Patient enrolled within 6 weeks of their fracture. The closed fracture
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Superficial Incisional Surgical Site Infection (SSI) | Within 30 days of the patient's last planned fracture management surgery | Guided by the Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network reporting criteria (2017): Date of event for infection may occur from the date of fracture to 30 days after the definitive fracture management surgery; AND involves only skin and subcutaneous tissue of the incision; AND patient has at least one of the following: 1. purulent drainage from the superficial incision. 2. organisms identified from an aseptically obtained specimen from the superficial incision or subcutaneous tissue by a culture or non-culture based microbiologic testing method which is performed for purposes of clinical diagnosis or treatment 3. superficial incision that is deliberately opened by a surgeon, and culture or non-culture-based testing is not performed. AND patient has at least one of the following signs or symptoms: pain or tenderness; localized swelling; erythema; or heat. 4. diagnosis of a superficial incisional SSI by the surgeon. |
| Number of Participants With a Deep Incisional Infection | Within 90 days of the patient's last planned fracture management surgery | Guided by CDC's National Healthcare Safety Network Surgical Site Infection reporting criteria (2017): Deep Incisional Infection: Occurs within 90 days post definitive fracture management; & involves fascial/muscle layers; & has at least one of the following: 1. deep incision purulent drainage 2. a deep incision that dehisces, or is opened by a surgeon, and organism is identified by microbiologic testing; or microbiologic testing is not performed & has at least one of the following: fever (\> 38 °C); localized pain or tenderness 3. other evidence of deep incision infection on anatomical exam or imaging test |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Unplanned Fracture-Related Reoperation | Within 12 months of the patient's last planned operation | Common examples include any unplanned fracture-related surgery that is associated with an infection at the operative site or contiguous to it, a wound-healing problem, or a fracture delayed union or non-union. |
Countries
Canada, United States
Participant flow
Recruitment details
Recruitment occurred between August 21, 2018, and March 18, 2023 at 25 hospitals in the United States and Canada. Of these hospitals, 20 recruited patients with either open or closed fractures; 3 hospitals recruited patients with closed fractures only, and 2 recruited those with open fractures only.
Pre-assignment details
To ensure wide generalizability to routine practice, the protocol allowed prewashing of the operative extremity with alcohol or other antiseptics before performing the final skin antisepsis with the study solution. In addition to ensuring trial feasibility and protocol adherence, this decision pragmatically allowed the intact skin to receive mechanical scrubbing or partial alcohol antisepsis at the treating surgeon's discretion.
Participants by arm
| Arm | Count |
|---|---|
| Closed-Fracture Population Iodine Group The closed-fracture population consisted of adults (≥18 years old) who were undergoing surgical fixation of a closed lower-limb or pelvic fracture. We excluded patients who had a concurrent open fracture, had a medical contraindication to receive either trial intervention, or had a chronic or acute infection at or near the fracture site at the time of the index surgery.
The iodine-based treatment intervention is an antiseptic solution comprised of iodine povacrylex (0.7% free iodine) in 74% isopropyl alcohol. 3M™ DuraPrep™ \[3M Health Care, St Paul, MN\], will be the commercial product used. | 3,360 |
| Closed-Fracture Population Chlorhexidine Group The closed-fracture population consisted of adults (≥18 years old) who were undergoing surgical fixation of a closed lower-limb or pelvic fracture. We excluded patients who had a concurrent open fracture, had a medical contraindication to receive either trial intervention, or had a chronic or acute infection at or near the fracture site at the time of the index surgery.
The CHG intervention is an antiseptic solution comprised of 2% CHG in 70% isopropyl alcohol. ChloraPrep® \[CareFusion Inc., Leawood, KS, USA\] will be the product used. | 3,425 |
| Open-Fracture Population Iodine Group The open-fracture population consisted of adults (≥18 years old) who had an open upper-limb or lower-limb fracture warranting surgical fixation. In addition, the patient's open fracture must have received surgical débridement within 72 hours after injury. We excluded patients with open fractures of the hand and those who had received previous surgical debridement at a nonparticipating hospital.
The iodine-based treatment intervention is an antiseptic solution comprised of iodine povacrylex (0.7% free iodine) in 74% isopropyl alcohol. 3M™ DuraPrep™ \[3M Health Care, St Paul, MN\], will be the commercial product used. | 854 |
| Open-Fracture Population Chlorhexidine Group The open-fracture population consisted of adults (≥18 years old) who had an open upper-limb or lower-limb fracture warranting surgical fixation. In addition, the patient's open fracture must have received surgical débridement within 72 hours after injury. We excluded patients with open fractures of the hand and those who had received previous surgical debridement at a nonparticipating hospital.
The CHG intervention is an antiseptic solution comprised of 2% CHG in 70% isopropyl alcohol. ChloraPrep® \[CareFusion Inc., Leawood, KS, USA\] will be the product used. | 846 |
| Total | 8,485 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Closed Fractures | Death | 86 | 71 | 0 | 0 |
| Closed Fractures | Incarceration | 1 | 4 | 0 | 0 |
| Closed Fractures | Lost to Follow-up | 62 | 36 | 0 | 0 |
| Closed Fractures | Withdrawal by Subject | 19 | 29 | 0 | 0 |
| Open Fractures | Death | 0 | 0 | 11 | 6 |
| Open Fractures | Incarceration | 0 | 0 | 1 | 0 |
| Open Fractures | Lost to Follow-up | 0 | 0 | 15 | 8 |
| Open Fractures | Withdrawal by Subject | 0 | 0 | 6 | 2 |
Baseline characteristics
| Characteristic | Closed-Fracture Population Chlorhexidine Group | Total | Open-Fracture Population Chlorhexidine Group | Closed-Fracture Population Iodine Group | Open-Fracture Population Iodine Group |
|---|---|---|---|---|---|
| Age, Continuous | 53.6 years STANDARD_DEVIATION 20.4 | 47.0 years STANDARD_DEVIATION 19.3 | 44.2 years STANDARD_DEVIATION 18.1 | 45.3 years STANDARD_DEVIATION 20.2 | 45.0 years STANDARD_DEVIATION 18.3 |
| American Society of Anesthesiologist (ASA) Physical Score Class III or higher | 1673 Participants | 4070 Participants | 383 Participants | 1600 Participants | 414 Participants |
| American Society of Anesthesiologist (ASA) Physical Score Class I or II | 1752 Participants | 4415 Participants | 463 Participants | 1760 Participants | 440 Participants |
| BMI Healthy weight (18.5 - 24.9 kg/m^2) | 1106 Participants | 2676 Participants | 250 Participants | 1068 Participants | 252 Participants |
| BMI Obesity (>30.0 kg/m^2) | 1215 Participants | 2926 Participants | 289 Participants | 1111 Participants | 311 Participants |
| BMI Overweight (25.0-29.9 kg/m^2) | 1024 Participants | 2679 Participants | 294 Participants | 1082 Participants | 279 Participants |
| BMI Underweight (<18.5 kg/m^2) | 80 Participants | 204 Participants | 13 Participants | 99 Participants | 12 Participants |
| Current smoker | 722 Participants | 2046 Participants | 282 Participants | 753 Participants | 289 Participants |
| Diabetes of any type | 445 Participants | 1059 Participants | 64 Participants | 470 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 181 Participants | 463 Participants | 47 Participants | 170 Participants | 65 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3244 Participants | 8022 Participants | 799 Participants | 3190 Participants | 789 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Injury Severity Score (ISS) | 8.9 units on a scale STANDARD_DEVIATION 6.2 | 11.1 units on a scale STANDARD_DEVIATION 7.2 | 12.9 units on a scale STANDARD_DEVIATION 8 | 9.0 units on a scale STANDARD_DEVIATION 6.2 | 13.4 units on a scale STANDARD_DEVIATION 8.5 |
| Number of included fractures per participant One | 3240 Participants | 7962 Participants | 771 Participants | 3169 Participants | 782 Participants |
| Number of included fractures per participant Three | 23 Participants | 65 Participants | 7 Participants | 25 Participants | 10 Participants |
| Number of included fractures per participant Two | 162 Participants | 458 Participants | 68 Participants | 166 Participants | 62 Participants |
| Race/Ethnicity, Customized Race Asian | 147 Participants | 326 Participants | 17 Participants | 140 Participants | 22 Participants |
| Race/Ethnicity, Customized Race Black | 480 Participants | 1422 Participants | 214 Participants | 501 Participants | 227 Participants |
| Race/Ethnicity, Customized Race Central or South American | 7 Participants | 14 Participants | 1 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Indigenous | 33 Participants | 81 Participants | 12 Participants | 27 Participants | 9 Participants |
| Race/Ethnicity, Customized Race Missing Data | 43 Participants | 88 Participants | 8 Participants | 30 Participants | 7 Participants |
| Race/Ethnicity, Customized Race Multiracial | 4 Participants | 13 Participants | 4 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 5 Participants | 10 Participants | 1 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 2706 Participants | 6531 Participants | 589 Participants | 2652 Participants | 584 Participants |
| Sex/Gender, Customized Sex Female | 1739 Participants | 4090 Participants | 309 Participants | 1730 Participants | 312 Participants |
| Sex/Gender, Customized Sex Male | 1686 Participants | 4394 Participants | 537 Participants | 1629 Participants | 542 Participants |
| Sex/Gender, Customized Sex Missing Data | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 145 / 3,360 | 140 / 3,425 | 13 / 854 | 13 / 846 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 1,177 / 3,360 | 1,212 / 3,425 | 430 / 854 | 368 / 846 |
Outcome results
Primary
Number of Participants With a Deep Incisional Infection
Guided by CDC's National Healthcare Safety Network Surgical Site Infection reporting criteria (2017): Deep Incisional Infection: Occurs within 90 days post definitive fracture management; & involves fascial/muscle layers; & has at least one of the following: 1. deep incision purulent drainage 2. a deep incision that dehisces, or is opened by a surgeon, and organism is identified by microbiologic testing; or microbiologic testing is not performed & has at least one of the following: fever (\> 38 °C); localized pain or tenderness 3. other evidence of deep incision infection on anatomical exam or imaging test
Time frame: Within 90 days of the patient's last planned fracture management surgery
Population: Outcome data for surgical-site infection were missing for 4.5% of the patients in the closed-fracture population and for 2.8% of those in the open-fracture population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Closed-Fracture Population Iodine Group | Number of Participants With a Deep Incisional Infection | 29 Participants |
| Closed-Fracture Population Chlorhexidine Group | Number of Participants With a Deep Incisional Infection | 54 Participants |
| Open-Fracture Population Iodine Group | Number of Participants With a Deep Incisional Infection | 21 Participants |
| Open-Fracture Population Chlorhexidine Group | Number of Participants With a Deep Incisional Infection | 20 Participants |
Primary
Number of Participants With a Superficial Incisional Surgical Site Infection (SSI)
Guided by the Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network reporting criteria (2017): Date of event for infection may occur from the date of fracture to 30 days after the definitive fracture management surgery; AND involves only skin and subcutaneous tissue of the incision; AND patient has at least one of the following: 1. purulent drainage from the superficial incision. 2. organisms identified from an aseptically obtained specimen from the superficial incision or subcutaneous tissue by a culture or non-culture based microbiologic testing method which is performed for purposes of clinical diagnosis or treatment 3. superficial incision that is deliberately opened by a surgeon, and culture or non-culture-based testing is not performed. AND patient has at least one of the following signs or symptoms: pain or tenderness; localized swelling; erythema; or heat. 4. diagnosis of a superficial incisional SSI by the surgeon.
Time frame: Within 30 days of the patient's last planned fracture management surgery
Population: Outcome data for surgical-site infection were missing for 4.5% of the patients in the closed-fracture population and for 2.8% of those in the open-fracture population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Closed-Fracture Population Iodine Group | Number of Participants With a Superficial Incisional Surgical Site Infection (SSI) | 20 Participants |
| Closed-Fracture Population Chlorhexidine Group | Number of Participants With a Superficial Incisional Surgical Site Infection (SSI) | 27 Participants |
| Open-Fracture Population Iodine Group | Number of Participants With a Superficial Incisional Surgical Site Infection (SSI) | 6 Participants |
| Open-Fracture Population Chlorhexidine Group | Number of Participants With a Superficial Incisional Surgical Site Infection (SSI) | 9 Participants |
Secondary
Number of Participants With an Unplanned Fracture-Related Reoperation
Common examples include any unplanned fracture-related surgery that is associated with an infection at the operative site or contiguous to it, a wound-healing problem, or a fracture delayed union or non-union.
Time frame: Within 12 months of the patient's last planned operation
Population: Primary and secondary outcomes were evaluated using a complete case analysis. For that reason, the overall number of participants analyzed differs from the numbers provided under the Participant Flow module.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Closed-Fracture Population Iodine Group | Number of Participants With an Unplanned Fracture-Related Reoperation | 164 Participants |
| Closed-Fracture Population Chlorhexidine Group | Number of Participants With an Unplanned Fracture-Related Reoperation | 179 Participants |
| Open-Fracture Population Iodine Group | Number of Participants With an Unplanned Fracture-Related Reoperation | 126 Participants |
| Open-Fracture Population Chlorhexidine Group | Number of Participants With an Unplanned Fracture-Related Reoperation | 114 Participants |