Efficacy of Peri-Incisional Multimodal Drug Injection Following Operative Management of Femur Fractures

The purpose of this study is to determine the efficacy and safety of a peri-incisional
multimodal injection for post-operative pain control following operative management of femur
fractures. Patients will be identified by way of direct presentation to the orthopaedic
trauma service with an acute femur fracture. If the patient meets the parameters for study
enrollment (inclusion/exclusion criteria) the patient will be approached for introduction of
the study by a member of the surgical team. If the patient is agreeable to study enrollment,
he/she will have to complete the written informed consent process. This study protocol has
received formal approval from the University of Iowa Institutional Review Board.

The study design is a prospective, randomized, double-blind comparative trial. Patients will
be randomly assigned to the two treatment groups: peri-incisional multimodal injection and
control (no injection). In order to create balanced cohorts with respect to intervention,
randomization will be completed in a block format across six discrete surgical techniques:
proximal femur open reduction and internal fixation (dynamic hip screw, trochanteric
stabilizing plate), distal femur open reduction and internal fixation (lateral peri-articular
locking plate), cephalomedullary fixation, other intramedullary fixation (antegrade or
retrograde intramedullary device without fixed angle construct into the femoral head),
percutaneous fixation, and arthroplasty (hemiarthroplasty or total hip arthroplasty).
Randomization will be performed with use of Microsoft Excel (Microsoft, Redmond, Washington)
to generate random numbers. The patients enrolled in the investigation as well as the nursing
staff performing the post-operative assessments are blinded to treatment allocation.

Each patient will be treated with standard of care techniques chosen by the treating surgeon
regardless of whether or not the patient decides to enroll in the study. Written informed
consent will be obtained for the surgical procedure in addition to and independent from the
study consent. All surgical procedures will be completed under general anesthesia. No spinal,
regional, or preemptive anesthesia/analgesic regimen will be employed per study protocol.
Surgical drain placement and pharmacologic venous thromboembolism prophylaxis will not be
standardized. Post-operative pain management will continue per the institutional standard of
care with a combination of intravenous and oral narcotic analgesia. The post-operative pain
regimen will not be specified nor altered by the study protocol.

Patients randomized to the peri-incisional injection cohort will receive a single
intra-operative injection while the subject is under general anesthesia following completion
of fracture fixation/instrumentation. The local anesthetic cocktail includes 400 mg of 0.75%
ropivacaine (53.33 mL), 0.6 mg of 1 mg/mL epinephrine (0.6 mL), 5 mg of 0.5 mg/mL morphine
sulfate (10 mL), and 36.07 mL 0.9% sodium chloride solution. All pharmacologic agents in the
anesthetic cocktail are FDA approved. For intra-articular proximal femur procedures the
cocktail will be evenly distributed between the deep (synovium, capsule, periosteum, gluteus
musculature) and superficial (fascia lata, vastus lateralis, subcutaneous plane) tissues
prior to wound closure. The same pattern will be followed for extra-articular proximal femur
procedures without direct injection of the synovium and capsule. The injection will be
similarly distributed between the deep (synovium, capsule, periosteum) and superficial
(quadriceps musculature, subcutaneous plane) tissues prior to wound closure for distal femur
procedures. Injections for intramedullary nails will be placed around the nail entry site
into bone and into the superficial tissues at both the entry site and cross lock locations.
All infiltrations will be completed with a blunt trochar to minimize the risk of
intravascular injection.

The primary outcome is visual analog pain scores over the first two post-operative days.
Patients will be instructed to use a 10-cm visual analog scale to describe their current
level of comfort with end points of zero corresponding to "no pain" and ten corresponding to
"the most extreme possible pain." Pain assessments will be completed while patients are at
rest at standardized intervals immediately prior to surgery, in the post-anesthesia care unit
(captured as the mean of all individual data points), and every 4 hours following surgery for
the first two post-operative days. Visual analog pain scores are collected and charted by
nursing staff on the inpatient ward. All nursing staff will remain blinded to the treatment
allocation. Physician staff that have knowledge of the intra-operative treatment and
randomization are not involved in recording any outcome measures.

The secondary outcome measures are total narcotic consumption, wound complications, and
drug-related side effects. Narcotic consumption will be recorded every eight hours for the
first two post-operative days and transformed into narcotic equivalents. Every fifteen
minutes in the post-anesthesia care unit and every four hours for the first two
post-operative days nursing personnel will monitor the patients via direct observation and
query for medication side effects related to ropivacaine toxicity including blurred vision,
hearing problems, transient peripheral paralysis, dizziness, convulsion, uncontrolled muscle
contraction, hypotension, bradycardia, and new onset arrhythmia. Anesthesiology staff will
also perform two standardized post-operative assessments in the recovery room and on the
first post-operative day to screen for adverse effects related to the injection.

An a priori power analysis was completed for sample size determination for the primary
outcome measure. A preliminary retrospective analysis revealed a standard deviation of 2.5 on
the visual analog pain scale twelve hours following surgery (unpublished data). Prior
literature has suggested that a change of 1.0-1.3 points on the visual analog scale is
clinically significant. Therefore, the investigators determined a total of 44 patients were
required per study group in order to detect a 1.5 point difference on the visual analog scale
with a power of 80% and a P-value of 0.05. The Student t test and the chi-squared test of
association will be used to compare continuous and categorical variables between the two
groups, respectively. Statistical significance is defined as p <0.05.

Patient confidentiality will be maintained at all times. Only approved research team
personnel will review the medical records. Only the minimal data necessary to answer the
research questions will be obtained. Collected electronic data will be stored on password
protected servers. Written informed consent documents will be stored in a locked filing
cabinet in the Department of Orthopaedics and Rehabilitation at the University of Iowa
Hospitals and Clinics. Upon publication and completion of data analysis all information with
patient identifiers will be destroyed.

Inclusion Criteria:

- Patients who sustained an acute femur fracture in any anatomic region (subcapital,
basicervical, intertrochanteric, subtrochanteric, diaphyseal, distal metaphyseal, or
distal articular)

- Age ≥18 years

- Indicated for definitive operative management at a single Level 1 trauma center

Exclusion Criteria:

- Revision procedures

- Temporizing procedures (irrigation and debridement, external fixation)

- Regular narcotic use

- Psychiatric illness

- Dementia

- Neuromuscular deficit

- Allergy/intolerance to cocktail ingredients

- Clinical status that precludes verbal pain assessment (e.g. major intracranial trauma)

- Refusal to participate