Efficacy of Surgical-Site, Multimodal Drug Injection Following Operative Management of Femoral Fractures: A Randomized Controlled Trial

Koehler, Daniel MD; Marsh, J. Lawrence MD; Karam, Matthew MD; Fruehling, Catherine MA; Willey, Michael MD

Journal of Bone & Joint Surgery - American Volume:
doi: 10.2106/JBJS.16.00733
Scientific Articles

Background: Multimodal analgesia inclusive of periarticular injection with a local anesthetic agent has been rapidly assimilated, with demonstrated safety and efficacy, into the care of patients undergoing elective lower-extremity arthroplasty. The present study was performed to evaluate the efficacy and safety of a surgical-site, multimodal drug injection for postoperative pain control following operative management of femoral fractures.

Methods: There were 102 patients undergoing operative intervention (plate fixation, intramedullary device, or arthroplasty) for a broad range of femoral fracture patterns who were prospectively randomized either to receive an intraoperative, surgical-site injection into the superficial and deep tissues containing ropivacaine, epinephrine, and morphine or to receive no injection. Visual analog scale (VAS) scores were recorded at regular intervals as the primary outcome measure. Narcotic consumption and medication-related side effects were also monitored.

Results: The injection group demonstrated significantly lower VAS scores (p < 0.05) than the control cohort in the recovery room and at the 4, 8, and 12-hour postoperative time points. The median score (and interquartile range) was 1.6 (0 to 4.0) for the injection group and 3.2 (1.3 to 5.7) for the control group immediately postoperatively, 1.0 (0 to 3.0) for the injection group and 5.0 (2.0 to 7.0) for the control group at 4 hours, 2.0 (0 to 4.0) for the injection group and 5.0 (2.0 to 6.8) for the control group at 8 hours, and 3.5 (0 to 5.0) for the injection group and 5.0 (2.0 to 8.0) for the control group at 12 hours. Additionally, narcotic consumption was significantly lower (p = 0.007) in the injection group (5.0 mg [1.3 to 8.0 mg]) compared with the control group (9.7 mg [3.9 to 15.6 mg]) over the first 8 hours following the surgical procedure. No cardiac or central nervous system toxicity was observed secondary to infiltration of the local anesthetic.

Conclusions: Surgical-site injection with a multimodal analgesic cocktail provides improved pain control and reduces narcotic utilization over the first postoperative day, with no observed adverse effects attributable to the local injection, across a diverse orthopaedic trauma population undergoing operative intervention for femoral fractures.

Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Author Information

1Department of Orthopaedic Surgery and Rehabilitation, University of Iowa Hospitals and Clinics, Iowa City, Iowa

E-mail address for D. Koehler: daniel-koehler@uiowa.edu

Article Outline

Although new techniques of multimodal pain management have been developed for many elective musculoskeletal surgical procedures1-20, these analgesic protocols have been incompletely integrated into the care of patients with orthopaedic trauma21-25. Perioperative pain management following femoral fractures continues to follow traditional analgesic protocols that heavily depend on parenteral narcotic administration despite notable adverse effects including nausea, emesis, pruritus, constipation, ileus, urinary retention, confusion, altered mental status, somnolence, respiratory depression, and risk of dependency26-28.

Optimally, an analgesic regimen should have minimal adverse effects, should limit pain at its site of origin, and should maintain muscle control to allow for early postoperative mobilization. Periarticular injection utilizing local anesthetics has recently been supported in the lower-extremity arthroplasty literature as a means of accomplishing these objectives1,2,4-8,10-12,14-20. Local anesthetics block pain conduction at the peripheral site of infiltration and avoid many of the side effects associated with systemic narcotic utilization29,30. Level-I therapeutic evidence from the lower-extremity arthroplasty literature has demonstrated this multimodal analgesic technique to be safe and effective and to result in reduced narcotic consumption in the early postoperative period1,2,10-12,15-18,20.

The objective of the present study was to assess the efficacy and safety of a surgical-site, multimodal drug injection following operative management of femoral fractures. Our hypothesis was that the injection cohort would demonstrate an improved pain profile and would utilize less parenteral narcotic analgesia in the early postoperative period.

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Materials and Methods


Subjects were patients who sustained a femoral fracture in any anatomic region (subcapital, basicervical, intertrochanteric, subtrochanteric, diaphyseal, distal metaphyseal, or distal articular), who were ≥18 years of age, and who were indicated for definitive operative management by one of three fellowship-trained orthopaedic traumatologists at a single Level-1 trauma center. Patients undergoing temporizing procedures, including irrigation and debridement and external fixation, were not considered for study enrollment. There were 104 consecutive patients, with an age range of 29 to 97 years, who underwent definitive surgical management of femoral fractures between May 2015 and May 2016 and were considered eligible. The exclusion criteria were revision procedures, regular narcotic use, psychiatric illness, dementia, neuromuscular deficit, medication allergy, end-stage renal or hepatic dysfunction, clinical status that precluded verbal pain assessment (e.g., major intracranial trauma), and unwillingness to participate. Patients who subsequently developed delirium after operative intervention were also excluded from the analysis because of an inability to collect quantified pain assessments. The study protocol was approved by the institutional review board, and all patients provided informed consent preoperatively. Consent was obtained by a physician member of the surgery team. The study was registered in the ClinicalTrials.gov Protocol Registration System (NCT02793947).

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Study Design

This study was a prospective, randomized controlled trial with 2 parallel arms. Patients were randomly assigned to the 2 treatment groups: surgical-site injection and control (no injection). To create balanced cohorts with respect to intervention, simple randomization was completed in a block format across 6 discrete surgical techniques: proximal femoral plate fixation (dynamic hip screw or trochanteric stabilizing plate), distal femoral plate fixation (lateral periarticular locking plate), cephalomedullary fixation, other intramedullary fixation (antegrade or retrograde intramedullary device), percutaneous fixation, and arthroplasty (hemiarthroplasty or total hip arthroplasty via posterior approach). Randomization was performed via Microsoft Excel to generate random numbers. Group allocations were made by a research associate who did not participate in study recruitment or outcomes assessments. Allocations were concealed on a password-protected database accessible only to the research associate and were revealed to the surgery team 1 hour before procedure commencement. The patients and the nursing staff who performed the postoperative assessments were blinded to treatment allocation.

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Surgical Procedure

All patients were treated with standard-of-care techniques chosen by the treating surgeon. Written consent was obtained for all patients prior to the surgical procedure. All patients had a general anesthetic; spinal anesthesia, regional anesthesia, and intraoperative administration of long-term narcotic analgesics were prohibited by study protocol. No preemptive scheduled analgesic regimen was employed. Suction drain placement and pharmacologic deep vein thrombosis prophylaxis were not standardized. Calf sequential compression devices were used for each patient. A combination of intravenous and oral agents was employed after the surgical procedure to maintain patient comfort. Intravenous analgesia was administered with use of a computerized patient-controlled analgesia system (morphine: 1-mg bolus, 10-minute lockout, no basal; hydromorphone: 0.1-mg bolus, 10-minute lockout, no basal). Patients were instructed by the nursing staff to push the patient-controlled analgesia button for moderate-severe pain (visual analog scale [VAS] ≥ 4). Titration of the patient-controlled analgesia parameters was permitted for inadequate pain control (VAS > 7). The decision to discontinue the pump was determined by the surgical team without standardized criteria. Oral analgesics were also available for postoperative pain control, including hydromorphone (2 to 4 mg every 4 hours), oxycodone (5 to 10 mg every 4 hours), hydrocodone and acetaminophen (5 and 500 mg, 1 to 2 doses every 4 hours), and acetaminophen (650 mg every 6 hours). Only a single oral narcotic analgesic was ordered in addition to acetaminophen. Nurses were instructed to offer this as-needed medication to patients at standardized intervals every 4 hours when performing pain assessments. Inpatient narcotic consumption was recorded as morphine equivalents and any side effects were documented1,10.

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Surgical-Site Injection Group

The local anesthetic cocktail totaling 100 mL was prepared by combining 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 of 0.9% sodium chloride solution. The intraoperative injection was performed while the patient was under general anesthesia following completion of fracture fixation and instrumentation. For hip arthroplasties, the cocktail was evenly distributed between the deep tissues (synovium, capsule, periosteum, gluteus musculature) and superficial tissues (fascia lata, vastus lateralis, subcutaneous plane) prior to wound closure. For non-arthroplasty procedures involving the proximal part of the femur, the injection was evenly distributed between the deep and superficial soft tissues in an extra-articular pattern without direct injection of the synovium or capsule. The injection was similarly distributed between the deep tissues (periosteum) and superficial tissues (quadriceps musculature, subcutaneous plane) prior to wound closure for distal femoral procedures, avoiding intra-articular placement. Injections for intramedullary nails were placed around the nail entry site into bone and into the superficial tissues (muscle, fascia, subcutaneous plane) at both the entry-site and cross-lock locations. The entire 100-mL volume was administered for all patients. All infiltrations were completed with a 16-gauge, spinal-length blunt-tipped trocar with a distal side port to minimize the risk of intravascular injection. Careful attention was paid to avoid injection in the area of the traversing major neurovascular bundles. Fluoroscopic assistance was not employed.

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Outcome Measures

The primary outcome was VAS scores over the first 2 postoperative days. Patients were instructed to use a 10-cm VAS to describe their current level of comfort, with end points of 0 corresponding to no pain and 10 corresponding to the most extreme possible pain. Pain assessments were completed while patients were at rest immediately prior to the surgical procedure, in the post-anesthesia care unit (captured as the mean of all individual data points), and every 4 hours following the surgical procedure for the first 48 hours. VAS scores were collected by nursing staff on the inpatient ward. All nursing staff remained blinded to the treatment allocation. Physician staff who had knowledge of the intraoperative randomization were not involved in recording any outcome measures.

The secondary outcome measures were total narcotic consumption, wound complications, and drug-related side effects. Narcotic consumption was recorded every 8 hours for the first 2 postoperative days and was transformed into narcotic equivalents according to a conversion table (Table I)31. Every 15 minutes in the post-anesthesia care unit and every 4 hours for the first 2 postoperative days, nursing personnel monitored 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 also performed 2 standardized postoperative assessments in the recovery room and on the first postoperative day to screen for adverse effects related to the injection. Delirium screening was performed by the primary physician team. Delirium was defined to be an acute confusional state representing a decline from baseline cognitive function with loss of orientation, disorganized characteristics, or psychotic features with fluctuating patterns of intensity32.

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Statistical Analysis

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 VAS 12 hours following the surgical procedure (unpublished data). Prior literature has suggested that a difference of 1.0 to 1.3 points on the VAS is clinically important33. Therefore, we determined that a total of 44 patients were required per group to detect a 1.5-point difference on the VAS (power = 80%, p = 0.05). The investigation concluded when the sample size goal was obtained. No interim analyses were performed.

For intergroup comparisons, the data distributions were tested for normality using the Shapiro-Wilk test. The primary and secondary outcome measures failed the assumption of normality and were analyzed with the Mann-Whitney U test, with results depicted as medians and interquartile ranges. The chi-square or Fisher exact test was used to analyze categorical descriptive variables, as appropriate. Significance was defined as p < 0.05.

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Of the 104 patients eligible for the study, 47 were randomized to the injection cohort, 55 were randomized to the control cohort, and 2 declined to participate. Seven patients (2 in the injection group and 5 in the control group) were excluded following randomization because of early postoperative mortality (n = 1) and postoperative delirium (n = 6) (Fig. 1). The single patient who experienced an early postoperative mortality was an 83-year-old man managed with a cephalomedullary nail for an intertrochanteric hip fracture who, via surrogate decision-makers, elected for compassionate withdrawal of care on postoperative day 1 following development of hypoxemic respiratory failure in the setting of congestive heart failure, bronchiectasis, and alpha-1-antitrypsin deficiency. The prevalence of delirium was 2.2% in the surgical-site injection cohort compared with 9.1% in the control cohort (p = 0.216). The remaining 95 subjects (30 men and 65 women) were included in the final analysis. There was no difference between the groups in any of the demographic characteristics including age, sex, weight, height, body mass index (BMI), American Society of Anesthesiologists (ASA) physical status classification34, smoking status, or surgical intervention (Table II).

The surgical-site injection group demonstrated significantly lower VAS scores than the control cohort at several postoperative time points; the median (and interquartile range) was 1.6 (0 to 4.0) for the injection group and 3.2 (1.3 to 5.7) for the control group in the recovery room (p = 0.017), 1.0 (0 to 3.0) for the injection group and 5.0 (2.0 to 7.0) for the control group at 4 hours (p < 0.0001), 2.0 (0 to 4.0) for the injection group and 5.0 (2.0 to 6.8) for the control group at 8 hours (p = 0.009), and 3.5 (0 to 5.0) for the injection group and 5.0 (2.0 to 8.0) for the control group at 12 hours (p = 0.027). The greatest discrepancy in pain outcomes between the 2 groups was reported at 4 hours postoperatively. Although no significant differences were appreciated over the remainder of the first postoperative day, the injection cohort also had significantly lower pain scores (p = 0.010) at 32 hours: 3.0 (1.0 to 4.0) for the injection group compared with 5.0 (3.0 to 6.0) for the control group (Fig. 2). The highest mean pain level (and standard deviation) for the injection group was at 20 hours after the surgical procedure (VAS, 4.1 ± 2.5) compared with 4 hours postoperatively for the control group (VAS, 4.9 ± 3.0).

Narcotic consumption in morphine equivalents from 0 to 8 hours was significantly lower (p = 0.007) for the injection group (5.0 mg [1.3 to 8.0 mg]) compared with the control group (9.7 mg [3.9 to 15.6 mg]). No other significant differences were appreciated over the following 8-hour intervals or with aggregate narcotic consumption over the first 2 postoperative days (28.0 mg [11.3 to 37.3 mg] compared with 34.8 mg [16.8 to 52.0 mg]; p = 0.072) (Fig. 3).

No cardiac or central nervous system toxicity was observed secondary to local infiltration of the anesthetic cocktail. There were no cases of transient peripheral nerve palsy affecting either the sciatic or common peroneal distributions. There were no patients who developed compartment syndrome or symptomatic pulmonary embolus. One wound complication was identified in each group, with persistent postoperative drainage requiring negative wound vacuum therapy and compressive dressings for resolution. A single, superficial, surgical-site infection was managed with oral antibiotics in the control group. There were no significant differences in the prevalence of wound or infectious complications between the 2 groups.

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Multimodal analgesia inclusive of periarticular injection is now commonly utilized in the care of patients undergoing elective lower-extremity arthroplasty, and the efficacy and safety profiles are excellent1,2,4-8,10-12,14-20. Although intraoperative and perioperative anesthesia protocols have evolved over recent years for management of lower-extremity musculoskeletal trauma, surgical-site injection remains a seldom-employed tool in the analgesic arsenal at the current time21-25. To our knowledge, only a single study20 has described its use in the posttraumatic setting for patients undergoing bipolar hemiarthroplasty. This investigation demonstrates the efficacy and safety profile of one such surgical-site injection across a heterogeneous orthopaedic trauma population.

Surgical-site injection is a particularly attractive adjunct for postoperative pain control in the trauma patient as it has an excellent safety profile, preserves motor function, and can limit adverse effects associated with systemic narcotics. Previous work assessing plasma concentrations of ropivacaine following periarticular injection with the same dosing parameters as those employed in the present study found that no patients reached an intravascular concentration at which side effects can occur and the plasma concentrations were 2.5 times less than reported toxic levels1,2,15. The safety of this intervention has been further demonstrated by the absence of clinical cardiac or central nervous system toxicity across numerous therapeutic investigations employing local anesthetic injections1,2,4,8,15,16. Following periarticular injection, limb function is preserved, which allows for early mobilization and rehabilitation. Although transient peroneal nerve palsies have been occasionally reported in the total knee arthroplasty literature18, these palsies completely resolved in <48 hours and can be limited by avoiding excessive infiltration in the area of the common peroneal nerve along the posterolateral aspect of the knee capsule2,35. In contrast, other effective perioperative analgesic options including continuous epidural, lumbar plexus, and femoral and sciatic nerve blocks result in diminished motor control and prolonged time to physical therapy milestones13,36-43. The preservation of motor function with the surgical-site injection technique may lead to a decreased prevalence of in-hospital falls compared with femoral or sciatic nerve blocks. Further, surgical-site injections can be applied in the operating room without substantial change to the duration of the case1,2 or requirement for subspecialized anesthesia personnel4.

Reducing parenteral narcotic consumption is one of the overarching goals of multimodal pain management27. When compared with control cohorts, periarticular injection has been shown to significantly reduce narcotic consumption1,2,15,20, which decreased narcotic-associated adverse effects including nausea, emesis, rash, and pruritus in 2 recently published meta-analyses17,19. Less dependence on systemic narcotics may prove especially valuable in the elderly population in whom opioid adverse effects are potentiated because of physiologic changes including modified volumes of distribution and reduced drug clearance44.

The present study demonstrated that a ropivacaine-based anesthetic cocktail significantly reduced (p = 0.007) postoperative pain (0 to 12 hours), which translated to reduced early narcotic consumption (0 to 8 hours) following operative fixation of femoral fractures. No adverse effects were observed that were directly attributable to the local injection. In the current investigation, the injection cohort had a trend toward less postoperative delirium when compared with the control group (2.2% compared with 9.1%), and, although not significant, this may represent a potential advantage of decreased narcotic consumption. It should be noted that both groups were advanced in age (72.8 ± 15.2 years for the injection group compared with 70.0 ± 15.2 years for the control group) and comorbidity status (ASA physical status classification: 2.8 ± 0.6 for the injection group compared with 2.8 ± 0.7 for the control group). In addition to narcotic use, advanced age, multiple comorbidities, preoperative cognitive impairment, and dependent living status have all been identified as independent risk factors for the development of postoperative delirium following hip fracture45.

Ropivacaine is a long-acting analgesic that blocks afferent pain signals, with properties similar to bupivacaine but with fewer cardiovascular and neurotoxic adverse events29,30,46,47. The addition of epinephrine allows for vasoconstriction via its action on α-adrenergic receptors, thereby slowing the release of ropivacaine into the vascular system and prolonging its local action48. Despite the slow release profile, one potential challenge with implementation of this analgesic technique may be mitigating rebound pain as the efficacy of the local analgesic agent diminishes. Finally, as opioid receptors are known to be expressed in posttraumatic tissues within hours of surgical trauma, morphine is included in the cocktail solution to alter the sensory input to the central nervous system49,50.

This study had several limitations. First, the study population was diverse, including a heterogeneous collection of both injury patterns and surgical interventions. Although this diversity offers support for the generalizability of the analgesic technique, further investigations are required to establish the efficacy of this multimodal protocol for the individual surgical procedures considered. Second, the randomization technique employed resulted in an uneven treatment allocation. If one surgical intervention had proved to be substantially more painful than others, this distribution may have biased the overall results. Further, stratified randomization was not employed, so the cohorts may have been imbalanced with respect to fracture severity or baseline medical comorbidity, which could have similarly skewed the study outcomes. Third, no plasma concentrations were obtained to directly assess pharmacokinetics and drug toxicity levels. Safety parameters were inferred on the basis of prior studies1,2,15 and the absence of identified cardiac or central nervous system toxicity. Our investigation focused exclusively on the early postoperative period. Although we did not expect that the cocktail injection would result in any significant change in pain profiles beyond the first 48 hours because of its rapid metabolism, longer-term observational studies would have been required to assess effects on subacute and chronic pain profiles. Additionally, the heterogeneous nature of the study population obligated nonuniform rehabilitation protocols, which limited the ability to assess the direct impact of the injection on patient mobilization. The study was also limited because of the lack of a standardized postoperative narcotic protocol. Such a homogeneous protocol would better allow for direct intergroup comparisons with respect to narcotic demand and consumption, which instead were accounted for via conversion to morphine equivalents in the present study design. Finally, the present investigation did not assess the impact of this analgesic technique on elapsed operative time or cost, both of which may impact providers’ decisions in the adoption of this technique.

In conclusion, surgical-site injection with a multimodal analgesic cocktail resulted in improved pain control and decreased early postoperative narcotic utilization with no apparent risks across a broad orthopaedic trauma population. This intervention may secondarily limit medication-related adverse effects in a predominantly elderly population.

Investigation performed at the Department of Orthopaedic Surgery and Rehabilitation, University of Iowa Hospitals and Clinics, Iowa City, Iowa

A commentary by Thomas A. DeCoster, MD, is linked to the online version of this article at jbjs.org.

Disclosure: There was no external source of funding for this study. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of this article (http://links.lww.com/JBJS/A153).

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