Therapeutic evaluation of immunomodulators in reducing surgical wound infection.

Despite many advances in infection control practices, including prophylactic antibiotics, surgical site infections (SSIs) remain a significant cause of morbidity, prolonged hospitalization, and death worldwide. Our innate immune system possesses a multitude of powerful antimicrobial strategies which make it highly effective in combating bacterial, fungal, and viral infections. However, pathogens use various stealth mechanisms to avoid the innate immune system, which in turn buy them time to colonize wounds and damage tissues at surgical sites. We hypothesized that immunomodulators that can jumpstart and activate innate immune responses at surgical sites, would likely reduce infection at surgical sites. We used three immunomodulators; fMLP (formyl-Methionine-Lysine-Proline), CCL3 (MIP-1α), and LPS (Lipopolysaccharide), based on their documented ability to elicit strong inflammatory responses; in a surgical wound infection model with Pseudomonas aeruginosa to evaluate our hypothesis. Our data indicate that one-time topical treatment with these immunomodulators at low doses significantly increased proinflammatory responses in infected and uninfected surgical wounds and were as effective, (or even better), than a potent prophylactic antibiotic (Tobramycin) in reducing P. aeruginosa infection in wounds. Our data further show that immunomodulators did not have adverse effects on tissue repair and wound healing processes. Rather, they enhanced healing in both infected and uninfected wounds. Collectively, our data demonstrate that harnessing the power of the innate immune system by immunomodulators can significantly boost infection control and potentially stimulate healing. We propose that topical treatment with these immunomodulators at the time of surgery may have therapeutic potential in combating SSI, alone or in combination with prophylactic antibiotics.

Implementation of a risk-stratified approach to prevent postoperative nausea and vomiting in an institution with high baseline rates of prophylaxis.

BACKGROUND AND AIMS: Although a risk-adjusted approach to preventing postoperative nausea and vomiting (PONV) is generally recommended, the successful implementation of such practice without mandated protocols remains elusive. To date, such a strategy has never been adapted to curb high baseline rates of prophylaxis. MATERIAL AND METHODS: We conducted an observational study on a cohort of patients undergoing elective surgery before and after the implementation of a quality improvement initiative including a risk-stratified approach to prevent PONV. The primary outcome was the number of prophylactic interventions administered. Secondary outcome included the repetition of ineffective medications and the need for rescue medication in the post-anesthesia care unit (PACU). RESULTS: A total of 636 patients were included; 325 patients during the control period and 311 after the intervention. The educational program failed to reduce the amount of prophylactic antiemetics administered (2.0 vs. 2.6, P < 0.001) and the repeat administration of ineffective medications for rescue (16% vs. 20%, P = 0.15). More patients in the intervention group required rescue medication compared to the control group (16.9% vs. 9.7%; P = 0.04). CONCLUSION: Implementation of best practices to combat PONV remains elusive. Our results indicate that difficulties in changing provider behavior also apply to institutions with high prophylactic antiemetic administration rates.

Randomized Trial of Static and Articulating Spacers for Treatment of the Infected Total Hip Arthroplasty.

BACKGROUND: The purpose of this randomized clinical trial is to compare perioperative and postoperative variables between static and articulating spacers for the treatment of chronic periprosthetic joint infection (PJI) complicating total hip arthroplasty (THA). METHODS: Fifty-two patients undergoing resection arthroplasty as part of a 2-stage exchange for PJI at 3 centers were randomized to either a static (n = 23) or articulating spacer (n = 29). The primary endpoint was operative time of the second-stage reimplantation and power analysis determined that 22 patients per cohort were necessary to detect a 20-minute difference. Seven patients were lost to follow-up, 4 were never reimplanted, and one died before discharge after reimplantation. Forty patients were followed for a mean 3.2 years (range 2.0-7.1). RESULTS: There were no differences in operative time at second-stage reimplantation (143 minutes static vs 145 minutes articulating, P = .499). Length of hospital stay was longer in the static cohort after stage 1 (8.6 vs 5.4 days, P = .006) and stage 2 (6.3 vs 3.6 days, P < .001). Although it did not reach statistical significance with the numbers available for study, nearly twice as many patients in the static cohort were discharged to an extended care facility after stage 1 (65% vs 30%, P = .056). CONCLUSION: This randomized trial demonstrated that the outcomes of static and articulating spacers are similar in the treatment of THA PJI undergoing 2-stage exchange arthroplasty. The significantly longer length of hospital stay associated with the use of static spacers may have important economic implications for the health care system.

A Randomized Trial of Static and Articulating Spacers for the Treatment of Infection Following Total Knee Arthroplasty.

BACKGROUND: There is no consensus whether the interim antibiotic spacer utilized in the 2-stage exchange arthroplasty should immobilize the joint or allow for motion. The purpose of this multicenter, randomized clinical trial was to compare static and articulating spacers as part of the 2-stage exchange arthroplasty for the treatment of chronic periprosthetic joint infection complicating total knee arthroplasty as defined with use of Musculoskeletal Infection Society criteria. METHODS: Sixty-eight patients undergoing 2-stage exchange arthroplasty were randomized to either a static (32 patients) or an articulating (36 patients) spacer. An a priori power analysis determined that 28 patients per group would be necessary to detect a 13° difference in range of motion between groups. Six patients were excluded after randomization, 6 died, and 7 were lost to follow-up before 2 years. RESULTS: Patients in the static group had a hospital length of stay that was 1 day greater than the articulating group after stage 1 (6.1 compared with 5.1 days; 95% confidence interval [CI], 5.3 to 6.9 days and 4.6 to 5.6 days, respectively; p = 0.032); no other differences were noted perioperatively. At a mean of 3.5 years (range, 2.0 to 6.4 years), 49 patients were available for evaluation. The mean motion arc was 113.0° (95% CI, 108.4° to 117.6°) in the articulating spacer group, compared with 100.2° (95% CI, 94.2° to 106.1°) in the static spacer group (p = 0.001). The mean Knee Society Score was higher in the articulating spacer cohort (79.4 compared with 69.8 points; 95% CI, 72.4 to 86.3 and 63.6 to 76.1, respectively; p = 0.043). Although not significantly different with the sample size studied, static spacers were associated with a greater need for an extensile exposure at the time of reimplantation (16.7% compared with 4.0%; 95% CI, 0.6% to 38.9% and 0.5% to 26.3%, respectively; p = 0.189) and a higher rate of reoperation (25.0% compared with 8.0%; 95% CI, 9.8% to 46.7% and 1.0% to 26.0%, respectively; p = 0.138). CONCLUSIONS: Articulating spacers provided significantly greater range of motion and higher Knee Society scores at a mean of 3.5 years. Static spacers were associated with a longer hospital stay following removal of the infected implant. When the soft-tissue envelope allows and if there is adequate osseous support, an articulating spacer is associated with improved outcomes. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Early Treatment With Metformin in a Mice Model of Complex Regional Pain Syndrome Reduces Pain and Edema.

BACKGROUND: Metformin, an adenosine monophosphate (AMP)-activated protein kinase activator, as well as a common drug for type 2 diabetes, has previously been shown to decrease mechanical allodynia in mice with neuropathic pain. The objective of this study is to determine if treatment with metformin during the first 3 weeks after fracture would produce a long-term decrease in mechanical allodynia and improve a complex behavioral task (burrowing) in a mouse tibia fracture model with signs of complex regional pain syndrome. METHODS: Mice were allocated into distal tibia fracture or nonfracture groups (n = 12 per group). The fracture was stabilized with intramedullary pinning and external casting for 21 days. Animals were then randomized into 4 groups (n = 6 per group): (1) fracture, metformin treated, (2) fracture, saline treated, (3) nonfracture, metformin treated, and (4) nonfracture, saline treated. Mice received daily intraperitoneal injections of metformin 200 mg/kg or saline between days 14 and 21. After cast removal, von Frey force withdrawal (every 3 days) and burrowing (every 7 days) were tested between 25 and 56 days. Paw width was measured for 14 days after cast removal. AMP-activated protein kinase downregulation at 4 weeks after tibia fracture in the dorsal root ganglia was examined by immunohistochemistry for changes in the AMP-activated protein kinase pathway. RESULTS: Metformin injections elevated von Frey thresholds (reduced mechanical allodynia) in complex regional pain syndrome mice versus saline-treated fracture mice between days 25 and 56 (difference of mean area under the curve, 42.5 g·d; 95% CI of the difference, 21.0-63.9; P < .001). Metformin also reversed burrowing deficits compared to saline-treated tibial fracture mice (difference of mean area under the curve, 546 g·d; 95% CI of the difference, 68-1024; P < .022). Paw width (edema) was reduced in metformin-treated fracture mice. After tibia fracture, AMP-activated protein kinase was downregulated in dorsal root ganglia neurons, and mechanistic target of rapamycin, ribosomal S6 protein, and eukaryotic initiation factor 2α were upregulated. CONCLUSIONS: The important finding of this study was that early treatment with metformin reduces mechanical allodynia in a complex regional pain syndrome model in mice. Our findings suggest that AMP-activated protein kinase activators may be a viable therapeutic target for the treatment of pain associated with complex regional pain syndrome.

AMP-activated protein kinase (AMPK) activator drugs reduce mechanical allodynia in a mouse model of low back pain.

BACKGROUND AND OBJECTIVES: Intervertebral disc herniation is one of the common causes of low back pain. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator drugs have been shown to reduce pain in several animal models. The present study examines if early treatment with the drug metformin, an indirect AMPK activator, and/or O304, a new direct AMPK activator, can reduce the mechanical hypersensitivity that develops after lumbar disc puncture in mice. METHODS: The L4/L5 and L5/L6 discs in male and female mice were exposed via a retroperitoneal approach and a single puncture was made at the midline of each disc. Mice were randomized into four drug treatment groups: (1) vehicle; (2) metformin 200 mg/kg; (3) O304 200 mg/kg; (4) metformin 100 mg/kg plus O304 100 mg/kg; plus one untreated sham surgery group. Drugs were administered by oral gavage starting 7 days after disc puncture and repeated for six more days. Mechanical allodynia in the plantar hindpaw was measured presurgery and up to day 28. RESULTS: 7 days after disc puncture, female mice had lower von Frey thresholds than male mice, difference -0.46 g, 95% CI -0.34 to -0.60, p<0.001. Gender adjusted von Frey area under the curve's (AUC's) between days 7 and 28 for metformin and/or O304 were greater (reduced allodynia) compared with vehicle-treated mice. The difference of mean AUC's was: metformin, 41.1 g*d, 95% CI of the difference 26.4 to 54.5, O304, 44.7 g*d, 95% CI of the difference 31.0 to 57.4, drug combination: 33.4 g*d; 95% CI of the difference 18.1 to 46.9. No gender by treatment interactions were observed. CONCLUSIONS: Lumbar disc puncture in mice produces consistent mechanical hypersensitivity, and postinjury treatment with AMPK activator drugs (indirect and direct) reduces the mechanical hypersensitivity.

Antihyperalgesia effect of AMP-activated protein kinase (AMPK) activators in a mouse model of postoperative pain.

BACKGROUND AND OBJECTIVES: AMP-activated protein kinase (AMPK) activator drugs decrease hypersensitivity in mice with pain. This study examines if postsurgery treatment with the prototype AMPK activator metformin and a new mechanism-specific AMPK activator, O304, after plantar hindpaw incision in mice, would reduce mechanical hypersensitivity and produce changes in the AMPK pathway in the dorsal root ganglion (DRG). METHODS: To create postoperative pain, an incision was made in the left plantar hindpaw. Animals were randomized into four oral gavage drug treatment groups (n=8/group): (1) vehicle, (2) metformin 200 mg/kg, (3) O304 200 mg/kg and (4) O304 200 mg/kg plus metformin 200 mg/kg. Drug gavages were performed 4 hours postsurgery and were repeated for 3 days. Mechanical hypersensitivity was measured with von Frey filaments. Changes in phosphorylated AMP-activated protein kinase alpha subunit, phosphorylated mechanistic target of rapamycin and phosphorylated eukaryotic initiation factor 2 alpha in DRG neurons were examined by immunohistochemistry. RESULTS: O304 or metformin increased von Frey thresholds (reduced mechanical hypersensitivity) in plantar incision mice versus vehicle-treated incision mice between days 1 and 4 (difference of mean area under the curve, O304: 2.24 g*day; 95% CI of the difference 0.28 to 4.21, p=0.011; metformin: 2.56 g*day; 95% CI of the difference 1.71 to 3.41, p<0.001). The drug combination further elevated von Frey thresholds. In the vehicle-treated group, the AMP-activated protein kinase alpha subunit was downregulated and mechanistic target of rapamycin and eukaryotic initiation factor 2 alpha were upregulated in DRG neurons; these deficits were reversed by the AMPK activator treatments. CONCLUSIONS: Early treatment with the mechanism-specific AMPK activator O304 or the prototype AMPK activator metformin reduces mechanical hypersensitivity in a postoperative pain model in mice. These drugs also normalize the AMPK pathway in the DRG.

High Failure at a Minimum 5-Year Follow-Up in Primary Total Hip Arthroplasty Using a Modular Femoral Trunnion.

BACKGROUND: Modular femoral trunnions enable the surgeon to independently adjust offset, leg length, and anteversion in total hip arthroplasty (THA). However, modularity may result in an increased risk of fretting and corrosion along with a higher risk of implant dissociation or fracture. The purpose of this study is to evaluate mid-term survivorship of THAs using a cementless modular system. METHODS: A consecutive series of 221 patients who underwent a primary THA using the ALFA II modular stem by a single surgeon between 2002 and 2004 were reviewed. Survivorship of the ALFA II modular hip system was evaluated at a minimum of 5 years postoperatively. RESULTS: Of the 221 patients, 28 (12.7%) died from causes unrelated to the surgery before adequate follow-up, and 64 (29.0%) patients were lost to follow-up. The remaining 129 patients had a mean 6.5-year (range: 5-8 years) follow-up. All-cause survivorship of the modular stem system was 81% (95% confidence interval = 69-90) at a mean 6.5-year follow-up. Of the 25 (19.4%) cases requiring revision surgery, 52.0% was for dissociation of the modular components, 32.0% was for fracture of the prosthesis, 12.0% was for instability/multiple dislocations, and 4.0% was for chronic septic THA. Body mass index (odds ratio = 1.080) and offset (odds ratio = 1.254) were independent risk factors for mechanical failures of the modular stem system. CONCLUSION: The modular stem hip system of interest in this study demonstrates a high failure rate at mid-term follow-up, and we caution against the use of similar designs in primary THAs.

Acute postoperative pain is an independent predictor of chronic postsurgical pain following total knee arthroplasty at 6 months: a prospective cohort study.

BACKGROUND: Approximately 15% of patients report persistent knee pain despite surgical success following total knee arthroplasty (TKA). The purpose of this study was to determine the association of acute-postsurgical pain (APSP) with chronic postsurgical pain (CPSP) 6 months after TKA controlling for patient, surgical and psychological confounding factors. METHODS: Adult patients with osteoarthritis undergoing primary elective tricompartmental TKA, with the operated knee the primary source of preoperative pain, were studied between March 2011 and February 2017. Patients received standard operative management and a perioperative multimodal analgesia regimen. The primary outcome was CPSP at 6 months. The primary variable of interest was the APSP (weighted mean pain score) for 72 hours postoperatively. Patient, surgical and psychological confounders were assessed using binary logistic regression. RESULTS: 245 cases were analyzed. The incidence of CPSP was 14% (95% CI 10% to 19%). Median APSP values were 4.2 (2.2-5.0) in the CPSP group and 2.8 (1.8-3.7) without CPSP, difference 1.4 (95% CI 0.1 to 1.8, p=0.005). The unadjusted odds for CPSP with an increase of 1 in APSP was 1.46 (95% CI 1.14 to 1.87, p=0.002)). After multivariable risk adjustment, the OR for CPSP for an increase of 1 in the APSP was 1.53 (95% CI 1.12 to 2.09, p=0.008). CONCLUSIONS: APSP is a risk factor for CPSP following TKA even after adjusting for confounding variables such as pain catastrophizing, anxiety, depression and functional status. Studies are needed to determine if APSP is a modifiable risk factor for the development of CPSP.

Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain.

BACKGROUND AND OBJECTIVES: Ketamine has been shown to reduce chronic pain; however, the adverse events associated with ketamine makes it challenging for use outside of the perioperative setting. The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) has a therapeutic effect in mice models of depression, with minimal side effects. The objective of this study is to determine if (2R,6R)-HNK has efficacy in both acute and chronic mouse pain models. METHODS: Mice were tested in three pain models: nerve-injury neuropathic pain, tibia fracture complex regional pain syndrome type-1 (CRPS1) pain, and plantar incision postoperative pain. Once mechanical allodynia had developed, systemic (2R,6R)-HNK or ketamine was administered as a bolus injection and compared with saline control in relieving allodynia. RESULTS: In all three models, 10 mg/kg ketamine failed to produce sustained analgesia. In the neuropathic pain model, a single intraperitoneal injection of 10 mg/kg (2R,6R)-HNK elevated von Frey thresholds over a time period of 1-24hours compared with saline (F=121.6, p<0.0001), and three daily (2R,6R)-HNK injections elevated von Frey thresholds for 3 days compared with saline (F=33.4, p=0.0002). In the CRPS1 model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 4 days compared with saline (F=116.1, p<0.0001). In the postoperative pain model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 5 days compared with saline (F=60.6, p<0.0001). CONCLUSIONS: This study demonstrates that (2R,6R)-HNK is superior to ketamine in reducing mechanical allodynia in acute and chronic pain models and suggests it may be a new non-opioid drug for future therapeutic studies.

Local Vancomycin Effectively Reduces Surgical Site Infection at Implant Site in Rodents.

BACKGROUND AND OBJECTIVES: Infected implantable devices represent a clinical challenge, because the customary option is to surgically remove the device, and that is associated with substantial cost and morbidity to the patient, along with patient dissatisfaction with the physician. Although prophylactic systemic antibiotics and sterile technique are the mainstay of prevention of surgical site infection (SSI) after implant, the incidence of SSI remains relatively high. Although some surgeons add local antibiotic at implant site during surgery, there is no scientific research to demonstrate if there is a benefit. METHODS: Rats and mice were randomly assigned to 4 treatment groups: systemic vancomycin alone, local vancomycin alone, combined systemic and local vancomycin, and untreated. After systemic vancomycin or saline preinjection, a surgical incision was performed for placement of a metal disc, and local vancomycin or saline was injected in the superficial tissue pocket created. The metal disc (implant) was placed in that space, followed by local injection of Staphylococcus aureus bacteria and wound closure. After 1 and 6 days, samples of the tissue surrounding the disc implant, the disc itself, and the spleen (systemic infection marker) were processed, and bacterial levels assayed. RESULTS: In both mice and rats, local vancomycin was more potent in reducing tissue SSI, implant infection, and spleen infection than systemic vancomycin at 1 day after induction of bacteria to a surgical wound. At 6 days, in both mice and rats, local vancomycin was again more potent in reducing tissue SSI than systemic vancomycin. CONCLUSIONS: This study suggests that local vancomycin should be added to systemic vancomycin to reduce SSI with cardiac pacemaker, defibrillator, implantable pulse generator of neurostimulator, or intrathecal pump implants.

Incidence and Changing Trends of Shoulder Stabilization in the United States.

PURPOSE: To determine the incidence and demographic characteristics of shoulder stabilization in the United States, with particular focus on age, sex, and inpatient versus outpatient treatment. METHODS: The National Hospital Discharge Survey and the National Survey of Ambulatory Surgery databases were searched using a combination of International Classification of Diseases, Ninth Revision diagnosis and procedure codes, encompassing open and arthroscopic shoulder stabilization procedures. Incidence was determined using National Survey of Ambulatory Surgery, National Hospital Discharge Survey, and US census data, and the results were stratified by age, sex, facility, and concomitant diagnoses. Data were analyzed between 1994 and 2006, the most recent year for which data are available within these sources. RESULTS: The incidence of shoulder stabilization in the United States was 5.84 per 100,000 person-years (n = 15,514; 95% confidence interval, 11,975-19,053) in 1994 to 1996 and 6.89 per 100,000 person-years (n = 20,588; 95% confidence interval, 16,254-24,922) in 2006 (P = .0697). The number of inpatient procedures decreased significantly whereas the number of outpatient procedures increased significantly over the same period (P < .0001 for both). The incidence of stabilization increased in patients aged 45 to 64 years (P < .0001) and patients aged 65 years or older (P = .0008) but was unchanged in patients aged 44 years or younger (P = .4745). The average age of patients undergoing stabilization increased over the study period, from 30 years to 47 years for inpatients (P = .01) and from 27 years to 34 years for ambulatory patients (P = .05). The incidence of stabilization increased significantly in male patients (P = .0075) but remained stable in female patients (P = .8057) over the same period. Diagnoses related to rotator cuff pathology and shoulder derangement were the most common concurrent diagnosis codes. CONCLUSIONS: The overall incidence of shoulder stabilization in the United States is 6.89 per 100,000 person-years. The incidence increased by 18% between 1994 and 2006. During the study period, shoulder stabilization shifted to become a largely outpatient procedure, and the average age increased significantly. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Continuous Adductor Canal Blocks Provide Superior Ambulation and Pain Control Compared to Epidural Analgesia for Primary Knee Arthroplasty: A Randomized, Controlled Trial.

BACKGROUND: Adductor canal blocks (ACBs) are an alternative to femoral nerve blocks that minimize lower extremity weakness. However, it is unclear whether this block will provide analgesia that is equivalent to techniques, such as epidural analgesia. The purpose of this randomized controlled trial was to compare continuous ACBs with epidural analgesia for primary total knee arthroplasty. METHODS: Following institutional review board approval, 145 patients were randomized to 1 of 3 groups: combined spinal-epidural (CSE), spinal + continuous ACB (CACB), or general + CACB. Epidural analgesia was used postoperatively in the CSE group, and an adductor canal catheter was used in the CACB groups. Power analysis determined that 84 patients per group were needed to demonstrate a 35% increase in ambulation with an alpha of 0.05 at a power of 90%. RESULTS: At interim analysis, 13 patients were removed for protocol deviations, leaving 45 in CSE, 41 in spinal + CACB and 46 in general + CACB groups. Patient demographics were similar in all comparisons suggesting appropriate randomization. Patients in the CACB groups walked further on postoperative day 1, 2, and 3 (P = .02). Mean daily pain scores were lower in the CACB groups (4.1 CSE, 3.0 spinal + CACB, 3.4 general + CACB, P = .009). There was no significant difference in total opioid consumption between groups (158 morphine equivalents CSE, 149 spinal + CACB, and 172 general + CACB). More patients reported being "very satisfied" in CACB groups (68% general + CACB, 63% spinal + CACB, and 36% CSE; P = .001). CONCLUSION: Continuous adductor analgesia provides superior ambulation, lower pain scores, faster discharge, and greater patient satisfaction when compared to epidural analgesia for primary total knee arthroplasty.

Oral Ketamine for Acute Pain Management After Amputation Surgery.

Objective: Intravenous ketamine has been shown to provide postoperative analgesia in many clinical trials, in particular to reduce opioid consumption. The primary objective of this pilot study is to determine if multiple dosing over a three-day perioperative period with oral ketamine is a safe treatment method for acute pain after amputation surgery. Methods: Three consented subjects (age 57-60 years) undergoing elective amputation of the lower extremity were included in the study (Institutional Review Board and Food and Drug Administration Investigational New Drug approved). An analgesic dose of oral ketamine (1.0 mg/kg) was administered one hour before surgery. Eight hours after the preoperative dose, a second dose was given. On the first postoperative day, subjects received oral ketamine (1.0 mg/kg) three times per day; and on the second postoperative day, this dose was reduced to 0.5 mg/kg three times per day. The primary outcome measure was the incidence of adverse events. Results: No serious and unexpected adverse events occurred; therefore, no subject required a dose reduction. The numerical rating score for postoperative pain of the body part adjacent to the amputation site ranged from 0.5-4.0. Morphine milligram equivalent opioid doses were in the range of 0-17.5 mg on the first postop day and 1.0-4.0 mg on the second postop day. Conclusions: Our pilot study suggests that oral ketamine is safe to use at 1 mg/kg three times per day, as well as convenient for hospital floor and potential home use. Future studies will determine if the perioperative oral ketamine also reduces the incidence of chronic stump or phantom limb pain.

Biochemical and Pharmacological Characterization of a Mice Model of Complex Regional Pain Syndrome.

BACKGROUND AND OBJECTIVES: Complex regional pain syndrome is a challenging disease to treat. Recently, a mouse fracture model of complex regional pain syndrome has been developed that has many signs of the clinical syndrome. However, many aspects of the sensory neuron biochemistry and behavioral and pharmacological characterization of this model remain to be clarified. METHODS: Mice were randomly assigned to fracture/cast or control (naive) groups. Fracture/cast mice underwent a closed distal tibia facture, with hindlimb wrapped in casting tape for 3 weeks. After cast removal, mice were tested for mechanical allodynia, burrowing behavior, and motor ability over a 12-week period. Protein immunohistochemistry was performed for substance P, calcitonin gene-related peptide, tropomyosin receptor kinase A, nerve growth factor, Nav1.7, and transient receptor potential cation-channel V1, colocalized in neurons, in the ipsilateral lumbar dorsal root ganglia (DRGs). Analgesic drugs were tested for pain-relieving efficacy. RESULTS: Mechanical allodynia was greater in the ipsilateral hindpaw (P = 0.0002) in the fracture/cast group versus the control group, over the 3- to 12-week period. The amount of burrowing material removed was decreased (P = 0.0026), and there were deficits in spontaneous motor-rearing behavior (P = 0.018). Immunostaining of substance P, calcitonin gene-related peptide, Trk A receptor, nerve growth factor, Nav1.7, and transient receptor potential cation-channel V1 all demonstrated up-regulation in the DRGs of fracture mice versus controls (all P < 0.05). Morphine, pregabalin, ketamine, acetaminophen, and dexamethasone transiently increased force withdrawal thresholds on the ipsilateral (fracture) side and improved burrowing activity after injection (all P < 0.05). Ketorolac improved only burrowing. CONCLUSIONS: Persistent pain-related behavior was demonstrated in this mouse fracture/cast model with wide-scale DRG up-regulation of pain mediators. Antihyperalgesic drugs reduced mechanical allodynia and improved burrowing.

Oral and Intravenous Tranexamic Acid Are Equivalent at Reducing Blood Loss Following Total Hip Arthroplasty: A Randomized Controlled Trial.

BACKGROUND: Tranexamic acid is an antifibrinolytic that has been shown to reduce blood loss and the need for transfusions when administered intravenously in total hip arthroplasty. Oral formulations of the drug are available at a fraction of the cost of the intravenous preparation. The purpose of this randomized controlled trial was to determine if oral and intravenous formulations of tranexamic acid have equivalent blood-sparing properties. METHODS: In this double-blinded trial, 89 patients undergoing primary total hip arthroplasty were randomized to receive 1.95 g of tranexamic acid orally 2 hours preoperatively or a 1-g tranexamic acid intravenous bolus in the operating room prior to incision; 6 patients were eventually excluded for protocol deviations, leaving 83 patients available for study. The primary outcome was the reduction of hemoglobin concentration. Power analysis determined that 28 patients were required in each group with a ±1.0 g/dL hemoglobin equivalence margin between groups with an alpha of 5% and a power of 80%. Equivalence analysis was performed with a two one-sided test (TOST) in which a p value of <0.05 indicated equivalence between treatments. RESULTS: Forty-three patients received intravenous tranexamic acid, and 40 patients received oral tranexamic acid. Patient demographic characteristics were similar between groups, suggesting successful randomization. The mean reduction of hemoglobin was similar between oral and intravenous groups (3.67 g/dL compared with 3.53 g/dL; p = 0.0008, equivalence). Similarly, the mean total blood loss was equivalent between oral and intravenous administration (1,339 mL compared with 1,301 mL; p = 0.034, equivalence). Three patients (7.5%) in the oral group and one patient (2.3%) in the intravenous group were transfused, but the difference was not significant (p = 0.35). None of the patients in either group experienced a thromboembolic event. CONCLUSIONS: Oral tranexamic acid provides equivalent reductions in blood loss in the setting of primary total hip arthroplasty, at a greatly reduced cost, compared with the intravenous formulation. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

The Mark Coventry, MD, Award: Oral Antibiotics Reduce Reinfection After Two-Stage Exchange: A Multicenter, Randomized Controlled Trial.

BACKGROUND: Many patients develop recurrent periprosthetic joint infection after two-stage exchange arthroplasty of the hip or knee. One potential but insufficiently tested strategy to decrease the risk of persistent or recurrent infection is to administer additional antibiotics after the second-stage reimplantation. QUESTIONS/PURPOSES: (1) Does a 3-month course of oral antibiotics decrease the risk of failure secondary to infection after a two-stage exchange? (2) Are there any complications related to the administration of oral antibiotics after a two-stage exchange? (3) In those patients who develop a reinfection, is the infecting organism different from the initial infection? METHODS: Patients at seven centers randomized to receive 3 months of oral antibiotics or no further antibiotic treatment after operative cultures after the second-stage reimplantation were negative. Adult patients undergoing two-stage hip or knee revision arthroplasty for a periprosthetic infection who met Musculoskeletal Infection Society (MSIS) criteria for infection at the first stage were included. Oral antibiotic therapy was tailored to the original infecting organism(s) in consultation with an infectious disease specialist. MSIS criteria as used by the treating surgeon defined failure. Surveillance of patients for complications, including reinfection, occurred at 3 weeks, 6 weeks, 3 months, 12 months, and 24 months. If an organism demonstrated the same antibiotic sensitivities as the original organism, it was considered the same organism; no DNA subtyping was performed. Analysis was performed as intent to treat with all randomized patients included in the groups to which they were randomized. A log-rank survival curve was used to analyze the primary outcome of reinfection. At planned interim analysis (enrollment is ongoing), 59 patients were successfully randomized to the antibiotic group and 48 patients to the control group. Fifty-seven patients had an infection after TKA and 50 after a THA. There was no minimum followup for inclusion in this analysis. The mean followup was 14 months in the antibiotic group and 10 months in the control group. RESULTS: Patients treated with oral antibiotics failed secondary to infection less frequently than those not treated with antibiotics (5% [three of 59] versus 19% [nine of 48]; hazard ratio, 4.37; 95% confidence interval, 1.297-19.748; p = 0.016). Three patients had an adverse reaction to the oral antibiotics severe enough to cause them to stop taking the antibiotics early, and four patients who were randomized to that group did not take the antibiotics as directed. With the numbers available, there were no differences between the study groups in terms of the likelihood that an infection after treatment would be with a new organism (eight of nine in the control group versus one of three in the treatment group, p = 0.087). CONCLUSIONS: This multicenter randomized trial suggests that at short-term followup, the addition of 3 months of oral antibiotics appeared to improve infection-free survival. As a planned interim analysis, however, these results may change as the study reaches closure and the safety profile may yet prove risky. Further followup of this cohort of patients will be necessary to determine whether these preliminary results are durable over time. LEVEL OF EVIDENCE: Level I, therapeutic study.

Aseptic Lymphocytic-Dominated Vasculitis-Associated Lesions Scores Do Not Correlate With Metal Ion Levels or Unreadable Synovial Fluid White Blood Cell Counts.

BACKGROUND: Failed metal-on-metal (MoM) bearings are being increasingly encountered with little information to guide evaluation for aseptic lymphocytic-dominated vasculitis-associated lesions (ALVAL). It is often assumed that elevated metal ion levels correlate with the occurrence of ALVAL. Our purpose was to determine the utility of the erythrocyte sedimentation rate, C-reactive protein, synovial white blood cell count, differential (%PMN), and serum metal ion levels in diagnosing ALVAL. METHODS: We identified 80-failed MoM total hip arthroplasties. Tissue was examined under light microscopy and graded on a scale of ALVAL severity. Mean laboratory values were compared between groups and receiver operating curves generated with an area under the curve to determine test performance and optimal cutoffs. RESULTS: ALVAL scores were graded as low in 30 (37.5%), moderate in 39 (49%), and severe in 8 (10%), with 3 being unreadable. No clear cutoff values for erythrocyte sedimentation rate, C-reactive protein, or synovial white blood cell count could be determined to reliably diagnose moderate or severe ALVAL. Furthermore, serum metal levels had no correlation with ALVAL score. The best test to diagnose ALVAL was the synovial fluid monocyte percentage with an optimal cutoff value of 39% and area under the curve of 69% (moderate testing performance). CONCLUSION: The diagnosis of ALVAL remains challenging, with most of the screening tests being unreliable. Although serum metal ion levels are typically elevated in failed MoM bearings, higher levels do not appear to correlate with ALVAL grade. Elevated synovial fluid monocytes may provide diagnostic utility for ALVAL, suggesting a possible delayed-type hypersensitivity reaction.