Systemic Diclofenac Sodium Reduces Postoperative rhBMP-2 Induced Neuroinflammation: A Rodent Model Study.

STUDY DESIGN: This is a basic science, animal research study. OBJECTIVE: This study aims to explore, in rodent models, the effectiveness of systemic nonsteroidal anti-inflammatory drugs in reducing recombinant human bone morphogenetic protein-2 (rhBMP-2) induced neuroinflammation. SUMMARY OF BACKGROUND DATA: rhBMP-2 is increasingly used to augment fusion in lumbar interbody fusion surgeries, although it can cause complications including postoperative radiculitis. MATERIALS AND METHODS: Eighteen 8-week-old Sprague-Dawley rats underwent Hargreaves testing to measure the baseline thermal withdrawal threshold before undergoing surgical intervention. The L5 nerve root was exposed and wrapped with an Absorbable Collagen Sponge containing rhBMP-2. Rats were randomized into 3 groups: (1) Low dose (LD), (2) high dose (HD) diclofenac sodium, and (3) saline, receiving daily injection treatment. Hargreaves testing was performed postoperatively on days 5 and 7. Seroma volumes were measured by aspiration and the nerve root was then harvested for hematoxylin and eosin, immunohistochemistry, Luxol Fast Blue staining, and real-time quantitative polymerase chain reaction. The Student t test was used to evaluate the statistical significance among groups. RESULTS: The intervention groups showed reduced seroma volume, and a general reduction of inflammatory markers (MMP12, MAPK6, GFAP, CD68, and IL18) compared with controls, with the reduction in MMP12 being statistically significant ( P = 0.02). Hematoxylin and eosin and immunohistochemistry of the nerve roots showed the highest macrophage density in the saline controls and the lowest in the HD group. Luxol Fast Blue staining showed the greatest extent of demyelination in the LD and saline groups. Lastly, Hargreaves testing, a functional measure of neuroinflammation, of the HD group demonstrated a minimal change in thermal withdrawal latency. In contrast, the thermal withdrawal latency of the LD and saline groups showed a statistically significant decrease of 35.2% and 28.0%, respectively ( P < 0.05). CONCLUSION: This is the first proof-of-concept study indicating that diclofenac sodium is effective in alleviating rhBMP-2-induced neuroinflammation. This can potentially impact the clinical management of rhBMP-2-induced radiculitis. It also presents a viable rodent model for evaluating the effectiveness of analgesics in reducing rhBMP-2-induced inflammation.

Effects of Antihypertensive Drugs on Outcomes of Breast Reconstruction.

BACKGROUND: Angiotensin receptor blocker (ARB), a commonly used antihypertensive drug, is reported to affect wound healing and flap survival in animal models. However, this has not been elucidated in a clinical series. This study aimed to investigate the impact that perioperative use of ARB has on outcomes after breast reconstruction. METHODS: Patients who underwent immediate breast reconstruction using a tissue expander or a deep inferior epigastric perforator (DIEP) flap were reviewed. The patients were categorized according to the types of antihypertensive medications as follows: the ARB group consisted of hypertensive patients treated with ARB alone or a combination of ARB and other drugs; the non-ARB group included those receiving drugs other than ARB; and the control group did not receive any medication. The effects of antihypertensive drugs on the development of complications were evaluated. RESULTS: The study analyzed 1390 cases including 999 cases of tissue-expander insertion and 391 cases of DIEP flap reconstruction. With regard to tissue-expander reconstruction, the rates of seroma, reoperation, reconstruction failure, and overall complications were significantly higher in the ARB group than in the other two groups. Compared with no medication, ARB use was an independent risk factor for these complications. With regard to DIEP flap reconstruction, the ARB group showed a significantly higher rate of fat necrosis and significantly greater odds for the development of overall perfusion-related complications and fat necrosis than the control group after adjustment for other variables. CONCLUSIONS: Perioperative administration of ARB might be associated with adverse outcomes after breast reconstruction.

Postoperative Seroma Formation After Posterior Cervical Fusion with Use of RhBMP-2: A Report of Two Cases.

CASE: We present 2 cases of postoperative seroma formation following posterior cervical fusion with the use of recombinant human bone morphogenetic protein-2 (rhBMP-2). CONCLUSION: Although some who advocate for the off-label use of rhBMP-2 in patients undergoing posterior cervical spine fusion believe it to be safe, relatively little has been published regarding complication rates. We believe that rhBMP-2 carries a risk of seroma formation in patients who undergo posterior cervical fusion, which necessitates the use of a postoperative drain. Surgeons should have a low threshold for obtaining postoperative magnetic resonance imaging in a symptomatic patient.

[Complications of intrathecal baclofen therapy]. / Oslozhneniya intratekal'noi terapii baklofenom.

AIM: To analyze complications of intrathecal baclofen therapy and identify high-risk groups. MATERIAL AND METHODS: We implanted 52 pumps to spastic patients for chronic intrathecal baclofen infusion. Two groups of patients were distinguished: 23 patients with spinal spasticity (group 1) and 29 patients with cerebral spasticity (group 2). The mean patient age was 37.2±14.6 years in group 1 and 17.3±10.3 years in group 2. Surgery was performed according to a standard procedure. A Medstream (Codman) pump was implanted in 10 cases, and a Synchromed II (Medtronic) pump was implanted in the remaining 42 cases. RESULTS AND DISCUSSION: Complications developed in 12 (23%) patients. We divided complications into 3 groups: baclofen underdose, baclofen overdose, and others. Insufficiency of intrathecal therapy was observed in 7 cases, which was caused by catheter migration (5 cases) and pump dysfunction (2 cases). In one case, baclofen overdose was observed after air travel. Other complications included 4 cases of persistent peri-implant seroma and infectious complications. Groups with a high risk of complications were identified based on an analysis of the results. Patients with severe dystonia of the trunk muscles have an increased risk of spinal catheter migration. Pronounced communicating hydrocephalus is associated with the risk of cerebrospinal fluid leak through a catheter shaft channel. Weakness of the axial musculature can lead to progression of scoliotic deformity. CONCLUSION: In some cases, chronic intrathecal baclofen therapy can be accompanied by various complications. This technique should be carefully used in patients from high-risk groups.

The effect of enoxaparin on seroma and mesh-tissue adhesion in a hernia model.

The aim of this study was to investigate whether enoxaparin (ENX) administration would increase seroma risk and worsen mesh tissue recovery in an experimental rat hernia repair model. Fifty-six adult male Wistar-Albino rats were included in the study. Rats were equally and randomly separated into seven groups: Group 1, Control, only subcutaneous dissection was performed; group 2, Sham, Hernia defect was primary sutured; Group 3, Prolene mesh; Group 4, Dual mesh; Group 5, ENX + Sham; Group 6, ENX + Prolene mesh; Group 7, ENX + Dual mesh. ENX was subcutaneously injected at a dose of 180 U/kg per day for 7 days. Rats were killed after the amount of subcutaneous seroma was determined by ultrasound on day 7 following the surgical procedure. Mesh-tissue healing was evaluated using histopathological and immunohistochemical (CD31) staining methods. The mean seroma amount significantly increased in Groups 5-7 compared to Groups 2-4. CD31 immunostaining showed a reduction in neovascularization in Groups 6 and 7, compared to Groups 3 and 4. Neovascularization decreased and hemorrhage, necrosis and oedema findings remarkably increased in Groups 6 and 7, when compared to Groups 3 and 4. Fibroblastic activity and inflammation were more prominent in Groups 3 and 4. It should be kept in mind that ENX interferes with inflammation, which is desired in the early period of healing and leads to an increase in overall seroma amount with anti-coagulant effects, which in turn may disrupt wound healing and mesh-tissue adhesions, as was indicated in our study.

Characterizing the host response to rhBMP-2 in a rat spinal arthrodesis model.

STUDY DESIGN: Prospective, randomized, controlled preclinical trial. OBJECTIVE: This study seeks to characterize the localized and systemic host response to recombinant human bone morphogenetic protein-2 (rhBMP-2) in a well established rodent spine arthrodesis model utilizing cytokine analysis and magnetic resonance imaging (MRI). SUMMARY OF BACKGROUND DATA: Although high fusion rates are achieved with rhBMP-2 in the spine, several complications have also been reported, including a localized response leading to radiculitis and seroma formation. The mechanism in which this occurs clinically is yet unknown. METHODS: One hundred female Fischer rats underwent a posterolateral intertransverse lumbar spinal fusion, with paraspinal muscle tissue resection, using iliac crest autograft, type I absorbable collagen sponge (ACS), 10- or 100-µg rhBMP-2/ACS. The animals underwent magnetic resonance imaging evaluation, serum cytokine analysis, manual palpation, and gross tissue inspection at 2, 4, 7, 10, and 21 days, postoperatively. RESULTS: Qualitative evaluation of MR images demonstrated a transient fluid collection at the surgery site in the rhBMP-2 animals as early as 4 and 7 days that was greater than the autograft or ACS groups. Quantitative analysis on T2-weighted axial images demonstrated greater signal intensity in the rhBMP-2 animals compared with the ACS and autograft groups in a time-dependent fashion. Higher concentrations of several cytokines were also detected at 2, 4, and 7 days, including interleukin 1ß, interleukin 18, tumor necrosis factor α, macrophage inflammatory protein 1α, and monocyte chemotactic protein 1 in animals treated with rhBMP-2/ACS relative to ACS alone. CONCLUSION: Our data suggest that the in vivo host response to rhBMP-2 in an animal model may be associated with circulating proinflammatory and osteoclastic cytokines.

Minimizing the severity of rhBMP-2-induced inflammation and heterotopic ossification with a polyelectrolyte carrier incorporating heparin on microbead templates.

STUDY DESIGN: A rodent model of posterior spinal fusion. OBJECTIVE: The aim of this study was to evaluate the efficacy of low-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered with a heparin based polylectrolyte complex (PEC) carrier in facilitating posterior spinal fusion while concurrently minimizing seroma and heterotopic ossification. SUMMARY OF BACKGROUND DATA: rhBMP-2 is being used to augment spinal fusion. However, complications such as heterotopic ossification and local soft tissue swellings have been reported. These are attributed to supraphysiological amount of rhBMP-2 and the poor modulation capacity of absorbable collagen sponge. METHODS: Forty rats were randomized into 6 groups as follows. Group I: absorbable collagen sponge without rhBMP-2 (n = 4); group II: positive control, absorbable collagen sponge + 10 µg rhBMP-2 (n = 4); group III: alginate-(poly-L-lysine)-heparin (PEC) without rhBMP-2 (n = 8); group IV: PEC + 4.5 µg rhBMP-2 (n = 8); group V: PEC + 1.5 µg rhBMP-2 (n = 8); group VI: PEC + 0.5 µg rhBMP-2 (n = 8). RESULTS: Between postoperative days 5 and 7, seroma was observed in all rhBMP-2 implanted groups irrespective of carrier and dose. However, the rate and size of seroma differed considerably. Although all animals (100%) in positive control group showed seroma, only one animal (12.5%) in group VI developed seroma at the implant site. The size of seroma in group VI was significantly smaller than that in positive control group. Micro-computed tomography evaluation revealed comparable mean fusion scores in all rhBMP-2 implanted groups. More importantly, although new bone was well contained within the cage in group VI, heterotopic ossification beyond the cage was observed in positive control group. CONCLUSION: A new carrier has demonstrated capacity to minimize seroma formation as well as heterotopic ossification associated with rhBMP-2 by reducing the efficacious dose needed for consistent fusion. The results of this study indicate that PEC alginate microbeads may represent a new opportunity to define an efficient rhBMP-2 carrier.

Postoperative cervical myelopathy and cord compression associated with the use of recombinant bone morphogenetic protein-2 in posterior cervical decompression, instrumentation, and arthrodesis: a report of two cases.

STUDY DESIGN: Case report. OBJECTIVE: Two cases are presented in which the use of recombinant bone morphogenetic protein-2 (rh-BMP-2) in a posterior cervical decompression and instrumented arthrodesis may have contributed to seroma formation and cord compression. SUMMARY OF BACKGROUND DATA: The use of rh-BMP-2 has been proven effective in promoting bone formation in anterior lumbar spine arthrodesis. Whether rh-BMP-2 is safe and/or effective in the cervical spine has not been determined. Adverse effects when it is used for anterior cervical fusion procedures have been reported but its role in posterior cervical decompression and instrumented fusions has yet to be determined. METHODS: We report on two cases. The first is a 68-year-old man presenting with a substantial decline in his neurologic status approximately 2 weeks after surgery. The second is a 44-year-old man presenting with a substantial decline in his neurologic status approximately 5 days after surgery. Both complications occurred after a posterior cervical laminectomy and instrumented arthrodesis when rh-BMP-2 was used as a bone graft substitute. RESULTS: Both patients were found to have a moderate-to-large seroma causing severe compression on the spinal cord and were urgently taken to an operating room for evacuation of the seromas. Both showed improvement of their neurologic status immediately after surgery. As rh-BMP-2 is known to occasionally cause seroma formation it is postulated that it may have been the cause of the seromas. CONCLUSION: Caution should be exercised with rh-BMP-2 use in posterior cervical applications when a laminectomy has been performed. The safe and effective dose and technique for application have yet to be determined. Seroma formation is possible, which can cause acute stenosis with cord compression and neurologic compromise.

Inflammatory characteristics of rhBMP-2 in vitro and in an in vivo rodent model.

STUDY DESIGN: In vivo and in vitro model. OBJECTIVE: Investigate soft-tissue inflammation caused by rhBMP-2. SUMMARY OF BACKGROUND DATA: Although rhBMP-2 produces excellent rates of fusion in the spine, dysphagia and respiratory compromise have occurred when used in the neck. The mechanism of the swelling and inflammatory response has yet to be fully elucidated. METHODS: ELISA kits (IL-6, IL-10, TNF-α) were used to measure cytokine levels at different concentrations of rhBMP-2. Absorbable collagen sponges were implanted with or without different concentrations of rhBMP-2 into the backs of rats subcutaneously (SC) and intramuscularly (IM). Magnetic resonance imaging was used to measure inflammation at 3 hours and 2, 4, and 7 days. The inflammatory volumes were measured and compared using MIPAV software. Rats were killed after 7 days and studied. RESULTS: IL-6, IL-10, and TNF-α release was dose-dependent. Soft-tissue edema after rhBMP-2 implantation was also dose-dependent, peaking at 3 hours SC, after SC and IM implantations, and on day 2 IM after IM implantation. All formed a granuloma-type mass after SC insertion. The mass was much larger in the 10 and 20 µg/10 µL (high-concentration) groups. The inflammatory response did not diffuse across physiologic barriers (subcutaneous fascia). Both high-dose groups were associated with encapsulated hematomas and a significant increase in the inflammatory zone. CONCLUSION: Swelling and inflammation after rhBMP-2 use are dose-dependent. Swelling may be due to direct contact as well as spread in the plane of access. The causes are a robust inflammatory reaction as well as sterile seroma and encapsulated hematoma formation.

Late hematoma, seroma, and galactocele in breasts injected with polyacrylamide gel.

Late hematoma or seroma and galactocele caused by augmentation mammaplasty have been reported in patients with silicon breast prostheses but are extremely rare in patients injected with polyacrylamide gel (PAAG). In a retrospective survey, the incidence, clinical manifestations, and management of late hematoma, seroma, and galactocele in 28 of 2,610 patients who underwent breast augmentation with PAAG injection were investigated, and 5 typical cases are presented. The diagnostic and managing methods for this complication have been assessed. The incidence of late hematoma or seroma was 0.65% and that of galactocele was 0.35% among patients with PAAG-injected breast augmentations. The clinical onsets of such late PAAG complications were of two types: rapid enlargement in 17 patients and progressive expansion in another 11 patients. Aspiration, ultrasound, and magnetic resonance imaging (MRI) are useful and sensitive tools for diagnosis. Foreign body reaction, PAAG-related tissue necrosis and fibrosis, and granuloma were shown, and the bacterial cultures in all 12 cases were negative. Needle aspiration with pressure dressing has been advocated as a reliable method for small diseases, and surgical exploration with irrigation-vacuum drainage and evacuation with capsulectomy have been considered more effective for recurrent, large, and long-term cases. In conclusion, these late complications rarely present after large-volume injections of PAAG for breast augmentation. The PAAG-related pathologic inflammatory tissue changes are suggested as the pathogenesis for the complication. Trauma and breastfeeding are considered to be stimulating factors.

Formation of painful seroma and edema after the use of recombinant human bone morphogenetic protein-2 in posterolateral lumbar spine fusions.

BACKGROUND: The use of bone morphogenetic proteins for fusion augmentation in spine surgery has increased dramatically in recent years. Information is continually emerging regarding the effectiveness and safety profile of these compounds. OBJECTIVE: We have noted an increased incidence in sterile seroma formation and painful edema after the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for posterolateral lumbar fusion. We present a retrospective review to determine the incidence of seroma formation and to discuss its clinical implications. METHODS: We retrospectively reviewed the operative reports of patients who underwent posterolateral lumbar fusion with the addition of rhBMP-2. We identified all patients who required surgical exploration of a postoperative sterile seroma. RESULTS: Of the 130 patients who underwent posterolateral lumbar fusion with rhBMP-2, 6 (4.6%) were returned to the operating room for exploration of a sterile seroma. The total amount of rhBMP-2 delivered to the posterolateral space per patient was 2.1 to 14.7 mg (mean, 8.4 mg per patient). The patients were returned to the operating room 5 to 13 days (mean, 7.7 days) after their initial surgery, and infection was ruled out in all cases by intraoperative cultures. CONCLUSION: There seems to be an increased incidence of formation of sterile seroma and painful edema in the lumbar region after posterolateral fusion with rhBMP-2. This report, along with other series highlighting the potential complications of bone morphogenetic proteins, suggests that more caution should be used when these compounds are used. Further studies are required to better define the risks and benefits of using bone morphogenetic proteins for spine surgery.

Complications of hydroxyapatite bone cement reconstruction of retrosigmoid craniotomy: two cases.

Hydroxyapatite bone cement is a versatile material used to reconstruct many types of bony surgical defects, and its applications have been widely reported in the literature. Still, complications of its use do occur. We describe 2 cases of hydroxyapatite resorption and subsequent seroma formation in patients who had undergone retrosigmoid craniotomy. The presentation in both cases mimicked a CSF leak. In both cases, the fragmented cement was removed, and the patient experienced no further complications. While hydroxyapatite cement is a highly useful product for the reconstruction of some craniofacial or skull base defects, we believe that it should not be used for the reconstruction of retrosigmoid/suboccipital craniotomies because it is associated with unacceptably high complication rates. Surgeons must exercise caution in selecting candidates for hydroxyapatite reconstruction of cranial defects.

Alveolar ridge augmentation using implants coated with recombinant human bone morphogenetic protein-2: histologic observations.

BACKGROUND: Studies using ectopic rodent, orthotopic canine, and non-human primate models show that bone morphogenetic proteins (BMPs) coated onto titanium surfaces induce local bone formation. The objective of this study was to examine the ability of recombinant human BMP-2 (rhBMP-2) coated onto a titanium porous oxide implant surface to stimulate local bone formation including osseointegration and vertical augmentation of the alveolar ridge. MATERIAL AND METHODS: Bilateral, critical-size, 5 mm, supra-alveolar, peri-implant defects were created in 12 young adult Hound Labrador mongrel dogs. Six animals received implants coated with rhBMP-2 at 0.75 or 1.5 mg/ml, and six animals received implants coated with rhBMP-2 at 3.0 mg/ml or uncoated control. Treatments were randomized between jaw quadrants. The mucoperiosteal flaps were advanced, adapted and sutured to submerge the implants for primary intention healing. The animals received fluorescent bone markers at weeks 3, 4, 7 and 8 post-surgery when they were euthanized for histologic evaluation. RESULTS: Jaw quadrants receiving implants coated with rhBMP-2 exhibited gradually regressing swelling that became hard to palpate disguising the contours of the implants. The histologic evaluation showed robust bone formation reaching or exceeding the implant platform. The newly formed bone exhibited characteristics of the adjoining resident Type II bone including cortex formation for sites receiving implants coated with rhBMP-2 at 0.75 or 1.5 mg/ml. Sites receiving implants coated with rhBMP-2 at 3.0 mg/ml exhibited more immature trabecular bone formation, seroma formation and peri-implant bone remodelling resulting in undesirable implant displacement. Control implants exhibited minimal, if any, bone formation. Thus, implants coated with rhBMP-2 at 0.75, 1.5 and 3.0 mg/ml exhibited significant bone formation (height and area) compared with the sham-surgery control averaging (+/-SD) 4.4+/-0.4, 4.2+/-0.7 and 4.2+/-1.2 versus 0.8+/-0.3 mm; and 5.0+/-2.2, 5.6+/-2.2 and 7.4+/-3.5 versus 0.7+/-0.3 mm(2), respectively (p<0.01). All the treatment groups exhibited clinically relevant osseointegration. CONCLUSIONS: rhBMP-2 coated onto titanium porous oxide implant surfaces induced clinically relevant local bone formation including vertical augmentation of the alveolar ridge and osseointegration. Higher concentrations/doses were associated with untoward effects.