See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/257613254 10:3482. Adverse effects associated with high dose rhBMP-2 use in anterior cervical spine fusion Article in The Spine Journal · July 2005 DOI: 10.1016/j.spinee.2005.05.084 CITATIONS READS 96 242 7 authors, including: Lisa B E Shields Christopher Brian Shields Norton Healthcare Norton Healthcare 98 PUBLICATIONS 1,372 CITATIONS 190 PUBLICATIONS 4,234 CITATIONS SEE PROFILE SEE PROFILE All content following this page was uploaded by Lisa B E Shields on 13 December 2016. The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document and are linked to publications on ResearchGate, letting you access and read them immediately. SPINE Volume 31, Number 5, pp 542–547 ©2006, Lippincott Williams & Wilkins, Inc. Adverse Effects Associated With High-Dose Recombinant Human Bone Morphogenetic Protein-2 Use in Anterior Cervical Spine Fusion Lisa B. E. Shields, MD,* George H. Raque, MD,* Steven D. Glassman, MD,† Mitchell Campbell, MD,† Todd Vitaz, MD,* John Harpring, MD,* and Christopher B. Shields, MD* Study Design. A retrospective review of patients who underwent an anterior cervical fusion using recombinant human bone morphogenetic protein (rhBMP)-2 with an absorbable collagen sponge (INFUSE姞; Medtronic Sofamor Danek, Minneapolis, MN). Objective. To ascertain the complication rate after the use of high-dose INFUSE姞 in anterior cervical fusions. Summary of Background Data. The rhBMP-2 has been primarily investigated in lumbar spine fusions, where it has significantly enhanced the fusion rate and decreased the length of surgery, blood loss, and hospital stay. Methods. We present 151 patients who underwent either an anterior cervical discectomy and fusion (n ⫽ 138) or anterior cervical vertebrectomy and fusion (n ⫽ 13) augmented with high-dose INFUSE姞 between July 2003 and March 2004. The rhBMP-2 (up to 2.1 mg/level) was used in the anterior cervical discectomy and fusions. Results. A total of 35 (23.2%) patients had complications after the use of high-dose INFUSE姞 in the cervical spine. There were 15 patients diagnosed with a hematoma, including 11 on postoperative day 4 or 5, of whom 8 were surgically evacuated. Thirteen individuals had either a prolonged hospital stay (⬎48 hours) or hospital readmission because of swallowing/breathing difficulties or dramatic swelling without hematoma. Conclusions. A significant rate of complications resulted after the use of a high dose of INFUSE姞 in anterior cervical fusions. We hypothesize that in the cervical area, the putative inflammatory effect that contributes to the effectiveness of INFUSE姞 in inducing fusion may spread to adjacent critical structures and lead to increased postoperative morbidity. A thorough investigation is warranted to determine the optimal dose of rhBMP-2 that will promote cervical fusion and minimize complications. Key words: rhBMP-2, INFUSE姞, anterior cervical discectomy and fusion, cervical vertebrectomy, cervical fusion, complications. Spine 2006;31:542–547 From the Departments of *Neurological Surgery and †Orthopedic Surgery, University of Louisville School of Medicine, Louisville, KY. Acknowledgment date: October 26, 2004. First revision date: December 7, 2004. Second revision date: February 7, 2005. Third revision date: March 11, 2005. Acceptance date: March 14, 2005. The device(s)/drug(s) that is/are the subject of this manuscript is/are not FDA-approved for this indication and is/are not commercially available in the United States. No funds were received in support of this work. One or more of the author(s) has/have received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript: e.g., honoraria, gifts, consultancies, royalties, stocks, stock options, decision making position. Address correspondence and reprint requests to Christopher B. Shields, MD, Department of Neurological Surgery, School of Medicine, University of Louisville, Louisville, KY 40292; E-mail: cbshields1@aol.com 542 Anterior cervical discectomy and fusion (ACDF) is a widely practiced surgical procedure for the treatment of cervical spondylosis and disc herniation. This intervention initially used autogenous bone, most commonly from the iliac crest, as the interbody graft. The morbidity resulting from graft-site harvest may affect up to 30% of patients, and include neurologic damage, chronic pain, and risk of infection.1,2 This staggering percentage led to the use of bone graft substitutes, including homologous bone and a family of growth factors known as bone morphogenetic proteins (BMPs). Both recombinant human bone morphogenetic protein-2 and -7 (rhBMP-2 and OP-1) have been used in the clinical setting in place of autogenous bone graft, and for bone augmentation and repair.3,4 The rhBMP-2 has been capable of osteoinduction, specifically, the ability to induce de novo bone formation at a nonbony site.5 It has been studied extensively in lumbar spine fusions using animal models6 –12 and in human beings.1,13–17 Lumbar fusion using rhBMP-2 has reduced the operating time, blood loss during surgery, and hospital stay, and has reflected a higher fusion rate at 24 months compared to lumbar fusion using autogenous bone. The success of a fusion using rhBMP-2 is dependent on a triad of factors, including site, dose, and carrier specificity.18 The INFUSE威 Bone Graft (Medtronic Sofamor Danek, Minneapolis, MN) combines rhBMP-2 with an absorbable collagen sponge to induce osteogenesis.19 The Food and Drug Administration has approved the use of a type-I collagen sponge enhanced with rhBMP-2 in combination with a tapered, threaded fusion cage (LTCAGE威; Medtronic Sofamor Danek) for the treatment of lumbar degenerative disc disease.20 Although less attention has been focused on the use of rhBMP-2 in anterior cervical spine fusions, both animal21–23 and human24 studies have shown favorable outcomes. The primary feature was the ability of rhBMP-2 to enhance significantly the rate of fusion without associated adverse effects. We reviewed the cases of 151 patients who underwent either an ACDF or anterior cervical vertebrectomy and fusion using a higher dose of INFUSE威 than had been previously studied, over an 8-month period. Materials and Methods Patient Data. A total of 151 patients underwent either an ACDF (n ⫽ 138) or vertebrectomy (n ⫽ 13) using INFUSE威 High-Dose Recombinant Human Bone Morphogenetic Protein-2 • Shields et al 543 Bone Graft between July 2003 and March 2004. There were 62 men (41.0%) and 89 women (59.0%) included in the study. The ages ranged between 28 and 80 years, with a mean age of 49.9 years. All individuals had pursued conservative treatment before surgical intervention. Preoperative imaging studies revealed spondylosis in 112 (74.2%) patients and a disc herniation in 39 (25.8%). The following preoperative symptoms were reported: neck pain in 148 (98.0%), arm pain in 136 (90.0%), arm numbness in 106 (70.2%), and arm weakness in 84 patients (55.6%). A total of 30 (20.0%) patients had undergone previous cervical surgical procedures, including an anterior discectomy in 29 and an anterior vertebrectomy in 1. Numerous behavioral or medical conditions associated with an increased risk during anterior cervical surgery were documented: cigarette smoking in 59 patients (39.1%), hypertension in 53 (35.1%), diabetes mellitus in 15 (9.9%), rheumatoid arthritis in 2 (1.3%), Coumadin (Bristol-Myers Squibb Co., Princeton, NJ) use in 2 (1.3%), and 1 patient each of the following—prior radiation to the cervical region, factor V Leiden mutation (clotting disorder), hemochromatosis, von Willebrand disorder, acetylcholinesterase inhibitor deficiency, or fish allergy in 1 patient each. Graft and rhBMP-2. Of the 138 patients who underwent an ACDF, 135 received a resorbable poly(D,L-lactic acid) cage (HYDROSORB 228; Medtronic Sofamor Danek), with a collagen carrier enhanced with rhBMP-2 within the graft, while 3 patients received the homologous bone graft (CORNERSTONE威; Medtronic Sofamor Danek), with the rhRMP-2-laden collagen carrier inserted in the graft. A titanium mesh cage (PYRAMESH 228 ; Medtronic Sofamor Danek) was used in all 13 individuals who underwent an anterior cervical vertebrectomy and fusion. A total of up to 2.1 mg of rhBMP-2 per level in the ACDFs was reconstituted as a 1.4 mL solution and soaked in a sponge measuring 2.5 ⫻ 5.0 cm. The total surface area of the sponge was 12.5 cm2 (0.112 mL solution/cm2). The rhBMP-2 was placed within the construct in the ACDFs, with a higher amount used in the anterior cervical vertebrectomy and fusions. Surgical Technique ACDF and Anterior Cervical Vertebrectomy and Fusion. A right-sided incision was made in the cervical area. An intraoperative lateral cervical spine radiograph was used to confirm the appropriate level or levels. The modified Smith-Robinson technique was subsequently performed. At completion of the decompression in the ACDFs, cartilaginous endplates were decorticated followed by wound irrigation with copious amounts of bacitracin-containing solution. The cage or graft was selected, filled with INFUSE威, tapped into the disc space, and countersunk 1 mm. Additional INFUSE威 was frequently placed lateral and anterior to the graft (under the plate) within the disc space. An anterior cervical plate (ZEPHYR 228; Medtronic Sofamor Danek) was then placed. An intraoperative radiograph confirmed proper alignment and fixation of the bone graft and plate. Vocal cord monitoring was used throughout the surgical procedure. At completion of the decompression in the anterior cervical vertebrectomy and fusions, the foramina were opened bilaterally. A PYRAMESH 228 cage was appropriately sized, cut, and contoured for the vertebrectomy defect. The cage was packed with a combination of local bone and INFUSE威, and impacted into the defect. Additional INFUSE威 was packed an- Table 1. A Total of 151 Patients Underwent Either an ACDF or an Anterior Cervical Vertebrectomy and Fusion Using INFUSE姞 Procedure No. (%) ACDF (n ⫽ 138) 1-Level 2-Level adjacent 3-Level adjacent 2-Level noncontiguous Anterior vertebrectomy and fusion (n ⫽ 13) 1-Level 2-Level 3-Level 4-Level 61 (44.2) 68 (49.3) 6 (4.3) 3 (2.2) 4 (30.8) 5 (38.5) 3 (23.1) 1 (7.7) terior and lateral to the cage. Drill sites were formed bilaterally in the vertebral bodies, and a cervical plate was subsequently placed with 13-mm screws. An intraoperative lateral cervical radiograph showed appropriate positioning of the plate and cage. Results Surgical Outcomes A total of 138 patients underwent either a 1, 2, or 3-level adjacent ACDF, or a noncontiguous 2-level ACDF (Table 1). There were 13 individuals who underwent a 1, 2, 3, or 4-level anterior vertebrectomy. The anterior approach solely was used in 149 patients, while 3 patients underwent a 2 in 1 procedure, consisting of both anterior and posterior cervical approaches on the same day. A drain was surgically placed in 35 (25.4%) of 138 patients who underwent an ACDF and in 8 (61.5%) of 13 patients who underwent an anterior cervical vertebrectomy and fusion. The majority of individuals were released from the hospital within 24 hours of their surgery. Complications Hematoma. There were 15 (9.9%) patients diagnosed with a hematoma after undergoing anterior cervical surgery using INFUSE威 (Table 2). Eleven patients were diagnosed with a hematoma on the fourth or fifth postoperative day, consisting of 7 and 4 patients, respectively. There were 8 patients who underwent surgical evacuation of the hematoma (Figures 1, 2). Of these individuals, 4 had undergone a 2-level adjacent ACDF, 2 a 1-level vertebrectomy, and 2 a 2-level vertebrectomy. There was 1 patient who had previously undergone a 1-level ACDF, while 3 previously underwent a 2-level ACDF. Of the 7 Table 2. Presence of a Hematoma After Anterior Cervical Spine Fusion Postoperative Day (Previous Anterior Cervical Fusion) Procedure 1-Level 2-Level 1-Level 2-Level ACDF ACDF vertebrectomy vertebrectomy Less than Day 4 Days 4 or 5 1 (1) 0 (0) 1 (1) 1 (0) 4 (1) 5 (1) 1 (1) 1 (1) 544 Spine • Volume 31 • Number 5 • 2006 Figure 1. Cervical computerized tomography indicates an extensive postoperative hematoma (outlined by arrowheads) in the retropharyngeal space that displaces the trachea anteriorly at the level of the allograft INFUSE姞 construct. The hematoma is predominantly on the right side, and is 2.0-cm thick, 5.5-cm wide, and 8.5-cm long. The horizontal black radiolucency posterior to the hematoma represents a plate artifact. The hematoma was evacuated. patients diagnosed with a hematoma who did not undergo evacuation of the hematoma, 4 had undergone a 1-level ACDF, 2 a 2-level adjacent ACDF, and 1 a 2-level noncontiguous ACDF. There was 1 patient who had previously undergone a 2-level ACDF and another who previously underwent a 1-level ACDF. A drain was placed in 7 patients (46.7%) who had a hematoma at the index procedure. Prolonged Hospital Stay (>48 hours) or Readmission for Swallowing/Breathing Difficulties Without Hematoma or Reoperation. There were 13 (8.6%) patients who had either a prolonged hospital stay (⬎48 hours) (n ⫽ 5) or readmission to the hospital (n ⫽ 8) after undergoing anterior cervical surgery using INFUSE威 (Table 3). Their complaints included dysphagia, respiratory difficulties, and incisional swelling. There were 6 patients who were readmitted on either postoperative day 3 or 4. Eight individuals had undergone a 2-level ACDF, 3 a 1-level ACDF, 1 a 2-level vertebrectomy, and 2 a 1-level vertebrectomy. Only 1 patient in this category had undergone previous anterior cervical surgery. There were 3 (23.1%) patients who underwent placement of a drain at the index procedure. Additional Complications. There were 10 patients (6.6%) who had a myriad of additional complications after an- Figure 2. Gadolinium-enhanced cervical computerized tomography that indicates extensive symmetrical hemorrhage (arrowheads) located anterior to the allograft INFUSE姞 construct. The hematoma encircles the carotid arteries (circular enhancing structures within the hematoma), causing marked anterior displacement of the trachea and esophagus. The hematoma is 4.0-cm thick, 7.0-cm wide, and 12.0-cm long. The hematoma was evacuated. terior cervical surgery using INFUSE威, including syndrome of inappropriate secretion of antidiuretic hormone (SIADH), collapse of the upper lobe of the right lung, Horner syndrome, vocal cord palsy, superficial Table 3. Prolonged Hospital Stay (>48 hs) or Readmission for Swallowing/Respiratory Difficulties or Incisional Swelling Without Evidence of Hematoma Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 Procedure Prolonged Stay or Readmission (POD) Previous Anterior Cervical Fusion 1-Level ACDF 2-Level ACDF 2-Level ACDF 2-Level ACDF 2-Level vertebrectomy 1-Level ACDF 1-Level ACDF 2-Level ACDF 2-Level ACDF 2-Level ACDF 2-Level ACDF 2-Level ACDF 1-Level vertebrectomy Prolonged stay Prolonged stay Prolonged stay Prolonged stay Prolonged stay Readmission (2) Readmission (4) Readmission (3) Readmission (3) Readmission (3) Readmission (3) Readmission (5) Readmission (4) 1-Level ACDF POD indicates postoperative day. High-Dose Recombinant Human Bone Morphogenetic Protein-2 • Shields et al 545 Table 4. Complications After Anterior Cervical Spine Fusion Besides Hematoma or Swallowing/ Respiratory Difficulties Patient 1 2 3 4 5 6 7 8 9 10 Previous Anterior Cervical Fusion Complication Procedure SIADH Collapse of right upper lobe of lung Horner syndrome Horner syndrome Vocal cord palsy Vocal cord palsy Superficial stitch abscess Implant dislodgement Implant dislodgement Graft resorption 2-Level ACDF 3-Level vertebrectomy (2 in 1) 1-Level ACDF 1-Level ACDF 1-Level ACDF 1-Level ACDF 2-Level ACDF 1-Level ACDF 1-Level ACDF 1-Level ACDF 2-Level vertebrectomy 1-Level ACDF 1-Level ACDF 1-Level ACDF stitch abscess, implant dislodgement, and graft resorption (Table 4). Discussion The rhBMP-2 has been investigated in lumbar spinal fusions in several prospective randomized human clinical trials since 1997.1,13–17 In these previous studies, patients in both the investigational groups who received rhBMP-2 on an absorbable collagen sponge (INFUSE威 Bone Graft) and those in the control groups who received autogenous iliac crest bone graft had an improvement in clinical outcome, however, mean operating time, blood loss, and hospital stay were less in the rhBMP-2 groups.1,13–15,17 Furthermore, the investigational patients had a higher fusion rate at 24 months.1,13–17 Based on clinical data, the Food and Drug Administration has advised that rhBMP-2 be approved as the first complete bone graft substitute for spinal fusion.5,25 Although the experience with rhBMP-2 in anterior cervical fusion is far more limited, both animal and human pilot studies have been performed. Takahashi et al22 studied the effect of 0, 5, and 50 ␮g of rhBMP-2 added to a porous hydroxyapatite graft in goats that underwent a 3-level anterior discectomy. A solid fusion was noted in goats that received 50 ␮g of rhBMP-2. Zdeblick et al23 studied the effect of a cervical intervertebral device filled with either autogenous bone graft or rhBMP-2 in 21 Alpine goats that underwent a 3-level ACDF. They reported a higher arthrodesis rate and accelerated bone formation in the group treated with a rhBMP-2-filled BAK device compared to the groups that underwent placement of an autogenous bone-filled BAK device that was either a standard titanium device or hydroxyapatitecoated. Baskin et al24 conducted a human pilot study in anterior cervical discectomy and interbody fusion. The investigational group received a fibular allograft containing a rhBMP-2-laden collagen carrier followed by placement of an anterior cervical plate. The control group received a fibular allograft filled with cancellous iliac crest autograft followed by plating. The 33 patients underwent either a 1-level or 2-level arthrodesis. Both groups had significant improvement in both neck and arm pain, as well as a 100% fusion rate at 6 months. The patients in the rhBMP-2 group avoided the pain, scarring, and morbidity associated with harvesting bone from the iliac crest. Important differences exist in both rhBMP-2 dose and delivery mechanism between the technique used in the study by Baskin et al24 as compared to our cases. Baskin et al24 used 0.4 mL (0.6 mg) of reconstituted rhBMP-2 solution distributed on a 1.5 ⫻ 2.5-cm sponge within the bone graft per level of the fusion. In our study, up to 2.1 mg of rhBMP-2 per level was reconstituted as a 1.4 mL solution and soaked in a sponge measuring 2.5 ⫻ 5.0 cm. One sponge per level was used in the ACDFs that was placed within and occasionally on the lateral surface of a resorbable cage. In this respect, the surface area of the sponge in the study by Baskin et al24 was 3.75 cm2 (0.107 mL solution/cm2), whereas ours was 12.5 cm2 (0.112 mL solution/cm2) per level. The concentration of Baskin et al’s and our rhBMP-2 mixture was nearly identical. Also, an even higher amount of rhBMP-2 was used in our study during the anterior vertebrectomies and fusions compared to the ACDFs. The relevance, if any, of using a resorbable cage for the ACDFs in our study versus a Smith-Robinson style interbody allograft as used in the study by Baskin et al24 is unknown. The anterior surgical approach for the treatment of neural compression by either a disc herniation or osteophyte has gained in popularity and is associated with a low postoperative morbidity (approximately 3%).26 A compilation of reports representing more than 700 cases of anterior cervical fusion showed that the most frequent postoperative complications included dysphagia, hoarseness, and hematomas.27 The incidence of dysphagia after ACDF has varied between 11% and 67%.28 Smith-Hammond et al28 reported a significant increase in swallowing complaints after anterior cervical fusion, with the majority of patients recovering within 2 months. Radiologic evidence of dysphagia was significantly associated with an age of patients older than 60 years, although was not related to surgical level, instrumentation, or operating time. Hoarseness has been reported as being transient in 8% of patients and permanent in 2%.29 Tew and Mayfield30 presented the incidence of complications of 500 surgical procedures with the anterior cervical approach as: recurrent laryngeal palsy, 4 cases, including 1 permanent (0.8%), and 1 case (0.2%) each of hematoma, infection, and Horner syndrome. Although the reported incidence of recurrent laryngeal nerve palsy is approximately 1%, it has been reported as high as 11%.31 Other complications may include graft extrusion or resorption,32 a dural tear and cerebrospinal fluid leak,25 or a superficial or deep wound infection.33,34 546 Spine • Volume 31 • Number 5 • 2006 In this series, a total of 35 (23.2%) patients had complications after undergoing an anterior cervical fusion using INFUSE威. Although the lack of a prospective design and concurrent control group is an obvious shortcoming of the study, this rate of complications is markedly higher than either historical literature controls or our anecdotal clinical experience. The complications seen in 28 of these patients are most likely related to the use of high-dose INFUSE威. Specifically, hematomas that occurred both more frequently and after the immediate postoperative period, extensive swallowing and respiratory difficulties, and dramatic neck swelling beyond the area of the incision, represented a different clinical presentation than our prior experience. The remaining complications do not appear to be related to the use of INFUSE威, including the SIADH, collapse of a lung, Horner syndrome, hoarseness/vocal cord palsy, superficial stitch abscess, implant dislodgement, and graft resorption. There were 15 patients who had a hematoma after undergoing an anterior cervical fusion augmented with high-dose INFUSE威. Eleven individuals were diagnosed with the hematoma on postoperative days 4 or 5. There were 11 cases that were ACDFs, and 4 were anterior vertebrectomies and fusions, reflecting 7.9% of the total ACDFs and 30.8% of the total vertebrectomies. This finding may be a result of the higher amount of INFUSE威 placed within and beside the cage during the vertebrectomy procedure. A prior ACDF may also serve as a potential risk factor. There were 6 individuals diagnosed with a hematoma who had previously undergone an anterior cervical fusion, including 2 with a 1-level ACDF and 4 with a 2-level ACDF. Of the 4 patients who underwent a vertebrectomy and fusion, and had a hematoma develop after surgery, 3 had previously undergone a 2-level ACDF. The risk of complications may be considerably increased in patients who undergo an anterior cervical vertebrectomy and fusion, and who have had a previous anterior cervical fusion. A total of 13 patients had complications other than a hematoma after the anterior cervical fusion, including swallowing/respiratory difficulties and incisional swelling. These patients either remained in the hospital for longer than 48 hours after their cervical surgery or were readmitted to the hospital. There were 11 individuals who had undergone an ACDF, while 2 underwent an anterior cervical vertebrectomy and fusion. Compared to the hematoma group, in which 6 of the 15 individuals had undergone a previous anterior cervical fusion, only 1 patient in the nonhematoma group had previously undergone an anterior cervical fusion, consisting of a 1-level ACDF. In addition, only 2 patients in the nonhematoma group underwent an anterior cervical vertebrectomy and fusion compared to 4 individuals in the hematoma group. The data suggest that the rate of complications seen in this series may be related to the dose of INFUSE威 used. Baskin et al24 used a rhBMP-2 dose of 0.6 mg/level without reported complications, as opposed to the dose of up to 2.1 mg/level of rhBMP-2 for the ACDF procedures in this study. Furthermore, a higher percentage of complications occurred after anterior cervical vertebrectomy and fusion, in which an even larger amount of rhBMP-2 was used. It is also possible that the complication rate could be related to surgical technique, the use of a resorbable implant, or placement of INFUSE威 outside of the implant. Regardless of graft material, the risk of a hematoma developing may be increased with extensive surgical exposure, such as associated with a vertebrectomy compared to an ACDF. Furthermore, previous anterior cervical spine surgery may also increase the risk of hemorrhage because hemostasis is more difficult to attain within the vicinity of a scar. However, the hematomas associated with highdose INFUSE威 differ from those resulting as a complication after anterior cervical fusion without the use of INFUSE威 in that the former are encountered despite the use of a drain, in a higher frequency, and at a later date (specifically, postoperative day 4 or 5). Almost half the patients who had a postoperative hematoma had a drain placed as a component of their surgical procedure. Cervical computerized tomography may prove beneficial after surgery to differentiate between hematoma and edema, yet may be deferred in cases when a patient’s compromised condition necessitates immediate cervical exploration. The present review represents the largest reported series treated with an anterior cervical fusion using INFUSE威. The high complication rate is alarming and warrants intense scrutiny. The favorable effect of INFUSE威, specifically early osteogenesis, may include an inflammatory reaction that can dissipate to critical structures within the cervical area. Although a myriad of complications, including dysphagia, hoarseness, and hematoma, have been associated with anterior cervical fusion before the use of INFUSE威, the rate of complications in this series implies a causal relationship to the use, or potentially misuse, of INFUSE威. This study emphasizes the risk associated with application of new technologies in areas in which extensive clinical experience is not available. Further investigation is necessary to determine the optimal surgical technique and dose of rhBMP-2 that will effectively enhance anterior cervical fusion, but minimize complications. Key Points ● The rhBMP-2 promotes bone formation and enhances the rate of spinal fusion. ● This study raises the possibility that the use of up to 3.5 times the previously published dose of INFUSE威 may lead to postoperative morbidity, such as hematomas, dysphagia, and excessive edema, after anterior cervical fusion. ● Determination of the optimal dose of rhBMP-2 is warranted to decrease the likelihood of complications after anterior cervical fusion. High-Dose Recombinant Human Bone Morphogenetic Protein-2 • Shields et al 547 Acknowledgment The authors thank J. Timothy Burger, MD, and Yi Ping Zhang, MD, for their contributions to this study. The authors also thank Norton Healthcare and the Kentucky Spinal Cord and Head Injury Research Trust for their support. Dr. Christopher B. Shields holds the Norton Hospital Chair in Neurosurgery. References 1. Boden SD, Zdeblick TA, Sandhu HS, et al. 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