Intraoperative high-dose epinephrine infiltration in cleft palate repair.

OBJECTIVE: Local infiltration of epinephrine before surgical procedures is a well-accepted technique to promote vasoconstriction. Typically, the dose of epinephrine is limited by the co-administration of local anesthetic as well as the risk for arrhythmogenesis and hemodynamic changes. In addition, some controversy exists regarding the acceptable dose of epinephrine given to children. This retrospective review examines the use and safety of "high-dose" epinephrine in palatoplasty at our cleft-craniofacial center. DESIGN: A retrospective review of epinephrine use in primary palatoplasty at a tertiary children's hospital from 2003 to 2007 was performed. Operative and anesthetic records were reviewed for hypertension (systolic blood pressure, >120 or diastolic blood pressure, >70) and tachycardia (>190 beats per min) as defined by the American Heart Association guidelines, as well as dysrhythmias, intraoperative complications, and postoperative complications. RESULTS: A total of 102 patients who underwent consecutive primary palatoplasties performed by a single surgeon were identified. After the induction of anesthesia and before incision, the patients received an initial epinephrine infiltration (without local anesthetic) up to a maximum 10 µg/kg. The average total dose of epinephrine administered during palatoplasty was 12.8 µg/kg (range, 3.2-75.0 µg/kg). Doses up to a maximum of 10 µg/kg were administered as needed at 30-minute intervals. No instances of clinically unstable tachycardia or hypertension occurred. A total of 21.6% of the patients (22/102) experienced an instance of hypertension, and only 13.7% of these (14/102) were related to epinephrine administration. One (1%) postoperative fistula was identified. CONCLUSIONS: Locally infiltrated high-dose epinephrine during palatoplasty can be safely used as a means of vasoconstriction. Doses reaching a maximum of 10 µg/kg, administered as needed at 30-minute intervals, do not seem to be a significant risk for hemodynamic instability, intraoperative complications, or postoperative complications.

Pediatric craniofacial fractures due to violence: comparing violent and nonviolent mechanisms of injury.

BACKGROUND: This study examines the epidemiologic data of pediatric craniofacial fractures secondary to violence, comparing these data to craniofacial fractures sustained from all other causes. METHODS: A retrospective review was completed on all patients who presented to the emergency department of a major urban children's hospital from 2000 to 2005 with a craniofacial fracture. Data were compared between patients with fractures due to violent and nonviolent mechanisms. Socioeconomic analysis was performed using Geographic Information System mapping and 2000 US Census data by postal code. RESULTS: One thousand five hundred twenty-eight patients were diagnosed with skull and/or facial fractures. Isolated skull fractures were excluded, leaving 793 patients in the study. Ninety-eight children were injured due to violence, and 695 were injured from a nonviolent cause. Patients with violence-related fractures were more likely to be older, male, and nonwhite and live in a socioeconomically depressed area. A greater number of patients with violence-related injuries sustained nasal and mandible angle fractures, whereas more patients with non-violence-related injuries sustained skull and orbital fractures. Those with violence-related craniofacial fractures had a lower percentage of associated multiorgan system injuries and a lower rate of hospital admissions and intensive care unit admissions. The rate of open reduction and internal fixation for craniofacial fractures was similar in both groups. CONCLUSIONS: Patients with violence-related fractures had fewer associated serious injuries and lower morbidity and lived in a more socioeconomically depressed area. The information gained from this descriptive study improves our ability to characterize this population of pediatric patients and to identify the associated constellation of injuries in such fractures.

BMP-2-mediated regeneration of large-scale cranial defects in the canine: an examination of different carriers.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered on an absorbable collagen sponge is a U.S. Food and Drug Administration-approved therapy shown to be an effective means of generating bone formation in multiple clinical settings. However, the optimum dose and delivery of rhBMP-2 to the calvaria are undetermined. The aim of the authors' study was to investigate the use of rhBMP-2 in addressing calvarial defects in a large-animal model through a variety of modifications to this U.S. Food and Drug Administration-approved therapy. METHODS: Twenty-three adult canines underwent the creation of a standard calvarial defect and received either no treatment, 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge, 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge with corticocancellous chips, 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge with MasterGraft Granules, or 0.4 mg/ml rhBMP-2 in a compression-resistant matrix carrier. Direct comparisons of defect radiopacity were performed at 0, 8, 16, and 24 weeks postoperatively before the animals were euthanized. All specimens were evaluated qualitatively with histology. RESULTS: Surgical control animals had an average defect radiopacity of 32.7 percent at study completion compared with an average of 99.95 percent across all treatment groups. Ectopic bone formation was found consistently in all treatment groups with varying degrees of severity. Regenerated bone thickness, compactness, and organization varied qualitatively between groups. CONCLUSIONS: Treatment with 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge with MasterGraft Granules showed the least amount of ectopic bone formation and the most compact bone formation within the defect, and produced reasonably consistent bony thickness across the defect. Future studies should focus on spatial regulation of rhBMP-2 to minimize unwanted bone formation.

Novel animal model of calvarial defect in an infected unfavorable wound: reconstruction with rhBMP-2.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered on an absorbable collagen sponge has been shown to induce the healing of acute, primary, large-scale calvarial defects in rabbits. However, clinical circumstances often require the reconstruction of a previously infected and chronically scarred wound. This study was designed to evaluate the efficacy of rhBMP-2/absorbable collagen sponge to improve healing in the previously infected, unfavorable calvarial defect model. METHODS: Subtotal defects were made in the calvariae of 15 adult New Zealand White rabbits. The bone flap was inoculated with Staphylococcus aureus and replaced in situ. After a 2-week infection period, animals underwent bone flap removal and a 10-day course of antibiotic therapy. On postoperative day 42, the defect was exposed and treated with (1) no intervention/control (group 1; n = 5), or (2) absorbable collagen sponge with 0.43 mg/ml of rhBMP-2 (group 2; n = 10). Bone growth was analyzed with serial computed tomographic imaging and postmortem histology. Percentage bone healing was compared between groups using the t test. RESULTS: The treatment group (group 2) demonstrated statistically more healing (55.6 percent) compared with the control group (group 1) (29 percent; p < 0.01). However, rhBMP-2-induced bone was not histologically or radiographically similar to native bone, lacking both continuity and a well-defined diploic space. CONCLUSIONS: These data suggest that rhBMP-2-treated collagen sponges may be useful for the repair of calvarial defects following infection. However, the osseous healing observed in this study was significantly less than previous reports in acute, noninfected models and was dissimilar to native bone. Further work is needed to optimize treatment of the previously infected calvarial wound with rhBMP-2.

Direct comparison of progenitor cells derived from adipose, muscle, and bone marrow from wild-type or craniosynostotic rabbits.

BACKGROUND: Reports have identified cells capable of osteogenic differentiation in bone marrow, muscle, and adipose tissues, but there are few direct comparisons of these different cell types. Also, few have investigated the potential connection between a tissue-specific abnormality and cells derived from seemingly unrelated tissues. In this article, the authors compare cells isolated from wild-type rabbits or rabbits with nonsyndromic craniosynostosis, defined as the premature fusion of one or more of the cranial sutures. METHODS: Cells were derived from bone marrow, adipose, and muscle of 10-day-old wild-type rabbits (n = 17) or from age-matched rabbits with familial nonsyndromic craniosynostosis (n = 18). Cells were stimulated with bone morphogenetic protein-4 (BMP4), and alkaline phosphatase expression and cell proliferation were assessed. RESULTS: In wild-type rabbits, cells derived from muscle had more alkaline phosphatase activity than cells derived from either adipose or bone marrow. The cells derived from craniosynostotic rabbit bone marrow and muscle were significantly more osteogenic than those derived from wild-type rabbits. Adipose-derived cells demonstrated no significant differences. Although muscle-derived cells were most osteogenic in wild-type rabbits, bone marrow-derived cells were most osteogenic in craniosynostotic rabbits. CONCLUSIONS: These results suggest that cells from different tissues have different potentials for differentiation. Furthermore, cells derived from rabbits with craniosynostosis were different from cells from wild-type rabbits. Interestingly, cells derived from the craniosynostotic rabbits were not uniformly more responsive compared with wild-type cells, suggesting that specific tissue-derived cells may react differently in individuals with craniosynostosis.

BMP-4 response in wild-type and craniosynostotic rabbit bone cells.

BACKGROUND: Craniosynostosis results from improper regulation of bone formation. Investigations of cells derived from patients with craniosynostosis suggest that craniosynostotic bone-derived cells have increased osteogenic or proliferative capacities compared with other cells. Research into the pathogenesis of craniosynostosis using cells derived from children has been hindered by small sample sizes and inappropriate control cell populations. The authors hypothesized that cells derived from suture-associated regions of bone from craniosynostotic rabbits were more osteogenic and proliferative than bone cells derived from wild-type rabbits. METHODS: This study used cells derived from a colony of rabbits with congenital, nonsyndromic craniosynostosis (n = 20) or from age-matched wild-type rabbits (n = 20). Bone cells derived from either suture-associated or non-suture-associated bone were challenged with osteogenic stimuli and assessed for osteogenic differentiation. RESULTS: The results suggest a high level of variability among cells derived from different individual rabbits. Also, craniosynostotic bone cells have a larger response to recombinant human bone morphogenetic protein 4 stimulation relative to baseline expression of alkaline phosphatase, although overall alkaline phosphatase expression was higher in wild-type bone cells. Cell proliferation showed some differences at 3 days in culture, but no differences were found at 7 days in culture. CONCLUSIONS: This study suggests that bone cells in this rabbit model of craniosynostosis are generally similar to wild-type cells. Also, because of variability, it is necessary to have larger sample sizes than are normally available in human studies. Therefore, cells from the rabbit model may be a powerful in vitro model for further craniosynostosis research.

Effects of flutamide therapy on craniofacial growth and development in a model of craniosynostosis.

Research has implicated the faulty regulation of transforming growth factor beta signaling as one mechanism for premature calvaria suture fusion. Androgens have been shown to increase the expression and activity of the transforming growth factor beta, resulting in increased osteoblast proliferation and differentiation and possibly premature suture fusion. The present study was designed to test the hypothesis that flutamide, an androgen receptor-blocking agent, would "rescue" a coronal suture destined to fuse and improve craniofacial growth in a familial rabbit model of craniosynostosis. Thirty rabbits with delayed-onset, coronal suture synostosis were examined via longitudinal cephalometry. The rabbits were divided into 4 groups: (1) sham surgical controls (n = 10), (2) bovine serum albumin (500 ng) protein controls (n = 6), (3) flutamide diluent controls (n = 6), and (4) flutamide (15 mg dissolved in ethanol) experimental group (n = 8). At 10 days of age, radiopaque amalgam markers were implanted in all rabbits on either side of the coronal suture to monitor sutural growth. At 25 days of age, the bovine serum albumin, ethanol, and flutamide were combined with a slow-resorbing collagen vehicle and injected subperiosteally above the coronal suture into the respective groups. Although results revealed a slight but significant increase in coronal suture marker separation in flutamide-treated rabbits compared with controls at 42 days of age, few significant differences were noted for craniofacial growth and intracranial volume among groups. Results suggest that androgen receptor-blocking using flutamide may only provide a transient rescue to suture fusion in this model. Further research is needed to investigate the effects of hormones on suture development and maintenance.

Inkjet-based biopatterning of bone morphogenetic protein-2 to spatially control calvarial bone formation.

The purpose of this study was to demonstrate spatial control of osteoblast differentiation in vitro and bone formation in vivo using inkjet bioprinting technology and to create three-dimensional persistent bio-ink patterns of bone morphogenetic protein-2 (BMP-2) and its modifiers immobilized within microporous scaffolds. Semicircular patterns of BMP-2 were printed within circular DermaMatrix human allograft scaffold constructs. The contralateral halves of the constructs were unprinted or printed with BMP-2 modifiers, including the BMP-2 inhibitor, noggin. Printed bio-ink pattern retention was validated using fluorescent or (125)I-labeled bio-inks. Mouse C2C12 progenitor cells cultured on patterned constructs differentiated in a dose-dependent fashion toward an osteoblastic fate in register to BMP-2 patterns. The fidelity of spatial restriction of osteoblastic differentiation at the boundary between neighboring BMP-2 and noggin patterns improved in comparison with patterns without noggin. Acellular DermaMatrix constructs similarly patterned with BMP-2 and noggin were then implanted into a mouse calvarial defect model. Patterns of bone formation in vivo were comparable with patterned responses of osteoblastic differentiation in vitro. These results demonstrate that three-dimensional biopatterning of a growth factor and growth factor modifier within a construct can direct cell differentiation in vitro and tissue formation in vivo in register to printed patterns.

Nasal tip complications of primary cleft lip nasoplasty.

BACKGROUND AND PURPOSE: Complications of primary nasoplasty, at the time of definitive primary cheiloplasty, are underreported in the literature. This study endeavors to examine the occurrences of these complications at our cleft-craniofacial center, in an effort to identify causative factors and management strategies. A case series of patients with postoperative nasal complications after primary cleft lip nasal surgery is presented. METHODS: A retrospective chart review of primary cleft lip nasal repairs was conducted at our cleft-craniofacial center between January 2003 and December 2007. Consecutive cases of 3 staff surgeons were evaluated. Specific data points included number and type of complications, subsequent required interventions, and relevant history, with particular attention paid to the details of the primary nasoplasty. RESULTS: Eighty-six primary cleft lip nasoplasties were completed between the years 2003 and 2007. Six complications (6.9%) related to the primary cleft lip nasoplasty were identified. Four patients (4.6%) experienced nasal tip infections; all 4 required surgical drainage. Twenty-four patients (27.9%) undergoing primary cleft lip and nose repair had postoperative nostril conformers placed, and 2 (8.3%) of them experienced complications deemed conformer related. CONCLUSIONS: Postoperative nasal complications of primary cheiloplasty occur and are likely underreported. In this series, complications resulted from infection, often occurring late, and secondary to the use of nostril conformers. Surgeon awareness and caregiver education, to identify the early signs of postoperative nasal complications, are critical to the successful treatment of these occurrences. Although this study did not intend on examining antibiotic use, the significance of nasal tip infections might support the regular use of antibiotics in this population, and the use of postoperative nostril conformers must be followed closely.

Demineralized bone matrix and resorbable mesh bilaminate cranioplasty: a novel method for reconstruction of large-scale defects in the pediatric calvaria.

BACKGROUND: Pediatric patients with large-scale calvarial defects often lose the osteogenic potential of their dura before developing a diploic space sufficient to facilitate harvest of split-thickness calvarial grafts. The authors present their experience using demineralized bone matrix and resorbable mesh bilaminate for the repair of large-scale cranial defects in pediatric patients. METHODS: A retrospective review of the Cleft-Craniofacial Center database at Children's Hospital of Pittsburgh was performed from 2003 through 2007. Patients who underwent cranioplasties using demineralized bone matrix and resorbable mesh bilaminate were identified. Indications, defect size, quantity of demineralized bone matrix used, complications, follow-up, and computed tomographic scans were reviewed. RESULTS: Eleven patients underwent 13 skull reconstructions using demineralized bone matrix and resorbable mesh bilaminate cranioplasty. Mean age was 3.6 years (range, 2.1 to 4.9 years); average defect size was 30.8 cm (range, 6.6 to 80.0 cm). Mean clinical follow-up was 29.3 months (range, 13.4 to 41.8 months). All patients had follow-up computed tomographic scans. The average time of follow-up scan was 18.7 months postoperatively (range, 6.9 to 32.6 months). Seven patients had immediate postoperative scans in addition to long-term follow-up scans, facilitating the calculation of a 98 percent average defect healing (range, 95 to 100 percent). All patients had clinically stable cranial reconstructions at follow-up. CONCLUSIONS: When autogenous bone is not available, demineralized bone matrix and resorbable mesh bilaminate cranioplasty is an alternative method of calvarial reconstruction when used in a healthy site free of scarring or infection. This cranioplasty technique has provided consistent bony regeneration, with no donor-site morbidity.

Reconstruction of osteomyelitis defects of the craniofacial skeleton.

Osteomyelitis of the craniofacial skeleton closely resembles osteomyelitis elsewhere in the body in its pathophysiology and medical management; subsequent reconstruction after debridement remains distinctly challenging. The goals of reconstruction must include the restoration of the complex and readily visible morphology of the cranium and face, as well as the adequate return of vital sensory, expressive, and digestive functions. In this article, the various reconstructive modalities will be discussed including pedicled and nonpedicled flaps with or without an osseous component, nonvascularized bone grafts, alloplastic implants, and bone regeneration using protein therapy. Although reconstruction of craniofacial defects after osteomyelitis commonly proves formidable, the satisfactory return of form and function remains a plausible reconstructive goal.