Nationwide practice patterns in the use of recombinant human bone morphogenetic protein–2 in pediatric spine surgery as a function of patient-, hospital-, and procedure-related factors

Clinical article

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Object

Current national patterns as a function of patient-, hospital-, and procedure-related factors, and complication rates in the use of recombinant human bone morphogenetic protein–2 (rhBMP-2) as an adjunct to the practice of pediatric spine surgery have scarcely been investigated.

Methods

The authors conducted a cross-sectional study using data from the Healthcare Cost and Utilization Project Kids' Inpatient Database. Univariate and multivariate logistic regression were used to calculate unadjusted and adjusted odds ratios and 95% confidence intervals, and p values < 0.05 were considered to be statistically significant.

Results

The authors identified 9538 hospitalizations in pediatric patients 20 years old or younger who had undergone spinal fusion in the US in 2009; 1541 of these admissions were associated with rhBMP-2 use. By multivariate logistic regression, the following factors were associated with rhBMP-2 use: patient age 15–20 years; length of hospital stay (adjusted odds ratio [aOR] 1.01, p = 0.017); insurance status (private [aOR 1.49, p < 0.001] compared with Medicaid); hospital type (nonchildren's hospital); region (Midwest [aOR 2.49, p = 0.008] compared with Northeast); spinal refusion (aOR 2.20, p < 0.001); spinal fusion approach/segment (anterior lumbar [aOR 1.73, p < 0.001] and occipitocervical [aOR 1.86, p = 0.013] compared with posterior lumbar); short segment length (aOR 1.42, p = 0.016) and midlength (aOR 1.44, p = 0.005) compared with long; and preoperative diagnosis (Scheuermann kyphosis [aOR 1.56, p < 0.017] and spondylolisthesis [aOR 1.93, p < 0.001]).

Conclusions

Use of BMP in pediatric spine procedures now comprises more than 10% of pediatric spinal fusion. Patient-related (age, insurance type, diagnosis); hospital-related (children's hospital vs general hospital, region in the US); and procedure-related (redo fusion, anterior vs posterior approach, spinal levels, number of levels fused) factors are associated with the variation in BMP use in the US.

Abbreviations used in this paper:aOR = adjusted odds ratio; DVT = deep venous thrombosis; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modifications; KID = Kids' Inpatient Database; LOS = length of hospital stay; rhBMP-2 = recombinant human bone morphogenetic protein–2.

Abstract

Object

Current national patterns as a function of patient-, hospital-, and procedure-related factors, and complication rates in the use of recombinant human bone morphogenetic protein–2 (rhBMP-2) as an adjunct to the practice of pediatric spine surgery have scarcely been investigated.

Methods

The authors conducted a cross-sectional study using data from the Healthcare Cost and Utilization Project Kids' Inpatient Database. Univariate and multivariate logistic regression were used to calculate unadjusted and adjusted odds ratios and 95% confidence intervals, and p values < 0.05 were considered to be statistically significant.

Results

The authors identified 9538 hospitalizations in pediatric patients 20 years old or younger who had undergone spinal fusion in the US in 2009; 1541 of these admissions were associated with rhBMP-2 use. By multivariate logistic regression, the following factors were associated with rhBMP-2 use: patient age 15–20 years; length of hospital stay (adjusted odds ratio [aOR] 1.01, p = 0.017); insurance status (private [aOR 1.49, p < 0.001] compared with Medicaid); hospital type (nonchildren's hospital); region (Midwest [aOR 2.49, p = 0.008] compared with Northeast); spinal refusion (aOR 2.20, p < 0.001); spinal fusion approach/segment (anterior lumbar [aOR 1.73, p < 0.001] and occipitocervical [aOR 1.86, p = 0.013] compared with posterior lumbar); short segment length (aOR 1.42, p = 0.016) and midlength (aOR 1.44, p = 0.005) compared with long; and preoperative diagnosis (Scheuermann kyphosis [aOR 1.56, p < 0.017] and spondylolisthesis [aOR 1.93, p < 0.001]).

Conclusions

Use of BMP in pediatric spine procedures now comprises more than 10% of pediatric spinal fusion. Patient-related (age, insurance type, diagnosis); hospital-related (children's hospital vs general hospital, region in the US); and procedure-related (redo fusion, anterior vs posterior approach, spinal levels, number of levels fused) factors are associated with the variation in BMP use in the US.

The use of autograft bone to achieve a spinal fusion is the gold standard by which all other grafting materials are judged. Its dependable rate of incorporation leading to a successful spinal arthrodesis has been documented.2 The potential benefits of using recombinant human bone morphogenetic protein–2 (rhBMP-2) over autograft or allograft bone are numerous. These may include decreased operating time, blood loss, donor site morbidity,9 transmission of infection associated with use of allograft,5 and rate of pseudarthrosis.10 In addition, its unlimited quantity and immediate availability make it useful in certain pediatric spine applications, although its cost may be prohibitive in some settings. There are concerns regarding the routine and so-called off-label substitution or supplementation of autologous or allograft bone graft with rhBMP-2. The most significant concerns involve the possibility of bony overgrowth, interaction with exposed dura mater, cancer risk, systemic toxicity, local toxicity, immunogenicity, osteoclastic activation, and effects on distal organs.44

The issue of whether rhBMP-2 is an adequate substitute or supplement for bone graft in achieving a successful fusion is being studied thoroughly. Several clinical studies have documented favorable results by using adult lumbar spine and anterior cervical spine models.6,9 Although BMP has been used with some frequency in pediatric oral maxillofacial reconstructions7,8,13–15,18,26,56 and reported in the treatment of congenital pseudarthrosis of the tibia,32,46 there have been few reports of rhBMP-2 use1,4,20,36,37,40 in pediatric spine fusions. One recent study31 of patients in the pediatric age group in the Nationwide Inpatient Sample database analyzed various factors associated with the use of BMP for specific diagnoses, including adolescent idiopathic scoliosis, Scheuermann kyphosis, congenital kyphosis, spondylolisthesis, and thoracolumbar fracture; procedures related to the occipitocervical and cervical spine were not included in this study.

The purpose of our study was to examine the nationwide practice patterns of occipitocervical, cervical, thoracic, lumbar, or lumbosacral spine fusion in which rhBMP-2 was used in pediatric patients by searching the Kids' Inpatient Database (KID). We suggest that patient-, hospital-, and procedure-related factors shape BMP use today.

Methods

Data Source

Data are from the 2009 KID developed by the Healthcare Cost and Utilization Project, sponsored by the Agency for Healthcare Research and Quality.25 The 2009 KID contains discharge-level data from more than 3.4 million pediatric hospitalizations from 4121 nonfederal community hospitals in 44 states. The KID allows for more precise national and regional estimates for pediatric conditions, clinical outcomes, and hospital services, which are otherwise difficult to analyze given that children make up a relatively small proportion of hospital stays. It is important to note that because the data in KID are a composite of deidentified state-level information, our unit of analysis is a patient discharge and not a patient.

To obtain national estimates, patient records were provided with weights by using the American Hospital Association roster of nonfederal community hospitals as the standard. Hospital data were stratified by the following 6 characteristics: ownership/control, bed size, teaching status, rural/urban location, US region, and status as a freestanding children's hospital.

Patient Selection

We selected records associated with spinal fusion surgery for patients up to 20 years of age. These records were identified using discharge diagnosis codes defined by the International Classification of Diseases, Ninth Revision, Clinical Modifications (ICD-9-CM). The following ICD-9-CM procedure codes representing spinal fusion surgeries were used: (81.00–81.08, and 81.30–81.39). In addition, procedures with ICD-9-CM (84.52) insertion of rhBMP-2 were identified. The unit of analysis in KID is a patient hospital discharge rather than a patient. Thus each hospitalization is tracked separately, without ability for outcomes follow-up over time.

Patient Characteristics

Patient characteristics obtained from the database include age (in years); sex; race (white, black, Hispanic, Asian or Pacific Islander, Native American, and other); in-hospital death; length of hospital stay ([LOS] in days); family income (by quartiles of median income in ZIP code); and primary payer (Medicaid, private, self-pay, or other).

Spine-related diagnoses were identified with the following ICD-9-CM codes for adolescent idiopathic scoliosis (737.30, 737.31, 737.39); Scheuermann kyphosis (732.0); congenital kyphosis (754.2, 737.31, and 737.32); spondylolisthesis (756.12 and 738.4); cervical fracture/dislocation (805.00–805.18, and 839.00–839.18); and thoracolumbar fracture (805.2, 805.3, 805.4, 805.5, 806.2, 806.3, 806.4, and 806.5). These are not inclusive of all diagnoses.31

Spine surgery–specific codes were used to characterize type, approach, segment, and length of spinal fusion—spinal fusions were identified with procedure codes 81.00–81.08. Separate codes for repeat spinal fusion surgery (81.30–81.39) were also included. Segment was classified as occipitocervical (81.01, 81.31); cervical (81.02, 81.03, 81.32, and 81.33); lumbar (81.04, 81.08, 81.34, and 81.38); and not otherwise specified (81.00, 81.30, and 81.39). Approach was classified as occipitocervical (81.01 and 81.31); anterior (81.02, 81.04, 81.06, 81.32, 81.34, and 81.36); posterior (81.03, 81.05, 81.07, 81.08, 81.33, 81.35, 81.37, and 81.38); and not otherwise specified (81.00, 81.30, and 81.39). Length was classified as short (81.62), mid (81.63), and long (81.64). Use of autograft was also identified: 77.70, 77.71, and 77.79.

We used ICD-9-CM procedure and diagnosis codes to create variables for the following inpatient hospital complications: meningitis (320–322, 326); wound dehiscence (998.30–998.33); wound infection (998.59); hematoma (998.11–998.13); fever (780.60–780.62); transfusion (99.01–99.09); and mechanical ventilation (96.70–96.79). Deep venous thrombosis (DVT) was identified with the following diagnosis codes: deep venous thrombosis (453.2, 453.40, 453.41, 453.42, 453.82–89, and 453.9); thrombophlebitis of the upper and lower extremities (451.11, 451.19, 451.2, 451.81, 451.83, 451.84, 451.89, and 451.9); and pulmonary embolism (415.11, 415.13, and 415.19).

Statistical Analysis

Descriptive statistics with weighted national estimates were conducted to evaluate the distribution of patient and hospital characteristics for those with or without rhBMP-2 use associated with their spinal fusion surgery. Patient and hospital characteristics across those with or without rhBMP-2 were compared with chi-square tests. Because KID is a sampled database, our results are reported as estimated values such as means and frequencies with 95% confidence intervals. These estimates represent national estimates for the associated year. Because of the sampling methodology, national medians cannot be obtained. Hence, continuous data are expressed as estimated means.

Standard errors were adjusted for stratification and clustering of the KID sampling design as described in the 2009 KID documentation published by the Agency for Healthcare Research and Quality.25 Because the data in KID are a composite of deidentified state-level information, our unit of analysis is a patient discharge. To evaluate the effect of patient and hospital characteristics on rhBMP-2 use in pediatric patients undergoing spinal fusion surgery, univariate and multivariate logistic regression were used to calculate unadjusted and adjusted odds ratios (aORs) and 95% confidence intervals. Two-sided tests were used, with p values < 0.05 considered to be statistically significant. All statistical analyses were performed with Stata version 12 software (StataCorp).

Results

We identified 9538 discharge records associated with spinal fusion surgery in pediatric patients up to 20 years of age in 2009. Because the database is a weighted national sample, this represents an estimated 14,264 cases of spinal fusion surgery in the US. Nearly 11% of these cases involved intraoperative BMP use (10.8%, 95% CI 9.0%–12.6%).

Patient-Related Factors

Patient demographics are summarized in Table 1. The majority of patients with spinal fusions were between the ages of 15 and 20 years (53.1%, 95% CI 51.2%–55.0%). Older age was a statistically significant predictor for BMP use in the multivariate logistic analysis (Table 2); 72.0% of patients in whom BMP was used were between the ages of 15 and 20 years compared with 50.8% in the non-BMP group. Sex and race were not significant predictors.

TABLE 1:

National estimates of spinal fusion surgery and BMP use in 2009*

VariableActual SampleNational Estimates% (95% CI)BMP GroupNon-BMP Groupp Value
No.% (95% CI)No.% (95% CI)
total (mean per 1000)953814,2641.9 (1.7–2.1)1541(1270-1811)12,723(11,196–14,250)
age in yrs<0.001
 <11218+++++
 1–9638976+++++
 10–143772569639.9 (38.4–41.5)36623.8 (19.7–27.8)533041.9 (40.3–43.5)
 15–205116757453.1 (51.2–55.0)110972.0 (67.1–76.9)646550.8 (49.0–52.6)
sex<0.001
 male3862576040.4 (39.2–41.6)70445.7 (42.4–49.0)505639.7 (38.5–41.0)
 female5676850459.6 (58.4–60.8)83754.3 (51.0–57.6)766760.3 (59.0–61.5)
race0.020
 white5367798956.0 (51.6–60.5)93260.5 (54.5–66.4)705755.5 (50.8–60.1)
 black1002150310.5 (9.0–12.1)1147.4 (5.3–9.5)138910.9 (9.3–12.5)
 Hispanic987147110.3 (8.3–12.3)1248.1 (5.5–10.6)134710.6 (8.4–12.7)
 other70810597.4 (5.2–9.7)1036.7 (4.8–8.6)9567.5 (5.1–9.9)
 NR1474224115.7 (10.8–20.6)26817.4 (11.0–23.8)197415.5 (10.4–20.6)
primary expected payer<0.001
 Medicaid2452370125.9 (23.8–28.1)27818.0 (15.0–20.9)342826.9 (24.6–29.3)
 private6186921364.6 (61.9–67.2)113173.0 (69.2–76.8)808363.5 (60.7–66.3)
 self-pay/other+++++++
 NR+++++++
died in hospital18260.2 (0.1–0.3)++++-
hospital bed size0.052
 small1099171912.1 (7.2–16.9)1157.4 (4.3–10.6)160412.6 (7.3–17.9)
 medium2252348524.4 (17.3–31.6)36123.5 (14.1–32.8)312424.6 (17.0–32.1)
 large5302768953.9 (47.3–60.5)96162.3 (53.1–71.6)672852.9 (45.8–59.9)
 NR88513719.6 (5.2–14.0)1046.8 (1.6–11.8)126710.0 (5.3–14.6)
hospital type<0.001
 nonchildren's2586368125.8 (21.6–30.0)67844.0 (35.5–52.5)300323.6 (19.3–27.9)
 children's general/specialty2521407028.5 (22.1–34.9)21313.8 (4.1–23.6)385730.3 (23.5–37.2)
 children's unit in general hospital3375488534.3 (28.0–40.5)49432.1 (23.1–41.1)439134.5 (28.0–41.0)
 NR1056162811.4 (6.9–15.9)15510.1 (4.6–15.6)147311.6 (6.8–16.3)
teaching hospital<0.001
 no97714149.9 (8.0–11.8)31720.6 (15.5–25.7)10978.6 (6.8–10.5)
 yes76761147980.5 (75.6–85.3)112072.7 (65.7–79.7)1035981.4 (76.4–86.5)
 NR88513719.6 (5.2–14.0)1046.8 (1.6–11.9)126710.0 (5.3–14.6)
region0.209
 Northwest1784248917.4 (11.9–23.0)18311.9 (7.0–16.7)230618.1 (12.0–24.2)
 Midwest2305347224.3 (18.2–30.5)47130.6 (21.2–40.0)300123.6 (17.3–29.9)
 South3260507835.6 (29.0–42.2)54035.0 (26.4–43.7)453835.7 (28.6–42.7)
 West2189322522.6 (16.5–28.8)34722.5 (16.4–28.6)287822.6 (16.0–29.2)
QRTL of ZIP code median income0.498
 0–25th2151324622.8 (20.6–25.0)34422.3 (18.6–26.0)290222.8 (20.5–25.1)
 26th–50th2260339123.8 (22.3–25.3)34122.1 (19.3–24.9)305024.0 (22.4–25.5)
 51st–75th2342350724.6 (23.1–26.1)36423.7 (20.7–26.6)314324.7 (23.2–26.2)
 76th–100th2598383926.9 (24.3–29.5)45129.3 (24.8–33.7)338826.6 (23.8–29.4)
 NR1872812.0 (1.5–2.4)412.7 (1.4–3.9)2401.9 (1.4–2.4)

NR = not reported; QRTL = quartile; + = no report for < 11 cases, per KID reporting rules.

In these categories, calculated total and added total differ by 1 due to rounding.

TABLE 2:

Multivariate logistic regression for BMP use

VariableaOR (95% CI)p Value
age in yrs
 <10.54 (0.07–3.97)0.548
 1–90.50 (0.34–0.75)0.001
 10–140.64 (0.53–0.76)<0.001
 15–20Ref
sex
 maleRef
 female0.99 (0.86–1.13)0.870
race
 whiteRef
 black0.96 (0.72–1.28)0.780
 Hispanic0.96 (0.68–1.37)0.823
 other1.04 (0.73–1.49)0.828
 NR0.86 (0.53–1.40)0.539
LOS1.01 (1.00–1.02)0.017
primary expected payer
 MedicaidRef
 private1.49 (1.23–1.82)<0.001
 other1.16 (0.87–1.56)0.310
 NR2.50 (0.39–16.04)0.333
hospital bed size
 smallRef
 medium1.77 (0.85–3.69)0.128
 large1.71 (0.91–3.23)0.097
 NR0.70 (0.25–1.90)0.478
hospital type
 nonchildren'sRef
 children's general/specialty0.40 (0.19–0.86)0.019
 children's unit in general hospital0.69 (0.46–1.03)0.070
 NR1.10 (0.64–1.92)0.725
region
 NortheastRef
 Midwest2.49 (1.27–4.89)0.008
 South1.71 (0.97–3.04)0.066
 West1.66 (0.98–2.85)0.066
refusion2.20 (1.67–2.90)<0.001
autograft0.96 (0.75–1.24)0.748
approach/level
 occipitocervical1.86 (1.14–3.04)0.013
 anterior cervical0.25 (0.15–0.41)<0.001
 posterior cervical1.08 (0.72–1.61)0.718
 anterior lumbar1.73 (1.32–2.26)<0.001
 posterior lumbarRef
 NR1.22 (0.60–2.50)0.582
segment length
 short1.42 (1.07–1.89)0.016
 mid1.44 (1.12–1.87)0.005
 longRef
 NR0.28 (0.15–0.53)<0.001
preop diagnosis
 idiopathic scoliosis0.56 (0.42–0.73)<0.001
 Scheuermann kyphosis1.56 (1.08–2.24)<0.017
 congenital scoliosis0.54 (0.35–0.81)0.003
 spondylolisthesis1.93 (1.46–2.55)<0.001
 cervical fracture/dislocation0.57 (0.41–0.81)0.002
 thoracolumbar fracture1.14 (0.96–1.50)0.375
constant0.06 (0.03–0.14)<0.001

Overall, the majority of children with spinal fusions had private insurance (64.6%, 95% CI 61.9–67.2). Private insurance was also a significant predictor for BMP use (aOR 1.49, 95% CI 1.23–1.82, p < 0.001).

Preoperative diagnosis was a statistically significant predictor for BMP use. In the multivariate logistic regression, Scheuermann kyphosis (aOR 1.56, 95% CI 1.08–2.24, p < 0.017) and spondylolisthesis (aOR 1.93, 95% CI 1.46–2.55, p < 0.001) were associated with increased odds of BMP use. Patients with a cervical fracture or dislocation (aOR 0.57, 95% CI 0.41–0.81, p = 0.002), congenital scoliosis (aOR 0.54, 95% CI 0.35–0.81, p = 0.003), and idiopathic scoliosis (aOR 0.56, 95% CI 0.42–0.73, p < 0.001) were less likely to receive BMP.

Hospital-Related Factors

Hospital characteristics are summarized in Table 1. Status as children's hospital was a significant predictor for BMP use in this population. Children's general/specialty hospitals had decreased odds of BMP use compared with nonchildren's hospitals (aOR 0.40, 95% CI 0.19–0.86, p = 0.019). Hospital bed size was not a significant predictor (Table 2).

Region was also found to be a significant predictor, with the Midwest having increased odds of BMP use compared with the Northeast (aOR 2.49, 95% CI 1.27–4.89, p = 0.008). The South and West also appeared to have increased BMP use compared with the Northeast, but neither of these regions reached statistical significance (p = 0.066, Table 2).

Procedure-Related Factors

Procedure-related factors were found to be significant predictors for BMP use. Both posterior occipitocervical and anterior lumbar approaches had increased odds of BMP use compared with posterior lumbar approaches (aOR 1.86, 95% CI 1.14–3.04, p = 0.013 and aOR 1.73, 95% CI 1.32–2.26, p < 0.001, respectively). An anterior cervical approach was found to have lower odds of BMP use compared with a posterior lumbar approach (aOR 0.25, 95% CI 0.15–0.41, p < 0.001).

Length of the spinal fusion was also a significant predictor. Both short- and midsegment fusions were more likely to involve BMP use compared with long-segment fusions (aOR 1.42, 95% CI 1.07–1.89, p = 0.016 and aOR 1.44, 95% CI 1.12–1.87, p = 0.005, respectively). In addition, patients undergoing redo surgery for failed fusion were more likely to receive BMP (aOR 2.20, 95% CI 1.67–2.90, p < 0.001) (Table 2).

Acute Complications

Complications are summarized in Table 3. Overall, rates of DVT, meningitis, wound infection, and wound dehiscence remained low (< 2%). Patients with intraoperative BMP use had lower rates of blood transfusion (15.5% vs 26.2%, p < 0.001).

TABLE 3:

Characteristics of spinal fusion surgery in 2009

VariableNational Estimates% (95% CI)BMP GroupNon-BMP Groupp Value
No.% (95% CI)No.% (95% CI)
total no. of patients14,264154112,723
refusion
 no13,66995.8 (95.2–96.4)140591.2 (89.1–93.3)12,26496.4 (95.8–97.0)<0.001
 yes5954.2 (3.6–4.8)1368.8 (6.7–10.9)4593.6 (3.0–4.2)
autograft
 no697848.9 (45.3–52.5)75949.3 (43.1–55.4)621948.9 (45.0–52.7)0.913
 yes728651.1 (47.5–54.7)78250.7 (44.6–56.9)650451.1 (47.3–55.0)
level
 occipitocervical2952.1 (1.6–2.5)573.7 (2.3–5.1)2381.9 (1.4–2.3)0.005
 cervical12929.1 (8.1–10.0)1217.9 (5.9–9.8)11719.2 (8.2–10.2)
 lumbar1257488.2 (87.0–89.3)134987.6 (84.9–90.2)11,22588.2 (87.0–89.5)
 NR1030.7 (0.6–0.9)140.9 (0.3–1.4)890.7 (0.5–0.9)
approach
 occipitocervical2952.1 (1.6–2.5)573.7 (2.3–5.1)2381.9 (1.4–2.3)0.009
 anterior12388.7 (7.8–9.5)16010.4 (8.4–12.4)10788.5 (7.6–9.4)
 posterior12,62888.5 (87.5–89.6)131085.0 (82.4–87.7)11,31889.0 (87.9–90.0)
 NR1030.7 (0.6–0.9)140.9 (0.3–1.4)890.7 (0.5–0.9)
segment length
 short377426.5 (24.7–28.2)69845.3 (39.7–50.9)307624.2 (22.4–25.9)<0.001
 mid305921.4 (19.6–23.3)37224.2 (21.4–26.9)268721.1 (19.1–23.1)
 long675147.3 (44.8–49.8)44528.9 (22.9–34.8)630649.6 (46.9–52.3)
 NR6804.8 (2.9–6.6)261.7 (0.9–2.5)6545.1 (3.1–7.2)
preop diagnosis
 idiopathic scoliosis787055.2 (53.0–57.3)53034.4 (28.8–40.0)734057.7 (55.4–59.9)<0.001
 Scheuermann kyphosis3292.3 (1.9–2.7)634.1 (2.9–5.3)2662.1 (1.7–2.5)<0.001
 congenital scoliosis13329.3 (8.0–10.6)865.6 (3.8–7.3)12469.8 (8.4–11.2)<0.001
 spondylolisthesis7385.2 (4.6–5.7)21814.1 (11.3–17.0)5204.1 (3.6–4.6)<0.001
 cervical fracture/dislocation7445.2 (4.5–5.9)704.5 (3.1–5.9)6745.3 (4.6–6.0)0.352
 thoracolumbar fracture10547.4 (6.4–8.4)22314.5 (11.2–17.7)8316.5 (5.6–7.5)<0.001
complication
 transfusion357525.1 (21.7–28.5)23915.5 (12.6–18.4)333626.2 (22.6–29.9)<0.001
 mechanical ventilation9156.4 (5.6–7.3)835.4 (3.9–6.9)8326.5 (5.6–7.5)0.200
 fever5994.2 (3.6–4.8)603.9 (2.3–5.4)5394.2 (3.6–4.8)0.676
 DVT54++++++
 meningitis16++++++
 wound infection970.7 (0.5–0.9)130.9 (0.3–1.4)840.7 (0.5–0.9)0.434
 wound dehiscence83++++++
 hematoma3132.2 (1.8–2.5)231.5 (0.8–2.2)2902.3 (1.9–2.6)0.102

The LOS, number of procedures and comorbidities, and total hospital costs are summarized in Table 4. There was a significant difference in the average cost of hospitalization between the BMP and non-BMP groups ($58,653.70 vs $53,420.50; p < 0.001). There were no significant differences in LOS.

TABLE 4:

Hospital resource utilization*

CategoryOverallBMP GroupNon-BMP Groupp Value
LOS in days7.3 (7.1–7.5)7.4 (6.8–8.1)7.3 (7.1–7.5)0.624
no. of procedures5.1 (5.0–5.1)6.2 (6.1–6.4)4.9 (4.9–5.0)<0.001
no. of diagnoses5.1 (5.0–5.1)5.3 (5.0–5.6)5.0 (4.9–5.1)0.046
no. of chronic conditions2.2 (2.2–2.2)2.1 (2.0–2.2)2.2 (2.2–2.3)0.024
total costs in $54,020.6 (53,147.1–54,894.2)58,653.7 (55,925.3–61,382.1)53,420.5 (52,499.9–54,341.1)<0.001

Values are expressed as the mean (95% CI).

Discussion

This BMP-based fusion technology has experienced a rapid increase in use in all types of routine spine fusion procedures, including anterior cervical discectomy and fusion, posterolateral lumbar and cervical fusions, posterior and transforaminal lumbar interbody fusions, and pediatric spine fusions.17 Cahill et al.11 noted that the nationwide use of BMP increased from 0.69% of all fusions in 2002 to 24.89% of all fusions in 2006, confirming the widespread application of this technology and its routine use in spine fusion surgery. Similarly, Jain et al.31 showed that the nationwide use of BMP in pediatric thoracic, lumbar, and sacral spine fusion surgery increased 3.4-fold from 2003 to 2009 (a 16% annual increase during the study period). We showed that a significant number of pediatric spinal fusion surgeries (> 10%) used BMP in 2009.

The osteoinductive role of rhBMP-2 is multifaceted; it acts as a chemotactic agent, a growth factor, and a differentiation factor.54 The FDA has approved rhBMP-2 as the first complete bone graft substitute for anterior interbody fusions of the adult lumbar spine.58 In clinical trials, investigators have demonstrated the usefulness of rhBMP-2 for single-level anterior interbody fusion of the adult lumbar spine, resulting in greater radiographic fusion rates, improved Oswestry pain and function scores, and higher overall clinical success over traditional bone grafting techniques.6,9

Although the FDA has only approved the use of rh-BMP-2–soaked absorbable collagen sponges for use in adult anterior lumbar interbody fusion, off-label applications have been reported.12,37 These off-label uses of rh-BMP-2 have been sparsely reported in the pediatric neurosurgical and orthopedic literature.1,4,20,31,36,37,40 We showed that the odds of BMP use in pediatric spine surgery increased with posterior occipitocervical and anterior lumbar fusion surgeries, whereas they decreased with anterior cervical approaches. This pattern probably reflects the recognition of an increased incidence of dysphagia with use of BMP in anterior cervical fusion surgery.51

Advantages of rhBMP-2

Biomechanically, the rhBMP-2–generated fusion mass is superior at 3 months compared with that generated by autograft.47,48 Findings have shown the fusion mass to be more mature, with more advanced remodeling and marrow formation, than that generated by autograft alone. Bone healing and remodeling may take up to 12–24 months.16 Our study demonstrates that BMP, due to its potential to increase fusion rate, is more likely to be used to salvage previously failed bony fusion.

Another advantage of rhBMP-2 is its potential role in promoting fusion in very young children (even though our analysis demonstrates older age as a factor for increased use of BMP). These patients, especially those undergoing occipitocervical fusion, have a very limited amount of bone available for local autograft; meanwhile, autograft harvest at remote donor sites such as the ribs or iliac crest carries added morbidity. In fact, our review of pediatric spinal fusions showed that BMP use and the application of autograft were uncoupled. The literature shows that in these cases the ability to promote fusion by adding rh-BMP-2 is advantageous.3,20,22,23,27,39,41–43,45,59,60

Moreover, we found that the complication rate in the BMP group versus the non-BMP group was low, including a statistically significant reduction in rates of blood transfusion and postoperative hematoma formation. However, there was no difference in LOS between the two cohorts.

Cancer Risk

Although an analysis of the possible long-term consequences of BMP in the pediatric age group is beyond the scope of our present study, we would be remiss if our discussion did not include at least a brief review of its cancer risk and other lasting safety concerns. Both BMPs and BMP receptors have been isolated from human tumors. However, in vitro studies suggest that rhBMP-2 has an antiproliferative effect on human tumor colony-forming units taken from breast, ovarian, lung, and prostate cancers, and on embryonal cell carcinoma and cerebellar neuroectodermal tumor cell lines.28,29,53,55 Detailed data from the preclinical safety studies of manufacturers failed to demonstrate any proliferative effects of rh-BMP-2 on human osteosarcoma, prostate, breast, tongue, and lung carcinoma cell lines; on the contrary, there was an inhibitory effect in all cases. In fact, rhBMP-2 was found to have no mutagenic activity.44

Recent systemic reviews and meta-analyses of the literature17,21,50 suggest that the cancer risk associated with rhBMP-2 may be dose dependent. The cancer risk was similar in the lower doses (4.2–4.8 mg) of rhBMP-2 (0.7%) and the control groups (0.7% and 0.9%). However, the cancer risk was 3.8% in the higher-dose (40 mg) rh-BMP-2 study.19

A recent large retrospective database study by Lad et al.34 looked at high-dose BMP and its relationship to cancer. The authors looked at BMP exposure and cancer risk at a national level by performing a retrospective cross-sectional study in which a large MarketScan database with at least a 24-month postoperative follow-up was used (mean postoperative follow-up between 49.7 and 55.6 months). Analysis showed a significant increase (31%) in benign tumors but not malignancies.34 Moreover, there was a significantly higher number of benign tumors of the spinal meninges in the BMP group.

Other Safety Concerns

There have been anecdotal reports of complications associated with rhBMP-2 use, with compressive bone formation adjacent to neural structures.12 This is particularly relevant after decompressive laminectomy or foraminotomy, in which raw bone surfaces are exposed.44 There is evidence to suggest that rhBMP-2 may lead to laminar reconstitution and neuroforaminal stenosis if it is implanted directly into the laminectomy site.38 The evidence in the literature suggests that if rhBMP-2 reaches a raw bone surface such as a laminectomy site or a decompressed neural foramen in sufficient concentration, new bone will form and may result in restenosis. Leakage of rhBMP-2 beyond the fusion area may lead to fusion of adjacent levels. Therefore, the key steps for safe rhBMP-2 use are careful placement away from raw decompressed areas and retention of the rhBMP-2 within the fusion area by the carrier used.

It is well established that BMPs play a role in the regulation of coupled osteoblastic and osteoclastic activity.30,33 It is possible that large doses of BMP may lead to localized areas of bone resorption.57 This is not desirable in spinal fusion, and strategies to prevent this include careful control of BMP doses and controlled release from the carrier. It is likely, however, that any observed radiolucencies are temporary and may represent accelerated healing patterns resulting from transient stimulation of osteoclasts.57

Several studies have reported adverse local events associated with the use of rhBMP-2. Facial edema, oral erythema, pain, and rhinitis have been reported in patients who received rhBMP-2 for maxillary floor augmentation.8 The use of higher than recommended doses of rhBMP-2 has been known to cause hematoma, dysphagia, and excessive edema after anterior cervical fusion.49,52 This may be due to the enhancement by rhBMP-2 of the initial inflammatory response that is seen during bone graft incorporation.35 This same enhanced inflammatory response may produce a hyperinflammatory response causing wound problems, allergic reactions, or other complications.24

Risk-Benefit Balance

At the present time, the risk-benefit balance of BMP use during routine spinal fusion surgery is undetermined. Moreover, the scarcity of BMP studies in the pediatric age group makes the endeavor to establish clinical indications for BMP use in spine fusion surgery in children even more daunting.

The average cost of hospitalization for those who received BMP and for those who did not was $58,653.70 and $53,420.50, respectively. The cost difference between these groups reached statistical significance (p < 0.001); the incremental difference is < 10%. Our finding has implications for the commonly held belief that BMP use is cost prohibitive.

Limitations of the Study

Our study was limited by the nature of the KID, which was designed to collect only discharge information from inpatient hospital admissions. Readmissions to the hospital are not linked by patient; thus clinical follow-up is unfortunately not available. We were not able to identify all specific operative indications. To our knowledge, the accuracy and consistency of the ICD-9-CM codes used to identify our study subjects' diagnoses and procedures have not been validated by independent chart review in this pediatric population. We have based our work on published methodologies used by multiple groups where available,31,61 although inaccuracy of coding is an unquantified and notable limitation. Furthermore, we were not able to identify specific types or doses of BMP used; we assumed that rhBMP-2 was used in the majority of cases. A distinction between local autograft versus autograft from more remote donor sites could not be identified, and therefore it was not possible to determine how BMP influenced the harvest of autograft from donor sites such as the rib and iliac crest in children. Data on costs are reported by KID as a representative of total inpatient costs, and are taken as a research tool. Thus caution should be used in interpreting numbers as precise markers of financial exchange for individual cases. Most importantly, the administrative database provides a limited cross-sectional perspective and does not allow longitudinal patient follow-up.

Conclusions

Despite the limitations of our study, analysis of the KID allowed us to identify and report nationwide patterns of BMP use in pediatric occipitocervical, cervical, thoracic, lumbar, and sacral spine fusions. Additionally, we identified patient-related (older age, private insurance, and diagnosis of Scheuermann kyphosis or spondylolisthesis); hospital-related (nonchildren's hospital and Midwest location); and procedure-related factors (posterior occipitocervical and anterior lumbar approaches, shortand mid-length segment fusion, and redo surgery for failed fusion) that were associated with increased BMP use. More studies are needed to classify clinical indications for BMP use in pediatric spine surgery.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Jea, Lam. Acquisition of data: Jea, Lam, Briceño. Analysis and interpretation of data: Jea, Lam, Harris. Drafting the article: Lam, Harris. Critically revising the article: Jea, Lam. Reviewed submitted version of manuscript: Jea, Lam, Sayama, Briceño, Luerssen. Approved the final version of the manuscript on behalf of all authors: Jea. Study supervision: Luerssen.

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    Fulkerson DHHwang SWPatel AJJea A: Open reduction and internal fixation for angulated, unstable odontoid synchondrosis fractures in children: a safe alternative to halo fixation? Report of 2 cases. J Neurosurg Pediatr 9:35412012

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    Ide HYoshida TMatsumoto NAoki KOsada YSugimura T: Growth regulation of human prostate cancer cells by bone morphogenetic protein-2. Cancer Res 57:502250271997

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Article Information

Address correspondence to: Andrew Jea, M.D., Division of Pediatric Neurosurgery, Texas Children's Hospital, 6621 Fannin St., Houston, TX 77030. email: ahjea@texaschildrens.org.

Please include this information when citing this paper: published online August 29, 2014; DOI: 10.3171/2014.7.PEDS1499.

© AANS, except where prohibited by US copyright law.

Headings

References

1

Abd-El-Barr MMCox JBAntonucci MUBennett JMurad GJPincus DW: Recombinant human bone morphogenetic protein-2 as an adjunct for spine fusion in a pediatric population. Pediatr Neurosurg 47:2662712011

2

Allen RTLee YPStimson EGarfin SR: Bone morphogenetic protein-2 (BMP-2) in the treatment of pyogenic vertebral osteomyelitis. Spine (Phila Pa 1976) 32:299630062007

3

Amhaz HHFox BDJohnson KKWhitehead WECurry DJLuerssen TG: Postlaminoplasty kyphotic deformity in the thoracic spine: case report and review of the literature. Pediatr Neurosurg 45:1511542009

4

Betz RRLavelle WFSamdani AF: Bone grafting options in children. Spine (Phila Pa 1976) 35:164816542010

5

Blanco JSSears CJ: Allograft bone use during instrumentation and fusion in the treatment of adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 22:133813421997

6

Boden SDZdeblick TASandhu HSHeim SE: The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine (Phila Pa 1976) 25:3763812000

7

Boyne PJ: Application of bone morphogenetic proteins in the treatment of clinical oral and maxillofacial osseous defects. J Bone Joint Surg Am 83-A Pt 2 Suppl 1S146S1502001

8

Boyne PJNath RNakamura A: Human recombinant BMP-2 in osseous reconstruction of simulated cleft palate defects. Br J Oral Maxillofac Surg 36:84901998

9

Burkus JKGornet MFDickman CAZdeblick TA: Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech 15:3373492002

10

Burkus JKGornet MFSchuler TCKleeman TJZdeblick TA: Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2. J Bone Joint Surg Am 91:118111892009

11

Cahill KSChi JHDay AClaus EB: Prevalence, complications, and hospital charges associated with use of bonemorphogenetic proteins in spinal fusion procedures. JAMA 302:58662009

12

Carlisle EFischgrund JS: Bone morphogenetic proteins for spinal fusion. Spine J 5:6 Suppl240S249S2005

13

Carstens MHChin MNg TTom WK: Reconstruction of #7 facial cleft with distraction-assisted in situ osteogenesis (DISO): role of recombinant human bone morphogenetic protein-2 with Helistat-activated collagen implant. J Craniofac Surg 16:102310322005

14

Chao MDonovan TSotelo CCarstens MH: In situ osteogenesis of hemimandible with rhBMP-2 in a 9-year-old boy: osteoinduction via stem cell concentration. J Craniofac Surg 17:4054122006

15

Chin MNg TTom WKCarstens M: Repair of alveolar clefts with recombinant human bone morphogenetic protein (rhBMP-2) in patients with clefts. J Craniofac Surg 16:7787892005

16

Czitrom ABiology of bone grafting and principles of bone banking. Weinstein SL: The Pediatric Spine: Principles and Practice New YorkRaven Press1994. 12851298

17

Devine JGDettori JRFrance JCBrodt EMcGuire RA: The use of rhBMP in spine surgery: is there a cancer risk?. Evid Based Spine Care J 3:35412012

18

Dickinson BPAshley RKWasson KLO'Hara CGabbay JHeller JB: Reduced morbidity and improved healing with bone morphogenic protein-2 in older patients with alveolar cleft defects. Plast Reconstr Surg 121:2092172008

19

Dimar JR IIGlassman SDBurkus JKPryor PWHardacker JWCarreon LY: Clinical and radiographic analysis of an optimized rhBMP-2 formulation as an autograft replacement in posterolateral lumbar spine arthrodesis. J Bone Joint Surg Am 91:137713862009

20

Fahim DKWhitehead WECurry DJDauser RCLuerssen TGJea A: Routine use of recombinant human bone morphogenetic protein-2 in posterior fusions of the pediatric spine: safety profile and efficacy in the early postoperative period. Neurosurgery 67:119512042010

21

Fu RSelph SMcDonagh MPeterson KTiwari AChou R: Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med 158:8909022013

22

Fulkerson DHHwang SWPatel AJJea A: Open reduction and internal fixation for angulated, unstable odontoid synchondrosis fractures in children: a safe alternative to halo fixation? Report of 2 cases. J Neurosurg Pediatr 9:35412012

23

Gressot LVPatel AJHwang SWFulkerson DHJea A: Iliac screw placement in neuromuscular scoliosis using anatomical landmarks and uniplanar anteroposterior fluoroscopic imaging with postoperative CT confirmation. Clinical article. J Neurosurg Pediatr 13:54612014

24

Hansen SMSasso RC: Resorptive response of rhBMP2 simulating infection in an anterior lumbar interbody fusion with a femoral ring. J Spinal Disord Tech 19:1301342006

25

Healthcare Cost and Utilization Project: Introduction to the HCUP Kids' Inpatient Database (KID) 2009. (http://www.hcup-us.ahrq.gov/db/nation/kid/kid_2009_introduction.jsp)[Accessed July 8 2014]

26

Herford ASBoyne PJRawson RWilliams RP: Bone morphogenetic protein-induced repair of the premaxillary cleft. J Oral Maxillofac Surg 65:213621412007

27

Hwang SWThomas JGBlumberg TJWhitehead WECurry DJDauser RC: Kyphectomy in patients with myelomeningocele treated with pedicle screw-only constructs: case reports and review. Report of 2 cases. J Neurosurg Pediatr 8:63702011

28

Iantosca MRMcPherson CEHo SYMaxwell GD: Bone morphogenetic proteins-2 and -4 attenuate apoptosis in a cerebellar primitive neuroectodermal tumor cell line. J Neurosci Res 56:2482581999

29

Ide HYoshida TMatsumoto NAoki KOsada YSugimura T: Growth regulation of human prostate cancer cells by bone morphogenetic protein-2. Cancer Res 57:502250271997

30

Itoh KUdagawa NKatagiri TIemura SUeno NYasuda H: Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-ϰB ligand. Endocrinology 142:365636622001

31

Jain AKebaish KMSponseller PD: Factors associated with use of bone morphogenetic protein during pediatric spinal fusion surgery: an analysis of 4817 patients. J Bone Joint Surg Am 95:126512702013

32

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