Complications in Children with Ehlers-Danlos Syndrome Following Spine Surgery: Analysis of the Pediatric National Surgery Quality Improvement Program Database

Journal Pre-proof Complications in Children with Ehlers-Danlos Syndrome following Spine Surgery: Analysis of the Pediatric National Surgery Quality Improvement Program Database Abhijith V. Matur, BS, Aria Nouri, MD MSc, Shenwen Huang, BS PhD, Nora C. Elson, MS, William Jeong, MD MBA, Karin S. Bierbrauer, MD, Francesco T. Mangano, DO, Joseph S. Cheng, MD MS PII:

S1878-8750(19)32476-3

DOI:

https://doi.org/10.1016/j.wneu.2019.09.046

Reference:

WNEU 13345

To appear in:

World Neurosurgery

Received Date: 10 July 2019 Revised Date:

7 September 2019

Accepted Date: 9 September 2019

Please cite this article as: Matur AV, Nouri A, Huang S, Elson NC, Jeong W, Bierbrauer KS, Mangano FT, Cheng JS, Complications in Children with Ehlers-Danlos Syndrome following Spine Surgery: Analysis of the Pediatric National Surgery Quality Improvement Program Database, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.09.046. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.

Title:

Complications in Children with Ehlers-Danlos Syndrome following Spine Surgery: Analysis of the Pediatric National Surgery Quality Improvement Program Database

Short Title:

Pediatric EDS and Spine Outcomes

Authors:

Abhijith V. Matur BS1, Aria Nouri MD MSc1, Shenwen Huang BS PhD1, Nora C. Elson MS1, William Jeong MD MBA1, Karin S. Bierbrauer MD1,2, Francesco T. Mangano DO1,2, Joseph S. Cheng MD MS1

Affiliations:

1

Department of Neurosurgery, University of Cincinnati College of Medicine, USA Division of Pediatric Neurosurgery, Cincinnati Children’s Hospital, USA

2

Corresponding author: Joseph S. Cheng MD, MS, FAANS, FACS Professor and Chairman, Department of Neurosurgery Frank H. Mayfield Chair of Neurosurgery University of Cincinnati College of Medicine PO Box 670515 Cincinnati, OH 45267-0515 [email protected] Office (513) 558-3556 Fax (513) 558-3361 Keywords: Spine; Pediatric; Ehlers-Danlos; complications; outcomes; connective tissue disorder Declarations of interest: Abhijith Matur None Aria Nouri None Shenwen Huang None Nora Elson None William Jeong None Karin S. Bierbrauer None Francesco T. Mangano None Joseph S. Cheng None

Matur INTRODUCTION Ehlers-Danlos Syndrome (EDS) is a group of connective tissue disorders in which patients exhibit skin fragility and joint hypermobility, which is directly related to underlying dysfunction in collagen.1 EDS can be caused by multiple genetic mutations.2 According to one study, scoliosis and spinal asymmetry account for around 23.4% of musculoskeletal related diagnoses in children with EDS, ranking it among the most common problems encountered in this group.3 Due to the rarity of EDS, however, it has been difficult to determine the demographics and outcomes of spine procedures in this patient population.3 As a result of collagen related connective tissue defects causing hypermobility, patients with EDS are especially prone to developing deformities of the spine, even during childhood.4 Spondylosis, kyphosis, and scoliosis are all strongly associated with EDS, primarily due to ligamentous laxity.2 As a result, corrective spine surgery is sometimes needed to address these issues and stabilize unstable regions of the spine when patients do not respond to conservative treatment.2,5 Without surgery many patients with EDS may experience severe scoliosis leading to sagittal imbalance and respiratory compromise.6,7 However, there have been case reports that suggest patients with EDS may be at increased risk for bleeding and wound healing difficulties due to vascular abnormalities and tissue fragility. 8,1,9,10 One study has also suggested that this predisposition to increased bleeding may be very common among patients with EDS and may, at least in part, be due to platelet dysfunction.11 It remains unclear what implications this may have for outcomes of pediatric spine surgery for these patients since there have been few large studies examining this problem. While there are no official recommendations or guidelines for perioperative care of pediatric patients with EDS, some studies have suggested a role for the use of desmopressin (DDAVP) to help

1

Matur control bleeding.12,13,14,15 However, it is unclear how successful DDAVP is in improving overall outcomes in pediatric spine surgery. Other recommendations such as the use of hypotensive anesthesia and avoiding blunt dissection near vessels during an anterior approach have also been proposed,8 but the overall safety of spine surgery in pediatric EDS patients remains undetermined. Given the rarity of the condition and that these reports of complications arise primarily from case reports and series that may represent extraordinary cases, it has been challenging to determine if children with EDS are truly at a higher risk of bleeding and other complications after spine surgery. With the development of the American College of Surgeons (ACS) Pediatric National Surgical Quality Improvement Program database (PNSQIP) it is now possible to interrogate this subject with a greater patient number, and it is thus the objective of the present study to investigate what types of spine surgeries pediatric patients with EDS receive and if they suffer from a higher rate of complications than patients receiving similar spine surgeries without EDS. METHODS STUDY DATA The PNSQIP database contains information from over 50 pediatric hospital nationwide. Patients are followed for up to 30 days and sampling of cases is done through 8-day cycles to ensure randomness of the data. The PNSQIP database is highly reliable, with only a 2% interrater disagreement rate. Our institutions did not require an IRB for this research as the pediatric NSQIP database deidentifies individual patient data and this retrospective study did not involve contact with patients or changes in patient care. Detailed methodology is available in the PNSQIP user guide from the ACS.16

2

Matur

DATA ANALYSIS Using SPSS 24 (IBM, Armonk, USA), data was analyzed from the PNSQIP database from 2012-2016. Patients with EDS were identified using the ICD-9 code 756.83, which encompasses EDS and its subtypes. The dataset was then restricted to surgeries performed by neurosurgery, pediatric neurosurgery, orthopedic surgery, or pediatric orthopedic surgery. CPT codes for spine procedures were then used to identify EDS patients who underwent spine surgery (Figure 1). Patients without EDS undergoing the same spine procedures as the EDS patients were identified using the same CPT codes. For the purposes of this study, a complication is defined as any deviation from the expected post-operative course within the 30 days following surgery as noted in the PNSQIP. Due to the small overall sample size, similar types of complications were grouped together to facilitate statistical analysis. Complications related to wound infection and healing were grouped to include the 3 defined categories of surgical site infection (SSI) in the PNSQIP (superficial incisional SSI, deep incisional SSI, organ/space SSI), as well as wound disruption and graft failure. Surgical site infection included those that occurred within 30 days of the procedure and were clearly associated with the operation and had multiple signs of infection. Infections were defined as superficial, deep, or organ/space if they involved the skin or subcutaneous tissue, deep soft tissue, and the anatomy of the operation, respectively. Wound disruption is defined as disruption or separation of the internal surgical wound layers within 30 days of the operation. Graft failure is defined as mechanical failure of a myocutaneous flap or skin graft within 30 days of operation requiring return to the OR.

3

Matur Infectious complications were similarly grouped to include urinary tract infection, pneumonia, and surgical site infections. Variables related to bleeding were not grouped and were analyzed separately as there were a sufficiently high number of cases within the dataset. Bleeding was defined as transfusion events within 72 hours of the operation or during the operation itself. In addition to complications, factors related to patient risk going into surgery were also analyzed. This included ASA classification as well as cardiac risk factors. The database was also interrogated for comorbid CNS abnormalities in EDS patients as well. STATISTICAL METHODS Chi-squared and Fisher’s exact tests were performed on categorical variables and independent samples t tests were used to analyze continuous variables. Analysis was done with attention to complications that would be expected in EDS patients, especially those related to wound disruption and bleeding in comparison to those pediatric patients undergoing the same spine procedures, but without EDS. RESULTS A total of 279 patients of 369,176 total patients were determined to have EDS (Table 1). Of these 279 patients with EDS, 56 (20%) were determined to have undergone a spine procedure. 46% were male and 54% were female (p=0.11). Mean age at surgery was 11.59 years (p=0.89) with a range of 1.77-17.33 years. Two patients were Black or African-American, two did not report race, and the remaining 52 were designated as White. Three patients identified as Hispanic, three were unknown, and 50 were non-Hispanic. Of the 56 EDS patients identified in this study, 37 of these patients underwent some type of arthrodesis procedure. Many of these patients underwent large multilevel fusions, with 14 EDS patients undergoing posterior arthrodesis of 13 or more levels. The next most common procedures were reinsertion of spinal

4

Matur hardware (n=12) and laminectomy (n=6). Reinsertion of spinal hardware (CPT 22849) includes the extension of growth rods as well as reoperation for the mechanical failure of an implant. Among the 6 laminectomies that were done, 4 were done for tethered cords while the remaining 2 were done for intradural lesions. The spine procedures performed on pediatric EDS patients are shown in Table 2. The 56 patients with EDS were matched with 21,434 patients without EDS who underwent the same procedures. Among patients with EDS, there were no instances of any neurological complication after surgery. None of the EDS patients required inotropic support at the time of surgery. There was no 30-day mortality and no hospital stay lasted longer than 30 days in this group. There were 4 patients that required unplanned reoperations, but this was not statistically different (p=0.12) and these children did not undergo the unplanned reoperation sooner (p=0.45) (Table 3). 41% of EDS patients required blood transfusions but this was not significant compared to non-EDS patients undergoing the same surgeries (n=23, p=0.58). The total amount transfused (p = 0.508) and time until transfusion was required (p=0.13) were not different between either group. Neither group were different in terms of duration of anesthesia (p=0.71), length of hospital stay (p= 0.40), days from operation to discharge (p=0.59), and total operation time (p=0.36). There was one EDS patient who suffered a pulmonary embolism, which was statistically significant (p=0.01). However, given that there was only one instance it is unclear if this truly represents an increased risk of pulmonary embolism in this population. There were only 2 wound related complications in the EDS group, but this was not significant (p=0.67). One patient had an organ/space SSI that required removal of hardware and one patient suffered a wound dehiscence. One patient contracted pneumonia, and this was the only other infection reported.

5

Matur Many of the EDS patients undergoing arthrodesis underwent multi-level fusions, with 14 of these patients undergoing posterior fusion of 13 or more levels and 15 undergoing posterior fusion of 7 to12 levels. Only one patient underwent anterior arthrodesis. EDS patients undergoing posterior arthrodesis were not more likely to require blood transfusions than those without EDS undergoing the same number of fusions, regardless of the number of levels being fused (Table 4). When they did require transfusions, EDS patients did not require more blood than those without EDS undergoing fusion of the same number of levels. In fact, for fusions involving 7 to 12 levels EDS patients required less blood than those without EDS when transfusion was required. A significant portion of EDS patients compared to non-EDS patients had a worse level of general systemic disease prior to surgery, as a significant portion of them had an American Society of Anesthesiologists (ASA) classification of 3 or greater (p=0.03) (Table 5). In addition, a strong association was found between EDS patients and having cardiac risk factors of any kind (p<0.001).

A significantly lower number of EDS patients had a structural CNS disorder

(p=0.02) compared to those without EDS, but the same was not true for neuromuscular disorder (p=0.30), cerebral palsy (n=1, p=0.09), or developmental delay (p=0.15). There was some overlap between these groups. DISCUSSION The PNSQIP data presented here shows that spine surgeries are among the most common procedures performed in pediatric patients with EDS. It has been shown here that most commonly these procedures involve arthrodesis to treat severe scoliosis, but also include reinsertion and removal of spinal hardware and laminectomy. While it has been commonly accepted that these patients are at increased risk of bleeding and other complications as a result

6

Matur of their connective tissue disorder, the data presented here shows that with the current standard of perioperative care for EDS this may not be the case.8,1,10 There was no difference in bleeding between EDS spine patients and spine patients without EDS undergoing the same procedure. When significant bleeding did occur, the EDS population did not require higher volumes at an earlier timepoint. Bleeding outcomes among EDS patients were also not significantly different in arthrodesis procedures, regardless of the number of levels being fused. Complications such as bleeding are relatively common in pediatric spine surgery but it does not appear that children with EDS are any more at risk than their peers.17 Much of the bleeding that has been described in case reports had been associated with avulsion and tearing of segmental and other arteries during an anterior spinal approach.8,18,10 Posterior approaches have also been previously described in the literature but without the degree of bleeding often associated with anterior approaches.19 All but one of the arthrodesis procedures included in the data set involved a posterior approach. The remaining procedures involved laminectomies and removal or reinsertion of spinal hardware. This suggests that a posterior approach may be a contributing factor in ensuring safety in this patient population. Other contributing factors likely include the use of DDAVP perioperatively.15 However, we are unable to confirm the use of DDAVP among patients in the data set. There was no difference in wound related or infectious complications found between either group. It is possible that there is a significant difference in occurrence of pulmonary embolism, but as this is based on only a single case in the EDS group it is unclear if this is a truly generalizable risk. A significant lower number of EDS patients undergoing spine surgery had comorbid structural CNS abnormalities than those without EDS undergoing the same procedure, but the implications of this are unclear. Additionally, an increased surgical risk was noted in EDS spine patients based on a significant difference in ASA score and the presence of cardiac

7

Matur risk factors of any kind. This is in line with previous studies suggesting an increased surgical risk in EDS.8,18,10 However, many of the previous studies suggesting an increased rate of complications have consisted of case reports and case series and it is unclear if these were simply unique cases of complications.8,20,5,19,10 It is surprising that this study was unable to confirm an increased risk of bleeding or wound healing difficulties in pediatric spine surgery patients with EDS. It is possible that given the rarity of EDS, the current understanding of surgical risk during spine surgery in this patient population may need to be revised. Given that EDS often affects multiple members of the same family, family history of complications during previous operations may be an important component of determining surgical risk for this patient population.21 The nature of complications in spine procedures in EDS patients had largely been unknown outside of a few case reports that suggested an increased bleeding risk and difficulties with wound healing. In this retrospective review, we show that this may not necessarily be the case and that spinal procedures performed on pediatric patients with EDS may not carry significant additional risk over the general population for intraoperative bleeding or complications related to wound healing. The use of a posterior approach along with the use of DDAVP among patients with EDS likely play a role in mitigating bleeding risk.12,15 While further research is necessary to validate the safety of spine surgery in pediatric EDS, the aim of this research was to provide better insight into the complications of spinal procedures in this etiology in order to inform management decisions. Future research is needed to address whether the data presented here is truly generalizable to all subtypes of EDS and whether complications appear in long-term follow up. LIMITATIONS

8

Matur Given the nature of the PNSQIP data, we are unable to address a number of the following questions. Firstly, we are unable to determine the exact indication for all the surgical procedures, although many of the arthrodesis procedures were done for kyphosis and scoliosis and 4 of the 6 laminectomies were done for tethered cords. Secondly, given that EDS is a chronic disease, longterm follow-up data on spinal surgeries would have been greatly desired, but based on the current available data we could not infer long term outcomes. Despite a large dataset, the number of patients reported herein remains small. However, we feel that this is simply due to the rarity of the condition. To our knowledge, this remains the largest study of any kind looking at outcomes of spine surgery in pediatric patients with EDS. Additionally, while our analysis consists of only descriptive statistics it is our hope that this data sheds further light on outcomes of spine surgery this particular patient population, which until now has largely come from case reports.1,8,9,10 CONCLUSION It has been previously reported that pediatric patients with EDS undergoing spine surgery appear to be at increased risk of surgical complications both because of their connective tissue disorder as well as other anesthesia and cardiac related risk factors. However, the present study does not support these suppositions. Overall, these results suggest that with the usual standard of perioperative care, spine surgery in pediatric EDS patients does not carry additional risk over the general populations for bleeding or postoperative complications related to wound healing. It remains unclear how pediatric EDS spine patients should be assessed for surgical risk and future studies should aim to determine this. Acknowledgements We wish to thank the Donald C. Harrison Health Sciences Library at the University of Cincinnati for their technical assistance and support. This research did not receive any specific

9

Matur grant from funding agencies in the public, commercial, or not-for-profit sectors. Declarations of interest: none.

REFERENCES 1.

De Paepe A, Malfait F. The Ehlers-Danlos syndrome, a disorder with many faces. Clin Genet. 2012;82(1):1-11. doi:10.1111/j.1399-0004.2012.01858.x

2.

Henderson FC, Austin C, Benzel E, et al. Neurological and spinal manifestations of the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet. 2017;175(1):195211. doi:10.1002/ajmg.c.31549

3.

Stern CM, Pepin MJ, Stoler JM, Kramer DE, Spencer SA, Stein CJ. Musculoskeletal Conditions in a Pediatric Population with Ehlers-Danlos Syndrome. J Pediatr. 2017;181:261-266. doi:10.1016/J.JPEDS.2016.10.078

4.

van Dijk FS, Mancini GMS, Maugeri A, Cobben JM. Ehlers Danlos syndrome, kyphoscoliotic type due to Lysyl Hydroxylase 1 deficiency in two children without congenital or early onset kyphoscoliosis. Eur J Med Genet. 2017;60(10):536-540. doi:10.1016/J.EJMG.2017.07.011

5.

Kobets AJ, Komlos D, Houten JK. Congenital cervical kyphosis in an infant with Ehlers-

10

Matur Danlos syndrome. Child’s Nerv Syst. 2018;34(7):1411-1415. doi:10.1007/s00381-0183750-9 6.

Jasiewicz B, Potaczek T, Tesiorowski M, Lokas K. Spine deformities in patients with Ehlers-Danlos syndrome, type IV - late results of surgical treatment. Scoliosis. 2010;5:26. doi:10.1186/1748-7161-5-26

7.

Natarajan D, Samartzis D, Wong Y-W, Luk KDK, Cheung KMC. Natural history of spinal deformity in a patient with Ehlers-Danlos syndrome: case report with 20-year follow-up. Spine J. 2011;11(7):e1-e4. doi:10.1016/j.spinee.2011.02.029

8.

Akpinar S, Gogus A, Talu U, et al. Surgical management of the spinal deformity in Ehlers-Danlos syndrome type VI. Eur Spine J. 2003;12:135-140. doi:10.1007/s00586002-0507-6

9.

Henneton P, Legrand A, Giunta C, Frank M. Arterial fragility in kyphoscoliotic EhlersDanlos syndrome. BMJ Case Rep. 2018;2018:bcr-2018-224423. doi:10.1136/bcr-2018224423

10.

Yang JS, Sponseller PD, Yazici M, Johnston CE. Vascular Complications From Anterior Spine Surgery in Three Patients With Ehlers-Danlos Syndrome. Spine (Phila Pa 1976). 2009;34(4):E153-E157. doi:10.1097/BRS.0b013e31818d58da

11.

Artoni A, Bassotti A, Abbattista M, et al. Hemostatic abnormalities in patients with Ehlers-Danlos syndrome. J Thromb Haemost. 2018;16(12):2425-2431. doi:10.1111/jth.14310

12.

Mast KJ, Nunes ME, Ruymann FB, Kerlin BA. Desmopressin responsiveness in children with Ehlers-Danlos syndrome associated bleeding symptoms. Br J Haematol. 2009;144(2):230-233. doi:10.1111/j.1365-2141.2008.07446.x

11

Matur 13.

Nuss R, Manco-Johnson M. Hemostasis in Ehlers-Danlos Syndrome. Clin Pediatr (Phila). 1995;34(10):552-555. doi:10.1177/000992289503401008

14.

Stine KC, Becton DL. DDAVP therapy controls bleeding in Ehlers-Danlos syndrome. J Pediatr Hematol Oncol. 1997;19(2):156-158.

15.

Wiesmann T, Castori M, Malfait F, Wulf H. Recommendations for anesthesia and perioperative management in patients with Ehlers-Danlos syndrome(s). Orphanet J Rare Dis. 2014;9:109. doi:10.1186/s13023-014-0109-5

16.

American College of Surgeons National Surgical Quality Improvement Program Pediatric “User Guide for the 2016 ACS NSQIP Pediatric Participant Use Data File (PUF)”; 2016. https://www.facs.org/-/media/files/quality-programs/nsqippeds/peds_nsqip_puf_userguide_2016.ashx?la=en

17.

Basques BA, Lukasiewicz AM, Samuel AM, et al. Which Pediatric Orthopaedic Procedures Have the Greatest Risk of Adverse Outcomes? J Pediatr Orthop. 2017;37(6):429-434. doi:10.1097/BPO.0000000000000683

18.

Vogel LC, Lubicky JP. Neurologic and vascular complications of scoliosis surgery in patients with Ehlers-Danlos syndrome. A case report. Spine (Phila Pa 1976). 1996;21(21):2508-2514.

19.

Liu Y, Gao R, Zhou X, Yuan W. Posterior Spinal Fusion for Scoliosis in Ehlers-Danlos Syndrome, Kyphoscoliosis Type. Orthopedics. 2011;34(6):228. doi:10.3928/0147744720110427-28

20.

Fang H, Liu P-F, Ge C, et al. Anterior cervical corpectomy decompression and fusion for cervical kyphosis in a girl with Ehlers-Danlos syndrome: A case report. World J Clin cases. 2019;7(4):532-537. doi:10.12998/wjcc.v7.i4.532

12

Matur 21.

Udén A. Collagen and bleeding diathesis in Ehlers-Danlos syndrome. Scand J Haematol. 1982;28(5):425-430.

13

Matur Figure 1. Patient selection. A diagram showing how patients were selected from the initial 369,176 patients in the PNSQIP from 2012-2016 Table 1. Demographics. Comparison of patient demographics between children with and without EDS undergoing spine surgery Table 2. Description of Procedures. Spine procedures in pediatric EDS patients from 20122016 PSNQIP database arranged by CPT code Table 3. Post-operative Complications. Comparison of patient complications after spine surgery between children with EDS and those without EDS. * Fisher’s exact test Table 4. Bleeding in Arthrodesis. Comparison of Bleeding events among EDS patients and non-EDS patients undergoing posterior arthrodesis. * Fisher’s exact test Table 5. Pre-operative Risk Factors. Comparison of patient risk factors in spine surgery between children with EDS and those without EDS. * Fisher’s exact test

14

EDS Without EDS P value 56 21434 Total 26/30 7739/13695 0.11 Sex (M/F) 11.59 11.51 0.89 Mean Age at Surgery (Years) 1.77-17.33 0-18.01 Age range (years) 42.94 42.39 0.85 Weight at time of surgery (kg) 138.35 143.18 0.18 Height at time of surgery (cm) Table 1. Demographics. Comparison of patient demographics between children with and without EDS undergoing spine surgery

CPT code 22800

Number of patients 7

Description Posterior arthrodesis for spinal deformity, up to 6 vertebral segments 22802 15 Posterior arthrodesis for spinal deformity, 7-12 vertebral segments 22804 14 Posterior arthrodesis for spinal deformity, 13 or more vertebral segments 22810 1 Anterior arthrodesis for spinal deformity, 4-7 vertebral segments 22849 12 Reinsertion of spinal fixation device 22852 1 Removal of posterior segmental instrumentation 63200 4 Lumbar laminectomy with release of tethered cord 63272 1 Lumbar laminectomy for excision of intraspinal lesion other than neoplasm 63287 1 Thoracolumbar laminectomy for biopsy/excision of intramedullary neoplasm Table 2. Description of Procedures. Spine procedures in pediatric EDS patients from 20122016 PSNQIP database arranged by CPT code

EDS Without EDS P value 25 (45%) 10023 (47%) 0.75 Overall Complications (any kind) 2 (4%) 597 (3%) 0.67* Wound related 2 (4%) 882 (4%) 1* Infection 23 (41%) 9592 (45%) 0.58 Bleeding requiring transfusion 1 (2%) 3 (0.01%) Pulmonary embolism 0.01* 1 (2%) 188 (0.9%) 0.39* Pneumonia 4 (7%) 718 (3%) 0.12* Unplanned reoperation 9 13.38 0.45 Days from operation to unplanned reoperation 443.87 503.76 0.51 Mean blood transfused (mL) 0.04 0.11 0.13 Days from operation until bleeding complication 321.52 329.15 0.71 Mean duration of anesthesia (minutes) 214.57 232.40 0.36 Mean operation time (minutes) 4.38 4.89 0.40 Mean length of total hospital stay (days) 4.18 4.49 0.59 Mean days from operation to discharge Table 3. Post-operative Complications. Comparison of patient complications after spine surgery between children with EDS and those without EDS. * Fisher’s exact test

Arthrodesis (posterior approach) ≥13 levels (CPT code 22804) Bleeding requiring transfusion Mean blood transfused (mL) 7-12 levels (CPT code 22802) Bleeding requiring transfusion Mean blood transfused (mL) ≤6 levels (CPT code 22800) Bleeding requiring transfusion Mean blood transfused (mL)

36 (64%) 14355 (67%) 14 (39%) 4958 (35%) 11 (79%) 3758 (76%) 1.0* 600 674 0.68 15 (42%) 7628 (53%) 8 (53%) 4873 (64%) 0.40 266 398 0.03 7 (19%) 1769 (12%) 2 (29%) 746 (42%) 0.71* 267 336.27 0.42 Table 4. Bleeding in Arthrodesis. Comparison of Bleeding events among EDS patients and non-EDS patients undergoing posterior arthrodesis. * Fisher’s exact test

EDS 27 (48%) 17 (30%) 4 (7%) 9 (16%) 3 (7%) 9 (16%) 9 (16%) 1 (2%) 3 (5%)

Without EDS 7446 (35%) 2418 (11%) 1884 (8%) 5230 (24%) 1933 (9%) 6697 (31%) 4686 (22%) 1847 (9%) 1602 (7%)

P value 0.03 <0.001 0.82* 0.15 0.48* 0.02 0.30 0.09* 0.80*

ASA classification ≥ 3 Cardiac risk factors Nutritional support Developmental delay Seizure disorder Structural CNS abnormality Neuromuscular disorder Cerebral Palsy Structural pulmonary or airway abnormality 1 (2%) 434 (2%) 1* Hematologic disorder Table 5. Pre-operative Risk Factors. Comparison of patient risk factors in spine surgery between children with EDS and those without EDS. * Fisher’s exact test

ABBREVIATIONS ASA DDAVP EDS PSNQIP

American Society of Anesthesiologists classification Desmopressin Ehlers-Danlos Syndrome Pediatric National Surgical Quality Improvement Program