Venous thromboembolism (VTE) is a major source of

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1 The Journal of TRAUMA Injury, Infection, and Critical Care Risk Factors for Venous Thromboembolism in Pediatric Trauma Monica S. Vavilala, MD, Avery B. Nathens, MD, PhD, MPH, Gregory J. Jurkovich, MD, Ellen Mackenzie, PhD, and Frederick P. Rivara, MD, MPH Background: Venous thromboembolism (VTE) is a major source of morbidity in critically ill trauma patients. Although the incidence and risk factors for VTE after trauma in adults have been well described, similar data regarding pediatric patients are lacking. Methods: Pediatric (age < 16 years) trauma patients with VTE were identified from a large administrative database collated from 19 states across the United States. Risk factors for VTE were identified using multivariate techniques. Results: Risk of VTE increased with age and Injury Severity Scores. VTE was clearly associated with head, thoracic, abdominal, lower extremity, and spinal injuries. Craniotomy, laparotomy, and spinal operations were also associated with VTE. The greatest risk of VTE was in children with venous catheters. Conclusion: Older children with high Injury Severity Scores, major vascular injury, craniotomy, or venous catheters are at risk for VTE. These data may help guide strategies geared toward screening and prophylaxis in injured children. Key Words: Deep venous thrombosis, Pulmonary embolus, Pediatric trauma. J Trauma. 2002;52: Venous thromboembolism (VTE) is a major source of morbidity in critically ill patients. 1 Approximately 10% to 30% of adults admitted to medical and surgical critical care units are reported to have deep venous thrombosis (DVT) when screened during the first week of intensive care unit admission. 2 Both surgery and trauma are known to be independent risk factors for the development of VTE. 3 Although the incidence and risk factors for VTE after trauma in adults have been well described, similar data to guide prophylaxis and screening after pediatric trauma are lacking. The incidence of VTE is generally considered to be lower in children than in adults. Rohrer et al. reported one case of DVT in a prospective study of 1,997 (0.05%) children under the age of 17 hospitalized with two or more risk factors. The patient who developed DVT was a 17-year-old boy hospitalized after a motor vehicle crash. 4 Andrew et al. reported a similar incidence of VTE in children hospitalized in Canada. 5 Both of these studies, however, included children hospitalized with diagnoses other than trauma. More recently, Grandas et al. published the only study of VTE in injured children. They reported three cases of DVT in 2,746 (0.1%) Submitted for publication November 6, Accepted for publication January 9, Copyright 2002 by Lippincott Williams & Wilkins, Inc. From the Departments of Anesthesiology (M.S.V.), Surgery (A.B.N., G.J.J.), and Pediatrics (M.S.V., F.P.R.), University of Washington, Harborview Injury Prevention and Research Center (A.B.N., G.J.J., F.P.R.), Seattle, Washington, Injury Research and Policy Center (E.M.), Johns Hopkins University, Baltimore, Maryland, and the National Study on Costs and Outcomes of Trauma Care (A.B.N., G.J.J., E.M., F.P.R.). Supported by grant R49/CCR from the Centers for Disease Control and Prevention. Address for reprints: Monica S. Vavilala, MD, Department of Anesthesiology, Harborview Medical Center, Box , 325 9th Avenue, Seattle, WA 98104; vavilala@u.washington.edu. children under 16 years of age admitted to a Level I pediatric trauma center over an 8-year period. Two patients had DVT in the extremities, and one patient had a pulmonary embolus (PE) without identifiable DVT. Risk factors included atriocaval shunt, subclavian central line, and antishock trousers; no DVT was documented in patients with head or spinal cord injuries. 6 The present study uses a large sample of admitted trauma patients to determine the incidence and risk factors for VTE in pediatric trauma. PATIENTS AND METHODS Subjects States maintaining a uniform hospital discharge reporting system were identified and hospital inpatient discharge data were obtained for either 1997 or 1998, the most recent years for which data were available. Individual state discharge databases were collated by Solucient (previously HBS International) (Bellevue, WA). Nineteen states had complete data for 1997 (California, Colorado, Massachusetts, Montana, New Jersey, Oregon, Pennsylvania, and Wisconsin) or 1998 (Arizona, Florida, Iowa, Illinois, Indiana, Maryland, Michigan, North Carolina, New York, Virginia, and Washington). The data from Minnesota were unique in that not all institutions in the state contributed to the database. The collated discharge database was then merged with data obtained from the American Hospital Association Annual Survey (1998), limiting the analysis to acute care hospitals. Patients with any International Classification of Diseases, Ninth Revision (ICD-9) discharge diagnosis ranging from 800 to 959, excluding elderly patients ( 65 years) with a diagnosis of a fracture of the femoral neck (820), late effects of injuries ( ), foreign bodies ( ), and burns ( ) were considered to be trauma victims. To ensure this cohort best represented acute admissions resulting from traumatic 922 May 2002

2 Venous Thromboembolism, Children, and Trauma injury, we further limited the analysis to patients with a principal diagnosis of trauma, those patients in whom the first diagnosis field was a trauma-related diagnosis, as defined above. This approach reduced the possibility of miscoding patients with iatrogenic injuries as trauma patients. To avoid including patients who were electively readmitted after traumatic injuries (e.g., removal of orthopedic hardware), we excluded patients whose admission type was classified as elective. Pediatric trauma patients were defined as patients 15 years of age and younger who fulfilled the above criteria. Venous Thromboembolic Disease Subjects with any ICD-9 discharge diagnoses of phlebitis or thrombophlebitis of the deep veins of the lower extremities, iliac vein, inferior vena cava, or other, unspecified veins or sites (451.1, , , 451.2, , 453.2, 451.2, 453.8, and 453.9) or those with involvement of the deep veins of the upper extremities (451.83, , and ) were considered to have deep venous thromboses. Subjects with any diagnoses of pulmonary embolus and infarction (415.1, , and ) were classified as such. For the purposes of this analysis, venous thromboembolic disease refers to either deep venous thromboses or pulmonary embolus as defined above. Risk Factors for Venous Thromboembolic Disease Several potential risk factors for venous thromboembolic disease were considered and abstracted from the database. Demographic parameters including age (0 4, 5 9, and years) and gender, along with several specific diagnoses and procedures, were identified and categorized by ICD-9 diagnoses or procedure codes. These included pelvic fractures ( ); spinal cord injuries ( , and ); and major vascular injuries involving the chest, abdomen, and extremities exclusive of the pulmonary vasculature, splanchnic, and renal vessels ( , , , , , , , , and ). We also considered severe head, chest, abdominal, spine, and extremity injuries to be potential risk factors. Specifically, injuries with an Abbreviated Injury Scale (AIS) score 3 were considered to be severe and were identified using an ICD-9 to AIS linkage algorithm, as previously described. 7,8 The Injury Severity Score (ISS), a global measure of anatomic injury severity, was calculated by summing the squares of the highest AIS severity scores from the three different body regions with the highest AIS scores. 9 A variety of procedures were considered to potentially increase the risk of venous thromboembolism, including craniotomy or craniectomy, laparotomy, central venous catheterization for monitoring of right atrial or pulmonary arterial (capillary wedge) pressure, operations on the spine, or operative reduction and internal fixation of lower extremity long bone fractures. These procedures were identified by ICD-9 procedure codes. Collectively, these five general categories included 251 different codes. Statistical Analysis Rates were calculated per 1,000 discharges. All risk factors in which the 95% confidence interval of the risk ratio excluded 1 were then entered in a multivariate stepwise (backward elimination) Poisson regression model to determine the independent association of these variables with VTE. 10 All such variables were initially included, and variables were removed and reentered into the model using a significance level for removal and reentry of 0.1 and 0.05, respectively. To estimate the relative risk of venous thromboembolism in the adult (age 15) versus the pediatric population, we constructed a second regression model using the terms identified as independent predictors in adults, with an additional binary variable representing age categorized as 15 or 15 years. In all analyses, point estimates of the incidence rate ratios were calculated and are presented along with their 95% confidence intervals. Analyses were conducted using Stata Statistical Software, Release 6.0 (Stata Corporation, College Station, TX). RESULTS There were 58,716 pediatric trauma-related discharges across the 19 states available for analysis. Forty-five patients had a discharge diagnosis of venous thromboembolism, resulting in a rate of 0.77 per 1,000 discharges. Of these 45 patients, 38 had isolated deep-venous thromboses, 6 had isolated pulmonary emboli, and a single patient had a diagnosis of both DVT and PE. Overall, patients with VTE were older (mean age, 11.5 vs. 8.5 years; p 0.001), and their injuries were more severe than patients without VTE (mean ISS, 17.1 vs. 6.2; p 0.001). Furthermore, the risk increased markedly both with increasing age and with increasing ISS (Table 1). There were no deaths in the cohort with VTE, whereas the mortality rate in the remaining patients was 1.0%. VTE was associated with severe (AIS score 3) head, thoracic, abdominal, lower extremity, and spinal injuries (Table 2). No such relationship was evident for severe upper extremity injuries. At 6.5 per 1,000 discharges, patients with severe spinal injuries were most likely to be affected. When specific injuries were considered, major vascular injury was most strongly associated with VTE (relative risk, 28.2; 95% confidence interval [CI], ), in addition to pelvic fractures and spinal cord injuries (relative risks of 4.4 and 7.9, respectively). Several procedures were associated with an increased risk of VTE including craniotomy, laparotomy, and operations on the spine (Table 3). The greatest risk, however, was in children with venous lines used for central pressure monitoring. In these patients, the relative risk of VTE was 39.9 (95% CI, ) and the absolute rate was 28.6 per 1,000 discharges. Volume 52 Number 5 923

3 The Journal of TRAUMA Injury, Infection, and Critical Care Table 1 Univariate Analysis of Risk Factors for Venous Thromboembolism after Trauma: Demographics and Injury Severity n 58,716 No Thromboembolism, n 58,671 (%) Thromboembolism, n 45 (%) Rate per 1,000 Trauma Discharges RR (95% CI) Age (yr) 5 14,180 (24.2) 3 (6.7) 0.2 Reference ,365 (29.6) 7 (15.6) ( ) ,126 (46.2) 35 (77.8) ( ) Gender Female 19,510 (33.3) 12 (26.7) 0.6 Reference Male 39,126 (66.7) 33 (73.3) ( ) Injury Severity Score 9 42,880 (73.0) 8 (17.8) 0.2 Reference ,945 (18.7) 16 (35.6) ( ) ,135 (5.3) 7 (15.6) ( ) 25 1,711 (2.9) 14 (31.1) ( ) Multivariate Analysis Two multivariate regression models were constructed to determine the independent predictors of venous thromboembolic disease in this cohort of trauma patients. In the first model, the ISS was allowed to compete with the other parameters found to be associated with VTE in univariate analysis. We constructed a second model without the ISS to provide greater insight into the types of injuries and risk factors associated with VTE, which may be useful in developing guidelines for screening and prophylaxis. In the first model, ISS was independently associated with VTE, with the greatest risk among patients with an ISS 25 (Table 4). Increasing age, craniotomy, and venous lines for central pressure monitoring were independently associated with VTE as well, as were major vascular injuries. When ISS was excluded from the model, major vascular injury and Table 2 Univariate Analysis of Risk Factors for Venous Thromboembolism after Trauma: Patterns of Injury n 58,716 No Thromboembolism, n 58,671 (%) Thromboembolism, n 45 (%) Rate per 1,000 Trauma Discharges RR (95% CI) Severe* injuries by AIS body region Head Absent 50,959 (87.1) 23 (51.1) 0.5 Reference Present 7,940 (12.8) 22 (49.9) ( ) Thorax Absent 56,519 (96.3) 35 (77.8) 0.6 Reference Present 2,146 (3.7) 10 (22.2) ( ) Abdomen Absent 57,409 (98.0) 40 (88.9) 0.7 Reference Present 1,191 (2.0) 5 (11.1) ( ) Upper extremity Absent 56,945 (97.1) 43 (95.6) 0.8 Reference Present 2,146 (2.9) 2 (4.4) ( ) Lower extremity Absent 54,988 (93.8) 36 (80.0) 0.7 Reference Present 3,631 (6.2) 9 (20.0) ( ) Spine Absent 58,366 (99.5) 43 (95.6) 0.7 Reference Present 305 (0.5) 2 (4.4) ( ) Specific injuries Pelvic fracture Absent 57,409 (97.9) 41 (91.1) 0.7 Reference Present 1,262 (2.2) 4 (8.9) ( ) Spinal cord injury Absent 58,333 (99.4) 43 (95.6) 0.7 Reference Present 338 (0.6) 2 (4.4) ( ) Major vascular injury Absent 58,417 (99.6) 40 (88.9) 0.7 Reference Present 254 (0.4) 5 (11.1) ( ) * Severe refers to AIS score. 924 May 2002

4 Venous Thromboembolism, Children, and Trauma Table 3 Univariate Analysis of Risk Factors for Venous Thromboembolism after Trauma: Procedures n 58,716 No Thromboembolism, n 58,671 (%) Thromboembolism, n 45 (%) Rate per 1,000 Trauma Discharges RR (95% CI) Central venous catheter Absent 58,569 (99.8) 42 (93.3) 0.7 Reference Present 102 (0.2) 3 (6.7) ( ) Craniotomy Absent 57,824 (98.5) 37 (82.2) 0.6 Reference Present 847 (1.4) 8 (17.8) ( ) Laparotomy Absent 57,227 (97.5) 38 (84.4) 0.7 Reference Present 1,444 (2.4) 7 (15.6) ( ) Spinal procedure Absent 58,489 (99.7) 44 (97.8) 0.8 Reference Present 182 (0.3) 1 (2.2) ( ) ORIF of lower extremity long bone fracture Absent 52,810 (92.0) 36 (84.4) 0.7 Reference Present 5,861 (8.0) 9 (15.6) ( ) ORIF, open reduction and/or internal fixation. central venous lines remained; severe injuries to the spine, head, and thorax were predictors, as were laparotomy and operative fixation of lower extremity fractures (Table 5). Notably, craniotomy significantly increased the risk of VTE over and above the presence of a severe head injury. In contrast, lower extremity injuries dropped out of the model, although their operative fixations were retained. There was a fivefold increase in risk of VTE in individuals 10 years and older compared with those under 5; the relative risk in individuals 10 years and older compared with those under 5 was equivalent to the risk of VTE with central venous catheter or craniotomy. Differential Risk in Adult versus Pediatric Trauma Population There were 534,487 adult trauma patients (age 16 years or greater) discharged across these 19 states, 3,342 of whom had a diagnosis of deep venous thrombosis or pulmonary embolism. The overall rate of VTE in this population was 6 Table 4 Independent Predictors of Venous Thromboembolism in the Pediatric Trauma Patient: Model 1 Parameter Adjusted Relative Risk (95% CI) Injury Severity Score 9 Reference ( ) ( ) ( ) Major vascular injury 15.5 ( ) Central venous line 5.3 ( ) Craniotomy 5.0 ( ) Age (yr) 5 Reference ( ) ( ) per 1,000 trauma discharges, compared with 0.77 per 1,000 discharges in those less than 15 years. The crude relative risk of VTE in adults versus children was 8.1 (95% CI, ). After adjusting for the same risk factors identified above, the relative risk was 7.2 (95% CI, ), irrespective of the model chosen. DISCUSSION The index of suspicion for VTE in children after trauma has traditionally been low because symptomatic VTE is uncommon. To the best of our knowledge, this is the largest systematic study describing the incidence and risk factors associated with VTE in pediatric trauma. The results of our analysis indicate that the incidence of VTE after pediatric trauma is approximately 0.08%. As expected, isolated DVT Table 5 Independent Predictors of Venous Thromboembolism in the Pediatric Trauma Patient: Model 2* Parameter Adjusted Relative Risk (95% CI) Major vascular injury 17.6 ( ) Central venous line 6.8 ( ) Severe spine injury 5.1 ( ) Craniotomy 5.0 ( ) Age (yr) 5 Reference ( ) ( ) Severe head injury 4.8 ( ) Severe thoracic injury 2.7 ( ) Open reduction/internal fixation of lower 2.5 ( ) extremity fracture Laparotomy 2.3 ( ) * Excludes Injury Severity Score. Volume 52 Number 5 925

5 The Journal of TRAUMA Injury, Infection, and Critical Care was more common (84%) than either isolated PE (13%) or combined DVT/PE (2%). The overall prevalence of VTE in the present study is similar to that reported by Grandas et al. 6 Data from 28,692 pediatric trauma patients enrolled in the National Pediatric Trauma Registry over a 5-year period suggest that the rate of PE in children may even be lower, approaching 0.07 per 1,000 discharges. 11 However, the risk of VTE was not uniform across age groups. Only 0.02% of children aged 0 to 4 years were diagnosed with DVT compared with 0.04% of children aged 5 to 9 years and 0.1% of children aged 10 to 15 years. Most cases of VTE occurred in adolescents. There were no cases of PE under the age of 5, and most cases of PE were diagnosed in adolescents. Age was also an independent predictor of VTE when subjected to multivariate analysis. The relationship between patterns of injury and VTE in children has previously been only poorly characterized. There is only one report of VTE in a series of adolescents with severe head injuries. 12 In the present study, we confirm the relationship between head injury and VTE. Severe injuries involving the thorax, spine, and major vessels also pose significant risk. Impaired venous return from the lower extremities and abnormal coagulation factors are thought to predispose patients with spinal cord injuries to VTE. 13 The independent association between ISS and VTE risk in pediatric trauma is consistent with reports of increased risk of VTE in adults with major trauma. 3 Furthermore, certain injury patterns in adults pose a significantly higher risk of VTE than others. 14 The associated risk factors for the development of VTE identified in this study are similar to what is reported in adult trauma. 3,5,14 16 Several interventions are independently associated with VTE in children including craniotomy, open reduction and internal fixation of lower extremity fractures, and, to a lesser extent, laparotomy and central venous catheter (CVC) placement. CVC-related thrombus formation is a known complication in adults and is recognized as a potential complication in both adult trauma and hospitalized children A recent randomized controlled trial comparing femoral to subclavian catheterization in critically ill patients found that thrombotic complications were found only with femoral lines. 24 Ours is the first report establishing CVC use as an independent predictor of VTE and describing the relative risk of VTE with CVC in pediatric trauma. There were no deaths associated with VTE in this cohort, a reflection of the relatively low rate of PE (0.12 per 1,000 discharges). Reports of mortality directly attributed to DVT/PE are variable. In a 50-year retrospective review of autopsy cases in children aged 1 month to 13 years, 8 of 17,500 (0.05%) sudden and unexpected deaths were attributed to pulmonary thromboembolism, suggesting that the burden of disease is not extraordinarily high. 25 The Canadian Thrombophilia Registry reported a mortality rate of 2.2% directly attributed to VTE; all children who died had CVCassociated thrombosis. It is possible that the lack of long-term follow-up in the present study underestimated the true incidence of VTE-associated mortality. 26 There are certain limitations that should be considered while interpreting the results of this study. The prevalence of VTE in adults in the present study is lower than the commonly cited 20% to 40%. 27,28 These prior reports are usually of trauma center populations undergoing routine screening for VTE. However, this report is based only on clinically significant VTE, which is known to be much less common than VTE diagnosed on active screening. 27,28 In addition, many of the patients in the present study were not seriously injured, and most were hospitalized in nontrauma centers. Although the magnitude of the problem is likely understated in the present study, the prevalence of VTE in children appears to be significantly lower than in adults. There are no data from large studies on the prevalence of VTE on the basis of active screening in injured children. In the present study, CVC was independently associated with a risk of thrombus formation. Unfortunately, it was not possible for us to determine site of access from the database. Hence, we cannot draw conclusions regarding preferred approach for access in critically ill children. We speculate that although there was probably a mixture of access sites, young children, in particular, had femoral venous cannulation. Given the many reports of DVT with femoral lines, we think that the incidence of VTE may be site-specific and that alternative routes of access may preferable in some patients. Finally, we do not know whether preexisting coagulation disorders or other medical histories were related to children s risk of VTE in this study. In conclusion, this report identifies the prevalence and specific risk factors for the development of VTE in pediatric trauma patients. Older children with specific injury patterns or those exposed to certain interventions (e.g., CVCs) are at higher risk for VTE. This population may benefit from routine prophylaxis and/or screening. Although there is little dispute regarding the value of testing symptomatic patients for DVT, the overall accuracy of screening ultrasound in the asymptomatic patient is less clear. Unfortunately, the lack of available data on VTE screening, VTE prophylaxis, or treatment of VTE in the general pediatric trauma population precludes any definitive recommendation with respect to evaluation and management ACKNOWLEDGMENTS We thank Chris Mack, MS, and Ben Strickland, BFA, BA, for their assistance in preparing this article. REFERENCES 1. Meissner M. Deep venous thrombosis in the trauma patient. Semin Vasc Surg. 1998;11: Attia J, Ray J, Cook D, et al. Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med. 2001;161: Heit J, Silverstein M, Mohr D, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based casecontrol study. Arch Intern Med. 2000;160: May 2002

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