Review article 389
Risk factors for venous thromboembolism in hospitalized children and adolescents: a systemic review and pooled analysis Seung-Ju Kima and Sanjeev Sabharwalb We performed a systematic review of published studies that evaluated the potential risk factors and outcomes of venous thromboembolism (VTE) in hospitalized children. A total of 761 VTE patients from six published studies were identified. The mean prevalence of VTE in children admitted to the hospital was 9.7/10 000 admissions. The presence of a central venous catheter was found to be the single most important predisposing cause of VTE, with a pooled percentage of 29%. Infection was the second most common cause of the disease (20%). Pulmonary embolism occurred in 15% (113/745) of the patients. The overall recurrence rate of VTE was 16% (74/464) and the mortality rate was 8% (59/704). Although uncommon, orthopedic surgeons need to be aware of the unique risk factors for
VTE among pediatric inpatients. Hospitalized children and adolescents with known risk factors for VTE should be considered candidates for VTE screening or prophylaxis. c 2014 Wolters Kluwer J Pediatr Orthop B 23:389–393 Health | Lippincott Williams & Wilkins.
Introduction
the following questions: (a) What are the common risk factors of VTE amongst children and adolescents? (b) Is the reported clinical outcome comparable with the prevalence noted in adult patients?
Venous thromboembolism (VTE) has long been recognized as an important comorbidity in hospitalized adults [1]. However, until recently, thromboembolic disease has been considered a rare entity among pediatric patients [2]. Despite the relatively low incidence in children [3], a steady increase in the diagnosis of VTE across all age groups in children’s hospitals in the USA has been reported [4,5]. Furthermore, there have been several recent reports suggesting underestimation of the diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) among children [5–7]. The majority of pediatric VTEs occur in hospitalized patients, especially in children with at least one identified risk factor. Reported risk factors for VTE among children include malignancy, sepsis, osteomyelitis, methicillin-resistant Staphylococcus aureus (MRSA) infection, congenital heart disease, trauma, inflammatory disease, congenital prothrombotic disorders, and the use of a central venous catheter (CVC) [4,8–11]. However, our current knowledge of the risk factors of VTE in children is confined to a few reviews from single institutions or from multicenter national registries in one country, even though the incidence rates and risk factors of VTE may differ between children of different ethnic backgrounds and nationalities [12–15]. Further understanding of the role of potential risk factors would require a pooled analysis. Moreover, there is limited information on the prevalence and outcomes of VTE among children seen in orthopedic practices. Therefore, we reviewed published articles that reported the risk factors of VTE in hospitalized children and asked c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 1060-152X
Journal of Pediatric Orthopaedics B 2014, 23:389–393 Keywords: children, risk factor, venous thromboembolism a Department of Orthopedic Surgery, KEPCO Medical Foundation, KEPCO Medical Center, Seoul, Korea and bDepartment of Orthopaedics, New Jersey Medical School, Newark, New Jersey, USA
Correspondence to Seung-Ju Kim, MD, PhD, Department of Orthopedic Surgery, KEPCO Medical Foundation, KEPCO Medical Center, 308 Uicheon-ro, Dobong-Gu, Seoul 132-703, Korea Tel: 82 2 901 3079; fax: 82 2 901 3684; e-mail: [email protected]
Materials and methods Literature search and study selection
We performed a systematic review of the available literature using multiple separate search strategies. A search was performed using the following databases: MEDLINE, PubMed, CINAHL, and Cochrane systematic reviews. Search terms included ‘venous thromboembolism’, ‘child’, and ‘risk factor’. The initial search was performed on 15 July 2012, and it was repeated on 15 August 2012 by one of the authors (S.J.K.) to ensure accuracy. No additional study was identified by repeating the search. The title, abstract, and full text were reviewed when the title or abstract suggested appropriateness of these publications and were discussed among the authors, and a decision was made on inclusion. The inclusion criteria included the following: (a) articles published from 1 January 1980 to 1 July 2012, (b) Englishwritten articles on humans, (c) electronic publications that reported cases of VTE, (d) retrospective or prospective series, (e) cases of VTE in children or adolescents (< 20 years old), and (f) only those articles that described the risk factors and evaluated the clinical outcomes of VTE. The exclusion criteria included any of the following: (a) adults (> 20 years old), (b) articles focusing on the prophylaxis of VTE, (c) cases with arterial events, (d) articles with VTE cases diagnosed before hospital DOI: 10.1097/BPB.0000000000000053
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
390 Journal of Pediatric Orthopaedics B 2014, Vol 23 No 4
admission, (e) articles without the clinical outcomes (PE, recurrence and mortality) of VTE, and (f) VTE cases under specific situations such as intensive care unit admission. Limits for the number of patients in each study or the minimum duration of follow-up were not used. A first search of the MEDLINE database yielded 53 articles and a second search of the PubMed database using the same search strategy yielded 301 articles. The literature search is summarized in Fig. 1. There were 63 articles that appeared in more than one of the four searches, yielding a total of 320 unique articles. We screened all relevant articles from retrospective, cross-sectional studies, clinical registries, and prospective studies. If there was any disagreement among authors on the inclusion of an article, the senior author (S.S.) made the final decision. A manual search was also performed
from the references of the selected articles to identify any important reports that had not been identified in the initial research. The full text of the six finally selected articles was then reviewed. Owing to a lack of prospective randomized studies, most of the larger cohorts giving an answer or at least an insight into clinical problems were selected for this review. Because of the heterogeneity of the literature reports covered in the systematic review, it was not possible to carry out a meta-analysis in accordance to the Preferred reporting items for systematic reviews and meta-analyses (PRISMA) conditions [16]. Studies of VTE in children predominantly started after the Canadian Registry of VTE in 1994 [3], although there were few isolated previous studies. The following data were extracted from the selected articles: demographics including the patient’s age and sex,
Fig. 1
CINAHL
PubMed
Medline
Cochrane
Search terms: venous thromboembolism, child, risk factor (January , 1980 – July, 2012)
53 articles identified
301 articles identified
9 articles identified
20 articles identified
383 article titles reviewed
63 duplicate articles excluded
320 abstracts reviewed
315 articles excluded based on exclusion criteria
5 articles reviewed
1 additional article identified form bibliography
Total of 6 articles reviewed
Flow diagram of the search criteria and strategy.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Risk factors for venous thromboembolism Kim and Sabharwal 391
tion. Associated risk factors were present in 94% of children diagnosed with VTE (332/352).
prevalence, medical conditions that might be potentially associated with VTE (malignancy, infection, trauma, surgery, and obesity), history of previous VTE, number of previous VTE episodes, diagnosis of VTE, locations of VTE, management of VTE, outcomes following VTE including clinical resolution, relapse of VTE, and death because of VTE.
Children with VTE received a variety of therapeutic interventions including anticoagulation therapy with heparin, thrombolytic therapy, oral anticoagulation therapy, and other therapy (observation, removal of CVC, thrombectomy, placement of the inferior vena cava filter). PE occurred in 16% (124/761) of the patients. The overall recurrence rate of VTE was 16% (74/464) and the mortality rate was 8% (59/704). Of the 59 children who died, 47 (80%) died because of underlying disease including osteosarcoma, sepsis with multiorgan failure, rhabdomyosarcoma, brain tumor, prematurity, and cardiac disease. Twelve patients (20%) died as a direct consequence of the thromboembolic disease such as PE and extending thrombus. Outcomes following the diagnosis of VTE are shown in Table 3.
Results A review of MEDLINE, PubMed, CINAHL, and Cochrane literature searches yielded a total of 761 VTE patients from six selected articles [3,5,10,17–19], which have been reported from 1994 to 2011. Patients with VTEs present on admission were excluded from the analyses because important risk factors were not available for analysis in those, including concurrent CVC use. Although complete data on all categories were not available in each of the six articles, data such as sex, underlying medical/surgical conditions, location of VTE, incidence of PE, recurrence, and mortality were collected. Three studies were reported in North America (two studies in the USA, one study in Canada), two studies were reported in Europe, and one study was reported in Asia (Table 1). A total of 331 male and 430 female patients were included in the study. The mean prevalence of VTE in children admitted to the hospital in our pooled analysis was 9.7/10 000 admissions according to the four articles [3,5,17,18]. The presence of thrombus was confirmed with an advanced imaging study, typically with ultrasound or venogram for DVT and ventilation/ perfusion scans or computed tomography for PE. Locations of thrombosis were available for 69% of patients (525/761). Of these, DVT in the upper venous system was present in 136/525 patients (26%) and in the lower venous system in 389/525 patients (74%).
Discussion Studies describing the epidemiology, risk factors, and outcomes of VTE at pediatric tertiary care medical centers remain limited in number and geographic scope. Therefore, we performed a systemic review of the pertinent literature on VTE in hospitalized children. To our knowledge, this is the first pooled analysis showing the risk factors and outcomes of VTE in children with a review of the literature. In adults, fractures and surgery are two well-known risk factors of VTE [20,21]. However, our results of the pooled analysis of the reported cases of VTE in children showed that the presence of CVC was the single most important predisposing cause of VTE. Unlike in adults, the CVC has been consistently shown in the literature to
A total of eight potential risk factors were identified. The associated risk factors for the patients are presented in Table 2. The presence of CVC was found to be the single most prevalent predisposing risk factor associated with VTE in children. CVC was present in 29% (210/727) of the patients diagnosed with VTE. Infections including osteomyelitis, septic arthritis, septicemia, and local infection was the second most common (20%) associated risk factors of the disease. Miscellaneous risk factors included cystic fibrosis, use of oral contraceptives, congenital diaphragmatic hernia, cleft palate with dehydration, renal dialysis, fibrosing mediastinitis, diabetes, sickle cell disease, and lower extremity venous malformaTable 1
Table 2
Risk factors in children with venous thromboembolism Number of patients with risk factor/ number of available patients with VTE (%)
Risk factors Central venous catheter Infection Surgery Malignancy Trauma Heart disease Nephrotic syndrome Obesity No risk factor
210/727 153/752 78/664 79/761 65/732 59/761 18/430 7/260 20/352
(29) (20) (12) (10) (9) (8) (4) (3) (6)
VTE, venous thromboembolism.
Summary of data on venous thromboembolism in children on the basis of available studies
References Andrew et al. [3] Sandoval et al. [5] Sirachainan et al. [18] Tuckuviene et al. [19] Van Ommen et al. [10] Wright and Watts [17] Total
Number of patients
Age (years)
137 78 24 331 99 92 761
0.1–18 0–17 1.3–18 0–18 0–18 0–20 0–20
Percentage male (male/female) 50 47 58 32 52 47 43
(69/68) (43/35) (14/10) (109/222) (52/47) (44/48) (331/430)
Prevalence of VTE
Country
5.3/10 000 admissions 7.6/10 000 admissions 3.9/10 000 admissions Not available Not available 21.9/10 000 admissions 9.7/10 000 admissions
Canada USA Thailand The Netherlands Denmark USA
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392
Journal of Pediatric Orthopaedics B 2014, Vol 23 No 4
Table 3
Outcomes of venous thromboembolism in children on the basis of available studies Number of patients/number of available VTE patients (%)
References Andrew et al. [3] Sandoval et al. [5] Sirachainan et al. [18] Tuckuviene et al. [19] Van Ommen et al. [10] Wright and Watts [17] Total
Pulmonary embolism 22/137 4/78 7/24 61/331 10/99 20/92 124/761
Recurrence of VTE
(16) (5) (29) (18) (10) (22) (16)
23/137 9/64 6/23 9/57 7/99 20/84 74/464
(17) (14) (26) (16) (7) (24) (16)
Mortality of VTE 13/137 6/64 3/23 1/55 16/99 20/326 59/704
(10) (9) (13) (2) (16) (6) (8)
VTE, venous thromboembolism.
be a clinically important risk factor for VTE in children [9,22]. To minimize the risk for CVC-related VTE, it has been suggested that CVC in the upper venous system should be placed on the right side and in the internal jugular vein. If subclavian vein placement is necessary, CVC insertion by venous cut-down appears preferable over the percutaneous approach [9]. This is probably because of the fact that the subclavian vein takes a sharp curve at the site of CVL entry; endothelial damage at the opposite wall of the vein may occur when introducing the dilatator or catheter sheath. In our pooled analysis, infection was the second most common associated risk factor of VTE. Children with infection such as musculoskeletal sepsis, osteomyelitis, and Panton–Valentine leukocidin toxin-positive MRSA infections are at an increased risk of developing VTE [11]. Staphylococcal virulence factors have been reported to potentially play a role in VTE formation [23]. Other common risk factors for VTE were identified to include pediatric patients with surgery, malignancy, trauma, heart disease, and nephrotic syndrome, respectively. VTE is not a rare event in critically ill children after trauma [24]. Paffrath et al. [25] reported that independent risk factors for VTE development following trauma included injury severity, the number of operative procedures, and the presence of pelvic injury with abbreviated injury scale (AIS) > 2. Knudson et al. [26] reported that a lower extremity fracture with AIS Z 3, a head injury with AIS Z 3, the need for major operative procedures, or the presence of a venous injury were associated with VTE. Children with spinal cord injuries are also at a higher risk for VTE [27,28]. Most patients with thrombosis after trauma are associated with several factors, including poor perfusion and immobility [24]. For such highrisk patients, mechanical prophylaxis using intermittent pneumatic compression devices and early ambulation should be considered [29–31]. The role of chemoprophylaxis is currently not well established, and should be individualized after consultation with other subspecialists. VTE among children can lead to a clinically significant mortality and morbidity. Although reported VTE-specific mortality in children may be low, ranging from 0 to 2% [32,33], considerably higher all-cause mortality reflects the severity of underlying conditions (e.g. sepsis, cancer, and congenital cardiac disease) among children with VTE. In our review, the overall mortality rate was
8%. These findings show the importance of the recognition and treatment of VTE with high-risk factors in hospitalized pediatric patients. Although the incidence of VTE is relatively low in the pediatric population, the consequences are quite severe and can be fatal. Our study has some limitations. First, this is a pooled analysis of several retrospective case series with a heterogeneous cohort of patients. Consequently, not all the data that we sought to include in our analysis were consistently available in the chosen studies. Certain variables, such as patient’s ethnic background, age, and length of follow-up, were not specified or were not presented in sufficient detail to allow meaningful statistical inferences and comparisons. Therefore, we could not carry out a comparative study with non-VTE patients owing to a lack of data pertaining to a control group of pediatric inpatients. Second, VTE in children is a very rare condition for orthopedic surgeons and the patients included in this study include all the hospitalized pediatric patients. However, there have been several recent reports suggesting underestimation of the diagnosis of DVT and PE among children [4–7]. Given that PE can be fatal and is one of the causes of sudden death following lower extremity injury including surgery, it is imperative that orthopedic surgeons treating children should be aware of this potentially fatal condition [34]. Moreover, with the increased prevalence of risk factors such as childhood obesity and osteomyelitis secondary to MRSA, the number of cases of thromboembolism among children may be increasing [4,35]. According to a recent survey of members of the Pediatric Orthopedic Society of North America [36], 59% of the respondents acknowledged having encountered at least one child (< 18 years old) with the diagnosis of VTE (DVT and/or PE) in their practice. Conclusion
Our pooled analysis has helped to further elucidate the risk factors and outcomes of VTE among children. Hospitalized children with indwelling CVC, certain infections, or malignancy should be considered candidates for VTE screening. VTE in children contributes toward clinically significant morbidity and mortality. Prospective multicenter studies involving larger number of children and adolescents with diagnoses relevant to orthopedic surgery are needed to delineate the actual
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Risk factors for venous thromboembolism Kim and Sabharwal 393
prevalence of VTE and establish evidence-based guidelines for the prevention of this potentially fatal condition.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Risk factors for venous thromboembolism in hospitalized children and adolescents: a systemic review and pooled analysis Seung-Ju Kima and Sanjeev Sabharwalb We performed a systematic review of published studies that evaluated the potential risk factors and outcomes of venous thromboembolism (VTE) in hospitalized children. A total of 761 VTE patients from six published studies were identified. The mean prevalence of VTE in children admitted to the hospital was 9.7/10 000 admissions. The presence of a central venous catheter was found to be the single most important predisposing cause of VTE, with a pooled percentage of 29%. Infection was the second most common cause of the disease (20%). Pulmonary embolism occurred in 15% (113/745) of the patients. The overall recurrence rate of VTE was 16% (74/464) and the mortality rate was 8% (59/704). Although uncommon, orthopedic surgeons need to be aware of the unique risk factors for
VTE among pediatric inpatients. Hospitalized children and adolescents with known risk factors for VTE should be considered candidates for VTE screening or prophylaxis. c 2014 Wolters Kluwer J Pediatr Orthop B 23:389–393 Health | Lippincott Williams & Wilkins.
Introduction
the following questions: (a) What are the common risk factors of VTE amongst children and adolescents? (b) Is the reported clinical outcome comparable with the prevalence noted in adult patients?
Venous thromboembolism (VTE) has long been recognized as an important comorbidity in hospitalized adults [1]. However, until recently, thromboembolic disease has been considered a rare entity among pediatric patients [2]. Despite the relatively low incidence in children [3], a steady increase in the diagnosis of VTE across all age groups in children’s hospitals in the USA has been reported [4,5]. Furthermore, there have been several recent reports suggesting underestimation of the diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) among children [5–7]. The majority of pediatric VTEs occur in hospitalized patients, especially in children with at least one identified risk factor. Reported risk factors for VTE among children include malignancy, sepsis, osteomyelitis, methicillin-resistant Staphylococcus aureus (MRSA) infection, congenital heart disease, trauma, inflammatory disease, congenital prothrombotic disorders, and the use of a central venous catheter (CVC) [4,8–11]. However, our current knowledge of the risk factors of VTE in children is confined to a few reviews from single institutions or from multicenter national registries in one country, even though the incidence rates and risk factors of VTE may differ between children of different ethnic backgrounds and nationalities [12–15]. Further understanding of the role of potential risk factors would require a pooled analysis. Moreover, there is limited information on the prevalence and outcomes of VTE among children seen in orthopedic practices. Therefore, we reviewed published articles that reported the risk factors of VTE in hospitalized children and asked c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 1060-152X
Journal of Pediatric Orthopaedics B 2014, 23:389–393 Keywords: children, risk factor, venous thromboembolism a Department of Orthopedic Surgery, KEPCO Medical Foundation, KEPCO Medical Center, Seoul, Korea and bDepartment of Orthopaedics, New Jersey Medical School, Newark, New Jersey, USA
Correspondence to Seung-Ju Kim, MD, PhD, Department of Orthopedic Surgery, KEPCO Medical Foundation, KEPCO Medical Center, 308 Uicheon-ro, Dobong-Gu, Seoul 132-703, Korea Tel: 82 2 901 3079; fax: 82 2 901 3684; e-mail: [email protected]
Materials and methods Literature search and study selection
We performed a systematic review of the available literature using multiple separate search strategies. A search was performed using the following databases: MEDLINE, PubMed, CINAHL, and Cochrane systematic reviews. Search terms included ‘venous thromboembolism’, ‘child’, and ‘risk factor’. The initial search was performed on 15 July 2012, and it was repeated on 15 August 2012 by one of the authors (S.J.K.) to ensure accuracy. No additional study was identified by repeating the search. The title, abstract, and full text were reviewed when the title or abstract suggested appropriateness of these publications and were discussed among the authors, and a decision was made on inclusion. The inclusion criteria included the following: (a) articles published from 1 January 1980 to 1 July 2012, (b) Englishwritten articles on humans, (c) electronic publications that reported cases of VTE, (d) retrospective or prospective series, (e) cases of VTE in children or adolescents (< 20 years old), and (f) only those articles that described the risk factors and evaluated the clinical outcomes of VTE. The exclusion criteria included any of the following: (a) adults (> 20 years old), (b) articles focusing on the prophylaxis of VTE, (c) cases with arterial events, (d) articles with VTE cases diagnosed before hospital DOI: 10.1097/BPB.0000000000000053
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
390 Journal of Pediatric Orthopaedics B 2014, Vol 23 No 4
admission, (e) articles without the clinical outcomes (PE, recurrence and mortality) of VTE, and (f) VTE cases under specific situations such as intensive care unit admission. Limits for the number of patients in each study or the minimum duration of follow-up were not used. A first search of the MEDLINE database yielded 53 articles and a second search of the PubMed database using the same search strategy yielded 301 articles. The literature search is summarized in Fig. 1. There were 63 articles that appeared in more than one of the four searches, yielding a total of 320 unique articles. We screened all relevant articles from retrospective, cross-sectional studies, clinical registries, and prospective studies. If there was any disagreement among authors on the inclusion of an article, the senior author (S.S.) made the final decision. A manual search was also performed
from the references of the selected articles to identify any important reports that had not been identified in the initial research. The full text of the six finally selected articles was then reviewed. Owing to a lack of prospective randomized studies, most of the larger cohorts giving an answer or at least an insight into clinical problems were selected for this review. Because of the heterogeneity of the literature reports covered in the systematic review, it was not possible to carry out a meta-analysis in accordance to the Preferred reporting items for systematic reviews and meta-analyses (PRISMA) conditions [16]. Studies of VTE in children predominantly started after the Canadian Registry of VTE in 1994 [3], although there were few isolated previous studies. The following data were extracted from the selected articles: demographics including the patient’s age and sex,
Fig. 1
CINAHL
PubMed
Medline
Cochrane
Search terms: venous thromboembolism, child, risk factor (January , 1980 – July, 2012)
53 articles identified
301 articles identified
9 articles identified
20 articles identified
383 article titles reviewed
63 duplicate articles excluded
320 abstracts reviewed
315 articles excluded based on exclusion criteria
5 articles reviewed
1 additional article identified form bibliography
Total of 6 articles reviewed
Flow diagram of the search criteria and strategy.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Risk factors for venous thromboembolism Kim and Sabharwal 391
tion. Associated risk factors were present in 94% of children diagnosed with VTE (332/352).
prevalence, medical conditions that might be potentially associated with VTE (malignancy, infection, trauma, surgery, and obesity), history of previous VTE, number of previous VTE episodes, diagnosis of VTE, locations of VTE, management of VTE, outcomes following VTE including clinical resolution, relapse of VTE, and death because of VTE.
Children with VTE received a variety of therapeutic interventions including anticoagulation therapy with heparin, thrombolytic therapy, oral anticoagulation therapy, and other therapy (observation, removal of CVC, thrombectomy, placement of the inferior vena cava filter). PE occurred in 16% (124/761) of the patients. The overall recurrence rate of VTE was 16% (74/464) and the mortality rate was 8% (59/704). Of the 59 children who died, 47 (80%) died because of underlying disease including osteosarcoma, sepsis with multiorgan failure, rhabdomyosarcoma, brain tumor, prematurity, and cardiac disease. Twelve patients (20%) died as a direct consequence of the thromboembolic disease such as PE and extending thrombus. Outcomes following the diagnosis of VTE are shown in Table 3.
Results A review of MEDLINE, PubMed, CINAHL, and Cochrane literature searches yielded a total of 761 VTE patients from six selected articles [3,5,10,17–19], which have been reported from 1994 to 2011. Patients with VTEs present on admission were excluded from the analyses because important risk factors were not available for analysis in those, including concurrent CVC use. Although complete data on all categories were not available in each of the six articles, data such as sex, underlying medical/surgical conditions, location of VTE, incidence of PE, recurrence, and mortality were collected. Three studies were reported in North America (two studies in the USA, one study in Canada), two studies were reported in Europe, and one study was reported in Asia (Table 1). A total of 331 male and 430 female patients were included in the study. The mean prevalence of VTE in children admitted to the hospital in our pooled analysis was 9.7/10 000 admissions according to the four articles [3,5,17,18]. The presence of thrombus was confirmed with an advanced imaging study, typically with ultrasound or venogram for DVT and ventilation/ perfusion scans or computed tomography for PE. Locations of thrombosis were available for 69% of patients (525/761). Of these, DVT in the upper venous system was present in 136/525 patients (26%) and in the lower venous system in 389/525 patients (74%).
Discussion Studies describing the epidemiology, risk factors, and outcomes of VTE at pediatric tertiary care medical centers remain limited in number and geographic scope. Therefore, we performed a systemic review of the pertinent literature on VTE in hospitalized children. To our knowledge, this is the first pooled analysis showing the risk factors and outcomes of VTE in children with a review of the literature. In adults, fractures and surgery are two well-known risk factors of VTE [20,21]. However, our results of the pooled analysis of the reported cases of VTE in children showed that the presence of CVC was the single most important predisposing cause of VTE. Unlike in adults, the CVC has been consistently shown in the literature to
A total of eight potential risk factors were identified. The associated risk factors for the patients are presented in Table 2. The presence of CVC was found to be the single most prevalent predisposing risk factor associated with VTE in children. CVC was present in 29% (210/727) of the patients diagnosed with VTE. Infections including osteomyelitis, septic arthritis, septicemia, and local infection was the second most common (20%) associated risk factors of the disease. Miscellaneous risk factors included cystic fibrosis, use of oral contraceptives, congenital diaphragmatic hernia, cleft palate with dehydration, renal dialysis, fibrosing mediastinitis, diabetes, sickle cell disease, and lower extremity venous malformaTable 1
Table 2
Risk factors in children with venous thromboembolism Number of patients with risk factor/ number of available patients with VTE (%)
Risk factors Central venous catheter Infection Surgery Malignancy Trauma Heart disease Nephrotic syndrome Obesity No risk factor
210/727 153/752 78/664 79/761 65/732 59/761 18/430 7/260 20/352
(29) (20) (12) (10) (9) (8) (4) (3) (6)
VTE, venous thromboembolism.
Summary of data on venous thromboembolism in children on the basis of available studies
References Andrew et al. [3] Sandoval et al. [5] Sirachainan et al. [18] Tuckuviene et al. [19] Van Ommen et al. [10] Wright and Watts [17] Total
Number of patients
Age (years)
137 78 24 331 99 92 761
0.1–18 0–17 1.3–18 0–18 0–18 0–20 0–20
Percentage male (male/female) 50 47 58 32 52 47 43
(69/68) (43/35) (14/10) (109/222) (52/47) (44/48) (331/430)
Prevalence of VTE
Country
5.3/10 000 admissions 7.6/10 000 admissions 3.9/10 000 admissions Not available Not available 21.9/10 000 admissions 9.7/10 000 admissions
Canada USA Thailand The Netherlands Denmark USA
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Journal of Pediatric Orthopaedics B 2014, Vol 23 No 4
Table 3
Outcomes of venous thromboembolism in children on the basis of available studies Number of patients/number of available VTE patients (%)
References Andrew et al. [3] Sandoval et al. [5] Sirachainan et al. [18] Tuckuviene et al. [19] Van Ommen et al. [10] Wright and Watts [17] Total
Pulmonary embolism 22/137 4/78 7/24 61/331 10/99 20/92 124/761
Recurrence of VTE
(16) (5) (29) (18) (10) (22) (16)
23/137 9/64 6/23 9/57 7/99 20/84 74/464
(17) (14) (26) (16) (7) (24) (16)
Mortality of VTE 13/137 6/64 3/23 1/55 16/99 20/326 59/704
(10) (9) (13) (2) (16) (6) (8)
VTE, venous thromboembolism.
be a clinically important risk factor for VTE in children [9,22]. To minimize the risk for CVC-related VTE, it has been suggested that CVC in the upper venous system should be placed on the right side and in the internal jugular vein. If subclavian vein placement is necessary, CVC insertion by venous cut-down appears preferable over the percutaneous approach [9]. This is probably because of the fact that the subclavian vein takes a sharp curve at the site of CVL entry; endothelial damage at the opposite wall of the vein may occur when introducing the dilatator or catheter sheath. In our pooled analysis, infection was the second most common associated risk factor of VTE. Children with infection such as musculoskeletal sepsis, osteomyelitis, and Panton–Valentine leukocidin toxin-positive MRSA infections are at an increased risk of developing VTE [11]. Staphylococcal virulence factors have been reported to potentially play a role in VTE formation [23]. Other common risk factors for VTE were identified to include pediatric patients with surgery, malignancy, trauma, heart disease, and nephrotic syndrome, respectively. VTE is not a rare event in critically ill children after trauma [24]. Paffrath et al. [25] reported that independent risk factors for VTE development following trauma included injury severity, the number of operative procedures, and the presence of pelvic injury with abbreviated injury scale (AIS) > 2. Knudson et al. [26] reported that a lower extremity fracture with AIS Z 3, a head injury with AIS Z 3, the need for major operative procedures, or the presence of a venous injury were associated with VTE. Children with spinal cord injuries are also at a higher risk for VTE [27,28]. Most patients with thrombosis after trauma are associated with several factors, including poor perfusion and immobility [24]. For such highrisk patients, mechanical prophylaxis using intermittent pneumatic compression devices and early ambulation should be considered [29–31]. The role of chemoprophylaxis is currently not well established, and should be individualized after consultation with other subspecialists. VTE among children can lead to a clinically significant mortality and morbidity. Although reported VTE-specific mortality in children may be low, ranging from 0 to 2% [32,33], considerably higher all-cause mortality reflects the severity of underlying conditions (e.g. sepsis, cancer, and congenital cardiac disease) among children with VTE. In our review, the overall mortality rate was
8%. These findings show the importance of the recognition and treatment of VTE with high-risk factors in hospitalized pediatric patients. Although the incidence of VTE is relatively low in the pediatric population, the consequences are quite severe and can be fatal. Our study has some limitations. First, this is a pooled analysis of several retrospective case series with a heterogeneous cohort of patients. Consequently, not all the data that we sought to include in our analysis were consistently available in the chosen studies. Certain variables, such as patient’s ethnic background, age, and length of follow-up, were not specified or were not presented in sufficient detail to allow meaningful statistical inferences and comparisons. Therefore, we could not carry out a comparative study with non-VTE patients owing to a lack of data pertaining to a control group of pediatric inpatients. Second, VTE in children is a very rare condition for orthopedic surgeons and the patients included in this study include all the hospitalized pediatric patients. However, there have been several recent reports suggesting underestimation of the diagnosis of DVT and PE among children [4–7]. Given that PE can be fatal and is one of the causes of sudden death following lower extremity injury including surgery, it is imperative that orthopedic surgeons treating children should be aware of this potentially fatal condition [34]. Moreover, with the increased prevalence of risk factors such as childhood obesity and osteomyelitis secondary to MRSA, the number of cases of thromboembolism among children may be increasing [4,35]. According to a recent survey of members of the Pediatric Orthopedic Society of North America [36], 59% of the respondents acknowledged having encountered at least one child (< 18 years old) with the diagnosis of VTE (DVT and/or PE) in their practice. Conclusion
Our pooled analysis has helped to further elucidate the risk factors and outcomes of VTE among children. Hospitalized children with indwelling CVC, certain infections, or malignancy should be considered candidates for VTE screening. VTE in children contributes toward clinically significant morbidity and mortality. Prospective multicenter studies involving larger number of children and adolescents with diagnoses relevant to orthopedic surgery are needed to delineate the actual
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Risk factors for venous thromboembolism Kim and Sabharwal 393
prevalence of VTE and establish evidence-based guidelines for the prevention of this potentially fatal condition.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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