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Chylothorax in children with congenital heart disease: Incidence of thrombosis
Thrombosis Research 132 (2013) e83–e85
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Chylothorax in children with congenital heart disease: Incidence of thrombosis☆ M.E. Bauman a,b,⁎, Conrad Moher b, A.K. Bruce a, S. Kuhle c,d, Satvinder Kaur b, M.P. Massicotte a a
Stollery Children’s Hospital, University of Alberta, Edmonton, AB Canada University of Alberta, Edmonton, AB Canada Department of Pediatrics, Dalhousie University, Halifax, NS Canada d Department of Obstetrics & Gynaecology, Dalhousie University, Halifax, NS Canada b c
a r t i c l e
i n f o
Article history: Received 15 March 2013 Received in revised form 6 June 2013 Accepted 11 June 2013 Available online 2 July 2013 Keywords: Congenital heart disease Chylothorax Thrombosis
a b s t r a c t Postoperative chylothorax is a frequently encountered pathology occurring in up to 4% of patients undergoing surgery for repair of congenital heart disease. Symptomatic thrombosis is associated with chylothorax and may contribute to its severity and duration. Furthermore, vessel thrombosis resulting in persistent vessel occlusion may impede future treatments, diagnostic studies and cardio-surgical interventions. The objective of this study was to determine the incidence of upper system thrombosis in pediatric congenital heart patients with confirmed chylothorax with ultrasound screening of all patients diagnosed with chylothorax. All pediatric patients with confirmed with chylothorax underwent doppler ultrasound of the upper venous system as per hospital standard. This retrospective cohort study enrolled all children between February 1, 2010-August 2012, post cardiac surgery with confirmed chylothorax to determine the incidence of all thrombosis. There were 1396 children who underwent 1396 cardiac surgical procedures during the study time with 760 undergoing cardiopulmonary bypass. Development of chylothorax occurred in 54 of 1396, 3.9% (95%CI 3.0;5.0) procedures in all children. In those children with chylothorax, 28 of 54 episodes, 51.8% (95%CI 38.9;64.6) had confirmed VTE. The 51.8% incidence in this study demonstrates a 2.6 fold increase in risk of thrombosis compared to 20% in children with heart disease and central venous lines and may result in serious clinical consequences. The contribution of upper venous system thrombosis to chylothorax is unknown. Often, clinical suspicion of chylothorax exists, however the lack of a standardized approach to objective diagnosis results in delayed confirmation. Approaches to therapy either treatment of confirmed thrombosis or prevention of thrombosis in patients with chylothorax require formal evaluation. Future studies are urgently needed. © 2013 Elsevier Ltd. All rights reserved.
Introduction Postoperative chylothorax is a frequently encountered pathology occurring in up to 4% of patients undergoing surgery for repair of congenital heart disease [1]. The continuous loss of chyle is a challenging problem to treat and is associated with increased morbidity and mortality. It has been associated with prolonged ventilator dependence, increased length of hospital stay and associated nosocomial infections, malnutrition and central venous line related thrombosis [2]. Factors which increase patient risk for thrombosis include the presence of a central venous line, central venous hypertension in addition to an overall increased risk for thrombosis in children with congenital heart disease due to acquired coagulopathies [3–7] A retrospective review of 30 pediatric patients with chylothorax demonstrated that 26.7 percent of patients with chylothorax were symptomatic for
☆ The authors have no financial disclosures. ⁎ Corresponding author at: 3-585 11405 87 Ave, Edmonton, Alberta, Canada T6G 2B7. E-mail address: [email protected] (M.E. Bauman). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.06.014
thrombosis and confirmed by ultrasound. However, screening of all patients with chylothorax for thrombosis was not performed [2]. The objective of this study was to determine the incidence of upper system thrombosis in pediatric congenital heart patients with confirmed chylothorax. Secondary objectives were to determine if any variables identified may be associated with an increased risk for thrombosis. Methods Stollery Children’s Hospital, University of Alberta is one of two pediatric cardio-surgical centers for children across Western Canada. Chylothorax diagnoses were confirmed in all children based on four criteria accepted to be diagnostic of the presence of chylothorax including white blood cell count > 1000 109/L, lymphocytes > 80%, triglycerides >1.1 mmol/L, and chest tube losses of more than 10 ml /kg/day for more than 3 days. Given the proposed increased risk for thrombosis in children diagnosed with chylothorax post cardio surgical repair, the routine care for children at this institution with chylothorax was to perform a doppler ultrasound by radiologists
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trained in pediatric sonography of the upper venous system in all children with confirmed chylothorax to assess for thrombosis. Children with confirmed thrombosis on ultrasound were anticoagulated with heparin / enoxaparin until the clot resolved to a maximum of three months. All pediatric patients were objectively evaluated for chylothorax and those with confirmed chylothorax (fulfilling 3 or more of the 4 criteria diagnostic for chylothorax (see above). This retrospective cohort study enrolled all children between February 1, 2010-August 2012, post cardiac surgery with confirmed chylothorax. Data collected included variables that are reported to predict the development of chylothorax and potential thrombosis including demographic data, gender, age (years), weight (kg), date of confirmed diagnosis of chylothorax, central venous line (CVL) data including indwell time (days), and, ultrasound diagnosed location of thrombus, cardiopulmonary bypass times (minutes), aortic clamp time (minutes), chylothorax duration (days), and central venous pressure (CVP) (mmHg). ARISTOTLE scores [8] were calculated using underlying cardiac diagnosis and type of cardiac surgical procedure. In this study, the right atrial CVP collected for each patient was the highest value documented in the first post-operative week. This study was approved by the University of Alberta Health Ethics Board. Statistical Analysis Descriptive statistics were presented as mean (SD), median (range), or relative frequencies as applicable. Clinical characteristics were compared between children with and without thrombosis using t-test, Mann-Whitney U test, or Chi-Squared test as appropriate. A p-value b 0.05 was considered statistically significant. All statistical analyses were done using Stata/SE version 12 (Stata Corp., College Station, TX, USA). Results There were 1396 cardiac surgical procedures in 1396 children during the study time with 760 undergoing cardiopulmonary bypass. Development of chylothorax occurred in 54 of 1396, 3.9% (95%CI 3.0;5.0) procedures in all children, with 48 of 760, 6.3% (95%CI 4.8;8.3) and 6 of 636, 0.9% (95%CI 0.4;2.0) in the presence or absence of CPB, respectively, yielding an incidence ratio of 6.7 (95%CI 2.9;15.5). In those children with chylothorax, 28 of 54 episodes, 51.8% (95%CI 38.9;64.6) had confirmed VTE, with 24/28 and 4/6 occurring in the presence or absence of CPB, respectively, for an incidence ratio of 0.75 (95%CI 0.4;1.4) p = 0.441. Twenty of 28 VTE were non occlusive in nature with the majority occurring in the right internal jugular vein (54%). Clinical characteristics of the sample (overall and stratified by VTE status) are shown in Table 1. Children with chylothorax
and VTE had a significantly longer PICU stay, and a longer CVL indwell time than those without VTE. Discussion This is the first study to diagnostically assess all cardio-surgical children with confirmed chylothorax for the presence of upper venous system thrombosis. The incidence of thrombosis in this cohort is 51.8% compared with 26.7% reported by McCulloch et al. [2]who evaluated symptomatic thrombosis. The three most important factors associated with the development of thrombosis are blood composition, vessel wall integrity and blood flow [9]. Abnormalities in each dimension have been reported in children with congenital heart disease. Blood composition is altered in children b 4 years of age with congenital heart disease, with decreased levels of procoagulant and inhibitor proteins of coagulation, including antithrombin [3–7]. Children with cyanotic heart disease develop polycythemia resulting in increased viscosity, decreased levels of inhibitors of coagulation, including antithrombin [3–6]. In addition, children with chylothorax have been demonstrated to have further decreased levels of antithrombin due to losses through chylous drainage [10]. Vessel wall integrity is damaged during placement of venous catheter. Blood flow is altered by the cardiac physiology and altered vascular pressures [11]. The Canadian Registry for CVL related thrombosis demonstrates that asymptomatic thrombosis resulted in mortality and morbidity [12], although, within this study 5 of 28 thrombi were occlusive, all thrombosis, including those with clinical symptoms prompting ultrasound, and those without obvious clinical symptoms have serious consequences. These consequences include loss of venous access which may prevent further staged surgeries in patients with single ventricle physiology and anatomy [13], cardiac transplant, post thrombotic syndrome (pain, swelling, distended collateral vessels) [13,14], pulmonary embolism, infection [15], and stroke in children with left to right shunting [16]. In this study, of the 28 children who developed thrombosis, there were 6 of 13 children with single ventricle physiology and anatomy compared with 11 of 15 children with other cardiac diagnoses (ventricular septal defect, atrial septal defect, atrial ventricular septal defect, pulmonary atresia, transposition of the great arteries, tetralogy of fallot). McCulloch et al. [2] reported cardiopulmonary bypass to be an independent risk factor for children with chyle for upper venous thrombosis. However, in this study CPB was not found to be a risk factor as 24/28 and 4/6 upper venous thrombosis occurred in the presence or absence of CPB, respectively, for an incidence ratio of 0.75 (95%CI 0.4;1.4) p = 0.441. Of note, within our institution, post cardiac surgical children receive unfractionated heparin (UFH) or low molecular weight heparin
Table 1 Demographic and surgical characteristics.
Total surgeries (n = 1396) CPB (n = 760) Non-CPB (n = 636) Median age Weight Male gender Median length of PICU stay Median ARISTOTLE score History of thrombosis Median CVL indwell time Median CVP ECMO Mean aortic clamp time (CPB patients only)
Diagnosed with Chylothorax
Chylothorax with thrombosis
Chylothorax without thrombosis
p-value
54 48
28 24
26 24
0.441
6
4
2
-
5.3 mo (10d - 13.4y) 5.8 kg (2.5 - 30.3) 57% (31) 6 d (1 - 61) 8 (3 - 14.5) 13% 5 d (1 - 14) 14.5 mmHg (54 - 36) 2% (1) 43.7
4.7 mo (11d - 13.4y) 5.0 kg (2.5 - 30.3) 64% (18) 9 (1 - 19) 9 (3 - 14.5) 14% 6.5 d (1 - 14) 15.5 mmHg (5 - 36) 4% (1) 55.8
6.0 mo (10d - 4.3y) 6.4 kg (2.7 - 15.0) 50% (13) 3 (1 - 61) 7.5 (3 - 14.5) 12% 2.5 d (1 - 14) 14 mmHg (4 - 31) 0 32.3
0.421 0.295 0.289 0.003 0.510 0.622 b0.001 0.630 0.331 0.072
M.E. Bauman et al. / Thrombosis Research 132 (2013) e83–e85
(LMWH) for 3-5 days or until the child has the upper system central line removed and has oral/G-tube intake. Sub-therapeutic anti factor Xa levels (UFH b 0.35 u/ml, LMWH b0.5 u/ml) [11] are targeted with the aim to maintaining vessel patency and preventing thrombosis. Despite this approach, in this study 50% of children with single ventricle physiology and anatomy developed upper venous system thrombosis. Children with other cardiac diagnoses do not receive anticoagulation. If thrombosis was confirmed, in the absence of contraindications, children were treated with therapeutic dose heparin (anti factor Xa levels 0.35 to 0.7 u/ml) and transitioned to low molecular weight heparin (anti factor Xa levels 0.5 to 1.0 u/ml) until the clot resolved or 6 weeks to 3 months, in neonates and children >3 months of age, respectively. Central venous line duration was significantly longer, at 7.43 compared to 3.5 days (p b 0.05) in children who developed thrombosis. The majority of thromboses occurred in the right internal jugular vein which was consistent with line placement. This finding is consistent with McCulloch et al. [2] who demonstrated that CVL in dwell time was 5 to 6 days longer in children who developed thrombosis. Central venous lines are the most significant risk factor for children who develop thrombosis [17]. Central venous line indwell time is not reported to be associated with incidence of thrombosis in children without chylothorax [18]. However, this cohort differs as central venous line dwell time is associated with increased incidence of thrombosis. This study has limitations including the retrospective design allowing only for assessment of associated factors. Causality can only be determined in a prospective clinical study. Although, the use of Doppler ultrasound to diagnose thrombosis has not been demonstrated to have increased sensitivity for neck vessels, there are no anatomic structures that would interfere with the test thus may be accurate. However, decreased sensitivity for vessels within the thoracic cage compared to venography has been demonstrated [19]and thus the total incidence of thrombosis may be underestimated. In addition, the chronological development of chylothorax and thrombosis is unknown, and in this study 21% of thrombosis were symptomatic and as a result were diagnosed 4 days prior to the confirmation of chylothorax, as all confirmatory measures of chylothorax had not yet been performed. Given that the highest CVP was collected per patient, this may provide a false representation of significance for developing thrombosis. Despite the use of anticoagulation; unfractionated heparin or low molecular weight heparin targeting subtherapeutic levels prescribed in all children in this study, upper venous system thrombosis is demonstrated in 52% of children with chylothorax within this institution. Perhaps in the absence of this nominal amount of anticoagulation, the incidence of thrombosis would be greater than that reported. Intensification of anticoagulation may decrease thrombosis however this approach requires safety and efficacy testing in prospective studies. Conclusions This study suggests that one of every two children diagnosed with chylothorax have upper venous thrombosis. The contribution of upper venous system thrombosis to chylothorax is unknown. Often, clinical suspicion of chylothorax exists, however the lack of a standardized approach to objective diagnosis results in delayed confirmation. Approaches to therapy either treatment of confirmed thrombosis or prevention of
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thrombosis in patients with chylothorax require formal evaluation. Future studies are urgently needed.
Conflict of Interest Statement No conflict of interest.
References [1] Milonakis M, Chatzis AC, Giannopoulos NM, Contrafouris C, Bobos D, Kirvassilis GV, et al. Etiology and management of chylothorax following pediatric heart Surgery. J Card Surg 2009;24(4):369–73. [2] McCulloch MA, Conaway MR, Haizlip JA, Buck ML, Bovbjerg VE, Hoke TR. Postoperative chylothorax development is associated with increased incidence and risk profile for central venous thromboses. Pediatr Cardiol 2008;29(3):556–61. [3] Odegard KC, McGowan Jr FX, DiNardo JA, Castro RA, Zurakowski D, Connor CM, et al. Coagulation abnormalities in patients with single-ventricle physiology precede the Fontan procedure. J Thorac Cardiovasc Surg 2002;123(3):459–65. [4] Odegard KC, McGowan Jr FX, Zurakowski D, DiNardo JA, Castro RA, Del Nido PJ, et al. Procoagulant and anticoagulant factor abnormalities following the Fontan procedure: Increased factor VIII may predispose to thrombosis. J Thorac Cardiovasc Surg 2003;125(6):1260–7. [5] Odegard KC, McGowan Jr FX, Zurakowski D, DiNardo JA, Castro RA, Del Nido PJ, et al. Coagulation factor abnormalities in patients with single-ventricle physiology immediately prior to the Fontan procedure. Ann Thorac Surg 2002;73(6):1770–7. [6] Odegard KC, Zurakowski D, DiNardo JA, Castro RA, McGowan Jr FX, Neufeld EJ, et al. Prospective longitudinal study of coagulation profiles in children with hypoplastic left heart syndrome from stage I through Fontan completion. J Thorac Cardiovasc Surg 2009;137(4):934–41. [7] Odegard KC, Zurakowski D, Hornykewycz S, DiNardo JA, Castro RA, Neufeld EJ, et al. Evaluation of the Coagulation System in Children with Two-Ventricle Congenital Heart Disease. Ann Thorac Surg 2007;83(5):1797–803. [8] Lacour-Gayet F, Clarke D, Jacobs J, Comas J, Daebritz S, Daenen W, et al. The Aristotle score: A complexity-adjusted method to evaluate surgical results. Eur J Cardiothorac Surg 2004;25(6):911–24. [9] Virchow R. Thrombosis and embolie. Gesammelte Abhandlungen zur wissenshaftlichen Medicin. Canton, Masschusetts: Science History Publications; 1856 219–732. [10] Bernet-Buettiker V, Waldvogel K, Cannizzaro V, Albisetti M. Antithrombin activity in children with chylothorax. Eur J Cardiothorac Surg 2006;29(3):406–9. [11] Monagle P, Chan AKC, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-Göttl U, et al. Antithrombotic therapy in neonates and children: Antithrombotic therapy and prevention of thrombosis. American college of chest physicians evidencebased clinical practice guidelines, 141(2 Suppl.). Chest, 9th ed.; 2012. p. e737S–801S. [12] Massicotte MP, Dix D, Monagle P, Adams M, Andrew M. Central venous catheter related thrombosis in children: Analysis of the Canadian registry of venous thromboembolic complications. J Pediatr 1998;133(6):770–6. [13] Monagle P, Adams M, Mahoney M, Ali K, Barnard D, Bernstein M, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000;47(6):763–6. [14] Kuhle S, Koloshuk B, Marzinotto V, Bauman M, Massicotte P, Andrew M, et al. A cross-sectional study evaluating post-thrombotic syndrome in children. Thromb Res 2003;111(4–5):227–33. [15] Randolph AG, Cook DJ, Gonzales CA, Andrew M. Benefit of heparin in peripheral venous and arterial catheters: Systematic review and meta-analysis of randomised controlled trials. Br Med J 1998;316(7136):969–75. [16] Monagle P, Cochrane A, McCrindle B, Benson L, Williams W, Andrew M. Thromboembolic complications after fontan procedures–the role of prophylactic anticoagulation.[comment]. J Thorac Cardiovasc Surg 1998;115(3):493–8. [17] Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009;124(4):1000–8. [18] Male C, Julian JA, Massicotte P, Gent M, Mitchell L, Group PS. Significant association with location of central venous line placement and risk of venous thrombosis in children. Thromb Haemost 2005;94(3):516–21. [19] Male C, Chait P, Ginsberg JS, Hanna K, Andrew M, Halton J, et al. Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase. Thromb Haemost 2002;87(4):593–8.
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Chylothorax in children with congenital heart disease: Incidence of thrombosis☆ M.E. Bauman a,b,⁎, Conrad Moher b, A.K. Bruce a, S. Kuhle c,d, Satvinder Kaur b, M.P. Massicotte a a
Stollery Children’s Hospital, University of Alberta, Edmonton, AB Canada University of Alberta, Edmonton, AB Canada Department of Pediatrics, Dalhousie University, Halifax, NS Canada d Department of Obstetrics & Gynaecology, Dalhousie University, Halifax, NS Canada b c
a r t i c l e
i n f o
Article history: Received 15 March 2013 Received in revised form 6 June 2013 Accepted 11 June 2013 Available online 2 July 2013 Keywords: Congenital heart disease Chylothorax Thrombosis
a b s t r a c t Postoperative chylothorax is a frequently encountered pathology occurring in up to 4% of patients undergoing surgery for repair of congenital heart disease. Symptomatic thrombosis is associated with chylothorax and may contribute to its severity and duration. Furthermore, vessel thrombosis resulting in persistent vessel occlusion may impede future treatments, diagnostic studies and cardio-surgical interventions. The objective of this study was to determine the incidence of upper system thrombosis in pediatric congenital heart patients with confirmed chylothorax with ultrasound screening of all patients diagnosed with chylothorax. All pediatric patients with confirmed with chylothorax underwent doppler ultrasound of the upper venous system as per hospital standard. This retrospective cohort study enrolled all children between February 1, 2010-August 2012, post cardiac surgery with confirmed chylothorax to determine the incidence of all thrombosis. There were 1396 children who underwent 1396 cardiac surgical procedures during the study time with 760 undergoing cardiopulmonary bypass. Development of chylothorax occurred in 54 of 1396, 3.9% (95%CI 3.0;5.0) procedures in all children. In those children with chylothorax, 28 of 54 episodes, 51.8% (95%CI 38.9;64.6) had confirmed VTE. The 51.8% incidence in this study demonstrates a 2.6 fold increase in risk of thrombosis compared to 20% in children with heart disease and central venous lines and may result in serious clinical consequences. The contribution of upper venous system thrombosis to chylothorax is unknown. Often, clinical suspicion of chylothorax exists, however the lack of a standardized approach to objective diagnosis results in delayed confirmation. Approaches to therapy either treatment of confirmed thrombosis or prevention of thrombosis in patients with chylothorax require formal evaluation. Future studies are urgently needed. © 2013 Elsevier Ltd. All rights reserved.
Introduction Postoperative chylothorax is a frequently encountered pathology occurring in up to 4% of patients undergoing surgery for repair of congenital heart disease [1]. The continuous loss of chyle is a challenging problem to treat and is associated with increased morbidity and mortality. It has been associated with prolonged ventilator dependence, increased length of hospital stay and associated nosocomial infections, malnutrition and central venous line related thrombosis [2]. Factors which increase patient risk for thrombosis include the presence of a central venous line, central venous hypertension in addition to an overall increased risk for thrombosis in children with congenital heart disease due to acquired coagulopathies [3–7] A retrospective review of 30 pediatric patients with chylothorax demonstrated that 26.7 percent of patients with chylothorax were symptomatic for
☆ The authors have no financial disclosures. ⁎ Corresponding author at: 3-585 11405 87 Ave, Edmonton, Alberta, Canada T6G 2B7. E-mail address: [email protected] (M.E. Bauman). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.06.014
thrombosis and confirmed by ultrasound. However, screening of all patients with chylothorax for thrombosis was not performed [2]. The objective of this study was to determine the incidence of upper system thrombosis in pediatric congenital heart patients with confirmed chylothorax. Secondary objectives were to determine if any variables identified may be associated with an increased risk for thrombosis. Methods Stollery Children’s Hospital, University of Alberta is one of two pediatric cardio-surgical centers for children across Western Canada. Chylothorax diagnoses were confirmed in all children based on four criteria accepted to be diagnostic of the presence of chylothorax including white blood cell count > 1000 109/L, lymphocytes > 80%, triglycerides >1.1 mmol/L, and chest tube losses of more than 10 ml /kg/day for more than 3 days. Given the proposed increased risk for thrombosis in children diagnosed with chylothorax post cardio surgical repair, the routine care for children at this institution with chylothorax was to perform a doppler ultrasound by radiologists
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M.E. Bauman et al. / Thrombosis Research 132 (2013) e83–e85
trained in pediatric sonography of the upper venous system in all children with confirmed chylothorax to assess for thrombosis. Children with confirmed thrombosis on ultrasound were anticoagulated with heparin / enoxaparin until the clot resolved to a maximum of three months. All pediatric patients were objectively evaluated for chylothorax and those with confirmed chylothorax (fulfilling 3 or more of the 4 criteria diagnostic for chylothorax (see above). This retrospective cohort study enrolled all children between February 1, 2010-August 2012, post cardiac surgery with confirmed chylothorax. Data collected included variables that are reported to predict the development of chylothorax and potential thrombosis including demographic data, gender, age (years), weight (kg), date of confirmed diagnosis of chylothorax, central venous line (CVL) data including indwell time (days), and, ultrasound diagnosed location of thrombus, cardiopulmonary bypass times (minutes), aortic clamp time (minutes), chylothorax duration (days), and central venous pressure (CVP) (mmHg). ARISTOTLE scores [8] were calculated using underlying cardiac diagnosis and type of cardiac surgical procedure. In this study, the right atrial CVP collected for each patient was the highest value documented in the first post-operative week. This study was approved by the University of Alberta Health Ethics Board. Statistical Analysis Descriptive statistics were presented as mean (SD), median (range), or relative frequencies as applicable. Clinical characteristics were compared between children with and without thrombosis using t-test, Mann-Whitney U test, or Chi-Squared test as appropriate. A p-value b 0.05 was considered statistically significant. All statistical analyses were done using Stata/SE version 12 (Stata Corp., College Station, TX, USA). Results There were 1396 cardiac surgical procedures in 1396 children during the study time with 760 undergoing cardiopulmonary bypass. Development of chylothorax occurred in 54 of 1396, 3.9% (95%CI 3.0;5.0) procedures in all children, with 48 of 760, 6.3% (95%CI 4.8;8.3) and 6 of 636, 0.9% (95%CI 0.4;2.0) in the presence or absence of CPB, respectively, yielding an incidence ratio of 6.7 (95%CI 2.9;15.5). In those children with chylothorax, 28 of 54 episodes, 51.8% (95%CI 38.9;64.6) had confirmed VTE, with 24/28 and 4/6 occurring in the presence or absence of CPB, respectively, for an incidence ratio of 0.75 (95%CI 0.4;1.4) p = 0.441. Twenty of 28 VTE were non occlusive in nature with the majority occurring in the right internal jugular vein (54%). Clinical characteristics of the sample (overall and stratified by VTE status) are shown in Table 1. Children with chylothorax
and VTE had a significantly longer PICU stay, and a longer CVL indwell time than those without VTE. Discussion This is the first study to diagnostically assess all cardio-surgical children with confirmed chylothorax for the presence of upper venous system thrombosis. The incidence of thrombosis in this cohort is 51.8% compared with 26.7% reported by McCulloch et al. [2]who evaluated symptomatic thrombosis. The three most important factors associated with the development of thrombosis are blood composition, vessel wall integrity and blood flow [9]. Abnormalities in each dimension have been reported in children with congenital heart disease. Blood composition is altered in children b 4 years of age with congenital heart disease, with decreased levels of procoagulant and inhibitor proteins of coagulation, including antithrombin [3–7]. Children with cyanotic heart disease develop polycythemia resulting in increased viscosity, decreased levels of inhibitors of coagulation, including antithrombin [3–6]. In addition, children with chylothorax have been demonstrated to have further decreased levels of antithrombin due to losses through chylous drainage [10]. Vessel wall integrity is damaged during placement of venous catheter. Blood flow is altered by the cardiac physiology and altered vascular pressures [11]. The Canadian Registry for CVL related thrombosis demonstrates that asymptomatic thrombosis resulted in mortality and morbidity [12], although, within this study 5 of 28 thrombi were occlusive, all thrombosis, including those with clinical symptoms prompting ultrasound, and those without obvious clinical symptoms have serious consequences. These consequences include loss of venous access which may prevent further staged surgeries in patients with single ventricle physiology and anatomy [13], cardiac transplant, post thrombotic syndrome (pain, swelling, distended collateral vessels) [13,14], pulmonary embolism, infection [15], and stroke in children with left to right shunting [16]. In this study, of the 28 children who developed thrombosis, there were 6 of 13 children with single ventricle physiology and anatomy compared with 11 of 15 children with other cardiac diagnoses (ventricular septal defect, atrial septal defect, atrial ventricular septal defect, pulmonary atresia, transposition of the great arteries, tetralogy of fallot). McCulloch et al. [2] reported cardiopulmonary bypass to be an independent risk factor for children with chyle for upper venous thrombosis. However, in this study CPB was not found to be a risk factor as 24/28 and 4/6 upper venous thrombosis occurred in the presence or absence of CPB, respectively, for an incidence ratio of 0.75 (95%CI 0.4;1.4) p = 0.441. Of note, within our institution, post cardiac surgical children receive unfractionated heparin (UFH) or low molecular weight heparin
Table 1 Demographic and surgical characteristics.
Total surgeries (n = 1396) CPB (n = 760) Non-CPB (n = 636) Median age Weight Male gender Median length of PICU stay Median ARISTOTLE score History of thrombosis Median CVL indwell time Median CVP ECMO Mean aortic clamp time (CPB patients only)
Diagnosed with Chylothorax
Chylothorax with thrombosis
Chylothorax without thrombosis
p-value
54 48
28 24
26 24
0.441
6
4
2
-
5.3 mo (10d - 13.4y) 5.8 kg (2.5 - 30.3) 57% (31) 6 d (1 - 61) 8 (3 - 14.5) 13% 5 d (1 - 14) 14.5 mmHg (54 - 36) 2% (1) 43.7
4.7 mo (11d - 13.4y) 5.0 kg (2.5 - 30.3) 64% (18) 9 (1 - 19) 9 (3 - 14.5) 14% 6.5 d (1 - 14) 15.5 mmHg (5 - 36) 4% (1) 55.8
6.0 mo (10d - 4.3y) 6.4 kg (2.7 - 15.0) 50% (13) 3 (1 - 61) 7.5 (3 - 14.5) 12% 2.5 d (1 - 14) 14 mmHg (4 - 31) 0 32.3
0.421 0.295 0.289 0.003 0.510 0.622 b0.001 0.630 0.331 0.072
M.E. Bauman et al. / Thrombosis Research 132 (2013) e83–e85
(LMWH) for 3-5 days or until the child has the upper system central line removed and has oral/G-tube intake. Sub-therapeutic anti factor Xa levels (UFH b 0.35 u/ml, LMWH b0.5 u/ml) [11] are targeted with the aim to maintaining vessel patency and preventing thrombosis. Despite this approach, in this study 50% of children with single ventricle physiology and anatomy developed upper venous system thrombosis. Children with other cardiac diagnoses do not receive anticoagulation. If thrombosis was confirmed, in the absence of contraindications, children were treated with therapeutic dose heparin (anti factor Xa levels 0.35 to 0.7 u/ml) and transitioned to low molecular weight heparin (anti factor Xa levels 0.5 to 1.0 u/ml) until the clot resolved or 6 weeks to 3 months, in neonates and children >3 months of age, respectively. Central venous line duration was significantly longer, at 7.43 compared to 3.5 days (p b 0.05) in children who developed thrombosis. The majority of thromboses occurred in the right internal jugular vein which was consistent with line placement. This finding is consistent with McCulloch et al. [2] who demonstrated that CVL in dwell time was 5 to 6 days longer in children who developed thrombosis. Central venous lines are the most significant risk factor for children who develop thrombosis [17]. Central venous line indwell time is not reported to be associated with incidence of thrombosis in children without chylothorax [18]. However, this cohort differs as central venous line dwell time is associated with increased incidence of thrombosis. This study has limitations including the retrospective design allowing only for assessment of associated factors. Causality can only be determined in a prospective clinical study. Although, the use of Doppler ultrasound to diagnose thrombosis has not been demonstrated to have increased sensitivity for neck vessels, there are no anatomic structures that would interfere with the test thus may be accurate. However, decreased sensitivity for vessels within the thoracic cage compared to venography has been demonstrated [19]and thus the total incidence of thrombosis may be underestimated. In addition, the chronological development of chylothorax and thrombosis is unknown, and in this study 21% of thrombosis were symptomatic and as a result were diagnosed 4 days prior to the confirmation of chylothorax, as all confirmatory measures of chylothorax had not yet been performed. Given that the highest CVP was collected per patient, this may provide a false representation of significance for developing thrombosis. Despite the use of anticoagulation; unfractionated heparin or low molecular weight heparin targeting subtherapeutic levels prescribed in all children in this study, upper venous system thrombosis is demonstrated in 52% of children with chylothorax within this institution. Perhaps in the absence of this nominal amount of anticoagulation, the incidence of thrombosis would be greater than that reported. Intensification of anticoagulation may decrease thrombosis however this approach requires safety and efficacy testing in prospective studies. Conclusions This study suggests that one of every two children diagnosed with chylothorax have upper venous thrombosis. The contribution of upper venous system thrombosis to chylothorax is unknown. Often, clinical suspicion of chylothorax exists, however the lack of a standardized approach to objective diagnosis results in delayed confirmation. Approaches to therapy either treatment of confirmed thrombosis or prevention of
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thrombosis in patients with chylothorax require formal evaluation. Future studies are urgently needed.
Conflict of Interest Statement No conflict of interest.
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