- Email: [email protected]
Pulmonary embolism—experience at a single children's hospital
Thrombosis Research (2007) 119, 699 — 703
intl.elsevierhealth.com/journals/thre
REGULAR ARTICLE
Pulmonary embolism—experience at a single children’s hospital B Madhvi Rajpurkar a,*, Indira Warrier a, Meera Chitlur a, Cynthia Sabo b, Mary Jane Frey b, Wendy Hollon a, Jeanne Lusher a a
Division of Hematology Oncology, Carman and Ann Adams Department of Pediatrics, Children’s Hospital of Michigan, Wayne State University, Detroit, Michigan, USA b Detroit Medical Center, Detroit, Michigan, USA Received 29 September 2005; received in revised form 27 April 2006; accepted 22 May 2006 Available online 31 July 2006
KEYWORDS Pulmonary embolism; Pediatric; Anticoagulation therapy
Abstract Introduction: Pulmonary embolism in children is a rare, potentially life threatening condition. The clinical characteristics of pediatric pulmonary embolism have not been well studied and the exact incidence in children is not known. We report a case series of fourteen patients with pulmonary embolism and describe their clinical characteristics. Materials and methods: Inpatient and outpatient clinic charts of patients with proven pulmonary embolism (PE) followed at the Hemostasis and Thrombosis Center at Children’s Hospital of Michigan were reviewed for relevant clinical and laboratory information. Results: All patients with PE were symptomatic but accurate diagnosis of PE was often delayed in the outpatient setting. Screening testing with D-dimer was normal in 40% of patients. Acquired risk factors and lower extremity clots were more common in patients analyzed. Treatment regimens differed but most patients had resolution of pulmonary emboli on follow-up. Conclusions: A high index of suspicion is needed for the diagnosis of pediatric PE. DDimer may be normal in some children with PE. Pediatric multicenter trials are
Abbreviations: PE, pulmonary embolism; IRB, Institutional Review Board; HIPAA, Health Insurance Portability and Accountability Act; IBD, inflammatory bowel disease; MTHFR, methylene tetrahydrofolate reductase; DVT, deep venous thrombosis; MRA, magnetic resonance imaging. B This research was presented as a poster presentation at the Annual American Society of Hematology Meeting, December 2004, San Diego. * Corresponding author. Division of Hematology Oncology, Children’s Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201, USA. Tel.: +1 313 745 5515; fax: +1 313 745 5237. E-mail address: [email protected] (M. Rajpurkar). 0049-3848/$ - see front matter D 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2006.05.016
700
M. Rajpurkar et al. needed to evaluate clinical characteristics, risk factors, long-term outcome and effects of PE on pulmonary and cardiac function. D 2006 Elsevier Ltd. All rights reserved.
Introduction Pulmonary embolism (PE) represents pulmonary arterial obstruction either by endogenous or exogenous emboli or local thrombus formation [1]. It is a potentially life threatening disorder. The exact incidence in pediatrics is unknown and depends upon the underlying disease, tests used for diagnosis and the index of suspicion. Current data from the National Hospital Discharge Survey reported the incidence to be 0.9 in 100,000 children overall and was highest in infants 1—23 months of age [2]. There appears to be a second peak in the incidence of PE in teenagers 15—17 years of age [2]. The incidence in black children was estimated to be 2.38 times higher than in white children [2]. However, a number of autopsy studies have estimated the incidence to be as high as 0.73—4.2% which indicates that clinical features of PE are often masked and that PE is often misdiagnosed [3]. In addition, optimal methods for screening and diagnosis of PE in children have not been established and available data are extrapolated from adults. Also, the duration of treatment for pulmonary embolism has not been defined and the role of thrombolysis in acute PE without cardiovascular collapse is controversial. Currently, the long-term implications of PE on pulmonary and cardiac function are unknown in children. Keeping this in mind, we conducted a retrospective study of the clinical characteristics, risk factors, treatment strategies and outcome of patients with PE followed at the Hemostasis and Thrombosis Center at Children’s Hospital of Michigan. The study was conducted in compliance with IRB and HIPAA regulations at our institution.
Materials and methods Inpatient and outpatient clinic charts of patients with documented PE, followed at the Hemostasis and Thrombosis Center at Children’s Hospital of Michigan were reviewed for demographic data such as age, sex and ethnicity. Patients who had PE after cardiovascular surgery for congenital heart disease were not included as these were thought to have a different pathogenesis. Historical data including the presence and type of
symptoms, time to accurate diagnosis of PE and treatment prior to the diagnosis were reviewed. The role of D-dimer as a screening test was evaluated. Methods used to diagnose PE were noted and data available on the clinical and laboratory thrombotic risk factors were evaluated. Initial and follow-up antithrombotic regimens, duration of treatment and complications thereof were noted. When available, follow-up data on resolution of PE were evaluated.
Results Demographic data Fourteen patients were diagnosed with PE between January 2001 to October 2004. Of these, seven were males and seven females; seven were Caucasian and seven African American. Mean age of presentation was 16 years (range 9—29 years); there were two patients with ventricular-atrial shunts who were over the age of 18 years but were followed at Children’s Hospital of Michigan as deemed by their primary physician.
Clinical features Average time to accurate diagnosis of PE was 7 days (range 1—21 days). Only 4/14 (29%) patients were diagnosed on the day of presentation. Three of these four (75%) were in-patient at the time of diagnosis. On the contrary, all patients presenting in the outpatient setting had a significant delay in time to accurate diagnosis. Eight patients (57%) were diagnosed as other respiratory conditions prior to establishing an accurate diagnosis of PE and received treatment with antibiotics. All patients were symptomatic with either chest pain (71%) or dyspnea on exertion (79%). Six patients (43%) were hypoxemic and three (21%) presented with acute cardiovascular collapse.
Diagnostic studies Chest radiography studies were available on 10 patients. Seven (70%) of these had abnormal nonspecific findings. However, all patients were diagnosed with a spiral chest computerized tomography. D-Dimer results (Advanced D-dimer test, Dade
Pulmonary embolism in children Behring using SysmexR CA-1500; sensitivity 100%, negative predictive value 100%) prior to initiation of therapy were available in 10/14 patients and were normal in four patients (40%). Interestingly, there was no correlation between a normal D-dimer value and delayed time to diagnosis of PE. A presumed source of PE was found in 10/14 patients (71%). Lower extremity clots were present on ultrasound examination in 6/14 patients (43%). Sites of additional clots are indicated in Fig. 1.
Clinical risk factors Multiple risk factors were present in 12 patients (85%). One patient had no identifiable clinical or laboratory risk factor. Seven children (50%) were obese (BMI N 30 kg/m2). A central venous catheter was present in one patient. Other risk factors included oral contraceptive use and systemic lupus erythematosus in two patients each (14%). Ventriculo-atrial shunts and inflammatory bowel disease (IBD) were present in three patients each (21%). Prolonged immobilization (N4 days) was noted in four patients (29%). This criterion for duration of immobilization was used as in adults immobilization N 4 days was found to have a significantly higher risk of fatal PE [4]. Five patients (36%) had undergone recent (within preceding 14 days) surgery (four neurosurgical procedures, one abdominal surgery) and none of the post surgical patients had received thrombosis prophylaxis.
Laboratory risk factors Antithrombin III (Stachrom ATIII, Diagnositica Stago, Parsippany, NJ), Protein S (Bioclot Protein S, Trinity Biotech plc, Bray, Co., Wicklow, Ireland) and Protein C (Staclot Protein C, Diagnostica
Figure 1
Sites of additional clots.
701 Stago, Parsippany, NJ) activities were measured using the ACL300 Plus and were found to be normal in all patients. Mutation analysis for Factor V Leiden, Prothrombin G20210A and C677T MTHFR mutation was carried out using the Invader Assay [5]. One patient was heterozygous for the Prothrombin G 20210A mutation. Seven (50%) were heterozygous for C677T MTHFR mutation but only one patient had a concomitant elevated homocysteine level. None of the patients had the Factor V Leiden mutation. Anticardiolipin antibodies were tested using the ELISA reagent kits, INOVA Diagnostics Inc. (San Diego, CA) [6]. Lupus anticoagulant (LA) testing was performed according to the ISTH standard [7]. Anticardiolipin antibodies (normal range— IgG b 5GPL, IgM b 5MPL) were elevated in 21% and LA was positive in 41% of patients at the time of diagnosis (four patients had a positive LA on at least two occasions, one patient died prior to repeat testing).
Treatment Initial treatment consisted of unfractionated heparin (to achieve a therapeutic PTT of 60—85 s) in 11 (79%), dose adjusted (to achieve an anti-Xa level between 0.5 and 1 unit/ml) low molecular weight heparin (LMWH), enoxaparin in one (7%) and catheter directed thrombolysis (tissue plasminogen activator, 0.5 mg/kg/h for 6 h) in two patients (14%). Interestingly, four of the five post-surgical patients were hypoxemic (one had concomitant cardiovascular collapse) and were ineligible for thrombolysis due to the recent surgery. Follow-up treatment consisted of dose adjusted LMWH in 12 and oral anticoagulants (target INR 2— 2.5) in two patients. Eight patients received therapy for 12 months following the episode and are currently off all anticoagulants. Five patients remain on prolonged anticoagulation (N 12 months) due to continued presence of risk factors. Anticoagulant therapy, in general, was well tolerated. However, one patient with IBD on oral anticoagulant therapy had recurrent gastrointestinal bleeding necessitating blood transfusion. One additional patient on LMWH (with a therapeutic anti-Xa level) died secondary to an intracranial hemorrhage and was found to have a co-incidental carotid aneurysm. Thirteen patients (78%) had follow-up spiral CT scans at 6 months after the episode. Of these, 11 patients show a resolution of previous PE. Two patients had partial resolution. There were no symptomatic recurrent thrombotic events. However, long-term effects on pulmonary and cardiac function are not available.
702
Discussion In our pediatric case series, PE was often missed. This may be due to the fact that the presenting symptoms of PE are similar to more common childhood disorders like pneumonia. Delay in accurate diagnosis of childhood PE was more often in the outpatient setting. Hence, a high index of suspicion is needed and PE should be included as a differential diagnosis in pediatric patients with chest pain or dyspnea on exertion. The D-dimer test is known to be highly sensitive for excluding PE in adults, especially when coupled with a clinical diagnostic algorithm. In adults, an elevated D-dimer test was shown to be sensitive in 97% of cases and had a negative predictive value of 99.6% [8]. However, its use as an initial screening test for PE in children has not been systematically evaluated. In our series, 40% of children with a documented PE had a normal quantitative D-dimer. Clearance of the D-dimer fragments by the liver, due to the delay in diagnosis, may be a possible explanation. However, this was not demonstrated in our study because three of the four patients with a normal D-dimer value were diagnosed on the first day of clinical symptoms. Another possibility is that peripheral small pulmonary artery thrombi may not give rise to elevated D-dimer. In our series, there was no correlation of a normal D-dimer value with either peripheral artery thrombi or with presence of hemodynamic/respiratory compromise. The implications of missing peripheral symptomatic PE due to a normal D-dimer screening test are currently unknown. Multiple risk factors are often implicated in the pathogenesis of PE in children. In our series, acquired risk factors were commonly seen. The highest association was seen with obesity which was present in 50% of the children with PE. PE is associated with documented DVT in 30—60% of cases [1]. A report from the Canadian Pediatric Thrombophilia Registry documented clots in the upper venous system to be more common in children with PE. In contrast, in our case series, PE was associated with lower extremity venous clots. Also, CVL related thrombosis has been reported to be the most common source of PE [1,9]. This was not found in our case series. This may be due to the fact that PE associated with CVL may be silent and a systematic study of all children with CVL may be needed to document the exact prevalence. Abnormal chest radiograms were often seen in patients and the findings were not specific. The diagnosis of PE was made by spiral CT in our case series. Currently, there are no published studies
M. Rajpurkar et al. documenting the sensitivity and specificity of clinical evaluation and diagnostic imaging either alone or in combination for diagnosis of PE in children. Protocols are often extrapolated from adults with little justification for their applicability to children. Currently, the options available for radiologic evaluation of PE in children are ventilation perfusion scintigraphy, spiral CT angiography, magnetic resonance angiography (MRA) and pulmonary angiography. Pulmonary angiography has been hailed as the bgold standardQ technique for diagnosis of PE and also has the advantage of providing simultaneous hemodynamic information that may be useful in patient management. In reality, even in adults, this test is infrequently performed. In addition, the lack of adequate venous access in children makes this test impractical to perform as a diagnostic procedure. Use of nuclear medicine imaging is also on the decline because of the high percentage of indeterminate studies and the poor inter-observer correlation [8]. Contrast enhanced MRA has been used in adults but also has certain disadvantages like sufficient spatial resolution for reliable evaluation of peripheral pulmonary arteries, lack of general availability, relatively long waiting times and most importantly in children the lack of breath holding capability [8,10]. Hence, in most institutions, spiral CT is becoming the first line imaging test for the assessment of patients with suspected PE. With spiral CT, a specific cause of patients’ symptoms and important additional diagnosis can be established in most cases. In addition to intravascular thromboembolic filling defects, additional findings like parenchymal infarction, pleural effusion vascular remodeling and oligemia can be readily visualized. The main impediment for spiral CT has been its limitation in the accurate detection of small peripheral arterial emboli. In addition, the implications of potential radiation exposure, especially to the breast area in young adolescent girls, are currently unknown. PE has a wide clinical spectrum ranging from small subsegmental embolism with no clinical impact to life threatening large central and bilateral clots associated with cardiovascular collapse. The role of thrombolysis in adults with PE is still controversial. Thrombolytic therapy has been approved in adult patients with either cardiovascular collapse or patients who have documented right ventricular dysfunction on echocardiography or elevated troponin levels. The role of thrombolytic therapy in patients with small pulmonary emboli without hemodynamic compromise is currently unknown. In adults, it was found that the rate of death or recurrent PE within 2 weeks of diagnosis was 10% in
Pulmonary embolism in children a cohort of 399 patients followed by the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) group. The lowest all cause mortality rate of 9% was among those treated with thrombolytic therapy [11]. In our series, only two patients received thrombolytic therapy. In addition, four patients were ineligible for thrombolysis as they had had recent surgery (within prior 14 days). Also, in adults, there seems to be an inverse association between duration of symptoms and improvement on lung scan reperfusion after thrombolysis. After controlling for age and initial lung scan defect size, there was 0.7% less reperfusion per additional day of symptoms [11]. Less clot lyses on angiography immediately following thrombolysis was observed in the quintile of patient with longest duration of symptoms (greater than 6 days) [11]. In our series, the mean time to accurate diagnosis of PE was 7 days. This has immense implications in the pediatric population with PE. Either the patients may not be eligible or may have relatively low benefit from thrombolysis. In our series, in general, antithrombotic therapy was well tolerated. Bleeding related to anticoagulant therapy was aggravated, in one child, by the presence of co-existing conditions. Most patients had long-term resolution of PE. The cumulative incidence of symptomatic chronic thromboembolic pulmonary hypertension after PE in adults has been reported to be 3.8% at 2 years [12]. This information was not available in our patients. Currently, the implications of PE on pulmonary and cardiac function are unknown in children.
Conclusions This report is limited by the small number of patients included in the study; however we believe that this is the first report that has specifically analyzed clinical features of pediatric PE. It is apparent that a high index of suspicion is needed for prompt and accurate diagnosis of pediatric PE. Pediatric multicenter trials are needed to evaluate clinical characteristics, risk factors, long-term outcome and effects of PE on pulmonary and cardiac function. The role of D-dimer as screening test for PE in children and the impor-
703 tance of spiral CT scan in early diagnosis of pediatric PE needs to be evaluated. Long-term follow-up is indicated with specific attention to assess the possible implications of radiation dose to young adolescent girl’s breast tissue. Specific treatment protocols to address the duration and choice of anticoagulation therapy need to be developed for children with PE.
References [1] Babyn PS, Gahunia HK, Massicotte P. Pulmonary thromboembolism in children. Pediatr Radiol 2005. [2] Stein PD, Kayali F, Olson RE. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr 2004;145(4):563 – 5. [3] van Ommen CH, Peters M. Venous thromboembolic disease in childhood. Semin Thromb Hemost 2003;29(4):391 – 404. [4] Monreal M, Kakkar AK, Caprini JA, Barba R, Uresandi F, Valle R, et al. The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients. Findings from the RIETE registry. J Thromb Haemost 2004;2(11):1892 – 8. [5] Hessner MJ, Friedman KD, Voelkerding KV, Huber S, Ryan D, Nuccie B, et al. Multisite study for genotyping of the factor II (prothrombin) G20210A mutation by the invader assay. Clin Chem 2001;47(11):2048 – 50. [6] Lewis S, Keil LB, Binder WL, DeBari VA. Standardized measurement of major immunoglobulin class (IgG, IgA, and IgM) antibodies to beta2glycoprotein I in patients with antiphospholipid syndrome. J Clin Lab Anal 1998;12(5): 293 – 7. [7] Brandt JT, Barna LK, Triplett DA. Laboratory identification of lupus anticoagulants: results of the Second International Workshop for Identification of Lupus Anticoagulants. On behalf of the Subcommittee on Lupus Anticoagulants/ Antiphospholipid Antibodies of the ISTH. Thromb Haemost 1995;74(6):1597 – 603. [8] Schoepf UJ, Goldhaber SZ, Costello P. Spiral computed tomography for acute pulmonary embolism. Circulation 2004;109(18):2160 – 7. [9] Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994;83(5):1251 – 7. [10] Kanne JP, Lalani TA. Role of computed tomography and magnetic resonance imaging for deep venous thrombosis and pulmonary embolism. Circulation 2004;109(12 Suppl 1): I15 – 21. [11] Goldhaber SZ, Bounameaux H. Thrombolytic therapy in pulmonary embolism. Semin Vasc Med 2001;1(2):213 – 20. [12] Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350(22):2257 – 64.
intl.elsevierhealth.com/journals/thre
REGULAR ARTICLE
Pulmonary embolism—experience at a single children’s hospital B Madhvi Rajpurkar a,*, Indira Warrier a, Meera Chitlur a, Cynthia Sabo b, Mary Jane Frey b, Wendy Hollon a, Jeanne Lusher a a
Division of Hematology Oncology, Carman and Ann Adams Department of Pediatrics, Children’s Hospital of Michigan, Wayne State University, Detroit, Michigan, USA b Detroit Medical Center, Detroit, Michigan, USA Received 29 September 2005; received in revised form 27 April 2006; accepted 22 May 2006 Available online 31 July 2006
KEYWORDS Pulmonary embolism; Pediatric; Anticoagulation therapy
Abstract Introduction: Pulmonary embolism in children is a rare, potentially life threatening condition. The clinical characteristics of pediatric pulmonary embolism have not been well studied and the exact incidence in children is not known. We report a case series of fourteen patients with pulmonary embolism and describe their clinical characteristics. Materials and methods: Inpatient and outpatient clinic charts of patients with proven pulmonary embolism (PE) followed at the Hemostasis and Thrombosis Center at Children’s Hospital of Michigan were reviewed for relevant clinical and laboratory information. Results: All patients with PE were symptomatic but accurate diagnosis of PE was often delayed in the outpatient setting. Screening testing with D-dimer was normal in 40% of patients. Acquired risk factors and lower extremity clots were more common in patients analyzed. Treatment regimens differed but most patients had resolution of pulmonary emboli on follow-up. Conclusions: A high index of suspicion is needed for the diagnosis of pediatric PE. DDimer may be normal in some children with PE. Pediatric multicenter trials are
Abbreviations: PE, pulmonary embolism; IRB, Institutional Review Board; HIPAA, Health Insurance Portability and Accountability Act; IBD, inflammatory bowel disease; MTHFR, methylene tetrahydrofolate reductase; DVT, deep venous thrombosis; MRA, magnetic resonance imaging. B This research was presented as a poster presentation at the Annual American Society of Hematology Meeting, December 2004, San Diego. * Corresponding author. Division of Hematology Oncology, Children’s Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201, USA. Tel.: +1 313 745 5515; fax: +1 313 745 5237. E-mail address: [email protected] (M. Rajpurkar). 0049-3848/$ - see front matter D 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2006.05.016
700
M. Rajpurkar et al. needed to evaluate clinical characteristics, risk factors, long-term outcome and effects of PE on pulmonary and cardiac function. D 2006 Elsevier Ltd. All rights reserved.
Introduction Pulmonary embolism (PE) represents pulmonary arterial obstruction either by endogenous or exogenous emboli or local thrombus formation [1]. It is a potentially life threatening disorder. The exact incidence in pediatrics is unknown and depends upon the underlying disease, tests used for diagnosis and the index of suspicion. Current data from the National Hospital Discharge Survey reported the incidence to be 0.9 in 100,000 children overall and was highest in infants 1—23 months of age [2]. There appears to be a second peak in the incidence of PE in teenagers 15—17 years of age [2]. The incidence in black children was estimated to be 2.38 times higher than in white children [2]. However, a number of autopsy studies have estimated the incidence to be as high as 0.73—4.2% which indicates that clinical features of PE are often masked and that PE is often misdiagnosed [3]. In addition, optimal methods for screening and diagnosis of PE in children have not been established and available data are extrapolated from adults. Also, the duration of treatment for pulmonary embolism has not been defined and the role of thrombolysis in acute PE without cardiovascular collapse is controversial. Currently, the long-term implications of PE on pulmonary and cardiac function are unknown in children. Keeping this in mind, we conducted a retrospective study of the clinical characteristics, risk factors, treatment strategies and outcome of patients with PE followed at the Hemostasis and Thrombosis Center at Children’s Hospital of Michigan. The study was conducted in compliance with IRB and HIPAA regulations at our institution.
Materials and methods Inpatient and outpatient clinic charts of patients with documented PE, followed at the Hemostasis and Thrombosis Center at Children’s Hospital of Michigan were reviewed for demographic data such as age, sex and ethnicity. Patients who had PE after cardiovascular surgery for congenital heart disease were not included as these were thought to have a different pathogenesis. Historical data including the presence and type of
symptoms, time to accurate diagnosis of PE and treatment prior to the diagnosis were reviewed. The role of D-dimer as a screening test was evaluated. Methods used to diagnose PE were noted and data available on the clinical and laboratory thrombotic risk factors were evaluated. Initial and follow-up antithrombotic regimens, duration of treatment and complications thereof were noted. When available, follow-up data on resolution of PE were evaluated.
Results Demographic data Fourteen patients were diagnosed with PE between January 2001 to October 2004. Of these, seven were males and seven females; seven were Caucasian and seven African American. Mean age of presentation was 16 years (range 9—29 years); there were two patients with ventricular-atrial shunts who were over the age of 18 years but were followed at Children’s Hospital of Michigan as deemed by their primary physician.
Clinical features Average time to accurate diagnosis of PE was 7 days (range 1—21 days). Only 4/14 (29%) patients were diagnosed on the day of presentation. Three of these four (75%) were in-patient at the time of diagnosis. On the contrary, all patients presenting in the outpatient setting had a significant delay in time to accurate diagnosis. Eight patients (57%) were diagnosed as other respiratory conditions prior to establishing an accurate diagnosis of PE and received treatment with antibiotics. All patients were symptomatic with either chest pain (71%) or dyspnea on exertion (79%). Six patients (43%) were hypoxemic and three (21%) presented with acute cardiovascular collapse.
Diagnostic studies Chest radiography studies were available on 10 patients. Seven (70%) of these had abnormal nonspecific findings. However, all patients were diagnosed with a spiral chest computerized tomography. D-Dimer results (Advanced D-dimer test, Dade
Pulmonary embolism in children Behring using SysmexR CA-1500; sensitivity 100%, negative predictive value 100%) prior to initiation of therapy were available in 10/14 patients and were normal in four patients (40%). Interestingly, there was no correlation between a normal D-dimer value and delayed time to diagnosis of PE. A presumed source of PE was found in 10/14 patients (71%). Lower extremity clots were present on ultrasound examination in 6/14 patients (43%). Sites of additional clots are indicated in Fig. 1.
Clinical risk factors Multiple risk factors were present in 12 patients (85%). One patient had no identifiable clinical or laboratory risk factor. Seven children (50%) were obese (BMI N 30 kg/m2). A central venous catheter was present in one patient. Other risk factors included oral contraceptive use and systemic lupus erythematosus in two patients each (14%). Ventriculo-atrial shunts and inflammatory bowel disease (IBD) were present in three patients each (21%). Prolonged immobilization (N4 days) was noted in four patients (29%). This criterion for duration of immobilization was used as in adults immobilization N 4 days was found to have a significantly higher risk of fatal PE [4]. Five patients (36%) had undergone recent (within preceding 14 days) surgery (four neurosurgical procedures, one abdominal surgery) and none of the post surgical patients had received thrombosis prophylaxis.
Laboratory risk factors Antithrombin III (Stachrom ATIII, Diagnositica Stago, Parsippany, NJ), Protein S (Bioclot Protein S, Trinity Biotech plc, Bray, Co., Wicklow, Ireland) and Protein C (Staclot Protein C, Diagnostica
Figure 1
Sites of additional clots.
701 Stago, Parsippany, NJ) activities were measured using the ACL300 Plus and were found to be normal in all patients. Mutation analysis for Factor V Leiden, Prothrombin G20210A and C677T MTHFR mutation was carried out using the Invader Assay [5]. One patient was heterozygous for the Prothrombin G 20210A mutation. Seven (50%) were heterozygous for C677T MTHFR mutation but only one patient had a concomitant elevated homocysteine level. None of the patients had the Factor V Leiden mutation. Anticardiolipin antibodies were tested using the ELISA reagent kits, INOVA Diagnostics Inc. (San Diego, CA) [6]. Lupus anticoagulant (LA) testing was performed according to the ISTH standard [7]. Anticardiolipin antibodies (normal range— IgG b 5GPL, IgM b 5MPL) were elevated in 21% and LA was positive in 41% of patients at the time of diagnosis (four patients had a positive LA on at least two occasions, one patient died prior to repeat testing).
Treatment Initial treatment consisted of unfractionated heparin (to achieve a therapeutic PTT of 60—85 s) in 11 (79%), dose adjusted (to achieve an anti-Xa level between 0.5 and 1 unit/ml) low molecular weight heparin (LMWH), enoxaparin in one (7%) and catheter directed thrombolysis (tissue plasminogen activator, 0.5 mg/kg/h for 6 h) in two patients (14%). Interestingly, four of the five post-surgical patients were hypoxemic (one had concomitant cardiovascular collapse) and were ineligible for thrombolysis due to the recent surgery. Follow-up treatment consisted of dose adjusted LMWH in 12 and oral anticoagulants (target INR 2— 2.5) in two patients. Eight patients received therapy for 12 months following the episode and are currently off all anticoagulants. Five patients remain on prolonged anticoagulation (N 12 months) due to continued presence of risk factors. Anticoagulant therapy, in general, was well tolerated. However, one patient with IBD on oral anticoagulant therapy had recurrent gastrointestinal bleeding necessitating blood transfusion. One additional patient on LMWH (with a therapeutic anti-Xa level) died secondary to an intracranial hemorrhage and was found to have a co-incidental carotid aneurysm. Thirteen patients (78%) had follow-up spiral CT scans at 6 months after the episode. Of these, 11 patients show a resolution of previous PE. Two patients had partial resolution. There were no symptomatic recurrent thrombotic events. However, long-term effects on pulmonary and cardiac function are not available.
702
Discussion In our pediatric case series, PE was often missed. This may be due to the fact that the presenting symptoms of PE are similar to more common childhood disorders like pneumonia. Delay in accurate diagnosis of childhood PE was more often in the outpatient setting. Hence, a high index of suspicion is needed and PE should be included as a differential diagnosis in pediatric patients with chest pain or dyspnea on exertion. The D-dimer test is known to be highly sensitive for excluding PE in adults, especially when coupled with a clinical diagnostic algorithm. In adults, an elevated D-dimer test was shown to be sensitive in 97% of cases and had a negative predictive value of 99.6% [8]. However, its use as an initial screening test for PE in children has not been systematically evaluated. In our series, 40% of children with a documented PE had a normal quantitative D-dimer. Clearance of the D-dimer fragments by the liver, due to the delay in diagnosis, may be a possible explanation. However, this was not demonstrated in our study because three of the four patients with a normal D-dimer value were diagnosed on the first day of clinical symptoms. Another possibility is that peripheral small pulmonary artery thrombi may not give rise to elevated D-dimer. In our series, there was no correlation of a normal D-dimer value with either peripheral artery thrombi or with presence of hemodynamic/respiratory compromise. The implications of missing peripheral symptomatic PE due to a normal D-dimer screening test are currently unknown. Multiple risk factors are often implicated in the pathogenesis of PE in children. In our series, acquired risk factors were commonly seen. The highest association was seen with obesity which was present in 50% of the children with PE. PE is associated with documented DVT in 30—60% of cases [1]. A report from the Canadian Pediatric Thrombophilia Registry documented clots in the upper venous system to be more common in children with PE. In contrast, in our case series, PE was associated with lower extremity venous clots. Also, CVL related thrombosis has been reported to be the most common source of PE [1,9]. This was not found in our case series. This may be due to the fact that PE associated with CVL may be silent and a systematic study of all children with CVL may be needed to document the exact prevalence. Abnormal chest radiograms were often seen in patients and the findings were not specific. The diagnosis of PE was made by spiral CT in our case series. Currently, there are no published studies
M. Rajpurkar et al. documenting the sensitivity and specificity of clinical evaluation and diagnostic imaging either alone or in combination for diagnosis of PE in children. Protocols are often extrapolated from adults with little justification for their applicability to children. Currently, the options available for radiologic evaluation of PE in children are ventilation perfusion scintigraphy, spiral CT angiography, magnetic resonance angiography (MRA) and pulmonary angiography. Pulmonary angiography has been hailed as the bgold standardQ technique for diagnosis of PE and also has the advantage of providing simultaneous hemodynamic information that may be useful in patient management. In reality, even in adults, this test is infrequently performed. In addition, the lack of adequate venous access in children makes this test impractical to perform as a diagnostic procedure. Use of nuclear medicine imaging is also on the decline because of the high percentage of indeterminate studies and the poor inter-observer correlation [8]. Contrast enhanced MRA has been used in adults but also has certain disadvantages like sufficient spatial resolution for reliable evaluation of peripheral pulmonary arteries, lack of general availability, relatively long waiting times and most importantly in children the lack of breath holding capability [8,10]. Hence, in most institutions, spiral CT is becoming the first line imaging test for the assessment of patients with suspected PE. With spiral CT, a specific cause of patients’ symptoms and important additional diagnosis can be established in most cases. In addition to intravascular thromboembolic filling defects, additional findings like parenchymal infarction, pleural effusion vascular remodeling and oligemia can be readily visualized. The main impediment for spiral CT has been its limitation in the accurate detection of small peripheral arterial emboli. In addition, the implications of potential radiation exposure, especially to the breast area in young adolescent girls, are currently unknown. PE has a wide clinical spectrum ranging from small subsegmental embolism with no clinical impact to life threatening large central and bilateral clots associated with cardiovascular collapse. The role of thrombolysis in adults with PE is still controversial. Thrombolytic therapy has been approved in adult patients with either cardiovascular collapse or patients who have documented right ventricular dysfunction on echocardiography or elevated troponin levels. The role of thrombolytic therapy in patients with small pulmonary emboli without hemodynamic compromise is currently unknown. In adults, it was found that the rate of death or recurrent PE within 2 weeks of diagnosis was 10% in
Pulmonary embolism in children a cohort of 399 patients followed by the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) group. The lowest all cause mortality rate of 9% was among those treated with thrombolytic therapy [11]. In our series, only two patients received thrombolytic therapy. In addition, four patients were ineligible for thrombolysis as they had had recent surgery (within prior 14 days). Also, in adults, there seems to be an inverse association between duration of symptoms and improvement on lung scan reperfusion after thrombolysis. After controlling for age and initial lung scan defect size, there was 0.7% less reperfusion per additional day of symptoms [11]. Less clot lyses on angiography immediately following thrombolysis was observed in the quintile of patient with longest duration of symptoms (greater than 6 days) [11]. In our series, the mean time to accurate diagnosis of PE was 7 days. This has immense implications in the pediatric population with PE. Either the patients may not be eligible or may have relatively low benefit from thrombolysis. In our series, in general, antithrombotic therapy was well tolerated. Bleeding related to anticoagulant therapy was aggravated, in one child, by the presence of co-existing conditions. Most patients had long-term resolution of PE. The cumulative incidence of symptomatic chronic thromboembolic pulmonary hypertension after PE in adults has been reported to be 3.8% at 2 years [12]. This information was not available in our patients. Currently, the implications of PE on pulmonary and cardiac function are unknown in children.
Conclusions This report is limited by the small number of patients included in the study; however we believe that this is the first report that has specifically analyzed clinical features of pediatric PE. It is apparent that a high index of suspicion is needed for prompt and accurate diagnosis of pediatric PE. Pediatric multicenter trials are needed to evaluate clinical characteristics, risk factors, long-term outcome and effects of PE on pulmonary and cardiac function. The role of D-dimer as screening test for PE in children and the impor-
703 tance of spiral CT scan in early diagnosis of pediatric PE needs to be evaluated. Long-term follow-up is indicated with specific attention to assess the possible implications of radiation dose to young adolescent girl’s breast tissue. Specific treatment protocols to address the duration and choice of anticoagulation therapy need to be developed for children with PE.
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