We identified 82 potentially relevant studies from PubMed, Scopus, and Google Scholar. At first, duplicate studies were removed (n= 20). Subsequently, we conducted abstract and title screening of 62 articles, leading to the exclusion of 51 studies. This was followed by full text review of 11 articles, with the final involvement of six studies that were eligible according to our inclusion criteria (PRISMA; Figure 1) The six articles reported a total of 258 patients with massive, submissive, or nonmassive pulmonary embolisms Table 1. Three of the articles included were retrospective cohort studies [3,4,11], while the other three were case series [8,12,13]. Patient baseline chacartesics and risk factors are demonstrated in detail in Tables 2 & 3.
3.1 Background
The Bragança et al. study spanned a 13-year period, with 29 episodes of pediatric PE that were reported in 27 patients, with an average of 2.2 episodes per year or 9.52 per 10,000 admissions [4]. The majority of patients were adolescents, with a mean age of 14.1 years, and predominantly Caucasian. Substantial proportions of patients had identifiable risk factors, including oral contraception, positive family history, obesity, immune mediated disorders, and history of thrombophilia. Notably, the application of various diagnostic criteria showed varied sensitivity rates among the patient population [4].
On the other hand, Belsky et al.'s study identified eight patients with submassive PE, with a median age of 15 years [12]. All patients presented with right ventricular dysfunction, and the cohort underwent catheter-directed thrombolysis (CDT). Thrombolysis was generally well tolerated, with most patients demonstrating either complete or partial thrombus resolution [12].
Akam-Venkata et al.'s cohort consisted of nine patients, predominantly females, with a median age of 16 years [8]. The majority of patients were obese and presented with acute symptoms, including dyspnea and chest pain. Catheter-directed therapy, including the use of EkoSonic ultrasound-accelerated thrombolysis, was employed with varying outcomes, with a notable mortality rate of 22% [8].
3.2 Symptoms and Classifications
Symptoms of PE varied across studies. Bragança 2021 noted thoracalgia, dyspnea, deep vein thrombosis (DVT), syncope, fever, anxiety, palpitations, and hemoptysis within their patient population [4]. Belsky 2019 reported that all patients with submassive PE exhibited echocardiographic evidence of right ventricular dysfunction, with some patients demonstrating symptoms consistent with right-sided heart failure [12]. Akam-Venkata 2018 observed dyspnea, chest pain, and hemoptysis as common presenting symptoms [8].
3.3 Disease Severity and Classification
Mortality rates varied across the included studies. Ross et al. reported 18% mortality among their cohort, with 9% attributed to PE-related deaths [3]. Pelland-Marcotte et al. noted a 6% mortality rate related to PE [11], while Ji et al. reported one patient death due to cardiopulmonary failure following unsuccessful thrombectomy [13].
Regarding severity classification of PE, Pelland-Marcotte et al. classified 7% of their patients as having submassive PE and 22% as having massive PE [11]. Ji et al. 2019 reported on nine patients with massive and/or submassive PE [13]. These severe forms of PE were associated with younger age and various underlying conditions, particularly cardiac disorders. Furthermore, Bragança 2021 found that most cases were non-massive (46.4%), followed by submassive (39.3%) and massive (14.3%) PE [4]. Belsky 2019 cohort focused on submassive PE patients, emphasizing the presence of right ventricular dysfunction [12]. While patients in the Akam-Venkata et al. study treated patients with massive and submassive PE [8].
3.4 Prognosis and Mortality
Overall, the prognosis varied among patients with PE. Ross et al. reported that survivors had excellent outcomes with no sequelae from PE or recurrence of PE during a median follow-up of 16 months [3]. Pelland-Marcotte et al. observed a median follow-up period of 2.4 years, during which 19% of patients experienced unfavorable outcomes related to PE [11]. Ji et al. reported no recurrence of PE during a mean follow-up of 6 months among surviving patients [13]. Bragança 2021 reported a mortality rate of 6.9% (2/29) [4]. Akam-Venkata and colleagues observed a mortality rate up to 22%, among patients with massive PE with deaths occurring due to delayed diagnosis and poor response to treatment [8].
Interestingly, Belsky et al. showed favorable outcomes in patients undergoing CDT, with most patients exhibiting thrombus resolution and normal right ventricular function on follow-up [12]. Akam-Venkata 2018 noted favorable outcomes with catheter-directed therapy and anticoagulation, with most patients experiencing resolution of thrombi and normalization of right ventricular function [8].
3.6 Right Ventricular Strain
Akam-Venkata 2018 found that patients commonly exhibited RV strain and pulmonary infarct [8]. Preprocedural signs of PE included depressed RV function, septal flattening, tricuspid regurgitation, and elevated pulmonary artery (PA) pressures. Postprocedural improvements were noted in RV function, although persistent RV dysfunction was observed in some cases across various studies.
3.7 Computed Chest Tomography
Computed tomography (CT) pulmonary angiography was the primary modality for diagnosing PE across the studies, with varying rates of lobar, segmental, and subsegmental involvement [3,4,8,11–13].
3.8 Age
In Bragança's 2021, patients had a mean age of 14.1 years, ranging from newborns to adolescents [4]. Belsky 2019 reported a median age of 15 years among submassive PE patients [12]. Akam-Venkata 2018 observed a median age of 16 years among massive PE patients [8]. Patients with massive and/or submassive PE tended to be younger compared to those with non-massive PE, as reported by Pelland-Marcotte et al. and Ji et al [11]. Overall, the median ages across studies ranged from 14.1 to 16 years, with adolescents comprising the majority of patients.
3.9 Sex
Across the studies, there was a predominance of female patients, particularly among those with massive PE, as reported by Ross 2020 and Ji 2019 [3,13]. Overall, females were more predominant in the cohorts, ranging from 62.9% to 66.67%.
3.10 Comorbidities
Patients in the Bragança et al. demonstrated significant comorbidities including obesity, oral contraception use, positive family history, immunomediated disorders, and thrombophilia were identified in a significant proportion of patients [4].
3.11 Treatment and Management
In Bragança et al.'s study, the management of pediatric PE included a range of treatment modalities tailored to individual patient presentations [4]. Anticoagulation therapy was initiated in all but one patient, with unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or both initially used, followed by warfarin. Fibrinolysis with recombinant tissue plasminogen activator (alteplase) was performed in four patients who exhibited significant right ventricular dysfunction, two of whom presented with hemodynamic instability indicative of massive PE. Surgical thrombectomy was conducted in two patients with intracardiac thrombi. Supportive treatment measures such as oxygen therapy, aminergic support, and venoarterial extracorporeal membrane oxygenation (ECMO) were employed in select cases of respiratory failure and hemodynamic compromise. During follow-up, three patients transitioned to non-vitamin K antagonist oral anticoagulants (NOACs) after a period of warfarin therapy. The average length of hospitalization was 22.5 days [4].
Belsky et al.'s study focused on catheter-directed thrombolysis as the primary treatment modality for submassive PE in pediatric patients [12]. Four patients underwent thrombus maceration and pharmacomechanical lysis, while all patients received CDT via pulmonary artery infusion catheter. The median time from PE diagnosis to initiation of lytic therapy was 6.8 hours, with a median duration of lytic therapy of 17.8 hours. Post-lysis pulmonary arteriograms were performed for all patients to assess thrombus burden, with thrombolysis terminated upon sufficient reduction of thrombus burden to allow restoration of antegrade venous flow. Thrombolysis was well tolerated, with no patients developing major or clinically relevant non-major bleeding. Post-lysis, patients remained on therapeutic anticoagulation therapy for a median of 6.1 months. Follow-up screening echocardiograms showed complete thrombus resolution in four patients, partial resolution in one patient, and one patient without follow-up imaging [12].
Akam-Venkata et al. employed various treatment modalities for pediatric PE, including CDT and ultrasound-accelerated thrombolysis using the EkoSonic endovascular system [8]. Three patients received preceding systemic thrombolytic therapy. The time from PE diagnosis to CDT varied, with a median duration of 8 hours. All patients received CDT except for one who underwent mechanical thrombectomy using due to bleeding risk associated with thrombolysis. Five patients received ultrasound-accelerated thrombolytic therapy, with varying durations of tissue plasminogen activator infusion. Outcomes following treatment were mixed, with seven patients responding to catheter-directed therapy and concomitant anticoagulation therapy, while two patients experienced mortality due to delayed diagnosis and poor response to treatment [8].
Pelland-Marcotte et al.'s focused on using anticoagulation as the primary treatment modality [11]. Most patients received anticoagulation alone using UFH or LMWH, or both, as initial and long-term therapy. A small proportion of patients also received vitamin K antagonists or direct oral anticoagulants as part of ongoing clinical trials. Among patients with massive or submassive PE, aggressive therapies such as systemic thrombolysis, CDT, or thrombectomy were employed in nearly half of the cases. Additionally, supportive therapies including inotropes, pulmonary vasodilators, and ECMO were utilized in a significant proportion of patients with massive or submassive PE [11].
In Ross et al.'s study, patients with MPE received aggressive interventions, including surgical embolectomy, CDT, or systemic thrombolysis [3]. Among the MPE group, four patients presented with sudden cardiac arrest, necessitating prompt intervention. Surgical embolectomy was performed in three patients, CDT in three patients, and systemic thrombolysis in one patient. Notably, two additional patients progressed from SMPE to MPE during hospitalization and received thrombolysis and catheter-based therapy as initial treatment for MPE. For patients with SMPE, initial management primarily involved systemic thrombolysis, with surgical embolectomy performed in one patient with concomitant right ventricular thrombus. No additional reperfusion therapy was administered to SMPE patients unless progression to MPE occurred during hospitalization. Overall, patients with MPE had higher rates of hospitalization, major comorbidities, central venous catheter use, critical illness, immobility, and postoperative status compared to patients with SMPE. Additionally, MPE patients had a significantly higher mortality rate before discharge. However, both MPE and SMPE groups had similar rates of primary reperfusion attempts [3].
In Ji 2019 study, patients underwent percutaneous aspiration catheter-directed thrombolysis (PA CDT) with tPA infusion tailored to the extent and severity of PE [13]. The duration of tPA infusion varied based on clot burden and clinical response, with some patients requiring extended infusion periods beyond standard protocols. Supportive measures such as respiratory support, including mechanical ventilation and high-flow nasal cannula, were utilized in all patients before intervention. Additionally, three patients required venoarterial ECMO cannulation due to severe cardiopulmonary compromise [13].
3.12 Outcome and Follow-up
In Ross et al., among the survivors with follow-up, including those who experienced cardiac arrest, most had excellent outcomes with no sequelae from PE or recurrence of PE during a median follow-up period of 16 months [3]. However, one survivor developed chronic thromboembolic pulmonary hypertension (CTEPH) and later died from related complications. On the other hand, Pelland-Marcotte and colleagues reported a 19% rate of pulmonary embolism-related unfavorable outcomes, including pulmonary embolism-related death or recurrence/progression of PE [11]. The mortality rate within 30 days was 8%, with additional patients experiencing major or clinically relevant non-major bleeding during acute treatment. A subset of patients was eventually diagnosed with CTEPH. Most patients in the Ji 2019 study demonstrated either complete or partial resolution of thrombus, accompanied by improvements in mean pulmonary artery pressure and clinical variables [13]. However, complications such as bradyarrhythmias and hypertension were observed in a subset of patients post-CDT, though these were transient and resolved without long-term sequelae. All surviving patients were maintained on anticoagulation therapy, with no reported recurrence of PE during follow-up.
In Belsky et al., four patients showed complete thrombus resolution, one showed partial resolution, and one did not undergo follow-up imaging [12]. During a median follow-up period of 11 months, patients responded well to catheter-directed therapy and concomitant anticoagulation, with no evidence of right ventricular hypertension suggestive of CTEPH. However, two patients with systemic lupus erythematosus experienced recurrent PE while on enoxaparin. Two patients also experienced minor gastrointestinal bleeding, which was managed medically without requiring blood transfusion. On the other hand, seven patients in the Akam-Venkata et al. cohort responded to catheter-directed therapy and concomitant anticoagulation therapy [8]. The median length of hospital stay after catheter-directed therapy was 8 days. During a median follow-up of 11 months, surviving patients maintained normal right ventricular size and systolic function on follow-up echocardiography. However, two deaths were reported, one due to delayed diagnosis of massive PE after surgical intervention and the other following a poor response to preceding systemic thrombolysis.
Future Directions
Future directions for studies on pediatric PE should aim to address several key areas to further enhance our understanding and management of this complex condition. Firstly, there is a need for larger prospective studies with standardized protocols, focusing on refining and validating classification systems for pediatric PE severity to guide appropriate risk stratification and treatment decisions. Additionally, there is a growing interest in exploring novel diagnostic modalities, including biomarkers and advanced imaging techniques, to improve early detection and risk assessment in pediatric patients with suspected PE. Furthermore, research efforts should continue to conduct a comparative assessment regarding the safety and efficacy of emerging therapeutic interventions, such as catheter-directed therapy and novel anticoagulants, in managing pediatric PE, particularly in sub-massive and massive cases. Finally, propensity matched and randomized control trials with extended follow-up periods are needed to assess long-term outcomes, including the risk of recurrent PE and development of chronic thromboembolic pulmonary hypertension, in pediatric patients with PE. This could potentially lead to optimization of diagnostic and therapeutic strategies to improve outcomes and quality of life for children and adolescents with PE.
Limitations
This systematic review has several limitations. First, the retrospective nature of the included studies may have led to incomplete or inconsistent documentation of patient characteristics, treatment modalities, and outcomes, potentially affecting the accuracy and reliability of the findings. Second, the heterogeneity among the included studies, such as variations in study designs, patient populations, diagnostic criteria, and treatment protocols, may limit the generalizability and comparability of the results. Additionally, the limited number included studies restricted our ability to perform a meta-analysis, which was mitigated by performing a comprehensive qualitative systematic review. Despite these limitations, this systematic review provides a comprehensive overview of the current evidence and highlights the need for further research to address existing gaps and uncertainties in the management of pediatric PE.