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Curr Pediatr Res 2013; 17 (1): 31-36 ISSN 0971-9032

Causes of pulmonary hypertension among children.
Hanaa H. Banjar
Al-Faisal University, Riyadh, Kingdom of Saudi Arabia
Section Pediatric Pulmonolgy, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh,
Kingdom of Saudi Arabia.
Abstract
Report of Pulmonary hypertension in the Arab country is limited. We carried out a retro-
spective chart review of all referred patients to pulmonary clinic with documented Pulmo-
nary Hypertension based on cardiac catheterization and or Echocardiogram during 2 years
period (March 2008 to February 2010). Our aim is to identify the different causes of Pulmo-
nary Hypertension and treatment modalities in a tertiary care center in Saudi Arabia and
their outcomes. A total of 114 patients with confirmed Pulmonary Hypertension. Mean age
at diagnosis 3.1. 55 (48%) males, 59 (52%) females. The most common causes of Pulmonary
Hypertension were: Congenital Heart Disease in 100 (87.7%) patients. Others were: Con-
genital anomalies in 100 (87.7%). Down Syndrome in 44 (38.5%). Unknown syndrome in 32
patients (28%). 11 patients (10%) due to congenital lung anomalies. 11 patients (10%) due
to Chronic Lung Disease, 2 patients due to living in high altitude, 2 patients with obesity, 2
patients with Alagile syndrome, and 2 patients with idiopathic Pulmonary Arterial Hyper-
tension. Factors that are related to development of Pulmonary Hypertension at presentation
were: Common AtrioVentricular Canal (P value = 0.05), Obstructive sleep apnea (P value =
0.02), a female sex (P value =0.05). Factors that contributed to persistence of Pulmonary
Hypertension at Follow up were: presence Congenital Heart Disease (P value=.05), un-
closed Atrial Septal Defect (P value = 0.03)


Key words: Pulmonary hypertension, Congenital heart disease, Congenital anomalies.

Introduction

blood flow, which leads to endothelial dysfunction and progressive vascular remodeling and, thus, increased Pulmonary arterial hypertension is defined as the mean pulmonary arterial pressures more than 25mm Hg at rest or more than 30mm Hg with exercise no matter what age Mortality associated with Pulmonary hypertension is ex- (British Cardiac Society Guidelines and Medical Practice tremely elevated. Once diagnosis has been confirmed Committee, 2001), or Tricuspid regurgitation with a Dop- mean survival among adults is 2.8 years and less than 1 pler velocity of more than 2.5 m/sec. In pediatric patients, it is defined as systolic pulmonary artery pressure exceeds 50% of systolic systemic pressure [1-10]. Uncontrolled studies suggest that prostacyclin analogues and phosphodiesterase type 5 inhibitors may have benefits Although Pulmonary hypertension related to Congenital in advanced pulmonary vascular disease. Bosentan sig- Heart Disease shares similar lung histology with idio- nificantly reduced pulmonary vascular resistance and sig- pathic Pulmonary Arterial hypertension, differences do nificantly increased 6 minute walk distance without com- exist between these etiologies. Management of Pulmonary promising peripheral oxygen saturation, in patients with hypertension related to Congenital Heart Disease can in- Eisenmenger’s syndrome [8]. These data suggest that tar- volve surgical correction of the cardiac defect and or geted therapies are beneficial in the Pulmonary Hyperten- treatment of the Pulmonary hypertension, depending on sion related to Congenital Heart Disease population [3-9]. the underlying cardiac defect and status of disease pro- gression. Patients with cardiac defects which result in left In children, approximately 40% of cases of Pulmonary to right shunting are at risk of developing Pulmonary hy- hypertension are idiopathic [10-15], around 6% are heri- pertension, owing to the increased shear stress and table,10-15 with the remaining mainly associated with con- circumferential stretch induced by increased pulmonary genital heart disease and few associated with Connective Curr Pediatr Res 2013 Volume 17 Issue 1 31 tissue diseases, Human Immunodeficiency Virus or portal Statistical consideration
hypertension [11]. A number of drugs have been ap- Descriptive analysis of congenital heart diseases, value of proved for the treatment of Pulmonary hypertension in Pulmonary Artery Pressure at presentation and Pulmonary adults, including endothelin receptor antagonists, Prosta- Artery Pressure at follow up were analyzed. cyclin analogues and phosphodiesterase type 5 inhibitors Major outcome: measurements of pulmonary artery pres- [5,9,12,17]. Although these drugs are used in paediatric sure from follow up Echocardiogram or cardiac catheriza- patients [17] none have been approved for the treatment The statistical analysis of data was done by using the In this report, we identify the different causes of pediatric software package Statistical Analysis System version 9.2 pulmonary hypertension in a tertiary care center in Saudi (Statistical Analysis System Institute Inc., Cary, North Carolina, United States of America). Descriptive statistics for all the continuous variables are reported as mean more Material and Methods
or less standard deviation while categorical variables are reported as frequencies and percentages. The categorical Retrospective chart review of Pediatric Patients, age 0 to variables were compared by using Chi-square test. The 16 years with confirmed “Pulmonary hypertension by statistical level of significance is set at P value less than cardiac catheterization and or Echocardiogram studies” that were referred to pulmonary services at a tertiary care center in Riyadh, Saudi Arabia for evaluation due to cough, recurrent chest infection and cyanosis during 2 A total of 114 patients with confirmed Pulmonary hyper- years period Jan 2008 to Dec 2010. The later is a center tension. Mean age at diagnosis 3.1 up to 3.8 years, 55 for cardiac and genetic diseases referrals. (48%) males, 59 (52%) females. Ninety Seven (85%) are alive, 4 (3.5%) died and 13 (11.5%) lost follow up. The Demographic, clinical, diagnostic, morbidity and mortal- most common causes of Pulmonary hypertension were ity data will be collected. Type of medical and, surgical found to be: Congenital Heart Disease in 100 (87.7%) patients. The most common Congenital Heart Disease that caused Pulmonary Hypertension are: Atrial Septal Defect Only patients who had mean “pulmonary arterial pres- 76 (66.6%), Ventricular Septal Defect 63 (55%), Com- sures more than 25mmHg or Tricuspid regurgitation with mon Atrio Ventricular Canal 39 (34%), Patent Ductus a Doppler velocity of more than 2.5 m/sec or systolic Arteriosus 16 (14%), Tetralogy of Fallot in 11 patients pulmonary artery pressure exceeds 50% of systolic sys- (10%), and total anomalous pulmonary venous return in temic pressure” are included in the study. 2 patients (1.7%) (Table1). Fifty Six of 100 patients with The study was approved by the institutional Research Congenital Heart Disease had repair of their cardiac de-
Table 1. Congenital heart disease and Pulmonary hypertension Total 100 of 114 patients (87.7%)
Type of defect
Number of patients (%)
Ventricular Septal Defect and Other Defect Patent Ductus Arteriosus and Other Defect Partial Anomalous Pulmonary Venous Return 32 Curr Pediatr Res 2013 Volume 17 Issue 1 Causes of pulmonary hypertension among children

Table 2. Type of congenital anomalies: Total 100 of 114
Other congenital anomalies as Skeletal Dysplasia, CHARGE association (Choanal Atresia, Heart Defect, Anal Defect, Renal Anomalies, Genital Defect and Eye Type of Congenital anomalies
Number (%)
Anomalies), and 32 patients with unknown syndrome (Table 2). 11 patients (10%) due to congenital lung anomalies as Diaphragmatic hernia in association with lung hypoplasia, and congenital lobar emphysema (Table 2). 11 patients (10%) due to Chronic Lung Disease 2 pa- tients due to living in high altitude, 2 patients with obe- sity, 2 patients with Alagile syndrome, and 2 patients with idiopathic Pulmonary arterial hypertension . Obstructive sleep apnea was detected on 31 (27%). Asthma 33 (30%), CHARGE – Choanal Atresia, Heart Defect, Anal Defect, Renal Anomalies, Genital Defect and Eye Anomalies. Factors that affected the severity of Pulmonary hyperten- €- Patients may have combined anomalies
sion more than 35 mmHg at presentations were: female sex P value less than 0.0150, and presence of congenital Recurrent Chest Infection 41 (36%), 32 (28%) required heart disease P value less than 0.0001. (Table 3) Oxygen, Gastro esophageal reflux in 36 (32%). Sixty Nine of 114 patients (60.5%) were started on vaso- dilators. Sildenafil (Revatio) was the most common drug Other causes of Pulmonary hypertension were: Congeni- used in 40 patients (35%). Sildenafil alone in 24 patients tal anomalies in 100 (87.7%), Down syndrome in (35%), or in combination with Bosentan (Tracleer) in 11 44(28%), Thirty-nine of 44 patients (88%) with Down patients (16%), or inhaled Ventavis (Iloprost) in 5 patients
Table 3. Comparison Tables of Pulmonary Artery Pressurein relation to clinical condition (Total 67 patients)
Variable
Variable
Less than or equal to
More than
combination with Bosentan or Sildenafil in one patient Bosentan was given for a total of 21 patients (18%). Bosentan alone in 6 patients (8.6%) , or in combination with Sildenafil in 14 patients (20%), or with Iloprost in Seventy five patients (66%) continued to have Pulmonary one patients (1.5%). Inhaled Ventavis in a total of 8 pa- hypertension at Follow up, and the factors that contrib- tients (4%), Ventavis alone in 2 patients (2.8%), or in uted to persistence of Pulmonary hypertension at Follow up were: presence Congenital Heart Disease P value Curr Pediatr Res 2013 Volume 17 Issue 1 equal 0.05, un closed Atrial Septal Defect P value equal Van Loon et al [22] described the outcome of a national Discussion
Pulmonary hypertension from 1993 to 2008, 52 consecu- tive children with idiopathic Pulmonary hypertension Many reports have described different causes of Pulmo- (constant number equals 29) or systemic to pulmonary nary hypertension in the pediatric population [18-21]. shunt-associated Pulmonary hypertension (constant num-ber equals 23) underwent baseline and follow-up assess-ments. Treatment was initiated depending on functional Van Loon et al. [18] described the clinical presentation of class, acute pulmonary vaso reactivity response, and drug pediatric pulmonary arterial hypertension and the difficul- ties in how to classify pediatric Pulmonary hypertension Children for whom second-generation drugs were avail-able had improved survival compared to their predicted There were a total of 63 children seen at a national refer- survival (1, 3, and 5year survival rates 93%, 83%, and ral center for pediatric Pulmonary hypertension under- 66% versus 79%, 61%, and 50%, respectively). However, went a diagnostic work-up for diagnosis of Pulmonary this improved survival was observed only in patients for Hypertension and associated conditions and for assess- whom second generation drugs became available during ment of the explanatory role of associated conditions for the Pulmonary Hypertension. Subsequently, Pulmonary No improved survival was observed in patients for whom drugs were available already at diagnosis. Baseline vari- Her results showed that, Idiopathic (like) Pulmonary arte- ables associated with decreased survival included higher rial hypertension (number equal 29; 46%), Pulmonary functional class, higher pulmonary-to-systemic arterial hypertension related to Congenital Heart Disease (num- pressure ratio, lower cardiac index, and higher serum lev- ber 2 equal 3; 37%), Pulmonary hypertension related els of N terminal probrain natriuretic peptide and uric Connective Tissue disease (number equal 2; 3%), Pul- acid. After start of second-generation drugs, functional monary Hypertension related disorders of respiratory sys- class, 6 minute walking distance, and N terminal probrain tem and or Hypoxemia (number equal 8; 12%), and natriuretic peptide improved but gradually decreased after Chronic Thromboembolic Disease related Pulmonary Hy- longer follow up. Her conclusion was that the survival of pediatric Pulmonary hypertension seemed improved since the introduction of second-generation drugs only in se- Her conclusion was that Pediatric Pulmonary Hyperten- lected patients for whom these drugs became available sion frequently presented with associated conditions and during their disease course. Start of second generation syndromal abnormalities. However, detailed evaluation of drugs initially induced clinical improvements, but these this complex presentation revealed that associated condi- effects decreased after longer follow up [22]. tions are not always explanatory for the Pulmonary Hy- Gatzoulis [23] mentioned that: Surgery must be per-formed prior to the onset of high pulmonary vascular re- In our study, congenital heart disease was the most com- sistance. At this stage, early changes may be reversible mon cause of Pulmonary hypertension in our pediatric after correction of the cardiac defect. If surgery is de- population with Pulmonary hypertension even in patients layed, it is less effective. Correction of a ventricular septal who had total repair of their cardiac defect (as 56/100 defect at age of 6 months results in normal pulmonary patients had repair). The other interesting finding is that vascular resistance after 12 months; however, while de- many congenital anomalies were associated with Pulmo- laying surgery until age of 2 yrs results in a reduction in nary hypertension specially Down syndrome in 38% of resistance, normalization is not achieved [24]. It is, there- Pulmonary hypertension population, and un-known syn- fore, prudent that surgery should be very early in children drome in 32 patients (28%) which is not described before with a massively increased blood flow [25]. with that magnitude. Also, female preponderance with Pulmonary hypertension as a factor of increasing the in- Prostacyclin Synthase is reduced in patients with Pulmo- cidence of Pulmonary hypertension, in addition to the nary Arterial hypertension, resulting in inadequate pro- presence of Congenital Heart Disease at presentation (Ta- duction of Prostacyclin (a vasodilator with anti prolifera- ble 3). Persistence of Pulmonary hypertension at follow tive effects), and the Prostacyclin analogues, Epopros- up was also related to Congenital Heart Disease and un- tenol, Treprostinil and Iloprost, have been a traditional mainstay of the treatment of idiopathic Pulmonary Arte- rial hypertension. There are few data for Pulmonary hy-pertension related to Congenital Heart Disease, but the 34 Curr Pediatr Res 2013 Volume 17 Issue 1 Causes of pulmonary hypertension among children benefits appear to be similar. In an uncontrolled study of Transplantation surgery, either by heart and lung trans- 20 children with Pulmonary Arterial hypertension related plant or a lung transplant plus corrective cardiac surgery, to Congenital Heart Disease (mean age 15 yrs), 1 yr of is the only potentially curative option for Pulmonary hy- prostacyclin therapy improved hemodynamic and quality pertension- Congenital Heart Disease. This approach is, however, not without limitations. The 10yr survival for a transplanted heart/lung is around 30 to 40%, which is low In a mixed population of 39 children with Pulmonary hy- compared with the expected survival of patients with Eis- pertension of various etiologies (including patients with enmenger syndrome, making it difficult to determine op- Pulmonary hypertension related to Congenital Heart Dis- timum timing for transplant. The need for transplant ease, epoprostenol improved survival (84% at 3 yrs), might, however, be delayed by the use of targeted thera- functional status, exercise tolerance and ability to thrive. pies. A retrospective study of 43 patients with Eisen- [27]. However, the intravenous delivery of these drugs is menger syndrome found that the mean time to death or a drawback, both practically and owing to the risk of in- inscription on the active transplant waiting list was sig- fection. Among 39 children, 38% had catheter associated nificantly longer for those treated with prostacyclin ana- problems, with 43 prescriptions for antibiotics, and 0.33 logues or endothelin receptor antagonists (7.8 yrs) com- Hickman line changes per patient, per year [27]. pared with those who did not receive targeted therapy (3.4 yrs; P value equals 0.006) [32]. However, delaying the Phosphodiesterase type 5 inhibitors, such as sildenafil need for transplant may not be beneficial for a disease and tadalafil, inhibit the degradation of Phosphodiesterase with slow progression; especially in the presence of any type 5, the enzyme responsible for hydrolyzing the vaso- age restrictions for acceptance onto the transplant list. The dilatory cyclic guanosine monophosphate. These com- criteria and prognostic indicators for transplant in this pounds enable vasodilation in Pulmonary Arterial hyper- population are unclear and warrant consideration tension, although there are limited data on their efficacy for Pulmonary Hypertension related to Congenital Heart In Conclusion: Congenital anomalies are common asso- Disease. A 12 month, open label study of children with ciation with Pulmonary hypertension in the pediatric Pulmonary hypertension (number of patients equals 14, population. Further studies are needed to identify the role of whom 10 exhibited Pulmonary Hypertension related to in the progression of Pulmonary Arterial Hypertension. Congenital Heart Disease reported improvements in exer- cise capacity and haemodynamics with Sildenafil.28 Simi- In summary
larly, a 6 month, prospective, open label trial of sildenafil therapy found a significant reduction in systolic and mean Pulmonary hypertension is a common disease and should pulmonary artery pressures and pulmonary vascular resis- be diagnosed and treated early before it becomes resistant tance, and improved cyanosis and functional capacity, in to vasodilators. Early closure of Congenital Heart defect patients with Eisenmenger syndrome [29]. A prospective, open label study of 21 patients with Pul- Acknowledgments
monary hypertension related to Congenital Heart Disease (including 15 with Eisenmenger syndrome) reported that I would like to acknowledge the help of Dr Abdelmuniem 16 weeks’ treatment with Bosentan resulted in clinical, Al-Dalee from Bio Statistics, Epidemiology, and scien- exercise, and haemodynamic improvements.30 Similarly, tific computing in the Research Center at King Faisal in an open label, prospective, multicentre study, Thirty Specialist Hospital and Research Centre for his valuable three patients with Pulmonary hypertension related to contribution regarding statistical method. Congenital Heart Disease (of whom 23 had Eisenmenger syndrome) showed improvements in functional status and exercise capacity after Bosentan treatment for a mean of References
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Comparative analysis of clinical trials and evidence- 36 Curr Pediatr Res 2013 Volume 17 Issue 1

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