<abstract xmlns="http://www.w3.org/1999/xhtml">

<p>Pulmonary hypertension (PH) is a pathophysiological condition that includes multiple clinical situations and can complicate most cardiovascular and respiratory diseases<sup><xref ref-type="bibr" rid="j_rjc.2020.31.4.893_ref_001">1</xref></sup>. Step by step diagnosis and reviewing contemporary treatment approaches would significantly impact the prognosis of pediatric patients with PH. Management of children with PH requires a multidisciplinary team with experience. PH is frequently associated with cardiac and pulmonary diseases with chronic hypoxia, obstructive respiratory disorders, chest malformations, pneumonia, acute respiratory distress, and can also develop during late phases of cystic fibrosis, bronchial asthma, bronchiectasis. Updated definition of PH at the world symposium (HTAP, Nice, 2018) includes values of pulmonary artery pressure >20 mmHg and using pulmonary vascular resistance (PVR) indexed to the body surface to identify pre-capillary PH, PVR≥3 WU×m<sup>2</sup> <sup><xref ref-type="bibr" rid="j_rjc.2020.31.4.893_ref_005">5</xref></sup>. Cardiac catheterization represents the gold standard in diagnosing PH, being the most precise method of measuring the blood pressure (BP) in the pulmonary artery and offering valuable information about cardiac output, arterial pressure, and the response to pulmonary vasodilators<sup><xref ref-type="bibr" rid="j_rjc.2020.31.4.893_ref_002">2</xref>,<xref ref-type="bibr" rid="j_rjc.2020.31.4.893_ref_003">3</xref></sup>. The specific modern treatment with endothelin receptor inhibitors significantly improves the disease's clinical course and brings better parameters at instrumental investigations<sup><xref ref-type="bibr" rid="j_rjc.2020.31.4.893_ref_008">8</xref></sup>.</p>
</abstract>

Pulmonary hypertension (PH) is a pathophysiological condition that includes multiple clinical situations and can complicate most cardiovascular and respiratory diseases1. Step by step diagnosis and reviewing contemporary treatment approaches would significantly impact the prognosis of pediatric patients with PH. Management of children with PH requires a multidisciplinary team with experience. PH is frequently associated with cardiac and pulmonary diseases with chronic hypoxia, obstructive respiratory disorders, chest malformations, pneumonia, acute respiratory distress, and can also develop during late phases of cystic fibrosis, bronchial asthma, bronchiectasis. Updated definition of PH at the world symposium (HTAP, Nice, 2018) includes values of pulmonary artery pressure >20 mmHg and using pulmonary vascular resistance (PVR) indexed to the body surface to identify pre-capillary PH, PVR≥3 WU×m2 5. Cardiac catheterization represents the gold standard in diagnosing PH, being the most precise method of measuring the blood pressure (BP) in the pulmonary artery and offering valuable information about cardiac output, arterial pressure, and the response to pulmonary vasodilators2,3. The specific modern treatment with endothelin receptor inhibitors significantly improves the disease's clinical course and brings better parameters at instrumental investigations8.


<div xmlns="http://www.w3.org/1999/xhtml">
<sec id="j_rjc.2020.31.4.893_s_001"><div>CASE REPORT</div>
<p>A 6-years-old boy is admitted to the cardiology department with complaints of high fatigue, weakness, excessive sweating, and dry caught. Clinical examination revealed growth and development retardation (16 kg (25P), 105 cm (25P), 14.5 kg/m<sup>2</sup>). The pale skin, periorbital circles, peripheral cyanosis with finger clubbing, and poorly subcutaneous adipose tissue are observed. No edemas were remarked. BP 90/55 mm/Hg measured on the right hand, SpO<sub>2</sub> - 96% at arms and 85% at feet, respiratory rate - 26/min. The limits of relative and absolute cardiac dullness are enlarged. On auscultation: moderate tachycardia with pronounced pulmonic component of the second heart sound and pulmonary valve regurgitation murmur.</p>
<p>The patient is born from the second pregnancy, accompanied by multiple acute viral respiratory infections, chronic fetal and placental insufficiency, chronic intrauterine hypoxia, and born prematurely at 29 weeks with a weight of 2100 grams and a height of 47 cm. After birth, echocardiography shows the presence of patent arterial duct (PAD). The alimentation is exclusively artificial. There is an insufficient weight addition in the first year of life, the child weight being just 8100 grams. The child is immunized according to the national vaccination plan. There is no history of cardiac diseases in the family.</p>
<p>Several chronological events can describe the patient's clinical condition. In 2019, at the age of 4, the boy started attending kindergarten, where he is inactive, prefers to stay alone, and does not participate in activities and games with other children. There are no abnormalities at echocardiography and no data for pulmonary hypertension or cardiac malformations. In 2020, at the age of 5, a dry cough appeared, and after a while, there is evident perioral cyanosis during physical effort, the child is tired, inert and also there is dyspnea which makes him refuse to play. At echocardiography, there is a right atrium walls hypertrophy (5mm), right atrium dilatation (16 mm), thickening of the mitral valve with insufficiency of I–II grades, severe pulmonary hypertension – 75–80 mmHg (<a ref-type="fig" href="#j_rjc.2020.31.4.893_fig_001">Figure 1</a>).</p>
<figure id="j_rjc.2020.31.4.893_fig_001" position="float" fig-type="figure"><h2>Figure 1</h2>
<figCaption><p>Echocardiography. Tubular PAD 5–6 mm with laminar shunt right-left in systole and left-right in diastole. Aortic cross laminar flux. Significant right ventricle hypertrophy. TAPSE 1.6cm, without regurgitation in tricuspid valve. LAS, IVS without changes. Dilated inferior vena cava.</p></figCaption>
<img xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_rjc.2020.31.4.893_fig_001.jpg" src="https://sciendo-parsed.s3.eu-central-1.amazonaws.com/647364ad4e662f30ba53c607/j_rjc.2020.31.4.893_fig_001.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&amp;X-Amz-Date=20240523T031501Z&amp;X-Amz-SignedHeaders=host&amp;X-Amz-Expires=18000&amp;X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20240523%2Feu-central-1%2Fs3%2Faws4_request&amp;X-Amz-Signature=d107136874ccf6d002e6778c7656752b24a396bfc13985df79da4231e6f21300" class="mw-100"/>
</figure>
<p>Further investigations are recommended at this stage. Later, in February 2020, the patient is investigated by CT Angiography (CTA) and is diagnosed with congenital cardiac malformation - PAD (7 mm in length and 9×7 mm in diameter) with high flow, the aortic and pulmonary connections of the PAD are not obstructive, the pulmonary artery trunk is extremely dilated (19×18 mm), right pulmonary artery dilatation 10 mm, left pulmonary artery 9mm, dilatation of right atrium and ventricle with severe pulmonary hypertension (<a ref-type="fig" href="#j_rjc.2020.31.4.893_fig_002">Figure 2</a>). In March 2020, the child is hospitalized in the surgical department with clinical signs of pulmonary hypertension, where a cardiac catheterization is performed and confirms the diagnosis of pulmonary hypertension. In order to estimate the possibility of surgical intervention on cardiac malformation, in March 2020, during another cardiac catheterization, multiple measurements are made with trying of PAD closing (<a ref-type="table" href="#j_rjc.2020.31.4.893_tab_001">Table 1</a>).</p>
<figure id="j_rjc.2020.31.4.893_fig_002" position="float" fig-type="figure"><h2>Figure 2</h2>
<figCaption><p>CT angiography. Persistent arterial duct with large dimensions: length 7mm, diameter 9×7mm. Pulmonary artery dilatation, right atrium and right ventricle dilatation.</p></figCaption>
<img xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_rjc.2020.31.4.893_fig_002.jpg" src="https://sciendo-parsed.s3.eu-central-1.amazonaws.com/647364ad4e662f30ba53c607/j_rjc.2020.31.4.893_fig_002.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&amp;X-Amz-Date=20240523T031501Z&amp;X-Amz-SignedHeaders=host&amp;X-Amz-Expires=18000&amp;X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20240523%2Feu-central-1%2Fs3%2Faws4_request&amp;X-Amz-Signature=42744c9ce1a4a4eac3f54a7ef00ae24f5950155430803e5a27a551a7bb8fec95" class="mw-100"/>
</figure>
<table-wrap id="j_rjc.2020.31.4.893_tab_001" position="float"><label>Table 1</label><caption><p>The parameters of cardiac catheterization</p></caption>
<table frame="box" rules="all">
<thead>
<tr>
<th align="left" valign="middle"><bold>Parameters of cardiac catheterization</bold></th>
<th align="center" valign="middle"><bold>Values</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">RV Max dP/dt [mmHg/sec]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">938</td>
</tr>
<tr>
<td align="left" valign="top">RV Max dP/dt/P [l/sec]</td>
<td align="center" valign="top">22</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">HB [G/100 ml]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">9.56</td>
</tr>
<tr>
<td align="left" valign="top">Cardiac Output [l/min]</td>
<td align="center" valign="top">11:25 3.52</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">Cardiac Index [l/min/m<sup>2</sup>]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">5.75</td>
</tr>
<tr>
<td align="left" valign="top">Venous Site</td>
<td align="center" valign="top">PA</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">Heart Site</td>
<td style="background-color: #E6E7E8" align="center" valign="top">AO</td>
</tr>
<tr>
<td align="left" valign="top">Heart rate</td>
<td align="center" valign="top">98.00</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">Stroke Volume [ml/beat]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">35.97</td>
</tr>
<tr>
<td align="left" valign="top">SVi [ml/beat/m<sup>2</sup>]</td>
<td align="center" valign="top">58.73</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">O<sub>2</sub> consumption [ml/min]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">118.3</td>
</tr>
<tr>
<td align="left" valign="top">Predicted Pulm Vasc Resist [dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>]</td>
<td align="center" valign="top">1.73</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">Predicted Syst Vasc Resist [dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">27.42</td>
</tr>
<tr>
<td align="left" valign="top">Pulm Vasc Resistance [dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>]</td>
<td align="center" valign="top">1.590,.91</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">PVR IX [(dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>)<sup>*</sup>m<sup>2</sup>)]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">974.44</td>
</tr>
<tr>
<td align="left" valign="top">Total Pulm Resistance [dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>]</td>
<td align="center" valign="top">1.670.45</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">TPR IX [(dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>)<sup>*</sup>m<sup>2</sup>)]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">1.023.12</td>
</tr>
<tr>
<td align="left" valign="top">Syst Vascular Resistance [dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>]</td>
<td align="center" valign="top">1.545.45</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">SVR IX [(dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>)<sup>*</sup>m<sup>2</sup>)]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">946.60</td>
</tr>
<tr>
<td align="left" valign="top">TSR [dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>]</td>
<td align="center" valign="top">1.727.27</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">TSR IX [(dynes<sup>*</sup>sec/cm<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_005">5</a></sup>)<sup>*</sup>m<sup>2</sup>)]</td>
<td style="background-color: #E6E7E8" align="center" valign="top">1.057.96</td>
</tr>
<tr>
<td align="left" valign="top">PVR/SVR res ratio</td>
<td align="center" valign="top">1.03</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">TPR/TSR res ratio</td>
<td style="background-color: #E6E7E8" align="center" valign="top">0.97</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>According to existing data (Pulmonary Vascular Resistance 1.590 dynes*sec/cm<sup>5</sup>, Systemic Vascular Resistance 1.545 dynes*sec/cm<sup>5</sup>, PVR/SVR res ratio 1.03) the surgery is questionable, and pharmacological treatment is recommended starting with Sildenafil. In July 2020, the patient is investigated by echocardiography, and the pulmonary hypertension is still persistent 70 mmHg. The ECG (December 2020) reveals a sinus rhythm, heart rate 93/min, arrhythmia, right atrium and right ventricle hypertrophy. There are no specific important laboratory findings in the blood stream. In the same period, the patient is included in a rare disease program in the Republic of Moldova PH and starts his combined treatment with Bosentan and Sildenafil. The patient is frequently investigated to monitor his clinical stage and the response to treatment, measuring clinical parameters and comparing their values in time (<a ref-type="table" href="#j_rjc.2020.31.4.893_tab_002">Table 2</a>).</p>
<table-wrap id="j_rjc.2020.31.4.893_tab_002" position="float"><label>Table 2</label><caption><p>The dinamics of the efficiency criteria for Bosentan and Sildenafil treatment</p></caption>
<table frame="box" rules="all">
<thead>
<tr>
<th align="left" valign="middle"><bold>Parameters</bold></th>
<th align="center" valign="middle"><bold>Before Therapy</bold></th>
<th align="center" valign="middle"><bold>After 1 month</bold></th>
<th align="center" valign="middle"><bold>After 3 months</bold></th>
<th align="center" valign="middle"><bold>After 4 months</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">Heart rate beat/min</td>
<td style="background-color: #E6E7E8" align="center" valign="top">93</td>
<td style="background-color: #E6E7E8" align="center" valign="top">99</td>
<td style="background-color: #E6E7E8" align="center" valign="top">72</td>
<td style="background-color: #E6E7E8" align="center" valign="top">75</td>
</tr>
<tr>
<td align="left" valign="top">Blood pressure mm/Hg</td>
<td align="center" valign="top">90/60</td>
<td align="center" valign="top">91/55</td>
<td align="center" valign="top">90/60</td>
<td align="center" valign="top">90/60</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">Saturation O<sub>2</sub> % hand/leg</td>
<td style="background-color: #E6E7E8" align="center" valign="top">97/68</td>
<td style="background-color: #E6E7E8" align="center" valign="top">99/70</td>
<td style="background-color: #E6E7E8" align="center" valign="top">96/76</td>
<td style="background-color: #E6E7E8" align="center" valign="top">97/80</td>
</tr>
<tr>
<td align="left" valign="top">6MWT (six minutes walk test) steps</td>
<td align="center" valign="top">420</td>
<td align="center" valign="top">427</td>
<td align="center" valign="top">485</td>
<td align="center" valign="top">500</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">MeanPAP</td>
<td style="background-color: #E6E7E8" align="center" valign="top">70</td>
<td style="background-color: #E6E7E8" align="center" valign="top">45</td>
<td style="background-color: #E6E7E8" align="center" valign="top">40–42</td>
<td style="background-color: #E6E7E8" align="center" valign="top">43</td>
</tr>
<tr>
<td align="left" valign="top">RVSP</td>
<td align="center" valign="top">70</td>
<td align="center" valign="top">45</td>
<td align="center" valign="top">42</td>
<td align="center" valign="top">43</td>
</tr>
<tr>
<td style="background-color: #E6E7E8" align="left" valign="top">CI</td>
<td style="background-color: #E6E7E8" align="center" valign="top">3.55</td>
<td style="background-color: #E6E7E8" align="center" valign="top">2.3</td>
<td style="background-color: #E6E7E8" align="center" valign="top">3.06</td>
<td style="background-color: #E6E7E8" align="center" valign="top">2.64</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="j_rjc.2020.31.4.893_s_002"><div>DISCUSSIONS</div>
<p>Pulmonary arterial hypertension (PAH) is a disabling progressive disease characterized by an increase of pulmonary vascular resistance (PVR) caused by the vascular structural remodeling of pulmonary arteries, and frequently results in right ventricular failure 6. Cardiac catheterization has long served as the „gold standard” for the anatomic and physiological assessment of patients with CHD (Congenital Heart Diseases). The direct measurement of pressures within cardiac compartments and major vessels helps to classify patients according to risk, evaluate pharmaceutical involvement and indicate a need for intervention. Cardiac catheterization and angiography have significantly facilitated the diagnosis and the care of children with CHD and have increased the safety of surgery for CHD. There is an unwritten general rule that a contrast-enhanced computed tomography (CT) scan to be undertaken before cardiac catheterization, as it will allow a precise approach to cardiac catheterization, and limit the radiopaque contrast required. CT scanning is beneficial to determine pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, or interstitial lung disease, the denial or evaluation of congenital lung or heart malformations (e.g., anomalous systemic or pulmonary drainage, pulmonary sequestration, aortopulmonary collaterals, lung hypoplasia, pulmonary vein stenosis, airway malformations), and the degree of parenchymal lung disease in bronchopulmonary dysplasia (BPD). There is a broad consensus that a diagnostic cardiac catheterization with acute vasoreactivity testing be undertaken at least once in any patient with significant pulmonary hypertension, mainly if specific pulmonary hypertensive therapy is recommended. In general, it is welcomed to repeat cardiac catheterization 6–12 months after initiating targeted PHVD therapy<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_003">3</a>,<a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_007">7</a></sup>. Endothelin-1 (ET-1) represents the key mediator in the pathogenesis of IPAH, with high concentrations in the plasma. Bosentan, an endothelin receptor antagonist, has been approved in Food and Drug Administration (FDA) to effectively improve IPAH when administered in recent studies<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_008">8</a></sup>.</p>
<p>In pediatric IPAH (Idiopathic pulmonary arterial hypertension), plasma endothelin levels are elevated, and ECE activity is enhanced. As a result, ET-1 is highly expressed in the lung. The overproduction of ET or over activation of ET-A receptors and low levels of ET-B receptors will come up with intense vasoconstriction of vessels and stimulate matrix production and cell proliferation, which resulting in fibrosis and inflammation of PAH. Furthermore, the levels of ET-1 are closely related to the levels of PVR. In this way, endothelin receptor antagonists are important in the treatment of IPAH. In <italic>European Medicines Agency</italic> (EMA), <italic>Food and Drug Administration</italic> (FDA), and <italic>China Food and Drug Administration</italic> (CFDA) emphasize that bosentan is recommended for the treatment of PAH to improve effort tolerance and symptoms in patients with WHO functional class III. The effectiveness has been demonstrated in primary PAH (idiopathic and familial), PAH secondary to scleroderma without significant interstitial pulmonary disease, congenital systemic-to-pulmonary shunts, and Eisenmenger syndrome<sup><a ref-type="bibr" href="#j_rjc.2020.31.4.893_ref_004">4</a></sup>.</p>
<p>Maybe in our clinical case there is a genetic predisposition for earlier development and rapid progression of the disease, so further genetic investigation are needed.</p>
</sec>
<sec id="j_rjc.2020.31.4.893_s_003"><div>CONCLUSIONS</div>
<p>The presented clinical case demonstrates the severe and progressive course of pulmonary hypertension, which causes rapid invalidation and a considerable decrease in life quality. On the other hand, modern pharmacological approaches with specific therapy (endothelin receptor antagonist -Bosentan) reveal new perspectives of an effective treatment in similar cases and considerably improve the prognosis. All that is mentioned calls for responsibility and high professionalism regarding pulmonary hypertension since specific therapy initiated promptly represents the main source of life expectancy.</p>
</sec>
</div>

Pulmonary Hypertension in Children - New Insights of Diagnosis and Management

„Nicolae Testemitanu” University of Medicine and Pharmacy

Romanian Journal of Cardiology

This work is licensed under the Creative Commons Attribution 4.0 International License.

{"article-title":"Pulmonary Hypertension in Children - New Insights of Diagnosis and Management"}

Pulmonary hypertension (PH) is a pathophysiological condition that includes multiple clinical situations and can complicate most cardiovascular and respiratory...

Pulmonary Hypertension in Children - New Insights of Diagnosis and Management

Article Category: Case Presentation

Publicado en línea: 05 may 2022

Páginas: 893 - 896

DOI: https://doi.org/10.47803/rjc.2020.31.4.893

Palabras clave
pulmonary hypertension, endothelin receptors, pulmonary vascular resistance, cardiac catheterization, target therapy

© 2021 Ina Palii et al., published by Sciendo

This work is licensed under the Creative Commons Attribution 4.0 International License.

Pulmonary Hypertension in Children - New Insights of Diagnosis and Management

Article Category: Case Presentation

Publicado en línea: 05 may 2022

Páginas: 893 - 896

DOI: https://doi.org/10.47803/rjc.2020.31.4.893

Palabras clavepulmonary hypertension, endothelin receptors, pulmonary vascular resistance, cardiac catheterization, target therapy

© 2021 Ina Palii et al., published by Sciendo

This work is licensed under the Creative Commons Attribution 4.0 International License.

Palabras clave
pulmonary hypertension, endothelin receptors, pulmonary vascular resistance, cardiac catheterization, target therapy