Case - PH on Riociguat

Background

Pulmonary hypertension (PAH) is associated with a poor prognosis, and if left untreated, it can lead to right ventricular (RV) failure and death. The insidious progression of pulmonary vascular disease with RV maladaptation and intercurrent respiratory exacerbations may act as important precipitating factors for acute decompensation (1).

As clinicians involved in the management of these infants, we recognize the need for alternative agents with a reassuring safety profile that effectively reduce pulmonary vascular resistance (PVR), reverse maladaptive processes, and minimize exposure to multiple medications (polypharmacy) (1). In this report, we present a case of idiopathic pulmonary hypertension in a baby currently undergoing treatment with Riociguat, an oral soluble guanylate cyclase (sGC) stimulator approved for the treatment of PAH and chronic thromboembolic pulmonary hypertension (CTEPH) in adults (2) (3).

Case Description

The infant is a 5-month-old term baby boy who is critically ill with pulmonary hypertension of unknown etiology. He currently requires inhaled nitric oxide (iNO), Bosentan, subcutaneous treprostinil at 90 ncg/kg/min, and the recently added agent Riociguat.

He was born at 39+2 weeks to a healthy mother. The pregnancy and elective repeat cesarean section delivery were uneventful, and no resuscitation maneuvers were required. The Apgar scores were 9/9, and the birth weight was 3450 g.

At 24 hours of life, he was transferred to the neonatal intensive care unit (NICU) due to suspected transient tachypnea of the newborn (failed the congenital heart disease screening), as he required increased oxygen support for desaturations. On the third day of life (DOL 3), an echocardiogram was performed due to persistent oxygen requirement (high-flow nasal cannula - HFNC - 6 L/min, FiO2 35-40%), revealing the presence of pulmonary hypertension (PH). He was initiated on iNO (20 ppm) and, eventually sildenafil due to failure of weaning of the iNO. After reducing the oxygen requirements to 25-30%, the iNO dose was decreased to 15 and then 10 ppm. Other attempts to discontinue iNO was made but were unsuccessful, as tricuspid regurgitation (TR), indicating elevated right atrial (RA) - right ventricular (RV) pressure gradient, increased to > 125 mmHg each time. Bosentan was added to the treatment regimen, and a decision was made to perform cardiac catheterization as previous studies had failed to determine the cause of PH.

The infant did show some improvements, tolerating a progressive decrease in iNO to 10 ppm until DOL 30, when he experienced an acute pulmonary hypertensive crisis during the induction of anesthesia for diagnostic catheterization. He was intubated and required an increase in iNO to 20 ppm, as well as inotropic and vasopressor support (Epinephrine, norepinephrine, milrinone), and continuous rocuronium infusion. Epoprostenol was added to the management of PH (along with iNO, Bosentan, Sildenafil, and Milrinone), and ECMO was contemplated but not needed.

The baby received the dexamethasone for respiratory inflammation post-near cardiac arrest in the cathetrization laboratory, and cardiovascular medications were progressively reduced. He was extubated on DOL 36 and placed on HFNC, with a gradual tapering of iNO. A transition from intravenous to subcutaneous prostacyclin (Treprostinil) therapy was implemented.

Other diagnostic investigations revealed notable findings. The CT angiogram (Figure 1) indicated that aberrant venous drainage from the posterior segment of the right upper lobe to the superior vena cava (SVC) was present but unlikely contributive to the clinical manifestations. A CT chest scan identified additional areas where there were abnormal hypertrophic aberrant pulmonary segmental arteries associated with hypertrophic pulmonary veins that return to the pulmonary venous system. Pulmonary arteriovenous (AV) malformations were also suspected, thought to be a reactional process to the significant pulmonary hypertension. No features indicative of interstitial lung disease were observed. Genetic testing using the Pulmonary Artery Hypertension Panel yielded negative results, ruling out any genetic abnormalities. Developmental lung disease and neonatal crisis panel were also negative. Microaspirations were also excluded as a contributing factor using a videofluoroscopic swallow study. Otorhinolaryngology ruled out any signs of airway anomalies.

After conducting a comprehensive literature review to explore novel management approaches and discussions with world experts, the decision was made to initiate treatment with Riociguat. To ensure optimal efficacy, a washout of sildenafil was performed prior to initiating Riociguat. The current treatment regimen includes a combination of inhaled nitric oxide (iNO) at a dosage of 20 ppm, treprostinitl, bosentan, and riociguat, with dose adjustments following the literature guidelines. Respiratory support is provided through high-flow nasal cannula (HFNC) with a flow rate of 13 liters per minute and a fraction of inspired oxygen (FiO2) of 40-50%. Comprehensive alveolocapillary dysplasia panel is pending and discussions regarding lung transplantation are ongoing. Otherwise, the infant is developing adequately as per the neonatal neurodevelopmental team. 

Figure 1 - CT with 3D reconstruction and selected Echocardiography metrics

On DOL 116, a repeat attempt for cardiac catheterization was performed and was successful for obtaining some information, but had to be prematurily stopped before pulmonary biopsy could be done, due to near-arrest event during wedge pressure evaluation. It revealed that the right ventricular (RV) pressure was measured at 133/8 mmHg, which is approximately 154% of the systemic pressure. The mean pulmonary artery pressure (PAP) was found to be 79 mmHg, and the left pulmonary artery (LPA) wedge pressure was approximately 15 mmHg. This was on iNO 20 ppm, Treprostinil 90 ncg/kg/min, Milrinon, Sildenafil and Bosentan, with 100% FiO2. LPA wedge was 15 mmHg.  Due to the immediate onset of a pulmonary hypertension crisis upon balloon insufflation, a pulmonary reactivity test (or reverse reactivity testing) could not be conducted. Inotropic-vasopressor support (Epinephrine, norepinephrine, milrinone) was initiated to manage the crisis. The patient continued with the previous pulmonary hypertension management regimen and required mechanical ventilation for a duration of five days. Figure 2 illustrates the progression of the patient's hospital stay.

Discussion

Managing pulmonary hypertension presents significant challenges, particularly in chronic cases where polypharmacy is often necessary, and an idiopathic etiology is not uncommon.

The underlying causes of hypoxic respiratory failure (HRF) and persistent pulmonary hypertension of the newborn (PPHN) appear consistent across different cohorts. In the NICHD-NRN cohort, meconium aspiration syndrome was the most prevalent cause of HRF in near-term/term infants (41%), followed by idiopathic pulmonary hypertension (17%), pneumonia (14%), and respiratory distress syndrome (13%) (2). In our particular case, there was no indications that there was consumption of any agents promoting prenatal ductal closure. As well, these infants tend to present very early in post-natal life with severe hypoxic respiratory failure, which was not the case for our patient.

The most widely accepted mechanism of idiopathic pulmonary hypertension involves exaggerated pulmonary vascular constriction and maladaptive pulmonary vascular remodeling, with eventual hyperplasia and obliteration of the pulmonary vasculature. It is hypothesized that vasoconstriction may be triggered by various factors, including hypoxemia, medications, toxins, sympathetic tone, and autoimmune responses in individuals with genetic predisposition (4). Proliferative vasculopathy and right ventricular (RV) maladaptation play crucial roles in the progression of the disease. The maladaptive phenotype, known as heterometric adaptation, occurs when the RV undergoes irreversible decompensation following a phase of significant adaptation (5). Animal in vivo experiments support the notion that chronic pressure overload leads to RV hypertrophy but necessitates additional factors such as myocardial apoptosis, fibrosis, and capillary rarefaction to drive RV failure (5). Consequently, there is a need for interventions that can mitigate heterometric adaptation and facilitate long-term medical stability (1). 

Nitric oxide (NO) synthesis may be impaired in patients with pulmonary hypertension (PH), leading to inadequate cyclic guanosine monophosphate (cGMP) signaling, despite the inhibition of cGMP metabolism by phosphodiesterase type-5 inhibitors (PDE5i) such as with the use of sildenafil (6). This could explain why some patients fail to achieve treatment goals with sildenafil. Moreover, research suggests that other phosphodiesterases can degrade cGMP in the presence of PDE5 inhibition, reducing the effectiveness of these agents (7).

Riociguat exerts its therapeutic effects through a dual mechanism of action. It increases cGMP production by directly stimulating soluble guanylate cyclase (sGC) via an NO-independent binding site and enhances NO-induced activation of sGC. Studies conducted on rat and human pulmonary arteries have demonstrated that riociguat is a more potent vasodilator than sildenafil and exhibits three-fold greater efficacy under hypoxic conditions (7). The authors of these studies hypothesized that the observed difference may be attributed to low basal NO activity, leading to insufficient cGMP levels despite strong PDE5 inhibition (7). Additionally, soluble guanylate cyclase inhibitors have been associated with antiproliferative properties, reversal of right ventricular (RV) hypertrophy, and increased cardiac output, without stimulating the renin-angiotensin system (1)(6).

In conclusion, riociguat has been shown to be an alternative for the management of PH in newborns and infants. Its unique biochemical profile makes it an interesting alternative for idiopathic PH, with the potential to mitigate RV maladaptation. In the case of our patient, an important treatment goal is to discontinue inhaled nitric oxide (iNO), enabling continuation of therapy at home. Only case reports are available regarding its use in the neonatal and infantile population, and more studies are needed prior to widespread use of this therapy in the context of pediatric pulmonary hypertension.