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A 61-year-old Caucasian female is admitted to the hospital in September 2018 with shortness of breath on exertion and increased fatigue during daily activities. Her symptoms, once mild, have been worsening for several years, she explains.

Medical History

The patient has severe congenital kyphoscoliosis of the thoracic spine (Figure). Attempted surgical correction when she was 10 years of age was not successful. She is New York Heart Association (NYHA) functional class IV, but has never smoked and has no history of prior drug abuse.

She explains that she first noticed becoming short of breath in mid-2015. In June 2016, to rule out a cardiac etiology, clinicians perform a transthoracic echocardiography (TTE). This identifies signs of right ventricular overload with an elevated right ventricular systolic pressure (RSVP) of 90 mm Hg.

In July 2016, right heart catheterization confirms a diagnosis of pulmonary hypertension (PH). At that time, the patient begins long-term oxygen therapy (LTOT) concomitantly with off-label treatment with the endothelin receptor antagonist ambrisentan at 5 mg once daily (OD). She also receives supportive therapy with spironolactone 25 mg OD, torsemide 10 mg OD, and atorvastatin 20 mg OD.

At Admission

Assessments during her current admission reveal peripheral edema and mild acrocyanosis. Lung auscultation reveals bilaterally diminished breath sounds at the bases. She has mild tachycardia (92 beats per minute) and low blood pressure 100/60 mm Hg; otherwise, her vital signs are within normal range. The patient also has severe hypoxemia, with 75% peripheral oxygen saturation (SpO2).

Transthoracic echocardiography (TTE) at admission reveals:

• Dilatation of right ventricle and left atrium
• Tricuspid regurgitation grade I–II with tricuspid annular plane systolic excursion of 2.9 cm
• Right ventricular systolic pressure (RVSP) of 65 mm Hg
• Preserved ejection fraction of 65%

Chest computer tomography (CT) with intravenous contrast shows bilateral basal hypoventilation, focal atelectasis in right basal lobe, and prominent thoracic malformation. There is no evidence of pulmonary embolism. Test results for anti-nuclear antibody and extractable nuclear antigen panel are negative.

Several hours after being admitted to the hospital and receiving supplemental oxygen therapy by non-rebreathing face mask (12 L/minute), the patient's SpO2 declines to 64%.

Her blood count showed minor erythrocytosis (5.51 × 10¹²/L), with normal range white cell count, blood biochemistry (chem-8) findings, and serum brain natriuretic peptide (80.8 pg/mL).

Clinicians immediately discontinue treatment with ambrisentan, and initiate treatment with an inhaled prostanoid every 4 hours (iloprost 5 μg via nebulizer), complemented by supplemental oxygen via simple face mask (5 L/minute).

Pulmonary function tests reflect the CT evidence of a highly restrictive ventilation pattern with largely maintained diffusing capacity (DLCO 74% of predicted) and lung permeability (DLCO/VA 145% of predicted).

The Days Following

There is gradual improvement in the patient's condition in the days following her admission. Her SpO2 level increases to over 90% with a corresponding increase in functional capacity to NYHA class III.

By day 4 of hospitalization, the patient's 6-minute walk test (6MWT) result is 241 meters, a marked improvement from her day 2 results of 153 meters.

Because the patient is unable to afford inhaled prostanoids as a long-term therapy, she is switched back to ambrisentan.

Treatment and Outcome

On day 4, the patient is discharged in satisfactory condition, with recommendation to continue LTOT and to begin non-invasive positive pressure ventilation therapy.

Case Follow-up

A follow-up right heart catheterization performed in February 2019 revealed similar hemodynamic parameter values compared to the values obtained during the initial diagnosis in July 2016, with a slight improvement in pulmonary vascular resistance, from 6 to 5.62.

The patient remains in NYHA class III with moderate exertional dyspnea. On the repeated 6MWT, she covers 260 meters.

Discussion

Clinicians reporting their experience with a patient with kyphoscoliosis complicated by pulmonary hypertension (PH) note that their provides insight into a long-term vasodilator therapy in this clinical context.

Given that kyphoscoliosis is encountered relatively rarely in clinical practice, and PH is often not diagnosed in a timely manner, in the absence of guidelines, they urge clinicians to direct their attention to identifying patients who might benefit from vasoactive agents in addition to ventilation/oxygenation therapy.

Respiratory complications are a common entity for restrictive chest wall diseases such as kyphoscoliosis. When such anatomical distortions are severe, patients have an increased risk of respiratory failure associated with poor clinical outcomes due to resulting malformation of the thoracic cavity.

Alveolar hypoventilation often develops due to a combination of reduced lung volume, increased thoracic muscle workload, and restriction in thoracic chest wall compliance and movements of diaphragm. As in two other alveolar hypoventilation disorders, obesity hypoventilation syndrome and obstructive sleep apnea, when hypoxia is aggravated, the resulting vasoconstrictive response increases pulmonary vascular resistance – ultimately resulting in development of pulmonary hypertension (PH).

Pulmonary hypertension is defined as an increase in mean pulmonary artery pressure ≥25 mm Hg, assessed by right heart catheterization (RHC) in the 2015 European Society of Cardiology (ESC) guidelines.

In patients with kyphoscoliosis, alveolar hypoventilation is one of the main contributors to the development of PH. This results in the condition being classified into the third of 5 groups: PH due to lung disease and/or hypoxia.

Although a single group, authors note that the pathogenic mechanism differs. PH develops either in the setting of lung disease or in a state of hypoxemia and alveolar hypoventilation with the absence of structural changes.

are determined based on the condition underlying the pulmonary hypertension. Due to the relative rarity of kyphoscoliosis with concomitant PH, therapeutic regimens have remained largely unchanged, authors note.

Current treatment recommendations are limited to ventilatory support. The potential benefits of use of pulmonary arterial hypertension (PAH)-approved vasoactive medications remain largely unexplored.

Since kyphoscoliosis complicated by PH was first observed several decades ago, reports of novel therapeutic approaches remain scarce.

of 1,344 adults with PH enrolled in a recent registry found that none were affected by kyphoscoliosis. Similarly, a study of 362 children with confirmed PH noted only two with kyphoscoliosis.

As in other alveolar hypoventilative disorders, treatment focuses on improvement of oxygenation state and ventilator support. Long-term oxygen therapy (LTOT) remains central to slowing respiratory decline, although now it is rarely used on its own. Instead, combined treatment with LTOT and non-invasive ventilation has proven more effective against pulmonary vasoconstriction. While this approach is associated with improved long-term survival and exercise capacity, it remains unable to prevent the cardiopulmonary deterioration of the kyphoscoliosis patient.

There is little data on the use of vasoactive medication in patients with PH secondary to deformative thoracic diseases, case authors write. They cite two reports: in a case of PH secondary to Potts disease, in a short-term emergency setting, inhaled nitric oxide was reported to result in marked improvement of cardiopulmonary condition; and in a patient with severe kyphoscoliosis and many years of nocturnal noninvasive positive-pressure ventilation, who was just diagnosed with PH, initiation of phosphodiesterase-5 inhibitor and oxygen therapy produced clinical improvement.

Authors note the importance of addressing safety concerns when using a PAH-approved vasoactive drug in patients with PH with concomitant lung disease. Vasoactive drugs oppose hypoxic vasoconstriction in poorly ventilated lung areas, creating a ventilation-perfusion mismatch, subsequently impairing blood oxygenation. However, they add, these concerns might not be attributable to PH in kyphoscoliosis, as the analysis of lung parenchyma in these patients has shown no structural abnormalities with the exception of focal atelectasis. It can be expected that the deterioration of blood oxygenation is reduced to minimum in these cases.

In their case, authors note their initial decision to commence monotherapy with an endothelin receptor antagonist that is currently approved for treatment of pulmonary arterial hypertension (PAH), because of the extent of PH progression at the time of diagnosis.

However, clinicians note that the endothelin receptor antagonist could not be excluded as a cause for the declining state of the patient at the time of admission. As an alternative, they selected an inhaled prostanoid, based mainly on its mode of distribution. They explain that because this drug primarily accesses well-ventilated lung segments, the treatment does not interfere with hypoxic vasoconstriction and does not worsen oxygenation.

Ultimately, there was no evidence of concomitant lung disease on CT imaging or the pulmonary function test – leading case authors to conclude that ambrisentan is unlikely to have caused the patient's severe hypoxemia.

Subsequently, they deemed it safe to continue the oral vasodilator. Considering the progressive nature of PH in kyphoscoliosis, despite ventilatory and oxygen treatment, they propose that adding a vasoactive medication offers a safe means of combating cardiopulmonary decline, in a long-term setting as well as an acute setting.

Pulmonary hypertension in kyphoscoliosis is associated with a high mortality rate, which persists despite use of current management options.

To date, the use of PAH-approved drugs for kyphoscoliosis-related PH have been associated with positive outcomes and may limit progression of disease.

Given the relative rarity of kyphoscoliosis in clinical practice, and frequent delays in diagnosis of PH which inevitably seems to follow, these case authors urge clinician awareness in identifying patients – via individual evaluation – who might benefit from vasoactive agents in addition to ventilation/oxygenation therapy.

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