[HKU Medical Grand Rounds] Challenges in management of pulmonary hypertension
Pulmonary arterial hypertension (PAH) is challenging in diagnosis and clinical management. We report an illustrative case to highlight the importance of proper diagnosis, risk assessment and clinical management for patients with PAH.
Patient presentation and history
A 22-year-old lady with gradually progressive shortness of breath on exertion for a few years presented with reduced exercise tolerance (<2 flights of stairs) associated with bilateral lower limb swelling as well as abdominal bloating and discomfort. She reported no orthopnoea, paroxysmal nocturnal dyspnoea, chest pain, palpitation, dizziness, syncope, haemoptysis, fever or constitutional symptoms.
The patient was born in Hong Kong with unremarkable growth and developmental history. She reported no significant past medical illness and no known drug allergy. She was a nonsmoker and nondrinker with no regular use of over-the-counter medications, herbs, weight-control agents or illicit drugs. She had normal and regular menstruation and had been sexually inactive. She had no travel history in the preceding years.
Examination revealed a body weight of 47.3 kg, height of 176 cm, blood pressure of 102/61 mm Hg, heart rate of 79 bpm, and oxygen saturation of 93 percent on room air. Jugular venous pressure was elevated with large V wave and bilateral lower limb pitting oedema up to the mid shin. There was no scar on the precordium. Left parasternal heave was present with no thrill. First heart sound was normal, with loud pulmonary component (P2) in the second heart sound. Grade 3/6 pan-systolic murmur was noted over the left lower sternal border. Chest auscultation was clear. Liver was mildly enlarged and pulsatile on abdominal examination. Skin and joints were unremarkable.
Clinical and laboratory investigations
Routine blood test revealed white blood cell count of 5.3 x 109/L, haemoglobin of 16 g/d, platelet count of 151 x 109/L, and normal alanine aminotransferase (26 U/L) and aspartate aminotransferase (20 U/L) with mildly elevated total bilirubin level (25 µmol/L). Urea and creatinine were 5.7 mmol/L and 90 µmol/L, respectively. Arterial blood gas on room air revealed pH of 7.45, pCO2 of 4.0 kPa, pO2 of 8.3 kPa, HCO3 of 21 mEq/L, base excess of -2 and oxygen saturation of 92.1 percent. Electrocardiogram revealed sinus rhythm at 79 bpm with right axis deviation, right bundle branch block and T wave inversion over V1–6. Chest X-ray revealed increased cardiothoracic ratio of 68 percent (abnormal, >50 percent), increased hilar-to-thoracic ratio of 48 percent (abnormal, >44 percent), prominent main pulmonary artery shadow, and dilated right descending pulmonary artery at 25 mm (abnormal, 17 mm), with no evidence of pulmonary congestion. (Figure) Clotting profile was unremarkable except significantly elevated d-dimer level, at 2,749 ng/mL (normal <500 ng/mL).
Contrast CT thorax did not reveal any lung parenchymal disease or pulmonary arterial filling defect. Ventilation-perfusion (VQ) scan revealed low probability of pulmonary thromboembolism. Blood tests for thyroid function, autoimmune markers, anti-cardiolipin antibody, lupus anticoagulant, hepatitis B surface antigen, anti-hepatitis C antibody, and anti-HIV antibody were all unremarkable.
Echocardiogram revealed preserved left ventricular systolic function with ejection fraction of 55 percent, grossly dilated and mildly impaired right ventricular systolic function, D-shaped interventricular septum during systole and diastole, normal left atrial size, severely dilated right atrium, and normal mitral and aortic valve with moderate-to-severe tricuspid regurgitation. Maximal velocity of tricuspid regurgitation jet was 3.58 m/s.
Cardiac MRI revealed no congenital abnormality, no septal defect, no signs of arrhythmogenic right ventricular dysplasia (ARVD) or Ebstein’s anomaly, no evidence of intracardiac shunting, as well as grossly dilated right atrium, right ventricle and pulmonary arteries. Cardiac catheterization revealed mean right atrial pressure of 7 mm Hg, pulmonary artery pressure of 42/25 mm Hg (mean, 32 mm Hg), mean pulmonary capillary wedge pressure of 6 mm Hg, cardiac output of 2.1 L/min, cardiac index by thermodilution method of 1.36 L/min/m2, pulmonary arterial saturation of 57.7 percent, pulmonary vascular resistance of 12.4 Wood’s unit, no evidence of significant intracardiac shunting, and negative vasoreactive study. Six-minute walk distance was 400 m and cardiopulmonary exercise test revealed maximal oxygen consumption (VO2max) of 11.7 mL/kg/min (about 30 percent predicted) with respiratory exchange ratio (RER) of 0.92.
The patient was diagnosed to have idiopathic PAH and started on sildenafil and warfarin. She was referred to the lung transplant team for assessment. Subsequently, she had an episode of ankle pain and received an NSAID from a GP, but soon developed significant desaturation and shock afterwards, with saturation of 60 percent on 100 percent oxygen via facial mask, sinus tachycardia (up to 130 bpm), oliguria and metabolic acidosis. Urgent contrast CT thorax ruled out pulmonary embolism. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated for pulmonary hypertension (PH) crisis. With VA-ECMO support, bosentan and continuous intravenous (IV) infusion of iloprost were started, and she was listed for lung transplantation with high priority. Her condition was subsequently stabilized with triple therapy, and VA-ECMO was successfully weaned off while sildenafil, bosentan and continuous IV iloprost infusion were continued.
Unfortunately, no suitable lung donor was available after >6 months of in-hospital waiting with continuous IV iloprost infusion. Therefore, as per the patient’s request, continuous IV iloprost infusion was gradually weaned off in a very slow manner, which was successful with no major rebound phenomenon. She was subsequently discharged with maintenance sildenafil and bosentan as she refused inhaled iloprost. Comprehensive reassessment 1 year after hospital discharge revealed absence of right heart failure symptoms or signs, absence of symptom progression with WHO functional class II, absence of syncope, 6-minute walk distance of 480 m, VO2max of 13.8 mL/kg/min (37 percent predicted), N-terminal pro-brain natriuretic peptide (NT-proBNP) of 1,391 ng/L, right atrium end systolic area >26 cm2 with no pericardial effusion on echocardiogram, as well as mean right atrial pressure of 7 mm Hg and cardiac index of 2.37 L/min/m2. (Table 1) The patient expressed the wish to be off the lung transplant list as she was satisfied with her functional status and had resumed work after hospital discharge. She was therefore removed from the lung transplant list in 2018 after detailed review by cardiology and pulmonary transplant teams with detail discussion with herself and her family.
However, subsequent serial reassessment in 2019 showed slow progression of symptoms with WHO functional class III, reduced 6-minute walk distance (from 480 m to 400 m), right atrial end systolic area >26 cm2 with no pericardial effusion on echocardiogram, and increased NT-proBNP (2,460 ng/L). Despite the progression, the patient and her family showed great reluctance towards relisting for lung transplantation and were reluctant to receive treatment with inhaled or infusion iloprost. Selexipag was therefore started at a dose of 400 µg in two divided doses per day for medical stabilization, and uptitrated in weekly increments of 400 µg/day as per standard practice. The patient was able to tolerate up to 1,600 µg in two divided doses per day, with no further uptitration performed due to significant headache, nausea and diarrhoea despite symptomatic medical treatment. These symptoms gradually subsided after 3 weeks while the selexipag dose was maintained at 1,600 µg in two divided doses per day, and the patient remained clinically stable pending serial comprehensive PH risk reassessment to guide the appropriate timing for relisting for lung transplantation.
The presented case highlights several important aspects in managing patients with PH.
Firstly, correct diagnosis of PAH is of paramount importance to guide appropriate therapy. As recommended by the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guideline on PH management, every patient suspected of having PH based on noninvasive assessment (eg, echocardiogram) should undergo right heart catheterization to make a definitive diagnosis and collect important haemodynamic information for proper PH classification.1 Comprehensive clinical classification of PH can be found in the ESC/ERS guideline,1 and it is important to rule out other potentially treatable causes (eg, chronic thromboembolic PH) before the diagnosis of idiopathic PH is made.
Secondly, there are different PAH-specific medications that act on different pathways, such as the cyclic guanosine monophosphate (cGMP) pathway, endothelin receptor pathway and prostacyclin pathway. PAH-specific medications should be initiated except in patients with idiopathic PAH who are vasoreactive on right heart catheterization, in which case calcium channel blockers were shown to have a beneficial effect.1 Although there is evidence showing superiority of initial combination therapy vs initial monotherapy,2 it is acceptable to start treatment with monotherapy with risk reassessment to guide the need for sequential combination therapy, in view of financial and practical concerns.1,3
Thirdly, VA-ECMO is a well-recognized modality for short-term mechanical extracorporeal support in pulmonary crisis, as a bridge to either lung transplantation or medical optimization.1,4,5 In our patient who unfortunately had PH crisis while on monotherapy with the phosphodiesterase-5 inhibitor sildenafil, additional bosentan (an endothelin receptor antagonist) and IV iloprost (a prostacyclin analogue) were used to improve her underlying PH as epoprostenol was not available in Hong Kong.6 With the use of triple combination therapy including parenteral prostanoid, the patient was eventually stabilized and weaned off from VA-ECMO.
Lastly, serial comprehensive risk assessment is crucial to evaluate treatment efficacy and guide the timing of medical therapy escalation as well as referral for lung transplantation. Risk assessment tools currently available include the REVEAL score and the risk model illustrated in the 2015 ESC/ERS guideline as shown in Table 2.1,7 It is important not to rely on any single parameter. Instead, multiple complimentary parameters should be used to assess the overall risk profile because evaluation with a single parameter is usually insensitive and sometimes misleading. As illustrated in the serial risk reassessment in this case, the patient’s clinical condition deteriorated about 1 year after being removed from the lung transplant list despite combination therapy with sildenafil and bosentan. Taking her preference into account, selexipag, a recently available oral selective IP prostacyclin-receptor agonist shown to reduce the composite endpoint of death and complications from PH (eg, hospitalization, need for parenteral prostanoid therapy or lung transplantation), was added to stabilize her PH.
In conclusion, comprehensive assessment including right heart catheterization is crucial to correctly diagnose and guide appropriate therapy for PAH. Serial multiparameter risk assessment is important to guide treatment adjustment and the timing of lung transplantation referral.