Case Discussion [Case presentation] This 37 year-old woman was sent to the ED due to progressive dyspnea, abdominal distension and puffy face for one month. According to patient’s statement, she denied any other systemic diseases, including hypertension, diabetes mellitus, or asthma history. She didn’t smoke or drink. Her mother died of primary pulmonary hypertension at the age of 65 year-old, two years after the diagnosis. She had an uneventful life until she suffered from progressive exertional dyspnea, easy fatigability 5 years ago. She had childbirth at the age of 24 and 27 year-old and there were no complications found. Initially, she came to a local clinic and no definite diagnosis was told. Due to progressive dyspnea, she visited to a medical center, where pulmonary hypertension was informed after workups. Her symptoms improved a little after medication including diuretics, and digoxin. However, she lost of follow-up one year later, and begun to take Chinese herb drugs since then. On arrival at our ED, her blood pressure was 110/70 mmHg, body temperature was 36 oC, respiratory rate was 30/ min and pulse rate was 80/ min. Her consciousness was clear. The pupils were isocoric and prompt to light reflex. The conjunctiva was not pale and the sclera was slightly icteric. The neck was supple, and jugular veins were engorged. There was neither goiter nor lymphadenopathy noted. The breathing sounds were clear. The heartbeats were regular. RV heave was noted. Narrowing of S2 splitting, P2 accentuation and grade II/VI midsystolic murmur were heard at left lower sternal border. The abdomen was soft and distended. Shifting dullness was noted. Liver span was 14 cm along the right mid-clavicle line. Mild tenderness was at right upper quadrant area and hepato-jugular reflex was noted. There was pitting edema was noted over her legs. Her hemogram was within normal limit. (WBC 5000/μL, Hb 12g/dL, Plt 118K/μL). Abnormal liver function was noted. (T-Bil 2.8mg/dl, GOT 150 U/L, GPT 168 U/L). Arterial blood gas disclosed respiratory alkalosis under O2 nasal cannula 4L/min. [pH 7.31, PCO2 24.1 mmHg, PO2 77.3 mmHg, HCO3- 16 mEq/l, Base excess –1.1mEq/l]. Normal plasma D- dimmer level was disclosed by ELISA . Chest X ray [Fig 1] and CT [Fig 2] showed clear field, increased cardiac size and pulmonary trunk enlargement. ECG disclosed RV strain [Fig 3]. Pulmonary ventilation and perfusion scan disclosed low probability of pulmonary embolism. Transthoracic UCG showed dilated right ventricle, moderate TR, and RV systolic hypertension, and no evidence of intra-cardiac shunt or other anomaly. A cardiac cath was performed, and pulmonary hypertension was noted (MPA 74/38mmHg). Under the impression of primary pulmonary hypertension, oxygen, diuretics and digoxin were described. Continuous infusion of prostacyclin was tried, and her condition gradually stabilized. She was discharged smoothly with the prostacyclin infusion pump. [Discussion] Primary pulmonary hypertension (PPH)，泛指所有原因不明之肺動脈高壓症。診斷前需排除次發性之原因，包括肺部疾病 (如吸煙病史、慢性組塞性肺病 (COPD)、肺間質病變 (interstitial lung disease)等)，心臟疾病 (如先天性心臟病、瓣膜性疾病等)，自體免疫性疾病、HIV或藥物 (fenfluramine-phentermine)等原因引起之肺動脈高壓症。PPH之病理變化為肺動脈及肺小動脈之medial hypertrophy及其他之血管變化，包括肺小動脈原位性血栓 (thrombotic pulmonary arteriopathy)。 PPH之盛行率不明，發病族群以女性為多 (佔63%)，年齡以20至40歲之間為主，最常見之初期症狀為氣促，約佔80%，疲倦、昏倒或雷諾氏現象 (Raynaud phenomenon) 也多有報告。部分病人有家族史，為Autosomal Dominant方式遺傳，但penetrance則不一定。 臨床之症狀表現以右心衰竭為主，理學檢查以P2心音增強，三尖瓣逆流及週邊水腫為多見。最常見死因為右心衰竭 (47%)，而猝死 (sudden death) 亦佔有26 %，且絕大部分發生於NYHA Functional class IV的患者中。 在實驗室檢查中，大部分之檢查均為正常範圍內；當肝功能異常時，多為右心衰竭後，引起的肝臟充血所致。心電圖以右心房心室擴大引起之變化為多。CXR中可能可見main pulmonary artery 及其分枝之擴大，及肺部血流減少之現象。在心臟超音波中，以右心擴大，左心大小正常或略小，三尖瓣逆流及右心室收縮壓升高之表現為主。然而這些檢查均無絕對之專一性，仍須由臨床表現或其他檢查排除次發性肺動脈高壓疾病。而右心導管之檢查仍為目前判定肺動脈高壓有無之黃金標準，並可同時排除許多心臟疾病及肺動脈栓塞疾病的存在。 目前的治療方式，包括O2 therapy, digoxin, diuretics 等。至於vasodilator therapy，根據目前文獻，則可能只對部分之病人有效。 可利用adenosine、prostacyclin或NO測試立即之反應，而對有反應之病人可考慮長期給calcium channel blockers 或 continuous prostacyclin infusion therapy。至於抗凝血劑之效果則不明。至於接受heart-lung 或 lung transplantation的時機，則應該在病人處於NYHA Fc III或IV，對藥物治療反應不佳，或藥效反應開始減弱時，開始考慮並接受移植之評估。 繼續教育考題 1. (E)  The GOLD STANDARD for the diagnosis of pulmonary hypertension is A CXR B ECG C Chest CT scan D UCG E Right heart catherization 2. (E) Which of the following clinical signs would likely lead to a diagnosis of PRIMARY PULMONARY HYPERTENSION? A Examination of the jugular venous pulse shows a prominent v wave B P2 accentuation C There is an audible midsystolic murmur along the sternal border D A fourth sound could be heard over the left lower sternal border E All of the above 3. (A) Which of the following statement regarding to right-sided heart failure is NOT TRUE? A Jugular vein engorgement is common in right ventricular infarction B Pulsus paradoxus is observed frequently in patients with cardiac tamponade, and sometimes associated with pulmonary diseases with wide swings in intrathoracic pressure C In patients with right-sided infective endocarditis, the history of intravenous drug abuse should be considered D Right ventricular dilatation by the cardiac echo is not specific to primary pulmonary hypertension E Oxygen desaturation frequently increases during sleep in patients with COPD 4. (E) Which of the following statement regarding to pulmonary hypertension is NOT TRUE A Drug history of fenfluramine-phentermine could be associated with pulmonary hypertension B UCG is indicated to rule out possible structural heart diseases (e.g. ASD, VSD. PDA, valvular heart diseases) C The absence of changes on the ECG can not rule out cor pulmonale D Digoxin and diuretics are appropriate treatment for right ventricular failure E Vasodilators are widely used to treat pulmonary hypertension 5. (D) Which of the following test results would be highly useful in EXCLUDING the diagnosis of PULMONARY EMBOLISM?  A Normal PaO2 by ABG B Absence of right heart strain on ECG C  Intermediate probability pulmonary ventilation and perfusion scan  D Normal plasma level of D-dimmer by enzyme-linked immunosorbent assay (ELISA) E Normal CT scan of the chest 6. (B) Which of the following of statements regarding SECONDARY pulmonary hypertension is true? A The pulmonary hypertension that results from left ventricular failure brings about right ventricular failure B Patients with proximal pulmonary artery thromboembolism will show two or more segmental perfusion defects on ventilation-perfusion scanning C Cough is frequently present in patients with interstitial fibrosis D Systematically administrated vasodilators are beneficial in treating pulmonary hypertension associated with interstitial fibrosis E The ECG is most reliable in diagnosing the etiology of the pulmonary hypertension 7. (B) Which of the following statements regarding primary pulmonary hypertension (PPH) is true?  A PPH primarily affects the large pulmonary arteries B Sudden death accounts for a significant portion of all PPH-related death C PPH often recognized early by abnormal CXR or ECG showing RVH D Obtaining a family history is not beneficial in the diagnosis of PPH E Exclusion secondary cause of pulmonary hypertension is important 8. (A) Which of the following statement regarding to PPH is NOT TRUE?  A α blocker has great value in treatment of right-sided heart failure B The studies of calcium channel blocker (CCB) and prostacyclin therapy have confirmed a survival benefit in selected patients with PPH C Neither of CCB and prostaclyclin should be started empirically in all patients with PPH D Prostacyclin therapy requires intravenous infusion in patients with PPH E The efficacy of vasodilator agents in patients with secondary pulmonary hypertension is much less impressive and predictable than in PPH 9. (C) Which of the following statement regarding to PPH is NOT TRUE? A The incidence is unknown B The onset of age mostly around 20-40 year-old C Male is predominate D The signs of right heart failure is predominate E 7 % are familial, the mode is autosomal dominant with variable penetrance 10. (E) Which of the following statement regarding to prostacyclin is true? A One of the most potent vasodilator is known at present B Gold standard of testing the vasodilatation response in patients with PPH C Vasodilatation in only 1/3 of all PPH patients D It is a bridging therapy to transplantation due to beneficial clinical response E All of the above

答案解說 右心導管之檢查仍為目前判定肺動脈高壓有無之黃金標準，並可同時排除許多心臟疾病及肺動脈栓塞疾病的存在。 PPH的臨床之症狀表現以右心衰竭為主，理學檢查以P2心音增強，JVP的v wave會增強，可聽見mid-systolic murmur along the sternal borders and sometimes in the pulmonic area，a right-sided S4 can be heard at the left lower sternal border，及週邊水腫為多見。 RV infarction時不會出現jugular vein engorgement；其他的敘述均為正確。 Vasodilator在次發性肺動脈高壓中效果不佳，甚至使氣體交換變差，在PPH中可能只對部分之病人有效。可利用adenosine、prostacyclin或NO測試立即之反應，而對有反應之病人可考慮長期給calcium channel blockers 或 continuous prostacyclin infusion therapy。 肺栓塞的診斷的黃金標準為pulmonary angiography，但是對subsegmental emboli之診斷率低。非侵襲性檢查中以核醫檢查中pulmonary ventilation/ perfusion scan最有參考價值。而正常的 plasma level of D-dimmer by ELISA可用來排除肺栓塞的診斷。 肺動脈高壓可能肇因於LV failure，但是不一定完全解釋RV failure的嚴重性。Interstitial fibrosis的病人以dyspnea症狀為最常見。 Vasodilator在次發性肺動脈高壓中效果不佳，甚至可能惡化。ECG 的表現為非特異性，故不一定診斷出病因。 PPH之病理變化為肺動脈及肺小動脈之medial hypertrophy及其他之血管變化，最常見死因為右心衰竭 (47%)，而猝死 (sudden death) 亦佔有26 %，且絕大部分發生於NYHA Functional class IV的患者中。CXR和ECG不一定會有明顯之變化。部分病人有家族史，所以詳細之家族史將有幫助。PPH泛指所有原因不明之肺動脈高壓症。診斷前需排除次發性之原因。 目前文獻顯示α blocker對PPH的治療效果並不明確。其餘敘述均正確。 PPH之盛行率不明，發病族群以女性為多，年齡以20至40歲之間為主，臨床表現以右心衰竭為主。部分病人有家族史，為Autosomal Dominant方式遺傳，但penetrance則不一定。 目前的治療方式，包括O2 therapy, digoxin, diuretics 等。至於vasodilator therapy，根據目前文獻，則可能只對部分之病人有效。可利用adenosine、prostacyclin或NO測試立即之反應，而對有反應之病人可考慮給calcium channel blockers 或 continuous prostacyclin infusion therapy，作為接受heart-lung 或 lung transplantation的橋樑，當藥物治療反應不佳，或藥效反應開始減弱時，應開始考慮並接受移植之評估。