Acute beryllium disease is an acute alveolitis due to the direct effects of high-dose inhal ed beryllium fumes. There is subsequent widespread airway oedema and pulmonary oedema, whic h causes dyspnoea, cyanosis, and widespread inspiratory crepitations. CXR shows pulmo- nary oedema. It may be self-limiting if mild, but if severe is usually fatal. Corticosteroids m ay prevent progression, but the patient is often left with residual pulmonary impairment Su bacute and chronic berylliosis is a hypersensitivity-type skin or pulmonary disease that oc curs a long time after beryllium exposure in a minority of individuals. It can be clinicall y indistinguishable from sarcoidosis. It has also been seen in the wives of beryllium worke rs and those who live near beryllium re \201 neries. Inhalation of beryllium or the exposu re of beryllium to a skin abrasion causes initial sensitization in 2 \200\22319% of exposed individuals. Only low levels of exposure are required for this. There is a cell-mediated i mmune response, with the produc- tion of numerous in \202 ammatory cytokines, which cause granulomatous in \202 ammation. Following a long latent period, which may be months to 10 years plus after exposure, non-caseating granulomatous tissue reactions occur in the lungs or on the skin. Similar to sarcoidosis. There is a genetic predisposition to the response t o beryllium exposure and it is HLA-mediated (HLA-DPB1(Glu69)). HLA status could be used to identify workers at high risk of berylliosis (but is not routinely used at present). Clinical features of chronic berylliosis \200 Symptoms Cough, dyspnoea. Macular skin lesions, which do not spontaneously resolve Signs No clubbing or crepitations in early disease, but both occur with established \201 brosis. Hepato/splenomegaly and macular skin lesions. Do not get uveitis or erythema nodosum. Investigations \200 CXR Fine reticulonodular appearance throughout both lungs. Finer nodules than those seen in sarcoidosis. Progression to irregular intersti- tial \201 brosis, with irregular linear opacities seen in the lung bases. Hilar lymphadenopathy can occur, but always in associatio n with interstitial lung disease HRCT Subpleural micronodular change, thickened interlobula r septae, traction bronchiectasis, and honeycombing. There may be ground-glass shadowing BA L High levels of T-lymphocytes PFTs Restrictive defect, with decreased KCO \200 BERYLLIOSIS 371 Pathology Non-caseating granuloma. May be indistinguishable from sarcoidosis. May develop i rregular \201 brosis with bulla and cyst formation No single test to distinguish berylliosis from sarcoidosis. Management Corticosteroids to t ry and prevent disease progression. Continue inde \201 nitely as few patients gain complet e resolution of symp- toms, CXR or PFTs. Annual screening of beryllium-exposed workers with CXR. If they develop breathlessness or skin rashes, this may be an indica- tion to start o ral steroids to delay progression to interstitial \201 brosis. Prognosis Progressive dise ase, although those with very low exposure who develop CXR changes may \201 nd they resol ve. Associated delayed skin sensitivity (anergy) to tuberculin. Granulomata do not spontane ously resolve, although can be excised if causing problems, such as troublesome lesions on the skin. Interstitial \201 brosis occurs in the lungs, which is pro- gressive and leads to cyanosis and death. Other complications include pneumothorax, hypercalcaemia, hypercalci uria, and nephrocalcinosis. Differential diagnosis \200 \200 Sarcoidosis Tuberculosis. In clinic \200 Ask patients with suspected sarcoidosis about possible exposure to beryllium Monitor PFTs a nd CXR to assess disease response or progression. This page intentionally left blank 373 Chapter 37 Pneumothorax Clinical features and investigations 374 Initial management 376 Further management 378 Trea tment algorithm for primary pneumothorax 380 Treatment algorithm for secondary pneumothorax 381 Speci \201 c situations 382 CHAPTER 37 Pneumothorax 374 Clinical features and investigations De \201 nition A pneumothorax is air in the pleural s pace. May occur with apparently normal lungs (primary pneumothorax) or in the presence of u nderlying lung disease (secondary pneumothorax). May occur spontane- ously or following tra uma. Epidemiology \200 \200 Annual incidence of primary pneumothorax is around 9 per 100 000 Primary pneumothoraces occ ur most commonly in tall thin men aged between 20 and 40. They are less common in women (ma le : female 5: 1) \200\224consider the possibility of underlying lung disease (e.g. lym- ph angioleiomyomatosis, catamenial pneumothorax) Cigarette smoking is a major risk factor for pneumothorax, increasing the risk by a factor of 22 in men and 9 in women. The mechanism is unclear; a smoking-induced in \202 ux of in \202 ammatory cells may both break down elas tic lung \201 bres (causing bulla formation) and cause small airways obstruction (increas ing alveolar pressure and the likelihood of interstitial air leak) May rarely be familial. Causes and pathophysiology Primary Pathogenesis is poorly understood; they are presumed to occur following an air leak from apical bullae, although small airway in \202 ammation is often also present and may contribute by increasing airways resistance. Secondary \200 Underlying diseases include: COPD (60% of cases), asthma, interstitial lung disease, necrot izing pneumonia, tuberculosis, PCP, cystic \201 brosis, Langerhans cell histiocytosis, ly mphangioleiomyomatosis, Marfan \200\231s syndrome, oesophageal rupture, lung cancer, catame nial pneumothorax, and pulmonary infarction Pneumothorax may be the \201 rst presentation of the underlying disease. Clinical features \200 Classically presents with acute onset of pleuritic chest pain and/or breathlessness. Breath lessness is often minimal in young patients and is more severe in secondary pneumothorax Si gns of pneumothorax include tachycardia, reduced expansion, hyper-resonant percussion note, and quiet breath sounds on the pneumothorax side. These are frequently absent in small pne umotho- races. Hamman \200\231s sign refers to a \200\230click \200\231 on auscultation in time with the heart sounds, due to movement of pleural surfaces with a left-sided pneumoth orax May feel \200\230bubbles \200\231 and \200\230crackles \200\231 under the skin of th e torso and neck if there is subcutaneous emphysema Presents in ventilated patients with ac ute clinical deterioration and hypoxia or increasing in \202 ation pressures. CLINICAL FEATURES AND INVESTIGATIONS 375 Investigations \200 CXR is the diagnostic test in most cases, revealing a visible lung edge and absent lung mar kings peripherally. Blunting of the ipsilateral costophrenic angle due to bleeding into the pleural space is common. Pneumothoraces are dif \201 cult to visualize on supine \201 l ms: look for a sharply delineated heart border, hemidiaphragm depression, and increased luc ency on the affected side \200 Width of the rim of air surrounding the lung on CXR may be used to classify pneumothoraces into small (rim of air <2 cm) and large ( \211 2 cm). A 2-cm rim of air approximately equat es to a 50% pneu- mothorax in volume Tiny pneumothoraces that are not apparent on PA CXR ma y be visible on lateral chest or lateral decubitus radiographs CXR appearance may also show features of underlying lung disease, although this can be dif \201 cult to assess in the presence of a large pneumothorax CT chest may be required to differentiate pneumothorax from bullous disease, and is useful in diagnosing unsuspected pneumothorax following trauma and in looking for evidence of unde rlying lung disease ABGs frequently show hypoxia and sometimes hypercapnia in sec- ondary p neumothorax Prognosis \200 Average of 30% (range 16 \200\22354% in studies) of primary pneumothoraces recur, most with in 2 years. Continued smoking increases the risk of recurrence. Risk of recurrence increase s with each subsequent pneumothorax: risk of recurrence is around 30% after a \201 rst pn eumo- thorax, about 40% after a second, and >50% after a third Mortality of secondary pneum othorax 10% Recurrence of secondary pneumothorax occurs in 39 \200\22347%, and is asso- cia ted with age, pulmonary \201 brosis, and emphysema. Recurrence rates may be as high as 80 % in patients with Langerhans cell histiocytosis or lymphangioleiomyomatosis. \200 Further information Sahn SA, Heffner JE. Spontaneous pneumothorax. NEJM 2000, 342: 868 \200 \22374 CHAPTER 37 Pneumothorax 376 Initial management There is considerable variation amongst clinicians regarding optimal pne u- mothorax management. The treatment algorithms presented on pp 380 \200\2231 follow the B TS guidelines. General management points \200 Management is determined by the degree of breathlessness and hypoxia, evidence of haemodyna mic compromise, the presence and severity of any underlying lung disease, and to some exten t the pneumothorax size Severe breathlessness out of proportion to pneumothorax size may be a feature of impending tension pneumothorax Secondary pneumothorax has a signi \201 cant mortality (10%), and should be managed more aggressively. Treat also the underlying disease . Aspiration \200 \200 Procedure described on p 779 Halt the procedure if painful, or if the patient coughs excess ively; do not aspirate >2.5 L of air, as this suggests a large air leak and aspiration is l ikely to fail Ideal timing of repeat CXR following aspiration is unknown; it may be advisab le to wait several hours before performing the CXR, in order to detect slow air leaks Aspir ation is successful if the lung is fully or nearly re-expanded on CXR If initial aspiration of a primary pneumothorax fails, repeat aspiration should be considered (unless \211 2.5 L has already been aspirated). At least one-third of patients will respond to second aspir ation, although the optimal timing of repeat aspiration is unclear. Chest drainage \200 \200 Procedure described on p 757 Associated with signi \201 cant morbidity and even mortality, and not required in the majority of patients with primary spontaneous pneu- mothorax Small (10 \200\22314F) drains are suf \201 cient in most cases; consider large-bore (24 \200 \22328F) drain in secondary pneumothorax with large air leak, severe subcutaneous emphysema , or in mechanically ventilated patients Never clamp a bubbling chest drain (risk of tensio n pneumothorax) When air leak appears to have ceased, clamping of the drain for several hou rs followed by repeat CXR may detect very slow or intermittent air leaks, thereby avoiding inappropriate drain removal; this is contro- versial, however, and should only be considere d on a specialist ward with experienced nursing staff. Addition of washing-up liquid to wat er in underwater seal bottle aids visualization of bubbling in very slow air leaks. \200 INITIAL MANAGEMENT 377 If drain water level does not swing with respiration, the drain is kinked (check underneath dressing, as tube enters skin), blocked, clamped, or incorrectly positioned (drainage hole s not in pleural space; check CXR) Heimlich \202 utter valves (or thoracic vents) are an alternative to under- water bottle drainage, and are being used increasingly in some center s. They allow greater patient mobilization, and sometimes out-patient management of pneumot horax. Oxygen All hospitalized patients should receive high \202 ow (10 L/min) inspired oxygen ( unless CO2 retention is a problem). This reduces the partial pres- sure of nitrogen in bloo d, encouraging removal of air from the pleural space and speeding up resolution of the pneu mothorax. Persistent air leak \200 \200 De \201 ned as continued bubbling of chest drain 48 h after insertion Consider drain sucti on ( \200\22310 to \200\22320 cmH2O), insertion of large-bore drain, and/or thoracic surgi cal referral Check that persistent bubbling is not the result of \200\230outside \200\231 air being sucked down the drain, e.g. following drain displacement such that a hole lies ou tside the pleural cavity, or, if enlargement of the drain track occurs, allowing outside ai r to enter and then be released down the drain. Discharge Prior to discharge, discuss \202 ying and diving (see p 378), and advise to ret urn to hospital immediately if breathlessness worsens. Document this in medical notes. CHAPTER 37 Pneumothorax 378 Further management Out-patient follow-up \200 Repeat CXR to ensure resolution of pneumothorax and normal appearance of underlying lungs D iscuss risk of recurrence and emphasize smoking cessation, if appropriate Ascent to altitud e with a pneumothorax is potentially hazardous. Guidelines recommend that patients should n ot \202 y for at least one week from the resolution of spontaneous pneumothorax on CXR. T his time interval is arbitrary, however, and patients should understand that there is a hig h initial risk of recurrence that falls with time, and they may wish to avoid \202 ying f or a longer period, e.g. 1 year Advise never to dive in the future, unless patient has unde rgone a de \201 nitive surgical procedure. Surgical management Indications for cardiothoracic surgical referral \200 \200 \200 \200 \200 \200 Second ipsilateral pneumothorax First contralateral pneumothorax Bilateral spontaneous pneu mothorax Persistent air leak (>5 \200\2237 days of drainage) Spontaneous haemothorax Profes sions at risk (e.g. pilots, divers) after \201 rst pneumothorax. Note that these are guidelines only, and patient choice will also in \202 uence the decisi on for surgical intervention. Surgical treatments aim to repair the apical hole or bleb, and close the pleural space. Opt ions: \200 Video-assisted thoracoscopic surgery (VATS) Recurrence rates are higher than for open thora cotomy (4% vs. 1.5%), although less invasive pro- cedure and probably shorter hospital stay . Pleural abrasion (rather than talc poudrage) is usually favored for closure of the pleura l space. Often the procedure of choice in young patients with primary pneu- mothorax Open t horacotomy Apical bleb resected, pleural space closed by pleural abrasion or parietal pleur ectomy. Effective procedure with a recurrence rate <1%, but probably prolonged recovery rat es compared with VATS Transaxillary minithoracotomy uses a relatively small axillary incisi on and may be a less invasive alternative to open thoracotomy. FURTHER MANAGEMENT 379 Chemical pleurodesis \200 \200 \200 Talc or tetracycline most commonly used; procedure described on p 775 Can be performed via intercostal drain or at VATS Failure rates around 10 \200\22320%, and some concern about th e long-term safety of intrapleural talc; therefore not recommended in younger patients Cons ider pleurodesis via intercostal drain only as a last resort in older patients with recurre nt pneumothorax in whom surgery would be high risk (e.g. patients with severe COPD) Likelih ood of successful pleurodesis in the setting of an incompletely re-expanded lung with a per sistent air leak remains uncertain, although it may be attempted if surgery is not an optio n. CHAPTER 37 Pneumothorax 380 Treatment algorithm for primary pneumothorax no Breathless and/or pneumothorax large?* (rim of air >2cm on CXR) yes Aspiration successful fails Consider repeat aspiration successful Discharge (with follow-up) fails Intercostal drain * successful Persistent leak Remove drain 24 hours after full re-expansion and cessation of air leak, and discharge Consider drain suction Thoracic surgical referral after 7 days of air leak Fig. 37.1 Treatment algorithm for primary pneumothorax. Some disagreement exists regarding this point: in the setting of a relatively asymptomatic patient with a large pneumothorax, the risk of intervention may outweigh the risk of the pn eumothorax, and conservative management may be considered. TREATMENT ALGORITHM FOR SECONDARY PNEUMOTHORAX 381 Treatment algorithm for secondary pneumothorax Consider in-patient observation without aspi ration in relatively asympto- matic patients with tiny (<1 cm) pneumothoraces. Breathless and age >50 and large pneumothorax (rim of air >2cm on CXR)? no Aspiration yes successful fails Observe for 24 hours; then consider discharge Intercostal drain Persistent leak Successful Remove drain 24 hours after full re-expansion and cessation of air leak, and discharge Consider suction Thoracic surgical referral after 5 days or consider chemical pleurodesis Fig. 37.2 Treatment algorithm for secondary pneumothorax. Further information Henry M et al. BTS Guidelines for the management of spontaneous pneumot horax. Thorax 2003; 58 (suppl. II): ii39 \200\22352 CHAPTER 37 Pneumothorax 382 Speci \201 c situations Tension pneumothorax \200 Pneumothorax acts as a one-way valve, with air entering the pleural space on each inspirati on and unable to escape on expiration. The progressive increase in pleural pressure compres ses both lungs and mediastinum and inhibits venous return to the heart, leading to hypotens ion and potentially cardiac arrest Occurrence is not related to pneumothorax size, and tens ion can occur with very small pneumothoraces in the context of air trapping in the lung fro m obstructive lung disease Typically presents with acute respiratory distress, agitation, h ypoten- sion, raised jugular venous pressure, and tracheal deviation away from the pneumoth orax side. Reduced air entry on affected side May present with cardiac arrest (pulseless el ectrical activity), or with acute deterioration in ventilated patients. 3 Management of a t ension pneumothorax \200 If strong clinical suspicion, give high- \202 ow oxygen and insert large-bore cannula into second intercostal space in mid-clavicular line on side of pneumothorax Do not wait for a CXR if patient seriously compromised or cardiac arrest has occurred Do not wait for a CXR i f the diagnosis is clinically certain Hiss of escaping air con \201 rms diagnosis Aspirate air until the patient is less distressed and then insert chest drain in mid-axillary line, leaving cannula in place until \201 nished and the underwater seal is bubbling satisfact orily. \200 \200 Iatrogenic pneumothorax \200 Causes include transbronchial biopsy, transthoracic needle lung biopsy, subclavian line ins ertion, mechanical ventilation, pleural aspiration, pleural biopsy, external cardiac massag e, and percutaneous liver biopsy Presentation may be delayed, even several days after proce dure Most cases do not require intervention and improve with observation, although aspirati on is sometimes required Drainage is seldom needed, although is more commonly required in p atients with COPD. The exception is mechanically ventilated patients, who will require an i ntercostal drain in the majority of cases. \200 Traumatic pneumothorax \200 Up to half may not be clinically apparent or visible on CXR; chest CT is required for diagn osis Majority of patients require intercostal drain. Ensure adequate analgesia; intercostal nerve block may be required Consider VATS early if persistent air leak. SPECIFIC SITUATIONS 383 Subcutaneous (or \200\230surgical \200\231) emphysema \200 \200 Occurs as air tracks below skin under pressure from the pleural space May result from large air-leaks, particularly in the presence of under- lying lung disease, such as COPD. Also m ay occur if chest drain is blocked or displaced so that holes lie subcutaneously Harmless i n majority of cases, although rarely may result in signi \201 cant respiratory compromise from upper airway compression Treat with high- \202 ow (10 L/min) inspired oxygen (unless CO2 retention a problem). Check that the drain is patent (swinging, bubbling) Management if unwell: oxygen, large-bore chest drain on suction. If the airway is compromised, consider anesthetizing and incising areas of affected skin, and \200\230milking \200\231 out subcut aneous air; subcutaneous drains are sometimes used, and in rare cases tracheostomy is requi red. Pneumothorax in HIV \200 Most commonly occurs as a result of PCP. Empirical treatment of PCP is advised (see p 478) Use of nebulized pentamidine may increase the risk of pneumothorax Consider early intercost al drainage and surgical referral. \200 Pneumothorax in cystic \201 brosis \200 \200 \200 Associated with severe underlying lung disease Subsequent ipsilateral and contralateral pne umothorax common Manage as for secondary pneumothorax, although intercostal drainage freque ntly required Give course of intravenous antibiotics In cases of persistent air leak despit e suction, discuss management with cardiothoracic surgical team at local transplant center. Partial pleurectomy is effective in preventing recurrence. Pleurodesis renders later trans plant technically more dif \201 cult, but it is not an absolute contraindication to transp lantation. \200 Catamenial pneumothorax \200 \200 \200 Pneumothorax occurring at the same time as menstruation Usually recurrent Pathogenesis is u nknown; possibilities include pleural endometriosis or transfer of air into pleural spaces through a diaphragmatic defect from the peritoneal cavity at menstruation Treatment options : VATS, pleurodesis, ovulation-suppressing drugs. Re-expansion pulmonary oedema \200 Occurs in up to 14% of cases following treatment, and causes breath- lessness and cough wit h evidence of oedema in the re-expanded lung (and sometimes both lungs) on CXR More common in young patients with large primary pneumothoraces, and may be associated with late presen tations to hospital May be precipitated by early use of suction (<48 h) Self-resolving in m ost cases, although may rarely be fatal. \200 This page intentionally left blank 385 Chapter 38 Pulmonary hypertension Classi \201 cation 386 Idiopathic pulmonary arterial hypertension (IPAH) 388 IPAH: clinica l features 390 IPAH: general management 392 IPAH: disease-targeted therapy 394 IPAH: surgic al treatments, end of life care, and future developments 396 Non-idiopathic pulmonary hypertension: causes 398 Non-idiopathic pulmonary hypertension: ma nagement 400 CHAPTER 38 Pulmonary hypertension 386 Classi \201 cation De \201 nition Pulmonary hypertension is a mean pulmonary artery pres- sure (PAP) >25 mmHg with a pulmonary capillary or left atrial pressure <15 mmHg. A rise in pulmonary artery pressure can be due to: Increased pulmonary blood \202 ow, e.g . atrial septal defect with left to right shunting Increased resistance in the pulmonary va scular bed, e.g. vascular remodeling in pulmonary arterial hypertension Elevated pulmonary venous pressure, e.g. left ventricular failure. CLASSIFICATION 387 WHO classi \201 cation of pulmonary hypertension, 2003 1. Pulmonary arterial hypertension \200 Idiopathic pulmonary arterial hypertension (IPAH, previously known as primary pulmonary hyp ertension) Familial pulmonary arterial hypertension (FPAH) Related to: \200 \200 \200 \200 \200 \200 Collagen vascular disease Congenital systemic to pulmonary shunts Portal hypertension HIV i nfection Drugs/toxins: anorectic agents (fen \202 uramine, dexfen \202 uramine), rape see d oil, others Very likely causes: amphetamine, L-tryptophan Possible: methamphetamine, coca ine, chemotherapy agents Other (glycogen storage diseases, haemoglobinopathies, myelo- prol iferative disorders, hereditary haemorrhagic telangiectasia, splenectomy) \200 \200 Associated with signi \201 cant venous or capillary involvement \200 \200 \200 Pulmonary veno-occlusive disease Pulmonary capillary haemangiomatosis Sickle cell disease 2. Pulmonary venous hypertension \200 \200 Left-sided atrial or ventricular heart disease Left-sided valvular heart disease 3. Pulmonary hypertension associated with hypoxaemia \200 \200 \200 \200 \200 Chronic obstructive pulmonary disease Interstitial lung disease Sleep disordered breathing Alveolar hypoventilation disorders Chronic high-altitude exposure 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease \200 \200 Thromboembolic obstruction of proximal pulmonary arteries Obstruction of distal pulmonary a rteries \200 Pulmonary embolism (thrombus, tumor, ova, parasites, foreign material) 5. Pulmonary hypertension associated with miscellaneous disorders \200 In \202 ammatory \200 \200 \200 Extrinsic compression of the central pulmonary veins \200 \200 Langerhans cell histiocytosis Sarcoidosis Other Fibrosing mediastinitis Lymphadenopathy/tumors CHAPTER 38 Pulmonary hypertension 388 Idiopathic pulmonary arterial hypertension (IPAH) De \201 nition Idiopathic pulmonary arte rial hypertension (IPAH), previ- ously called primary pulmonary hypertension (PPH), is a ra re disease of uncertain etiology. It is de \201 ned as a mean pulmonary artery pressure >2 5 mmHg at rest (or >30 mmHg on exercise) with a pulmonary capillary or left atrial pressure <15 mmHg. By de \201 nition there is no demonstrable cause. The presence of resting pulmo nary hypertension is signi \201 cant, as more than 70% of the vascular bed must be lost fo r the pulmonary arterial pressure to rise. Epidemiology The incidence of IPAH in Europe and the USA is 1 \200\2232 cases per million population per year. The mean age at diagnosis is 36, with a female preponderance of about 2:1. Although rare, it is important to diag- nose , as it affects a young age group and has an extremely poor outcome without treatment. Path ophysiology Vasoconstriction and secondary thickening of periph- eral \200\230resistance \200\231 blood vessels in association with smooth muscle cell and endothelial cell prolifer ation and thrombosis lead to raised pulmonary vascular resistance. The mechanism for this i s poorly understood, but the identi \201 cation of a mutation in BMPR2, which is present i n 70% of familial cases of PAH, has improved understanding. BMPR2, bone morphogenetic prote in receptor type II, is a receptor in the transforming growth factor beta (TGFB) receptor s uperfamily and is an important regulator of apop- tosis and proliferation. It is hypothesiz ed that defective signaling via this pathway may result in abnormal endothelial proliferati on and cell growth in response to various insults, with an inability to terminate the proli f- erative response to injury. Due to incomplete disease penetrance in the presence of a mu tation in BMPR2 (15 \200\22320%), it is thought that the genetic abnormality may have to be accompanied by some additional environ- mental factor, e.g. hypoxia to cause PAH. Allelic variations in the serotonin transporter have also been identi \201 ed. An imbalance between prostacyclin (a potent vasodilator and platelet inhibitor) and thrombo xane A2 (a potent vasoconstrictor and platelet agonist) has been identi \201 ed in PAH. Un favorable imbalances between other regulators of vascular tone and smooth muscle cell growt h, including endothelin-1, nitric oxide, and serotonin have also been implicated in the dis ease. Acute hypoxia causes reversible changes in vascular tone, with chronic hypoxia inducing str uctural vascular remodeling, which can add signi \201 - cantly to morbidity in certain lun g diseases. IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION (IPAH) 389 Etiology \200 Idiopathic IPAH This is a disease for which, strictly speaking, no cause is found, although a number of risk factors have been identi \201 ed, and BMPR2 mutations may be present in up to 25%. The identi \201 ed risk factors for IPAH have in common an ability to damage th e pulmonary endothelium, which may provoke an excessive proliferative response, progressing to IPAH. Familial IPAH A familial predisposition is seen in 6 \200\22310% of IPAH cases, w here the disease is transmitted in an autosomal dominant fashion. Incomplete penetrance and anticipation are seen, with presentation at a younger age in successive generations. The r esponsible gene has been localized to chromosome 2 (locus 2q 31 \200\22332). Abnormal cardi ovascular responses to exercise have been demonstrated in asymptomatic car- riers of BMPR2. Associations \200 Anorexigens are associated with the development of PAH, with an increased incidence with lo nger duration of use. A raised PAP can occur after only 4 weeks of drug use. CNS stimulants Cocaine and methamphetamine are associated with the development of PAH. Scleroderma Post m ortem studies show histological changes con- sistent with PAH in up to 80% of patients with scleroderma spec- trum disease, including SLE, mixed connective tissue disease, and RA. Th e reported lifetime incidence of PAH in scleroderma varies, but may be about 15%. In all of these diseases there is a strong association between PAH and Raynaud \200\231s phenomenon, suggesting pathological similarities between these two conditions. HIV PAH is found in HIV infected individuals, regardless of the route of infection. The incidence is about 0.5%, 6 \200\22312 times higher than the general population. The development of PAH is independent of CD4 cell count, but is associated with duration of infection. The mechanism is unclear. Portal hypertension PAH is seen in up to 5% of patients with portal hypertension, increasi ng with duration of liver disease. The mecha- nism is uncertain, but it appears that cirrho sis without portal hyper- tension is insuf \201 cient for the development of PAH. Heredita ry haemorrhagic telangiectasia PAH occurs in around 15% of patients with HHT, an autosomal dominant vascular dysplasia. Mutations in the ALK-1 receptor (also in the TGFB receptor sup er- family) are implicated. Prognosis is variable, depending on haemodynamic compromise with cardiac index, right atria l pressure, and mean pulmonary artery pres- sure at presentation being linked to prognosis. The median survival in NYHA functional class 3 (symptomatic on mild exertion) is 2.8 years and 6 months in NYHA class IV (symptomatic at rest) without treatment. CHAPTER 38 Pulmonary hypertension 390 IPAH: clinical features The symptoms of idiopathic pulmonary arterial hypertension are non- speci \201 c, leading to an average delay in diagnosis of 3 years from \201 rst symptoms . Presenting features \200 Exertional breathlessness, due to the inability to increase cardiac output with exercise Ch est pain (right heart angina) Syncope, due to a fall in systemic blood pressure on exercise Palpitations Oedema, or other signs of right-sided \202 uid overload. \200 \200 \200 Examination Signs consistent with right heart \202 uid overload and right ventricular hyp ertrophy are associated with advanced disease and include: \200 \200 \200 \200 \200 \200 \200 \200 Raised JVP, with giant V waves Right ventricular heave Wide splitting of S2 with loud P2 Mu rmur of tricuspid regurgitation Hepatomegaly Ascites Peripheral oedema Cyanosis. Investigations These are aimed at making a diagnosis of idiopathic pul- monary arterial hyp ertension by excluding possible underlying causes for the pulmonary hypertension. In 85% of patients presenting with symptoms caused by established pulmonary hypertension, a CXR and ECG will be abnormal. \200 CXR may show enlarged pulmonary arteries and an enlarged cardiac silhouette, with pruning o f peripheral vessels ECG Right atrial hypertrophy, right axis deviation, and RVH Arterial b lood gas Hypoxia and hypocapnia (correlating with disease severity), with a fall in oxygen saturation on exercise Pulmonary function tests The lung volumes may be normal, or show a m ild restrictive or obstructive defect with a reduced TLCO (late in the disease course) HRCT chest to exclude underlying lung disease Ventilation \200\223perfusion scanning/CTPA to ex clude chronic thromboem- bolic disease as a cause. V/Q is more sensitive than CTPA Echocard iography The most useful diagnostic test in pulmonary hyper- tension. Typically shows enlar gement of right-sided cardiac chambers with paradoxical interventricular septum movement, a nd tricuspid regurgitation. The systolic pulmonary artery pressure can be estimated from th e velocity of the tricuspid regurgitant jet, using Doppler tech- niques, and the estimated right atrial pressure from the IVC caliber. Pericardial effusions may be present and repres ent a poor prognosis \200 \200 IPAH: CLINICAL FEATURES 391 Right heart catheterization to con \201 rm the pulmonary artery pressure, pulmonary capill ary wedge pressure and cardiac output (with a Swann \200\223 Ganz catheter, by thermodiluti on or Fick). Vasodilator testing (usually with inhaled nitric oxide) should be performed to identify patients who will respond to calcium-channel blockers. Also needed to exclude a l eft to right intracardiac shunt. Selective pulmonary angiography is rarely required as CTPA and V/Q can detect nearly all cases of thromboembolic disease Blood tests Routine tests, i ncluding autoantibodies (anti-centromere antibody, anti SCL-70, and RNP) if connective tiss ue disease suspected as a cause, HIV, TSH, thrombophilia screen, serum ACE. CHAPTER 38 Pulmonary hypertension 392 IPAH: general management The diagnosis of idiopathic pulmonary arterial hypertension is mad e when all other causes have been excluded. The management in this section applies to IPAH. General management \200 Anticoagulation All patients with pulmonary hypertension are at risk of venous thromboembol ism and in situ pulmonary arterial thrombosis, and therefore should be on life-long warfari n. A small thrombus can have catastrophic effects in a patient who is already severely comp romised. Studies show an increased survival with warfarin in IPAH, which may re \202 ect r eversal of an underlying pro-thrombotic state, as well as the prevention of in situ thrombu s formation. Additional bene \201 cial effects are seen when combined with a vasodilator. There is no published data on the use of warfarin in other causes/associations of pulmonary hypertension Long-term oxygen Hypoxaemia is due to reduced cardiac output, ven- tilation/p erfusion mismatching, and right \200\223left shunting through a patent foramen ovale. Added oxygen may reduce any further rise in PAP resulting from additional hypoxic pulmonary vaso constriction Diuretics and digoxin Diuretics may be useful for the treatment of oedema, but excess preload reduction may limit their usefulness. Digoxin has been shown to improve car diac output acutely in IPAH, though its longer-term effects are not known Immunization Annu al in \202 uenza and one-off pneumococcal vaccination Contraception may be required, as pr egnancy is poorly tolerated in IPAH with a 30 \200\22350% mortality. \200 A National Pulmonary Hypertension Service was set up in the UK in 2001 to coordinate diagno sis and treatment in \201 ve regional centers, recognizing the need to provide best care (with complex interventions) and optimize funding for expensive treatments. The \201 ve U K centers are: \200 London \200\224Hammersmith Hospital (general) \200 \200 \200 Cambridge \200\224Papwor th Hospital Shef \201 eld \200\224Royal Hallamshire Hospital Newcastle \200\224Freeman Hos pital Glasgow \200\224Western In \201 rmary Royal Brompton Hospital (adult congenital heart disease) Royal Free Hospital (connective ti ssue disease) Great Ormond Street Hospital for Children (children) \200 \200 \200 Recent guidelines suggest referral to a specialist center after CXR, ECG, simple spirometry , and echocardiogram (but not cardiac catheterization, as this should be done in parallel w ith a vasodilator study in a specialist center). Recommendations on the management of pulmonary hypertension in clinical practice. Heart 200 1; 86: S1 This page intentionally left blank CHAPTER 38 Pulmonary hypertension 394 IPAH: disease-targeted therapy In IPAH there is impaired production of the vasodilators nit ric oxide and prostacyclin, and over-production of the vasoconstrictor endothelin by the pu lmonary endothelium. Imbalance of these factors also leads to vascular remodeling. Vasodila tor responsiveness is measured during right heart catheterization with incremental doses of a short-acting vasodilator, such as inhaled nitric oxide, or intravenous epoprostenol or a denosine. A posi- tive vasodilator response is de \201 ned as a drop in mean pulmonary art erial pressure by more than 10 mmHg to less than 40 mmHg with an unchanged or increased car diac output. Only about 5-10% of patients are responders. Vasoresponders should be consider ed for \201 rst-line therapy with calcium- channel blockers. Non-responders should receiv e prostacyclin analogs, endothelin receptor antagonists, and/or phosphodiesterase inhibitor s. Calcium-channel blockers (CCBs) \200 High-dose nifedipine (30 \200\223240 mg daily) and diltiazem (120 \200\223900 mg daily) are recommended in patients with a positive acute vasodilator response. They should then be fo llowed to determine if they are long- term CCB responders (about 2/3). This group has an ex cellent prog- nosis (>90% 10-year survival). CCBs should not be used in those with a negati ve vasodilator challenge, as they may increase mortality. Side-effects include hypotension and oedema, which may limit use Amlodipine has more selective vasodilating properties, and at doses of 2.5 \200\2235 mg daily may be useful in those intolerant of the other agents, o r if right ventricular function is impaired Calcium antagonists should be started in hospit al and titrated with careful monitoring Verapamil is not used, because of its negative inot ropic effects. \200 Prostacyclin analogs Prostacylin is a potent vasodilator. It inhibits platelet aggregation, and has antiproliferative and cytoprotective proper- ties. Side-effects include jaw pain, diarrhea, and arthralgias. \200 Epoprostenol This potent vasodilator acts via increasing intracellular cAMP. It is a prosta cyclin analog (PGI2). It is the only drug shown to improve survival in a randomized control led trial. It probably has its effects as a selective pulmonary vasodilator, and potentiall y through vascular remodeling and platelet adhesion. It also improves exercise capacity and haemodynamics. It is inactive within the circulation after 5 min and therefore needs to be given by continuous intravenous infu- sion via a portable pump and Hickman line. Pump fail ure can be life- threatening. Side-effects include jaw pain, diarrhea, headache, \202 ush ing, and nausea and are usually dose related Treprostinil is a prostacyclin analog that can be given as a continuous subcutaneous infusion, as it has greater in vivo stability than e popros- tenol. It improves symptoms, exercise capacity, and pulmonary haemo- dynamics. Pain at the infusion site is the major side-effect Beraprost is the \201 rst orally active pr ostaglandin analog, with a half-life of about 40 min. A qds dose has been shown to increase 6-min walk distance, without improvement in pulmonary haemodynamics, but initial improveme nts have not been maintained at 9 and 12 months, and it is not used in the UK IPAH: DISEASE-TARGETED THERAPY 395