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 Iloprost is a prostacyclin analog and is more potent than epopros- tenol. It has a half-lif e of 25 min and can be given by continuous intrave- nous infusion or nebulizer (6 \200\2239 times a day) Even though patients may be vasodilator non-responders, they may bene \201 t from long-term treatment with disease-targeted therapy Prostaglandin treatment doubles the time on the lung transplantation waiting list, and improves transplantation outcomes. Impr oved haemo- dynamics may lead to some patients coming off transplant waiting lists Failure to show improved exercise capacity following one month \200\231s treatment with prostagland in therapy is often considered an indication for lung transplantation Tolerance develops to intravenous prostaglandin therapy, with increasing dose requirements over time. The mechan ism for this is unclear. Endothelin receptor antagonists Endothelin is a powerful vasocon- strictor and pro-in \202 ammatory mediator, and causes smooth muscle cell pro- liferation. Plasma levels raised in some forms of pulmonary hypertension. \200 Bosentan is an oral endothelin receptor A and B antagonist that has been shown to improve exercise capacity, haemodynamics, and time to c linical worsening. It is the \201 rst oral therapy approved for the treatment of IPAH and PAH related to connective tissue disease. Side-effects include liver enzyme abnormalities. Three-year survival for a cohort of mainly WHO functional class III patients starting on b osentan is greater than 85%. The major side-effect is reversible liver transaminitis, causi ng discontinuation in approximately 3% Sitaxentan is a selective endothelin type A receptor antagonist. The type B receptor on the endothelium clears endothelin from the circulation, but also contributes to vasoconstriction on the smooth muscle cell. There is no clear evid ence for superiority over the dual blockade of bosentan, although liver side-effects may be lower Ambisentan is another selective type A blocker, with a different struc- ture from si taxentan and bosentan, giving it a better liver safety pro \201 le. It has not yet receive d a UK license. Phosphodiesterase inhibitors e.g. sildena \201 l augment the vasodila- tory effects of nit ric oxide and improve exercise capacity and haemody- namics in IPAH in patients in function al classes II and III. Current practice Start patients with a negative vasodilator response on one of the above three classes of drug. Unwell patients in NYHA func- tional class IV w ill usually start on an infusion of epoprostenol, but if unable to cope with the practicali ties of a continuous infusion, will be considered for other treatment modalities. Functiona l class III patients usually start on an endothelin-receptor antagonist, given the long-ter m data available for these agents. Functional class II patients may be considered for silde - na \201 l or endothelin receptor antagonists. As in many other diseases, such as asthma or systemic hypertension, when patients are failing on mono- therapy, other therapies may b e added. Data for various combinations are available from case series and some randomized s tudies, but larger studies are needed to show unequivocal bene \201 t. CHAPTER 38 Pulmonary hypertension 396 IPAH: surgical treatments, end of life care, and future developments Surgical treatments At rial septostomy Creation of a right \200\223left shunt by balloon atrial septo- stomy aims to increase systemic blood \202 ow by bypassing the pulmonary circulation, particularly i n patients with syncope or severe right heart failure. It is a palliative procedure and can be used for symptom control prior to transplantation, with the defect being closed at the time of trans- plant. Arterial desaturation occurs following the procedure, but is normally offset by the increased cardiac output seen with increased oxygen delivery. It is not indi cated in severe left heart failure or in patients with impaired left ventricular function. Transplantation Improves survival and quality of life in patients with pul- monary hyperten sion. In those with preserved left ventricular function, lung transplant is the procedure o f choice. Return of normal right ventricular function is found after transplantation. \200 As for all diseases needing transplantation, timing of referral and operation is crucial, a s organ availability is limited The incidence of obliterative bronchiolitis appears to be h igher post-transplantation for IPAH than in transplantation for other diseases, although th e reason for this is uncertain. End of life care Palliative care may be warranted to improve symptoms such as fatigue, brea thlessness, abdominal bloating, nausea, and pain (see p 713). Future developments Combinati on therapies are likely to be used more frequently in the future. A number of agents are cu rrently being investigated, including vasoactive intestinal peptide (VIP) and drugs with an ti-proliferative effects such as simvastatin, imatinib, and rapamycin. This page intentionally left blank CHAPTER 38 Pulmonary hypertension 398 Non-idiopathic pulmonary hypertension: causes The majority of patients with pulmonary hyper tension seen by a respira- tory specialist will have PHT due to chronic hypoxic lung diseas e, such as COPD. In this case, the pulmonary hypertension is often an incidental \201 ndi ng in a patient with a chronic respiratory disease. Chronic hypoxia causes pulmonary vasoco nstriction and in the longer term vascular remodeling. \200 A signi \201 cant proportion of COPD patients will develop PHT, possibly up to 25%. The le vel of PAP in these patients is much lower than that seen in patients with IPAH COPD with p ulmonary hypertension has a much poorer prognosis than COPD without pulmonary hypertension. In patients with a PAP <25 mmHg, the 5-year survival is >90%. In those with a PAP >45 mmHg , the 5-year survival is <10%. Whether this is due to the pulmo- nary hypertension itself, or whether the pulmonary hypertension is a marker of worse hypoxia and disease severity is unclear PHT in COPD was thought to be due to hypoxia and emphysematous destruction of the v ascular bed, but neither of these factors correlates well with PAP. Cigarette smoke may hav e a direct effect on the intrapul- monary vessels, with the up-regulation of mediators lead ing to aberrant vascular structural remodeling and physiological changes in vascular functi on Alveolar hypoventilation, e.g. due to neuromuscular disease. Both alveolar hypoxia and hype rcapnia produce pulmonary vasoconstriction, thereby increasing pulmonary artery pressures. Chronic thromboembolic pulmonary hypertension (CTEPH) is a frequent cause of pulmonary hype rtension. Recent data suggest that CTEPH occurs in up to 4% of cases of acute non-fatal pul monary embo- lism, higher than previously thought. Pathogenesis is uncertain, with no consi stent defect in \201 brinolytic activity demonstrated. Natural history of pulmonary throm boemboli is resolution or near total resolution of clot, with restoration of normal pulmona ry haemodynamics within 30 days in 90% of patients. Right-sided pressures return to normal in most patients by 2 weeks. In CTEPH, thromboemboli do not resolve, forming endothelialize d \201 brotic obstructions of the pulmonary vascular bed. In situ thrombosis and vascular remodeling of small distal pulmonary arteries also contribute. Peripheral IPAH-like vascul opathic changes are also seen, which has led some to suggest that IPAH and CTEPH are a cont inuum of disease; in situ thrombosis in IPAH can be extensive, and it is possible that in s itu, rather than embolic, thrombus may be more important in CTEPH. Neovascularization from bronchial and intercostal arteries develops through residual adhesions between the chest wa ll and visceral pleura. The clinical deterioration parallels the loss of right ventricular functional capacity. Risk factors for CTEPH include increasing age, idiopathic PE, and a la rger perfusion defect. Splenectomy is associated, possibly by inducing a pro-thrombotic sta te due to loss of \201 ltering function of the spleen. Antiphospholipid antibodies are pr esent in 10 \200\22320% of patients. The NON-IDIOPATHIC PULMONARY HYPERTENSION: CAUSES 399 diagnosis is not usually made until advanced pulmonary hypertension is present. Progressive pulmonary hypertension seems to result from changes in the small peripheral resistance ves sels in the vascular bed, as opposed to being due to progressive pulmonary events. Secondar y hyper- tensive changes, probably induced by high pulmonary artery pressures, lead to incr emental increases in right ventricular afterload, with increasing pulmonary hypertension, u ltimately leading to right ventricular failure. Collagen vascular disease PAH develops in a bout 15% of patients with scleroderma, and is most frequently seen as an isolated phenomeno n in patients with limited cutaneous disease. Also occurs secondary to inter- stitial lung disease with a very poor prognosis. Life expectancy is <1 year in patients with collagen va scular disease, isolated pulmonary hyperten- sion, and a gas transfer of <25% of normal. Ob literation of the alveolar capillaries and arteriolar narrowing is induced by both the prim ary vas- cular disease and any interstitial \201 brosis. Other connective tissue diseases , including rheumatoid arthritis and SLE, can also lead to secondary pulmo- nary hypertensi on. There is an association with Raynaud \200\231s phenomenon and a female predominance is seen. Drugs and toxins Damage to the pulmonary artery endothelium can be caused by drugs, e .g. anorectic agents such as fen \202 uramine, dexfen- \202 uramine, cocaine, and amphet amines. The clinical syndrome can be indistinguishable from IPAH. A careful history must th erefore be taken. The absolute risk for pulmonary hypertension with anorectic agents is 28 cases per million person-years of exposure. Pulmonary hypertension can develop within weeks of starting the drug. Pulmonary arteritis PHT secondary to Beh et \200\231s or Takayashu \200\231s arteritis is associated with systemic arteritis in the supra-aortic trunk. Typica l lesions are seen at pulmonary angiography, with in situ thrombosis and false aneurysms. H IV infection Pulmonary hypertension is seen in up to 1 in 200 people who are HIV positive, in the absence of AIDS. It is hypothesized that HIV- infected macrophages release vasoactiv e cytokines that lead to endothelial damage and proliferation. Antiretroviral drugs may hav e a bene \201 cial effect on pulmonary haemodynamics. Congenital heart disease and shunts Pressure overload caused by systemic to pulmonary shunts, e.g. ventricular septal defect an d patent ductus arteriosus, lead to PAH. The role of atrial septal defects in the developme nt of PAH is uncertain, with some suggesting they may be bystanders in IPAH. Portal hyperte nsion Porto-pulmonary hypertension, seen in patients with portal hypertension (of whatever cause), is probably due to the failure of the liver to remove vasoactive substances from th e portal circula- tion, with their resultant accumulation and presentation to the pulmonary arterial endothelium. Hyperthyroidism is also recognized as a cause. CHAPTER 38 Pulmonary hypertension 400 Non-idiopathic pulmonary hypertension: management In this group of patients the diagnosis i s usually made from echocardiog- raphy, and the treatment is optimal management of the unde rlying lung disease, with the addition of oxygen and diuretics. Recent guidelines on the ma nagement of pulmonary hypertension suggest that the management protocol for patients with i diopathic pulmonary arterial hypertension (see p 392) may also be suitable for patients wit h secondary hypertension, but there is no evidence for most of these treatments in this con text. In par- ticular, evidence for treating pulmonary hypertension in hypoxic COPD, other than with long-term oxygen therapy, does not exist. Current studies will establish if agent s such as bosentan or sildena \201 l are of bene \201 t in patients with secondary causes of pulmonary hypertension. Disease-speci \201 c management \200 Chronic thromboembolic pulmonary hypertension Patients with chronic thromboembolic pulmonar y hypertension have a 5-year survival of <10%, if the PAP >50 mmHg. Pulmonary thromboendart erectomy is the treatment of choice for proximal obstructive disease. This is the surgical removal of organized thrombotic material, and aims to strip away the pulmonary arterial end othelium, starting proximally and extending out to remove all clot in the subsegmental leve ls. It is done on cardiopulmonary bypass with circulatory arrest. The PAP usually falls wit hin 48 h of surgery. Operative mortality is <10% in experienced hands Scleroderma Very few patients with scleroderma-associated PAH have a positive vasodilator response and the signi \201 cance of it, when present, is uncertain. These patients are treated similar to vasod ilator non- responder IPAH algorithms. Patients with systemic sclerosis should be screened annually for pulmonary hypertension, even if no symptoms are present Pulmonary hypertension associated with left heart disease should not be treated with pulmonary vasodilators as th ese will increase \202 ow to an already overloaded left heart. Treatment should be aimed at the left-sided cardiac abnormality. Further information Recommendations on the management of pulmonary hypertension in clinical practice. Heart 2001; 86 (S1): i1 \200\223i13 Peacock A. Primary pulmonary hypertension. Thorax 1999; 54: 1107 Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical p ractice guidelines. Chest 2004; 126: suppl. Pulmonary arterial hypertension. N Engl J Med 2004; 351: 1655 \200\22365 Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351: 1425 \200\22336 Patient group, www.pha-uk.com 401 Chapter 39 Pulmonary thromboembolic disease Epidemiology and pathophysiology 402 Etiology 404 Clinical features 406 Diagnosis of acute PE 408 Investigations 410 Special circumstances 414 Rare causes 416 CHAPTER 39 Pulmonary thromboembolic disease 402 Epidemiology and pathophysiology De \201 nition A pulmonary embolism (PE) is a clinically signi \201 cant obstruction of part or all of the pulmonary vascular tree, usually caused by thrombus from a distant site. Epidemiology \200 The overall annual incidence is 60 \200\22370/100 000, with a UK annual death rate of 100/m illion. The estimated overall population incidence of DVT is 0.5 per 1000 person years PE m ay account for up to 15% of all post-operative deaths. It is the commonest cause of death f ollowing elective surgery, and the commonest cause of maternal death Post mortem studies ha ve consistently shown a frequency of 7 \200\2239%, and large in-patient studies have shown a frequency of around 1%, with a mortality of 0.2%. The mortality is much higher in patient s with serious underlying comorbid disease The incidence is likely to be stable, but improv ed diagnostic methods mean that it is probably reported more frequently. Pathophysiology \200 75% of thrombi are generated in the deep venous system of the lower limbs and pelvis, proba bly initiated by platelet aggregation around venous valve sinuses. Activation of the clotti ng cascade leads to thrombus formation, with Virchow \200\231s triad (venous stasis, injury to the vessel wall, and increased blood coaguability) predisposing to thrombus formation. Venous stasis is increased by immobility and dehydration, and leads to local accumulation o f platelets and clotting factors. In addition, coagulation factors may be altered in variou s disease states, e.g. in the acute phase response, malignancy, and autoimmune disease 20% of leg thrombi embolize, with a higher incidence in above than below knee clots. Large clot s may lodge at the bifurcation of the main pulmonary arteries, causing haemodynamic comprom ise. Smaller clots will travel more distally, infarcting the lung and causing pleuritic pai n. These are more commonly multiple and bilateral, and are found most often in the lower lo bes, where blood \202 ow is greatest Thrombi can also develop in the right heart followin g myocardial infarction Septic emboli are found in endocarditis, in association with intrav en- tricular septal defects (paradoxical emboli), AV shunts, or central venous access. Haemodynamic effects of PE depend on the size of the clot and which area of the pulmonary v ascular tree it subsequently obstructs, as well as the pre-existing state of the myocardium and pulmonary parenchyma. \200 As the pulmonary vasculature in a healthy lung has a large capacitance, the mean pulmonary artery pressure (PAP) does not rise until at least 50% of the vascular bed has been occlude d As the PAP rises, right ventricular afterload increases, with a resulting increase in rig ht ventricular end-diastolic pressure. EPIDEMIOLOGY AND PATHOPHYSIOLOGY 403 The right ventricle will start to fail acutely as the PAP reaches over 40 mmHg This causes a reduction in pulmonary blood \202 ow, leading to reduced left ventricular \201 lling and a reduction in systemic blood pressure Adequate blood volume for right-sided heart \201 lling is vital. The secondary effects are much worse if right-sided \201 lling canno t be maintained, e.g. if the patient is dehydrated, hypovolaemic, or erect Hypoxia results from reduced cardiac output, low mixed venous PaO2 and higher perfusion to the remaining al veoli, leading to ventilation/per- fusion mismatching in the unaffected lung Hypoxia will b e worse if there is a larger premorbid V/Q spread, e.g. in the elderly and in those with pr e-existing lung disease. It is therefore possible for a young healthy person to have a norm al PaO2 and A \200\223a gradient following a PE A patient with a PAP of \211 40 mmHg canno t have acute PE as this pressure cannot be achieved acutely. In this setting, the raised PA P raises the possibility of chronic thromboembolic disease, pulmonary hypertension, or anot her cause. CHAPTER 39 Pulmonary thromboembolic disease 404 Etiology Risk factors can be divided into major and minor factors. This division is importa nt for an assessment of clinical probability. Risk factors for venous thromboembolism (VTE) Major risk factors (relative risk x 5 \200\22320) Surgery Major abdominal/pelvic surgery Orthopedic surgery (especially lower limb) Post-operative intensive care Obstetrics Late pregnancy (higher incidence with multiple births) Cesarean section Pre-eclampsia Malignancy Pelvic/abdominal Metastatic/advanced Lower limb problems Fracture, varicose veins Reduced mobility Hospitalization Institutional care Previous proven VTE Minor risk factors (relative risk x 2 \200\2234) Cardiovascular Congenital heart disease Congestive cardiac failure Hypertension Central venous access Super \201 cial venous thrombosis Oestrogens Oral contraceptive pill (especially third-generation higher estrogen containing) Hormone replacement therapy Miscellaneous Occult malignancy Neurological disability Thrombotic disorders Obesity In \202 ammatory bowel disease Nephrotic syndrome Dialysis Myeloproliferative disorders Beh et \200\231s disease etiology 405 Risk of malignancy Occult cancer will be present in 7 \200\22312% of patients presenting wi th idiopathic venous thromboembolism (VTE). Malignancy may be detected by careful clinical assessment, routine blood tests, and chest radiography. Screening for malignancy in these p atients is not rec- ommended, unless suspected clinically. These patients are more likely t o have a poor prognosis, because of regional spread or distant metastases at diagnosis. Inherited thrombophilias \200 25 \200\22350% of patients with VTE have an identi \201 able inherited throm- bophilia, e. g. antiphospholipid syndrome, de \201 ciency of antithrombin III, a prothrombin gene defec t, protein C or protein S de \201 ciency These usually need to interact with an additional acquired risk factor to cause VTE Factor V Leiden de \201 ciency is present in 5% of the population and 20% of patients presenting with thrombosis Current recommendations do not ad vocate routine screening for inheritable thrombophilias, unless in speci \201 c circumstan ces (see below), as the number needed to test to prevent an episode of VTE would be very hi gh. In addition, detecting a heritable thrombophilia does not predict a signi \201 cantly higher rate or earlier occurrence of VTE in the absence of a secondary risk factor Thrombophilia testing is recommended in: \200 \200 \200 Patients with recurrent venous thrombosis Patients <40 with venous thrombosis with no obvio us risk factors First venous thromboembolism with a clear family history in \201 rst- deg ree relatives Thrombosis secondary to pregnancy, oral contraceptive pill, hormone replaceme nt therapy Thrombosis at an unusual site \200\224cerebral, mesenteric, portal, or hepatic v eins All but factor V Leiden de \201 ciency and the prothrombin gene mutation need to be tested for when the patient is off anticoagulants. \200\230Economy class syndrome \200\231 refer s to thromboembolic disease associa- tion with long distance sedentary travel, with an incr easing incidence of disease with increasing distance traveled. A 2001 study of 135.29 milli on passengers showed an incidence of PE of 1.5 cases/million for travel over 5000 km, compa red with 0.01 cases/million for travel under 5000 km. For travel over 10 000 km, the incide nce increased to 4.8 cases/million. CHAPTER 39 Pulmonary thromboembolic disease 406 Clinical features Acute PE typically presents in four main ways. \200 Pulmonary infarction and haemoptysis (in 60%) pleuritic pain. Arterial blood gasses may be normal, and ECG changes uncommon. Localizing signs may be present, e.g. pleural rub Isol ated dyspnoea (in 25%) De \201 ned as acute breathlessness in the absence of hemorrhage or circulatory collapse. The thrombus is more likely to be central, with hypoxia on blood gas ses. The patient may have sudden onset and unexplained breathlessness, in the presence of r isk factors for VTE Collapse, poor reserve (in 10%) May be due to a small PE, often in an e lderly patient with limited cardiorespiratory reserve. These patients can rapidly decompens ate with even a relatively small PE. The clinical \201 ndings may be non-speci \201 c an d re \202 ect the underlying disease process, rather than the PE itself Circulatory collap se in a previously well patient Hypotension loss of consciousness in 1%. Usually due to extensive pulmonary artery occlusion from massive PE causing marked hypoxia and hypocapnia (due to hyperventilation) and acute right heart failure, with chest pain due to right heart angina, raised JVP, and fainting on sitting up. ECG may be normal, show sinus tachycardia or right heart strain. Echocardiogram shows pulmonary hypertension and right ventricular fa ilure. These patients have the highest mortality, up to 30%. Chronic thromboembolic disease This typically presents with more insidious onset breathless ness over the course of weeks \200\223months due to increasing load of recurrent small volu me clot. See p 398. Dyspnoea and tachypnoea (a respiratory rate >20) are the commonest presenting features and are absent in only 10% of patients. Consider PE in the differential diagnosis of: \200 \200 \200 \200 \200 Unexplained shortness of breath Collapse New onset atrial \201 brillation Signs consisten t with right heart failure Pleural effusion CLINICAL FEATURES 407 Examination of a patient with PE \200 \200 \200 \200 \200 \200 May be normal Tachycardia and tachypnoea are common Atrial \201 brillation Reduced chest movement (due to pain) Pleural rub Classically loud P2 and splitting of the second heart so und, with a gallop rhythm (acute right heart strain) Hypoxia (with hypocapnia due to hyperv entilation, and an increased alveolar \200\223arterial gradient), but PaO2 may be in the no rmal range in young healthy individuals Low-grade fever Signs of DVT (common, in around 25% ) Right heart failure \200\224low cardiac output and raised JVP with reduced BP and perfusi on pressure \200 \200 CHAPTER 39 Pulmonary thromboembolic disease 408 Diagnosis of acute PE The diagnosis of a pulmonary embolism can be dif \201 cult and invol ves a clinical assessment of probability. This takes risk factors, clinical presenta- tion, and clinical signs into account. Investigations are then performed, that may add weight to the clinical decision, rather than being stand-alone diag- nostic tests. Therefore the est imation of the pre-test clinical probability of PE is of vital importance in interpreting t he results of the tests performed. Pre-test clinical probability scoring systems One exampl e is the BTS pre-test clinical probability scoring system, shown in the box below. A standard assessment of pre-test clinical probability might include: \200 (a) Patient has clinical features compatible with PE: \200 \200 \200 Plus 2 other fac tors: \200 \200 (a) plus 1 and 2: HIGH pre-test clinical probability (a) plus 1 or 2: I NTERMEDIATE pre-test clinical probability (a) alone: LOW pre-test clinical probability raised respiratory rate haemoptysis pleuritic chest pain 1. Absence of another reasonable clinical explanation 2. Presence of a major risk factor (s ee box, p 426) \200 \200 The Wells and Geneva pre-test probability scores are similar to the above, but include sepa rate scores for clinical features such as heart rate, haemoptysis, and blood gas estimates (Geneva). Local scoring systems may be in place. These scoring systems should always be use d with the D-dimer result. D-dimer has an important role in diagnosing and excluding PE, an d should only be used with a pre-test clinical probability assessment following careful cli nical evaluation by an experienced clinician. D-dimers are sensi- tive for thromboembolism, but not speci \201 c. They are rarely in the normal range in cases of acute thromboemboli sm, but are not a valid screening test for PE alone. D-dimers are generated as a result of \201 brinolysis, which occurs in many clinical situations, including sepsis, post surgery , pneumonia, neoplasia, in \202 ammatory disease, pregnancy, and advanced age. \200 Only a normal result (which excludes PE) is of clinical value \200 An abnormal result (howeve r high) does not necessarily imply a signi \201 cantly increased probability of PE The sen sitivity ranges from 87% to 99%, depending on the assay used (ELISA (Vidas) or red cell agg lutination (SimpliRED)). Speci \201 city is poorer, around 60 \200\22370% (so a large numb er of false positives) The different assays have different performance characteristics and these should be known before incorporating them into diagnostic algorithms DIAGNOSIS OF ACUTE PE 409 D-dimer testing for excluding PE has been validated as an out-patient test, but not in in-p atient groups A low or intermediate pre-test clinical probability score, combined with a ne gative D-dimer has a 92% sensitivity at excluding PE Modi \201 ed Geneva score Age >65 years 1 point Previous DVT or PE 3 points Surgery or fracture within 1 month 2 points Active malignancy 2 points Unilateral lower limb pain 3 points Haemoptysis 2 points Heart rate 75 \200\22394 bpm 3 points Heart rate >95 bpm 5 points Pain on limb palpation & unilateral oedema 4 points Low probability 0 \200\2233 points Intermediate probability 4 \200\22310 points High probability \211 11 points D-dimer test interpretation \200 A negative D-dimer test reliably excludes PE in patients with a low (SimpliRED) or intermed iate pre-test clinical probability (Vidas). These patients do not need further imaging A ne gative test is unhelpful in those with a high clinical probability and therefore should not be done in this situation A positive result needs further investigation, but does not nece ssarily imply PE The D-dimer becomes less useful the longer the period spent in hospital (i .e. increasing false positives), due to clot formation at vene- puncture sites, venous stas is due to bed rest, etc. Assessment and documentation of pre-test clinical probability in PE is paramount. This enab les accurate clinical assessment, and may obviate the need for imaging. An alternative explanation should be sought when PE is excluded. CHAPTER 39 Pulmonary thromboembolic disease 410 Investigations \200 ECG Non-speci \201 c changes are frequent. Most commonly sinus tachycardia. Atrial \201 brillation, right bundle branch block, anterior T-wave inversion (indicating R ventricular strain) are common. The S1Q3T3 pattern is uncommon CXR A good quality departmental CXR is r equired. No speci \201 c fea- tures are characteristic in PE, but it may reveal another pa thology. Small effusions are present in 40% (80% are exudates, 20% transudates). Focal in \201 ltrates, segmental collapse, and a raised hemi-diaphragm can also occur Arterial blood gas may be normal, especially in the young and healthy. Hypoxia and hypocapnia, due to hyp erventilation, with an increased A \200\223a gradient are more common D-dimer (see p 408) T roponin and natriuretic peptides are sensitive markers of right ven- tricular dysfunction a nd early data suggest a raised troponin predicts poorer prognosis CTPA is the gold standard investigation, and is now recommended as the initial imaging technique in suspected non-ma ssive PE. It has a sensitivity of >95%, and may enable an alternative diagnosis to be made if PE is excluded. Advances in imaging mean that a 16-slice multi-detector row scanner can image the entire chest with resolution approaching 1 mm, requiring a breath-hold of less th an 10 s. Emboli can be detected in sixth-order pulmonary vessels, which are so small that t heir clinical relevance is uncertain. CTPA should be performed within 1 h in suspected mass ive PE, and within 24 h of suspected non-massive PE. The sensitivity and speci \201 city o f CTPA depends on the location of the emboli, with lower sensitivity for clot con \201 ned to the segmental or sub-segmental pulmonary vessels compared with more central clot. CTPA needs specialist reporting. \200 In those with a high clinical probability but negative CTPA the options are: \200 PE has been excluded, stop anticoagulation, or Perform further imaging (leg ultrasound, con ventional pulmonary angiogram, venous phase CT to include the legs) In one large prospective multicentre study, with all patients investigated with CTPA and le g ultrasound, those with negative tests and low or intermediate clinical probability were n ot anticoagulated. Only 0.2% had a de \201 nite PE after 3 months of follow-up. Those with negative tests but high clinical probability were investigated further, and PE was identi \201 ed in 5% (Musset D et al. Lancet 2002; 360: 1914). A volume of 100 \200\223150 ml contrast media is required for CTPA, which poses a substanti al risk of nephropathy (in patients with renal insuf \201 ciency and diabetes) and sometim es \202 uid overload (patients with impaired left ventricular function). In these patient s, leg ultrasound and/or isotope lung scanning might be safer \201 rst line investigation s. INVESTIGATIONS 411