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What is a PE?

PE, or pulmonary embolism, is an obstruction of part or whole of the pulmonary arterial tree by thrombus that has become detached from its site of formation - usually in the peripheral venous system and carried to the lung via the right heart.


What factors predispose to PE?

These are summarized in Virchow's triad:
1) Venous stasis (e.g. CCF)
2) Increased blood coagulability
3) Damage to vessel endothelium (e.g. peripheral vascular disease)

Conditions producing these include immobility, surgical or accidental trauma, heart disease, pregnancy, oral contraceptives, obesity and intravascular catheters.


What are the morphological features of venous thrombi?

These thrombi are formed in areas of less active blood flow most often in veins of the lower extremities (and in the periprostatic or other pelvic veins).

They are dark red with a higher concentration of RBCs than arterial thrombi. Lines of Zahn are not prominent or may be absent altogether.

They are often associated with concurrent venous inflammatory changes. Inflammation of veins from thrombus formation is referred to as thrombophlebitis.


How does the size of the thrombus affect where it lodges in the lung? What is a saddle embolus?

Large emboli impact in major pulmonary arteries or sit at the bifurcation of both the right and left main trunks - "saddle embolus".

Small emboli lodge in more peripheral segmental arteries.


What type of infarct do PE's cause?

Infarction is necrosis resulting from ischaemia caused by obstruction of blood flow. The necrotic tissue is referred to as an infarct.

Infarcts can either be anaemic of hemorrhagic.
Hemorrhagic infarcts are red infarcts, in which red cells ooze into the necrotic area. They occur characteristically in the lung and gastrointestinal tract as the result of arterial occlusion. These sites are loose, well vascularised tissues with redundant arterial blood supplies (in the lung from the pulmonary and bronchial systems; in the GIT from multiple anastomoses between branches of mesenteric artery) and a haemorrhage into the infarct occurs from the non-obstructed portion of the vasculature.


What diseases predispose to increased coagulation?

Thrombotic disorders are classified as either anti-thrombotic (haemorrhagic) leading to pathologic bleeding states such as haemophilia and vWD. They can also be prothrombotic leading to hypercoagulability with pathologic thrombus.

These can be summarised as:
1) Hereditary thrombophilias (factor V liden, protein C and S deficiency, prothrombin 20210A transition etc)
2) Antiphospholipid syndrome
3) DIC
4) Heparin induced thrombocytopaenia (HIT) syndrome


How is the heart affected by a PE?

The heart can undergo structural changes following a PE which leads to impaired function. Acute right ventricular dilatation can occur with massive obstruction of the pulmonary artery. This leads to acute RVF. Systemic shock is due to decreased pulmonary blood flow leading to decreased left ventricular filling and output. There is an additional effect of hypoxia on heart muscle function.

Right ventricular hypertrophy tends to occur in cases of recurrent pulmonary thromboembolism causing pulmonary hypertension.


What are the results of a PE?

These are highly dependent on the size of the embolus and the status of the cardiopulmonary system:

1) Silent: up to 80% of emboli are clinically silent because they are small and are often lysed by fibrinolysins. Infarction does NOT occur in these circumstances, and in the absence of significant myocardial disease (e.g. HF) because of adequate collateral bronchial circulation

2) Infarction

3) Recurrent emboli

4) Sudden death: massive embolism with obstruction of a large artery can result in death or acute right sided heart failure followed by death

5) Circulatory shock: with massive emboli

6) Chronic pulmonary hypertension: an uncommon but important cause which may be difficult to diagnose

7) Abscess: some infarcts become secondarily infected and form abscesses. Alternatively an embolus may be septic


What is the most common cause of pulmonary infarction?

Infarction is usually associated with an embolism but may rarely occur due to a primary vascular thrombosis associated with an abnormal circulation - e.g. in pulmonary hypertension


What is the macroscopic appearance of pulmonary infarction?

The lower lobes are involved in 75% of cases. The infarcts are pyramidal in shape and haemorrhagic with their base on the pleural surface, over which there is a fibrinous reaction.


What are the results of pulmonary infarction?

These vary with the size and multiplicity of the infarcts:
1) Pulmonary dysfunction: due to loss of lung tissue
2) Pulmonary vascular obstruction
3) Pleurisy and pleural effusion: often haemorrhagic
4) Healing: resulting in a fibrous scar
5) Septic infarction: primary septic embolism or secondary infection leading to abscess formation


What is a fat embolism?

This is an example of a non-thrombotic emobolism. Fat emboli tend to occur following fracture of long bones and are sometimes fatal. Clinically they present with cerebral signs (e.g. confusion, dysphasia), dyspnoea, and petechial rash. This is called the fat embolism syndrome.


What are the features of an amniotic fluid embolus?

This is an incredibly rare event but release of amniotic fluid into the circulation in labour can result in sudden cardiovascular collapse or ARDS. Foetal squamous cells are seen in the pulmonary vessels.


How does an air embolism occur?

Air can enter the circulation after trauma or surgery to the great veins or by faulty apparatus or techniques with intravascular therapy. If quantities of air are large enough, sudden cardiovascular collapse occurs due to functional obstruction to the pulmonary circulation and acute right heart failure.


What is Caisson disease?

This is decompression sickness. Rapid decompress releases bubbles of nitrogen as well as oxygen and carbon dioxide into the blood. Nitrogen bubbles cause problems in the CNS and bones particularly, and in pulmonary vessels can produce obstruction.


What are the clinical features of a PE?

The clinical features of pulmonary embolism depend on the size and severity of embolism. Broadly speaking important features in at risk patients to watch out for include: dyspnoea, pleuritic chest pain, haemoptysis, syncope, fever.

Signs: pyrexia, cyanosis, tachypnoea, tachycardia, hypotension, raised JVP, pleural rub, pleural effusion, calf swelling (look for cause).

If an acute minor PE is associated with infarction it tends to produce pleuritic chest pain, haemoptysis and fever.


How should suspected PE be investigated? What are the ECG features of PE?

Consider the diagnosis of PE in all patients with unexplained breathlessness, pleuritic pain, haemoptysis or sudden collapse.

Chest x ray, ECG and arterial blood gases are essential first line investigations:
- CXr: may be normal; can show dilated pulmonary artery small effusion, wedge shaped opacities or cavitation (rare)
- ECG: may be normal or show tacchycardia, RBBB, RV strain (inverted T in V1 to V4) or classic S1Q3T3 pattern
- ABG: hypoxia and hypocapnia (due to hyperventilation)

FBC, U&E and baseline clotting important


What is the role of the D-dimer in diagnosing PE?

D-dimer is useful in excluding a PE but not in confirming it - i.e. only perform in those patients WITHOUT a high probability of a PE. A negative D-dimer test effectively excludes a PE in those with low or intermediate clinical probability and imaging is NOT required. However a positive test does not prove a diagnosis of a PE and imaging is required.

(Wells score suggests that score of >3 carries a high probability of a PE)


What is the gold standard investigation for PE?

CTPA is the recommended first line imaging modality which can show a clot down to the 5th order pulmonary arteries.

V/Q scanning is now rarely performed except on young patients (e.g. females) because the dose of radiation may be too high.


What is the management of a PE?

1) Anticoagulate with LMWH
2) Start warfarin
3) Stop heparin* when INR is >2 and continue warfarin for a minimum of 3 months, aim for an INR of 2-3

Warfarin has a prothrombotic effect for the first 72 hours so heparin cover is required.

For a massive PE:
1) Thrombolysis with alteplase 10mg IV over 1 min then 90mg IV over 2h
2) Consider placement of a vena caval filter in patients who develop emboli despite adequate anticoagulation


What is the mechanism of action of Heparin?

Heparin is a mucopolysaccharide that binds to and activates a circulating natural anticoagulant protein called antithrombin. The heparin anti-thrombin complex inhibits the action of a number of activated clotting factors in the coagulation cascade (IXa, Xa, XIa and XIIa). It also binds directly to thrombin and inhibits its ability to convert fibrinogen to fibrin.


What are the 2 forms of heparin?

Heparin can be used as an unfractionated molecule or as low molecular mass molecules.

Unfractionated heparin has a very short half life, which depends on the dosage and route of administration. LMWHs have a much longer duration of action and half life because they do not bind to plasma proteins or to endothelial cells (like unfractionated forms do). LMHW is the drug of choice in pregnant women requiring anticoagulation.

Examples of low molecular weight heparin include ENOXPARIN (clexane) and TINZAPARIN


How should heparin be monitored?

For unfractionated heparin, the degree of anticoagulation is monitored by measuring the activated partial thromboplastin time (APPT) with the aim of therapy to keep the APPT between 1.5 and 2 times as normal.

As LMWH have much more predictable effects, provided that the correct dosage is given, routine monitoring is not required.


What are the contraindications for using heparin?

- bleeding disorders
- recent severe bleeding
- severe hypertension
- severe liver disease


What are the common side effects of heparin?

- haemorrhage
- osteoporosis - usually only after prolonged use
- heparin induced thrombocytopaenia
- hyperkalaemia
- urticaria and angiodema


What are the significant drug interactions to be aware about with heparin?

Reversal of heparin: 1mg protamine sulphate neutralises 80-100 units of heparin. Protamine is given by very slow IV injection (over a period of 10-15 mins). As a result of the short half life of heparin, the amount of protamine sulphate decreases with time after heparin has been given.


What type of heparin and how much is required for prophylaxis of DVTs?

ENOXAPARIN 20-40mg s.c.o.d. In preoperative patients, give first dose 2 hours before surgery.


How is a DVT treated?

ENOXAPARIN 1.5mg/kg s.c.o.d for 5 days minimum and until adequate oral anticoagulation is established.

Start warfarin therapy day on day 1 using dosage titration to achieve a stable INR of 2.0-3.0

For first DVT continue oral anticoagulation for 3 months.
For second DVT continue anticoagulation for 6 months.
For third or subsequent DVT, investigate for an underlying cause and give warfarin for life.


What dose of heparin is needed to treat a PE?

ENOXAPARIN 1.5mg/kg s.c.o.d until adequate oral anticoagulation achieved.

Start warfarin therapy on day 1 using dosage titration to achieve stable INR of 2.0-3.0

For first episode of PE continue treatment for minimum of 3 months .
For second episode or subsequent PE, investigate for an underlying cause and give warfarin for life.


What is pulmonary oedema?

This is a condition characterised by abnormal accumulation of extravascular fluid within the lung.


Outline the pathogenesis of pulmonary oedema?

The capillary wall is normally fairly permeable to water and small molecules, but not to proteins. Alveolar cells are much less permeable to all substances. Normally, due to the balance between the hydrostatic pressure forcing fluid out of the capillaries and colloid osmotic pressure preventing such loss, only a small amount of fluid passes into the interstitium.

This drains to the peribronchial/ perivascular space where it enters the lymphatic channels. If excess fluid passes out of the capillaries and the flow rate exceeds the lymphatic drainage capacity, accumulation within the peribronchial space and then the interstitium occurs. Fluid eventually passes into the alveolar spaces.


What is the aetiology of pulmonary oedema?

There are a number of causes of pulmonary oedema, most of which relate to alterations in Starlings forces regulating fluid movement across capillary membranes.:
1) Increased capillary hydrostatic pressure
2) Increased capillary permeability - e.g. ARDS
3) Decreased plasma oncotic pressure
4) Lymphatic obstruction
5) Decreased interstitial pressure - large mechanical forces acting on the interstitium, e.g. rapid expansion of the lung after evacuation of a large pleural effusion
6) Unknown or uncertain mechanisms - e.g. neurogenic pulmonary oedema following traumatic brain injury


How does increased capillary hydrostatic pressure cause pulmonary oedema?

This is the commonest cause of pulmonary oedema and occurs in a number of circumstances. Increased capillary hydrostatic pressure limits reabsorption at the venous end of capillaries leading to increased fluid extravasation.

1) Left sided heart failure: in MI, aortic valve disease, mitral regurgitation and tachyarrhythmias
2) Pulmonary venous hypertension: e.g. in mitral stenosis
3) Constrictive pericarditis or pericardial effusion
4) Fluid overload: e.g. excess infusion of crystalloid solutes


Give some causes of decreased plasma oncotic pressure?

Hypoproteinaemia due to:
- malnutrition
- Nephrotic syndrome
- IV infusion of hypotonic solutes
- Liver failure


What is the appearance of the lung in pulmonary oedema?

The lungs are heavy and congested. Fluid flows from the cut surfaces and is often sen in the large airways of fatal cases.

Microscopically there is filling of alveoli with proteinaceous fluid, widening of the interstitium and congestion of the capillaries.


What are the effects of pulmonary oedema?

Respiratory dysfunction which can lead to type 1 respiratory failure (hypoxic) caused by ventilation perfusion imbalance due to filling of alveoli with fluid and airway narrowing from peribronchial fluid accumulation.


What are the X ray findings in pulmonary oedema?

The X ray findings depend on whether the cause is cardiogenic or non cardiogenic.

In cardiogenic cases there can be:
- bilateral alveolar shadowing: oedema in the alveoli; if acute cardiogenic cause shadowing spreads out from the hilar in a "bats wing" appearance
- upper lobe diversion: lower zone hypoxia causes hypoxic pulmonary vasoconstriction diverting blood to the upper lobes
- Kerley B lines: horizontal lines that reach the pleural surface; caused by fluid between the interlobular septa
- cardiomegaly
- cardiac pathology signs: e.g. stenostomy wires, prosthetic valve, pacemaker

In non cardiogenic cases there can be:
- diffuse alveolar shadowing: present in both upper and lower lobes
- normal heart size (but this can also occur in cardiogenic cases as well!)


What is chronic passive venous congestion?

This is caused by chronic left sided heart disease - e.g. myocardial failure due to ischaemia, mitral stenosis or hypertensive heart disease.

The lung is firm, fibrous and brown, with congestion of alveolar vessels, fibrous thickening of the alveolar walls and pigmented macrophages - "heart failure cells" in the alveoli. There can also be atheroma in larger vessels.

The main effect is pulmonary hypertension.


What is pulmonary hypertension?

A pulmonary arterial pressure of > 25mmHg at rest.
Normally, pulmonary pressures are much lower than the systemic system.


What are the normal flow rates and pressures in the pulmonary circulation?

Normal pulmonary blood flow is 5-8L/min at rest. Normal pressures are 16-17mmHg, and with exercise the flow rate increases up to 16L/min but the pressure does not change significantly.

The pulmonary circulation transmits the total right ventricular output with minimum resistance through the lungs. The vessels are therefore compliant and thin walled. Elastic arteries extend as far as the end of the cartilagenous bronchi and the muscular arteries are short, ending at the level of the respiratory bronchioles.

The arterioles soon lose their muscle and consist mostly of intima, external elastic tissue and adventitia.


What mechanisms are responsible for pulmonary hypertension?

1) Precapillary: caused by increased flow or by increased resistance. Alveolar walls are normal

2) Capillary: due to destruction of alveoli or distortion of the alveolar capillary bed

3) Postcapillary: from passive congestion of alveolar parenchyma

There are several types of pulmonary hypertension that are currently grouped using the Dana Point (2008) classification.


What conditions comprise group 1 causes of pulmonary hypertension?

Group 1 PH, also termed pulmonary arterial hypertension (PAH) comprised heritable (hPAH) and idiopathic PAH (iPAH) and also PH associated with a number of other conditions (aPAH) such as connective tissue disease.

Both hPAH and iPAH are characterised by a decreased expression of bone morphogenic protein receptor type 2 (BMPR2) which, usually in hPAH and sometimes in iPAH is associated with mutations in the BMPR2 gene.


What conditions are included in groups 2-5 in the Dana point classification?

Groups 2-5 are forms of secondary PH:
- Group 2 are caused by left heart disease, chiefly ventricular failure or mitral and/or aortic valve disease which results in increased left atrial pressure that backs up across the pulmonary artery (post capillary)

- Group 3 PH is associated with lung diseases such as COPD, obstructive sleep apnoea and cystic fibrosis. The common factor being the presence of alveolar hypoxia

- Group 4 PH is associated with chronic thromboembolic disease with a persistent blockage of pulmonary arteries arising from venous thromboembolism

- Group 5 represents PH associated with a heterogeneous set of conditions such as CML, sarcoidosis and thyroid disease


What is pulmonary eosinophilia?

This is a group of rare diseases, mainly of unknown aetiology, which cause chest X ray abnormalities associated with raised eosinophil count in peripheral blood.

Diseases included in this category include:
(i) acute eosinophilic pnuemonia
(ii) chronic eosinophilic pneumonia
(iii) hypereosinophilic syndrome
(iv) Churg-Strauss syndrome

Other diseases that cause pulmonary disease in association with eosinophilia are: asthma, fungal diseases (including allergic bronchopulmonary aspergillosis, parasitic infection (e.g. filariasis), drug reactions, polyarteritis nodosa and Hodgkins disease.


What is Loffler's syndrome?

This is eosinophilia + transient chest X ray infiltrates lasting 4-6 weeks. It is often related to drugs and parasitic worms.


Who is affected by acute and chronic pulmonary eosinphillia?

Acute and chronic eosinophilic pneumonia are more common in women, peak incidence is 40-50 years. Fifty percent of patients have asthma. Eosinophilic pneumonia responds well to treatment and recurrence is uncommon.

Chronic disease responds less well to treatment and recurrence may require long term steroid treatment.

They are both characterised by fever, dry cough, dyspnoea, chest pain and weight loss.


What is hypereosinophillic syndrome?

This is very rare , is usually of unknown cause (although it occurs more often in the tropics where it may relate to parasitic infection). It often responds poorly to treatment. Complicating cardiac failure can occur and carries a poor prognosis.

Clinical features include cough, malaise, and cardiac failure (due to myocardial infiltration).


What is Churg-Strauss syndrome?

This is a rare form of pulmonary vasculitis affecting small and medium sized vessels. It occurs in patients with asthma. Antineutrophil cytoplasmic antibodies (ANCA) is commonly positive. Untreated vasculitis has a poor prognosis (renal involvement). Vasculitis often responds well to treatment and relapse is unusual. IgE is also raised.


What vasculitides affecting the lungs are not associated with eosinophilia?

1) Rheumatoid arthritis: pleural disease (thickening, effusion). Localised nodules or more diffuse fibrosing alveolitis can occur
2) SLE: pleural inflammation ("pleurisy") is very common. Fibrosing alveolitis occurs but is rare
3) Wegener's granulomatosis


What is Wegener's granulomatosis?

WG is a multisystem vasculitis involving small and medium sized vessels associated with ANCA.
The aetiology of WG is unknown but may involve an infectious agent. >90% of patients with WG first seek attention due to symptoms arising from the upper and lower respiratory tracts.


What upper airway symptoms are common in WG?

Nasal/ sinus disease leads to congestion and nose bleeds. Nasal septum perforation leading to saddle nose occurs in up to 30% of cases.

Subglottic stenosis occurs in 20% and causes breathlessness (which may be severe), voice change and cough. The diagnosis of subglottic stenosis is suggested by flow-volume loops; this responds very poorly to systemic therapy but may respond to mechanical dilation and local injection of corticosteroids.


What lower airway symptoms are encountered in WG?

- Parenchymal disease: two thirds of those with parenchymal involvement have symptoms, one third only have asymptomatic CXR abnormalities
- Variable changes: bilateral nodular infiltrates, cavitatary disease and pulmonary haemorrhage
- 15% have stenosis of endobronchial airways leading to cough, wheezing, breathlessness and haemoptysis


What renal disease occurs in WG?

Glomerulonephritis occurs in WG. It may progress rapidly to renal failure with no or few symptoms. Renal failure is common (affecting up to 40-50%) and end stage renal failure requiring dialysis occurs in some 10%. It is detected by dipstick urine testing (red cells, casts, increased creatinine).


How is Wegener's diagnosed?

The diagnosis is made from a biopsy showing a necrotizing vasculitis with granuloma formation in a clinically relevant setting. Antibodies against neutrophil cytoplasm are found, in two staining patterns:
- Cytoplasmic ANCA (cANCA): the antigen is proteinase-3. cANCA is found in 70-90% of WG. Though cANCA has a high specificity and sensitivity for WG, it should not be relied on in isolation.
- Perinuclear ANCA (pANCA): the antigen is usually myeloperoxidase. Found in 5-10% of WG but also in many other conditions.


What is the treatment of WG?

Untreated WG has a VERY HIGH mortality. Treatment with cyclophosphamide and prednisolone dramatically reduces morbidity and mortality: 75% achieve complete disease remission.

Drug related side effects (sepsis from immunosuppression, late malignancy) are common. Pneumocystis infection is so common that septrin prophylaxis is justified.


What is Goodpasture's syndrome?

This results from immune attack by an antibody against lung and renal glomerular basement membrane. Pulmonary haemorrhage (causing anaemia, haemoptysis and respiratory failure) occurs usually some days to months before renal failure. Anti-GBM antibodies are found, and less frequently a positive ANCA.Treatment is with immunosuppression and plasma exchange.


What is idiopathic pulmonary haemosiderosis?

This is a similar disease to Goodpastures (though renal involvement is uncommon) occurring in young children (>7 years).

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