Pulmonary Hypertension and Thromboembolism

Question 1

Define Pulmonary Hypertension

Answer 1

Pulmonary arterial systolic pressure > 30 mm Hg (tricuspid)

+/-

Pulmonary arterial diastolic pressure > 19 mmHg (pulmonic)

Normal Mean pulmonary arterial pressure is 14 mmHg

Question 2

Describe the pulmonary vasculature and determinants of pulmonary arterial pressure

Answer 2

• Blood flows from the right ventricle through network of thin walled arteries, capilliaries and veins to return to the left atrium
• Pulmonary resistance is ~ 1/6 that of the systemic circulation
• The right venticle requires ~ 1/5 the energy of the left venticle to move blood through the pulmonary circulation

Pulmonary Arterial Pressure is determined by

• RV cardiac output
• Pulmonary vascular resistance
• Pulmonary venous pressure

Pulmonary hypertension develops when there is imbalance in factors that control pulmonary vascular resistance, vasodilatation, platelet activation and smooth muscle cell proliferation

Question 3

List the three major inducers of pulmonary vasoconstriction

Answer 3

1. Hypoxia
2. Endothelin-1
3. Serotonin / thromboxane

Question 4

Describe the mechanisms by which pulmonary vasoconstriction occurs and the physiological benefits

Answer 4

1. Hypoxia induced vasoconstriction
   
   • Physiological response to shunt deoxygenated blood to better ventilated regions of lung
   • Acutely beneficial
   • Chronic hypoxaemia can lead to pulmonary hypertension
2. Endothelin-1 is released from the vascular endothelium in response to changes in blood flow, vascular stretch and thrombin concentrations
   
   • Vasoconstriction
   • Smooth muscles growth
   • Increased collagen synthesis
   • Promotes vascular remodelling
3. Thromboxane A
   
   • Produced in the endothelial cells and platelets
   • Conteracts prostacyclin, a potent vasodilator.
   • Is a potent vasoconstrictor
   • Activates platelets - causing release of serotonin, platelet derived growth factor and other peptides
   • PDGF induces proliferation and migration of smooth muscle cells

Question 5

Discuss the regulators of pulmonary vasodilatation

Answer 5

1. Prostacyclin (PGI2)
   
   • Produced by the pulmonary artery endothelium
   • Potent vasodilator
   • Inhibits platelet activation
   • Counteracts thromboxane A2 and prevents platelet release of serotonin
2. Nitric Oxide
   
   • Synthesised in the pulmonary artery endothelium
   • Inhibits platelet activation
   • Inhibits smooth muscle proliferation
   • NO activates cyclic guanosine monophosphate (cGMP) –> causes vasodilatation
   • Limited by cGMP inactivation by phosphodiesterase 5 (PDE5) isoenxyme

Question 6

List the 5 underlying causes of pulmonary hypertension as described in humans

Answer 6

1. Pulmonary arterial hypertension
2. Left heart failure associated PH
3. Respiratory disease / hypoxia associated PH
4. Chronic thromboembolic associated PH
5. Unclear / multifactorial

Question 7

List known causes of the various types of pulmonary hypertension

List mechanisms by which the disease causes pulmonary hypertension

Answer 7

1. Primary pulmonary hypertension
   
   • Congenital systemic to pulmonary shunting
   • (as seen with right to left shunting PDA)
   • Heartworm disease - vascular damage, intimal proliferation and fibrosis
   • Genetic aberrations resulting in polymorphisms in the PDE5 molecule - reduced expression of cGMP, therefore reduced NO mediated vasodilatation
2. Left sided heart failure
   
   • Elevated pulmonary venous pressures
   • Reactive pulmonary arterial vasoconstriction
   • Chronic hypoxia
   • Decreased NO availability
   • Increased endothelin 1 expression
   • Desensitization to natriuretic peptides
3. Chronic pulmonary disease
   
   • Pneumonia, chronic tracheobronchial disease, pulmonary fibrosis, pulmonary neoplasia
   • Chronic hypoxaemia
4. Chronic embolic or thromboembolic disease
   
   • Heartworm disease
     
     • Direct embolisation and obstruction of the pulmonary artery increases arterial pressures
5. Miscellaneous
   
   • Myeloproliferative disease including polycythaemia vera
   • Granulomatous disease
   • Chronic IMHA
   • Neoplasia

Question 8

Pulmonary hypertension

Describe typical historical or clinical findings

Answer 8

History

• Chronic cough
• Exercise intolerance
• Syncope

Physical examination

• Abnormal lung sounds
  
  • Crackles, wheezes, harsh/increased sounds
• Cyanosis
• Ascites
• Left or right sided heart murmurs
• Split or loud S2

Question 9

Pulmonary Hypertension

Discuss the Echo findings with pulmonary hypertension

Answer 9

• Cardiac catheterisation is the ‘gold standard’ but rarely utilised in veterinary patients
• Echo provides a reasonable estimate of pulmonary pressures
  
  • As long as there is a regurgitant jet through the tricuspid or pulmonic valves
  • TR velocity >2.8 m/s = ~ 31 mmHg = mild PH
  • TR velocity 2.8-3.5 m/s = mild PH (31-50 mmHg)
  • TR velocity 3.5-4.3 m/s = moderate PH (50-75 mmHg)
  • TR velocity > 4.4 m/s = severe PH (> 75 mmHg)
• Pulmonic diastolic regurgitation jet > 2.2 m/s = > 199 mmHg = mild PH
• May see RA dilatation with and without RH Failure
  
  • Note - add 10 mmHg with RA dilatation and 15 mmHg with right atrial dilatation and heart failure to pulmonary arterial pressure estimates
• May see RV hypertrophy (concentric or eccentric)
• Septal flattening
• RV systolic dysfunction can be assessed via:
  
  • TAPSE
  • right ventricular systolic time interval
  • right sided tissue Doppler imaging
  • TEI index of myocardial performance
  • main pulmonary artery to aorta ratio
  • pulmonary artery distensibility index

Question 10

Pulmonary Hypertension

Discuss the treatment options

Answer 10

1. Directly treat any underlying cause
   
   • manage left heart failure, treat respiratory disease is possible
2. Prostacyclin analogs - cost prohibitive and not proven in canine patients
3. Endothelin antagonists - cost prohibitive and not proven in canine patients
4. Phosphodiesterase 5 inhibitors
   
   • sildenafil, vardenafil, tadalafil
   • Increase cGMP –> increased NO –> vasodilation
   • decrease cardiac remodelling
   • decrease fibrosis
   • decrease apoptosis
   • increased left heart function
5. Phosphodiesterase 3 inhibitor - pimobendan
   
   • Also a calcium sensitizer
   • Primarily used for left heart failure but reduction in TR velocity has been reported
6. Thromboxane inhibition
   
   • aspirin or clopidogrel
   • Theoretical use only - no studies
7. Imatinib
   
   • PDGF and PDGF receptor inhibitor

Question 11

Pulmonary Thromboembolism

List the major causes of PTE

Answer 11

1. Cardiac disease
2. corticosteroid administration
3. DIC
4. IMHA
5. hyeradrenocorticism
6. Endocarditis
7. IV catheter placement
8. Pancreatitis
9. Neoplasia
10. PLN / PLE
11. Sepsis
12. Surgery
13. Trauma

Question 12

Pulmonary Thromboembolism

Describe the pathophysiological consequences of PTE

Answer 12

• Partial or complete obstruction of the pulmonary artery or its branches
• Hypoxaemia due to ventilation perfusion mismatch
• Hyperventilation
• Ventilation - perfusion mismatch (High VQ ratio at site of PTE - reduced VQ elsewhere due to shunting of blood)
• Haemodynamic complications depend on the extent/severity together with the presence of pre-existing cardiopulmonary disease
• With time, can see atelectasis, pulmonary oedema and pleural effusion

Question 13

Pulmonary Thromboembolism

Discuss potential clinical and historical findings

Answer 13

Note: PTE is not a primary disease process, but arises secondary to other disease processes.

• Dyspnoea
• Tachypnoea
• Lethargy
• Reduced arterial blood gas (PaO2)
  
  • Increased A-a gradient
• Clinical signs attributable to the predisposing cause - heart murmur, anaemia, signs of Cushing’s disease, etc

Question 14

Pulmonary Thromboembolism

How can we establish a diagnosis?

Answer 14

• High index of suspicion
  
  • Pulmonary signs with no prior evidence of cariac or pulmonary disease
  • Known predisposing cause for thromboembolism
  • Hypoxaemia should be responsive to oxygen supplementation (increased ventilation and increased PAO2)
• Thromboelastography
  
  • Provides a global evaluation of coagulation and fibrinolysis
  • Non-specific
• CT-angiography (simultaneous bolus and thoracic scan)
• Nuclear scintigraphy - ventilation/perfusion scans
• D-dimers - non-specific. Low or normal D-dimer essentially excludes PTE.

Presumptive diagnosis may be all that is achievable in many clinical settings.

Question 15

Pulmonary Thromboembolism

Discuss the therapeutic approach

Answer 15

• Support the patient while attempting to minimise thrombus growth and prevent recurrence
• Thrombolytic therapy - streptokinaseurokinase or tissue plasminogen activating factor - limited evidence for use
• Catheter directed local infusion of thrombolytics
• Heparin - LMW or Unfractionated
• Supportive care
  
  • Oxygen supplementation
  • IV fluids - judicious use
  • Sildenafil (to reduce reflex vasoconstriction
  • Bronchodilators
• Longer term - anti-platelet drugs to minimise recurrence
  
  • aspirin or clopidogrel