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Case 1 - pulmonary embolism

A 73 year-old woman with long-standing congestive cardiac failure presented to her GP with sudden onset of dyspnoea at rest, associated with haemoptysis and pleuritic chest pain. In the preceding week, she had experienced several short-lived episodes of dyspnoea at rest. Her GP organised admission to hospital, concerned about the possibility of pulmonary thromboemboli.

  • Dyspnoea is a symptom - subjective "breathlessness"
  • Mechanisms:
    • Hypoxaemia - central sensing of hypoxaemia by chemoreceptors (increase in the drive to breathe that is excessive for the amount of activity we are doing - perceived as inappropriate for our activity level)
    • Increased resistance to airflow (asthma, inflammation in the lungs in pneumonia)
      • Inflammation triggers sensors in the lungs to increase the work of breathing
    • Decreased compliance of the lungs
      • Increased work of respiratory muscles perceived as dyspnoea
    • Obstruction of pulmonary arteries (stretching)
      • E.g. pulmonary embolism
    • If you're sensitive to hypercapnia (not a "blue bloater" with COPD) you could be dyspnoeic
    • Psychogenic: Panic
  • Classic combination of features for pulmonary embolism
    • Sudden onset of dyspnoea associated with haemoptysis and pleuritic chest pain: typically associated with infarction and embolism
    • Pulmonary embolism with infarction → haemoptysis, pleuritic chest pain and dypsnoea
      • Infarction leads to pleurisy, haemorrhage into infarction leads to haemoptysis
      • Several short lived episodes: could be smaller emboli that underwent rapid thrombolysis
      • Differentials
        • Pneumonia (would have fever)
        • Abscess
        • Tuberculosis
        • Lung malignancy
  • Risk factors
    • 73 year old
    • Long standing CCF
    • Venous-thromboembolism risk
      • Stasis and reduced venous return from the lower limbs → RH failure → increased pressure in systemic circulation
      • Immobility from CCF
    • Diuretics → mainstay of treatment for cardiac failure
      • May have resulted in dehydration → prothrombotic effect increased due to increased viscosity of blood
      • Virchow’s triad – hypercoaguability, changes in the vessel wall, abnormal blood flow
      • She has changes in the vessel wall due to venous return problems from CCF
    • Hyper-oestrogenic states / pregnancy / OCP → estrogen → hypercoaguable state
      • NB this lady is old and probably does not apply
    • Fam hx
      • Thrombophilias (hypercoaguable state)
      • Factor 5 (Leiden) – mutations present in 5-15% of all caucasians
    • Most common hereditary cause of thrombophilias
  • Virchow's triad can be used to classify risk factors
    • Abnormalities of the blood (hypercoagulability)
      • Post-menopausal so not hyperoestrogenic
      • Diuretic treatment for CCF - dehydration
    • Abnormalities of flow (e.g. stasis) - CCF
    • Endothelial damage - none relevant
  • Protective Factors
    • Estrogen


  • Investigations
    • Chest X-ray
      • Linear collapse in the mid-zone of R lung
      • Small pleural effusions
      • Bilateral small pulmonary embolism
      • Mainly used to rule out differential diagnosis
      • Usually normal
  • ECG: S1Q3T3 (S wave in lead 1, Q wave in lead 3, inverted T in lead 3)
    • RVH in long-standing, usually just see sinus tachycardia
    • D-dimer test (for low pretest probability of pulmonary embolism. If negative, you can rule out pulmonary embolism. If +, you need to do imaging
      • Fibrin degradation product
      • Elevated in bloodstream for ppl with intravascular thrombosis
      • Good negative predictive value if within reference range i.e. high specificity
      • This is because if person does not have any risk factors this is a good test to run before CT and any other following tests
      • This person has high pre-test probability so proceed straight to imaging
    • V/Q lung scan (preferred in people with previously normal resp. function, non-pregnant, non obese)
      • Perfusion scan will show a lack of perfusion to a lung segment
      • Nuclear scan
      • Radioactive albumin is injected
      • Segmental or lobar Ventilation perfusion mismatch = sign of PE
      • Superceded by pulmonary CT angiogram
      • Does not have a high positive predictive value
      • Not very sensitive for PE especially in the event of declining lung function in the patient
      • Often equivocal because the ventilation scan is not normal (because of preexisting lung disease)
    • CT pulmonary angiogram
      • Inject a dye and do a CT scan.
      • See lack of contrast filling in vessels due to obstruction of an artery with an embolus
      • Distal to obstructions are areas of wedge-shaped pulmonary infarction with the base of the wedge on the pleural surface, and the apex on the artery
      • Better than ordinary pulmonary angiogram
  • DVT Venogram
    • IV contrast injected into veins of lower limbs → x-ray taken as contrast is transported up to IVC
    • Shows large trickle defect → large propagating DVT in left lower limb
    • Invasive → risk of reaction to IV contrast
    • Rarely done these days, though it is the gold standard
  • Venous doppler ultrasound
    • Highly sensitive and specificity for DVT
    • Non-invasive
    • Large advantage over DVT venogram
  • Pathology specimen
    • Embolus in a branch of the pulmonary artery, with a triangle pointing to it (wedge in 3D), base of wedge on the surface of the lung


Slide 1

  • Left half: Chronic changes - aerated lung
    • Capillaries --> wall destroyed due to congestion
    • Brown material in lungs --> "haemosiderin" (break down product of haem in red blood cells)
      • Haemosiderin and haemosiderin-laden macrophages
    • Noninflamed pleura
    • Thickened and fibrotic due to chronic passive venous congestion that occurs due to long-standing cardiac failure, leads to blood leaking out of pulmonary capillaries and the lysed RBCs release haemosiderin (RBCs with haemosiderin = heart failure cells)
    • Fibrosis is secondary to irritation
  • Right half: Acute changes - non-aerated lung, eosinophilic
    • Part of the clot from more proximal clot which has broken off from the main clot
    • Haemmorhage
    • Inflamed pleura
    • Coagulative necrosis: ghosting outlines of alveolar cells, nuclear fragments
    • Artefacts = wavy appearance; jittering the microtome as it cuts the section
    • Eosinophilic material filling alveolar spaces = lysed RBCs
    • This area = haemorrhagic pulmonary infarction
    • Upper right hand part of section: branch of a pulmonary artery filled by a fragment of a thromboembolus. This helps us say this is caused by thromboembolism (though this particular fragment is too distal, probably caused by a larger proximal one)
    • Fibrinous pleurisy overlying the haemorrhagic infarction - pleuritic chest pain and coughed up blood, SOB due to hypoxaemia caused by obstruction to pulmonary arterial flow --> impaired oxygenation of blood

Slide 2

  • Femoral vein with intravascular thrombus
    • 2 CT septae are cross sections through valve
    • In the middle is a thrombus
  • Venous thrombi vs post-mortem clot
    • Thrombus – adherent to wall and propagates; laminated structure (layer of fibrin and platelets, trapped red cells, then more fibrin/platelets)
    • Post-mortem clot – not adherent to vessel wall, separates into red cells and plasma (currant jelly and chicken fat). No laminations present in post-mortem clot since laminations occur due to conditions of flow.
      • Congealed plasma supernatant = plasma. Red cells = currant jelly.
  • Diagnosis
    • Thrombus or post-mortem clot
    • Fibrin will be present in both
  • Thrombus
    • Laminations occur due to flow
    • Lighter and darker areas
    • Lighter – RBC
    • Darker – fibrin and platelets
    • At the origin of the valve leaflet – development of new granulation tissue in the thrombus growing in from the vessel wall
    • Fibroblasts and macrophages in this region
    • Shows that it must have been attached to the vessel wall → body is responding to this structure
      • Starting to grow blood vessels into the thrombus -- the process of organising the thrombus
    • Hence cannot be post-mortem clot with this granulation etc.
  • Macroscopic Abnormalities
    • Connective tissue septi traversing the valves → must be a vein
    • NB: most emboli go to lower lobes of lungs due to gravity

Outcomes

  • The majority of thromboemboli have no clinical consequences
  • 10% - haemorrhagic infarct
  • 10% - haemmorhage with no infarct
  • 10% - massive emboli that cause sudden death
  • Rare - organisation of thrombus leading to incorporation in walls - narrowing of the artery - pulmonary hypertension
  • Rare - AV shunt in patent foramen ovale - paradoxical embolus (embolus into the arterial side of circulation)
  • Poorer outcomes: CCF, COPD - lower CO so lower collateral supply, resulting in infarction

Case 2 - primary pancreatic cancer

  • Saddle embolus - straddles the bifurcation of the pulmonary artery (obstructing RV outflow)
    • No evidence of infarction - instakill
    • Tissue on the left side of the specimen - deep vein from the leg with propagating thrombus
  • Vein in the lower limb
    • Shows propagating venous thrombus
    • Pale thrombus → infarction not haemorrhagic
    • Most DVT start in the deep veins of the calf
    • Increased risk when they propagate into larger vessels
  • How does cancer cause hypercoaguability of the blood
    • Especially visceral adenocarcinomas like pancreatic (also stomach, colon, gallbladder)
    • Mucin is produced from these cancers → activate coagulation cascade (Factor 10) --> greatly increased risk of thrombosis
    • Troussets Syndrome → migratory thrombophlebitis (inflammation due to thrombus in veins)
      • This is a result of the hypercoagulable state induced by visceral adenocarcinomas
    • Also immobility predisposes
  • Cause of sudden death
    • Obstruction of output of right side of heart, so no blood is getting back to left side of the heart, so zero CO, no oxygenation of brainstem, and person dies soon afterwards
  • Prior to sudden death, there can be repeated episodes of SOB - can sometimes find emboli and haemmorhage/infarction in the lungs
    • Fibrin exists in the venous thrombus, different to clot
    • Haemmorhage is most likely to occur at the base rather than the apex
    • Early diagnosis is necessary - if you notice the cardinal signs, you can treat to prevent sudden death
      • Half are asymptomatic - collateral flow by superficial veins
  • DVT common in hospital
    • Orthopedics, oncology
  • DVT signs
    • Calf pain/tenderness
    • Compare diameters of two calves with a tape measure (swelling)
    • Area distal to the thrombus is warmer than proximal (due to inflammation/swelling)

Case 3: CCF and pneumonia

A 78 year old woman, debilitated by congestive cardiac failure, was admitted to hospital with a 4 day history of cough and fever. The cough had become productive of yellow sputum over the last 2 days. She also complained of increasing weakness and lassitude (weakness). Examination revealed signs of patchy lower lobe consolidation.

  • Consolidation
    • Dullness to percussion
    • Bronchial breath sounds
    • Increased vocal resonance
  • Lab findings
    • Neutrophil leococytosis
    • CRP increases as a result of the acute phase reaction, IL1 and TNFa cause a) fever (hypothalamus) b) neutrophilia (bone marrow) c) acute phase proteins in the liver (e.g. CRP - plays a role in opsonisation)
    • ABGs: hypoxaemia came first, because of filling of alveoli (like having a pulmonary shunt). Hypoxaemia sensed by medullary chemoreceptors, that increases the drive to breath --> increase in ventilation --> hypocapnia --> respiratory alkalosis
    • Sputum: Strep. pneumoniae. Blood: Strep. pneumoniae.
  • Provisional Diagnosis
    • Pneumonia: patchy consolidation,fever, cough producing sputum
  • Crackles and then if completed consolidated then we get bronchial breathing
  • FBC
    • CRP more used than ESR
    • ABGs
  • Respiratory alkalosis (acute with no metabolic compensation)
  • pCO2 is low
  • Hypoxaemia came first
  • Increase in alveolar ventilation → blowing of CO2 → respiratory alkalosis is in response to this
  • Hypoxaemia caused by pneumonia via
  • Blood going through capillaries which are consolidated – you get unoxygenated blood from consolidated + oxygenated from normal alveoli → MIX of oxygenated and unoxygenated blood in the lungs → hypoxaemia
  • Not the main cause consolidation of alveoli which impairs lung function
  • How to know it was a good sputum sample
    • Bad: saliva (microscopically: epithelial cells)
    • Pure growth: no saliva, no epithelial cells
    • Does NOT guarantee pneumonia → Could be bronchitis
  • CHEST-X-RAY will help differentiate pneumonia from bronchitis
  • Chest X-Ray (MOST IMPORTANT diagnostic tool for pneumonia) - finding Strep. pneumoniae does not diagnose pneumoniae - could be bronchiolitis etc. Blood culture + only occurs in a small proportion of pneumonias.
    • Distorted image because she was slouching in bed
    • Lots of patchy consolidation in both lung fields
    • Heart grossly enlarged: boot-shaped heart, left ventricle projects to axilla. Pulmonary venous hypertension, upper lobe blood diversion. Kerley B lines due to interstitial pulmonary oedema
    • Also has patchy consolidation throughout both lung fields
  • Bronchopneumonia
    • Common among Indigenous North Americans
    • Heart is enlarged
  • Just make out the left heart border
  • Diameter of cardiac shadow: chest > 50%
  • Left ventricle is dilated
  • The apex beat displaced to mid-axilla
  • CCF predisposes to pneumonia
    • Fluid retained in the lungs (alveolar spaces)
    • Nice medium for bacterial growth
    • Defences against infection in this area – alveolar macrophages → do not function well with fluid (liquid substrate)
    • Hypostatic pneumonia where all the fluid is
    • Organism in the blood stream → strep pneumococcus

The woman died the next day. Specimen 1300.15 and Virtual slide 3 (linked from http://vslides.unsw.edu.au) were prepared from tissues removed at autopsy.

  • Macroscopic: patches of consolidation in the lower lobe of the lung. In the top/middle, these patches become confluent - indicating that the host has poorly localised the infection, leading to a poorer prognosis
  • VSlide:
    • Patchy consolidation with congested alveolar spaces. Soap bubble appearance due to fluid in alveolar spaces
    • Bronchiole: lumen filled with pus (neutrophils, proteinaceous exudate and necrotic material). Suppurative bronchiolitis (how it starts - a few days of cough which becomes productive)
    • Then since she has CCF, she has a lot of fluid in alveolar lumen. Organisms proliferate in this fluid
    • Fibrinosuppurative exudate + neutrophils fills the alveolar spaces, causes consolidation
    • Some parts of the lung have very little inflammation, but in these alveolar spaces there is congestion with proteinaceous fluid (might be the earliest stage of pneumonia or oedema fluid present in lungs as a result of CCF)
    • Bronchopneumonia: patchy inflammation in different stages in progress in different parts of the lung
    • Cause of death:
      • Sepsis; release of vascular mediators, widespread vasodilation, drop in TPR, lower BP, lower perfusion of vital organs and death
      • Hypoxaemia may have made CCF worse, and a downward spiral --> death
  • Overall pattern of abnormalities
    • Patchy consolidation → poor response to treatment and/or poor immune response → becomes confluent (BAD ☹) → death
  • Diagnosis
  • Evolution of Clinical Symptoms
  • Signs

• Reasoning behind Death o Bacteraemia o Septic shock • Caused by host immune response to bacteraemia • The peptidoglycans and gram positive cell walls of bacteria cocci • Activation IL-1, IL-6, TNF-alpha • Secondary mediators released → Nitric Oxide → Causes inappropriate vasodilation → drop in peripheral vascular resistance → hypotension → impaired perfusion in vital organs (such as kidneys, brains etc.) → shock → death o Cardiac failure may have been exacerbated by this infection → increased demand on failing LV → decompensated cardiac failure → hypoxaemia → death • SLIDE o Infection spread into surrounding alveoli o Bronchopneumonia pathogenesis • Infection of airways → spread to alveoli o Lots of exudates present o Pus = neutrophils + exudates + necrotic debris of cells o Fibrinosuppurative exudates → Fibrin in exudates binds it together → consolidation of airspaces o Features of bronchopneumonia • Multi-focal patches • Some non-effected alveoli too • Airway of unaffected alveoli → appear like soap bubbles → coalesce with each other → few alveoli air spaces → they need to hyperinflate to compromise

Case 4: ARDS

  • Very low pO2 - barely sustaining life

How would you interpret these results?

  • Acidosis
    • Retention of CO2, and also sepsis (increasing production of lactic acid)
  • Hypoxaemia
  • Hypercapnia
  • Mixed respiratory and metabolic acidosis
    • Hypoventilated
    • Metabolic caused by sepsis and increased lactic acid production
  • She is in shock → anaerobic organs → lactic acid build up → metabolic acidosis

She was intubated and ventilated with 100% oxygen, but her arterial oxygen saturation remained dangerously low. A diagnosis was made of acute respiratory distress syndrome (ARDS). Treatment was ineffective and she died in the Intensive Care Unit several days later. Virtual slide 4 (linked from http://vslides.unsw.edu.au) was prepared from tissue obtained at autopsy.

  • CXR with ARDS: almost white out
  • If you see a CXR like this: Introduce a catheter (Swan-Gans catheter) to measure the pulmonary arterial wedge pressure. If it's normal, then it's ARDS
    • If abnormally high, treat CCF rather than ARDS

Slide 4: ARDS

  • Alveolar interstitium is hugely thickened, and filled with inflammatory cells e.g. macrophage
  • Little aeration of lung
  • Higher power
    • Alveolar walls have lost alveolar epithelial lining cells to necrosis
    • Have deep eosinophilic membrane lining the walls of the alveoli → hyaline membranes
      • Consist of fibrin and alveolar cell debris and surfactant
    • This blocks exchange of oxygen across alveolar membrane → contributes to hypoxaemia in this condition
    • Lungs become very stiff and noncompliant due to inflammation
    • Lack of surfactant (loss of type 2 pneumocytes) → without surfactant alveolar collapse with expiration making them very difficult to expand on inspiration (despite very high drive to breathe, she cannot ventilate her lungs) → hypoventilation → respiratory acidosis
      • Even with assisted ventilation and oxygen, you can't adequately oxygenate the lungs. You need to remove the underlying cause (in this case, it's gram negative sepsis)
    • Pattern of disease is diffuse alveolar damage
  • Oedema in alveolar interstitium → stiffening of lungs → compliance of lung is reduced → hypoxaemia → inability to self-ventilate
    • Diffuse alveolar damage
  • ARDS
    • Epithelial/endothelial injury
    • Interstitial/alveolar oedema
    • Interstitial inflammation
  • Some causes of ARDS
    • Non-environmental causes
      • Major trauma, burns – shock length
      • Gram-negative septicaemia
      • Diffuse pulmonary infections – viral pneumonia e.g. influenza (complication is ARDS → death)
      • Tumours, obstetric complications (amniotic fluid embolis)
    • Environmental agents
      • Inhalation of smoke, toxic gas
      • Ingestion of toxic chemicals
  • Diffuse alveolar damage in ARDS – hyaline membranes
    • Chest x-ray ARDS
    • White out of lung fields – INTENSE
      • Causes – severe pulmonary oedema from LH failure
  • ARDS
    • Need to demonstrate LV is not failing → tested by IV catheter (Swan-Ganns) in ICU → balloon stent is used in pulmonary arteries to measure pulmonary artery pressure → if normal then we diagnose ARDS → if elevated = Left sided heart failure
  • ARDS
    • Very poor prognosis unless underlying cause is treated e.g. sepsis
    • Even if survived – developed organisation of alveolar walls → some degree of pulmonary fibrosis → permanent pulmonary impairment of gas exchange
  • Sepsis
    • Release of TNF-alpha + IL-1 → causes endothelial cells to produce Il-8 → Il-8 is chemotractant for neutrophils → neutrophils activated to produce oxygen radicals + other harmful chemicals → damage alveolar epithelial cells → interstitial oedema occurs → Fibrinogen present → conversion of fibrinogen to fibrin in interstitium → hyaline membrane formation
  • Survives ARDS
    • Granulation tissue resulting in interstitial pulmonary fibrosis that results in a permanent decrease in lung compliance and a lower ability to oxygenate
    • ARDS can be treated with ECMO (extracorporeal membrane oxygenation) until the lesion in the lungs resolves/improves
      • Used in young, otherwise-well people who have had flu etc that results in ARDS