Respiratory Path III Dr Rotimi Adigun Hemodynamics, Vascular disturbances

1.Pulmonary Edema Topics Covered In This Lecture 2.Acute respiratory distress syndrome (ARDS) 3.SARS (Severe acute respiratory syndrome) 4.Pulmonary Embolism 5.Pulmonary Hypertension 49

Alveolar wall microscopy

Case History • 72 yr old extremely pleasant Caucasian male with a past medical history of CABG and multiple stents, unstable angina and myelodysplastic syndrome, presented with left arm pain • He was admitted, but died within 24 hours • A post mortem was performed.

Post mortem findings • Right lung weighed 1,100 g and the left lung weighed 750 g • Severe coronary atherosclerosis was noted • There was evidence of acute myocardial infarction and massive pulmonary edema 51

Causes of Pulmonary Edema • Hemodynamic disturbances - Increased hydrostatic pressure • Left sided congestive heart failure – Heavy wet lungs (basal regions of lower lobes) - Alveolar capillaries engorged - Intra-alveolar granular pink precipitate - Heart failure cells; brown discoloration - Impairs pulmonary function and predisposes to infection S. 52

Pulmonary Edema- Causes Hemodynamic Increased hydrostatic pressure • Left ventricular failure (common) • Excess IV fluids, Excess blood transfusion. Decreased oncotic pressure • Severe hypoproteinemia, Liver disease, Nephrotic syndrome Other • Lymphatic obstruction (carcinoma, rare) S. 53

Pulmonary edema--Causes Microvascular Injury • Damage to vascular endothelium • Leakage of fluid and proteins into interstitium and lumen • Diffuse edema is a contributor to acute respiratory distress syndrome S. 54

Microvascular injury • Infections: Pneumonia, septicemia • Inhaled gases: Oxygen, smoke • Liquid aspiration: Gastric contents • Drugs and chemicals:Chemotherapy agents, heroin, cocaine, paraquat poisoning • Shock, trauma • Radiation • Transfusion related S. 55

Adult(Acute) Respiratory Distress Syndrome (ARDS) Syn. Shock Lung Syndrome, Diffuse alveolar damage (DAD), Acute lung injury (ALI) (cf. RDS in neonates due to deficiency of surfactant) Clinical syndrome caused by diffuse alveolar damage

Mechanism of ARDS • Imbalance between pro-inflammatory and anti inflammatory cytokines • Toll like receptors activate NF-kB, a transcription factor controlling expression of pro-inflammatory genes Ultimately pro-inflamatory mediators such as IL-1,IL-8,TNF and thrombin are produced in Excess compared to the production of anti- Inflammatory mediators such as IL-10. Neutrophils play a major role in this process.

ALI, Early ARDS

ARDS morphology Endothelium necrosis Type I alveolar cells necrosis Fibrin Edema Waxy Hyaline membranes

Diffuse Alveolar Injury

Shock lung • Endothelial damage, damage to type 1 pneumocytes • Exudate, impaired gas exchange • Hyaline membrane (necrotic debris from epithelial cells plus edema fluid coagulate) • Type II pneumocyte necrosis=>loss of surfactant-=>microatelectasis S. 60

What Causes ARDS? • Infections* • Sepsis* • Head injuries* • Gastric aspiration* • Pancreatitis • Burns • Trauma • Fractures with fat embolism Infection, sepsis, head injuries and gastric aspiration Account for more than 50 %of cases.

Clinical features • Serious disorder • Respiratory difficulty- acute • Gasping for breath • Severe hypoxemia, cyanosis, unresponsive to oxygen(Diffusion defect-intrapulmonary shunt) • Bilateral infiltrates on chest X-ray • Absence of clinical features of LVF • High mortality: 40% in 190,000 ARDS cases/yr • Patchy distribution • Healing may result in diffuse interstitial fibrosis

Phases of ARDS • Exudation- 0-7 days • Proliferation - 1-3 weeks macrophages phagocytose dead cells and hyaline membrane, type II pneumonocytes proliferate mature in to type I cells • Fibrosis- TGF-β, PDGF S. 63

SARS (Severe acute respiratory syndrome) • First appeared in China in Nov 2002; last case 2004 • Cause -- Corona virus; 8000 cases; 774 deaths • 2-10 day incubation period;begins with dry cough, malaise, myalgia, fever, chills • 1/3rd fight infection, but 2/3rd progress to severe respiratory disease, shortness of breath, tachypnea, and pleurisy • 10% of patients die from illness • First transmitted through wild masked palm civets • Patho-physiology unknown; how virus moved from animals to humans unknown S. 64

Wild masked palm civet

Pulmonary embolism Pulmonary Infarction • Causes more than 50,000 US deaths/year • Large pulmonary embolus is a cause of sudden instantaneous death • Blood clots that occlude large pulmonary vessels are embolic arising mainly from the deep veins of the leg S. 65

Pulmonary embolism • 95% from deep leg veins • Sick, bedridden patients with pulmonary, cardiovascular disease, atherosclerosis ,OCP use • BIG embolus -> bifurcation of PA, sudden death from acute right heart failure - no time to develop any changes in lungs S. 66

Pulmonary embolism • MEDIUM -> hemorrhage, infarction only if circulatory status already compromized • SMALL -> usually no infarct because of dual supply, resolve ( lysis), - if recurrent- pulmonary hypertension S. 67

Saddle embolism

Pulmonary Infarction

Infarction • Clinically resembles myocardial infarction - chest pain, dyspnea, shock • Gross: Wedge shaped, hemorrhagic infarct, may be multiple • Micro: coagulation necrosis S. 68

Pulmonary hypertension • When pulmonary pressure reaches 1/4th of systemic levels(usually not more than 1/8 of Systemic Five distinct groups. Pulmonary arterial hypertension PH with left heart disease PH with lung disease PH with chronic thrombotic or embolic disease Miscellaneous

Pulmonary hypertension Underlying pathogenetic mechanism usually related to any of Increased pulmonary blood flow/pressure Increased pulmonary vascular resistance Increased left heart resistance to blood flow. Common etiologic factors includes: COPD or interstitial lung disease, Congenital heart disease, Recurrent thrombo-embolism, Connective tissue disease, obstructive sleep apnea. Idiopathic pulmonary arterial hypertension is a rare cause of pulmonary hypertension.

Pulmonary hypertension • Idiopathic pulmonary arterial hypertension/Primary PH Familial PH - BMPR2 locus mutations • Rare, young women,recurrent dyspnea ,syncope • Raynaud’s phenomenon (vasopasm of peripheral vessels) Characterised by obstruction to the lumen of Pulmonary vessels caused by proliferation of Endothelial cells,smooth muscle and intimal fibrosis. • • S. 73

BMPR2 bone morphogenetic protein receptor, type 2 (BMPR2) a cell surface molecule that binds to a variety of TGF-β pathway ligands It is normally inhibitory to vascular proliferation. Hence Loss of function mutation affecting the gene would lead to excessive vascular proliferation. Implicated in 50 % of cases of Primary pulmonary hypertension.

Figure 15-28 Pathogenesis of primary pulmonary hypertension Figure 15-28 Pathogenesis of primary pulmonary hypertension. See text for details.

Primary pulmonary hypertension- clinical • Symptoms appear late • Fatigue, dyspnoea • Syncope on exercise • Chest pain • Respiratory insufficiency, cyanosis • Cor pulmonale S. 80

Pulmonary hypertension • Secondary PH-endothelia dysfunction due to • COPD - Chronic bronchitis, emphysema, diffuse fibrosis • Congenital L-R shunts- VSD • Recurrent pulmonary Thrombo-embolism in small sized vessels Drugs-appetite suppressant(aminorex) Crotalaria spectabilis(Bush tea) S. 74

Pulmonary hypertension Morphology: Irrespepective of etiology, all PH have the following morphologic changes in common: -Medial hypertrophy affecting muscular and elastic arteries -Atheromas of pulmonary artery -Right ventricular hypertrophy

Pulmonary hypertension Mild - Elastic duplication Normal pulmonary artery Severe –Medial hypertrophy, intimal fibrosis 75

Pulmonary hypertension 76

Plexiform lesions S. 77

Plexiform Lesions Extreme changes. Seen in: Idiopathic and Primary PH Drug use HIV Characterised by the presence of a tuft of capillaries producing a web like network that spans the lumina of dilated arteries.

Morphology of pulmonary hypertension • Plexiform changes in severe varieties only (primary) • Necrosis of wall (fibrinoid) • Thrombosis • Rupture, bleed • Dilation lesions, angiomatoid lesions S. 79