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
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.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 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 Normal pulmonary artery Severe –Medial hypertrophy, intimal fibrosis duplication 75
Pulmonary hypertension S. 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