4Case 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.
5Post mortem findings• Right lung weighed 1,100 g and the left lung weighed 750 g• Severe coronary atherosclerosis was noted• There was evidence of acutemyocardial infarction and massive pulmonary edema51
6Causes 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 infectionS.52
7Pulmonary Edema- Causes HemodynamicIncreased hydrostatic pressure• Left ventricular failure (common)• Excess IV fluids, Excess blood transfusion.Decreased oncotic pressure• Severe hypoproteinemia, Liver disease, Nephrotic syndromeOther• Lymphatic obstruction (carcinoma, rare)S.53
8Pulmonary edema--Causes Microvascular Injury• Damage to vascular endothelium• Leakage of fluid and proteins into interstitium and lumen• Diffuse edema is a contributor toacute respiratory distress syndromeS.54
10Adult(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
11Mechanism of ARDS• Imbalance between pro-inflammatory and anti inflammatory cytokines• Toll like receptors activate NF-kB, a transcription factor controlling expression of pro-inflammatory genesUltimately pro-inflamatory mediators such asIL-1,IL-8,TNF and thrombin are produced inExcess compared to the production of anti-Inflammatory mediators such as IL-10.Neutrophils play a major role in this process.
15Shock lung • Endothelial damage, damage to type 1 pneumocytes • Exudate, impaired gas exchange• Hyaline membrane (necrotic debris fromepithelial cells plus edema fluid coagulate)• Type II pneumocyte necrosis=>loss of surfactant-=>microatelectasisS.60
16What Causes ARDS? • Infections* • Sepsis* • Head injuries* • Gastric aspiration*• Pancreatitis• Burns• Trauma• Fractures with fat embolismInfection, sepsis, head injuries and gastric aspirationAccount for more than 50 %of cases.
17Clinical 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
18Phases 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, PDGFS.63
19SARS (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 severerespiratory 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 unknownS.64
21Pulmonary 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 thedeep veins of the legS.65
22Pulmonary 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 lungsS.66
23Pulmonary embolism• MEDIUM -> hemorrhage, infarction only if circulatory status already compromized• SMALL -> usually no infarct because of dual supply, resolve ( lysis),- if recurrent- pulmonary hypertensionS.67
27Pulmonary hypertension • When pulmonary pressure reaches 1/4th of systemic levels(usually not more than 1/8 of SystemicFive distinct groups.Pulmonary arterial hypertensionPH with left heart diseasePH with lung diseasePH with chronic thrombotic or embolic diseaseMiscellaneous
28Pulmonary hypertension Underlying pathogenetic mechanism usually related to any ofIncreased pulmonary blood flow/pressureIncreased pulmonary vascular resistanceIncreased 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.
29Pulmonary hypertension • Idiopathic pulmonary arterial hypertension/Primary PHFamilial PH - BMPR2 locus mutations• Rare, young women,recurrent dyspnea ,syncope• Raynaud’s phenomenon (vasopasm of peripheral vessels)Characterised by obstruction to the lumen ofPulmonary vessels caused by proliferation ofEndothelial cells,smooth muscle and intimal fibrosis.••S.73
30BMPR2 bone morphogenetic protein receptor, type 2 (BMPR2) a cell surface molecule that binds to a variety of TGF-β pathway ligandsIt 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.
31Figure 15-28 Pathogenesis of primary pulmonary hypertension Figure Pathogenesis of primary pulmonary hypertension. See text for details.
33Pulmonary hypertension • Secondary PH-endothelia dysfunction due to• COPD - Chronic bronchitis,emphysema, diffuse fibrosis• Congenital L-R shunts- VSD• Recurrent pulmonaryThrombo-embolism in small sized vesselsDrugs-appetite suppressant(aminorex)Crotalaria spectabilis(Bush tea)S.74
34Pulmonary 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
38Plexiform Lesions Extreme changes. Seen in: Idiopathic and Primary PH Drug useHIVCharacterised by the presence of a tuft of capillaries producing a web like network that spans the lumina of dilated arteries.
39Morphology of pulmonary hypertension • Plexiform changes in severe varieties only (primary)• Necrosis of wall (fibrinoid)• Thrombosis• Rupture, bleed• Dilation lesions, angiomatoid lesionsS.79