Diseases of the Pulmonary Circulation

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Diseases of the Pulmonary Diseases of the Pulmonary CirculationCirculation

J.B. Handler, M.D.J.B. Handler, M.D.

University of New EnglandUniversity of New England

Physician Assistant ProgramPhysician Assistant Program

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AbbreviationsAbbreviations

PE- pulmonary embolusPE- pulmonary embolus DVT- deep vein thrombophlebitisDVT- deep vein thrombophlebitis CO- cardiac outputCO- cardiac output HF- heart failureHF- heart failure OCP- oral contraceptive pillOCP- oral contraceptive pill PAP- pulmonary artery pressurePAP- pulmonary artery pressure V/Q- ventilation/perfusionV/Q- ventilation/perfusion CVP- central venous pressureCVP- central venous pressure RR- respiratory rateRR- respiratory rate PP22- pulmonic valve component of - pulmonic valve component of

the 2the 2ndnd heart sound (S heart sound (S22)) Vit-vitaminVit-vitamin Dx- diagnosisDx- diagnosis INR- international normalized INR- international normalized

ratioratio

SS44- abnormal 4- abnormal 4thth heart sound heart sound NSST-T- non specific ST-T wave NSST-T- non specific ST-T wave

changeschanges ST- sinus tachycardiaST- sinus tachycardia ABG- arterial blood gasABG- arterial blood gas PuVR- pulmonary vascular PuVR- pulmonary vascular

resistanceresistance PPH- primary pulmonary PPH- primary pulmonary

hypertensionhypertension RAE- right atrial enlargementRAE- right atrial enlargement RVE- right ventricular RVE- right ventricular

enlargementenlargement SS22- second heart sound- second heart sound Rx- treatmentRx- treatment PTT- partial thromboplastin timePTT- partial thromboplastin time

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Pulmonary Thromboembolism Pulmonary Thromboembolism

Embolization of thrombus from the venous system Embolization of thrombus from the venous system into the pulmonary arterial circulation; common, into the pulmonary arterial circulation; common, serious and serious and life threateninglife threatening

200,000 annual mortality in USA200,000 annual mortality in USA– 33rdrd leading cause of leading cause of in-hospitalin-hospital deaths deaths

– Majority of deaths from PE Majority of deaths from PE unrecognized unrecognized until post-until post-mortemmortem

5-7% mortality rate of diagnosed cases with a 5-7% mortality rate of diagnosed cases with a 40-40-50% mortality rate of undiagnosed cases50% mortality rate of undiagnosed cases

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Pulmonary EmbolismPulmonary Embolism

The presence of DVT should always The presence of DVT should always sound an alarmsound an alarm. Prior DVT or PE carry a . Prior DVT or PE carry a substantial risk for subsequent PE. substantial risk for subsequent PE.

Symptoms: Often Symptoms: Often very difficult to very difficult to recognizerecognize as symptoms are not specific to as symptoms are not specific to PE.PE.– 97% of patients with PE will have at least one 97% of patients with PE will have at least one

of the following: of the following: tachypnea, dyspnea, tachypnea, dyspnea, pleuritic chest painpleuritic chest pain (infers infarction). About (infers infarction). About 1/3 of patients will have tachycardia.1/3 of patients will have tachycardia.

DVTDVT

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Pulmonary Thromboembolism Pulmonary Thromboembolism

DVT DVT is the most common site of development of is the most common site of development of thrombus. Usually thrombus. Usually popliteal and/or iliofemoralpopliteal and/or iliofemoral vein vein involvement with subsequent embolization (50-60%) involvement with subsequent embolization (50-60%) to the pulmonary circulation.to the pulmonary circulation.

Calf involvement alone carries much less risk of Calf involvement alone carries much less risk of significant embolism.significant embolism.– Calf vein propagation to popliteal and iliofemoral veins Calf vein propagation to popliteal and iliofemoral veins

occurs in 20% of patients with initial calf involvement. occurs in 20% of patients with initial calf involvement. Pelvic vein thrombosis also common source.Pelvic vein thrombosis also common source. 50% cases of PE lack characteristic symptoms; 50% cases of PE lack characteristic symptoms;

essential to have high index of suspicionessential to have high index of suspicion..

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Risk Factors for DVTRisk Factors for DVT

Venous stasisVenous stasis: Immobility, post-op (large : Immobility, post-op (large operations, orthopedic procedures), post stroke.operations, orthopedic procedures), post stroke.

Increased CVP: Decreased CO, CHF, pregnancy.Increased CVP: Decreased CO, CHF, pregnancy. Hypercoagulability: Meds (OCP), diseases Hypercoagulability: Meds (OCP), diseases

(malignancy), and (malignancy), and inherited- inherited- several forms:several forms:– Factor V Leiden: A hereditary hypercoagulability Factor V Leiden: A hereditary hypercoagulability

disorder; common (3% heterozygous incidence) in disorder; common (3% heterozygous incidence) in healthy adults. 20-30% of patients with DVT have this healthy adults. 20-30% of patients with DVT have this disorder.disorder.

– Factor V Leiden: Modified clotting factor V, resists Factor V Leiden: Modified clotting factor V, resists degradation by activated Protein Cdegradation by activated Protein Ccoagulation.coagulation.

Intracardiac PressuresIntracardiac Pressures

4-12

4-12

4-12

4-12 4-124-12

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PathophysiologyPathophysiology

Obstruction to pulmonary vascular bed by Obstruction to pulmonary vascular bed by thrombus.thrombus.

Vasoconstriction develops in the pulmonary Vasoconstriction develops in the pulmonary arteriolar bed (arteriolar bed (PuVRPuVR) as a result of:) as a result of:– Neurohumoral reflexes, Neurohumoral reflexes, hypoxiahypoxia, and tissue injury, and tissue injury

Result is Result is PAPPAP.. PAPPAPRt heart strain Rt heart strain COCO (RVH if PAP (RVH if PAP s s

over time) over time) RV failure: RV failure: Cor PulmonaleCor Pulmonale.. Impaired gas exchange: Impaired gas exchange: alveolar dead spacealveolar dead space

from vascular obstruction. from vascular obstruction.

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PathophysiologyPathophysiology

physiologic dead spacephysiologic dead space, , CO, hypoxemia and CO, hypoxemia and surfactant depletion result in atelectasis.surfactant depletion result in atelectasis.– Atelectasis contributes to shunting (below).Atelectasis contributes to shunting (below).

Right to left shunting plays a small role:Right to left shunting plays a small role:– Atelectasis.Atelectasis.– Large PE: Redirection of blood flow into “normal” Large PE: Redirection of blood flow into “normal”

lung but if inadequate alveolar reservelung but if inadequate alveolar reserveshunting.shunting. Loss of surfactant, edema and hemorrhage lead to Loss of surfactant, edema and hemorrhage lead to

decreased pulmonary compliance, work of decreased pulmonary compliance, work of breathing.breathing.

Ventilation/PerfusionVentilation/Perfusion

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SymptomsSymptoms

Dependent on number/size of the emboli Dependent on number/size of the emboli and pre-existing pulmonary status.and pre-existing pulmonary status.

Constellation of findings: Constellation of findings: dyspnea, dyspnea, pleuritic pleuritic (inspiratory)(inspiratory) chest pain and chest pain and tachypneatachypnea are predominant are predominant symptoms/signs; others include symptoms/signs; others include palpitations, wheezing and hemoptysis.palpitations, wheezing and hemoptysis.

Note: must have high index of suspicion in Note: must have high index of suspicion in order to make Dx in many patients.order to make Dx in many patients.

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SignsSigns

Signs: Increased RR, tachycardia, crackles, Signs: Increased RR, tachycardia, crackles, SS44 gallop, decreased S gallop, decreased S22 splitting with splitting with

increased Pincreased P22; friction rubs and cyanosis less ; friction rubs and cyanosis less

common.common. Clinical findings of Clinical findings of DVTDVT present in only present in only

30-40% of patients with PE but 60-70% 30-40% of patients with PE but 60-70% will have evidence of DVT by non-invasive will have evidence of DVT by non-invasive imaging (see below).imaging (see below).

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Investigational FindingsInvestigational Findings

ECG changes common: ST, NSST-T changes.ECG changes common: ST, NSST-T changes. ABG: Respiratory alkalosis, decreased POABG: Respiratory alkalosis, decreased PO2.2.

Plasma D-dimer: (>300-500ng/ml) a Plasma D-dimer: (>300-500ng/ml) a degradation degradation product of cross-linked fibrinproduct of cross-linked fibrin- usually elevated - usually elevated in presence of thrombus (97% sensitivity), but in presence of thrombus (97% sensitivity), but not specificnot specific (45%). Commonly combined with (45%). Commonly combined with other diagnostic studies (CT other diagnostic studies (CT angiography)angiography)predicts likelihood of PE. predicts likelihood of PE.

CxR: often abnormal- atelectasis, pleural CxR: often abnormal- atelectasis, pleural effusions, pleural based infiltrates; necessary to effusions, pleural based infiltrates; necessary to exclude other pulmonary pathology. exclude other pulmonary pathology.

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V/Q Lung ScanV/Q Lung Scan

Radioisotopes used to image ventilation and Radioisotopes used to image ventilation and perfusion. Defects develop in areas of lung perfusion. Defects develop in areas of lung that remain ventilated without perfusion; that remain ventilated without perfusion; inaccurate in presence of other pulmonary inaccurate in presence of other pulmonary pathology.pathology.

Graded low (normal), intermediate and high Graded low (normal), intermediate and high probability for PE.probability for PE.

Supplanted as diagnostic test by Helical CT Supplanted as diagnostic test by Helical CT angiography (below).angiography (below).

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Pulmonary Circulation ImagingPulmonary Circulation Imaging

Helical (spiral) CT AngiographyHelical (spiral) CT Angiography: Sensitive for : Sensitive for proximal vessel thromboembolismproximal vessel thromboembolism; overall 83% ; overall 83% sensitive, >90% specific; sensitive, >90% specific; alternative to V/Q alternative to V/Q scanning as a screening procedurescanning as a screening procedure. More often . More often done compared to V/Q.done compared to V/Q.

Pulmonary angiography: Pulmonary angiography: reference standardreference standard for for the Dx of PE- Invasive with 5% complication rate the Dx of PE- Invasive with 5% complication rate (contrast reaction, renal failure, arrhythmias) high (contrast reaction, renal failure, arrhythmias) high sensitivity, specifity. Indicated when V/Q or CT sensitivity, specifity. Indicated when V/Q or CT scans are indeterminate, DVT studies are negative, scans are indeterminate, DVT studies are negative, and PE still suspected clinically.and PE still suspected clinically.

Helical CT: Pulmonary EmbolusHelical CT: Pulmonary Embolus

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Pulmonary AngiographyPulmonary Angiography

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DVT StudiesDVT Studies

If Dx is uncertain and DVT is proven, likely If Dx is uncertain and DVT is proven, likely that PE is present if clinically suspected.that PE is present if clinically suspected.

Venous ultrasound with doppler: Non- Venous ultrasound with doppler: Non- invasive test of choice for DVT.invasive test of choice for DVT.

Contrast Venography: “reference standard”-Contrast Venography: “reference standard”-highly accurate and invasive, has been highly accurate and invasive, has been replaced by ultrasound which is non-replaced by ultrasound which is non-invasive and easier to perform.invasive and easier to perform.

Integrated Approach for Dx of PE: Integrated Approach for Dx of PE: Clinical Features + Diagnostic TestingClinical Features + Diagnostic Testing

Clinical feature Points

Clinical symptoms of DVT 3

Other diagnosis less likely than PE

3

Heart rate greater than 100 beats per minute

1.5

Immobilization or surgery within past 4 weeks

1.5

Previous DVT or PE 1.5

Hemoptysis 1

Malignancy 1

Total points  

Clinical Probability of PEClinical Probability of PE ScoreScore

PE likelyPE likely >4>4

PE unlikelyPE unlikely 44

Wells et. al

PE Unlikely PE Likely

D-dimer assay Helical CT-PA

Negative Positive

PE excluded

Normal Findings of PE

Rx for PEPE Excluded

Indeterminate

LE US or Pulm angiogram

Clinical Probability of PE

+ studyCurrent fig 9-1

- study

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Treatment of 1Treatment of 1stst PE PE Full anticoagulationFull anticoagulation for for minimum 6minimum 6 months or longer months or longer

depending on risk factors for recurrence.depending on risk factors for recurrence. Unfractionated Unfractionated heparinheparin: Binds to and potentiates : Binds to and potentiates

antithrombin IIIantithrombin III inactivates clotting factors IXa, Xa, inactivates clotting factors IXa, Xa, XIa, XIIa; retards additional thrombus formation.XIa, XIIa; retards additional thrombus formation.

Administered by continuous IV infusion and requires Administered by continuous IV infusion and requires frequent monitoring (highly protein bound) of PTT for frequent monitoring (highly protein bound) of PTT for dose adjustment; for 5-7 days.dose adjustment; for 5-7 days.

Wt. Based dosing: 80U/kg loading dose, then Wt. Based dosing: 80U/kg loading dose, then 18U/kg/hr18U/kg/hrgoal PTT 1.5-2.5x control (46-70 sec)goal PTT 1.5-2.5x control (46-70 sec)

Risks: Risks: BleedingBleeding, thrombocytopenia, thrombocytopenia..

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Low Molecular Weight HeparinLow Molecular Weight Heparin: depolymerized : depolymerized heparin, less protein and cellular bound, increased heparin, less protein and cellular bound, increased bioavailability; also given for 7 days. More predictive bioavailability; also given for 7 days. More predictive dose response, as/more effective than unfractionated dose response, as/more effective than unfractionated heparin. Decreased risk of hemorrhage and heparin. Decreased risk of hemorrhage and thrombocytopenia; 1-2x daily dosing (weight based) thrombocytopenia; 1-2x daily dosing (weight based) without need for lab testing. without need for lab testing.

WarfarinWarfarin- oral anticoagulant, blocks action of Vit K, - oral anticoagulant, blocks action of Vit K, inhibiting hepatic synthesis of Vit K dependent clotting inhibiting hepatic synthesis of Vit K dependent clotting factors (II, VII, IX, X). Initiated over 5-7 days (with factors (II, VII, IX, X). Initiated over 5-7 days (with patient on heparin) and continued for desired period of patient on heparin) and continued for desired period of time. Goal: INR (adjusted PT) of 2-3.time. Goal: INR (adjusted PT) of 2-3.

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Thrombolytic TherapyThrombolytic Therapy

Streptokinase, Urokinase and t-PA: directly lyse Streptokinase, Urokinase and t-PA: directly lyse intravascular thrombi and accelerate resolution of intravascular thrombi and accelerate resolution of emboli within emboli within 1st 24 hours1st 24 hours compared to standard compared to standard heparin therapy, heparin therapy, but do not decrease mortalitybut do not decrease mortality..

Indications: Indications: patients with massive PE at high patients with massive PE at high risk of death (unstable on heparin).risk of death (unstable on heparin).

Contraindications: active internal bleeding, stroke Contraindications: active internal bleeding, stroke in prior two months, surgery or trauma in prior 6 in prior two months, surgery or trauma in prior 6 weeks and uncontrolled hypertension.weeks and uncontrolled hypertension.

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Surgical InterventionsSurgical Interventions

Mechanical or surgical thrombus extraction- last Mechanical or surgical thrombus extraction- last resort in a dying patient.resort in a dying patient.

Vena caval interruption: Indicated in patients with Vena caval interruption: Indicated in patients with DVT/PE that cannot be anticoagulated or recurrent DVT/PE that cannot be anticoagulated or recurrent PE while already fully anticoagulated. Vena caval PE while already fully anticoagulated. Vena caval filter/umbrella can be introduced percutaneously filter/umbrella can be introduced percutaneously via internal jugular vein.via internal jugular vein.

Prognosis of PE Prognosis of PE if diagnosed: < 3% incidence of if diagnosed: < 3% incidence of death from death from recurrent PErecurrent PE if initial event is if initial event is recognized and adequately treated.recognized and adequately treated.

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Prevention of PEPrevention of PE

Identify patients at high risk for DVT: lengthy Identify patients at high risk for DVT: lengthy hospitalization/immobilization, orthopedic hospitalization/immobilization, orthopedic surgery, esp. hip repair (incidence of DVT 10-surgery, esp. hip repair (incidence of DVT 10-20% if untreated with prophylactic anticoagulation 20% if untreated with prophylactic anticoagulation and other measures).and other measures).

Strategies for prevention:Strategies for prevention:-early ambulation-early ambulation-elastic stockings-elastic stockings-mechanical compression devices-mechanical compression devices-anticoagulation.-anticoagulation.

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Pharmacologic ProphylaxisPharmacologic Prophylaxis

Patients with high risk for DVT and PEPatients with high risk for DVT and PE Low dosesLow doses (below full anticoagulation dose) of (below full anticoagulation dose) of

anticoagulants (anticoagulants (’s risk of bleeding) decreases ’s risk of bleeding) decreases incidence of DVT/PE:incidence of DVT/PE: Unfractionated Heparin Unfractionated Heparin Low molecular weight (LMW) heparin Low molecular weight (LMW) heparin

Sometimes continued as OP (warfarin/coumadin) Sometimes continued as OP (warfarin/coumadin) in patient likely to remain immobile.in patient likely to remain immobile.

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Pulmonary HypertensionPulmonary Hypertension

Pulmonary circulation is a low pressure system Pulmonary circulation is a low pressure system with high blood flow and low PuVR (200 with high blood flow and low PuVR (200 resistance units compared with 800-1000 RU for resistance units compared with 800-1000 RU for the systemic circulation. the systemic circulation.

In a variety of disease states (e.g. PE) there is In a variety of disease states (e.g. PE) there is constriction of smooth muscle in the walls of constriction of smooth muscle in the walls of pulmonary arteriolar resistance vessels.pulmonary arteriolar resistance vessels.

Pulmonary Hypertension is present when the PAP Pulmonary Hypertension is present when the PAP rises to a high level, inappropriate for a given rises to a high level, inappropriate for a given level of cardiac output.level of cardiac output.

PPH- rare idiopathic disorder in woman.PPH- rare idiopathic disorder in woman.

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Idiopathic (Primary) Pulmonary Idiopathic (Primary) Pulmonary HypertensionHypertension

No other underlying cardiopulmonary disease: An No other underlying cardiopulmonary disease: An arteriopathy. Medial hypertrophy, fibrosis and arteriopathy. Medial hypertrophy, fibrosis and recanalized thrombi are common pathology recanalized thrombi are common pathology findings; poor prognosis- mean survival post Dx is findings; poor prognosis- mean survival post Dx is 2-5 years.2-5 years.

Marked Marked PuVR and PAP.PuVR and PAP. Association: Association: anorexigensanorexigens, collagen-vascular , collagen-vascular

disease.disease.– FenflouramineFenflouramine appetite suppressants: Marked recent appetite suppressants: Marked recent

in PPH (U.S. and Europe); similar events in 1960’s in PPH (U.S. and Europe); similar events in 1960’s with Amrinox. Both taken off market.with Amrinox. Both taken off market.

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Secondary Pulmonary HTNSecondary Pulmonary HTN

Reduction of x-sectional area of the pulmonary Reduction of x-sectional area of the pulmonary vascular bed:vascular bed:– Vasoconstriction: Vasoconstriction: Hypoxia from any cause Hypoxia from any cause ((most most

important and potent stimulusimportant and potent stimulus), lactic acidosis. ), lactic acidosis. – Loss of vessels: Vasculitis, emphysema, interstitial dis.Loss of vessels: Vasculitis, emphysema, interstitial dis.

Obstruction of vessels: Multiple or recurrent PE.Obstruction of vessels: Multiple or recurrent PE. Chronically increased pulmonary Chronically increased pulmonary venousvenous pressure pressure

(HF, mitral stenosis).(HF, mitral stenosis). pulmonary blood flow: Congenital Ht Disease.pulmonary blood flow: Congenital Ht Disease. Once present, secondary structural changes occur Once present, secondary structural changes occur

resulting in further destruction of vessels.resulting in further destruction of vessels.

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Signs and SymptomsSigns and Symptoms

Dyspnea- initially exertional, then rest.Dyspnea- initially exertional, then rest. Retrosternal chest pain (mimics angina); fatigue Retrosternal chest pain (mimics angina); fatigue

and syncope result from decreased CO.and syncope result from decreased CO. Physical Exam: Narrowly split or single SPhysical Exam: Narrowly split or single S22, , PP22..

CxR: Dilated main PA with “pruning” of vessels.CxR: Dilated main PA with “pruning” of vessels. Echo-Doppler: best non-invasive tool: RAE, RVE; Echo-Doppler: best non-invasive tool: RAE, RVE;

elevated PA and RV systolic pressure.elevated PA and RV systolic pressure. Right heart cath: precise measurement of right Right heart cath: precise measurement of right

heart pressures essential to Dx and Rx.heart pressures essential to Dx and Rx.

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TreatmentTreatment

Treat underlying disease process if present.Treat underlying disease process if present. Supplemental chronic OSupplemental chronic O22 if hypoxemic. if hypoxemic.

Full anticoagulation: PPH onlyFull anticoagulation: PPH only Prostacyline (Prostacyline (Epoprostenol, Treprostinil)Epoprostenol, Treprostinil)::

via continuous IV infusion potent via continuous IV infusion potent pulmonary vasodilator; pulmonary vasodilator; symptoms and symptoms and mortality.mortality.

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TreatmentTreatment

BosentanBosentan (Tracleer): new oral endothelin-1 (Tracleer): new oral endothelin-1 receptor antagonist for chronic PAH; receptor antagonist for chronic PAH; symptoms.symptoms.

SildenafilSildenafil: inhibits phosphodiesterase type 5; : inhibits phosphodiesterase type 5; pulmonary vasodilator- improves symptoms.pulmonary vasodilator- improves symptoms.

Lung or heart/lung transplant: 50-65% 2 year Lung or heart/lung transplant: 50-65% 2 year survival. Better long term survival with bilateral survival. Better long term survival with bilateral (vs. unilateral) lung transplant.(vs. unilateral) lung transplant.