Grand Rounds Presentation 3/27/2015

SHORTNESS OF BREATH

Medical History Atrial fibrillation COPD HTN Mitral insufficiency Obesity

HPI

SOB for 2 weeks Orthopnea PND Weakness Lower extremity edema Weight gain

Surgical History Left rotator cuff repair Right total knee

arthroplasty

Family History Father-CVA, CAD Mother-CAD, Cancer

Social History Lives with husband Quit smoking-1ppd 50yrs Denies alcohol/drug use

77 YR F

Allergies NKDS

CASE #1

T98.3 P146 R24 BP 133/86 Pulse Ox 82% on room air

12.19

11.1

189

34.8

141

3.8

105

31

13

0.7147

BNP 1056 POC trop <0.02

Total bili 1.10 AST 10 ALT 26 Alk Phos 83 Albumin 2.7

Physical Examination General Appearance: pale, alert, awake,

conversant, oriented HEENT: AtNc, PERRLA, EOMI, JVD + Cardiovascular: Irregularly irregular,

pedal edema, 3+ pitting tibial edema Respiratory: Crackles, Oxygen-on 4L

NC GI: soft, nontender Extremitites: moves all; pitting edema Neuo: alert, oriented, normal speech

ADMITTING DX HOME MEDICATIONS

Home meds: Metoprolol Tratrate 23mg

PO BID Aspirine 81mg Daily Citalopram 20mg PO daily Tramadol 50mg Q6 prn Rivaroxaban 20 mg c Din Atrovastatin 10mg PO

daily Dronedarone 400mg BID Promethazine 25md PO

Q4 prn

New onset CHF Atrial fibrillation RVR

ED course ▪ Cardizem 60mfg PO▪ ASA 325mg▪ Lasix 20mg IV

ECHO

LVEF 65%, No RWMA Left atrium moderate-

severe dilation Mitral Valve prolapse

with moderate – severe regurgitation

R/LHC

Pulmonary artery pressure 55

Mean PCWP 27 EF 48%, 4+ mitral

regurgitation into enlarged left atrium

45 YR OLD MAN

Medical History Asthma

Surgical History Denies

Social History Broker Denies alcohol, drug use Quit smoking 5 yrs ago▪ 20 pack yr history

PROGRESSIVE DYSPNEA 8 months Attributed to asthma Not responding to

inhalers or oral steroids

Family History Sisters died of breast cancer Brother died of pulmonary

hypertension

CASE #2

Allergies NKDA

T98.3 P100 R20 BP 121/82 Pulse Ox 80% on room air

9.8

17

196

56

138

4.2

105

35

8

0.787

Physical ExaminationGeneral Appearance: alert, awake, orientedHEENT: AtNc, PERRLA, EOMI, JVD +Cardiovascular: Loud P2, S3, Grade 1, MRLE 1+ pitting edemaRespiratory: diffuse crackles, wheezesGI: soft, nontenderExtremitites: moves all; pitting edemaNeuo: alert, oriented, normal speech

Admitting DX Home Medications Home meds:

Albuterol Symbicort

Duonebs

New onset CHF Acute Asthma

Exacerbation ED course ▪ Bronchodilators▪ Oxygen▪ Lasix 40mg X1

ECHO

Tricuspid regurgitation

PAP of 75mmHg

RHC

PCWP 8

VQ scan pending to rule out embolism

Pulmonary Hypertension

Definition ClassificationPhysiology & PathophysiologySings and Symptoms Diagnostic Approach TreatmentPrognosis Follow up

Definition

WHO Classification of PHTN

Factors of Late Diagnosis

Symptoms Pulmonary arteries can withstand

changes in hemodynamic 10x the normal Delay in symptoms and signs

manifestation▪ With progressive decline cardiac output

Physiology – Regulation of pulmonary vascular tone

Endothelin Prostacylcin Nitric Oxide

Endothelin

Expressed on endothelial and smooth muscle cells Endothelial cell express Endothelin-B▪ vasodilation

Smooth muscle cells express Endothelin-A and B▪ A-vasoconstriction and cellular proliferation▪ B-vasoconstriction

PAH endothelin levels are elevated Down-regulation of ETB on endothelial cells and

up-regulation on smooth muscle cells Decrease in vasodilation, increased in vasoconstriction Leads to constriction, proliferation and hypertrophy

Nitric Oxide

Continuously produced in the endothelium Vasodilation inhibition of platelet aggregation inhibition of cellular proliferation thrombus formation inflammation

In PAH- levels are decreased, vasoconstriction and cellular proliferation

Prostacylcin

Produced in the endothelial cells Potent vasodilator

In PAH - Reduced Decreased vasodilation and anti-

proliferative effect

Group 1- Pathophysiology and Pathology

Vasoconstriction theory- imbalance between locally produced vasodilators

such as nitric oxide and prostacyclin and vasoconstrictors such as endothelin and thromboxane

New data reflects the role of vascular wall remodeling proliferating endothelial and smooth muscle cells abnormalities in the extracellular matrix ▪ predisposing factors are the mutations in the BMPR2 gene

that result in FPAH and some cases of sporadic IPAH▪ connective tissue disease, the possibility of an

autoimmune injury leading to casulopahty

Group 1- Pathophysiology and Pathology

Destructive vascular changes Inflammation vasoconstriction Cell proliferation/hypertrophy ▪ Tunica intima proliferation▪ Fibrotic changes of tunica intima- concentric and

eccentric▪ Tunica media hypertrophy ▪ Tunica adventitial thickening

Thrombotic lesions Plexiform lesions

Group 2- Pathophysiology and Pathology

Group 2: Left heart disease Enlarged and thickened pulmonary veins Pulmonary capillary dilation Interstitial edema Alveolar hemorrhage Distal pulmonary arteries may be

affected by medical hypertrophy and intimal fibrosis

Group 3- Pathophysiology and Pathology

Group 3 : Lung disease/Hypoxia Medial hypertrophy and intimal

obstructive proliferation of the distal pulmonary arteries

Various degree of destruction of the vascular bed in emphysematous or fibrotic areas

Group 4 &5- Pathophysiology and Pathology

Group 4: Chronic thromboembolic pulmonary hypertension Organized thrombi attached to pulmonary

arterial medial layer in the elastic pulmonary arteries replacing the normal intima

Complete occlusion of the lumen , or form different grade of stenosis , webs or bands

Group 5 Unclear/multifactorial Heterogeneous conditions with different

pathological pictures

Presentation

SYMPTOMS

Non-specific Early symptom s▪ Dyspnea▪ Fatigue▪ Weakness

Late Symptoms ▪ Angina▪ LE edema ▪ Abdominal fullness/pain▪ Syncope▪ Dyspnea at rest

SIGNS

Accentuated P2 Pansystolic murmur of

TR Diastolic murmur of

PR RV third heart sound Jugular vein distention Hepatomegaly Peripheral edema Ascites Cool extremities

Diagnostic Approach

Unexplained dyspnea Comorbidity/ high risk patients

Family history of PAH Connective tissue disease HIV Congenital heart disease Chronic liver disease

Diagnostic Approach

Identifying the presence of PHT Identifying the cause on the bases of

clinical classification Screening/diagnostic tools

Chest radiography Transthoracic Doppler echocardiography Ventilation and perfusion lung scan Chest high resolution computed

tomography Pulmonary angiography

Diagnostic Tools

CHEST RADIOGRAPHY

Central pulmonary arterial dilation with attenuation of peripheral pulmonary vasculature

Cardiomegaly , right ventricular enlargement

Help identify underlying pulmonary parenchymal disease –ILD, COPD, pulmonary vascular congestion due to left hear disease, pleural effusion

Diagnostic Tools

Low specificity & sensitivity Provides supportive evidence RVH, strain, right atrial dilation, left

atrial dilation

Electrocardiogram

Diagnostic Tools

TEE

Initial non-invasive test help screen/suggest diagnosis of PH

Identify valvular abnormalities , left atrial enlargement, myocardial abnormalities, pericardial effusion, ventricular enlargement, pressure

Congenital heart disease

Diagnostic Tools

VENTILATION AND PERFUSION LUNG SCAN

Distinguish CTEPH Multiple large

segmental perfusion defects

Normal VQ rules out Severity

Diagnostic Tools

Pulmonary Function Test

Blood test Uric acid, brain

natriuretic peptide, anticentromere antibodies, serum creatinine, thyroid function, antinuclrear antibodies, etc.

AccurateDiagnosis

Determines treatment course

Group 2-5 Treat underlying

disorder Group 1 PAH

Lung disease

Chronic PE

Heart failure

Vasoreactivity with RHC

RHC Required to confirm diagnosis Assess the severity of the

hemodynamic impairment Assess vasoreactivity of the

pulmonary circulation Short acting drugs

Inhaled NO, IV epoprostenol, IV adenosine

Benefit from long-term therapy with CCB

Positive acute response is mPAP >10mmHG to reach an absolute value of MPAP <40mmHg with concurrent increased or unchanged CO

Can be treated safely with high dose CCBs Only positive reactive 95% five-year survival

Treatment in PAH

Based on vasoreactivity and functional class New York Heart Association Functional

Class▪ Class I: No symptoms with ADL▪ Class II: some symptoms with ADL, slight

limitation ▪ Class III: symptoms with less than normal

ADL, increased limitation of physical activity ▪ Class IV: symptoms with any activity, even at

rest

No Treatment

Untreated = 6months Median survival rate is 2.8 yrs

WHO FC IV 6 months WHO FC III 2.5 yrs WHO FC I and II 6 yrs▪ Scleroderma ~1yr

Prognostic Factors

Prognosis

Therapeutic Approaches

No cure Goal

Symptomatic relief Quality of improvement Survival prolongation

Basic/ Supporitve Therapy PAH

Activity as tolerated, limit

Oxygen sat >90%, decrease hypoxic vasoconstriction-nocturnal desaturation

Diuretics AC – IPAH INR 2.0 – 2.5

(decrease in situ thrombosis)

Digoxin Avoid pregnancy Immunization –influenza

and pneumococcal

PAH specific therapy

Medical Surgical therapy

Atrial septostomy –decrease right sided pressure, improve left sided filling pressure

Transplant

Calcium channel blockers Endothelial Receptor

Antagonists Bodentan, Sitaxsentan,

Ambirisentan Phosphodiestaerases

Inhibitors Sildeneafil, Tadalafil,

Varadenafil Prostaglandins

Epoprostenol, Treprostinil, lloprost

Guanylate cyclase stimulant -Riociguat

Treatment of PAH

CCB Pt who show response to acute vasodilator

testing at the time of RHC Nifedipine, diltiazem, amlodipine ▪ Choice depends on pt’s baseline hear rate ▪ Relative bradycardic –nifedipine and amlodipine▪ Tachycardia – diltiazem

120-240mg nifedipine 240-720mg diltiazem 20mg amlodipine

Limiting factors hypotension, LE edmea Follow up – 3-4 month RHC, change in functional class Negative vasoreactivity should not be started on CCB-severe

side effects –hypotension, syncope, RV failure

Prostanoids

Prostacyclin Developed by endothelial cells Induce potent vasodilation of all vascular beds▪ Inhibitor of platelet aggregation, antiproliferative

▪ Synthesis of stable form

▪ Epoprostenol- an infusion pump and permanent tunnelled catheter

▪ Lloprost- IV, oral and aerosol administration ▪ Treprostinil- IV, SC

Epoprostenol Synthetic prostacyclin Half life of 3-5minutes, stable at room temperature for

~8hrs Administrated an infusion pump and permanent

tunnelled catheter Start at a dose 2-4ng/kg/min and increase at a rate

limited by side effects –flushing, headache, diarrhea, leg pain

Efficacy on three unblinded RCTS in patients with IPAH and in those with PAH associated with scleroderam ▪ Have shows that it improves symptoms, exercise capacity, and

hemodynamics ▪ Only treatment shown to improve survival in IPAH

Endothelin Receptor Antagonists

Endothelin-1 has vasoconstrictive and mitogenic effects pulmonary vascular smooth muscles-endothelin-A and B receptors

Bosertan- Oral Sitaxentan Ambrisentan

Bosertan Oral Dual endothelin-A and B receptor antagonist Started at dose of 62.5 mg BID and uptitrated to 125mg BID

after 4 weeks Five RCTs –Pilot, BREATHE-1, 2, 5 and EARLY Showed improvement in exercise capacity, functional class,

hemodynamics, echocardiographic Two RCT enrolled exclusively patients with WHO-FC II or patients

with Eisenmenger’s syndrome▪ Regulatory authority approval for its use in AHO- FC II and congenital

systemic –to-pulmonary shunts and Eisenmenger’s syndrome Side effects – increase in hepatic aminotransferases 10% , dose

dependent Liver function test monthly

Phosphodiestrease Inhibitors

Vasodilation and antiproliferative effects Sildenafil- Oral Tadalafil Vardenafil

Sildenafil Oral Selective inhibitor RCT – SUPER-1▪ 278 PAH patients treated with sildenafil 20,

40, 80mg tid▪ Favorable results on exercise capacity,

symptoms ▪ Side effects – headache, flushing, epistaxis

Combination Therapy

Fail monotherapy

Some Hemodynamics, exercise capacity and functional class improved

Follow up

Follow up