PULMONARY HYPERTENSION

BY DR ALLAN RAJULA

PATIENTS DETAILS

Patient name; EC Age; 32 years Sex; F

PRESENTING COMPLAINTS

Difficulty in breathing Chest pain Generalized body weakness Cough

HISTORY OF PC

Above Patient comes as a referral from MTRH where was admitted from 28/12/04 to 06/01/05 Progressive worsening of above symptoms Sought medical help when dyspnoeic at mild exertion and cough productive of pink frothy sputum No history of smoking, alcohol use

PAST MEDICAL HISTORY

Patient diagnosed to be asthmatic 3 years prior on basis of clinical symptoms

OBGY HX

Patient has five living children Last delivery was in February 2004 Subsequently began to use depot provera had 3 injections by time of admission at Eldoret Periods Irregular post delivery 5/28 prior to last pregnancy

SYSTEMIC INQUIRY

? History of right sided leg swelling spontaneous in onset around time of presenting complaints resolved on its own prior to admission

ON EXAMINATION

No pallor, jaundice, cyanosis, lymphadenopathy, oral thrush, edema, dehydration Vitals; BP 110/70, PR 98/min, O2 sats 94% on oxygen 10l/min

CARDIOVASCULAR SYSTEM

Of Significance; Prominent P2

RESPIRATORY SYSTEM

Tachypneic at 28/min obvious resp distress lungs clear.

OTHER SYSTEMS

No other anomalies found

INVESTIGATIONS

Full hemogram - Normal U/E/Cs normal LFTs - Tbil 18,direct 6, ALP 606, GGT 108, SGOT- 128 SGPT 80 Cardiac enzymes- normal including troponin Amylase normal HIV negative

FURTHUR INVESTIGATIONS

ECG sinus tachycardia right axis deviation, prominent p waves CXR slight depletion of pulmonary vascular markings on the right side 2D ECHO RA and RV markedly enlarged, PAP of 78, Ef 63%, left side normal, pulmonary valves normal CT ANGIO Massive bilateral pulmonary thromboembolism

MANAGEMENT

Initially in ICU, then HDU then General wards Pt put on oxygen, clexane, warfarin, INR maintained bn 2.5 and 3.5, clexane stopped on day 7. Thrombolysis considered but it was too late at this point to be of any use

SUBSEQUENT PROGRESS

Progressive improvement first 10 days of treatment improving from NYHA grade 4 to 3, o2 sats of 98 on oxygen, 90 of oxygen Developed dyspnea o2 sats 94 of oxygen Developed sacral edema pitting, gallop rhythm, tender hepatomegally.

SP

At this point consulted cardiologist Recommended low dose frusemide and aldactone and to contact cardiothoracic surgeons for embolectomy. Repeat Ct angio showed no progress in PTE but noted beginnings of cavitation on areas of lung distal to obstruction.

SP

Decision for embolectomy finally decided day 13 pt n husband advised and sought finances. Day 14 patient to be transferred to matta hos Day 15 patient left after clearing hospital bills Surgery booked for day 19 at matta

SP

At surgery Pulmonary vessels found to be clean and patent catheter pushed in up to 15cm into each vessel Pulmonary pressure found to be elevated by transducer Lung biopsy taken to look for possible interstitial disease

DISCUSSION
CURRENT MANAGEMENT OF PULMONARY HYPERTENSION

DEFINITION

PAH is a disease of the small pulmonary arteries characterized by progressive vascular proliferation and remodeling. Theres a progressive increase in pulmonary arterial pressures eventually leading to right sided failure and death

PATHOPHYSIOLOGY
Three main mechanisms; 1. Vasoconstriction 2. Remodeling of pulmonary vessel wall 3. Thrombosis in situ It is now evident that endothelial dysfunction has a significant role to play in the above. Chronic impairment of NO and PGI2 synthesis with over expression of endothelin1 promote vasoconstriction as well as remodeling.

NATURAL HX AND SURVIVAL

In the 80s it was shown that the mean survival of patients was 2.8yrs after diagnosis. Large prospective studies showed 68 to 77%, 40 to 56%, 22 to 38% at 1,3 and 5yrs V. poor prognosis with NYHA class 3,4+ right sided failure, decreased CO in pulHT 6 minute walk test now taking precedence over NYHA as a more objective assessment with strong independent association with mortality

CAUSES

Pulmonary hypertension a) Idiopathic b) Familial c) Associated with; -Collagen vascular disease -congenital left to right shunt -Portal hypertension -HIV -Others: type 1 GSD, gauchers dx, splenectomy, thyroid disorders, myeloproliferative disorders, hemoglobinopathies, HHTelangiectasia d) Associated with substantial venous or capillary involvement - pulmonary venooclusive disease - pulmonary capillary hemangiomatosis e) persistent primary pulmonary hypertension of newborn

CAUSES

Pulmonary hypertension with left heart disease a) left sided atrial or ventricular heart disease b) left sided valvular heart disease

CAUSES

Pulmonary hypertension associated with lung disease, or hypoxemia or both. a) COPD b) Interstitial lung disease c) sleep disorderd breathing d) Alveolar hypoventilation disorders e) Chronic exposure to high altitude d) developmental abnormalities

CAUSES

Pulmonary hypertension due to chronic thrombotic or embolic disease or both a) TE obstruction of proximal pulmonary arteries b) TE obstruction of distal pulmonary arteries c) non thrombotic pulmonary embolism (tumor, parasites, foreign material)

CAUSES

Miscellaneous; lymphangiomatosis, sarcoidosis, pulmonary langerhans cell histiocytosis, compression of pulmonary vessels by tumor, adenopathy, or fibrosing mediastinitis.

THERAPEUTIC STRATEGIES

Patients with PAH have restricted pulmonary circulation. Increased oxygen demand can worsen RVF s well as the PAH. Patients r however still encouraged to exercise within their limits to prevent overall deconditioning. Extreme caution in those with severe dx who develop dizziness, light headedness or severe dyspnea as they are at risk of life threatening syncope Chronic hypoxemia develops due to impaired cardiac output. In this situations ambulatory oxygen is required to keep oxygen saturations above 90%

Low dose diuretic therapy may achieve remarkable symptomatic improvement in patients with PAH n right sided heart failure. Cardiac glycosides not shown to have a role except in situations of cor pulmonale with left sided heart failure. Theoretically digoxin may have a role due to its sympatholytic effects, PAH has been shown to be partly due to neuro hormonal response. No studies have been done on this however. But certainly it should b useful in those patients with concomitant intermittent or chronic a fib.

Pregnancy and labor are contraindicated in this patients due to increased circulatory demands. IUCDs n BTLs are advised but in those too compromised to tolerate the above minor procedures, may give OCs with predominant progesterone if no hx of thromboembolic dx, or consider vasectomy of the partner. Anticoagulant therapy is not proven to be of benefit but the rational is that these people are predisposed to venous thromboembolism due to heart failure and the reduced physical activity i.e. develop sedentary lifestyles.

Warfarin has been shown in two small non randomized studies one retrospective n one prospective to be useful n this has been the basis of the current recommendation of an INR of between 1.5 and 2.5

CALCIUM CHANNEL BLOCKERS

Idea came into play as its thot that PAH may be partly due to pulmonary vasoconstriction. Uncontrolled studies indicate that long term management with high doses of CCBs may have long term benefit To asses those who will benefit, acute vasodilator challenge is performed, with a pulmonary artery catheter in situ, prostacyclin, nitrous oxide or adenosine is administered in a patient who has not received any inotropes or vasodilators in at least 36hrs Avoid CCBs for acute vasodilator response due to well documented life threatening hemodynamic compromise.

Unfortunately its unknown what magnitude of response will indicate that such a patient will have long term sustained benefit on CCBs In a retrospective analysis of 557 patients, less than 7% had long term beneficial response, and those who did had favorable vasodilator response, ie improvement of PAH by 10mmhg, to below 40mmhg, with normal or high cardiac output. Those not satisfying these did not benefit

PROSTACYCLIN THERAPY

The chief product of arachidonic acid it causes smooth muscle relaxation via increasing cAMP levels. Also prevents their growth. A potent inhibitor of platelet aggregation. First used in the 80s as intravenous epoprostenol, failure of acute hemodynamic response doesnt preclude long term benefit. A prospective randomized open trial of 81 patients having PAH with NYHA class 3 or 4 was conducted where participants were randomly assigned to receive either convectional therapy alone or with eponesterol

Convectional therapy consisted of warfarin, oxygen, oral vasodilators and diuretics. The group with eponesterol showed an increase in the 6 minute walk by 32m while the other a decrease by 15m with a p value <0.003. the eponesterol group had a decrease in MPAP of 8% compared with an increase of 3% in the convectional group Mean pulmonary vascular resistance decreased by 21% in eponesterol group and increased by 9% in convectional group p<0.01 Eight patients in the convectional group died and none in the eponesterol group

Another study of 178 patients survival rate at 1 yr was 85%, 58% for control group, 70% at 2 years,43% for control, 63% at 3 years, 33% for control and 55% at 5 years, 28% for control In general patients who remain at NYHA class 4 despite 3 months of therapy remain candidates for lung transplantation. Less response in patients with scleroderma and related conditions. Response noted in PHT associated with HIV, portal HTN, and CHD

Its given as an infusion due to its short half life of 3 mins and inactivation by low ph. Administered therefore via a perm subclavian catheter Limitations- costly, complicated, a/e ie diarrhea, jaw pain, leg pain, nausea, flushing but these r mild n dose related. Catheter related sepsis at 0.1 to 0.6 per year. In patients with vaso -occlusive disease severe pulm edema n death can occur possibly due to increased pulm perfusion with downstream vascular obstruction

SUBCUTANEOUS TREPOSTINIL

Was developed due to the catheter site complications associated with eponesterol Patients can safely b switched from eponesterol to trepostinil the sc infusion A randomized placebo controlled trial done using 470 patients with either primary pulmonary hypertension or secondary to collagen vascular disease or congenital left to right shunt. Overall over 12 weeks those on it as opposed to placebo had an improvement in the 6 minute walk of 16m n those with primary dx of 19m

It appears to improve indices of dyspnea, signs and symptoms of pulmonary hypertension Commonest side effect was injection site pain, which led to 8% of subjects discontinuing treatment.

ORAL BERAPROST

First biologically stable orally active prostacyclin analogue Reaches peak concentrations in 30 minutes with an elimination half life of 35 to 45 minutes In a 12 week randomized double blind study 130 patients with PHT of various causes There was an overall increase in the 6 minute walk test of 25m in the beraprost group Cardiovascular hemodynamics did not significantly improve Its benefit however is not sustained i.e. begins to wane of at 9 to 12 months, hence benefit of 3 month trials?

Its approved for use in Japan for treatment of PHT

ENDOTHELIN RECEPTOR ANTAGONISTS

Endothelin 1 besides its direct vasoconstricting properties also causes proliferation of vascular smooth muscles, acts as a co- mitogen, induces fibrosis, and is a proinflammatory mediator due to its capacity to enhance the expression of adhesion molecules Effects of endothelin 1 are mediated through ETa and ETb receptors. ETa receptor activation causes sustained vasoconstriction and proliferation of vascular smooth muscle cells, whereas ETb receptors mediate pulmonary endothelin clearance and induce production of nitric oxide and prostacyclin by endothelial cells.

BOSENTAN

2 randomized double blind placebo controlled trials have assessed its efficacy in management of PHTN In one study a 72m increase in the 6MWT was noted while in the second a 52m increase was noted with a 44m increase in those with secondary PHTN It is metabolized in the liver and may cause an elevation in aminotransferase level like its analogues, ambrisentan and sitaxsentan This effect is dose dependent

An echocardiographic study involving 85 patients showed that it improves cardiac index, right ventricular systolic function and left ventricular early diastolic filling leading to a decrease in right ventricular dilatation and an increase in left ventricular size Monthly monitoring of liver functions is mandatory No reports of liver failure or permanent liver dysfunction

SITAXSENTAN AND AMBRISENTAN

selectively work on ETa receptors Still under investigation A few cases of hepatitis reported and one of the cases was fatal

POTENTIAL FUTURE THERAPIES

NITRIC OXIDE; A potent vasodilator, it works by stimulating guanylate cyclase which in turn increases levels of cGMP A defect in its production is a proposed mechanism for PHT Shows good response as inhalation acutely, a few case reports show long term benefit An interruption in supply can cause hemodynamic interruption Suggested that l arginine, the substrate for NO synthase reduces PHTN

SILDENAFIL

Another proposed strategy for mgt of PHTN is by preventing the breakdown of NO dependent cGMP by phosphodiesterase type 5 inhibitors No studies on long term effect Studies show synergy in combo wit prostacyclin analogues e.g. iloprost Delivered intravenously

VASOACTIVE INTESTINAL PEPTIDE

A member of the super family that secretes glucagon - growth hormone releasing factor, it inhibits platelet activation and proliferation of vascular smooth muscle, and is a potent pulmonary vasodilator. Its inhalation led to significant functional and hemodynamic improvement in eight patients with primary pulmonary HTN

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Suggested as serotonin appears to be a key player in the pathogenesis of various types of human and experimental forms of PAH. Therapies such as fluoxetine have been suggested No trials exist on the use of these drugs in PAH

COMBINATION THERAPY

Adjunctive therapy with sildenafil or bosentan has produced favorable outcomes in patients already on oral, inhaled or intravenous prostacyclin analogues. Conversely a recent study showed that add on of sildenafil on patients already on vasodilators e.g. CCBs, epoprostenol or bosentan had minimal to no effect Overall need more studies with adequate statistical power to assess effect of combination therapy in patients with PAH

THE END