Pulmonary Hypertension

1
Pulmonary Hypertension
Dr Lisa Luckey, D.O. Internal Medicine Largo
Medical Center
2
History

• HPI Pt is a 74yo WF who was presented w/ c/o
  waking up from nap acutely SOB and shaking. Pt
  has a H/O O2 dependent COPD and found that her
  SOB improved at home w/ her O2. Pt denies F/C/S,
  URI symptoms and cough, CP/palpitations,
  N/V/D/C/abd pain. Pt was seen by cardiologist 1
  week ago for pre op risk stratification for L hip
  surgery. Per pt, she was o k to have surgery and
  no further workup was necessary. Pt also saw
  same cardiologist 1mo prior for f/u after her
  last admission. During that visit the pt was
  taken off of digoxin for her a fib and her
  medications were changed, to now include
  Lopressor and Lisinopril. Per old records pt had
  a R and L heart cath on 9/18/07, which showed
  normal cornary arteries, normal LV function w/
  and EF 55, and a PA pressure of 55, c/w
  moderate pulmonary HTN.
• In the ER the pt was noted to be hypotensive.
  She was given 1.7 L of NS and placed on a
  dopamine gtt. CXR showed b/l infiltrate,
  cardiomegaly, and vascular congestion. BNP was
  5151, but the pts creatinine was 2.1, likely ATN
  from hypotension.
• The pt was being treated as out pt for URI,
  which was still present on admission.
• The pt states her breathing was much worse than
  baseline. She admits to noticing a weight gain
  and increased edema for 1mo, since she has been
  chair-bound. Pt is currently resting in bed, w/
  SOB, still on dopamine gtt. Pt currently not on
  any med to control a fib. CEs are negative x 3.

3
History

• PMH Atrial fibrillation, HTN, OSA, O2 dependent
  COPD, Pulmonary fibrosis, Moderate Pulmonary HTN,
  GERD, H/O DVT, Lumbar spinal stenosis, Gout, OA,
  Restless leg synd.
• PSH Hysterectomy, Gastric bypass, B/L tubal
  ligation, T A, B/L cataract sx, IVC filter
  10/07, Cardioversion X 3, Cardiac Cath 9/18/07
• Social Retired, Lives w/ daughter. Quit smoking
  10yrs ago, only 7pk/yr smoking history. Admit to
  occasional ETOH use and denies use of illicit
  drugs.
• Family Mother ? _at_ 96 2 to ESKD and Uterine Ca
• Father ? _at_ 61 2 to MI
• Allergies Codeine (hives)

4
History

• Home meds
• Combivent up to 12 x daily
• Advair 250/50 1 puff BID
• Vitamin D 1 x week
• Oxycodone 10/650mg BID prn pain
• Lasix 40mg q am and 60mg _at_ noon
• KCl 10mEq daily
• Fentanyl 25mcg patch ? q 72hr
• Toprol XL 25mg daily
• Lisinopril 5mg daily
• Coumadin 2mg daily except 3mg on M and F
• Colchicine 0.6mg BID
• Allopurinol 300mg q HS
• Cardizem 360mg daily
• Trazodone 150mg q HS
• BiPAP q HS
• O2 4L via NC
• Bactrim DS (only took one pill of Rx)

• Hospital meds
• Lovenox 1mg/kg SQ daily
• Protonix 40mg BID
• Coumadin 2mg daily except 3mg on M and F
• Colchicine 0.6mg BID
• Allopurinol 300mg q HS
• Flagyl 500mg IV q 6hr
• Levaquin 750mg IV daily
• Dopamine gtt _at_ 10mcg/kg
• Zofran 4mg q 4hr prn N/V
• Morphine 2mg IV q 3-4hr prn pain

5
Physical

• VS 97.2 / 68 / 22 / 88/45 / 88 on 4L NC
• General AO x 3, Resp distress/dyspnea
• HEENT NC/AT, PERRL/EOMI, dry mucous membranes,
  tongue/uvula midline
• Neck Thick, supple, no JVD or bruit
• Lungs B/L rales and exp. Wheeze
• CV Irreg Irreg, no murmur noted
• Abd Morbidly obese, soft, NTND, BS, no R/G
• Ext 1 pitting edema, no clubbing or cyanosis

6
Labs

• ABG 7.36/54/141/99/30 on 100 NRM
• CBC WBC 9.24, H/H 8.8/30, PLT 175
• Coags PT 17, INR 1.7
• CMP Na 131, K 5.1, Cl 94, Bicarb 32, BUN 47,
• Creat 2.1, Glucose 124, Ca 8.8, Mg
  2.5
• Mb 64? 58? 52
• Trop I 0.02? 0.01 x 2
• Pro BNP 5151
• UA 2LE w/ 11-20 WBCs, few bacteria, and 3 bld
  w/ 4-10 RBCs

7
Imaging

• ECHO Normal LV and RV size w/ concentric
  hypertrophy and no wall motion abnormalities. EF
  60. Mild AR, and MR, w/ mild to moderate TR w/
  pulmonary systolic pressure of 55, c/w mod
  pulmonary HTN. Enlarged R and L atria.
• R and L heart cath Right atrial pressure was 10,
  right ventricle was 50/5, PA pressure 52/25 with
  mean of 37, aortic pressure 125/69, left
  ventricular pressure 128/8, pulmonary capillary
  wedge pressure 20. 2. Oxygen saturations
  Arterial oxygen saturation 96, right atrial
  oxygen saturation 56, pulmonary artery 57.2.
• Normal-appearing coronary arteries.
• Normal left ventricular function with EF of 65.
  
• Elevated right heart chamber pressures.
• Successful vascular closure.
• Normal left heart chamber pressures

8
Admit Assessment

• Hypotension secondary to hypovolemia and anemia
• Bradycardia. Pt was on metoprolol and cardizem as
  outpatient. Pt was admitted today and took meds
  prior to coming in.
• Dyspnea. Multifactorial.
• Anemia. Two units PRBCs ordered. Pt being worked
  up for GIB.
• UTI
• Chronic Atrial fibrillation. Pt currently in A
  fib w/ a rate in 50s-60s, and w/ subtherpeutic
  INR.

9
Admit Assessment

• Respiratory Acidosis. Pt w/ interstitial lung
  fibrosis, O2 dependent COPD, and OSA
• H/O Diastolic Dysfunction/Diastolic heart
  failure. Pro BNP is 5151, but pt w/ CKD and
  clinically dry, not likely AE CHF.
• Pulmonary HTN w/ PA pressure of 55
• O2 dependent COPD
• Idiopathic pulmonary Fibrosis
• OSA w/ BiPAP q HS. Pt somewhat non compliant w/
  BiPAP.
• Usually w/ HTN, but currently w/ low BP and
  dopamine gtt.
• ARF, likely secondary to ATN from hypotension and
  possible increased diuretic dose.

10
Admit Plan

• Will check Digoxin level. Pt had digoxin d/cd
  1 month ago, but will check level to confirm pt
  stopped med.
• Agree w/ PRBCs
• Agree w/ ABX
• Wean dopamine gtt as tolerated
• Lasix is on hold secondary to hypovolemia and
  hypovolemia
• Reassess heart rate once pt is euvolemic. Pt is
  currently in A fib, but rate is only in 50s. BB
  and CCB being held for now secondary to
  hypotension and bradycardia.

11
Hospital Course

• Pt weaned off dopamine gtt by day 2
• HR slowly began rising, cardizem and toprol were
  added back
• As kidney function recovered lisinopril was added
  back for additional BP control and diuretic was
  added back at a lower dose. Rather than going
  home w/ lasix 80mg daily, pt was discharged on
  40mg daily.
• Pt was discharged once kidney function and
  breathing returned to baseline.

12
Pulmonary Hypertension

• Pulmonary hypertension (PH) is defined as a mean
  pulmonary artery pressure greater than 25 mmHg at
  rest or 30 mmHg with exercise, as measured by
  right heart catheterization. It was previously
  defined as a systolic pulmonary artery pressure
  greater than 40 mmHg, which corresponds to a
  tricuspid regurgitant velocity on Doppler
  echocardiography of 3.0 to 3.5 m/sec.

13
Pulmonary Hypertension

• Normal pulmonary arterial pressure in a person
  living at sea level has a mean value of 1216 mm
  Hg. Pulmonary hypertension is present when mean
  pulmonary artery pressure exceeds 25 mm Hg at
  rest or 30 mm Hg with exercise.
• Mean pulmonary artery pressure (mPAP) should not
  be confused with systolic pulmonary artery
  pressure (sPAP), which is often reported on
  echocardiogram reports. A systolic pressure of 40
  mm Hg typically implies a mean pressure more than
  25 mm Hg.

14
Classification

• Group 1 PAH "Pulmonary arterial hypertension
  (PAH)". The following hemodynamic parameters
  characterize PAH
•       -  Mean pulmonary artery pressure gt25 mmHg
  at rest or
• gt30 mmHg with exercise, AND
• -  Pulmonary capillary wedge pressure lt15 mmHg,
  AND
• -  Pulmonary vascular resistance gt120
  dynes/sec/cm5, AND
• - Transpulmonary gradient gt10 mmHg,
  defined as the
• difference between the mean pulmonary
  arterial pressure
• and the pulmonary capillary wedge
  pressure

15
Classification

• Group 1 PAH Examples "Pulmonary arterial
  hypertension".
• 1. Idiopathic (IPAH)
• 2. Familial (FPAH)
• 3. Associated with (APAH)
• Collagen vascular disease
• Congenital systemic-to-pulmonary shunts
• Portal hypertension
• HIV infection
• Drugs and toxins
• Other (thyroid disorders, glycogen storage
  disease, Gaucher disease, hereditary hemorrhagic
  telangiectasia, hemoglobinopathies,
  myeloproliferative disorders, splenectomy)
• 4. Associated with significant venous or
  capillary involvement
• Pulmonary veno-occlusive disease (PVOD)
• Pulmonary capillary hemangiomatosis (PCH)
• 5. Persistent pulmonary hypertension of the
  newborn

16
Classification

• Group 2 PH "Pulmonary venous hypertension".
• Examples
• 1. Left-sided atrial or ventricular heart
  disease
• 2. Left-sided valvular heart disease
• Group 3 PH "Pulmonary hypertension associated
  with disorders of the respiratory system or
  hypoxemia".
• Examples
• 1. Chronic obstructive pulmonary disease
• 2. Interstitial lung disease
• 3. Sleep-disordered breathing
• 4. Alveolar hypoventilation disorders
• 5. Chronic exposure to high altitude
• 6. Development abnormalities

17
Classification

• Group 4 PH "Pulmonary hypertension caused by
  chronic thrombotic or embolic disease".
• Examples
• 1. Thromboembolic obstruction of proximal
  pulmonary arteries
• 2. Thromboembolic obstruction of distal
  pulmonary arteries
• 3. Non-thrombotic pulmonary embolism (tumor,
  parasites, foreign material)
• Group 5 PH These patients have PH caused by
  inflammation, mechanical obstruction, or
  extrinsic compression of the pulmonary
  vasculature (eg, sarcoidosis, histiocytosis X,
  lymphangiomatosis, compression of pulmonary
  vessels by adenopathy, and fibrosing
  mediastinitis).

18
Causes

• Ordinarily, the blood flows easily through the
  vessels in the lungs, so the blood pressure is
  usually much lower in the lungs. With pulmonary
  hypertension, the rise in blood pressure is the
  end result of a process that begins with changes
  in the cells that line the lungs' arteries. These
  changes cause the formation of extra tissue that
  eventually narrows or completely blocks the blood
  vessels. Scarring (fibrosis) usually also occurs,
  making the arteries stiff and narrow. This makes
  it harder for blood to flow, raising the pressure
  in the pulmonary arteries.

19
Signs and Symptoms

• Most patients with PH initially experience
  exertional dyspnea, lethargy, and fatigue, which
  are due to an inability to increase cardiac
  output with exercise. As the PH progresses and
  right ventricular failure develops, exertional
  chest pain (ie, angina), exertional syncope, and
  peripheral edema may develop. In most
  circumstances, angina is due to subendocardial
  hypoperfusion caused by increased right
  ventricular wall stress and myocardial oxygen
  demand. However, angina can also be caused by
  dynamic compression of the left main coronary
  artery by an enlarged pulmonary artery this risk
  is greatest for patients with a pulmonary artery
  trunk at least 40 mm in diameter

20
Signs and Symptoms

• Passive hepatic congestion may cause anorexia and
  abdominal pain in the right upper quadrant. Less
  common symptoms of PH include cough, hemoptysis,
  and hoarseness (ie, Ortner's syndrome) due to
  compression of the left recurrent laryngeal nerve
  by a dilated main pulmonary artery.
• Dizziness or syncope
• Lower extremity edema and eventually ascites
• Cyanosis of the lips and skin

21
Physical Exam

• The initial physical finding of PH is usually
  increased intensity of the pulmonic component of
  the second heart sound, which may even become
  palpable. The second heart sound is narrowly
  split or single in patients with PH and preserved
  right ventricular function. Splitting of the
  second heart sound widens as the right ventricle
  fails or if right bundle branch block develops.
• Auscultation of the heart may also reveal a
  systolic ejection murmur and, in more severe
  disease, a diastolic pulmonic regurgitation
  murmur. The right sided murmurs and gallops are
  augmented with inspiration.
• Right ventricular hypertrophy is characterized by
  a prominent A wave in the jugular venous pulse,
  associated with a right-sided fourth heart sound,
  and either a left parasternal heave or a downward
  subxiphoid thrust.

22
Physical Exam

• Right ventricular failure results in systemic
  venous hypertension. This can lead to a variety
  of findings such as elevated jugular venous
  pressure, a right ventricular third heart sound,
  and a high-pitched tricuspid regurgitant murmur
  accompanied by a prominent V wave in the jugular
  venous pulse if tricuspid regurgitation is
  present. In addition, hepatomegaly, a pulsatile
  liver, peripheral edema, and ascites may exist.
• Some patients with PH due to severe COPD develop
  edema even in the absence of right heart failure.
  The pathogenesis of edema in such patients is not
  well understood. It has been hypothesized that
  edema may develop in these patients due to
  hypercapnia or hypoxemia. Hypercapnia is
  associated with an appropriate increase in
  proximal bicarbonate reabsorption, which
  minimizes the fall in arterial pH. This increase
  in proximal bicarbonate transport also promotes
  the passive reabsorption of sodium chloride and
  water, and may contribute to edema formation.

23
Diagnosis

• Chest radiograph 
• The characteristic chest radiograph shows
  enlargement of the central pulmonary arteries
  with attenuation of the peripheral vessels
• Right ventricular enlargement and right atrial
  dilatation may also be seen.

24
Diagnosis

• Electrocardiography may demonstrate
• Right ventricular hypertrophy or strain
• Chronic right ventricular overload
• Right axis deviation
• R wave/S wave ratio greater than one in lead V1
• Incomplete or complete RBBB
• Increased P wave amplitude in lead II (P
  pulmonale) due to right atrial enlargement.

25
Right ventricular hypertrophy
26
Atrial Enlargement
27
Diagnosis

• Echocardiography  Echocardiography is performed
  to estimate the pulmonary artery systolic
  pressure and to assess right ventricular size,
  thickness, and function. In addition,
  echocardiography can evaluate right atrial size,
  left ventricular systolic and diastolic function,
  and valve function, while detecting pericardial
  effusions and intracardiac shunts.
• Echocardiography uses Doppler ultrasound to
  estimate the pulmonary artery systolic pressure.
  This technique takes advantage of the tricuspid
  regurgitation that usually exists. The maximum
  tricuspid regurgitant jet velocity is recorded
  and the pulmonary artery systolic pressure (PASP)
  is then calculated
•  PAP systolic      (4  x  tricuspid
  jet velocity squared)    RAP
• A systolic pulmonary artery pressure greater than
  40 mmHg is suggestive of PH. Doppler
  echocardiography is limited when an adequate
  tricuspid regurgitant jet can not be identified,
  or underlying cardiopulmonary disease alters
  cardiac function.
• Patients with PH may have echocardiographic signs
  of right ventricular pressure overload, including
  paradoxical bulging of the septum into the left
  ventricle during systole and hypertrophy of the
  right ventricular free wall and trabeculae. As
  the right ventricle fails, there is dilation and
  hypokinesis, septal flattening, right atrial
  dilation, and tricuspid regurgitation.

28
Severe right chamber dilation
29
Representation of echocardiographic findings in
secondary pulmonary hypertension
30
Diagnosis

• Pulmonary function tests  Pulmonary function
  tests (PFTs) are performed to identify and
  characterize underlying lung disease that may be
  contributing to PH. An obstructive pattern is
  suggestive of COPD, while restrictive disease
  suggests interstitial lung disease, neuromuscular
  weakness, or chest wall disease.It is usually
  severe interstitial lung disease or obstructive
  lung disease that produces PH. In most
  circumstances, PH should not be attributed to
  lung disease if the PFTs are only mildly
  abnormal.
• Overnight oximetry  Nocturnal oxyhemoglobin
  desaturation can be identified by overnight
  oximetery. It is common in patients with PH
  whether or not obstructive sleep apnea-hypopnea
  (OSAH) coexists and may prompt supplemental
  oxygen therapy during sleep. Overnight oximetry,
  however, is not an acceptable diagnostic test for
  OSAH. Polysomnography is the gold standard
  diagnostic test for OSAH and should be considered
  when the clinical suspicion for OSAH is high, or
  the results of overnight oximetry are discordant
  with clinical expectation.

31
Diagnosis

• V/Q scan  Ventilation-perfusion (V/Q) scanning
  is used to evaluate patients for thromboembolic
  disease. A normal V/Q scan accurately excludes
  chronic thromboembolic disease with a sensitivity
  of 90 to 100 percent and a specificity of 94 to
  100 percent . When the V/Q scan suggests that
  chronic thromboembolic disease exists, pulmonary
  angiography is necessary to confirm the positive
  V/Q scan and to define the extent of disease.
• Laboratory tests  Blood tests performed in the
  diagnostic evaluation of PH include
• HIV serology to screen for HIV-associated PH
• Liver function tests to screen for portopulmonary
  hypertension
• Antinuclear antibody (ANA)
• rheumatoid factor (RF)
• antineutrophil cytoplasmic antibody (ANCA)
• N-terminal pro-brain natriuretic peptide
  (NT-proBNP) is the precursor of brain natriuretic
  peptide (BNP). Both peptides are released from
  the myocardial tissue of the right and left
  ventricle when stretched. Increasing evidence
  suggests that NT-proBNP and BNP are helpful in
  diagnosing heart failure. It has been
  hypothesized that measurement of either peptide
  may also be helpful in the diagnosis of PH, since
  right heart failure often complicates PH.
  Preliminary data are promising, although accuracy
  diminishes if renal dysfunction exists.

32
Diagnosis

• Exercise testing  Exercise testing is most
  commonly performed using the six minute walk test
  (6MWT) or cardiopulmonary exercise testing.
• Right heart catheterization  Right heart
  catheterization is necessary to confirm the
  diagnosis of PH and accurately determine the
  severity of the hemodynamic derangements. PH is
  confirmed if the mean pulmonary artery pressure
  is greater than 25 mmHg at rest or 30 mmHg with
  exercise. An additional benefit of right heart
  catheterization is that the presence and/or
  severity of a congenital or acquired
  left-to-right shunt can be confirmed when
  noninvasive studies are not definitive.

33
Algorithm for investigation of suspected PH
34
Risk Factors

• Although anyone can develop pulmonary
  hypertension, older adults are more likely to
  have a secondary cause of their pulmonary
  hypertension and young people are more likely to
  have idiopathic pulmonary hypertension.
  Idiopathic pulmonary hypertension is more common
  in women vs. men.
• Another risk factor for pulmonary hypertension is
  a family history of the disease. Some genes could
  be linked to idiopathic pulmonary hypertension.
  These genes might cause an overgrowth of cells in
  the small arteries of your lungs, making them
  narrower.

35
Complications

• Right-sided heart failure (cor pulmonale). In
  this condition, your heart's right ventricle
  becomes enlarged and has to pump harder than
  usual to move blood through narrowed or blocked
  pulmonary arteries. Initially, the heart tries to
  compensate by thickening its walls and expanding
  the chamber of the right ventricle to increase
  the amount of blood it can hold. But this measure
  works only temporarily, and eventually the right
  ventricle fails from the extra strain.
• Blood clots. Clots are the end result of a
  complex process that helps stop bleeding after
  you've been injured. But sometimes clots form
  where they're not needed. A number of small clots
  or just a few large ones can lead to pulmonary
  hypertension, which is reversible with time and
  treatment. Having pulmonary hypertension makes it
  more likely you'll develop clots in the small
  arteries in your lungs, which is dangerous if you
  have narrowed or blocked blood vessels.
• Arrhythmia. Irregular heartbeats from the upper
  or lower chambers of the heart are complications
  of pulmonary hypertension. These can lead to
  palpitations, dizziness or fainting and can be
  fatal.
• Bleeding. Pulmonary hypertension can lead to
  bleeding into the lungs and hemoptysis.

36
Generalized Treatment

• Diuretics  Diuresis will diminish hepatic
  congestion and peripheral edema. However, it
  should be performed with caution to avoid
  decreased cardiac output (due to decreased right
  and/or left ventricular preload), arrhythmias
  induced by hypokalemia, and metabolic alkalosis
  (which can depress ventilation). Although less
  common, fluid can also be removed by dialysis or
  ultrafiltration.
• Oxygen therapy  Continuous oxygen administration
  remains the cornerstone of therapy in patients
  with group 3 PH. It is inferred that oxygen may
  benefit other groups of patients with PH plus
  resting, exercise-induced, or nocturnal
  hypoxemia. Oxygen should be considered for all
  patients with pulmonary hypertension plus
  hypoxemia. The flow of oxygen needed to correct
  hypoxemia should be determined by measurement of
  the oxygen saturation with therapy. Most often
  oxygen is administered at 1 to 4 L/min via nasal
  prongs and adjusted to maintain the oxygen
  saturation above 90 percent at rest and, if
  possible, with exercise and sleep. Supplemental
  oxygen will not significantly improve the oxygen
  saturation of patients with congenital heart
  disease and right-to-left shunt (Eisenmenger
  physiology).

37
Generalized Treatment

• Anticoagulation  Patients with PH are at
  increased risk for intrapulmonary thrombosis and
  thromboembolism, due to sluggish pulmonary blood
  flow, dilated right heart chambers, venous
  stasis, and a sedentary lifestyle. Even a small
  thrombus can produce hemodynamic deterioration in
  a patient with a compromised pulmonary vascular
  bed that is unable to dilate or recruit unused
  vasculature. It is generally accepted that
  anticoagulation is indicated in patients with
  IPAH, familial PAH, group 4 PH, or who are at
  high risk for thromboembolism (eg, atrial
  fibrillation, severe left heart failure). The
  anticoagulant of choice is warfarin, with a
  therapeutic goal of an International Normalized
  Ratio (INR) of approximately two.
• Digoxin  Digoxin therapy has been shown to have
  the following beneficial effects and drawbacks
  In patients with group 3 PH due to COPD and
  biventricular failure, digoxin improves left
  ventricular EF. However, patients with COPD may
  be more sensitive than most patients to digitalis
  toxicity and require close monitoring. In
  patients with supraventricular tachycardias
  associated with right ventricular dysfunction,
  digoxin helps control the heart rate. However,
  verapamil is preferred for multifocal atrial
  tachycardia unless there is concurrent left
  ventricular failure.

38
Generalized Treatment

• Exercise Exercise training improved the WHO
  functional class of PH and peak oxygen
  consumption. Despite the functional benefits,
  exercise training did not improve hemodynamic
  measures (eg, the pulmonary artery systolic
  pressure). Studies suggests that skeletal muscle
  training may play a major role in the treatment
  of patients with PH.
• Transplantation. In some cases, a lung or
  heart-lung transplant may be an option,
  especially for younger people who have idiopathic
  pulmonary hypertension. Major risks of any type
  of transplantation include rejection of the
  transplanted organ and serious infection, and you
  must take immunosuppressant drugs for life to
  help reduce the chance of rejection.

39
Advanced Therapy

• Most pharmacologic agents used to treat PH
  promote vasodilation and are antiproliferative.
  These include prostanoids (eg, epoprestenol,
  treprostinil, and iloprost), endothelin receptor
  antagonists (eg, bosentan), and
  phosphodiesterase-5 (PDE5) inhibitors (eg,
  sildenafil). Calcium channel blockers (primarily
  nifedipine) are also used but benefit only a
  small minority patients. Their limited benefit
  may reflect the fact that CCBs are pure
  vasodilators without antiproliferative effects
  and vasoconstriction is rarely the predominant
  abnormality.
• General approach  Patients with PH should
  undergo an invasive hemodynamic assessment and an
  acute vasoreactivity test prior to the initiation
  of advanced therapy. Patients with a positive
  vasoreactivity test can be given a trial of oral
  CCB therapy. In contrast, patients with a
  negative vasoreactivity test require advanced
  therapy with a prostanoid, endothelin receptor
  antagonist, or PDE5 inhibitor. Combination
  advanced therapy may be appropriate in truly
  refractory cases, although data are limited.
  Lastly, some patients will be refractory to all
  medical interventions. In these cases, lung
  transplantation or creation of a right to left
  shunt by atrial septostomy may be considered.

40
Advanced Therapy

• Vasoreactivity test  The acute vasoreactivity
  test involves administration of a short-acting
  vasodilator, then measuring the hemodynamic
  response with a right heart catheter. Agents
  commonly used for vasoreactivity testing include
  epoprostenol, adenosine, and inhaled nitric
  oxide
• Epoprostenol is infused at a starting rate of 1
  to 2 ng/kg per min and increased by 2 ng/kg per
  min every 5 to 10 minutes until a clinically
  significant fall in blood pressure, increase in
  heart rate, or adverse symptoms (eg, nausea,
  vomiting, headache) develop.
• Adenosine is administered intravenously in doses
  of 50 mcg/kg per min and increased every two
  minutes until uncomfortable symptoms develop or a
  maximal dose of 200 to 350 mcg/kg per min is
  reached.
• Inhaled nitric oxide administered at 10 to 20 ppm
  is selective for the pulmonary vasculature thus,
  it is often better tolerated than the intravenous
  agents.
• An acute vasoreactivity test is considered
  positive if mean pulmonary artery pressure
  decreases at least 10 mmHg and to a value less
  than 40 mmHg, with an increased or unchanged
  cardiac output, and a minimally reduced or
  unchanged systemic blood pressure. Patients with
  a positive vasoreactivity test are candidates for
  a trial of CCB therapy.
• Patients with portopulmonary hypertension are
  rarely vasoreactive and are at increased risk for
  adverse sequelae from pure vasodilator therapy.
  Therefore, vasoreactivity testing and calcium
  channel blocker therapy is not indicated in this
  group.

41
Advanced Therapy

• Ca channel blockers  Some patients who are
  vasoreactive and receive CCB therapy can achieve
  prolonged survival, as well as sustained
  functional and hemodynamic improvemen.
  Administration of CCB therapy can be initiated
  with nifedipine (30 mg/day) or diltiazem (120
  mg/day), then increased to the maximal tolerated
  dose. Systemic blood pressure, heart rate, and
  oxygen saturation should be carefully monitored
  during titration. Sustained release preparations
  of both nifedipine and diltiazem are available.
  Their use minimizes the adverse effects of
  therapy, which include systemic hypotension and
  edema. Amlodipine, a calcium channel blocker with
  more selective vasodilator properties has been a
  useful alternative for patients who are
  intolerant of the other agents. Patients who
  respond to CCB therapy should have maintenance of
  the response assessed after three to six months
  of treatment. Although calcium channel blockers
  may decrease pulmonary vascular resistance (PVR),
  they are also potent systemic vasodilators that
  reduce systemic vascular resistance (SVR) and can
  cause hypotension. In addition, CCBs may reduce
  hypoxic vasoconstriction, causing vasodilatation
  in arterioles supplying underventilated regions
  of the lung the net effect is worsening
  ventilation-perfusion mismatch and hypoxemia.

42
Advanced Therapy

• Prostanoids  Prostanoid formulations used to
  treat PH include intravenous epoprostenol
  (prostacyclin), subcutaneous treprostinil,
  intravenous treprostinil, and inhaled iloprost.
  All of these prostanoid formulations have the
  limitations of a short half-life.

43
Advanced Therapy

• Epoprostenol (FLOLAN)  It improves hemodynamic
  parameters, functional capacity, and survival in
  patients with IPAH. In patients with other types
  of group 1 PAH, intravenous epoprostenol improves
  hemodynamic parameters and functional capacity.
  Epoprostenol should be considered the first-line
  agent in patients with severe disease (ie, NYHA
  class IV), and in less severe disease (ie, NYHA
  class II or III).
• Epoprostenol is delivered continuously through a
  permanently implanted central venous catheter
  using a portable infusion pump. It is usually
  initiated at doses of 1 to 2 ng/kg per min and
  increased by 1 to 2 ng/kg per min every one to
  two days as tolerated. Once an initial level of 6
  to 10 ng/kg per min is achieved (usually within
  one to two weeks), most patients require dose
  increases of 1 to 2 ng/kg per min every two to
  four weeks to sustain the clinical effect. A
  maximal dose has not been established. Patients
  who have been receiving therapy for many years
  may receive doses as high as 150 to 200 ng/kg per
  min with sustained clinical and hemodynamic
  benefit. Excess doses may produce high output
  cardiac states. In this situation, the dose
  should be reduced, while monitoring for rebound
  pulmonary hypertension.
• Adverse effects. Side effects include jaw pain,
  diarrhea, and arthralgias. More severe adverse
  effects are usually attributable to the complex
  delivery system including thrombosis, pump
  malfunction, and interruption of the infusion.
  Central venous catheter infection can also
  contribute to the morbidity and mortality of
  continuous epoprostenol therapy.

44
Advanced Therapy

• Treprostinil  Treprostinil (Remodulin) can be
  administered as a subcutaneous or intravenous
  prostanoid therapy, although subcutaneous
  administration is uncommon due to severe pain at
  the injection site. It improves hemodynamic
  parameters, symptoms, exercise capacity, and
  survival in patients with group 1 PAH. Advantages
  of treprostinil include the option of continuous
  subcutaneous delivery, a longer half-life that
  may make interruption of the infusion less
  immediately life threatening, and no need for
  refrigeration, all of which allow more
  flexibility and ease in administration. For
  patients who desire the advantages associated
  with treprostinil administration, it can be
  offered as first line therapy. Based upon
  preliminary results, patients who are already
  receiving epoprostenol generally can be
  transitioned to treprostinil (subcutaneous or
  intravenous) without a significant loss of
  clinical efficacy. Reciprocally, epoprostenol can
  be given if the desired effect is not achieved
  with treprostinil.
• Iloprost  Inhaled iloprost (Ventavis) has
  theoretical advantages in targeting the lung
  vasculature and does not require intravenous
  administration.

45
Advanced Therapy

• Endothelin receptor antagonists  Endothelin-1 is
  a potent vasoconstrictor and smooth muscle
  mitogen. High concentrations of endothelin-1 have
  been recorded in the lungs of patients with both
  IPAH and other etiologies of group 1 PAH
  including scleroderma and congenital cardiac
  shunt lesions.
• Bosentan  Bosentan (Tracleer), a nonselective
  endothelin receptor antagonist, improves
  hemodynamics and exercise capacity in patients
  with group 1 PAH and delays clinical worsening.
  The mortality of bosentan-treated IPAH patients
  appears favorable. The major advantage of
  bosentan is its oral administration. The main
  adverse effect of bosentan therapy is
  hepatotoxicity, which appears to be more severe
  at higher doses. Liver function tests should be
  closely monitored during therapy and bosentan
  should not be used in patients with moderate or
  severe hepatic dysfunction, or in conjunction
  with cyclosporine or glyburide. It is also a
  potent teratogen meticulous contraception is
  required if bosentan is used by women with
  childbearing potential.
• Selective agents  Sitaxsentan and ambrisentan
  are selective type A endothelin-1 receptor
  antagonists that are administered orally.
  Preliminary data suggest that they improve
  exercise tolerance, WHO functional class,
  hemodynamics, and quality of life in patients
  with PAH. While there exist theoretical
  advantages to selective inhibition of the type A
  endothelin-1 receptor, no clinical advantage to
  selective inhibition has been demonstrated over
  nonselective inhibition. The selective agents are
  also associated with hepatotoxicity and require
  frequent monitoring of liver function tests.

46
Advanced Therapy

• PDE inhibitors  Sildenafil (Viagra, Revatio) is
  an orally administered cyclic GMP
  phosphodiesterase type 5 (PDE5) inhibitor that
  prolongs the vasodilatory effect of nitric oxide
  and is also used to treat erectile dysfunction.
  Sildenafil improves pulmonary hemodynamics and
  exercise capacity in patients with group 1 PAH.
  And sildenafil is associated with improved
  arterial oxygenation.
• Combination therapy  Limited experience suggests
  that bosentan (TRACLEER) can be used safely and
  effectively with epoprostenoL (FLOLAN) or
  treprostinil (REMODULIN). The benefits of
  bosentan plus sildenafil (REVATIO) are best
  described in patients with IPAH, and less so in
  scleroderma-associated PAH. Several small trials
  combining inhaled iloprost (VENTAVIS) and oral
  sildenafil (REVATIO) have reported improved
  outcome with combination therapy.

47
NEW YORK HEART ASSOCIATION FUNCTIONAL ASSESSMENT

• Class I
• Patients with pulmonary hypertension but without
  resulting limitation of physical activity.
  Ordinary physical activity does not cause undue
  dyspnea or fatigue, chest pain, or near syncope.
• Class II
• Patients with pulmonary hypertension resulting in
  slight limitation of physical activity. They are
  comfortable at rest. Ordinary physical activity
  causes undue dyspnea or fatigue, chest pain, or
  near syncope.
• Class III
• Patients with pulmonary hypertension resulting in
  marked limitation of physical activity. They are
  comfortable at rest. Less than ordinary physical
  activity causes undue dyspnea or fatigue, chest
  pain, or near syncope.
• Class IV
• Patients with pulmonary hypertension with
  inability to carry out any physical activity
  without symptoms. These patients manifest signs
  of right heart failure. Dyspnea and/or fatigue
  may even be present at rest. Discomfort is
  increased by any physical activity.