Educational Objectives Faculty Disclosure

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					Volume 28, Issue 15                                                                                               August 7, 2011

                                               PULMONARY HYPERTENSION
                  From Critical Care Conference, sponsored by the University of Vermont College of Medicine
                                  William E. Hopkins, MD, Associate Professor of Medicine,
                             Fletcher Allen Health Care/University of Vermont College of Medicine,
                                                        Burlington, VT
Case 1: woman, 52 yr of age, works as pharmacy technician;         Clinical approach: previously depended on whether primary
  initially evaluated for shortness of breath (SOB) and fa-          or secondary; World Health Organization classification has
  tigue; initial assessment pulmonary hypertension; echocar-         5 categories; group 1 — pulmonary arterial hypertension
  diography showed slightly dilated highly dysfunctional             (PAH); associated with occlusive vasculopathy in small
  right ventricle (RV), compared to left ventricle (LV); inva-       PAs and arterioles; group 2 — due to left heart disease; ele-
  sive hemodynamic assessment — right heart catheteriza-             vated LA pressure (regardless of cause, eg, systolic dys-
  tion; adequate left heart pressure measurement necessary           functional LV, diastolic dysfunction); group 3 — due to
  (sometimes requires catheterization of LV); patient’s mean         lung disease or other cause of hypoxemia (eg, obstructive
  right atrial (RA) pressure elevated at 10 mm Hg, and pul-          lung disease, restrictive lung disease); associated with sleep
  monary artery (PA) pressure severely elevated; mean pul-           apnea, daytime hypoventilation syndrome, long-term expo-
  monary capillary wedge pressure (PCWP) or left atrial              sure to high altitude, and lung disease in premature infants;
  (LA) pressure and LV end diastolic pressure (LVEDP) nor-           group 4 — chronic thromboembolic pulmonary hyperten-
  mal (indicates that problem not in left heart); cardiac output     sion; group 5 — miscellaneous (eg, myeloproliferative dis-
  (CO) and cardiac index (CI) decreased; pulmonary vascular          order, sarcoidosis); categorizing patients important, as
  resistance (PVR) severely elevated at 15 Wood units; vaso-         medications approved by Food and Drug Administration
  dilator challenge performed and determined that patient            only for group 1 patients and possibly harmful for patients
  nonresponsive in catheterization laboratory (developed sys-        with group 2 or 3 disease
  temic hypotension instead)                                       Group 1 (PAH): no difference pathologically, compared to
Normal pulmonary circulation: unique circulatory bed with              other groups; characterized by intimal and medial hyper-
  little to no resistance (fraction of systemic resistance);
                                                                       plasia; may have complete occlusive vasculopathy; plexi-
  highly accommodating; pulmonary pressure not increased,
                                                                       form lesions develop, where vessel attempts to recanalize
  regardless of how much CO increased; autoregulation not
  seen in lung; only way lung autoregulates by attempting to           itself; patient may develop fibrinoid necrosis of vessel;
  match ventilation and perfusion; only organ that receives            few patients respond to calcium-channel blockers (cause
  100% of CO; normal PCWP 12 mm Hg; transpulmonary                    systemic hypotension; pure vasodilators and of no bene-
  gradient — subtracting mean LA pressure or mean PCWP                 fit); PAH proliferative problem similar to cancer of blood
  from mean PA pressure should result in number 10 mm                 vessels; presently called idiopathic pulmonary arterial
  Hg; mean PA pressure increases in proportion to increase in          hypertension (IPAH; formerly primary pulmonary hyper-
  mean LA pressure; transpulmonary gradient divided by CO              tension [PPH])
  equals PVR in Wood units (multiply by 80 to convert to             Etiology: sometimes familial (can be autosomal dominant
  metric units)                                                        in inheritance pattern); toxin- and drug-induced (eg,
Definition of pulmonary hypertension: mean PA pressure                 fenfluramine and phentermine, dexfenfluramine, meth-
  25 mm Hg; normal mean PA pressure 20 mm Hg; bor-                   amphetamines, standard amphetamines, cocaine); associ-
  derline elevated PA pressure 21 to 24 mm Hg; high blood              ated with other disorders (eg, connective tissue disorders
  pressure of vessels of lungs                                         [especially scleroderma], congenital heart disease, liver
Symptoms: SOB number one complaint, but not specific to                disease, HIV infection, hemolytic anemias, especially
  pulmonary hypertension; fatigue (especially with right               sickle cell anemia); survival worsened if superimposed
  heart failure); edema (if RA pressure elevated enough);              upon other serious disorders; death mainly due to fail-
  syncope; chest pain (possibly due to inadequate blood flow           ure of RV; patient may also die from underlying prob-
  to hypertrophied RV)                                                 lem

                  Educational Objectives                                               Faculty Disclosure
  The goal of this program is to improve the management of pul-    In adherence to ACCME Standards for Commercial Support,
  monary hypertension. After hearing and assimilating this pro-    Audio-Digest requires all faculty and members of the planning
  gram, the clinician will be better able to:                      committee to disclose relevant financial relationships within
     1. Describe the normal pulmonary circulation.                 the past 12 months that might create any personal conflicts of
     2. Differentiate the 5 categories of pulmonary hyperten-      interest. Any identified conflicts were resolved to ensure that
         sion based on the World Health Organization classifica-   this educational activity promotes quality in health care and
         tion.                                                     not a proprietary business or commercial interest. For this pro-
     3. Elaborate on the 3 major categories of drugs for treat-    gram, the following has been disclosed: Dr. Hopkins is on the
         ment of group 1 pulmonary hypertension.                   Speakers’ Bureau for Actelion Pharmaceuticals. The planning
                                                                   committee reported nothing to disclose. In his lecture, Dr.
     4. Describe the pathophysiology of group 2 pulmonary
                                                                   Hopkins presents information that is related to the off-label or
                                                                   investigational use of a therapy, product, or device.
     5. Manage the obese patient with pulmonary hyperten-
                                    AUDIO-DIGEST EMERGENCY MEDICINE 28:15

 Pathophysiology: smooth muscle cell proliferation; may ul-         enough, pulmonary edema develops; one of body’s re-
    timately develop fibrosis in vessel wall; body attempts to      sponses to increase lymphatic drainage; increase in LA and
    revascularize or recanalize, leading to plexiform lesions       PV pressure leads to passive rise in PA pressure, and nor-
    (hallmark); 3 major pathways — altered; low nitric oxide        mal transpulmonary gradient maintained; one of responses
    (NO) levels in vessel wall, low prostacyclin levels, and        to increased PV pressure is increased PVR (mechanism to
    elevated endothelin levels; NO most potent vasodilator          deal with regional abnormalities in lung); eventually, ves-
    and also antiproliferative; prostacyclin second most po-        sels remodeled and appearance similar to that of PAH (does
    tent vasodilator (also antiproliferative); endothelin most      not improve with, eg, replacement of mitral valve); thera-
    potent vasoconstrictor but promitotic; net result vasocon-      pies utilized for group 1 able to relax and remodel PA and
    striction with significant cell proliferation when path-        increase flow into LA, increasing LA pressure and promot-
    ways altered                                                    ing development of pulmonary edema; in sense, increase in
 Pharmacotherapy: 3 major categories developed from under-          PVR protective mechanism to prevent pulmonary edema
    standing of pathways; prostanoid drugs, endothelin recep-       (but sometimes goes too far)
    tor antagonists (ERAs), and NO enhancers; prostanoids —        Obesity: epidemic of obesity leading to epidemic of pulmo-
    can replace prostacyclin with epoprostenol (Flolan); deliv-     nary hypertension; simultaneous RV and LV pressure trac-
    ered intravenously (IV); inhaled and subcutaneous forms         ing shows extremely close or simultaneous tracking of
    also available; administered IV as continuous (24 hr) infu-     diastolic pressures; obese patients may develop restrictive
    sions, using Broviac and single-lumen catheter; ERAs            cardiomyopathy; from hemodynamic perspective, identi-
    and NO enhancers (eg, sildenafil, tadalafil) administered       cal to amyloid heart disease; obese patients deposit fat in
    orally; prostanoids expensive ($100,000-$200,000 annu-          myocytes; fat measured through magnetic resonance spec-
    ally); ERAs — cost >$50 000 annually; IV therapy indi-          troscopy and correlated with impairment in ventricular fill-
    cated in severely ill patients; NO enhancers — NO binds         ing; due to chronically elevated LA pressure, prone to
    with soluble guanylate cyclase (sGC), converting guano-         significant pulmonary hypertension; paper shows that diet
    sine triphosphate (GTP) to cyclic guanosine monophos-           and exercise decrease fat deposition in myocytes and re-
    phate (cGMP; activator in cell that leads to smooth cell        verse process; if PA remodeled before process reversed, PA
    relaxation, by decreasing calcium in smooth muscle);            pressure may not decrease
    phosphodiesterase (PDE) breaks down cGMP to GMP and            Case: woman, 25 yr of age, went to local emergency depart-
    cyclic adenosine monophosphate (cAMP) to AMP; milri-            ment for chief complaint of SOB of 6-mo duration; hema-
    none PDE type 3 inhibitor; erectile dysfunction drugs are       tocrit of 52% and hemoglobin of 17.3 g/dL; PaO2 of 57 mm
    PDE type 5 inhibitors; PDE type 5 common in lung and            Hg and PaCO2 of 25 mm Hg; O2 saturation 88%; electro-
    has crossover to PDE type 6 (abundant in retina); good ev-      cardiography (ECG) showed RV hypertrophy; chest x-ray
    idence that drugs improve functional status (increase 6-        showed normal heart and lungs; chest CT showed mild
    min walk distance and delay clinical worsening); minimal        prominence of PAs, absence of pulmonary embolus, and
    data on survival and if available, compared to historical       normal-appearing parenchyma; transthoracic echocardiog-
    controls                                                        raphy showed D-shaped LV with normal systolic function,
Case 1 continued: patient started on IV treprostinil (Remod-        dilated RA and RV, moderate tricuspid regurgitation (TR),
 ulin); initially thought to have IPAH; 6 mo later, patient’s       PA systolic pressure of 40 to 50 mm Hg, with no clear-cut
 symptoms and hemodynamics slightly better; bosentan                atrial septal defect (ASD); transesophageal echocardiogra-
 (ERA) added; 1 yr later, PA systolic pressure decreased            phy led to conclusion that patient had ostium primum ASD
 from 107 mm Hg to 57 mm Hg; mean RA pressure and CO                with RV and RA enlargement and mild TR; left axis devia-
 normalized; PVR decreased from 15 Wood units to 4.3                tion always present in ostium primum ASD; if patient truly
 Wood units; patient went back to full-time work and doing          had ASD, should have had ostium secundum defect or si-
 well; risk for line infection present with constant IV infu-       nus venosus defect; at catheterization laboratory, PA pres-
 sion of medication                                                 sure 72/22 mm Hg and elevated RA pressure at 10 mm Hg;
Case 2: man, 72 yr of age, retired university professor; in late    concluded that patient had large ASD with bidirectional
 2002 or early 2003, presented with SOB on exertion; ini-           flow and acute pulmonic-to-systemic blood flow ratio
 tially diagnosed with severe pulmonary hypertension and            (Qp:Qs) of 1.3 to 1; patient sent for surgical repair; surgeon
 shown to have pulmonary emboli; patient returned after             determined that patient had ostium secundum defect and
 several years with no progression of disease; found to have        repaired it; patient developed suprasystemic PA pressure
 multiple pulmonary emboli; PA pressure 78/20 mm Hg,                with failure of RV in operating room (OR); placed back on
 with mean of 39 mm Hg; unable to obtain PCWP; LVEDP                pump, and fenestrated ASD patch placed to allow right-to-
 normal; CO in normal range at rest; PVR slightly elevated;         left shunt; administered NO; patient died on postoperative
 referred to University of California, San Diego, for pulmo-        day 4; lessons — repair of ASD in presence of significant
 nary thromboendarterectomy (PTE); all patients with pul-           pulmonary hypertension not indicated; greater risk for pa-
 monary hypertension require assessment for presence of             tient undergoing general anesthesia, spinal anesthesia, or
 chronic thromboembolic disease; ventilation/perfusion              local blocks if significant pulmonary hypertension present
 (V/Q) scan better method to assess for chronic thromboem-         Questions and answers: treatment decisions — more group 1
 bolic disease with, as opposed to spiral computed tomogra-         disease than previously thought; speaker treats patients
 phy (CT); CT better method for acute embolus, compared             who have group 3 disease with pulmonary hypertension
 to chronic remodeled embolus                                       significantly out of proportion to degree of lung disease
Group 2 pulmonary hypertension: those with elevated left            (off-label), although with potential for V/Q mismatch;
 heart pressures; presence of LA hypertension, regardless of        treatment for group 2 patients more difficult (may cause
 cause, leads to pulmonary venous (PV) hypertension; pul-           pulmonary edema), with accurate hemodynamic assess-
 monary capillary pressure increased, leading to pulmonary          ment required before treatment; if unable to obtain accurate
 capillary hypertension; if capillary hypertension significant      PCWP, obtain LVEDP; every patient carefully considered
                                              AUDIO-DIGEST EMERGENCY MEDICINE 28:15

  to determine whether drugs beneficial; warfarin (Couma-                            than thrombotic in situ; obesity — percentage of obese pa-
  din, Jantoven, Marevan) — used in patients with idiopathic                         tients with pulmonary hypertension unknown; echocar-
  or familial group 1 disease (only group with data); other                          diography good screening tool, although quality of image
  opinion that able to use warfarin in all patients with group                       often poor in these patients; consider underlying pulmo-
  1 disease (no data to justify); spontaneous thrombi in                             nary hypertension in patient who develops unanticipated
  lungs — believed by some that part of pathophysiology of                           problems in OR
  group 1 disease involves small in situ microthrombi; also
  thought that large-vessel thrombi embolic in origin, rather

Dr. Hopkins was recorded at Critical Care Conference, held September 30 to October 2, 2010, in Stowe, VT, and sponsored by the
University of Vermont College of Medicine. The Audio-Digest Foundation thanks Dr. Hopkins and the University of Vermont College
of Medicine for their cooperation in the production of this program.

                        Suggested Reading                                          rial hypertension. Chest, 2010 Nov;138(5):1234-9; Robbins IM
                                                                                   et al: Association of the metabolic syndrome with pulmonary
Arunthari V et al: Prevalence of acute vasoresponsiveness in
                                                                                   venous hypertension. Chest, 2009 Jul;136(1):31-6; Shehata ML
patients with pulmonary hypertension: treatment implications.
                                                                                   et al: Myocardial delayed enhancement in pulmonary hyperten-
South Med J, 2010 Jul;103(7):630-4; Dahiya A et al: Echocar-
                                                                                   sion: pulmonary hemodynamics, right ventricular function, and
diographic assessment of raised pulmonary vascular resistance:                     remodeling. AJR Am J Roentgenol, 2011 Jan;196(1):87-94; Soon
application to diagnosis and follow-up of pulmonary hyperten-                      E et al: Elevated levels of inflammatory cytokines predict sur-
sion. Heart, 2010 Dec;96(24):2005-9; Janda S et al: Diagnostic                     vival in idiopathic and familial pulmonary arterial hypertension.
accuracy of echocardiography for pulmonary hypertension: a                         Circulation, 2010 Aug 31;122(9):920-7; Taichman DB et al:
systematic review and meta-analysis. Heart, 2011                                   Wide variation in clinicians' assessment of New York Heart As-
Apr;97(8):612-22; Memtsoudis SG et al: Perioperative mortal-                       sociation/World Health Organization functional class in patients
ity in patients with pulmonary hypertension undergoing major                       with pulmonary arterial hypertension. Mayo Clin Proc, 2009
joint replacement. Anesth Analg, 2010 Nov;111(5):1110-6;                           Jul;84(7):586-92; Ulrich S et al: Chronic thromboembolic and
Ogawa A et al: Prednisolone ameliorates idiopathic pulmonary                       pulmonary arterial hypertension share acute vasoreactivity prop-
arterial hypertension. Am J Respir Crit Care Med, 2011 Jan                         erties. Chest, 2006 Sep;130(3):841-6.
1;183(1):139-40; Rich S et al: Long-term effects of epopros-
tenol on the pulmonary vasculature in idiopathic pulmonary arte-

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                                      AUDIO-DIGEST EMERGENCY MEDICINE 28:15

                                                    PULMONARY HYPERTENSION
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   1. True statement(s) about normal pulmonary circulation include:
        (A)   Has little or no resistance
        (B)   Highly accommodating, with no autoregulation based on metabolism
        (C)   Only circulation that receives 100% of cardiac output
        (D)   All the above

   2. Pulmonary hypertension is defined as a mean pulmonary artery pressure of _______ at rest.
        (A) 10 mm Hg                          (B) 20 mm Hg                              (C) 25 mm Hg                            (D) 30 mm Hg

   3. Which of the following is the most common complaint of patients with pulmonary hypertension?
        (A) Fatigue                                                            (C) Edema
        (B) Chest pain                                                         (D) Shortness of breath

   4. Based on the World Health Organization classification, pulmonary hypertension due to restrictive lung
      disease is classified as:
        (A) Group 1                            (B) Group 2                                (C) Group 3                              (D) Group 4

   5. Pulmonary hypertension secondary to sarcoidosis is classified as:
        (A) Group 2                            (B) Group 3                                (C) Group 4                              (D) Group 5

   6. Drugs available for treating pulmonary hypertension have been approved by the Food and Drug
      Administration only for patients with _______ pulmonary hypertension.
        (A) Group 1                            (B) Group 2                                (C) Group 3                              (D) Group 4

   7. Plexiform lesions are the hallmark lesions for which of the following classifications of pulmonary
        (A) Group 1                            (B) Group 2                                (C) Group 3                              (D) Group 4

   8. Which of the following substances produced by the endothelial cells of the pulmonary blood vessels is a
      potent vasoconstrictor?
        (A) Prostacyclin                                  (B) Nitric oxide                                        (C) Endothelin

   9. All patients with pulmonary hypertension need to be assessed for the presence of chronic thromboembolic
        (A) True                                                               (B) False

 10. Repair of atrial septal defect in the presence of significant pulmonary hypertension is:
        (A) Indicated                                                          (B) Not indicated

Answers to Audio-Digest Emergency Medicine Volume 28, Issue 14: 1-C, 2-D, 3-A, 4-A, 5-D, 6-C, 7-A, 8-C, 9-D, 10-B

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