AIRWAY DISEASES: MANAGING THE TOUGH ONES
From the 33rd Annual Vermont Family Medicine Review Course
| WHAT’S NEW IN ARDS AND MECHANICAL VENTILATION —Gilman B. Allen, MD, Assistant Professor of Medicine,
Division of Pulmonary Disease and Critical Care Medicine, University of Vermont College of Medicine, Burlington
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| Definition: acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) both acute in onset, hypoxemic, and
have bilateral infiltrates on chest x-ray consistent with pulmonary edema; pulmonary artery wedge pressure ≤18 mm Hg
(no clinical evidence of heart failure); only difference that ratio of partial pressure of O2 (PaO2 ) to fractional concentration
of inspired O2 (FiO2 ) <300 mm Hg in ALI and <200 mm Hg in ARDS; ARDS more severe subset of ALI
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| Pathogenesis: noncardiogenic pulmonary edema; in cardiogenic pulmonary edema—increased hydrostatic pressure
drives fluid across 3 barriers (endothelium of vasculature, interstitium of lung, and epithelium of alveolar space); cellular
mechanisms for active fluid transport out of alveolus into interstitium then to lymphatics intact; when left ventricular end
diastolic pressure normalized and patient treated for heart failure, clearing of protein-poor pulmonary edema fluid rapid
and easy; in noncardiogenic pulmonary edema—activation and disruption of endothelium present, allowing protein and
fluid to cross barrier into alveolar space; disruption of normal fluid-clearing mechanisms; tight junctions and epithelium
take long time to repair (not readily reversible); related to neutrophils and exudative cell lines entering alveolar space;
cells die through programmed cell death (apoptosis); necrotic debris along with proteins, particularly fibrin, generate
dense eosin-rich hyaline membranes that coat alveolar space (hallmark sign); areas of organizing pneumonia seen; alveolar
hemorrhages not uncommon
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| Pathophysiology: shunt and wasted ventilation; some fluid-filled alveoli collapse; blood running past fluid-filled alveoli,
allowing nonoxygenated blood back into venous return, leading to refractory hypoxemia and shunt; microthrombi in vasculature
cause wasted ventilation (air but no blood flow); decreased compliance and increased shunt lead to refractory
hypoxemia; increased dead space leads to wasted ventilation (patient’s CO2 elevated despite seemingly adequate minute
ventilation); decreased compliance, edema, and fluid lead to compression of lungs; when patient supine, weight of edematous
lung pushes down on dependent portions, causing lung to collapse; as result, ventilator “sees” less lung than in normal
patient (“baby lung”); sometimes, increased pulmonary vascular resistance seen, leading to pulmonary hypertension;
as pulmonary hypertension develops, back pressure created on right ventricle, causing right heart strain (seen on echocardiography;
associated with poor prognosis); classic radiographic findings in ARDS—diffuse airspace disease with
patchy areas of focal consolidation; pleural fluid; pneumothorax; traction bronchiectasis
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| Causes: direct forms of injury—pneumonia and aspiration of gastric contents; indirect lung injury—sepsis and trauma;
cardiopulmonary bypass rare cause; transfusion of blood products becoming widely recognized cause of transfusion-related
ALI
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| Risk factors for ARDS: alcoholism, due to lower levels of reduced glutathione in alveolar space (more prone to oxidant
injury of ARDS); patient more likely to progress to ARDS if septic; thought that diabetics have less risk of developing
ARDS (possibly related to decreased neutrophil function secondary to hyperglycemia or medications patient on before
admission); risk of dying from ARDS higher in—elderly (74 to >85 yr of age); blacks; chronic liver disease; malignancy;
alcoholics; sepsis (ARDS more common than with all other risk factors); trauma; trauma-related ARDS—may be different
condition altogether; patients usually younger, more frequently white, and have fewer comorbidities; lower hematocrit,
serum albumin, and platelets (play significant role in activation of inflammatory pathways that trigger ARDS);
lower markers of injury to epithelial and endothelial barriers; more ventilator-free and organ failure–free days; patients
less likely to develop multiorgan failure; patients off ventilator sooner and die less frequently
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| Treatment: surfactant therapy—investigated extensively; improves oxygenation and lung compliance, but not shown to
lower mortality; vasodilator therapy—inhaled and intravenous (IV); not proven beneficial; steroids—not proven beneficial
in early or late phase of ARDS; liquid ventilation—not effective; prone positioning—improves ventilation-perfusion
matching in some patients with severe ARDS; improves oxygenation but does not improve outcome; lower tidal
volumes—lower mortality; periodic deep inflation and using larger tidal volumes prevents atelectasis and improves oxygenation;
unknown whether improving oxygenation important in these patients; patients with ALI rarely die from hypoxemia
(die mostly from multiorgan dysfunction); poor correlation between oxygenation and outcome
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| Ventilator-induced lung injury: 2 proposed mechanisms—1) too much air driven in, and lungs become overdistended
(occurs at peak inspiration); 2) repeated alveolar closure and reexpansion when lung allowed to deflate; at end-exhalation,
lung collapses on itself, and reexpands on inspiration, causing shearing injury to lung; because ARDS heterogeneous
injury with some areas of lung remaining normal, amount of tidal volume delivered to injured lung makes
difference; study—demonstrated that ventilating injured lung with 6 mL/kg safer than previous standard of 12 mL/kg; effect
independent of lung compliance; led to broad recommendation of using low tidal volumes in patients with ALI; primary
outcomes (ie, death before discharge, breathing without assistance [off ventilator by day 28], number of ventilator-
free days, and number of days without failure of nonpulmonary organs) significantly reduced in low–tidal volume group;
less multiorgan dysfunction syndrome (probably accounts for reduced mortality)
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| Phenomena observed with low tidal volumes: progressive lung collapse, leading to derecruitment of lung (atelectasis);
causes hypoxemia and increased respiratory rate, sometimes leading to inefficient ventilation, making patient uncomfortable
and necessitating increased sedation; ARDS Clinical Trials Network—looked at whether improved oxygenation
with positive end-expiratory pressure (PEEP) makes difference; compared 2 strategies of higher PEEP; found no improvement
in overall survival; argued that subset of patients might improve with PEEP; Italian study showed existence of
responders and nonresponders; further studies warranted
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| Management of fluids: lungs filled with edema fluid, and dependent portions of lung collapse under weight of edematous
lung; question of whether to keep lungs “dry”; ARDS Clinical Trials Network compared liberal vs conservative fluid
strategies; conservative group off ventilator earlier but no improvement in survival; key—use conservative fluid strategy
only after patient stabilized and weaning off ventilator being considered
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| Management: at admission—basics (airway, breathing, circulation); early resuscitation and intubation if indicated; give
fluids up front, unless problem oxygenating patient; early involvement of intensivist; good IV access important; daily interruption
of sedation in intensive care unit (ICU) gets patient off ventilator sooner and leads to less delirium and posttraumatic
stress disorder (PTSD); prophylaxis for deep venous thrombosis; prevention of ventilator-associated
pneumonia—keep head of bed elevated; oral hygiene (eg, clean oropharynx); avoid nasogastric intubation (leads to sinusitis
and increased secretions); wash hands; early recognition of risk—patients should be transitioned early to low tidal
volumes to decrease risk for ARDS
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| Long-term outcomes: more patients surviving (mortality rate 30%); neurocognitive sequelae—study showed 73% of patients
had identifiable neurocognitive deficit at time of discharge; almost 50% had neurocognitive deficits by 1 and 2 yr;
moderate to severe depression common (16%-23%); anxiety and PTSD; impaired lung function—common; at 3, 6, and
12 mo after discharge, reduced vital capacity (VC) and forced expiratory volume at 1 sec (FEV1 ) 75% to 80% of predicted;
diffusing capacity 60% to 70% of predicted at 12 mo; only ≈50% of patients back to work by 12 mo; regardless of
age, sexual dysfunction present far out from discharge
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| MANAGEMENT OF COPD—Theodore W. Marcy, MD, MPH, Professor of Medicine and Medical Director, Pulmonary
Ambulatory Care Center, University of Vermont College of Medicine, and Pulmonologist, Fletcher Allen Health Care, Burlington
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| Definition of chronic obstructive pulmonary disease (COPD): evolving; characterized by air flow limitation; not
fully reversible; usually progressive (even if patient removed from environmental cause); associated with abnormal inflammatory
response to noxious particles or gases; has systemic manifestations
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| Epidemiology: significant increase in age-adjusted death rates (by 163%) due to COPD in United States from 1995 to
present; worldwide phenomenon as well; increasing in men, even faster in women (reflects epidemiology of cigarette use
in United States); Towards a Revolution in COPD Health (TORCH) study—mortality primary outcome; found approximately
one-third of patients with COPD die of respiratory illness; one-fourth die of cardiovascular disease due to shared
comorbidity from smoking and effects on coronary artery disease and heart failure; 21% died of cancer; lung cancer prevalence
increased in patients with COPD
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| Diagnosis and staging: National Health and Nutrition Examination Survey (NHANES) data show that majority of patients
who, by definition, had airflow limitation did not have current diagnosis of lung disease (including subset with
severe airflow limitation [FEV1 <50% of predicted]); spirometry used to define whether these patients with (eg, cough,
sputum production, shortness of breath, and/or exposure to risk factors) have airflow limitation; more controversial
whether screening spirometry should be performed on asymptomatic patients with exposure to risk factors; COPD
sometimes overdiagnosed (diagnosis made without spirometry; not all smokers develop COPD); key point that FEV1
often reduced from that predicted for individual; ratio of FEV1 to forced vital capacity (FVC) also reduced out of proportion
to reduction in FVC
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 | Staging systems: Global Initiative for Chronic Obstructive Lung Disease (GOLD) group—classifies severity of COPD
based on how much FEV1 decreased from predicted; guideline not perfect (not all patients with airflow limitation have
reduced FEV1 /FVC ratio); older people may not have COPD but have reduced ratio; also, COPD not just airflow limitation,
although airflow limitation can lead to hyperinflation that contributes to shortness of breath and exercise intolerance;
BODE index—body mass index (BMI), degree of airflow obstruction, dyspnea, and exercise capacity; grades
severity of COPD with more than just FEV1 ; includes ability to exercise (distance walked in 6 min); perceived sense of
dyspnea (based on modified Medical Research Council questionnaire); and BMI (higher score for underweight); better
predictor of survival than FEV1 alone
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| Pathogenesis: environmental exposure to irritative gas or particles (cigarette smoke most common); individual has genetic
make-up or other exposures that amplify effect to cause increased lung inflammation, which is exacerbated further with
oxidative stress or mix of proteases, leading to pathology of COPD; pathology different in different parts of lung; 1) loss
of elastic recoil and collapse of small airways caused by loss of lung architecture in alveolar parenchyma (apoptosis of
structural elements of lung); 2) increased airway resistance in small terminal airways with extensive inflammation (expansion
of inflammatory cells and associated fibrosis); both lead to airflow limitation; individual differences as to which
process predominant; some patients have more loss of parenchymal structure (emphysema), while others have more airway
fibrosis and inflammation (bronchiolitis); even among individuals with emphysema, differences seen in—
distribution of emphysema within lung, eg, upper-lobe predominant or diffuse; frequency of exacerbations (individuals
with frequent exacerba-tions tend to progress faster); degree of systemic manifestations; differences important
because—treatments that work in one phenotype may be detrimental in another (eg, lung volume reduction surgery improved
survival in subset of patients who had predominant upper-lobe emphysema with reduced exercise capacity but not
in those with diffuse emphysema); current drug trials—not attempting to distinguish different phenotypes; this could
give appearance of null effect, as different subpopulations respond differently
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| Therapies that improve survival: smoking cessation; in TORCH trial, 43% of patients with FEV1 <60% of predicted
were smokers at time of entry into trial; long-term O2 for hypoxemic COPD patients prolongs survival; during exacerbations,
using noninvasive ventilator approaches improves survival and reduces incidence of intubation
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| Therapies that improve symptoms: bronchodilators improve airflow limitation and by allowing lung to empty, reduce
hyperinflation; pulmonary rehabilitation works by improving nutrition and increasing exercise ability and training; it also
improves systemic manifestations and perceptions of dyspnea and, by breathing techniques, reduces hyperinflation; lung
transplantation in selected patients
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| Therapies that reduce exacerbations: tiotropium (Spiriva); TORCH study showed that combined fluticasone and salmeterol
(Advair) reduced exacerbations; vaccination; O2 has no impact on airflow limitation but causes improvement in
systemic manifestations, eg, reduces progression of pulmonary hypertension and improves exercise tolerance; lung volume
reduction surgery reduces airflow limitation and hyperinflation
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| Management of stable COPD: risk factor reduction, including cessation of cigarette smoking and reduction of occupational
or indoor pollution; influenza vaccination; exercise; for mild disease (reduced FEV1 /FVC ratio but FEV1 at or
above predicted)—based mainly of symptoms; short-acting bronchodilator for patient intermittently short of breath; no
evidence that asymptomatic patient benefits from use of inhaler; for more severe disease and persistent symptoms despite
short-acting bronchodilators—add long-acting bronchodilator (2 classes); tiotropium current long-acting muscarinic
antagonist (inhaled once-daily); salmeterol and formoterol long-acting β-agonists appropriate in patients whose
symptoms not controlled with short-acting bronchodilators; also appropriate for pulmonary rehabilitation programs that
combine education with supervised exercise programs; for those with more severe COPD (FEV1 <60% or with frequent
acute exacerbations)—data suggest adding combined corticosteroids with long-acting bronchodilators; some benefit
from addition of theophylline (some associated toxicity; aim for lower blood levels); for those with very severe COPD—
check arterial blood gases for evidence of hypoxemia; consider long-term O2 if patient hypoxemic at rest or with exercise;
determine whether patient candidate for surgery; patient must have stopped smoking long term
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| TORCH study: entry criteria included FEV1 <60% of predicted; randomized to 3 therapies, including placebo inhaler,
fluticasone (Flovent Diskus) alone, and fluticasone/salmeterol (Advair; highest dose of 500/50 used); followed for 3 yr;
primary outcome mortality; secondary outcomes FEV1 , symptoms, and exacerbations; Advair compared to placebo for
probability of death from any cause; mortality difference did not reach significance; however, exacerbations reduced and
quality of life improved, with evidence of less decline in lung function; mean adjusted change in FEV1 highest with combined
therapy, and intermediate with fluticasone or salmeterol alone, compared to placebo; caveats—high dropout rate
(highest in placebo); increased risk for pneumonia in patients who received fluticasone alone or with salmeterol (unexpected
outcome); no increased risk for death from pneumonia in fluticasone group; salmeterol appeared safe (no increased
risk for death); mortality for fluticasone alone significantly worse than in combination (opposite for asthma)
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Suggested Reading
Annane D: Glucocorticoids for ARDS: Just Do It! Chest 131:945, 2007; Burrill PD: Drug management of COPD. BMJ
334:864, 2007; Calfee CS et al: Nonventilatory treatments for acute lung injury and ARDS. Chest 131:913, 2007; Carr
SJ et al: Acute exacerbations of COPD in subjects completing pulmonary rehabilitation. Chest 132:127, 2007; Epub 2007
May 2. Famularo G et al: Transfusion-related acute lung injury. CMAJ 177:149, 2007; Garcia-Pachon E et al: Risk indexes
for COPD exacerbations I. Chest 131:1986; author reply 1987, 2007; Girard TD et al: Mechanical ventilation in
ARDS: a state-of-the-art review. Chest 131:921, 2007; Kiley JP et al: Treating COPD. N Engl J Med 356:867, 2007;
Kocks JW et al: Risk indexes for COPD exacerbations II. Chest 131:1986, 2007; Kollef M: Ventilator-associated pneumonia
and ventilator-induced lung injury: two peas in a pod. Crit Care Med 30:2391, 2002; La Vecchia C et al: Prevention
of death in COPD. N Engl J Med 356:2211, 2007; Marini JJ et al: Ventilatory management of acute respiratory
distress syndrome: a consensus of two. Crit Care Med 32:250, 2004; Meduri GU et al: Acute lung injury and acute respiratory
distress syndrome. Lancet 370:384; author reply 384, 2007; Naunheim KS: Lung-volume reduction surgery: a vanishing
operation? J Thorac Cardiovasc Surg 133:1412, 2007; Oba Y: Cost-effectiveness of long-acting bronchodilators
for chronic obstructive pulmonary disease. Mayo Clin Proc 82:575, 2007; Omron E: Inhaled corticosteroids and mortality
in COPD. Chest 131:939; author reply 940, 2007; Udobi KF et al: Acute respiratory distress syndrome. Am Fam Physician
67:315, 2003; Wheeler AP et al: Acute lung injury and the acute respiratory distress syndrome: a clinical review.
Lancet 369:1553, 2007.
Educational Objectives
| The goal of this program is to improve the management of acute respiratory distress syndrome (ARDS) and chronic
obstructive pulmonary disease (COPD). After hearing and assimilating this program, the clinician will be better able
to:
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| 1. Explain the pathophysiology of ARDS.
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| 2. Recognize the causes and risk factors for ARDS.
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| 3. Recommend treatment and management of fluids for patients with ARDS.
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| 4. Discuss the pathogenesis of COPD.
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| 5. Prescribe therapies for COPD that improve survival, improve symptoms, and reduce exacerbations.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Drs. Allen and Marcy were recorded at the 33rd Annual Vermont Family Medicine Review Course, held June 5-8, 2007, in
Burlington, VT, and sponsored by the University of Vermont College of Medicine. The Audio-Digest Foundation thanks
the speakers and the sponsor for their cooperation in the production of this program.
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