Diffuse Alveolar Hemorrhage (DAH)

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Diffuse Alveolar Hemorrhage (DAH)

• Internal Medicine Lecture
• Howard M. Mintz, M.D.
• October 14, 2004

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Hallmarks of DAH

• Hemoptysis (may be absent in 1/3 of cases)
• Diffuse pulmonary infiltrates
• Anemia
• Hypoxemic respiratory failure

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Etiologies of DAH

• Many causes and clinical syndromes

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Pathology of DAH

• 3 Broad histologic patterns identified
• Pulmonary capillaritis
• Bland pulmonary hemorrhage
• Diffuse alveolar damage

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Pulmonary Capillaritis I

• Most common of the histologic patterns
• First described by Spencer in 1957
• Neutrophilic interstitial infiltrate with
  fragmentation of neutrophils (leukocytoclasis)
  and pyknotic neutrophils with release of
  cytokines
• Nuclear dust in interstitium and alveolar spaces

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Pulmonary Capillaritis II

• Disruption of the interstitium and capillaries
  with leakage of blood and fibrin into alveolar
  spaces
• Edema of basement membrane with subsequent
  necrosis of interstitium and eventual fibrosis
• Neutrophils are seen lining the interstitium

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Diffuse Alveolar Damage

• Hyaline membrane formation, alveolar and
  interstitial edema, microthrombi, and capillary
  congestion are present
• See slide

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Bland Alveolar Hemorrhage

• RBCs in the alveolar spaces, but alveolar walls
  appear normal except for type II epithelial cell
  hyperplasia
• See slide

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Clinical Presentation of DAH I

• Patients often have an underlying known condition
• Hemoptysis can be acute or subacute, but
  typically presents within one week of onset
• Majority of patients are less than forty years
  old
• 1/3 do not have hemoptysis, but present with
  dyspnea and cough

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Clinical Presentation DAH II

• In patients without hemoptysis, diagnosis is
  confirmed by the presence of blood on serial BAL
• Anemia
• Pulmonary infiltrates
• Chest pain, nonspecific
• Symptoms of underlying disease processes

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History in DAH

• Careful drug history
• Smoking history
• History of underlying illnesses such as valvular
  heart disease, cytotoxic agents, drugs
• Social history, in particular cocaine usage
• History of any renal, skin, or eye diseases

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Physical Findings in DAH

• Nonspecific
• Fevers, rales, signs of consolidation
• Synovitis, iridocyclitis, myositis, palpable
  purpura

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Radiographic Findings in DAH

• Nonspecific, focal or generalized infiltrates
• Rapidly progressive bilateral infiltrates
• Interstitial fibrosis in presence of recurrent
  disease
• Kerleys B line suggestive of valvular etiology,
  also in conditions associated with myocarditis,
  venoocclusive disease

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Laboratory Findings in DAH I

• Low or falling hematocrit or hemoglobin
• In the setting of chronic or recurrent episodes,
  low serum iron
• Nonspecific elevations of white count
• Thrombocytopenia
• Elevation of ESR
• Proteinuria, microscopic hematuria, casts suggest
  glomerulonephrits

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Laboratory Findings in DAH II

• Hypoxemia
• Elevation of DLCO
• Restrictive pattern associated with fibrosis or
  obstructive patterns with marked emphysematous
  changes
• ANCA
• ABMA, IgG

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ANCA in DAH Diagnosis

• Antineutrophilic cytoplasmic antibodies
  (ANCA)first described in 1982 in association with
  pauci-immune glomerulonephritis
• ANCA described in association with Wegeners
  granulomatosis in 1985
• Subsequently described in microscopic polyangitis
  (MPA) and limited renal vasculitis

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ANCA Testing

• Indirect immunofluorescence assay (IIA) is more
  sensitive
• Enzyme link immunosorbent assay (ELISA) is more
  specific
• Best used in conjunction with IIA for screening
  and ELISA for confirmation
• Two relative antigens in vasculitic diseases,
  proteinase 3 (PR3) and myeloperoxidase (MPO)
• Antigens are found in neutrophils and monocytes
• PR3-ANCA and MPO-ANCA

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Immunofluorescence Patterns In Vasculitis

• Sera from patients with suspected ANCA related
  vasculitis are incubated in ethanol fixed
  neutrophils
• Two distinct patterns of fixation identified,
  c-ANCA with cytoplasmic pattern and p-ANCA with
  perinuclear pattern
• c-ANCA pattern is typically associated with
  antibodies against PR3
• p-ANCA is typically associated with antibodies
  against MPO
• See photographics

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Immunofluorescence Utility and Errors

• Tests are visually graded and inspected
• Tests are not specific and false positives and
  negatives can occur
• IIA testing should be confirmed with ELISA
  testing for PR3 and MPO

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Specific Examples of DAH

• Capillaritis-Microscopic Polyangiitis
• Diffuse Alveolar Damage-Crack Cocaine
• Bland Hemorrhage-Amiodarone

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Microscopic Polyangiitis (MPA) I

• Rare disease with prevalence estimated 3 cases
  per million
• Etiology is unknown
• Small vessel involvement including arterioles,
  venules, and or capillaries
• Immune complexes are not demonstrated
• Typical presentation is that of renal failure
  with glomerulonephritis and hemoptysis with
  capillaritis
• Histopathologically segmental distribution,
  neutrophilic infiltration, and fibrinoid necrosis
  (See slide)

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MPA II

• ANCA is positive in about 75 of patients
• p-ANCA is present with MPO by ELISA in 85 of
  patients
• c-ANCA is rare with PR3 by ELISA
• Systemic disease
• Skin manifestations including splinter
  hemorrhages and purpura
• Musculoskeletal with arthralgias, myalgias,
  arthritis
• Gastrointestinal with abdominal pain and GI
  hemorrhage
• Neurological with peripheral neuropathy

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MPA II

• ANCA is positive in about 75 of patients
• p-ANCA is present with MPO by ELISA in 85 of
  patients
• c-ANCA is rare with PR3 by ELISA
• Systemic disease
• Skin manifestations including splinter
  hemorrhages and purpura
• Musculoskeletal with arthralgias, myalgias,
  arthritis
• Gastrointestinal with abdominal pain and GI
  hemorrhage
• Neurological with peripheral neuropathy

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MPA III

• Prominent gastrointestinal signs and symptoms and
  lack of upper airway disease helps distinguish
  from Wegeners
• Classical polyarteritis nodosa rarely involves
  the lung
• 45 of patients have circulating immune complexes
  but tissue localization is rare, pauci-immune
  disease
• 33 of patients have antibodies to hepatitis C or
  B
• Treatment same as for Wegeners
• Survival about 65 with recurrence associated
  with tapering of therapy
• Case report in which MPA eventually developed
  features of WG

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The histologic section from a right middle lobe
open lung biopsy showed extensive hemorrhaging in
the alveolar spaces
Maimon, N. et al. Chest 20031242384-2387
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Pulmonary Interstitial Fibrosis MPA

• Report of six cases of PIF in which patients were
  ANCA positive and eventually diagnosed with MPA
• The diagnosis of PIF may precede that of MPA by
  many years
• See CT

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Diffuse alveolar consolidation with air
bronchogram involving the entire right lung field
Maimon, N. et al. Chest 20031242384-2387
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Cocaine History Mechanisms of Action

• First isolated from coca leaves in 1859
• Part of the original formulation of Coke, removed
  in 1906
• First reported deaths occurred in 1893
• Potent sympathomimetic and CNS stimulant based on
  its ability to block reuptake of catecholamines
  serotonin
• Cocaine HCL boiled with baking soda and extracted
  with ether or alcohol, yields heat stable Crack
  or Rock
• Smoked and reaches the CNS within seconds with
  half life of 60-90 minutes
• Frequently mixed with marijuana or tobacco

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Crack Cocaine with Diffuse Alveolar Damage

• Cocaine is abused in two forms, cocaine HCl and
  cocaine alkaloidal
• The alkaloidal form or crack cocaine is lipid
  soluble and resistant to thermal breakdown
• Rapidly absorbed from the lung via pulmonary
  capillary network
• Euphoria is similar to that of intravenous usage
• Smoking of crack is also associated with
  absorption of impurities, ignition products and
  thermal breakdown products of cocaine

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BAL in Crack Lung Users

• Up to 40 of of crack cocaine users have
  hemosiderin stained alveolar macrophages. lt1 of
  nonsmokers at autopsy have this finding. 9 of
  smokers have this finding.
• Endothelin (ET)-1, an endothelium-derived
  vasoconstrictor peptide, indicator of cell damage
  is also found in a higher proportion of crack
  cocaine users. ET-1 is found in a high proportion
  of BAL samples from crack users and is felt to
  be a marker of alveolar capillary damage
• BAL in crack cocaine users have an absolute
  increase in hemosiderin stained alveolar
  macrophages

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Iron content of alveolar macrophages (AM)
Janjua, T. M. et al. Chest 2001119422-427
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Ferritin content of alveolar macrophages recovered
Janjua, T. M. et al. Chest 2001119422-427
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Prominent hemosiderin-laden AMs in the BAL fluid
of a CS (left, A), which are absent in the BAL
fluid of a TS (middle, B) or a NS (right, C)
Baldwin, G. C. et al. Chest 20021211231-1238
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Increased percentage of hemosiderin-positive AMs
in the BAL specimen of cocaine smokers
Baldwin, G. C. et al. Chest 20021211231-1238
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Acute Lung Injury with Crack

• Typically develops within 1-48 hours
• 25 of users with develop respiratory symptoms
  including fever, cough, nonspecific chest pain,
  hemoptysis, back pain, hyperpnea, dyspnea,
  melanoptysis, wheezing
• Diffuse pulmonary infiltrates, eosinophilic
  pleural effusions, acute lung injury pattern
• Eosinophilia

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Crack Pulmonary Injuries I

• Barotrauma, ischemia, provocation of inflammatory
  damage, and direct cellular toxicity
• Barotrauma is the result of Valsalva maneuver
  after inhalation and the forceful inhalation of
  air into partners. Pneumothoraces,
  pneumomediastinum, and pneumopericardium
• Ischemia is the result of the vasoconstrictive
  properties
• Severe bronchospasm in patients with preexisting
  asthma

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Crack Cocaine Pulmonary Injuries II

• Case of bilateral infiltrates and bilateral hilar
  adenopathy mimicking sarcoid, probably induced by
  contaminants in crack
• The morphologic features of squamous metaplasia
  and mucus gland hypertrophy similar to that of
  cigarette smokers, possibly increased risk of
  lung cancer

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Microenvironment and Cocaine

• Cocaine inhibits alveolar macrophages ability to
  kill most bacteria and tumor cells in vitro
• Cocaine users are unable to kill bacteria using
  nitric oxide as an antibacterial effector
  molecule
• These changes may predispose to increase
  pulmonary infections in these users.
• Marijuana has similar adverse effects. Inhibits
  phagocytosis Staph aureus
• Both drugs frequent smoked together

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Distribution of Vc and DMCO in the
cross-sectional cohort is shown
Kleerup, E. C. et al. Chest 2002122629-638
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Chronic Exposure to Crack

• Pulmonary fibrosis
• Diffuse alveolar hemorrhage
• Hemosiderosis
• Pulmonary infarction
• Eosinophilic interstitial lung disease
• Bullous emphysema
• Medial artery hypertrophy
• Noncardiogenic pulmonary edema
• Increased risk of pneumonia, multifactorial
  problem

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Treatment of Crack Lung

• Need to make history of exposure
• Supportive
• Role of steroids unproven, helpful in those
  patients with bronchospasm
• Screen for HIV and concomitant drugs
• Drug treatment

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Amiodarone Lung Disease

• Drugs characteristics
• Expanding scope of the problem
• Clinical presentations
• Radiographic presentations
• Diagnosis and therapeutic options

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Trends in receipt of clinically serious, domestic
spontaneous adverse event reports (1,941) in
association with amiodarone (all forms) with
further indication of the subset of reports coded
for parenchymal lung injury (n 280)
Brinker, A. et al. Chest 20041251591-a-1592-a
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Incidence of atrial fibrillation in the therapy
group vs the control group
Kerstein, J. et al. Chest 2004126716-724
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Comparison of length of stay (los) in the
amiodarone group and the control group
Kerstein, J. et al. Chest 2004126716-724
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PHD Amiodarone Usage 1997-2003
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Characteristics of Amiodarone I

• Principal metabolite is desethyl-aminodarone or
  DEAm
• DEAm and amiodarone are toxic to lung tissue
• Propensity for accumulation in lung tissue with a
  ratio of plasma to lung of 1500
• DEAm and amiodarone also have a propensity to
  accumulate in the liver and skin
• Amiodarone and DEAm are localized in lysosomes
  and block the removal of phospholipids

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Characteristics of Amiodarone II

• Amiodarone drug levels do not predict the
  development of pulmonary toxicity
• DEAm levels are higher in patients who develop
  amiodarone pneumonitis that controls
• The foamy macrophage on BAL is characteristic of
  amiodarone exposure and its absence bespeaks
  against this diagnosis
• Clearance of amiodarone is very slow with
  biopsies demonstrating the drug after one year of
  cessation of therapy

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Characteristics of Amiodarone III

• Clinically the development of amiodarone
  infiltrates is associated with a prolonged
  radiographic resolution because of the prolonged
  deposition of this agent
• Each molecule of amiodarone and DEAm contain two
  iodines
• The presence of the iodines explains the frequent
  development of thyroid dysfunction in patients
  receiving amiodarone
• The iodine also explains the increase in CT
  density in liver and lung in patients diagnosed
  with pulmonary toxicity

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Amiodarone Pulmonary Toxicity

• First clinical description in 1980, although drug
  was introduced in 1969 in Europe
• Rat models have demonstrated the toxicity since
  1987
• The histological features of amiodarone toxicity
  are relatively distinctive in nature, foamy
  macrophages
• There is a relative dose relationship between
  total cumulative dose and incidence of toxicity
• Reintroduction of agent to patient with previous
  toxicity results in recurrence of syndrome

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Relationship Between Dose and Incidence of
Toxicity to Amiodarone

• Estimated that 50 of patients receiving 1200 mg
  per day will develop toxicity
• Estimated incidence 5 to 15 if dose is greater
  than or equal to 500 mg per day
• Estimated incidence 0.1 to 0.5 in dose is less
  than 200 mg per day
• Overall incidence is probably in the range of 4
  to 6

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Onset of Toxicity to Amiodarone

• Majority of cases will occur within one year of
  exposure
• May occur following loading intravenous dose
• Cases described after 10 years of therapy
• Can develop following cessation of therapy
• Toxicity increases in certain patient populations
  including advanced age, cardiac surgery,
  pulmonary surgery, ARDS, insertion of ICD
• Common denominator is exposure to high FIO2
  during surgery, similar to situation in bleomycin
  pulmonary toxicity and radiation

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Radiographic Presentations in Amiodarone
Pulmonary Toxicity

• Subacute pneumonitis
• Single of multiple subpleural masses
• Pulmonary fibrosis
• Organizing pneumonia
• ARDS
• Alveolar hemorrhage

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Subacute Amiodarone Pneumonitis

• Patchy or diffuse infiltrates
• Suggestion of RUL predominance on plain
  radiographic examination, usually not confirmed
  by HRCT, bilateral process
• Alveolar interstitial pattern on HRCT
• Increased attenuation on HRCT
• Pleural effusion rare

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Subpleural Masses in Amiodarone Lung Disease

• Single or multiple
• Typically abut the pleura
• Chest pain and pleural rub
• DDX includes pulmonary infarction, malignancy,
  pneumonia, lymphoma

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Pulmonary Fibrosis with Amiodarone

• Very uncommon, lt0.1 of cases
• Setting of prior acute pneumonitis from
  amiodarone or resolving phase of illness or as
  initial presentation
• Differs from idiopathic pulmonary fibrosis by the
  rapidity of disease progression and history of
  amiodarone usage
• Reticular infiltrates at the bases with typical
  signs symptoms of ILD
• Irreversible
• Not felt to be steroids responsive

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Organizing Pneumonia from Amiodarone

• Indistinguishable from other forms of organizing
  pneumonia
• Migratory infiltrates may occur
• See radiographs

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ARDS from Amiodarone

• Settings cardiac surgery, pulmonary resection,
  and following defibrillator implantation (J.
  Intern Medicine Med 2001, Liverani up to 10
  incidence) lung biopsy for diagnosis
• 50 fatality
• Rapidly progressive pulmonary infiltrates with
  hypoxemic respiratory failure
• Poorly responsive to therapy

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Subclinical Disease from Amiodarone

• Setting of chronic therapy
• Plain radiographs typically normal
• HRCT ground glass infiltrates
• Typically responds to cessation of drug
• Unclear if it is progressive
• Biopsy foamy cells and inflammatory cells evident
• Gallium scans positive, but T99 more sensitive

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Diagnosis and Management I

• Clinical lab increase in LDH sensitive, but not
  specific, increased ESR, and some leukocytosis
• PFTs most sensitive with reduction in DLCO as
  first abnormality.
• A fall in DLCO does not necessarily indicate
  pulmonary toxicity, only 1/3 of patients develop
  overt disease
• A fall of 15 is cutoff for sensitivity and 30
  for specificity according to Mayo study

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Diagnosis and Management II

• Stable DLCO is indicative of absence of toxicity,
  but fall should be confirmed with HRCT/nuclear
• No clear cut benefit to routine screening, but
  study for Canada suggests baseline chest x-ray
  and PFTs, serial studies in patients with new
  symptoms
• BAL is nonspecific, finding of foamy macrophages
  is not indicative of toxicity, only exposure
• HRCT and nuclear imaging important in
  confirmation of diagnosis
• KL6, high molecular weight, glycoprotein, type II
  pneumocytes, increased

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Diagnosis and Management III

• Cessation of drug is mainstay of therapy
• Steroids help in certain cases, but not uniformly
• Steroids must be tapered very slowly and over a
  prolonged period of time. Early mortality is
  increased in patients not started on steroids.
• Radiographic and PFT improvement follow clinical
  improvement
• Permanent reduction in DLCO is possible.
• Recurrent disease with cessation of steroids is
  frequently resistant to therapy

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Diagnosis and Management IV

• Steroids 0.75 mg/kg to 1.0 mg/kg or
  methylprednisolone or equivalent.
• Treat at least for six months, preferably for one
  year
• No reduction in dosage until objective evidence
  of improvement
• Incidence is higher in patients with COPD as is
  mortality
• Mortality up to 33
• 2/3 of patients will develop recurrent disease if
  reexposed to the medication, DO NOT RECHALLENGE!!

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Diagnosis and Management V

• Clinical clues to suggest condition would include
  concomitant skin discoloration, thyroid
  dysfunction, myeloid suppression,
  photosensitivity, corneal deposits with chronic
  therapy

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Potential Mechanism of Toxicity for Amiodarone

• Hamster alveolar macrophages are sensitive to
  amiodarone
• When amiodarone is added to preparation of
  hamster alveolar macrophages, the membrane
  potential declines
• Following the decline in the membrane potential,
  decline in intracellular ATP
• Decline in cell viability identified