ALIARDS: Adjuvant Therapy

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ALI/ARDSAdjuvant Therapy

• Thomas Genuit, MD, MBA, FACSDirector of Trauma
  Sinai Hospital BaltimoreAss. Professor
  SurgeryThe Johns Hopkins School of Medicine

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ARDS Tx. Approaches
Adjuvant Lung Therapy Inhaled NO, Prostacycline
(PGE2) Surfactant Therapy Corticosteroids Anti-inf
lammatory therapy NSAIDS, Vit C,E, PAF
inhibitor, anti-TNF, anti-IL 1, 8, NF-kB
Lisofylline, Pentoxyphylline O2 radical
scavengers, anti-oxidants a-Prot.-C (in
sepsis)C V V H Decrease Alv. EdemaDiuretics
ß2-agentsDopamine Enhanced alv.
Repairhepatocyte growth factorkeratocyte
growthfactor Nutrition therapyfatty acids,
anti-oxidants Gene-modulation
Sytemic Support Therapy Fluid Tx. and Cardiac
support Hypertonic solutionsInotropes, goal dir.
Tx. Source Control / Abx SIRS therapy Organ
support (MOF)
ARDS
Mechanical Lung Therapy Vent. Management Prone
position Tx. Recruitment maneuvers (partial)
liquid ventilation
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ARDS Adjuvant Therapy
Mechanical Lung Therapy Prone position Tx.
Adjuvant Lung Therapy Inhaled NO Surfactant
Therapy Corticosteroids
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Prone position Therapy

• ARDS an inhomogeneous disease process

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Prone position Therapy

• Restructuring of VQ-zones ? posterior
  atelectasis precedes co-exists w. inflamm.
  process
• Pleural pressures much ? in de-pendent parts of
  lungchest-wall expansion (ventilation) mainly
  anterior
• In prone position pressures and ventilation
  distribution more uniform gt VQ-redistribution

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Prone position Therapy

• Several studies since 1990s showed sign.
  improvement in
• Immediate and sustained oxygenation
• Resolution of posterior / dependent lung collapse
  and improvement of lung compliance
• Potential ALI-protective effect when instituted
  early(prevention of anterior alv. over-stretch
  and marginal zone open-close injury and
  posterior derecruitment)
• 65 - 75 of ARDS patients respond measurably
• CT suggested to identify patients w. predominant
  posterior disease
• Data on mortality equivocal

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Prone position Therapy
Voggenreiter G, et al. Crit Care Med
199927(11)2375-2382
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Prone position Therapy
Voggenreiter G, et al. Crit Care Med
199927(11)2375-2382
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Prone position Therapy

• Currently no clear guides
• To predict who will benefit (most)
• When to start therapy general consensus to
  begin early
• Length of time per cycle / day to prone, for max.
  effect
• When to stop therapy until clear improvement of
  mechanics and
  oxygenation allow significant
  ventilator weaning
• Proning is not w.o. risk
• Access to ETT, lines,
• Pressure injury to face, brachial plexus

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Prone position Therapy
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Surfactant Composition Fct.

• Produced by type II alveolar cells
• 90 (complex) phospholipids, 10 surfactant
  specific (apo-)proteins
• Matures after secretion cycling through
  conversion of (apo-)proteins and alteration of
  PLs (enzymes, O2)
• Decreases surface tension in alv. and small
  airways, preventing (low pressure) collapse
• Important role in immune defense through specific
  and non-specific mechanisms (collectins,
  bacteriostasis)

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Surfactant Changes in ARDS

• Decreased production / conversion of
  S(apo-)proteins
• Dilution / inactivation by plasma proteins and
  fluid (inflammatory leak CRP, Fibrinogen, )
  (117)
• Change of phospholipid composition ? function
  (i.e. neutrophil lipid peroxidation) (115, 118)

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Surfactant Changes in ARDS

• Time dependent variable
• 30 gt70 reduction (severity, /- etiology)
• regional differences
• changes begin before clinical ARDS (at risk pt.
  ?!)
• may persist for weeks

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Surfactant Changes in ARDS

• Result increased surface tension alveolar
  collapse decreased immune barrier /
  pro-inflammatory effect (filling of alveoli w.
  proteinaceous mat. migrated inflammatory cells)

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Surfactant Tx Studies

• 1970s Recognition of function and composition,
  PL
• 1980s Early animal studies bovine/porcine,
  SP-A, B
• 1990s Early human studies Refined function
  and composition r-human products, r-SP-B, C, D
• 2000 Phase II/III human studies Combination
  therapy studies

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Surfactant Tx Studies

• 1987 Lachmann (125) Delivery problems
• lt 30-50 of endotracheally admin.
  surfactantpresent in alveolus after 30 min.
• 1989 Chung (119) Component Problems
• Lipid moiety only modest surface activity at 37o
  w. CaCl repl. Soluble SP-A significantly
  contributes to function of surfactant preparation
• 1991 Robertson (112) Model Problems -gt Outcome
• SP-B restores nl. gas exchange in some animals w.
  severe parenchymal lesions effect of
  surfactant replacement depends on etiology of
  ARDS, animal model used and degree of lung injury

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Surfactant Tx Studies

• 2002-4 Spragg r-SP-C Multi-center approach
• early treatment increases 28-day survival but not
  overall survival

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Surfactant Tx Today

• Davidson et al. CC 2006 10(2)R41
  meta-analysis Adhhikari et al. Cochrane rev.
  2007, Ther.Resp.Med.
• 17 (20) adult human clinical trials 1996(0)-2006
  15(11) excl. all multi-center, 35-725 pts/trial
  total 1270 (1440) no SP, r-SP-C, bovine
  SP-B,C?PaO2FiO2 14 mmHg at 24 hours (0
  100)Increase in vent.-free days at 28 days (1-3,
  3 trials)no morality difference surfactant vs.
  control and between various preparations

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Adhikari, Cochrane review 2007
Davidson, Meta-analysis 2006
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Various Animal Models vs. human trials
Direct vs. systemic etiology
Early vs. late(r) stage ALI / ARDS
Dosing regimen delivery system
Porcine vs. bovine vs. r-human
ARDS risk pt. vs. mild vs. severe ARDS
Supportive Tx. differences and progress
SP-A, vs. SP-B, C vs. mixed products
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Surfactant Tx Future

• Identification of patient at risk / early ARDS -gt
  Therapy
• BAL, plasma SP levels, ARDS gene array
• may take advantage of anti-inflammatory/bactericid
  al properties of some surfactant preparations
  (3, 9, 19)
• ? Increased benefit in patients with direct lung
  injury (4)
• after cardiac surgery, lung transplant
• aspiration, pneumonia, radiation

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Surfactant Tx Future

• ? Combination with other therapy
• Inhaled NO
• Aerosolized dextran, cyclooxygenase inhibition,
• Steroid therapy (combining anti-inflamm.
  properties)

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Corticosteroids

• Inflammatory response in ALI/ARDS
• Early acute diffuse alveolar damage (DAD, ALI -gt
  ARDS, lt 7d)- capillary leak and vaso- stasis -
  leucocyte extravasation, acute phase cytokine
  release- activation of coagulation cascade,
  extravascular fibrin deposit- platelet
  activation, damage/dysfct. of Pneumocytes II
• Proliferation (ARDS, 7-28d)- further
  inflammatory cell recruitment, anti-body
  production, macrocytes fibroblast migration /
  proliferation, begin remodeling of
  extracellular matrix -gt partial repair vs.
  organization
• Late fibrosis (gt 28d)- fibroblast
  proliferation, epithelial growth, angiogenesis,
  collagen maturation- some patients have
  persistent marked inflammation in stage II, III

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Corticosteroids

• Mechanism of action
• Cytoplasmic heat-shock protein-bound GC receptors
• Regulate transcriptional activity of responsive
  genes
• Cell / tissue specific nuclear co-regulators
  enhance or diminish effects -gt cell / tissue /
  context-specific action
• Priming of innate immune response, suppression of
  adaptive immune response (TH-1) and promoting
  TH-2 tolerance.
• Increase opportunistic infections at higher doses
  ? opposite effect at lower doses (m7)

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Corticosteroids Studies

• 1984-87 Sprug, Bernhard, Weigeltearly high
  dose therapy not effective patients w.
  sepsis
• up to 30 mg/kg/day methylprednisolone
  varied duration

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Corticosteroids Studies

• 1991-2007 Meduri Defining the topic (24 papers)
• 1991 late ARDS Tx. / the Meduri protocol
• 1997-01 gluco-corticoid therapy and infection -
  lower dose steroids may be beneficial for
  phagocytic bacterial killing and suppress IRS,
  while higher doses suppress both(m7) - low dose
  steroids may be beneficial in sepsis, overcomming
  NFk-B inactivation of GCRs
• 2002-04 steroid resistance / prolonged Tx in
  unresolving ARDS - failure of activated GCRs to
  down-regulate transcription of inflammatory
  cytokines despite elevated circulating cortisol
  potentially reversible with prolonged GC
  supplementation

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Corticosteroids Studies

• 1991-2007 Meduri Defining the topic
• 2007 low dose early prolonged Tx. - 1mg/kg/d,
  up to gt 28 days reduction of ventilation, ICU
  stay and mortal (42 21) lower infection rate
• 2007 treatment of unresolving ARDS w.
  prolonged Tx - up to 3 mg/kg/d and gt30 days-
  gluco-corticoid inadequacy as one etiology for
  development of ARDS

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Corticosteroids Studies

• 2005 Lee Organ specific disease - low dose Tx.
• reduction of mortalit gt20 in post-op thoracic
  pts.
• 2006 Annane Prophylactic low dose Tx.in septic
  shock
• 177 pts., 50 mg Hydrocortisone q6 hours?
  Reduction of mortality 75 gt 53 (short-term)
  inconclusive if preventive for ARDS development
• 2006 Koontz Rescue Tx. for late ARDS in Trauma
• Trauma pts., improved oxygenation, ? vent. free
  days survival to discharge 78 (10)

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Corticosteroids Therapy
ALI / ARDS
At risk patient- Sepsis- Thor. surgery- Trauma
lt7 d
7-28 d
gt28 d
Ultra-low-dose 50-100 mgHydrocortisoneevery 6
hours? Duration (5-12-28d)
Low-dose1mg/kg/dayMethylpred.?duration
Meduri ProtocolLoad 2mg/kg 2mg/kg/d 1 to
14 1mg/kg/d 15 to 21.50mg/kg/d 22 to
28.25mg/kg/d 29 to 32pot. crossover d 7-10
Meduri Protocol vs. higher dose more prolonged
salvage therapyup to 3 mg/kg/d gt30 days
? Combination therapies
Absence of contraindications (Infection, HIV,
PUD, WD)Confirmed Diagnosis, XR/CT,
PaO2FiO2lt200, FiO2gt50,
? Use of which clinical lung function markers
? Use of BAL / systemic inflammatory markers /
NF-kB expression /
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Corticosteroids Studies

• 2006 Steinberg (NEJM) NHLBI multi-center trial
• 180 ARDS pts Meduri-protocol
• improved oxygenation and pulm. compliance ?
  ventilator free and shock free days, first 28
  days
• no significant ? in 60 / 180 day overall
  mortality
• Significant ? 60 180 day mortality in pts.
  enrolled gt 14 days no ? in infectious disease,
  but increased incidence of neuromuscular disease
• No support for the routine use of GCs in ARDS

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Corticosteroids Future

• The topic continues to evolve
• 2007 Hudson, Da, Combination therapy
• Inhaled NO Animal studies up-regulates
  gluco-corticoid receptors, blunts inflammation
  and may make steroids more effective (lung
  selective Tx?)
• a-Prot CARDS from sepsis highest mortality
  a-Prot C has been shown to reduce mortality ?
  combination w. steroids

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Inhaled Nitric Oxide

• Rel. new, 1980s endothelium-derived relaxing
  factor
• ARDS aveolar Hypoxia -gt local vasoconstriction
  -gt pulmonary Hypertension (children severe
  ARDS)
• I-NO is an ultra-short acting vasodilator
• Will affect mostly (marginally) ventilated areas
  -gt improve VQ mismatch
• Overall decrease of pulmonary resistance will
  improve cardiac function and DO2

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Inhaled Nitric Oxide

• I-NO has anti-inflammatory properties
• Will reduce local inflammatory response in the
  lung
• Most initial clinical trials premature neonates
  / meconium aspiration ARDS -gt favorable outcomes
• Since 1990s Adult clinical trials fail to
  demonstrate desired results

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Inhaled Nitric Oxide

• To date gt 200 trials in adults
• 2007, two Meta-analyses
• Sokol, Cochrane review 20 yrs, included 5 major
  studies and 535 patients Oxygen index, P/F
  ratio, vent.-free days, ILOS, HLOS, mortality
• Akhiklari, BMJ, included 12 trials and 1237
  patients mortality, duration of ventilation,
  pulm. arterial pressures, adverse events

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Inhaled NO Oxygenation

• At 12 - 24 hours !

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Inhaled NO Oxygenation

• ? No or Negative effect at 48 96 hours
• No difference in vent. free time (d 30-60-90),
  ILOS / HLOS

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Inhaled Nitric Oxide

• No difference
• Oxygen index (MAwP x FiO2 x100)/PaO2 after 48
  hours
• Vent. free time at 30 or 60 or 90 days
• ICU-LOS or HLOS

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Inhaled NO Mortality
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Inhaled NO Mortality

• No difference low vs. high dose I-NO
• No difference in mortality at 30 or 90 days
• No difference if cross-over allowed for
  non-responders
• Mortal. Variability 29-60

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Inhaled NO Side effects

• NO2 formation
• NO2, peroxynitrite and other NO metabolites may
  act synergistically w. other free radicals and
  cause further lung injury
• not clin. detected until very high doses of I-NO
  (gt80 ppm)lt 1-3 ppm
• Met-Hb formation
• not clin. detected (gt5) until high doses (gt 40
  ppm)
• Platelet dysfunction and bleeding
• NO blocks ADP and collagen induced adhesion/
  aggregation
• Rare effect

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Inhaled NO Side effects

• Kidney dysfunction
• Nearly ¾ of patients showed increased renal
  dysfct. (post hoc analysis)

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Inhaled NO Why, When, Future

• I-NO may yield improved results in some patients
• Premature Neonates / children (sev. Pulm HTN)
• ? Adults with severe pulm. HTN (CO improvement)
• ? Patients with initial OI gt 25 and
  immunosuppressed patients had increased /
  prolonged response to I-NO
• Combination therapy
• Cluco-corticoids in early ALI (inflammatory
  phase) and corticoid resistant patients
• Almitrine selective pulm. Vasoconstrictor
  (Gallart, 1998, 48 pts, low dose NO substantial
  immediate increase in PaO2 w.o increase in
  pulm. art. pressures.

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ARDS Summary of Adjuvant Tx.
Integrated Systematic Organ Specific
Treatment Approach
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ARDS Summary of Adjuvant Tx.

• Browner et al., Treatment of ARDS, Chest
  20011201347-67
• Adhikari et al., Pharm Treatment for Adults w.
  Acute Lung Injury and ARDS, http.thecochranelibrar
  y.com