surfactant in ards
TRANSCRIPT
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Surfactant in ALI/ARDS
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Surfactant
Biological agent present in lungs
Produced by type II pneumocytes
90% phospholipids ± Dipalmitoyl phosphatidylcholine (DPPC)
± Cholesterol
± Negatively charged phospholipids
10% proteins ± Four surfactant-associated proteins
± SP-A to D
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Function of surfactant Reduction of surface tension in alveoli
± Laplaces law Inverse relationship between surface tension and alveolar radius
Pressure required to overcome alveolar collapsing effect of surface tensionbecomes larger as alveolar radius decreases during expiration
± Stabilises alveoli at low transpulmonary pressures
Immune function ± SP-A and SP-D
Members of collectin protein family
Opsonise pathogens
Effects on phagocyte inflammatory response
Effects on regulation of pneumocytes
SP-B and SP-C ± Hydrophilic proteins
± Aids in the spread of surfactant in the terminal airways
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History of surfactant use 1929 Von Neergaard
± Physiological concept of resistance to lung expansion as a result of surface tension
1959 Avery and Mead ± BALs from premature neonates with RDS lacked low surface tension characteristics of
pulmonary surfactant
1990 Fujiwara Administered surfactant to premature neonates with RDS ± Reduced FiO2 and MAP
± Reduced PIE and pneumothoraces
± Reduced duration of O2 therapy and CLD
± Improved serial CXRs
1990 Surfactant replacement therapy introduced ± Significant drop in infant mortality rates
± Primarily attributed to fewer respiratory deaths among prems
1990 Moses et. al Surfactant replacement in meconium aspiration ± Resolved pulmonary hypertension
± Decreased air leaks
± Reduced ECMO and duration of IPPV
1995 Pandit et. al. postulated possible benefits in ARDS / other lung injury in
children and adults
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Surfactant types
Natural surfactant
± Only type currently in use (curosurf porcine,survanta bovine)
± Recovered from alveolar lavage or amniotic fluid
Synthetic/recombinant surfactant
± First generation were protein free
± Significantly less effective than natural surfactants
± Ongoing work to synthesise more effective surfactantsincluding proteins
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ALI/ARDS criteriaAmerican-European Consensus Conference on ARDS 1994
1. Acute onset of respiratory deficiency
2. Presence of a pre-disposing condition
3. Bilateral infiltrates (on frontal CXR)
4. Severe hypoxaemia
± PaO2/FiO2 < 200mmHg (ARDS)
± PaO2/FiO2 < 300mmHg (ALI)
5. No L sided heart failure ± Pulmonary wedge pressure < 18mmHg
± No clinical evidence of LA hypertension
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Animal studies
1995-1996 Liu et. al.
± Lung function decreased less in those that had
prophylactic surfactant
2000 Mora et. al.
± Confirmed surfactant deficiency at 48hrs
± Surfactant administered not as effective as expected ± Speculated BAL prior to surfactant might remove
inflammatory mediators
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Adult studies 1996 Anzueto et. al.
± Double blind RCT, 725 patients
± Continuous aerosolised synthetic exosurf
± No effect on survival, length of ventilation or length of stay
1997 Gregory et. al. ± Randomised, unblinded RCT, 59 patients ± Tracheal instillation of semi-synthetic survanta
± Significant improvement in oxygenation
± Insignificant reduction in mortality
2004 Spragg et. al. ± Double blind RCT, 448 patients ± Tracheal instillation of recombinant surfactant-specific protein C based
Venticute
± Acute improvement in oxygenation/ventilation
± No effect on length of ventilation or mortality
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Paediatric studies
1996 Willson et. al. ± Uncontrolled observational study, 29 patients
± Improvement in oxygenation/ventilation following dose
± 3 pneumothoraces, otherwise no adverse effects
1999 Willson et. al. ± Unblinded RCT, 42 patients
± Improvement in oxygenation, earlier extubation and discharge to ward
± No change in mortality or hospital stay
2003 Moller et. al. ± RCT, 38 patients
± Initial improvement in oxygenation
± No change in mortality or ventilator-free days
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Paediatric RCT 2005
Effect of Exogenous Surfactant (Calfactant) in
Pediatric Acute Lung Injury
A randomised controlled trial Willson et. al
JAMA 2005; 293 (4): 470-476
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Calfactant
Modified natural surfactant
Phospholipids, neutral lipids , SP-B and C frombovine lung
Obtained by saline lavage of newborn calf lungs Ratio of phospholipid : SP-B similar to natural
bovine surfactant
Biophysical and biological testing => activity equal
to natural surfactant Resistance to inhibition by proteins associated
with lung injury or by lysophospholipids
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Methods
21 PICUs across USA
Pediatric Acute Lung Injury and Sepsis
Investigator network Aiming for 300 patients in 2 years
Extended to 3 years July 2000 July 2003
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Patients Inclusion criteria
Age 1/52 21yrs
Respiratory failure
Bilateral parenchymal lung disease on CXR
Enrolment within 24hrs of mechanical
ventilation (extended to 48hrs after 50
patients) Oxygenation Index > 7 = (MAP x FiO2 x
100)/PaO2
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Patients Exclusion criteria
Corrected gestational age <37/40)
Status asthmaticus
Head Injury with GCS < 8
CLD with home O2 or diuretic use
Brain death
DNR/limitation of treatment
Ongoing CPR
Significant airway disease that might delay extubation
Uncorrected congenital heart disease Pre-existing myocardial dysfunction
Cardiogenic pulmonary oedema
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Patients Randomisation
Stratified to balance severity of lung injury
OI > 13
OI >7 and <13 ± Within 6hrs of initiation of mechanical ventilation
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Study protocol
2 doses of calfactant or placebo (air)
Blinded except to pharmacist and respiratorytherapist
Each dose ± 80ml/m2 or 3ml/kg under 10kg
± 4 equal aliquots into trachea
± Different position for each aliquot
±
With sedation/NMB ± Manual ventilation in 100% O2
2nd dose 12hrs later if OI remained > 7
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Study protocol
Ventilator guidelines
± TV < 8ml/kg
± FiO2 < 0.6
± PIP < 40
± PaCO2 40-60mmHg (5.3 7.9kPa)
BGs and vent settings recorded to D14 of
study No treatment with other surfactants
All other care determined by clinical team
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Outcomes
Ventilator-free days
Mortality
Acute effects
Length of stay / charges
Duration of O2
Failure of conventional ventilation Adverse events / safety
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Results
153 pts enrolled/consented, 1 withdrew
77 in treatment group, 75 in placebo
100% met ALI, 91% met ARDS criteria
No significant differences in groups
± Demographics ± Severity at randomisation
± Co-morbidities
Differences in number immunocompromised non-significant
Protocol violations ± 6 (3 in each group)had OI < 7 at start
± 2 (1 in each group) got non-protocol surfactant afterwards
Comparable adherence to ventilator guidelines
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Acute changes
Significant change in oxygenation in 12 hours
following each dose
1st
dose p 0.01 2nd dose p 0.02
Second dose required (OI > 7 at 12 hours)
±
Treatment group 70% ± Placebo group 79%
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Other outcomesClinical outcome
Treatment group
(n = 77)
Placebo group
(n = 75) P value
Ventilator free days mean (SD) 13.2 (10) 11.5 (10.5) 0.21
Failure of conventional ventilation 13 (21%) 26 (42%) 0.02
ECMO 3 (<1%) 3 (<1%) >0.99
NO 9 (12%) 10 (13%) 0.80
HFOV 7 (9%) 15 (20%) 0.07
PICU stay (days) mean (SD) 15.2 (13.3) 13.4 (11.6) 0.71
Hospital stay (days) mean (SD) 25.0 (22.5) 24.8 (32.3) 0.78
Oxygen therapy (days) mean (SD) 17.3 (16) 18.3 (31) 0.97
Hospital charges (1000$) 205 (220) 299 (640) 0.68
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Adverse effects
ComplicationTreatment group
(n = 77)
Placebo group
(n = 75)P value
Hypotension 9% 1% 0.005
Transient hypoxia 12% 3% 0.008
Air leaks 13% 16% 0.65Nosocomial
pneumonia6% 11% 0.40
Hypotension all resolved with volume
Hypoxia all resolved with slowing of drug instillationand/or transiently increased airway pressures
No patients removed from study due to complications
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Comparison with adult trials Difference in surfactant used
± Better than surfactant used in adult trials
± Presence of SP-B
± High level of resistance to inactivation
± Greater surface activity in animal lungs than others
(Exosurf/Survanta) ± Larger amount
Effect of improving lung function on mortality ± Unresolved respiratory failure significant cause of death in
83% ± Lack in improvement in oxygenation after intervention
strongly associated with mortality
± Adult studies of ARDS respiratory failure not such a significantcause of death
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Direct vs indirect ARDS/ALI
Retrospective analysis in Venticute study betterresponse in direct than indirect
In this study
± Direct ARDS/ALI treatment group 8% mortality
placebo group 37% mortality
p 0.007
±
Indirect ARDS/ALI Little effect
Majority of patients in adult studies - indirect
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Strengths
Multi-centre, RCT, blinded
Relevant to our population
Well matched treatment/placebo groups
± Demographics ± Diagnoses
± PIM/PRISM
± Severity of lung injury
Relevant outcome measures
All patients followed up to 28 days/hospital discharge
Intention to treat analysis
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Weaknesses
Groups less well matched in immune status Underpowered
± Initially wanted 300 patients for primary outcomevariable only got 152
± Mortality rates inconclusive ± Unable to look at subgroups
Duration of ventilation/hospital stay/charges might actually be more if patient improved
Mortality information for direct/indirect ARDS
Long term outcome measures
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Conclusion
Surfactant replacement attractive idea
Disappointing data in adults
Evidence of acute improvement in children
?Improvement in mortality insufficient evidence
Importance of type of surfactant
Importance of patient subgroups
± Direct vs indirect ± Age subgroups
± Co-morbidities / Immune function
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References
Advances with Surfactant, Turrell, D. Emerg
Med Clin N Am 2008; 26: 921-928
Effect of Exogenous Surfactant (Calfactant) inPediatric Acute Lung Injury, Willson et. al,
JAMA 2005; 293: 470-476
A critical appraisal of a randomised controlled
trial (Willson et. al JAMA 2005), Czaja, A.
Pediatr Crit Care Med 2007; 8(1): 50-53