surfactant in ards

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Surfactant in ALI/ARDS



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



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



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



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



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



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



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



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



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



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



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



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



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



Patients Randomisation

Stratified to balance severity of lung injury

OI > 13

OI >7 and <13 ± Within 6hrs of initiation of mechanical ventilation



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



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



Outcomes

Ventilator-free days

Mortality

Acute effects

Length of stay / charges

Duration of O2

Failure of conventional ventilation Adverse events / safety



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



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%



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



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



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



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



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



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



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



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

surfactant in ards

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