Surfactant

SurfactantSurfactantDr Varsha Atul ShahDr Varsha Atul Shah

IntroductionIntroduction

The lungs of preterm infants lack adequate The lungs of preterm infants lack adequate pulmonary surfactant, a constituent of the pulmonary surfactant, a constituent of the air-liquid interface, that normally lines the air-liquid interface, that normally lines the alveolar surfaces and terminal airways. alveolar surfaces and terminal airways.

RDS is due to surfactant deficiency, which RDS is due to surfactant deficiency, which increases the surface tension at the air-increases the surface tension at the air-liquid interface of the terminal respiratory liquid interface of the terminal respiratory units. This leads to atelectasis and units. This leads to atelectasis and increases ventilation perfusion mismatch. increases ventilation perfusion mismatch.

Composition of SurfactantComposition of Surfactant CompositionComposition — Pulmonary surfactant is a  — Pulmonary surfactant is a

complex mixture of lipids and proteins that complex mixture of lipids and proteins that lowers alveolar surface tension.lowers alveolar surface tension.

LipidLipid — Approximately 70 percent of the  — Approximately 70 percent of the lipid in surfactant is phosphatidylcholine lipid in surfactant is phosphatidylcholine species. Of this, approximately 60 percent species. Of this, approximately 60 percent is disaturated palmitoylphosphatidyl is disaturated palmitoylphosphatidyl choline (DPPC)choline (DPPC)

ProteinProtein — Surfactant also contains small  — Surfactant also contains small proteins. These consist of the hydrophobic proteins. These consist of the hydrophobic surfactant proteins SP-B and SP-C and the surfactant proteins SP-B and SP-C and the hydrophilic proteins SP-A and SP-Dhydrophilic proteins SP-A and SP-D

SP-B is required for normal pulmonary function. SP-B is required for normal pulmonary function. – Infants with a mutation in the SFTPB gene resulting Infants with a mutation in the SFTPB gene resulting

in deficient or abnormal SP-B expression have in deficient or abnormal SP-B expression have severe respiratory failure that is lethal in the severe respiratory failure that is lethal in the perinatal period.perinatal period.

– The intracellular functions of the protein were The intracellular functions of the protein were elucidated in a knockout mouse model with deletion elucidated in a knockout mouse model with deletion of the gene encoding SP-B; respiratory failure of the gene encoding SP-B; respiratory failure developed immediately after birth. In this mouse, developed immediately after birth. In this mouse, type II cells lack typical lamellar bodies, have type II cells lack typical lamellar bodies, have abnormal accumulation of lipid vesicles, and cannot abnormal accumulation of lipid vesicles, and cannot process SP-C precursor protein, indicating the role of process SP-C precursor protein, indicating the role of SP-B in the reprocessing, storage, and secretion of SP-B in the reprocessing, storage, and secretion of surfactant in type II respiratory epithelial cellssurfactant in type II respiratory epithelial cells

Composition of SurfactantComposition of Surfactant

SP-C promotes the formation of the SP-C promotes the formation of the phospholipid film lining the alveolus. phospholipid film lining the alveolus. The extent of its role in surfactant The extent of its role in surfactant function is uncertain. function is uncertain. – Humans with SP-C deficiency do not have Humans with SP-C deficiency do not have

respiratory distress at birth, but develop respiratory distress at birth, but develop interstitial pulmonary fibrosis in early interstitial pulmonary fibrosis in early childhood. childhood.

– The knockout mouse counterpart of this The knockout mouse counterpart of this human disorder develops a progressive human disorder develops a progressive pulmonary disorder with histological pulmonary disorder with histological features consistent with interstitial features consistent with interstitial pneumonitis. pneumonitis.

SP-A and SP-D are small hydrophilic proteins SP-A and SP-D are small hydrophilic proteins that are members of the collectin protein that are members of the collectin protein family. family.

The primary role of these proteins is in host The primary role of these proteins is in host defense of the lung. SP-A and SP-D facilitate defense of the lung. SP-A and SP-D facilitate the uptake and killing of bacterial and viral the uptake and killing of bacterial and viral pathogens by immune cells, and appear to pathogens by immune cells, and appear to have a direct antimicrobial role. have a direct antimicrobial role.

There are no studies in humans that support There are no studies in humans that support a role for these proteins in infants with RDS, a role for these proteins in infants with RDS, but there are animal studies suggesting an but there are animal studies suggesting an association with a deficiency of these proteins association with a deficiency of these proteins and a predilection for lung inflammation and and a predilection for lung inflammation and infection. infection.

Surface tensionSurface tension   Normal lung function requires patent alveoli Normal lung function requires patent alveoli

that are closely situated to appropriately that are closely situated to appropriately perfused capillaries. perfused capillaries.

Molecular forces of the water molecules in Molecular forces of the water molecules in the alveolar lining result in high surface the alveolar lining result in high surface tension and a tendency of the air spaces to tension and a tendency of the air spaces to collapse, especially at low volumes. collapse, especially at low volumes.

The hydrophilic and hydrophobic properties The hydrophilic and hydrophobic properties of DPPC result in a head-to-tail orientation in of DPPC result in a head-to-tail orientation in the air-liquid interface inside the alveolus.the air-liquid interface inside the alveolus.

When the alveolar volume decreases during When the alveolar volume decreases during exhalation and the fluid in the air-liquid exhalation and the fluid in the air-liquid interface is compressed, these surface-interface is compressed, these surface-active molecules in the interface are active molecules in the interface are squeezed together, excluding water squeezed together, excluding water molecules. molecules.

As a result, pulmonary surfactant reduces As a result, pulmonary surfactant reduces the surface tension of the liquid lining, the surface tension of the liquid lining, decreasing the pressure needed to keep decreasing the pressure needed to keep the alveoli inflated and maintaining the alveoli inflated and maintaining alveolar stability.alveolar stability.

According to LaPlace's law, the pressure According to LaPlace's law, the pressure (P) necessary to keep the sphere open is (P) necessary to keep the sphere open is proportional to the surface tension (T) and proportional to the surface tension (T) and inversely proportional to the radius (R) of inversely proportional to the radius (R) of the sphere, shown by the formulathe sphere, shown by the formula

                                                                    P = 2T/R P = 2T/R If the surface tension is high and the If the surface tension is high and the alveolar volume is small (ie, the radius is alveolar volume is small (ie, the radius is low), as occurs at end expiration, the low), as occurs at end expiration, the pressure necessary to maintain the pressure necessary to maintain the alveolus open is high.alveolus open is high.

Types of SurfactantTypes of Surfactant Natural SurfactantNatural Surfactant

– Three natural surfactants are commercially Three natural surfactants are commercially available: available: poractantporactant alfaalfa, calfactant, and , calfactant, and beractant beractant

– obtained by either animal lung lavage or by obtained by either animal lung lavage or by mincing lung tissue (eg, lung minces)mincing lung tissue (eg, lung minces)

– subsequently purified by lipid extraction, subsequently purified by lipid extraction, removing hydrophilic components that include removing hydrophilic components that include the hydrophilic surfactant proteins A and D. the hydrophilic surfactant proteins A and D.

– the purified lipid components retain surfactant the purified lipid components retain surfactant proteins B and C, neutral lipids, and surface proteins B and C, neutral lipids, and surface active phospholipids (PL) such as active phospholipids (PL) such as dipalmitoylphosphotidylcholine (DPPC). dipalmitoylphosphotidylcholine (DPPC).

– DPPC is the primary surface active component DPPC is the primary surface active component that improves alveolar surface tension. that improves alveolar surface tension.

SurfactantSurfactant OriginOriginSurfactant Surfactant protein B protein B contentcontent

Conc of Conc of phospholipidphospholipid Initial doseInitial dose Repeat dosing scheduleRepeat dosing schedule

Poractant Poractant alfaalfa

Porcine lung minces, lipid extraction with Porcine lung minces, lipid extraction with purification using liquid-gel purification using liquid-gel chromatographychromatography

0.38% of PL0.38% of PL 80 mg PL per 80 mg PL per mlml

2.5 ml/kg (200 2.5 ml/kg (200 mg/kg PL)mg/kg PL)

1.25 ml/kg (100 mg/kg PL) every 12 1.25 ml/kg (100 mg/kg PL) every 12 h as needed up to 2 total dosesh as needed up to 2 total doses

CalfactantCalfactant Calf lung lavage, lipid extractionCalf lung lavage, lipid extraction 0.74% of PL0.74% of PL 35 mg PL/ml35 mg PL/ml 3.0 ml/kg (105 3.0 ml/kg (105 mg/kg PL)mg/kg PL)

3.0 ml/kg (105 mg/kg PL) every 12 3.0 ml/kg (105 mg/kg PL) every 12 h as needed up to 3 total dosesh as needed up to 3 total doses

BeractantBeractantBovine lung minces, lipid extraction. Bovine lung minces, lipid extraction. Supplemented with DPPC, palmitic acid and Supplemented with DPPC, palmitic acid and tripalmitintripalmitin

0.044% of 0.044% of PLPL 25 mg PL/ml25 mg PL/ml 4.0 ml/kg (100 4.0 ml/kg (100

mg/kg PL)mg/kg PL)Repeat same dose every 6 h as Repeat same dose every 6 h as needed for total of 4 dosesneeded for total of 4 doses

Commercial Natural Surfactant Types and Composition

Synthetic SurfactantSynthetic Surfactant– currently no synthetic surfactant currently no synthetic surfactant

products available for clinical use. products available for clinical use. – the one synthetic product, Colfosceril the one synthetic product, Colfosceril

palmitate, that was available contained palmitate, that was available contained DPPC, cetyl alcohol, and tyloxapolDPPC, cetyl alcohol, and tyloxapol

– Withdrawn from market Withdrawn from market

So… Which is better?So… Which is better?

Compared with older synthetic Compared with older synthetic preparations without protein B and C preparations without protein B and C analogues, natural surfactants have been analogues, natural surfactants have been shown to be superior in clinical trials. shown to be superior in clinical trials.

In particular, natural preparations In particular, natural preparations permitted relatively lower inspired oxygen permitted relatively lower inspired oxygen concentration and ventilator pressuresconcentration and ventilator pressures

this in part resulted in a decrease in this in part resulted in a decrease in mortality rates and complications of RDS mortality rates and complications of RDS in preterm infants in preterm infants

In that case, why are we persisting in In that case, why are we persisting in research for synthetic surfactant?research for synthetic surfactant?– Decreased immunogenicity Decreased immunogenicity – Decreased potential to transmit animal-Decreased potential to transmit animal-

borne infectious agents borne infectious agents – Large quantities of material that is Large quantities of material that is

consistent in composition consistent in composition

The relative superiority of natural surfactant The relative superiority of natural surfactant compared to older synthetic surfactants (without compared to older synthetic surfactants (without protein B and C analogues), particularly in terms protein B and C analogues), particularly in terms of a decrease in mortality rate and risk of of a decrease in mortality rate and risk of developing pneumothorax, was best illustrated by developing pneumothorax, was best illustrated by a meta-analysis of 11 randomized controlled a meta-analysis of 11 randomized controlled studies of 4658 preterm infants (from 1975 to studies of 4658 preterm infants (from 1975 to 2000). The following results were reported:2000). The following results were reported:

– In 10 studies, patients treated with natural surfactant had In 10 studies, patients treated with natural surfactant had a a lower mortality ratelower mortality rate than those treated with synthetic than those treated with synthetic surfactant (15.8 versus 18.4 percent; RR 0.86, 95% CI surfactant (15.8 versus 18.4 percent; RR 0.86, 95% CI 0.76-0.98). 0.76-0.98).

– In nine studies, there was a In nine studies, there was a lower incidence of lower incidence of pneumothoracespneumothoraces in patients treated with natural in patients treated with natural surfactant than in patients treated with synthetic surfactant than in patients treated with synthetic surfactant (6.9 versus 10.9 percent; RR 0.63, 95% CI surfactant (6.9 versus 10.9 percent; RR 0.63, 95% CI 0.53-0.75). 0.53-0.75).

Natural vs Synthetic without protein analoguesNatural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. AUSoll RF; Blanco F SOCochrane Database Syst Rev 2001;(2):CD000144.

– In seven studies, there was a higher incidence of In seven studies, there was a higher incidence of intraventricular hemorrhage (IVH) in the patients intraventricular hemorrhage (IVH) in the patients treated with natural surfactant than in patients treated with natural surfactant than in patients treated with a synthetic preparation (34.2 treated with a synthetic preparation (34.2 versus 31.5 percent; RR 1.09, 95% CI 1.00-1.19). versus 31.5 percent; RR 1.09, 95% CI 1.00-1.19). However, there was However, there was no difference in risk for no difference in risk for severe IVHsevere IVH (defined as grades 3 and 4) (defined as grades 3 and 4) between the two groups. between the two groups.

– There was no difference between groups in the There was no difference between groups in the incidence of patent ductus arteriosus, sepsis, incidence of patent ductus arteriosus, sepsis, retinopathy of prematurity, bronchopulmonary retinopathy of prematurity, bronchopulmonary dysplasia (BPD), or chronic lung disease (CLD); dysplasia (BPD), or chronic lung disease (CLD); CLD was defined as an oxygen requirement at CLD was defined as an oxygen requirement at 36 weeks adjusted age. 36 weeks adjusted age.

One synthetic product, namedOne synthetic product, named lucinactantlucinactant, contains a 21 amino acid , contains a 21 amino acid peptide called KLpeptide called KL

positively charged lysine molecules (K) positively charged lysine molecules (K) are separated by 4 leucine molecules are separated by 4 leucine molecules (L). (L).

KL4 appears to mimic surfactant protein KL4 appears to mimic surfactant protein B and combines with phospholipids. B and combines with phospholipids.

The relative efficacy of this agent The relative efficacy of this agent compared to other synthetic surfactants compared to other synthetic surfactants and natural surfactants was evaluated and natural surfactants was evaluated in two well-designed studiesin two well-designed studies

Natural vs Synthetic with protein analogues

(1) 1294 preterm infants (gestational age less (1) 1294 preterm infants (gestational age less than 32 weeks) were assigned tothan 32 weeks) were assigned to– receive colfosceril palmitate, a synthetic surfactant receive colfosceril palmitate, a synthetic surfactant

without surfactant proteins, (509 patients)without surfactant proteins, (509 patients)– lucinactant (527 patients)lucinactant (527 patients)– or beractant, a natural surfactant(258 patients) or beractant, a natural surfactant(258 patients)

– All forms of surfactant were administered within 20 to All forms of surfactant were administered within 20 to 30 minutes after birth. 30 minutes after birth.

– Compared with colfosceril palmitate, lucinactant Compared with colfosceril palmitate, lucinactant significantly reduced the incidence of RDS at 24 hours significantly reduced the incidence of RDS at 24 hours of life (39 versus 47 percent) and BPD at 28 days (40 of life (39 versus 47 percent) and BPD at 28 days (40 versus 45 percent). No difference between lucinactant versus 45 percent). No difference between lucinactant and beractant in these outcomes. and beractant in these outcomes.

– In addition, mortality due to RDS at 14 days was In addition, mortality due to RDS at 14 days was significantly lower with lucinactant versus both significantly lower with lucinactant versus both colfosceril palmitate (5 versus 9 percent) and colfosceril palmitate (5 versus 9 percent) and beractant (5 versus 10 percent). beractant (5 versus 10 percent).

A multicenter, randomized, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of A multicenter, randomized, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome among very preterm infants. AUMoya FR; Gadzinowski J; Bancalari E; Salinas V; Kopelman B; respiratory distress syndrome among very preterm infants. AUMoya FR; Gadzinowski J; Bancalari E; Salinas V; Kopelman B; Bancalari A; Kornacka MK; Merritt TA; Segal R; Schaber CJ; Tsai H; Massaro J; d'Agostino R SOPediatrics 2005 Apr;115(4):1018-29Bancalari A; Kornacka MK; Merritt TA; Segal R; Schaber CJ; Tsai H; Massaro J; d'Agostino R SOPediatrics 2005 Apr;115(4):1018-29

(2) 252 preterm infants (gestational age less than (2) 252 preterm infants (gestational age less than 28 weeks), were randomly assigned 28 weeks), were randomly assigned

either lucinactanteither lucinactant or poractant alfa, a natural surfactantor poractant alfa, a natural surfactant within 30 minutes after birthwithin 30 minutes after birth No significant differences in survival without BPD No significant differences in survival without BPD

at 28 days of life and at 36 weeks postmenstrual at 28 days of life and at 36 weeks postmenstrual dates. dates.

In addition, no significant differences were In addition, no significant differences were observed in the incidence of grade 3 or 4 IVH, observed in the incidence of grade 3 or 4 IVH, NEC, PDA, pneumothorax, or retinopathy of NEC, PDA, pneumothorax, or retinopathy of prematurity. prematurity.

A major limitation of this study was enrollment A major limitation of this study was enrollment reached only one-half the sample size that was reached only one-half the sample size that was originally calculated.originally calculated.

A multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for A multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome. Sinha SK; Lacaze-Masmonteil T; Valls i Soler A; Wiswell TE; Gadzinowski J; Hajdu J; respiratory distress syndrome. Sinha SK; Lacaze-Masmonteil T; Valls i Soler A; Wiswell TE; Gadzinowski J; Hajdu J; Bernstein G; Sanchez-Luna M; Segal R; Schaber CJ; Massaro J; d'Agostino R. Pediatrics 2005 Apr;115(4):1030-8.  Bernstein G; Sanchez-Luna M; Segal R; Schaber CJ; Massaro J; d'Agostino R. Pediatrics 2005 Apr;115(4):1030-8.  

A meta-analysis of the two trials demonstratedA meta-analysis of the two trials demonstrated – no differences between infants treated with synthetic no differences between infants treated with synthetic

surfactant versus those who received animal derived surfactant versus those who received animal derived surfactant at 36 weeks adjusted gestational age in the surfactant at 36 weeks adjusted gestational age in the rates of mortality (RR 0.81, 95% CI 0.64-1.03)rates of mortality (RR 0.81, 95% CI 0.64-1.03) chronic lung disease (RR 0.99, 95% CI 0.84-1.18)chronic lung disease (RR 0.99, 95% CI 0.84-1.18) or the combined outcome of death and chronic lung or the combined outcome of death and chronic lung

disease (RR 0.96, 95% CI 0.82-1.12)disease (RR 0.96, 95% CI 0.82-1.12)Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress

syndrome. AUPfister R; Soll R; Wiswell T SOCochrane Database Syst Rev. 2007 Oct 17;(4):CD006069syndrome. AUPfister R; Soll R; Wiswell T SOCochrane Database Syst Rev. 2007 Oct 17;(4):CD006069

In a subsequent report, participants from both of In a subsequent report, participants from both of the two trials were evaluated at one year corrected the two trials were evaluated at one year corrected age age – There was no difference in survival rate between the There was no difference in survival rate between the

patients treated with lucinactant and those treated with patients treated with lucinactant and those treated with natural surfactant (74 versus 71 percent, OR 0.83; 95% natural surfactant (74 versus 71 percent, OR 0.83; 95% CI 0.61-1.12). CI 0.61-1.12).

– The incidences of posthospital readmissions and The incidences of posthospital readmissions and respiratory illnesses, and neurologic outcome did not respiratory illnesses, and neurologic outcome did not differ among the two groups.differ among the two groups.

Timing of surfactant Timing of surfactant administrationadministration

Surfactant is administered in preterm infants Surfactant is administered in preterm infants using three different timing strategies.using three different timing strategies.– Prophylactic surfactant therapy, which is administered at Prophylactic surfactant therapy, which is administered at

the time of delivery to infants at risk of RDS. the time of delivery to infants at risk of RDS. – Early therapy, which is administered by two hours of age Early therapy, which is administered by two hours of age

frequently before the diagnosis of RDS frequently before the diagnosis of RDS – Rescue surfactant therapy, which is given once the Rescue surfactant therapy, which is given once the

diagnosis of RDS is established. diagnosis of RDS is established. In all three strategies, surfactant therapy In all three strategies, surfactant therapy

improves mortality and morbidity in preterm improves mortality and morbidity in preterm infants when compared to untreated patients infants when compared to untreated patients

However, clinical trials suggest that prophylactic However, clinical trials suggest that prophylactic or early therapy is superior to rescue therapy or early therapy is superior to rescue therapy alone in infants at high-risk for RDS (below 30 alone in infants at high-risk for RDS (below 30 weeks gestation) weeks gestation)

Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Engle WA Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Engle WA Pediatrics. 2008 Feb;121(2):419-32 Pediatrics. 2008 Feb;121(2):419-32

Prophylactic or early versus Prophylactic or early versus rescue therapy alonerescue therapy alone

The decision to administer prophylactic or early The decision to administer prophylactic or early surfactant therapy versus rescue therapy is based surfactant therapy versus rescue therapy is based upon the identification of the infant at risk for upon the identification of the infant at risk for RDS who may benefit from preventive therapy.RDS who may benefit from preventive therapy.

The principal risk factor is The principal risk factor is gestational agegestational age, with , with infants less than 30 weeks gestational age being infants less than 30 weeks gestational age being at the highest risk for the development of RDS, as at the highest risk for the development of RDS, as well as having the highest risk of mortality and well as having the highest risk of mortality and morbidity associated with RDS.morbidity associated with RDS.

In at-risk infants, prophylactic or early treatment In at-risk infants, prophylactic or early treatment is associated with a decrease in morbidity and is associated with a decrease in morbidity and mortality compared to rescue treatment for mortality compared to rescue treatment for established RDS. This was best illustrated in two established RDS. This was best illustrated in two separate meta-analyses.separate meta-analyses.

The The first meta-analysisfirst meta-analysis compared early to compared early to rescue therapy in four randomized rescue therapy in four randomized controlled studies with 3459 patients. controlled studies with 3459 patients. Early treated patients received surfactant Early treated patients received surfactant preparation within the first two hours of preparation within the first two hours of life, while rescue treated patients received life, while rescue treated patients received surfactant after the diagnosis of RDS was surfactant after the diagnosis of RDS was established. Two of the studies used established. Two of the studies used natural surfactant and the other two natural surfactant and the other two synthetic preparations. synthetic preparations.

Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Yost CC; Soll RF Cochrane Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Yost CC; Soll RF Cochrane Database Syst Rev 2000;(2):CD001456Database Syst Rev 2000;(2):CD001456

The following results were reported:The following results were reported:– In all four studies, early treated patients had a In all four studies, early treated patients had a

significantly reduced mortality rate compared significantly reduced mortality rate compared to rescue treated patients (19.5 versus 22.3 to rescue treated patients (19.5 versus 22.3 percent; RR 0.87, 95% CI 0.77 to 0.99). percent; RR 0.87, 95% CI 0.77 to 0.99).

There was a significant decrease in There was a significant decrease in complications in early treated patients complications in early treated patients compared to rescue treated patients compared to rescue treated patients includingincluding– pneumothorax (11.9 versus 17.1 percent; RR pneumothorax (11.9 versus 17.1 percent; RR

0.70, 95% CI 0.59 to 0.82)0.70, 95% CI 0.59 to 0.82)– pulmonary interstitial emphysema (9.6 versus pulmonary interstitial emphysema (9.6 versus

14.8 percent; RR 0.63, 95% CI 0.59 to 0.82)14.8 percent; RR 0.63, 95% CI 0.59 to 0.82)– chronic lung disease (CLD) (8.7 versus 10.8 chronic lung disease (CLD) (8.7 versus 10.8

percent; RR 0.7, 95% CI 0.55 to 0.88). percent; RR 0.7, 95% CI 0.55 to 0.88). There were no differences in the incidences There were no differences in the incidences

of patent ductus arteriosus, intraventricular of patent ductus arteriosus, intraventricular hemorrhage (IVH), retinopathy of hemorrhage (IVH), retinopathy of prematurity, bronchopulmonary dysplasia prematurity, bronchopulmonary dysplasia (BPD), and necrotizing enterocolitis (NEC).(BPD), and necrotizing enterocolitis (NEC).

The The second meta-analysissecond meta-analysis compared compared prophylactic to rescue therapy in eight prophylactic to rescue therapy in eight randomized controlled studies with 2818 randomized controlled studies with 2818 patients.patients.

Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Soll RF; Morley CJ Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Soll RF; Morley CJ Cochrane Database Syst Rev 2001;(2):CD000510Cochrane Database Syst Rev 2001;(2):CD000510

All patients were treated with natural All patients were treated with natural surfactant preparations. surfactant preparations.

Prophylactic treated infants were intubated Prophylactic treated infants were intubated in the delivery room and received in the delivery room and received surfactant therapy prior to the first breath surfactant therapy prior to the first breath or immediately after intubation or or immediately after intubation or stabilization. stabilization.

Rescue treated patients received surfactant Rescue treated patients received surfactant after the diagnosis of RDS was established. after the diagnosis of RDS was established. Studies selected infants at high risk for RDS Studies selected infants at high risk for RDS using inclusion criteria of gestational age using inclusion criteria of gestational age less than 32 weeks gestation.less than 32 weeks gestation.

In seven studies, prophylactic treated patients had a In seven studies, prophylactic treated patients had a significantly reduced morality rate compared to significantly reduced morality rate compared to rescue treated patients (7.2 versus 11.7 percent; RR rescue treated patients (7.2 versus 11.7 percent; RR 0.61, 95% CI 0.48 to 0.77). 0.61, 95% CI 0.48 to 0.77).

In a secondary analysis of infants less than 30 In a secondary analysis of infants less than 30 weeks gestation, prophylactic therapy decreased weeks gestation, prophylactic therapy decreased mortality compared to rescue therapy (10.3 versus mortality compared to rescue therapy (10.3 versus 16.3 percent; RR 0.62, 95% CI 0.49 to 0.78). 16.3 percent; RR 0.62, 95% CI 0.49 to 0.78).

There were decreases in prophylactic treated There were decreases in prophylactic treated infants compared to those treated with rescue infants compared to those treated with rescue strategy instrategy in– pneumothorax (3.3 versus 5.4 percent; RR 0.62, pneumothorax (3.3 versus 5.4 percent; RR 0.62,

95% CI 0.42 to 0.89)95% CI 0.42 to 0.89)– pulmonary interstitial emphysema (12.2 versus pulmonary interstitial emphysema (12.2 versus

19.8 percent; RR 0.54, 95% CI 0.36 to 0.82). 19.8 percent; RR 0.54, 95% CI 0.36 to 0.82). There were no differences in the incidences of There were no differences in the incidences of

patent ductus arteriosus, IVH, retinopathy of patent ductus arteriosus, IVH, retinopathy of prematurity, BPD, and NEC between groups.prematurity, BPD, and NEC between groups.

These data indicate that for every These data indicate that for every 100 babies at high risk for RDS, 100 babies at high risk for RDS, prophylactic surfactant versus prophylactic surfactant versus rescue therapy alone would rescue therapy alone would result in five fewer deathsresult in five fewer deaths..

Prophylactic versus early therapyProphylactic versus early therapy Although there are no clinical trials that compare prophylactic Although there are no clinical trials that compare prophylactic

to early therapy, there is some indirect evidence to suggest to early therapy, there is some indirect evidence to suggest that prophylactic therapy is superior to later preventive (early) that prophylactic therapy is superior to later preventive (early) therapytherapy

Even short delays of administrationEven short delays of administration of surfactant may of surfactant may worsen outcomes. worsen outcomes. – In a randomized study of early versus delayed surfactant in In a randomized study of early versus delayed surfactant in

2690 infants at high risk for RDS, for example, the combined 2690 infants at high risk for RDS, for example, the combined outcome of death and BPD was reduced by 11 percent in outcome of death and BPD was reduced by 11 percent in patients who received surfactant before two hours of life patients who received surfactant before two hours of life compared to those treated at three hours of life.compared to those treated at three hours of life.

Early versus delayed neonatal administration of a synthetic surfactant--the judgment of OSIRIS. The OSIRIS Collaborative Early versus delayed neonatal administration of a synthetic surfactant--the judgment of OSIRIS. The OSIRIS Collaborative Group (open study of infants at high risk of or with respiratory insufficiency--the role of surfactant. Lancet 1992 Dec Group (open study of infants at high risk of or with respiratory insufficiency--the role of surfactant. Lancet 1992 Dec 5;340(8832):1363-95;340(8832):1363-9

– Although this study suggests earlier administration of Although this study suggests earlier administration of surfactant is beneficial, it did not directly compare surfactant is beneficial, it did not directly compare prophylactic administration in the delivery room to prophylactic administration in the delivery room to administration in the neonatal intensive care setting.administration in the neonatal intensive care setting.

Early versus delayed neonatal administration of a synthetic surfactant--the judgment of OSIRIS. The OSIRIS Collaborative Early versus delayed neonatal administration of a synthetic surfactant--the judgment of OSIRIS. The OSIRIS Collaborative Group (open study of infants at high risk of or with respiratory insufficiency--the role of surfactant. AUSOLancet 1992 Dec Group (open study of infants at high risk of or with respiratory insufficiency--the role of surfactant. AUSOLancet 1992 Dec 5;340(8832):1363-95;340(8832):1363-9

There is evidence suggesting that spontaneous breathing or There is evidence suggesting that spontaneous breathing or mechanical ventilation in infants with surfactant deficiency mechanical ventilation in infants with surfactant deficiency injures the lung within the first hour of life. injures the lung within the first hour of life. – This was demonstrated in an autopsy study of infants who This was demonstrated in an autopsy study of infants who

died before 12 hours of life. Nine infants who lived from one died before 12 hours of life. Nine infants who lived from one to ten hours had evidence of hyaline membrane disease by to ten hours had evidence of hyaline membrane disease by histology.histology.

How to administer How to administer surfactantsurfactant

For all of the surfactant replacement therapy For all of the surfactant replacement therapy trials, surfactant was instilled in liquid form via trials, surfactant was instilled in liquid form via the endotracheal tube. the endotracheal tube.

Some trials instilled all of the surfactant at once, Some trials instilled all of the surfactant at once, while others instilled it in smaller aliquots. Only while others instilled it in smaller aliquots. Only one very small trial compared a slow infusion with one very small trial compared a slow infusion with bolus administration of surfactant. bolus administration of surfactant.

It concluded that slow infusion was at least as It concluded that slow infusion was at least as effective as bolus therapy.effective as bolus therapy.

There is no evidence to support the practice of There is no evidence to support the practice of placing the infant in multiple different positions placing the infant in multiple different positions during the administration of surfactantduring the administration of surfactant

Hatchel R, Brune T, Franke N, Harms E, Jorch G. Sequential changes in compliance and resistance after bolus administration Hatchel R, Brune T, Franke N, Harms E, Jorch G. Sequential changes in compliance and resistance after bolus administration or slow infusion of surfactant in preterm infants. Intensive Care Med 2002;28:622-8or slow infusion of surfactant in preterm infants. Intensive Care Med 2002;28:622-8..

Should multiple or single doses of surfactant Should multiple or single doses of surfactant be usedbe used?? Two trials of multiple versus single doses of surfactant Two trials of multiple versus single doses of surfactant

replacement therapy (which included 394 babies in total) replacement therapy (which included 394 babies in total) have been reviewed. have been reviewed.

These studies compared infants treated with These studies compared infants treated with a single dose with [Soll RF. Multiple versus single dose natural a single dose with [Soll RF. Multiple versus single dose natural

surfactant extract for severe neonatal respiratory distress surfactant extract for severe neonatal respiratory distress syndrome (Cochrane Review). In: The Cochrane Library, Issue 4, syndrome (Cochrane Review). In: The Cochrane Library, Issue 4, 2004. Chichester, UK: John Wiley & Sons, Ltd. ]2004. Chichester, UK: John Wiley & Sons, Ltd. ]

either retreatment with up to three doses within the first 72 h for either retreatment with up to three doses within the first 72 h for infants who had a deterioration (shown by a 0.1 increase in the infants who had a deterioration (shown by a 0.1 increase in the fraction of inspired oxygen [FiO2] after an initial response) [Dunn fraction of inspired oxygen [FiO2] after an initial response) [Dunn MS, Shennan AT, Possmayer F. Single- versus multiple-dose MS, Shennan AT, Possmayer F. Single- versus multiple-dose surfactant replacement therapy in neonates of 30 to 36 weeks’ surfactant replacement therapy in neonates of 30 to 36 weeks’ gestation with respiratory distress syndrome. Pediatrics gestation with respiratory distress syndrome. Pediatrics 1990;86:564-71.]1990;86:564-71.]

or retreatment with up to three doses at 12 h and 24 h after the or retreatment with up to three doses at 12 h and 24 h after the initial dose for infants who remained intubated and required initial dose for infants who remained intubated and required oxygen . [Speer CP, Robertson B, Curstedt T, et al. Randomized oxygen . [Speer CP, Robertson B, Curstedt T, et al. Randomized European multicenter trial of surfactant replacement therapy for European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: Single versus severe neonatal respiratory distress syndrome: Single versus multiple doses of Curosurf. Pediatrics 1992;89:13-20.]multiple doses of Curosurf. Pediatrics 1992;89:13-20.]

– It should be noted that the babies studied were a It should be noted that the babies studied were a heterogeneous group with gestational ages that ranged heterogeneous group with gestational ages that ranged from 30 to 36 weeks in one study and a birthweight from 30 to 36 weeks in one study and a birthweight range of 700 g to 2000 g in the other. range of 700 g to 2000 g in the other.

– Meta-analysis of the trials showed a reduction in the risk Meta-analysis of the trials showed a reduction in the risk of pneumothorax (RR=0.51, 95% CI 0.30 to 0.88; ARD=–of pneumothorax (RR=0.51, 95% CI 0.30 to 0.88; ARD=–0.09, 95% CI –0.15 to –0.02) and a trend toward a 0.09, 95% CI –0.15 to –0.02) and a trend toward a reduction in mortality (RR=0.63, 95% CI 0.39 to 1.02; reduction in mortality (RR=0.63, 95% CI 0.39 to 1.02; ARD=–0.07, 95% CI –0.14 to 0.0). No complications ARD=–0.07, 95% CI –0.14 to 0.0). No complications associated with multiple dose treatment were identified associated with multiple dose treatment were identified (evidence level 1a).(evidence level 1a).

RecommendationRecommendation Infants with RDS who have persistent or recurrent oxygen Infants with RDS who have persistent or recurrent oxygen

and ventilatory requirements within the first 72 h of life and ventilatory requirements within the first 72 h of life should have repeated doses of surfactant. Administering should have repeated doses of surfactant. Administering more than three doses has not been shown to have a more than three doses has not been shown to have a benefit (grade A). benefit (grade A).

One RCT showed that for synthetic surfactants, babies who One RCT showed that for synthetic surfactants, babies who received three prophylactic doses rather than one had received three prophylactic doses rather than one had decreased oxygen and ventilatory needs in the first week of decreased oxygen and ventilatory needs in the first week of life and lower mortality at 28 days and one year of life life and lower mortality at 28 days and one year of life (evidence level 1b). (evidence level 1b). [Speer CP, Robertson B, Curstedt T, et al. [Speer CP, Robertson B, Curstedt T, et al. Randomized European multicenter trial of surfactant replacement therapy Randomized European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: Single versus multiple for severe neonatal respiratory distress syndrome: Single versus multiple doses of Curosurf. Pediatrics 1992;89:13-20.]doses of Curosurf. Pediatrics 1992;89:13-20.]

MECHANICAL VENTILATION AND CPAPMECHANICAL VENTILATION AND CPAP   Among infants without respiratory failure, a possibly Among infants without respiratory failure, a possibly

preferred alternative to help prevent atelectasis and preferred alternative to help prevent atelectasis and reduce the risk of BPD is continuous positive airway reduce the risk of BPD is continuous positive airway pressure (CPAP). pressure (CPAP).

Most of the data supporting the use of CPAP has been Most of the data supporting the use of CPAP has been observational. observational.

Results are less clear in the single trial comparing CPAP Results are less clear in the single trial comparing CPAP to intubation and ventilation. In this multicenter trial of to intubation and ventilation. In this multicenter trial of 610 infants who were born between 25 and 28 weeks 610 infants who were born between 25 and 28 weeks gestation, patients were assigned to nasal CPAP gestation, patients were assigned to nasal CPAP (pressure of 8 cm H2) or intubation and ventilation if (pressure of 8 cm H2) or intubation and ventilation if they required respiratory support at five minutes of age. they required respiratory support at five minutes of age. The administration of surfactant was not mandated and The administration of surfactant was not mandated and followed local clinical practice. followed local clinical practice.

Nasal CPAP or intubation at birth for very preterm infants. AUMorley CJ; Davis PG; Doyle Nasal CPAP or intubation at birth for very preterm infants. AUMorley CJ; Davis PG; Doyle LW; Brion LP; Hascoet JM; Carlin JB SON Engl J Med. 2008 Feb 14;358(7):700-8. LW; Brion LP; Hascoet JM; Carlin JB SON Engl J Med. 2008 Feb 14;358(7):700-8.

The following findings were noted:The following findings were noted: At 36 weeks corrected gestational age, there was At 36 weeks corrected gestational age, there was

no difference in the primary outcome of death or no difference in the primary outcome of death or BPD (defined as need for oxygen therapy) BPD (defined as need for oxygen therapy) between infants with CPAP versus those who between infants with CPAP versus those who were intubated (34 versus 39 percent, OR 0.8, were intubated (34 versus 39 percent, OR 0.8, 95% CI 0.58-1.12.). 95% CI 0.58-1.12.).

About half (46 percent) of the CPAP group were About half (46 percent) of the CPAP group were intubated during the first 5 days of life. Surfactant intubated during the first 5 days of life. Surfactant use was halved in the CPAP compared to the use was halved in the CPAP compared to the intubated group and days of ventilation were intubated group and days of ventilation were fewer. fewer.

There was, however, no difference in the fraction There was, however, no difference in the fraction of inspired oxygen (FiO2) or maximum PaCO2 of inspired oxygen (FiO2) or maximum PaCO2 during the two groups during the first five days of during the two groups during the first five days of life. life.

The risk of pneumothorax was greater in the The risk of pneumothorax was greater in the CPAP compared to the intubated group (9 versus CPAP compared to the intubated group (9 versus 3 percent). 3 percent).

This study was limited in that treatment was not This study was limited in that treatment was not masked and there were variations in other masked and there were variations in other interventions including administration of interventions including administration of surfactant and methylxanthine treatment (which surfactant and methylxanthine treatment (which is associated with a lower incidence of BPD). is associated with a lower incidence of BPD). Nevertheless, these results suggest that it may Nevertheless, these results suggest that it may be possible to initiate CPAP in preterm infants be possible to initiate CPAP in preterm infants born ≤28 weeks and treat them with surfactant born ≤28 weeks and treat them with surfactant only if they require intubationonly if they require intubation

INSURE (INtubate INSURE (INtubate SUrfactant and SUrfactant and

Extubate) protocolExtubate) protocol

This update includes complete data from three studies published in 2004 or after [Dani 2004, Texas This update includes complete data from three studies published in 2004 or after [Dani 2004, Texas Research Group, and Reininger 2005 (previously included as D'Angio 2003)] as well as Research Group, and Reininger 2005 (previously included as D'Angio 2003)] as well as methodological details and outcome data of the NICHD 2002 trial that was obtained from the methodological details and outcome data of the NICHD 2002 trial that was obtained from the investigators [NICHD 2002 (formerly Habermann 2002)]. investigators [NICHD 2002 (formerly Habermann 2002)].

Six randomized controlled trials of early surfactant Six randomized controlled trials of early surfactant administration with rapid extubation vs. selective surfactant administration with rapid extubation vs. selective surfactant and continued mechanical ventilation have been and continued mechanical ventilation have been completed. completed.

Review of these six trials suggests that early surfactant Review of these six trials suggests that early surfactant replacement therapy with extubation to NCPAP compared replacement therapy with extubation to NCPAP compared with later, selective surfactant replacement and continued with later, selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator mechanical ventilation with extubation from low ventilator support is associated with support is associated with – less need mechanical ventilationless need mechanical ventilation– lower incidence of BPD lower incidence of BPD – fewer air leak syndromes. fewer air leak syndromes. – In a subgroup comparison examining treatment threshold, a In a subgroup comparison examining treatment threshold, a

lower treatment threshold (FIO2 <= 0.45) confers greater lower treatment threshold (FIO2 <= 0.45) confers greater advantage in reducing the incidences of airleak syndromes and advantage in reducing the incidences of airleak syndromes and BPD; moreover a higher treatment threshold (FIO2 at study > BPD; moreover a higher treatment threshold (FIO2 at study > 0.45) had an increased incidence of PDA. These data suggest 0.45) had an increased incidence of PDA. These data suggest that treatment with surfactant by transient intubation using a that treatment with surfactant by transient intubation using a low treatment threshold (FIO2 < 0.45) is preferable to later low treatment threshold (FIO2 < 0.45) is preferable to later selective surfactant therapy by transient intubation using a selective surfactant therapy by transient intubation using a higher threshold for study entry (FIO2 > 0.45) or at the time of higher threshold for study entry (FIO2 > 0.45) or at the time of respiratory failure and initiation of mechanical ventilation.respiratory failure and initiation of mechanical ventilation.

Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome

Cochrane 2007Stevens TP, Harrington EW, Blennow M, Soll RF

What about indications other What about indications other than RDS?than RDS?

Secondary surfactant deficiency or dysfunction occurs in other Secondary surfactant deficiency or dysfunction occurs in other newborn respiratory disorders, including meconium aspiration newborn respiratory disorders, including meconium aspiration syndrome, pneumonia and pulmonary hemorrhage. A variety syndrome, pneumonia and pulmonary hemorrhage. A variety of substances, including albumin, meconium and blood inhibit of substances, including albumin, meconium and blood inhibit surfactant function. surfactant function.

Two RCTs in babies with severe meconium aspiration Two RCTs in babies with severe meconium aspiration syndrome have shown the benefits of surfactant replacement syndrome have shown the benefits of surfactant replacement therapy. therapy. – Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement

therapy for meconium aspiration syndromes. Pediatrics therapy for meconium aspiration syndromes. Pediatrics 1996;97:48-52. 1996;97:48-52.

– Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (Beractant) use in the treatment of Multicenter study of surfactant (Beractant) use in the treatment of term infants with severe respiratory failure. J Pediatr 1998;132:40-term infants with severe respiratory failure. J Pediatr 1998;132:40-7.7.

One studied infants requiring 100% oxygen with an One studied infants requiring 100% oxygen with an oxygenation index greater than 15, and the other studied oxygenation index greater than 15, and the other studied infants requiring more than 50% oxygen with an infants requiring more than 50% oxygen with an arterial/alveolar O2 tension ratio of less than 0.22. A arterial/alveolar O2 tension ratio of less than 0.22. A systematic review reported no differences in mortality or systematic review reported no differences in mortality or pneumothorax but it showed a decrease in the requirement for pneumothorax but it showed a decrease in the requirement for extracorporeal oxygenation(evidence level 1a).extracorporeal oxygenation(evidence level 1a).

The use of surfactant replacement therapy in neonatal The use of surfactant replacement therapy in neonatal pneumonia has not been adequately studied. A subgroup pneumonia has not been adequately studied. A subgroup analysis of near-term babies with respiratory failure from analysis of near-term babies with respiratory failure from the prospective RCT of Lotze et al, showed that those who the prospective RCT of Lotze et al, showed that those who had sepsis and were treated with surfactants had a 40% had sepsis and were treated with surfactants had a 40% decrease in the need for extracorporeal membrane decrease in the need for extracorporeal membrane oxygenation. Other case series of neonatal bacterial oxygenation. Other case series of neonatal bacterial pneumonia appear to show surfactant therapy to be pneumonia appear to show surfactant therapy to be beneficial (evidence level 4).beneficial (evidence level 4).

In controlled trials, exogenous surfactant therapy increases In controlled trials, exogenous surfactant therapy increases the incidence of pulmonary hemorrhage (30). However, the incidence of pulmonary hemorrhage (30). However, because haemoglobin and other blood components such as because haemoglobin and other blood components such as fibrinogen have been shown to have serious adverse effects fibrinogen have been shown to have serious adverse effects on surfactant function (31), surfactant replacement therapy on surfactant function (31), surfactant replacement therapy has also been used to treat pulmonary hemorrhage. There has also been used to treat pulmonary hemorrhage. There are no RCTs examining the use of surfactant replacement are no RCTs examining the use of surfactant replacement therapy in this condition. Pulmonary hemorrhage is often therapy in this condition. Pulmonary hemorrhage is often very acute and unpredictable, and leads to rapid very acute and unpredictable, and leads to rapid deterioration, which would make a formal RCT difficult. deterioration, which would make a formal RCT difficult.

However, the incidence of pulmonary hemorrhage in the However, the incidence of pulmonary hemorrhage in the most immature infants is as high as 28%, suggesting that most immature infants is as high as 28%, suggesting that there may be opportunity for a focussed trial in the future. there may be opportunity for a focussed trial in the future. One retrospective cohort study showed a substantial acute One retrospective cohort study showed a substantial acute improvement in oxygenation in babies with pulmonary improvement in oxygenation in babies with pulmonary hemorrhage who had significant clinical compromise when hemorrhage who had significant clinical compromise when they were given surfactant replacement therapy (evidence they were given surfactant replacement therapy (evidence level 4).level 4).

Intubated newborn infants with pulmonary hemorrhage Intubated newborn infants with pulmonary hemorrhage which leads to clinical deterioration should receive which leads to clinical deterioration should receive exogenous surfactant therapy as one aspect of clinical care.exogenous surfactant therapy as one aspect of clinical care.

Finally, for lung hypoplasia and congenital diaphragmatic Finally, for lung hypoplasia and congenital diaphragmatic hernia, only small case series have been reported and no hernia, only small case series have been reported and no conclusions can be made.conclusions can be made.

What are the risks of exogenous surfactant What are the risks of exogenous surfactant therapy?therapy?

The short-term risks of surfactant replacement therapy include The short-term risks of surfactant replacement therapy include bradycardia and hypoxemia during instillation, as well as bradycardia and hypoxemia during instillation, as well as blockage of the endotracheal tube. blockage of the endotracheal tube.

There may also be an increase in pulmonary hemorrhage There may also be an increase in pulmonary hemorrhage following surfactant treatment; however, mortality ascribed to following surfactant treatment; however, mortality ascribed to pulmonary hemorrhage is not increased and overall mortality is pulmonary hemorrhage is not increased and overall mortality is lower after surfactant therapy. The RR for pulmonary lower after surfactant therapy. The RR for pulmonary hemorrhage following surfactant treatment has been reported hemorrhage following surfactant treatment has been reported at approximately 1.47 (95% CI 1.05 to 2.07) in trials but, at approximately 1.47 (95% CI 1.05 to 2.07) in trials but, unfortunately, many of the RCTs on surfactant replacement unfortunately, many of the RCTs on surfactant replacement have not reported this outcome, nor have the data from autopsy have not reported this outcome, nor have the data from autopsy studies clearly defined the magnitude of this risk (evidence level studies clearly defined the magnitude of this risk (evidence level 1a). No other adverse clinical outcome has been shown to be 1a). No other adverse clinical outcome has been shown to be increased by surfactant therapy.increased by surfactant therapy.

– Pappin A, Shenker N, Hack M, Redline RW. Extensive intraalveolar pulmonary hemorrhage in infants dying after surfactant Pappin A, Shenker N, Hack M, Redline RW. Extensive intraalveolar pulmonary hemorrhage in infants dying after surfactant therapy. J Pediatr 1994;124:621-6. therapy. J Pediatr 1994;124:621-6.

There is often a very rapid improvement in gas exchange in There is often a very rapid improvement in gas exchange in surfactant-treated infants who are surfactant deficient. This is surfactant-treated infants who are surfactant deficient. This is accompanied by dramatic improvements in static pulmonary accompanied by dramatic improvements in static pulmonary compliance. In contrast, when dynamic compliance is compliance. In contrast, when dynamic compliance is measured, there is little acute change detected. This measured, there is little acute change detected. This discrepancy is explained by the large increase in functional discrepancy is explained by the large increase in functional residual capacity due to the recruitment of lung volume residual capacity due to the recruitment of lung volume (evidence level 1b).(evidence level 1b).

Therefore, the pressure volume loops of the lung are Therefore, the pressure volume loops of the lung are normalized, but unless administered pressures are reduced, normalized, but unless administered pressures are reduced, overdistension can occur. Hyperventilation with very low overdistension can occur. Hyperventilation with very low PCO2 can also sometimes accidentally occur. Thus, PCO2 can also sometimes accidentally occur. Thus, weaning of administered airway pressures and ventilator weaning of administered airway pressures and ventilator settings should be expected within a few minutes of the settings should be expected within a few minutes of the administration of natural surfactants, and the caregivers administration of natural surfactants, and the caregivers must be aware of the nature and speed of these changes.must be aware of the nature and speed of these changes.

Natural surfactants contain proteins (surfactant protein-A, Natural surfactants contain proteins (surfactant protein-A, surfactant protein-B) from bovine or porcine sources and surfactant protein-B) from bovine or porcine sources and questions have been raised about the immunological questions have been raised about the immunological effects. To date, there is no evidence that there are effects. To date, there is no evidence that there are immunological changes of clinical concern. immunological changes of clinical concern.

Approved surfactants are produced in accordance with Approved surfactants are produced in accordance with regulated standards of microbiological safety. However, regulated standards of microbiological safety. However, given the uncertainty about the methods of transmission of given the uncertainty about the methods of transmission of emerging pathogens such as prions, no comment can be emerging pathogens such as prions, no comment can be made at the present time about the potential transmission made at the present time about the potential transmission of such agents.of such agents.

What are the criteria for, What are the criteria for, and timing of, retreatment?and timing of, retreatment? There are extremely limited data comparing the different criteria for There are extremely limited data comparing the different criteria for

retreatment (they were decided arbitrarily in the two trials). Kattwinkel retreatment (they were decided arbitrarily in the two trials). Kattwinkel et al compared the relative efficacy of administering second and et al compared the relative efficacy of administering second and subsequent doses of a natural surfactant at low (FiO2 greater than subsequent doses of a natural surfactant at low (FiO2 greater than 0.30, still requiring intubation) and high (FiO2 greater than 0.40, mean 0.30, still requiring intubation) and high (FiO2 greater than 0.40, mean airway pressure greater than 7 cm H2O) thresholds after a minimum of airway pressure greater than 7 cm H2O) thresholds after a minimum of 6 h. They noted no benefits from retreating at the lower threshold, 6 h. They noted no benefits from retreating at the lower threshold, except in those babies with complicated RDS (evidence of perinatal except in those babies with complicated RDS (evidence of perinatal compromise or sepsis) who had a lower mortality with low threshold compromise or sepsis) who had a lower mortality with low threshold retreatment (evidence level 1b).retreatment (evidence level 1b).

Retreatment strategies may be dependent on which preparation is Retreatment strategies may be dependent on which preparation is used, as some are more prone to protein inactivation. The timing of used, as some are more prone to protein inactivation. The timing of retreatment has been fairly arbitrarily determined in most of the retreatment has been fairly arbitrarily determined in most of the surfactant trials, but comparisons of the timing of retreatment have surfactant trials, but comparisons of the timing of retreatment have been limited and there have been no comparisons of the timing of been limited and there have been no comparisons of the timing of retreatment between surfactant preparations.retreatment between surfactant preparations.

Figueras-Aloy et al randomly compared retreatment at 2 h and 6 h Figueras-Aloy et al randomly compared retreatment at 2 h and 6 h after the initial dose. There appeared to be some short-term after the initial dose. There appeared to be some short-term advantages to earlier redosing in the smallest infants, but the study advantages to earlier redosing in the smallest infants, but the study was small and no clinically important benefits were shown (evidence was small and no clinically important benefits were shown (evidence level 2).level 2).

RecommendationRecommendation Retreatment should be considered when there is a persistent or Retreatment should be considered when there is a persistent or

recurrent oxygen requirement of 30% or more and it may be given as recurrent oxygen requirement of 30% or more and it may be given as early as 2 h after the initial dose or, more commonly, 4 h to 6 h after early as 2 h after the initial dose or, more commonly, 4 h to 6 h after the initial dose (grade A). the initial dose (grade A).

How should ventilatory management How should ventilatory management after surfactant therapy be after surfactant therapy be

approached?approached? Because of the rapid changes in lung mechanics and the Because of the rapid changes in lung mechanics and the

ventilation/perfusion matching that occurs after rescue surfactant ventilation/perfusion matching that occurs after rescue surfactant therapy, and the prevention of serious lung disease by the therapy, and the prevention of serious lung disease by the prophylactic use of natural surfactants, many infants can be very prophylactic use of natural surfactants, many infants can be very rapidly weaned and extubated to nasal continuous positive airway rapidly weaned and extubated to nasal continuous positive airway pressure (CPAP) within 1 h of intubation and surfactant pressure (CPAP) within 1 h of intubation and surfactant administration. To do this, the premedication used for intubation administration. To do this, the premedication used for intubation should only cause a brief duration of respiratory depression and staff should only cause a brief duration of respiratory depression and staff must be trained and skilled in rapid ventilator weaning. Such must be trained and skilled in rapid ventilator weaning. Such weaning is often performed with few or no blood gases, relying weaning is often performed with few or no blood gases, relying instead on the infant’s clinical condition and spontaneous respiratory instead on the infant’s clinical condition and spontaneous respiratory effort and with consideration of the oxygen requirements as effort and with consideration of the oxygen requirements as determined from pulse oximetry and sometimes with the use of determined from pulse oximetry and sometimes with the use of transcutaneous CO2 measurements.transcutaneous CO2 measurements.

There is currently no proof that a rapid wean and extubation There is currently no proof that a rapid wean and extubation approach improves long-term outcomes compared with the more approach improves long-term outcomes compared with the more traditional weaning approach. In two small randomized trials, such traditional weaning approach. In two small randomized trials, such an approach led to a decrease in the need for more than 1 h of an approach led to a decrease in the need for more than 1 h of mechanical ventilation (evidence level 2b). Definitive mechanical ventilation (evidence level 2b). Definitive recommendations will require further evidence.recommendations will require further evidence.

RecommendationRecommendation Options for ventilatory management that are to be considered after Options for ventilatory management that are to be considered after

prophylactic surfactant therapy include very rapid weaning and prophylactic surfactant therapy include very rapid weaning and extubation to CPAP within 1 h (grade B). extubation to CPAP within 1 h (grade B).

SUMMARY AND SUMMARY AND RECOMMENDATIONRECOMMENDATION

Treatment and complications of respiratory distress syndrome in preterm infants – UptoDate.comTreatment and complications of respiratory distress syndrome in preterm infants – UptoDate.com

The administration of antenatal corticosteroid, and The administration of antenatal corticosteroid, and prophylactic or early surfactant therapy to high risk preterm prophylactic or early surfactant therapy to high risk preterm infants reduces the incidence and severity of RDS.infants reduces the incidence and severity of RDS.

ACS should be given to any pregnant woman at 24 to 34 ACS should be given to any pregnant woman at 24 to 34 weeks of gestation with intact membranes at high risk for weeks of gestation with intact membranes at high risk for preterm delivery (preterm delivery (Grade 1AGrade 1A))

Infants born at or before 30 weeks gestation be intubated Infants born at or before 30 weeks gestation be intubated and receive either prophylactic or early doses of natural and receive either prophylactic or early doses of natural surfactant preparation as soon as they are stable (surfactant preparation as soon as they are stable (Grade Grade 1A1A). ).

Although the relative efficacy of prophylactic or early doses Although the relative efficacy of prophylactic or early doses of natural surfactant preparations is unclear, we suggest that of natural surfactant preparations is unclear, we suggest that infants receive prophylactic therapy in the delivery room infants receive prophylactic therapy in the delivery room ((Grade 2BGrade 2B). ).

After administration of surfactant and if the infant is active After administration of surfactant and if the infant is active and exhibits spontaneous respiratory effort, we recommend and exhibits spontaneous respiratory effort, we recommend extubation and stabilization on CPAP rather than continued extubation and stabilization on CPAP rather than continued intubation and mechanical ventilation (intubation and mechanical ventilation (Grade 1BGrade 1B). ).

NOT administering prophylactic surfactant therapy for infants NOT administering prophylactic surfactant therapy for infants greater than 30 weeks gestation (greater than 30 weeks gestation (Grade 1BGrade 1B).).

Recommendations for neonatal surfactant therapyFetus and Newborn Committee, Canadian Paediatric Society (CPS)Paediatr Child Health 2005;10(2):109-16Reference No. FN05-01

What are the indications and benefits of surfactant What are the indications and benefits of surfactant replacement therapy?replacement therapy?

Surfactant replacement therapy, either as a rescue treatment or a Surfactant replacement therapy, either as a rescue treatment or a prophylactic natural surfactant therapy, reduces mortality (evidence prophylactic natural surfactant therapy, reduces mortality (evidence level 1a) and several aspects of morbidity in babies with RDS . level 1a) and several aspects of morbidity in babies with RDS .

These morbidities include deficits in oxygenation, the incidence of These morbidities include deficits in oxygenation, the incidence of pulmonary air leaks (pneumothorax and pulmonary interstitial pulmonary air leaks (pneumothorax and pulmonary interstitial emphysema) and the duration of ventilatory support (evidence level emphysema) and the duration of ventilatory support (evidence level 1a). 1a).

Surfactant replacement increases the likelihood of surviving without Surfactant replacement increases the likelihood of surviving without bronchopulmonary dysplasia (BPD, also known as chronic lung disease bronchopulmonary dysplasia (BPD, also known as chronic lung disease of the preterm) largely by improving survival rather than the incidence of the preterm) largely by improving survival rather than the incidence of BPD. of BPD.

Babies treated with surfactants have shorter hospital stays and lower Babies treated with surfactants have shorter hospital stays and lower costs of intensive care treatment compared with randomized control costs of intensive care treatment compared with randomized control infants receiving no surfactants. The increase in survival is achieved infants receiving no surfactants. The increase in survival is achieved with no increase in adverse neurodevelopmental outcome (evidence with no increase in adverse neurodevelopmental outcome (evidence level 1a).level 1a).

RecommendationRecommendation Intubated infants with RDS should receive exogenous surfactant Intubated infants with RDS should receive exogenous surfactant

therapy (grade A). therapy (grade A).

RecommendationsRecommendations Mothers at risk of delivering babies with less than Mothers at risk of delivering babies with less than

34 weeks gestation should be given antenatal 34 weeks gestation should be given antenatal steroids according to established guidelines steroids according to established guidelines regardless of the availability of postnatal regardless of the availability of postnatal surfactant therapy (grade A).surfactant therapy (grade A).

Intubated infants with RDS should receive Intubated infants with RDS should receive exogenous surfactant therapy (grade A).exogenous surfactant therapy (grade A).

Intubated infants with meconium aspiration Intubated infants with meconium aspiration syndrome requiring more than 50% oxygen syndrome requiring more than 50% oxygen should receive exogenous surfactant therapy should receive exogenous surfactant therapy (grade A).(grade A).

Sick newborn infants with pneumonia and an Sick newborn infants with pneumonia and an oxygenation index greater than 15 should receive oxygenation index greater than 15 should receive exogenous surfactant therapy (grade C).exogenous surfactant therapy (grade C).Intubated newborn infants with pulmonary Intubated newborn infants with pulmonary hemorrhage which leads to clinical deterioration hemorrhage which leads to clinical deterioration should receive exogenous surfactant therapy as should receive exogenous surfactant therapy as one aspect of clinical care (grade C).one aspect of clinical care (grade C).

Natural surfactants should be used in preference Natural surfactants should be used in preference to any of the artificial surfactants available at the to any of the artificial surfactants available at the time of publication of this statement (grade A).time of publication of this statement (grade A).

Infants who are at a significant risk for RDS Infants who are at a significant risk for RDS should receive prophylactic natural surfactant should receive prophylactic natural surfactant therapy as soon as they are stable within a few therapy as soon as they are stable within a few minutes after intubation (grade A).minutes after intubation (grade A).

Infants with RDS who have persistent or recurrent Infants with RDS who have persistent or recurrent oxygen and ventilatory requirements within the oxygen and ventilatory requirements within the first 72 h of life should have repeated doses of first 72 h of life should have repeated doses of surfactant. Administering more than three doses surfactant. Administering more than three doses has not been shown to have a benefit (grade A).has not been shown to have a benefit (grade A).Retreatment should be considered when there is Retreatment should be considered when there is a persistent or recurrent oxygen requirement of a persistent or recurrent oxygen requirement of 30% or more, and it may be given as early as 2 h 30% or more, and it may be given as early as 2 h after the initial dose or, more commonly, 4 h to 6 after the initial dose or, more commonly, 4 h to 6 h after the initial dose (grade A).h after the initial dose (grade A).

Options for ventilatory management that are to Options for ventilatory management that are to be considered after prophylactic surfactant be considered after prophylactic surfactant therapy include very rapid weaning and therapy include very rapid weaning and extubation to CPAP within 1 h (grade B).extubation to CPAP within 1 h (grade B).Intubated infants with RDS should receive Intubated infants with RDS should receive exogenous surfactant therapy before transport exogenous surfactant therapy before transport (grade C).(grade C).

Centres administering surfactant to newborn Centres administering surfactant to newborn infants must ensure the continuous on-site infants must ensure the continuous on-site availability of personnel competent and availability of personnel competent and licensed to deal with the acute complications licensed to deal with the acute complications of assisted ventilation and surfactant therapy of assisted ventilation and surfactant therapy (grade D).(grade D).Mothers with threatened delivery before 32 Mothers with threatened delivery before 32 weeks gestation should be transferred to a weeks gestation should be transferred to a tertiary centre if at all possible (grade B).tertiary centre if at all possible (grade B).

Infants who deliver at less than 29 weeks Infants who deliver at less than 29 weeks gestation outside of a tertiary centre should gestation outside of a tertiary centre should be considered for immediate intubation be considered for immediate intubation followed by surfactant administration after followed by surfactant administration after stabilization, if competent personnel are stabilization, if competent personnel are available (grade A).available (grade A).

Further research into retreatment criteria and Further research into retreatment criteria and the optimal timing of prophylactic therapy is the optimal timing of prophylactic therapy is required.required.

Other units’ protocols…Other units’ protocols…

The unexamined life is not worth livingThe unexamined life is not worth livingSocrates 499 BCSocrates 499 BC