Second Meeting of the Subcommittee of the Expert Committee on the

Selection and Use of Essential Medicines Geneva, 29 September to 3 October 2008

Proposal for the inclusion of surfactant in the WHO model list of essential medicines

Dirk Bassler & Christian Poets

Department of Neonatology, University Children's Hospital of Tuebingen, Tuebingen,

Germany

Tel +49 (0) 7071 2984742

Fax +49 (0) 7071 293969

Web page: http://www.med.uni-tuebingen.de/kinder/abteilung-4/

Table of Contents

Page No. 1. Synopsis 3

2. Summary statement of the proposal 4

3. Name of the organization(s) consulted and/or supporting the application 4

4. Examples of surfactant preparations by generic names 4

5. Formulation proposed for inclusion 4

6. Whether listing is requested as an individual preparation or as a group 4

7. Definition of respiratory distress syndrome (RDS) 4

8. RDS: epidemiological information on disease burden 5

9. Surfactant composition and function 6

10. Commercially available surfactant preparations 7

11. Summary of comparative effectiveness 8

11.1 Surfactant replacement for RDS 8

11.1.1 Prophylactic versus rescue surfactant 8

11.1.2 Natural versus synthetic surfactant 10

11.1.3 Surfactant administration 10

11.2 Surfactant replacement for respiratory disorders 12

other than RDS

11.2.1 Persistent pulmonary hypertension of the newborn (PPHN) 12

11.2.2 Meconium aspiration syndrome (MAS) 12

11.2.3 Neonatal pneumonia and sepsis 12

11.2.4 Congenital diaphragmatic hernia (CDH) 13

11.2.5 Neonatal pulmonary hemorrhage 13

11.2.6 Acute lung injury and acute 13

respiratory distress syndrome (ARDS) in adults

12. Methodological quality of surfactant studies 14

12.1 Prophylaxis studies 14

12.2 Treatment studies 14

13. Cost effectiveness of prevention and treatment of RDS 14

with exogenous surfactant

14. List of abbreviations 16

15. References 17

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1. Synopsis

Surfactant is proposed for the care of the newborn infant. It is specifically proposed for the

prophylaxis and/or treatment of respiratory distress syndrome (RDS) since there is robust

evidence that surfactant reduces mortality and pulmonary air leaks in preterm infants with or

at high risk for RDS. Surfactant may also be considered for infants with hypoxic respiratory

failure attributable to secondary surfactant deficiency (eg. meconium aspiration syndrome,

sepsis/pneumonia, and pulmonary hemorrhage).

Some differences between natural and synthetic surfactant have been highlighted, for

example a difference in terms of reduction in the risk of death and pneumothorax, favoring

the former. However, both animal-derived and synthetic surfactants are beneficial for

prophylaxis and rescue treatment of RDS in preterm infants and therefore listing in the World

Health Organization (WHO) Model List of Essential Medicines is requested as a group and

not as an individual preparation.

At present, neither early nasal continuous positive airway pressure (nCPAP) nor mechanical

ventilation and surfactant can be said to be superior for the prevention of death or

bronchopulmonary dysplasia (BPD) in very preterm infants. The methods complement each

other but the question regarding an optimal approach remains yet to be answered in future

studies. The ability to administer surfactant during nCPAP appears to be important in

Extremely Low Birth Weight (ELBW) infants and more mature infants with established RDS.

New modalities of surfactant administration (e.g. aerosolized surfactant; surfactant via

nasogastric tube) may in the future help to combine nCPAP and surfactant therapy more

effectively and safely.

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2. Summary statement of the proposal Surfactant is proposed for the inclusion in the WHO Model List of Essential Medicines for the

care of preterm infants with or at high risk for RDS, since both animal-derived and synthetic

surfactants have been shown to be beneficial for prophylaxis and rescue treatment of RDS in

preterm infants.

3. Name of the organization(s) consulted and/or supporting the application University Children's Hospital of Tuebingen, Department of Neonatology, Calwerstr. 7, 72076

Tuebingen, Germany

4. Examples of surfactant preparations by generic names Pumactant, Bovactant, BLES, Poractant alfa, Colfosceril palmitate, Calfactant, Surfactant-

TA, Lucinactant, Beractant etc.

5. Formulation proposed for inclusion The optimum dose of surfactant varies between different surfactant preparations and

generally is between 50 and 200 mg/kg (see table 1, page 7). Since the primary target

population consists of ELBW infants, a vial size for an anticipated body weight of 500g /

1000g would be desirable, although this cut-off is somewhat arbitrary.

6. Whether listing is requested as an individual preparation or as a group Listing is requested on the WHO Model List of Essential Medicines as a group of different

surfactant preparations (natural and synthetic).

7. Definition of RDS RDS is mainly a problem of prematurity and it is caused by insufficient production of

surfactant and structural immaturity of the lungs or, very rarely, by a genetic problem with the

production of surfactant associated proteins.

RDS was previously called hyaline membrane disease due to the characteristic pathological

finding seen in babies who died from RDS, "hyaline membranes”, waxy-appearing layers that

line the collapsed alveoli of the lung.

The clinical course of RDS is characterized by early tachypnea, tachycardia, chest wall

retractions, expiratory grunting, flaring of the nostrils and cyanosis during breathing efforts.

As the disease progresses, infants may develop respiratory failure and apnea, requiring

positive pressure support and/or full mechanical ventilation. Avery and Mead established the causal relationship of surfactant deficiency and RDS in

1959. Four years later, a baby boy born to then-President and Mrs. John F. Kennedy died of

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RDS. Research into active treatment options for RDS was enforced and in 1980 the first

successful use of exogenous surfactant therapy in preterm infants was reported (Fujiwara

1980). Since then randomized controlled trials (RCTs) have demonstrated that surfactant

therapy is not only well tolerated but also significantly reduces both neonatal mortality and

pulmonary morbidity.

8. RDS: epidemiological information on disease burden RDS has been reported in all races worldwide although there is a paucity of population-

based epidemiological studies. According to the few published studies, the overall incidence

of RDS is about 1% (Field 1987, Rubatelli 1998).

In the United States, RDS occurs in approximately 20,000-40,000 infants each year. In

4438 infants weighing between 501 and 1500 g, and 195 infants weighing 401 to 500 g born

at the 14 participating centers of the National Institute of Child Health and Human

Development (NICHD) Neonatal Research Network very low birth weight (VLBW) registry

between January 1, 1995 and December 31, 1996, RDS was the most frequent acute

pulmonary disease (50% of all VLBW infants). It was diagnosed in 78% of infants weighing

501 to 750 g and 26% of infants weighing 1251 to 1500 g. Fifty-two percent of this cohort

received surfactant therapy (Lemons 2001).

In comparison, RDS for VLBW infants was diagnosed in 71% of infants weighing 501 to

750 g and 23% of infants weighing 51 to 1500 g born in the NICHD Neonatal Research

Network between Jan. 1, 1997 and Dec. 31, 2002 (Fanaroff 2007). Fifty-eight percent of the

entire cohort were treated with surfactant. For the purpose of the study, an infant was

determined to have RDS if each of the following was true: required oxygen at 6 hours of life

continuing to age 24 hours, demonstrated clinical features within age 24 hours, need for

respiratory support to age 24 hours, and an abnormal chest x-ray within age 24 hours

(Fanaroff 2007).

Several risk factors for RDS have been identified. Multivariate regression analysis of

maternal and perinatal data demonstrated that gestational age, birth-weight, maternal age,

elective and emergency caesarean section (CS), and male sex were risk factors for RDS

(Dani 1999). Most importantly, the incidence of RDS increases with decreasing gestational

age and birth weight (Chard 1997).

Epidemiological data on the frequency of RDS in developing countries is difficult to obtain for

various reasons: most deliveries occur at home, accurate records are often unavailable and

epidemiological studies are sparse. Some believe that RDS is encountered less frequently in

developing countries than elsewhere, because premature infants might be more often small

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for their gestation and stressed in utero due to malnutrition or pregnancy-induced

hypertension. Other studies have reported a comparable or even higher incidence of RDS

than in the western world. In a prospective study of the prevalence of RDS in a consecutive

10,134 births at the Aga Khan University Hospital in Karachi, RDS was documented in 127

infants (1.2% births), with a prevalence of 12.8% among low birth weight infants (Bhutta

1997). The overall mortality for this group was 39%, with the highest mortality rate (68%)

among newborn infants < or = 1000 g birth weight. The data from Pakistan suggest that RDS

is a significant cause of morbidity and mortality in preterm infants with a comparable

prevalence rate to western figures. However, these findings might not be representative for

all developing countries since the data were obtained from a relatively well-nourished

hospital-born population (Bhutta 1997). Another prospective hospital-based study from

Pakistan reported a higher incidence of RDS than documented in studies from the Western

world (Ghaffor).

In a prospective unmatched case-control study of 256 neonates with RDS and 256 controls

that was conducted at the 70-bed Neonatal Unit of Muhimjbili Medical Centre in Dar es

Salaam in Tanzania to study risk factors and outcome during March to November 1995, RDS

contributed 6 per cent of all neonatal admissions. RDS was significantly associated with

lower birth weight, gestational age, birth asphyxia and male sex. Maternal hypertension with

or without albuminuria was inversely related to RDS. There was no significant association

between RDS and mode of delivery, antepartum hemorrhage or premature prolonged rupture

of membranes of more than 24 h. A total of 134 (52%) neonates with RDS died, 88% of

which occurred in the first 7 days of life, thus significantly contributing to perinatal mortality

(Mlay 2000).

Although neonatal care has changed dramatically over the last decades (introduction of

antenatal steroids, exogenous surfactant replacement, improved ventilatory support etc.), the

overall incidence of RDS remains relatively stable at about 1% (Field 1987, Rubatelli 1998).

This might be due to the increased number of viable ELBW infants (Koivisto2004) and

underlines the importance of RDS as a major neonatal morbidity.

9. Surfactant composition and function Pulmonary surfactant is essential for normal lung function and survival at birth. It has surface

tension-lowering properties, by which alveolar collapse is prevented and gas exchange is

facilitated. It has also been shown to play an important role in innate defense of the lung

(Haagsman 2008).

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Surfactant is synthesized by alveolar type II cells, stored in lamellar bodies that are

exozytosed and taken up into the monolayer lining the epithelial surface of the lung.

Surfactant is a complex mixture of interacting lipids and proteins. The lipid fraction is mainly

(60%) comprised of saturated phosphatidylcholine. Twenty-five percent of phospholipids are

unsaturated phosphatidylcholine species, whereas the remaining 15% are

phosphatidylglycerol and phosphatidylinositol (Jobe 1993). The protein fraction is made up

by four different types of apoproteins: the hydrophobic surfactant protein B (SP-B) and SP-C

and the hydrophilic SP-A and SP-D. SP-B and SP-C are lipophilic surfactant-associated

proteins that facilitate adsorption and spread of phospholipids to form a monolayer at the air–

liquid interface. SP-A and D are members of the collectin family of proteins, containing a

collagen-like domain as well as a carbohydrate-binding region. They are present in both

pulmonary and extrapulmonary tissue. Among their functions are binding, opsonisation and

clearance of microbes from the lung and regulation of immune cell activity (Kingma 2006). It

has recently been proposed that SP-B and SP-C may be involved in modulation of

pulmonary inflammation as well (Ryan 2006, Ikegami 2005).

The essential pulmonary role of surfactant is highlighted by the pathophysiology of RDS seen

in preterm infants (see chapter 7). The first successful trial of surfactant treatment for RDS

was reported in 1980 followed by numerous RCTs demonstrating the efficacy of surfactant

treatment in reducing pulmonary air leaks and mortality. The introduction of exogenous

surfactant administration for infants with RDS is generally considered one of the most

important advancements in the field of neonatology. Nowadays, the potential benefit of

surfactant therapy is evaluated in a wide range of respiratory disorders in both neonates and

pediatric as well as adult patients. Moreover, several disease entities of formerly unknown

origin have recently been linked to genetic disorders of surfactant metabolism.

10. Commercially available surfactant preparations Surfactants may be of animal or synthetic origin. Both types of surfactants have been

extensively studied in animal models and in clinical trials to determine the optimal timing,

dose size and frequency, route and method of administration. There are several different

types of surfactant preparation licensed for use in neonates with RDS (see table 1) including

synthetic and natural surfactants. The following table does not claim to be complete; it was

adapted from the European consensus guidelines on the management of neonatal RDS that

were published in 2007 (Sweet 2007).

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Table 1: Surfactant preparations (2007); adapted from the European consensus guidelines on the management of neonatal respiratory distress syndrome (Sweet 2007)

Generic name / Trade name Source Dose (volume)

Bovactant / Alveofact Bovine 50 mg/kg/dose (1,2 ml/kg)

BLES / BLES Bovine 135 mg/kg/dose (5 ml/kg)

Calfactant / Infasurf Bovine 105 mg/kg/dose (5 ml/kg)

Surfactant-TA / Surfacten Bovine 100 mg/kg/dose (3,3 ml/kg)

Beractant / Survanta Bovine 100 mg/kg/dose (4 ml/kg)

Poractant alfa / Curosurf Porcine 100-200 mg/kg/dose (1,25-2,5 ml/kg)

Pumactant / ALEC Synthetic No longer manufactured

Colfosceril / Exosurf Synthetic 64 mg/kg/dose (5 ml/kg)

Lucinactant / Surfaxin Synthetic Not licensed

11. Summary of comparative effectiveness

11.1 Surfactant replacement for RDS The European consensus guidelines on the management of neonatal RDS recommend that

infants with or at high risk of RDS should be given surfactant as this reduces mortality and

pulmonary air leak (Sweet 2007). In the following chapter we will review the supporting

evidence separately for different indications, administrations, and formulations.

11.1.1 Prophylactic versus rescue surfactant The prophylactic surfactant approach aims at delivering surfactant before the onset of

respiratory symptoms. This approach offers the theoretical advantage of a more

homogeneous surfactant distribution, a decrease in need for mechanical ventilatory support

thus minimizing barotrauma and lung injury. This approach has mainly been operationalized

in clinical studies as surfactant administration within a time frame of up to 30 minutes after

birth.

The rescue surfactant approach reserves surfactant for infants with established RDS, most

commonly within the first 12 hours after birth when prespecified threshold criteria for RDS are

met. This approach offers the theoretical advantage of only treating infants with clinical

disease thus eliminating the potential risks and costs of treating infants that would not need

to be treated.

Using either approach (prophylactic and rescue) has been demonstrated to improve clinical

outcome (Soll 2001, Soll 1998). Infants who receive prophylactic natural or synthetic

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surfactant extract have a decreased risk of pneumothorax, a decreased risk of pulmonary

interstitial emphysema, and a decreased mortality. In addition infants receiving prophylactic

natural surfactant have a decreased risk of the combined outcome of bronchopulmonary

dysplasia (BPD) or death (Soll 1997).

In a meta-analysis of 8 studies from the Cochrane Collaboration comparing prophylactic

versus selective use of surfactant in preventing morbidity and mortality in preterm infants,

significant improvement in clinical outcomes was noted with the prophylactic approach. The

meta-analysis supports a decrease in pneumothorax (Relative Risk (RR) 0,62; 95%

Confidence Interval (CI) 0,42-0,89), a decrease in the incidence of pulmonary interstitial

emphysema (RR 0,54; 95% CI 0,36-0,82), a decrease in mortality (0,61; 95% CI 0,48-0,77)

and a decrease in the incidence of BPD or death (RR 0,85; 95% CI 0,76-0,95) (Soll 2001).

Based on the available evidence, the European consensus guidelines on the management of

neonatal respiratory distress syndrome recommend that prophylactic surfactant (within 15

min of birth) should be given to almost all babies under 27 weeks’ gestation (Sweet 2007).

Prophylaxis should be considered for babies over 26 weeks but < 30 weeks’ gestation if

intubation is required in the delivery room or if the mother has not received prenatal

corticosteroids (Sweet 2007).

According to these guidelines untreated babies should receive early surfactant if there is

evidence of RDS such as increasing requirements for oxygen. However the timing for

intervention or when to intervene as RDS progresses is not specified in these guidelines and

the decision is left to the individual clinicians.

The most recent statement of the American Academy of Pediatrics (AAP) concludes that

surfactant should be given to infants with RDS as soon as possible after intubation

irrespective of exposure to antenatal steroids or gestational age (Engle 2008). Prophylactic

surfactant replacement is suggested to be considered for extremely preterm infants at high

risk of RDS, especially in infants who have not been exposed to antenatal steroids (Engle

2008).

Based on the above evidence and guidelines, the standard treatment for very preterm infants

is/was with assisted ventilation and surfactant (Lindner 1999). However, with recent changes

in neonatal care and insight that ventilation may be harmful to the lungs, it has been

hypothesized that the avoidance of ventilation might lead to less BPD. In the COIN trial, an

RCT in which 610 infants who were born at 25-to-28-weeks' gestation were assigned to

either CPAP or intubation and ventilation at 5 minutes after birth, there was no statistical

evidence of a difference in the combined outcome of death or BPD at 36 weeks' gestational

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age between the groups (Morley 2008). However, at 36 weeks' gestational age, only 9% of

infants in each group of survivors were receiving an oxygen concentration of 30% or more.

The benefits of CPAP included a lower risk of the combined outcome of death or the need for

oxygen therapy at 28 days and fewer days of assisted ventilation. A side effect of CPAP was

an increase in the number of pneumothoraces. Overall, starting early CPAP treatment in very

preterm infants was not detrimental.

At present, neither early nCPAP nor mechanical ventilation and surfactant can be said to be

superior. The methods complement each other but the question regarding an optimal

approach remains yet to be answered. The ability to administer surfactant during nCPAP

appears to be important in ELBW infants and more mature infants with established RDS.

New modalities of surfactant administration (e.g. aerosolized surfactant; surfactant via

nasogastric tube) may in the future help to combine nCPAP and surfactant therapy more

efficiently and safely. 11.1.2 Natural versus synthetic surfactant A variety of surfactant preparations has been developed and tested in clinical trials, including

synthetic surfactants and surfactants derived from animal sources. Both animal-derived and

synthetic surfactants are beneficial for prophylaxis and rescue treatment of RDS in preterm

infants. A systematic review from the Cochrane Collaboration comparing natural surfactant

extract to synthetic surfactant in the treatment or prevention of RDS identified 11 trials that

met the inclusion criteria (Soll 2001). The meta-analysis shows that the use of natural

surfactant rather than synthetic surfactant results in a significant reduction in the risk of

pneumothorax (RR 0,63; 95%CI 0,53-0,75) and mortality (RR 0,87; 95% CI 0,76-0,98). A

trend towards an increase in overall intraventricular hemorrhage (IVH) incidence with natural

surfactant was noted in the meta-analysis (RR 1,09; 95% CI 1,00-1,19).

The European Consensus Guidelines recommend that natural surfactants should be used in

preference to synthetic as they are more effective in reducing pulmonary air leaks and

mortality (Sweet 2007). In contrast, the most recent statement of the AAP emphasizes that

both animal-derived and synthetic surfactants decrease respiratory morbidity and mortality in

preterm infants with surfactant deficiency and that new synthetic surfactants with surfactant

protein-like activity are promising new treatments for surfactant-deficiency disorders (Engle

2008). For the purpose of this proposal, listing in the WHO Model List of Essential Medicines

is requested as a group of different surfactant preparations (natural and synthetic).

11.1.3 Surfactant administration

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To optimize surfactant administration, controlled trials have compared different treatment

procedures (bolus, infusion, multiple lumen endotracheal tube (ETT), side-hole adapter and

number of doses).

Bolus versus infusion Surfactant has been administered through an endotracheal tube either by bolus/fairly rapid

installation or slow infusion. In animal studies bolus administration has been shown to be

superior and lead to a more uniform distribution compared to infusion over 5, 30 or 45

minutes (Segerer 1996, Segerer 1993 Ueda 1994). Human data on this issue are sparse. A

small clnical trial enrolling 299 infants showed no significant differences in outcome

measures of fractional inspired oxygen, mean airway pressure, and arterial-alveolar ratio of

partial pressure of oxygen at 72 hours of life, or in the incidences of air leaks, pulmonary

interstitial emphysema, or death through 72 hours of life (Zola 1993). However, oxygen

desaturation occurred more often when bolus administration was used, whereas reflux into

the ETT occurred more often when the infusion technique was used.

Single lumen ETT bolus installation vs. dual-lumen ETT An RCT including one hundred ninety-eight infants (birth weight 600-2000 g) with RDS

needing mechanical ventilation with a fraction of inspired oxygen (FIO2) of 0.40 comparing

200 mg/kg of Curosurf, either by bolus instillation or by a simplified dosing technique (giving

the full dose in 1 minute via a dual-lumen endotracheal tube without positioning, interruption

of mechanical ventilation, or bagging) found fewer episodes of hypoxia and a smaller

decrease in heart rate and oxygen saturation in the dual-lumen group. Infants in the dual-

lumen group also had a lower total time exposure to supplemental oxygen but no difference

in patient relevant long term outcomes was found (Valls-i-Soler 1998).

Bolus vs. 1-minute infusion through a side-hole adapter Another RCT that compared the incidence of transient hypoxia and bradycardia, gas

exchange, ventilatory requirements and 28 day outcomes of two different surfactant dosing

procedures (bolus vs. surfactant given in 1 min via a catheter introduced through a side-hole

in the tracheal tube adaptor) in infants with RDS found no differences between the two

procedures (Valls-i-Soler 1997).

Repeated doses Most RCTs evaluating the effectiveness of surfactant used single doses. Since surfactant

was introduced in neonatal care, physicians have noted that some neonates respond only

transiently to surfactant therapy and the question arose whether multiple doses of surfactant

11

might be more effective than a single dose. Individual trials have shown that repeated doses

of surfactant (both natural and synthetic) given at intervals for predetermined indications

have decreased mortality and morbidity compared with single surfactant doses or placebo

(Hoeckstra 1991, Liechty 1991, Dunn 1990, Corbet 1995, Speer 1992). A systematic review

from the Cochrane Collaboration that compared multiple versus single dose natural

surfactant extract for severe neonatal RDS identified two RCTs (Dunn 1990, Speer 1992)

including 394 patients. Meta-analysis of these trials suggests a reduction in the risk of

pneumothorax (RR 0,51; 95% CI 0,3-0,88) and a trend towards a reduction in mortality (RR

0,63; 95% CI 0,39-1,02) (Soll 1999). At present there is insufficient evidence to recommend

the optimal number of fractional doses of surfactant (Zola 1993), however, the OSIRIS trial, a

large factorial RCT provided no evidence that a regimen including the option of a third and

fourth dose of a synthetic surfactant when signs of RDS persisted or recured was clinically

superior to a regimen of two doses (OSIRIS Collaborative Group 1992).

The optimal method of surfactant administration remains yet to be clearly proven. New

methods such as aerosolized surfactant and surfactant administered via a nasogastric tube

need testing in future controlled trials.

11.2 Surfactant replacement for respiratory disorders other than RDS 11.2.1 Persistent pulmonary hypertension of the newborn (PPHN) PPHN is the result of a failed normal circulatory transition after birth. It is a syndrome

characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left

extrapulmonary shunting of blood. With inadequate pulmonary perfusion, neonates develop

refractory hypoxemia, respiratory distress, and acidosis. PPHN is caused by a number of

medical conditions, including meconium aspiration syndrome (MAS), pneumonia and sepsis

and congenital diaphragmatic hernia (CDH). In some of these conditions surfactant has been

shown in controlled trials to be beneficial.

11.2.2 Meconium aspiration syndrome (MAS) The aspiration of meconium stained amniotic fluid before, during, and after birth can lead to

unfavorable pulmonary symptoms in the neonate, a condition that is called meconium

aspiration syndrome (MAS). Several constituents of meconium, especially the free fatty acids

(eg, palmitic, stearic, oleic), have a higher minimal surface tension than surfactant and strip it

from the alveolar surface. Thus MAS may lead to severe respiratory failure and secondary

surfactant insufficiency. In a systematic review from the Cochrane Collaboration, surfactant

replacement in full term/near term infants with severe MAS reduced the risk of requiring

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extracorporal membrane oxygenation (ECMO) (RR=0.64; 95%CI: 0.46-0.91) and the length

of hospital stay (Median (MD) – 8days; 95%CI: -14 to -3 days). (El Shaled 2007).

11.2.3 Neonatal pneumonia and sepsis

Like MAS pneumonia and sepsis cause surfactant inactivation, an influx of serum protein into

the alveolar space and the formation of hyaline membranes. A study showed that surfactant

therapy improved gas exchange in the majority of patients with GBS pneumonia, but the

response to surfactant was slower than in infants with RDS (Herting 2000). This study

recruited118 infants with respiratory failure, clinical and/or laboratory signs of acute

inflammatory disease, and Group B Streptococcus (GBS) infection proven by culture results

retrospectively from a database of patients treated with surfactant at 28 neonatal units

participating in European multicenter trials from 1987-1993 and prospectively from the same

units in the following years using a nonrandomized control group of 236 noninfected infants

from the same database. The beneficial findings of the study by Herting et al. have been

confirmed in subgroups of RCTs of infants with severe respiratory failure and other beneficial

findings (improved oxygenation and reduction in the need for ECMO) have been suggested

in these subgroup analyses (Lotze 1998, Lotze 1993).

11.2.4 Congenital diaphragmatic hernia (CDH)

The term „congenital diaphragmatic hernia (CDH)“ summarizes a variety of congenital birth

defects that involve abnormal development of the diaphragm. This allows the abdominal

contents to protrude into the chest thereby impeding proper lung formation. Newborns with

CDH often have severe respiratory distress and CDH may be associated with surfactant

insufficiency. However, the lungs of human infants with CDH show surfactant synthesis rates

similar to those from infants without CDH, but contain less phospholipids and

phosphatidylcholine per milligram of DNA than control infants and also show altered kinetics

(Finer 2004, Cogo 2003, 2004). Small case reports have reported a benefit of surfactant for

infants with CDH, but larger series of infants with CDH have not confirmed these findings and

even point to an increased rate of negative outcomes (use of ECMO, BPD, mortality) (Finer

2004, Van Meurs 2004, Lally 2004).

11.2.5 Neonatal pulmonary hemorrhage Neonatal pulmonary hemorrhage occurs mainly in preterm ventilated infants with severe

RDS who often have a persistent ductus arteriosus (PDA). The cause of hemorrhage is

thought to be due to a rapid lowering of intrapulmonary pressure, which facilitates left to right

shunting across a PDA and an increase in pulmonary blood flow. As is the case with

meconium, blood can lead to secondary surfactant inactivation. Due to the fact that neonatal

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pulmonary hemorrhage is an unpredictable complication, RCTs investigating the role of

surfactant are difficult to design and implement and a recent systematic review from the

Cochrane Collaboration did not identify any randomized trials evaluating the role of

surfactant in pulmonary hemorrhage (Azis 2008). However, evidence from observational

studies points to a benefit of surfactant therapy in neonatal pulmonary hemorrhage (Pandit

1995, Amizuka 2003).

11.2.6 Acute lung injury and acute respiratory distress syndrome in adults Adult respiratory distress syndrome (ARDS) is a diffuse pulmonary parenchymal injury

associated with noncardiogenic pulmonary edema. It results in severe respiratory distress

and hypoxemic respiratory failure with the pathologic hallmark being a diffuse alveolar

damage. In a meta-analysis of nine trials randomizing 1441 adult patients, surfactant showed

no effect on early mortality compared to control (RR 0.93; 95%CI: 0.77-1.12) in patients with

ARDS (Adhikari).

12. Methodological quality of surfactant studies 12.1 Prophylaxis studies The methodological quality of RCTs comparing prophylactic synthetic surfactant to control

treatment (sham air treatment or instillation of normal saline) in premature infants thought to

be at risk for developing RDS is generally high (Soll 1998). All studies included in the

corresponding Cochrane review assigned treatments by random allocation and sealed

enveloped were used in all seven studies. Investigators in these studies attempted to blind

treatment with most studies relying on a resuscitation team not responsible for ongoing care

of the infant to administer the intervention and control treatment. Most outcome assessors

were blinded and minimal exclusions were noted after randomization (Soll 1998).

The eight RCTs that are included in the Cochrane review on natural surfactant for the

prophylaxis of RDS are likewise of high methodological quality (Soll 1997). All studies

allocated assigned treatment by randomization and either used sealed enveloped (7 studies)

or coded vials (1 study). As in the studies using synthetic surfactant, blinding of treatment

was attempted by relying on a resuscitation team, not otherwise responsible for ongoing care

of the infants. Outcome assessors were mostly blinded and apart from one study (Kwong

1985), exclusion after randomization was minimal (Soll 1997).

12.2 Treatment studies There are 6 studies included in the Cochrane Review on synthetic surfactant for RDS in

preterm infants (Soll 1998). All included studies allocated treatment by randomization and

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treatment assignments were provided to participating centers by sealed envelopes. Blinding

of treatment and outcome assessment was mostly attempted by means of a resuscitation

and assessment team not otherwise involved in the care of the study infants. Follow-up of

short term (in hospital) outcomes was virtually complete while long-term follow-up rates

ranged from 84% to 100% of surviving infants (Soll 1998). 13. Cost effectiveness of prevention and treatment of neonatal RDS with exogenous surfactant There are several publications on the economics of neonatal care, including policies for

surfactant use (for an overview of the surfactant economics literature see Mugford 2006).

Models of cost-effectiveness showed surfactant to be an expensive but effective and cost

effective treatment (Mugford 1993). However, these models were dependent on the neonatal

technology in use and on the costs of neonatal care and prices of surfactant at the time. Most

importantly, little information was available about long term pulmonary and

neurodevelopmental outcomes. Despite being an effective therapy for RDS, surfactant has

failed to have a significant impact on the incidence of chronic lung disease in survivors.

Paradoxically the cost of neonatal care has increased as surviving infants are more immature

and consume a greater proportion of neonatal intensive care resources. Despite this,

surfactant has been and still is considered a safe and cost-effective therapy for RDS

compared with other therapeutic interventions in premature infants (Tubman 1990, Ainsworth

2002, Mugford 2006). Nevertheless, neonatal medicine has changed dramatically in recent

years and the current most efficient policy for use of surfactant depends on the concomitant

use of other therapies and technologies such as antenatal steroids and continuous positive

airway pressure. Furthermore, since surfactant has been adopted into routine neonatal

practice, the questions of economic impact have shifted to questions regarding the specific

preparations, number of doses, modes of administration, concomitant use of new

technologies such as nCPAP etc. Therefore, future economic studies addressing these new

issues and new economic models are needed.

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14. List of abbreviations

AAP American Academy of Pediatrics

ARDS Acute Respiratory Distress Syndrome

CDH Congenital Diaphragmatic Hernia

CI Confidence Interval

CS Caesarean Section

BPD Bronchopulmonary Dysplasia

ECG European Consensus Guidelines

ELBW Extremely Low Birth Weight

ETT Endotracheal Tube

DPPB Phosphatidylcholine

ECMO Extracorporeal Membrane Oxygenation

FiO2 Fraction of Inspired Oxygen

GBS Group B Streptococcus

IVH Intraventricular Hemorrhage

MAS Meconium Aspiration Syndrome

MD Median

nCPAP Nasal Continuous Positive Airway Pressure

NICHD National Institute of Child Health and Human Development

PDA Persistent Ductus Arteriosus

PPHN Persistent Pulmonary Hypertension

RCT Randomized Controlled Trial

RDS Respiratory Distress Syndrome

RR Relative Risk

SP-A Surfactant Protein A

SP-B Surfactant Protein B

SP-C Surfactant Protein C

SP-D Surfactant Protein D

VLBW Very Low Birth Weight

WHO World Health Organization

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