Surfactant and other respiratory therapy – what is the evidence?
Eric S. Shinwell, MD
Address for correspondence
Department of Neonatology, Kaplan Medical Center, Rehovot and Hebrew
University, Jerusalem, Israel
Tel: (972) 89441218
Fax: (972) 89441768
E-mail: eric_s@clalit.org.il
Introduction
Few preterm infants succumb nowadays to respiratory failure. However, the
combination of prematurity and prolonged mechanical ventilation often results in
Chronic Lung Disease (CLD) that may continue throughout infancy and early
childhood. This review will focus on current controversies in the respiratory care of
extremely preterm infants
Surfactant therapy – where are we and where to next?
Exogenous surfactant therapy in preterm infants with Respiratory Distress Syndrome
(RDS) dramatically reduces disease severity and neonatal mortality.(1) However, a
number of controversial questions remaining unresolved in surfactant research.
Surfactant in other respiratory conditions
In RDS, the primary pathogenesis results from immature and inadequate surfactant
production in alveolar type II cells. However, it is now recognized that inadequate
surfactant function may also result from biophysical inactivation.(2) This may be
seen in Meconium Aspiration Syndrome (MAS) where a number of factors in
meconium have been identified as specific surfactant inhibitors.(3) Likewise, serum
proteins that are secreted into the airways have a similar inhibitory effect on
surfactant function in patients with adult-type RDS, in both neonates and other age
groups.(4)
Since this recognition, a number of clinical trials of surfactant therapy have been
reported in attempts to treat these high-risk conditions. In MAS, two approaches have
been employed.(5,6) In early studies, surfactant was administered endotracheally as
in RDS and a modest, but inconsistent improvement in oxygenation was reported.
More recently, a technique of surfactant lavage has been developed to exploit both the
surface tension reducing properties, together with the detergent function in order to
remove particulate meconium. Initial studies of this technique have shown some
promise and larger trials are currently in progress.
ARDS is a major cause of acute respiratory failure in all age groups and thus much
interest has been generated in the potential of surfactant therapy in this condition.
Randomized controlled trials have demonstrated short-term improvement in
oxygenation, without any significant improvement in outcome.(7,8) The inconsistent
results that have been obtained may relate to the myriad of pathologic mechanism that
lead to the final common pathway of ARDS, together with variations in surfactant
preparation, dose and timing of administration.
"Designer surfactants" – the next generation of surfactants
Although surfactant therapy has been a dramatic success, concern still exists over the
administration of foreign proteins to immunologically immature infants.
Accordingly, a new generation of surfactant preparations has been developed that
contain chemically synthesized surfactant phospholipids, together with genetically
engineered biologically active fragments of surfactant proteins B and/or C.(9,10)
Initial clinical trials with these preparations appear very promising and they may enter
clinical practice in the near future.
Surfactant with CPAP – an alternative to endotracheal mechanical ventilation
Surfactant is administered intratracheally and then reaches the alveoli with the aid of
mechanical ventilation. However, once surfactant has improved lung compliance,
continued mechanical ventilation may not be required and indeed may cause lung
injury that may predispose to the development of Chronic Lung Disease (CLD). This
concern has led to a new approach with intubation and surfactant administration
followed by extubation to nasal Continuous Positive Airway Pressure (CPAP).(11)
This aims to provide a gentler form of respiratory support and hopefully to prevent reintubation for respiratory failure. However, although this approach seems attractive,
randomized trials have to date failed to show any benefit over the more conventional
approach of surfactant and mechanical ventilation as required.
New modes of Mechanical Ventilation
Conventional versus High Frequency Ventilation for RDS
Conventional ventilation of preterm infants employs time-cycled, pressure-limited
ventilation at rates and volumes that approximate tidal ventilation. Although this
form of ventilation is highly effective in producing effective gas exchange, it also
causes lung injury with inflammatory damage that may progress to CLD. High
frequency ventilation (HFV), by comparison, provides small volume breaths at a rate
of 10-15 cycles per second and, in experimental models, has been shown to cause less
lung injury. Accordingly, HFV has been suggested as perhaps a preferred mode of
ventilation for preterm infants with RDS. To date, there have been ten published
randomized controlled trials that met criteria for a Cochrane meta-analysis.(12)
Overall, there appears to be no benefit to either therapy in terms of mortality or CLD,
although the results are rather inconsistent between trials. Likewise, although concern
was raised in early trials regarding the possibility of an increased risk for
intraventricular hemorrhage, this has not been borne out in subsequent trials. Thus, in
summary, this remains an unresolved controversy.
Patient-triggered (Synchronized) Ventilation
Conventional ventilation is usually provided to infants in an intermittent mandatory
mode. However, it has long been recognized that mandatory inspiration against
spontaneous exhalation raises the risk for pulmonary air leak, such as pneumothorax
or pulmonary interstitial emphysema.(13) Technological progress has allowed for the
development of methods for providing ventilation that is synchronized to the infant’s
spontaneous ventilation. It has been observed that infants on synchronized ventilation
are more at ease and require less sedation. However, although randomized trials have
failed to conclusively show a benefit over conventional ventilation, synchronized
ventilation has become an established feature of most modern neonatal intensive care
units.
Newer modes of ventilation
There are currently a number of sophisticated modes of ventilation that allow fine
tuning of the ventilator wave form to each infant’s unique requirements.(14) Mostly
these are volume limited with or without pressure support. Although there is
convincing evidence of short-term improvement in pulmonary mechanics, these
techniques have not yet reached the stage of widespread routine use.
Summary
Supporting respiration in sick preterm infants remains a challenge that demands of the
neonatologist an up-to-date knowledge of the science together with just a sprinkling
of the art of medicine.
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