membrana hialina

Treat Respir Med 2005; 4 (6): 423-437REVIEW ARTICLE 1176-3450/05/0006-0423/$34.95/0 2005 Adis Data Information BV. All rights reserved.

Pathophysiology of Neonatal RespiratoryDistress SyndromeImplications for Early Treatment Strategies

Sean B. Ainsworth

Directorate of Women and Childrens Health, Forth Park Hospital, Kirkcaldy, Scotland, UK

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4231. Lung Volumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4242. Physiology of Gas Exchange in the Normal Newborn Lungs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425

2.1 Pulmonary Artery Pressure Changes after Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4252.2 Ventilation Perfusion Mismatching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4252.3 Vaso-Active Mediators Influencing Peripheral Vascular Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4252.4 Distribution of Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4262.5 Diffusion and Pulmonary Gas Exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426

3. Pathogenesis of Respiratory Distress Syndrome (RDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4264. Pulmonary Function in RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4275. Endogenous Surfactant in the Developing Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4296. Acute Physiological Effects of Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4307. Pulmonary Function in Neonates Post Surfactant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4318. Effects of Surfactant on the Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4319. Translating Physiology and Pathophysiology into Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432

9.1 Resuscitation Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4329.2 Ventilation Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4339.3 The Dose of Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4339.4 Re-Treatment with Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4349.5 Inhaled Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434

10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434

Neonatal respiratory distress syndrome (RDS) remains one of the major causes of neonatal mortality andAbstractmorbidity despite advances in perinatal care. The initial management of infants with RDS has almost becometoo routine with little thought about the pathophysiological processes that lead to the disease and how theclinician can use the existing therapeutic interventions to optimize care. The transition from fetus to infantinvolves many complex adaptations at birth; the most important is the function of the lungs as a gas exchangeorgan. Preterm surfactant-deficient infants are less well equipped to deal with this transition.

Optimum gas exchange is achieved through matching of ventilation and perfusion. In RDS, ventilation maybe affected by homogeneity of the airways with atelectasis and over distension, as hyaline membranes blocksmall airways. In turn this contributes to the inflammation that becomes bronchopulmonary dysplasia. Exoge-nous surfactant given early, particularly with positive end-expiratory pressure and, where necessary, gentleventilation, would seem to be the optimum way to prevent atelectasis. How this can be achieved in neonates aftersurfactant therapy is explored through a review of the normal physiology of the newborn lung and how this isaffected by RDS. The therapeutic interventions of resuscitation, exogenous surfactant, ventilation and inhalednitric oxide are discussed in relation to their effects and what are currently the optimum ways to use these.

424 Ainsworth

It is hoped that with a better understanding of the normal physiology in the newborn lung, and the effects ofboth disease and interventions on that physiology, the practising clinician will have a greater appreciation ofmanagement of preterm infants with, or at risk of, RDS.

Respiratory distress syndrome (RDS) is the most common respiratory support. Research into surfactant and gas exchangereason for neonatal intensive care. Despite advances in perinatal requires a multidisciplinary approach. Data from these disciplinescare RDS continues to be associated with significant mortality and must be correlated and analyzed to understand the processes. Thismorbidity.[1,2] On its introduction in the late 1980s and early is neither a review of surfactant composition and function, nor of1990s, exogenous surfactant was widely thought to be the panacea the wider issues of exogenous surfactant, instead the reader isfor all the problems associated with this disease. However, despite directed to other articles.[4,5] However, where relevant, data froma reduction in mortality with the use of exogenous surfactant, it published studies of existing surfactants will be used to illustratebecame apparent that increased survival rates in very preterm physiological principles being discussed.infants left both infants and institutions with a significant burdenof chronic lung disease.[3] The mechanisms leading to lung dam- 1. Lung Volumesage begin early, in some cases, antenatally. Postnatally, resuscita-tion maneuvers, oxygen and ventilation all interact to increase the Ventilation, whether natural or artificial, is a cyclical process ofrisk of lung damage. inspiration and expiration. The minute ventilation (MV) is that

This article reviews the physiology and pathophysiology of the volume of air which is expired in a period of 1 minute. The volumeimmediate postnatal changes in the lungs, how they differ in of air expired in a single breath is the tidal volume (VT) which ininfants with and without RDS, and also how they are affected by turn reflects the amount of air in the dead space (where no gastreatment strategies, especially exogenous surfactant. It is hoped exchange occurs) and the respiratory zone. MV and VT are relatedthat with a better understanding of the pathophysiology of RDS, such that; MV = VT respiratory frequency.the reader will understand more fully the role of early surfactant Spontaneous respirations occur at mid-range of the total lungtherapy and gentle mechanical ventilation to optimize the chances capacity, with a further two-thirds of total capacity available asof survival without lung damage. reserve in extreme circumstances. Reserve lung volumes are maxi-

Lungs of infants with RDS are said to be stiffer and that by mal volumes of gas above or below the tidal volume (figure 1).reducing the surface tension, surfactant improves compliance and Inspiratory reserve volume is the maximum volume of gas whichimproves outcomes. This is an over-simplification of many can be inspired from the peak of tidal volume. Expiratory reservepathophysiological processes that follow preterm delivery; actual volume (ERV) is the maximum volume that can be expired afterprocesses are extremely complicated and subject to a number of normal tidal expiration. The volume of gas that remains in thevariables, not least of which is exogenous surfactant therapy and lungs at the end of maximum expiration is the residual volume

Static pressure-volume curve of therespiratory system

Inspiratoryreservevolume

Inspiratorycapacity

Inspiratorycapacity

Tidalvolume

40 20 0 20 40

Expiratoryreservevolume

Functionalresidualcapacity

Totallung

capacity

Residualvolume

Pressure (cm H2O)

Fig. 1. Schematic representation of lung volumes and capacities as described in the review. In the disease-free normal lung, tidal volume changes occuralong the linear central portion of the static pressure-volume curve.

2005 Adis Data Information BV. All rights reserved. Treat Respir Med 2005; 4 (6)

Neonatal Respiratory Distress Syndrome 425

(RV). Functional residual capacity (FRC) is the volume of gas in sion of oxygen and carbon dioxide across the alveolar-capillarythe lung when the lung is at rest (i.e. the volume of gas in the lung barrier. An adequate alveolar gas volume (i.e. FRC) must beafter a normal tidal expiration), thus FRC = ERV + RV. A normal established shortly after birth and then be sustained. In newbornsFRC is important in determining optimum lung mechanics and without lung disease, the FRC is ~30 mL/kg,[8] corresponding withalveolar gas exchange. Understanding derivation of volumes in the volume of fetal lung fluid.[9] FRC is established as the fluid-ventilation helps to explain oxygenation and ventilation. filled lung empties and then fills with resident gas. This acts as an

intrapulmonary oxygen reservoir, smoothing out the periodic2. Physiology of Gas Exchange in the Normal changes in alveolar ventilation occurring during respiration. Hav-Newborn Lungs ing aerated the lungs it is important that ventilation-perfusion

matching is then maintained; a number of factors come into play inRespiration is gas exchange, specifically the exchange of car-the regulation of this.bon dioxide for oxygen. At the cellular level, gas exchange occurs

by diffusion according to the partial pressure gradient of the gas. 2.1 Pulmonary Artery Pressure Changes after BirthUnfortunately, in humans diffusion alone cannot fulfill the mini-mal cellular metabolic requirements. Therefore, gas exchange is After birth, pulmonary arterial pressure rapidly falls to ~50% ofenhanced by gas convection mechanisms with the back and forth in utero levels that previously equalled or exceeded systemicconvection of air through the same system of conducting pipes and levels. Changes are modulated by prostacyclin[10] and endogenousa pulmonary gas exchange area located at the terminal end of the nitric oxide (NO),[11] and other vasoactive substances selectivelyconducting airways. Tidal respiration implies that oxygen partial acting on pulmonary microvasculature.[12] Stimuli that affect pul-pressure (pO2) and carbon dioxide partial pressure (pCO2) will be, monary arterial pressure may have different responses at differentrespectively, lower and higher than in the environment.[6] ages. Newborn lambs have a vigorous hypoxic pulmonary vaso-

constrictive response unlike adult sheep,[13] and even 6 weeks afterAdequate lung ventilation and good perfusion are not enough tobirth there are differences in responses of the pulmonary vascula-ensure that blood passing through the lung is well oxygenated, andture to prostaglandin D2; vasodilatation in the newborn lamb, butthat CO2 is removed. For this gas exchange to take place therevasoconstriction after 6 weeks of age.[14]must be a matching of ventilation and perfusion. This requires

adequate ventilation of the distal air spaces and a functional2.2 Ventilation Perfusion Mismatchingcirculation in close proximity to those air spaces. This latter aspect

is often forgotten when considering ventilation and oxygenationHypoxic pulmonary vasoconstriction prevents localized venti-but is an integral part to the whole process of gas exchange in the lation-perfusion mismatching by reducing blood flow to parts ofbody. Ventilation and perfusion of the lung are well adjusted to

the lungs that are hypoventilated or not ventilated at all. As theeach other under normal conditions. The ventilated respiratory gas level of oxygen in the distal airways decrease, resistance of smallvolume per unit of time (minute volume) is only slightly larger

muscular arteries increases leading to shunting of blood intothan the blood volume traversing the lung over the same period ofventilated areas. There is, however, only a limited capacity totime (cardiac output). Thus, an appropriate balance between venti-cope, and with progressively larger areas of atelectasis and col-lation and perfusion is a prerequisite for effective respiratory gas lapse there is eventual ventilation-perfusion mismatching.[15] This

exchange in the lungs.[6] is particularly relevant in the case of a diseased neonatal lungNewly born infants are susceptible to hypoxemia. Firstly, levelswhere atelectasis can affect several lung regions simultaneously

of arterial oxygen in the fetus and newborn infants are lower thanand the situation may be further complicated by localized infectionin adults[7] thus, they have a smaller intravascular oxygen reserve.where inflammatory mediators inhibit vasoconstriction.Secondly, their FRC approaches airway closing volume where

atelectasis can develop easily. Thirdly metabolic demand for oxy- 2.3 Vaso-Active Mediators Influencing Peripheralgen in newborns rapidly depletes any intra-vascular and alveolar Vascular Resistanceoxygen. Susceptibility to hypoxemia is accentuated in preterminfants because of apnea due to an immature respiratory drive, and Catecholamines alter ventilation-perfusion matching by alter-lung segment collapse at the end of expiration, due to compliant ing pulmonary arterial pressure. In neonatal lambs, dopamine canchest walls. further increase the pulmonary arterial pressure and vascular resis-

Good gas exchange is vital in preventing hypoxemia. Integral tance already brought about by hypoxia, thus causing furtherto this is matching alveolar ventilation and pulmonary perfusion deterioration of intrapulmonary shunting and ventilation-perfusionsuch that alveolar oxygen and pulmonary capillary blood are in mismatching.[16] NO on the other hand can be beneficial; byclose proximity. There must be sustained effective respiration (or inducing both bronchodilatation and pulmonary vasodilatation itventilation) to replenish oxygen within the airways and free diffu- can have profound effects on gas exchange.[17] Compared with


426 Ainsworth

term infants, preterm infants have lower levels of endogenous NO. is a coagulum of sloughed cellular debris and proteinaceous exu-In term infants, endogenous NO production in the airways peaks date typically seen at the junction of the respiratory bronchiolesduring the first few hours of life, whereas in preterm infants this and alveolar ducts. Distal to this, terminal air sacs (which in thefeature is almost absent.[18] Preterm infants who are well, seem to preterm human infant are not truly alveoli as these only developadapt to lack of peak NO levels in the first few hours of life, and late in gestation or beyond) appear intact apart from a generalizedtheir endogenous NO levels rise over the first 24 hours.[18] Whilst reduction in volume and later secondary inflammatory infiltration.studies of exogenous NO have generally shown benefit in term Based on this histological appearance it would seem the limitationinfants with severe lung disease, results in preterm infants have to gas exchange in RDS arises at the gateway to the gas-been less clear cut with positive results in some studies,[19] and exchange unit rather than within the unit itself.[29]little or no effect in others.[20] Possible explanations for these Animal studies reveal multiple disturbances in the adaptation todifferences include severity of illness and extreme immaturity of

extra-uterine life of preterm newborns, including delayed clear-infants in some of the studies.[21]ance of fetal lung fluid,[30] increased permeability of the epithelialand endothelial barriers,[31] delayed lymphatic clearance[32] and an2.4 Distribution of Ventilationincreased pulmonary blood volume.[33] All can lead to obstruction

Although there are many studies of the postnatal changes in of small airways. In premature lambs there is a bi-directional fluxlung mechanics, few describe the distribution of ventilation within of proteins between the airways and the circulation consistent withthe lungs. In part, this is because of difficulties in performing the destruction of the epithelium in the terminal airways.[34] Thisanalyses in sick infants due to the need for multiple breath analy- leaves only the basement membrane as a barrier between the airses. Many infants have difficulty in clearing lung fluid because of spaces and the interstitial tissues. Surfactant deficiency and localimmature sodium[22] and water channel expression.[23] These chan- ischemia both contribute to the epithelial injury.nels should open after birth to carry water out of the airways.[24] In surfactant deficiency additional pressure is required to over-This is gestation-dependent and less efficient earlier in gesta-

come the higher surface tension at the air-tissue interface intion.[25] There is some evidence that the water channel known as terminal airways. Respiratory bronchioles and alveolar ducts areaquaporin 4 (AQP4) is up-regulated in preterm infants exposed to poorly supported structures in the immature lung and, undermaternal corticosteroids.[23] Increased content of lung liquid

conditions such as these, are susceptible to disruption throughreduces pulmonary compliance and impairs ventilation. Signifi-

shear forces, especially when the alveoli are over-distended. Un-cant heterogeneity can occur within lungs of preterm infants,

controlled increases in pressure, such as that exerted during posi-reflecting significant variations in the distribution of water and

tive pressure resuscitation, can lead to high tidal volumes andventilation.[26] In lungs affected by hyaline membrane disease,

over-distension, disrupting the epithelium.[35] Histological com-proteinaceous exudates occlude airways, either fully or partially, parisons between surfactant-deficient rabbits ventilated with eitherresulting in alveolar hypoventilation. In turn this can affect gase-

conventional mandatory ventilation or high frequency oscillationous exchange (figure 2).

ventilation, show that the amount of damage is related to themagnitude of changes in airway pressure (or rather VT) rather than2.5 Diffusion and Pulmonary Gas Exchangeaverage pressure per se.[36]

Once gases reach the alveolar-capillary interface there must be In one of the first studies of an exogenous surfactant,[37] investi-a rapid diffusion between terminal airways and blood. Movement gators suggested that their findings do not agree well with theof gases across the alveolar-capillary membrane is a passive suggestion that the syndrome results from the primary lack ofprocess. This was thought to be a rate-limiting step, but has never pulmonary surface-active materials and suggested that pulmona-been shown to be abnormal in any neonatal condition when taking

ry ischemia was central to the pathogenesis of RDS. Althoughinto account the size of the alveolar-capillary interface. No signifi- time has proved them wrong with respect to surfactant, theircant differences were seen for carbon monoxide diffusion capacity

statement about pulmonary ischemia did carry some truth the(commonly used in measurements) in preterm infants with and pathological lesion of hyaline membrane disease may representwithout RDS,[27] which were lower than those observed in healthy localized ischemic necrosis of the epithelia of terminal airways.term infants in a separate study.[28] Consistent with this are studies linking acute perinatal asphyxia to

the incidence and severity of RDS,[38] and a poorer response to3. Pathogenesis of Respiratory Distresssurfactant in asphyxiated infants.[39] Microscopically, vasocon-Syndrome (RDS)striction in arterioles, adjacent to respiratory bronchioles undergo-ing epithelial slough, support the idea that ischemia may beHyaline membrane disease is the name given to the histopatho-

logical appearance of established RDS (figure 3). The membrane involved in the pathophysiology of RDS.[40]



Normal patent acinus withnormal V/Q matching

Pulmonary arteriole(pO2 = 5.3 kPa, pCO2 = 6 kPa)

Acinus with partialobstruction of distalairway secondary tohyaline membrane

Pulmonary arterioleto pulmonary venous

connection bypassing alveoli(no V/Q matching therefore

pO2 = 5.3 kPa, pCO2 = 6 kPa)

Pulmonary venous connectiondraining alveolar region

with normal V/Q matching(pO2 = 17.6 kPa, pCO2 = 3.7 kPa)

Pulmonary venous connectiondraining alveolar regionwith low V/Q matching

(pO2 = 6.9 kPa, pCO2 = 5.9 kPa)Fig. 2. The effects of ventilation-perfusion (V/Q) matching on blood gas tensions within the lung. This schematic diagram of airway and vascular unitsshows the effects of varying degrees of ventilation on V/Q matching and resulting blood gas exchange within these units (reproduced from Truog,[6] withpermission). pO2 = partial pressure of oxygen; pCO2 = partial pressure of carbon dioxide.

Whichever mechanism predominates, the end result is disrup- 4. Pulmonary Function in RDStion of the respiratory epithelium and an influx of proteins into theairways. Apart from a purely mechanical action of blocking the Any discussion of the effects of RDS on pulmonary functionairway, this can also cause a secondary surfactant dysfunction must take into account gestational age, postnatal age, diseasethrough inactivation: surfactant may be simply denatured by the severity, the type and amount of respiratory support and whetherproteins, some of which are proteases; there may be immunologi- effective spontaneous respiration can (or does) occur.[42] Thecal phenomena (surfactant/anti-surfactant complexes have been effects of RDS on lung mechanics of a term 3kg infant, with andfound in both surfactant-treated and non-treated infants with without RDS is summarized in (figure 4). The following is aRDS[41]); there may also be biochemical phenomena secondary to discussion of the measurements of pulmonary function that arethe inflammatory infiltrate; and surfactant itself may become pertinent to RDS.sequestered in the fibrin rich hyaline membranes. Thus, existing Studies show that FRC is decreased in surfactant deficientlow levels of endogenous surfactant in preterm infants may be lungs.[8,43] This occurs as a result of displacement of the intra-further compromised. pulmonary gas volume by vascular congestion, interstitial edema


428 Ainsworth

day when a diuresis can be seen to coincide with clearance ofexcess lung fluid.[46]

The decrease in lung compliance that is one of the hallmarks ofRDS is the result of several factors: firstly, there is a decrease inthe number of ventilated terminal airspaces, secondly those air-spaces that are ventilated are relatively over-distended and thuscarry an increased recoil pressure, and thirdly, dynamic (but notstatic) compliance is decreased due to changes in the viscoelasticproperties of the lung and inhomogeneity of ventilation.[47] Lungresistance (the sum of lung airways resistance and lung tissueresistance) is 3- to 6-fold greater in newborn infants with RDScompared with newborn infants without RDS and is largely due tothe decrease in the cross-sectional area of patent airways leading todistal lung units.[48] Alveolar instability also affects compliance;when pressure across an unstable alveolus reaches a critical open-ing pressure, this alveolus opens suddenly, during expiration thesame alveolus will also close abruptly when a critical closing

Collapsed alveoli withinflammatory cellular infiltrate

Hyaline membrane

Fig. 3. The characteristic histological appearance in respiratory distresssyndrome is that of widespread collapse of distal air spaces and regularlydispersed dilated terminal bronchioles. The bronchioles are denuded andlined by anuclear eosinophilic hyaline membranes composed of both ne-crotic epithelial cells, and fibrin and other proteins leaking out of the capilla-ries (hematoxylin-eosin stain).

pressure is reached. Because the terminal airways are not uniformand proteinaceous exudation. Improvements in FRC mirror the in size, there is, in the surfactant deficient lung, a range of criticalimprovements in oxygenation that can be seen with distending opening and closing pressures. This leads to smaller airwaysairways pressure,[44] surfactant therapy[45] or the spontaneous reso- collapsing and a tendency for air to enter already open airways andlution that occurs in some infants on the second or third postnatal distend them further (figure 5).

VC120mL

VC55mL

IC40mL

IRV26mL

ERV15mL

RV25mL

FRC40mLRV

25mL

IC80mL

V16mL

V14mL

Physiologicaldead space

Normal 3kg infant 3kg Infant with respiratory distress

IRV64mL

ERV40mL

RV40mL

FRC80mL

RV40mL

Respiratory rate/minuteDead space/tidal volume ratioIntraesophageal pressure difference (cm H2O)Compliance (mL/cm H2O)Resistance (cm H2O/L/sec)Total work/breath (gm cm)Total work/minute (gm cm)

360.354.4

2940

1440

700.6

181.0

23111

7770

Physiologicaldead space

Fig. 4. The effects of respiratory distress syndrome on lung function in a 3kg infant (reproduced from Avery et al.,[42] with permission). ERV = expiratoryreserve volume; FRC = functional residual capacity; IC = inspiratory capacity; IRV = inspiratory reserve volume; RV = residual volume; V = (tidal) volume;VC = vital capacity.



Impaired excretion of carbon dioxide is not always a prominentfeature of RDS. Prior to the use of mechanical ventilation, surviv-ing infants could be seen to have only normal or slightly elevatedarterial carbon dioxide despite requiring significant amounts ofoxygen.[49] Spontaneously breathing infants with RDS have tidalvolumes of 46 mL/kg, the same as newborn infants with normallungs.[50] However, the dead space in lungs of infants with RDSmakes up a larger proportion of the tidal volume (6080% vs3040%);[42] to compensate for this, spontaneously breathing in-fants with RDS breathe faster.

5. Endogenous Surfactant in the Developing Lung

Effective lung function requires not only adequate surfactant,but also a sufficiently developed system for gaseous exchange, thedevelopment of chest wall rigidity and diaphragmatic musculatureand a mature respiratory drive. Terminal airways must be structur-ally developed enough to permit gas exchange before surfactantcan be effective. The degree of lung maturation at any gestationcan be variable and is under the influence of external factors suchas maternal, placental and fetal problems, and medical treatmentssuch as antenatal corticosteroids. Animal and clinical studiesprovide strong support that endogenous corticosteroids modulatethe development of a number of fetal tissues. In the human,amniotic fluid corticosteroids increase several-fold during thethird trimester in parallel with surfactant maturation.[51] In fetallungs glucocortocoids induce, through gene activation, a numberof proteins including all of the surfactant associated proteins andkey lipogenic enzymes.

The composition and quantities of surfactant change with fetalmaturity and this is reflected in the declining incidence of RDStowards term.[52-54] Surfactant is synthesized and stored in pulmo-nary type II cells after about 22 weeks gestation. Both the amountof surfactant and type II pneumocytes that produce it increase withgestation; preterm infants with RDS have surfactant pool sizes of

80

a

b

70

60

50

40

30

20

10

00 5 10 15 20 25 30 35

Volu

me

(mL/k

g) Volume A = 43mLRadius = R

Volume B = 4mLRadius = r

Lung unit BLung unit A

Pressure = P Pressure (cm H2O)

PLung unit A Lung unit B

Rr

Fig. 5. The effects of different opening pressures in the absence ofsurfactant. The graph shows two hypothetical idealized lung units. At pres-sure, lung unit B is just beginning to open (a). In the absence of surfactant,lung unit A has a radius of R, whereas lung unit B has a radius of r at apressure of P. If we apply the law of LaPlace to calculate surface tension(P = 2/r, where is the surface tension) then the pressure in lung unit Bwould have to be higher to maintain the smaller radius (b). In alveoli thatare connected, a pressure gradient will therefore exist and gas will travelfrom the higher pressure region in unit B to the lower pressure region inunit A (b). This would lead to lung unit A increasing in size, and possibleover distension, and collapse of lung unit B.

210 mg/kg,[55] at term the total surfactant pool is ~100 mg/kg,[56]in later life the pool decreases to ~60 mg/kg in tissue and 4 mg/kg surfactant stored in, but not yet released from, lamellar bodies thatin airspaces.[57] In general, the greater the quantity of endogenous are fused with the plasma membrane of type II cells.[61] Thesurfactant the better the compliance of the lung. However, even contents of these lamellar bodies are released as type II pneumo-small amounts of endogenous surfactant can have a dramatic cytes are strained during inspiration. Finally there is a sloweffect on compliance. Good improvements in compliance can be

replenishment pool of non-fused intracellular lamellar bodies andseen with endogenous surfactant levels of 1020 mg/kg,[58] where- de novo synthesis of surfactant.as it may take 100 mg/kg of exogenous surfactant to produce

In infants with RDS who do not receive exogenous surfactantsimilar improvements.[59]therapy, surfactant pool sizes increase during recovery overThe overall surfactant pool consists of various components.45 days to become comparable with that in infants without RDS,There is an alveolar pool of immediately available surfactantor those who received exogenous surfactant.[62] In preterm lambs,which includes that at the air-surface interface and includes thosesmall increases can be seen soon after birth and continue readi-lamellar bodies that are enclosed within the aqueous hypophasely.[63] This is mostly due to de novo synthesis. In rabbits it takes(figure 6). These lamellar bodies are readily incorporated into the~40 hours from phospholipid synthesis within the endoplasmicsurface layer during the respiratory cycle when surface tension isreticulum to secretion into the alveoli.[59] Low surfactant pool sizesvariable.[60] It has been proposed that there is another pool of


430 Ainsworth

salvage pathways. Lipid components of surfactant are secretedtogether with surfactant proteins as lamellar bodies to the aqueoushypophase. After film formation, these components are recycledby type II cells to be reprocessed into lamellar bodies or to becatabolized. Surfactant is also catabolized by macrophages. Therecycling efficiency exceeds 90% in preterm and term animals andis more efficient than in adult animals.[67,68]

6. Acute Physiological Effects of Surfactant

Although surfactant has a variety of functions including hostdefense,[4,5] in the short period after birth it is the reduction ofsurface tension that is important in the stability of small airwaysand alveoli. Surface tension arises from attractive forces betweenmolecules, and without it liquids would spontaneously form avapor. Water has a surface tension of 70 mN/m (70 dynes/cm) atbody temperature; this can be altered by a second substance (e.g.surfactant). In surfactant, phospholipids with hydrophilic (water-attracting) polar-head groups and hydrophobic (water-repelling)fatty acyl groups reduce surface tension. Phosphatidylcholine, themain surfactant phospholipid, can form a monolayer across an air-water interface that reduces surface tension to ~25 mN/m. Whenthe monolayer is compressed closer packing of molecules leads toa further fall in surface tension. If phosphatidylcholine is unsatu-rated then the minimum surface tension that can be reached is20 mN/m, however, endogenous surfactant contains saturated andunsaturated phosphatidylcholine, other phospholipids andsurfactant associated proteins; these reduce surface tension toalmost zero.[69]

The effect of surfactants on preterm lungs can be demonstratedby pressure-volume relationships using static or quasi-static infla-

Air-fluid interface

Alveolarmacrophage

Air spaceAqueous

hypophase

Type Ipneumocyte

Golgicomplex Type II

pneumocyte

Lamellarbodies

Tubularmyelin

Lipidvesicles

Nucleus

Lipid vesicles reusedby type II pneumocyte

Fig. 6. The surfactant cycle. Type II pneumocytes produce surfactant in theGolgi complex. It is stored prior to release in lamellar bodies and secretedinto the aqueous hypophase. The surfactant is transformed into tubularmyelin from which both multi-layer and monolayers are formed, beforeeventually forming the single monolayer. After the surfactant is used aproportion is taken up again as lipid vesicles by the type II cells andreused, other surfactant is lost through uptake by alveolar macrophages.

tion and deflation. From these it is possible to quantify the compli-ance of the lungs. The effects of surfactant deficiency is shown by

and the slow increase in these pools after birth explains why, notthe pressure-volume curve followed by the control animals (rab-

only, it is initially necessary to treat RDS with exogenousbits) in figure 7 where there is little lung expansion until a pressure

surfactant but also why it is usually unnecessary to continue toof 25 cmH2O is reached.[70] The surfactant deficient lungs alsoreplace surfactant after the first 12 days.collapse to zero volume when the pressure is decreased. In con-

Lung inflations increase surfactant in the airways.[64] This may trast, rabbits treated with whole sheep surfactant have a loweraccount for some of the physiological role of the sigh breath in opening pressure (~15cm H2O) and there is retention of volumenormal respirations. In term neonates ventilated with short periods when the pressure returns to zero. Thus, there is lung recruitmentof high tidal volumes, improvements can be seen in pulmonary during inspiration and greater retention of the recruitment duringmechanics.[65] This was initially ascribed to greater recruitment of expiration after exogenous surfactant the latter is a good indica-atelectatic lung; however, it now appears that this is due to tion of why surfactant can increase FRC.[71] Surfactants that con-extrusion of lamellar bodies from type II pneumocytes. In a tain surfactant-associated proteins show better pressure-volumenewborn rat model, a transient improvement in compliance was curves than those that do not (figure 7).[70] This is reflected in theassociated with increased surfactant,[66] but whether the same is better outcomes after treatment with animal-derived surfactants[72]true of the preterm (and therefore) surfactant deficient lung is or synthetic surfactants that contain protein mimics[73] thanunclear. Limited data suggest that in the surfactant deficient lung, surfactants that comprise only phospholipids.over-distension causes additional problems.[35] Pressure-volume curves also demonstrate that the response to

Surfactant metabolism is complicated by the multi-component surfactant is progressively less with delayed treatment.[74] Delay-nature of surfactant itself and the presence of active recycling or ing treatment with surfactant resulted in a greater influx of proteins



with surfactant inactivation and poorer lung function. Whilst inac- or colfosceril (Exosurf), treatment with the former led to im-tivation can be overcome by using more surfactant, the presence of proved static respiratory compliance after 3 and 12 hours, whereassurfactant seems to protect against the influx of the proteins in the compliance was essentially unchanged after treatment with thefirst place.[75] In addition, it is apparent that pulmonary compliance latter.[84] A similar difference in static respiratory compliance wasimproves only relatively slowly after surfactant treatment com- also seen in favor of the animal-derived surfactant beractantpared with improvements in FRC.[45] In clinical practice this is (Survanta) compared with colfosceril.[85]reflected by rapidly improving oxygenation but somewhat slower There may be some differences between various animal-de-improvements in ventilation (CO2 excretion). rived surfactants, but studies that compare these are few. Fewer

still compare pulmonary function. Studies comparing poractant7. Pulmonary Function in Neonates Post alfa and beractant in neonate respiratory distress syndrome showSurfactant Therapy earlier improvements in oxygenation (and by inference FRC) with

poractant alfa.[86,87] Comparisons of respiratory compliance afterFew studies have looked at FRC and pulmonary compliancetreatment with poractant alfa and beractant are not available, but in

after surfactant therapy in neonates;[71,76-83] those that do, fail toinfants treated with either poractant alfa or SFRI 1 (Alveofact),

show early improvement in compliance but demonstrate an im-compliance improved 3 hours after poractant alfa but no improve-provement in FRC within minutes of treatment. Compliance doesment in pulmonary compliance was seen until 24 hours afterimprove, albeit more slowly than FRC,[82] and only in studies thattreatment with SFRI 1.[83] Thus, there may be differences betweenlook at compliance beyond the first few hours (figure 8).[83] Thesethe various animal-derived surfactants but these are likely to be

changes in FRC and compliance are reflected in the speed withsmall and would require large, randomized, controlled trials to

which oxygen and ventilator settings need to be changed afterdemonstrate clear clinical superiority of one surfactant over thetreatment with surfactant; in contrast to delivery of oxygen whichother.

needs to be reduced rapidly, particularly after animal-derivedsurfactants, changes in ventilator settings are made more slowly.

8. Effects of Surfactant on theChanges in oxygenation have long been known to occur moreCardiovascular Systemquickly after treatment with animal-derived compared with prote-

in-free synthetic surfactants, but effects on compliance are less Surfactant instillation is often associated with hemodynamicclear. When infants were treated with poractant alfa (Curosurf 1) changes, although studies have shown contradictory results. Cere-

bral blood flow has been shown both to increase[88,89] and de-crease;[90] such changes may lead to both intraventricular hemor-rhage and periventricular leucomalacia. Likewise, studies of pul-monary arterial pressure and blood flow have also showncontradictory effects. Those who observed a fall in pulmonaryarterial pressure claim that a primary action of surfactant was toincrease total pulmonary blood flow;[91,92] but others reported nochange in pulmonary arterial pressure.[93] Research has suggestedthat pulmonary blood flow does typically increase after exogenoussurfactant administration,[94] although the mechanism for this re-mains unclear.

At birth systemic and pulmonary circulations are connected viaa large arterial duct and when surfactant is given in the minutes tohours after birth any changes in one compartment must affect theother. The balance of flow depends on vascular resistance on eachside of the duct. For example, pulmonary vasodilation increasesleft-to-right ductal steal, requiring an increased left ventricularoutput to maintain aortic flow beyond the duct. Major influenceson vascular tone are arterial oxygen and carbon dioxide. Factorswhich cause pulmonary vasodilation (low partial pressure of arte-rial carbon dioxide [PaCO2] and high partial pressure of arterialoxygen [PaO2])[95] simultaneously cause systemic and cerebral

90

Volu

me

(mL/k

g)

80

7060

50

40

30

20

10

00 5 10

Pressure (cm H2O)15 20 25 30 35

Natural sheepSP-BSP-ABCSP-CLH-20SP-AControls

Fig. 7. Pressure-volume curves from preterm rabbits after 30 minutes ofventilation with 3cm H2O positive end expiratory pressure. Animals weretreated with various surfactant preparations to show the differing effects ofthe surfactant-associated proteins and their effects on lung recruitment.The clear advantage of surfactants that contain surfactant protein (SP)-B(and to a lesser extent SP-C) can be seen by the larger volume and thehigher deflation lung volumes compared with surfactants that are devoid ofthese surfactant-associated proteins (reproduced from Rider et al.,[70] withpermission). LH-20 is a protein-free phospholipid mixture.

1 The use of trade names is for product identification purposes only and does not imply endorsement.


432 Ainsworth

20

18

16

14

12

10

8

6

4

2

0Pre-surfactant 1 hour 3 hours 6 hours 24 hours

Com

plia

nce

and

FRC

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

FiO

2

FRC (mL/kg)

FiO2

Static compliance(mL/kPa x kg)

Post-surfactant

Fig. 8. Changes in functional residual capacity (FRC), oxygen requirement and static compliance of neonates with severe respiratory distress disorder aftertreatment with poractant alfa or Alveofact (SF-RI 1). The graph shows marked changes in FRC within 1 hour of surfactant treatment and the relatedimproved oxygenation. Compliance, however, improved slowly and was significantly different from pre-treatment values at 3 hours post-therapy inporactant alfa-treated infants and at 24 hours in Alveofact-treated infants.[83] FiO2 = fraction of inspired oxygen.

vaso-constriction.[96-98] Thus, if swings in systemic, and particular- RDS previously discussed and their impact on the effectiveness ofly cerebral blood flow, are to be prevented large fluctuations in surfactant therapy.PaCO2 and high PaO2 must also be avoided and the clinician must

9.1 Resuscitation Practicespay close attention to both ventilation and oxygenation followingsurfactant administration.

There are several aspects of resuscitation that can impact uponSurfactant obviously acts within the lungs, but debate continuessurfactant therapy, both directly (i.e. when should we give

as to whether it acts as a primary pulmonary vasodilator. Unfortu-surfactant) and indirectly (i.e. the impact of resuscitation on the

nately studies of pulmonary arterial pressure and flow[91-93,99] havelungs). Most resuscitation guidelines have been drawn up with thelargely failed to report either PaO2 or PaCO2 values before andterm infant in mind and events that take place during resuscitation

after treatment. Therefore, results are difficult to interpret; forcan have profound effects on the preterm infants morbidity.

surfactant to act as a pulmonary vasodilator, the effects must beIn contrast to neonatal units, almost all newborn resuscitation isindependent of those resulting from improved gas exchange. Two

unmonitored other than by the clinical acumen of the personsgroups found a significant fall in pulmonary arterial pressure,involved. Experience is no substitute for monitoring; even exper-

coinciding with a fall in oxygen requirements after surfac-ienced anesthesiologists (i.e. the so-called educated hand) cannottant.[91,92,96] However, a third group reported no significantreliably detect changes in pulmonary compliance.[101] Being able

change.[93] Compared to historical data from infants with RDSto control ventilation is important as one of the major causes of

who did not receive surfactant,[100] pulmonary to systemic arteriallung damage is over-inflation. Uncontrolled inflations have beenpressure ratio fell more rapidly after surfactant replacement, butshown to cause widespread lung damage at histological level and,

we cannot say for certain whether the early changes were related toin turn, reduce the effectiveness of surfactant.[34] Traditionally,

ventilation practices, blood gas status, or surfactant itself. Theseover-inflation has been called barotrauma, implying that pres-

uncertainties may also be compounded by the type or dose ofsure is the main culprit; however, because of a stronger association

surfactant used, as these directly affect the speed of onset of actionbetween lung injury and lung volumes, a more appropriate term is

of the surfactant.volutrauma.[102] The relative effects of volume and pressure onlung injury was eloquently demonstrated by Hernandez and col-9. Translating Physiology and Pathophysiology intoleagues[103] who ventilated rabbits at high pressures. Those rabbitsClinical Practicewhose chest expansions were limited by external body casts had

This section looks at practices in the management of preterm less lung damage than those whose volumes were uncontrolled,infants with RDS and puts them into context of pathophysiology of even though pressures used were the same in both groups.



Just as over-distension can be deleterious, allowing lungs to 9.2 Ventilation Strategiescollapse at the end of expiration can also lead to lung damage,

Continuous positive airways pressure (CPAP) used in the deliv-especially when surfactant deficient. It requires considerablyery room (with and without surfactant), avoids the need for long-greater pressure to open atelectatic alveoli than to inflate thoseterm intubation and ventilation, and in experienced hands appearsalready open; these higher pressures can over-distend any airwaysto be an effective method of respiratory care for even the smallestalready open, generating shear forces and disrupting epithelium.infants.[113-115] The disadvantage is that those infants who developThis can occur quickly in surfactant deficient lungs.[104] TheRDS have their surfactant therapy delayed with the potentialhypothesis that damage occurs during periods of low lung volume,consequences that this can bring. Two studies have examined the

with recurrent collapse and re-expansion, is supported by theeffect of surfactant administration to infants on CPAP and foundprotective effect of positive end-expiratory pressure helping tothat it not only helps prevent the need for ventilation,[116] but alsokeep alveoli open.[105]the earlier the surfactant can be given the greater the effect.[117]

Surfactant should be given as early as possible. Most protein Preliminary data from the IFDAS (Infant Flow Driver Andleak occurs early in RDS and tails off over the first 24 hours of Surfactant) study (not yet published in full) suggest CPAP with orage.[106] In animal models exogenous surfactant protects against without surfactant is no different from surfactant and ventilation inprotein leak and the earlier the surfactant is given the more terms of mortality and chronic lung disease, but that CPAP caneffective it is in preventing any leak.[74,107] This fits well with reduce the need for surfactant therapy per se.[118] Additional dataoutcomes in the meta-analysis of prophylactic versus rescue are emerging about this mode of respiratory support[119] but moresurfactant where prophylaxis reduces mortality, pulmonary air large randomized trials are required to fully address this issue.leaks and chronic lung disease.[108] It would be expected that the With the advent of microprocessor technology, volume-surfactants that restore surfactant function the quickest are associ- targeted ventilators have been developed as alternatives to tradi-ated with better clinical outcomes; this can be seen in comparisons tional pressure-limited ventilators. They are capable of deliveringbetween animal-derived and protein-free synthetic surfac- consistent and, importantly, appropriate tidal volumes in smalltants.[72] The greatest benefit from prophylactic surfactant seems to preterm infants. It is suggested that these could provide an effec-be in more immature infants. Moderately mature infants (mean tive, safer means of ventilating the newborn infant. Evidence from

meta-analysis of four randomized controlled trials suggests thatgestation 32.8 weeks, birth weight ~2050g) with mild to moderatethere may be benefits particularly with respect to lung damageRDS, defined as fraction of inspired oxygen (FiO2 ) 0.4, did not(demonstrated by reduced rates of pneumothoraces and chronicbenefit from routine intubation to administer surfactant comparedlung disease at 36 weeks post-menstrual age).[120] However, morewith expectant management with subsequent intubation andsuitably powered studies are required.surfactant treatment as clinically indicated.[109]

Infants who are ventilated with conventional ventilation haveHow early should the first dose of surfactant be administered?cyclical lung volume changes that lead to alveolar disruptionKendig et al.[110] using calf lung surfactant extract, randomizedallowing protein leak. High frequency oscillatory ventilation651 infants to receive surfactant either before the first mechanical (HFOV) uses a higher mean airway pressure but with cyclicalbreath or after stabilization. There were no differences in mortalityvolumes that are smaller than physiological VTs. In comparison tobetween groups, but more infants in the pre-ventilation arm re-conventional ventilation, HFOV limits exudation of proteinaceousquired supplemental oxygen at 36 weeks and there were signifi-material in animals with RDS,[121,122] and when combined with

cantly more problems with surfactant administration. Does thisexogenous surfactant there is a greater reduction in lung injury

mean that a pre-ventilation surfactant administration strategy isthan if surfactant or HFOV had been used alone (figure 9).[123]incorrect? One possibility may lie in the differences in the way Early use of HFOV prolongs the effectiveness of any exogenous

surfactant was administered. In the pre-ventilation group it wassurfactant by reducing the protein leak.[124] Despite these benefits

administered as a single 3 mL/kg bolus, whereas the other groupof HFOV in early RDS, there is no clear evidence from systematic

received four aliquots of 0.75 mL/kg, 2 minutes apart. Just as lackreviews that longer-term outcomes are better than for conventional

of surfactant increases the opening pressure of the lungs, so too ventilation.[125]does an excess of lung fluid.[111] A larger volume of surfactant hasbeen shown to spread more homogeneously[112] but this was in an 9.3 The Dose of Surfactantanimal model more akin to acute RDS where there is surfactantdysfunction rather than RDS seen in the newborn where there is Most exogenous surfactants are given at a dose of 100 mg/kg ofsurfactant deficiency and some fetal lung fluid. It remains unclear phospholipids which fits well with the size of the surfactant pool infrom studies in human infants whether the volume of surfactant is term infants without RDS. Evidence from randomized controlledimportant. trials showed smaller doses were less effective[126-128] but that


434 Ainsworth

9.5 Inhaled Nitric Oxide

Inhaled NO has become a useful rescue therapy in term infantswith respiratory disease. By improving the ventilation and perfu-sion matching it allows greater oxygenation at lower ventilationthan is otherwise achievable. Endogenously released NO plays akey role in the lungs of the newly born infant. Although there areseveral studies of inhaled NO in preterm infants, the results havebeen variable in terms of outcomes.[19,20,131,132] Whereas there aresignificant reductions in oxygen requirements after starting in-haled NO, these do not translate into better long-term outcomes. Inparticular there is concern about the effects of NO on the develop-ing brain and the risks of intracranial bleeding.[19] Further researchis required into the use of inhaled NO in infants at risk or withRDS.

30

25

20

15

10

5

0CMV CMV + surfactant HFOV HFOV + surfactant

Prot

ein

debr

is (%

)

Fig. 9. Comparison between high frequency oscillatory ventilation (HFOV)with conventional mandatory ventilation (CMV) as a mode of ventilation ina preterm baboon model of respiratory distress syndrome, demonstratingthe effect of surfactant therapy on both modes of ventilation. HFOV result-ed in less radiographic injury, lower oxygenation and less alveolar protein-aceous debris, and HFOV was highly synergistic when combined withsurfactant (reproduced from Jackson et al.,[123] with permission). 10. Conclusions

higher doses confer no long-term advantage. Poractant alfa at Despite advances in antenatal and neonatal care, chronic lung200 mg/kg produced a more rapid reduction in oxygen require- disease remains a major problem and what we do to the infantments than at 100 mg/kg,[127] but this did not translate to better during the first minutes can play a role in its pathophysiology.longer-term outcomes. All of these studies of different doses were Using surfactant and ventilation to their best advantage couldperformed using a rescue strategy when the arterial/alveolar oxy- potentially improve outcomes further, but in the absence of largegen ratio (a/ADO2) was


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