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Alveoli are the spherical outcroppings of the respiratory bronchioles.
Pulmonary surfactant is a surface-active complex of phospholipids and proteins formed by type II alveolar cells.[1] The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic regions. By adsorbing to the air-water interface of alveoli, with hydrophilic head groups in the water and the hydrophobic tails facing towards the air, the main lipid component of surfactant, dipalmitoylphosphatidylcholine (DPPC), reduces surface tension.
As a medication, pulmonary surfactant is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[2]
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Alveoli can be compared to gas in water, as the alveoli are wet and surround a central air space. The surface tension acts at the air-water interface and tends to make the bubble smaller (by decreasing the surface area of the interface). The gas pressure (P) needed to keep an equilibrium between the collapsing force of surface tension (γ) and the expanding force of gas in an alveolus of radius r is expressed by the Young&#;Laplace equation:
P = 2 γ r {\displaystyle P={\frac {2\gamma }{r}}}
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Compliance is the ability of lungs and thorax to expand. Lung compliance is defined as the volume change per unit of pressure change across the lung. Measurements of lung volume obtained during the controlled inflation/deflation of a normal lung show that the volumes obtained during deflation exceed those during inflation, at a given pressure. This difference in inflation and deflation volumes at a given pressure is called hysteresis and is due to the air-water surface tension that occurs at the beginning of inflation. However, surfactant decreases the alveolar surface tension, as seen in cases of premature infants with infant respiratory distress syndrome. The normal surface tension for water is 70 dyn/cm (70 mN/m) and in the lungs, it is 25 dyn/cm (25 mN/m); however, at the end of the expiration, compressed surfactant phospholipid molecules decrease the surface tension to very low, near-zero levels. Pulmonary surfactant thus greatly reduces surface tension, increasing compliance allowing the lung to inflate much more easily, thereby reducing the work of breathing. It reduces the pressure difference needed to allow the lung to inflate. The lung's compliance, and ventilation decrease when lung tissue becomes diseased and fibrotic.[3]
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As the alveoli increase in size, the surfactant becomes more spread out over the surface of the liquid. This increases surface tension effectively slowing the rate of expansion of the alveoli. This also helps all alveoli in the lungs expand at the same rate, as one that expands more quickly will experience a large rise in surface tension slowing its rate of expansion. It also means the rate of shrinking is more regular as if one reduces in size more quickly the surface tension will reduce more, so other alveoli can contract more easily than it can. Surfactant reduces surface tension more readily when the alveoli are smaller because the surfactant is more concentrated.
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Surface tension draws fluid from capillaries to the alveolar spaces. Surfactant reduces fluid accumulation and keeps the airways dry by reducing surface tension.[4]
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Surfactant immune function is primarily attributed to two proteins: SP-A and SP-D. These proteins can bind to sugars on the surface of pathogens and thereby opsonize them for uptake by phagocytes. It also regulates inflammatory responses and interacts with the adaptive immune response. Surfactant degradation or inactivation may contribute to enhanced susceptibility to lung inflammation and infection.[5]
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Dipalmitoylphosphatidylcholine (DPPC) is a phospholipid with two 16-carbon saturated chains and a phosphate group with quaternary amine group attached. The DPPC is the strongest surfactant molecule in the pulmonary surfactant mixture. It also has a higher compaction capacity than the other phospholipids, because the apolar tail is less bent. Nevertheless, without the other substances of the pulmonary surfactant mixture, the DPPC's adsorption kinetics is very slow. This happens primarily because the phase transition temperature between gel to liquid crystal of pure DPPC is 41.5 °C, which is higher than the human body's temperature of 37 °C.[7]
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Phosphatidylcholine molecules form ~85% of the lipid in surfactant and have saturated acyl chains. Phosphatidylglycerol (PG) forms about 11% of the lipids in the surfactant, it has unsaturated fatty acid chains that fluidize the lipid monolayer at the interface. Neutral lipids and cholesterol are also present. The components for these lipids diffuse from the blood into type II alveolar cells where they are assembled and packaged for secretion into secretory organelles called lamellar bodies.[citation needed]
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Proteins make up the remaining 10% of the surfactant. Half of this 10% is plasma proteins but the rest is formed by the apolipoproteins, surfactant proteins SP-A, SP-B, SP-C, and SP-D. The apolipoproteins are produced by the secretory pathway in type II cells. They undergo much post-translational modification, ending up in the lamellar bodies. These are concentric rings of lipid and protein, about 1 μm in diameter.
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SP-A is also thought to be involved in a negative feedback mechanism to control the production of surfactant.[citation needed
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The SP proteins reduce the critical temperature of DPPC's phase transition to a value lower than 37 °C,[10] which improves its adsorption and interface spreading velocity.[11][12] The compression of the interface causes a phase change of the surfactant molecules to liquid-gel or even gel-solid. The fast adsorption velocity is necessary to maintain the integrity of the gas exchange region of the lungs.
Each SP protein has distinct functions, which act synergistically to keep an interface rich in DPPC during lung's expansion and contraction. Changes in the surfactant mixture composition alter the pressure and temperature conditions for phase changes and the phospholipids' crystal shape as well.[13] Only the liquid phase can freely spread on the surface to form a monolayer. Nevertheless, it has been observed that if a lung region is abruptly expanded the floating crystals crack like "icebergs". Then the SP proteins selectively attract more DPPC to the interface than other phospholipids or cholesterol, whose surfactant properties are worse than DPPC's. The SP also fastens the DPPC on the interface to prevent the DPPC from being squeezed out when the surface area decreases [12] This also reduces the interface compressibility.[14]
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Survanta, surrounded by devices for its application.There are a number of types of pulmonary surfactants available. Ex-situ measurements of surface tension and interfacial rheology can help to understand the functionality of pulmonary surfactants.[15]
Synthetic pulmonary surfactants
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Animal derived surfactants
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Even though the surface tension can be greatly reduced by pulmonary surfactant, this effect will depend on the surfactant's concentration on the interface. The interface concentration has a saturation limit, which depends on temperature and mixture composition. Because during ventilation there is a variation of the lung surface area, the surfactant's interface concentration is not usually at the level of saturation. The surface increases during inspiration, which consequently opens space for new surfactant molecules to be recruited to the interface. Meanwhile, during expiration the surface area decreases at a rate which is always in excess of the rate at which the surfactant molecules are driven from the interface into the water film. Thus, the surfactant density at the air water interface remains high and is relatively preserved throughout expiration, decreasing the surface tension even further. This also explains why the compliance is greater during expiration than during inspiration. [citation needed]
SP molecules contribute to increasing the surfactant interface adsorption kinetics, when the concentration is below the saturation level. They also make weak bonds with the surfactant molecules at the interface and hold them longer there when the interface is compressed. Therefore, during ventilation, surface tension is usually lower than at equilibrium. Therefore, the surface tension varies according to the volume of air in the lungs, which protects them from atelectasis at low volumes and tissue damage at high volume levels.[11][13][14]
Surface tension values Condition Tension (mN/m) Water at 25 °C 70 Pulmonary surfactant in equilibrium at 36 °C 25 Healthy lung at 100% of TLC 30 Healthy lung between 40 and 60% of TLC 1~6 Healthy lung below 40% of TLC <1[
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Surfactant production in humans begins in type II cells during the alveolar sac stage of lung development. Lamellar bodies appear in the cytoplasm at about 20 weeks gestation.[16] These lamellar bodies are secreted by exocytosis into the alveolar lining fluid, where the surfactant forms a meshwork of tubular myelin[17][18] Full term infants are estimated to have an alveolar storage pool of approximately 100 mg/kg of surfactant, while preterm infants have an estimated 4&#;5 mg/kg at birth.[19]
Club cells also produce a component of lung surfactant.[20]
Alveolar surfactant has a half-life of 5 to 10 hours once secreted. It can be both broken down by macrophages and/or reabsorbed into the lamellar structures of type II pneumocytes. Up to 90% of surfactant DPPC (dipalmitoylphosphatidylcholine) is recycled from the alveolar space back into the type II pneumocyte. This process is believed to occur through SP-A stimulating receptor-mediated, clathrin dependent endocytosis.[21] The other 10% is taken up by alveolar macrophages and digested.
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In late s von Neergaard[22] identified the function of the pulmonary surfactant in increasing the compliance of the lungs by reducing surface tension. However the significance of his discovery was not understood by the scientific and medical community at that time. He also realized the importance of having low surface tension in lungs of newborn infants. Later, in the middle of the s, Pattle and Clements rediscovered the importance of surfactant and low surface tension in the lungs. At the end of that decade it was discovered that the lack of surfactant caused infant respiratory distress syndrome (IRDS).[23][13]
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Different modes of surfactant administration have been studied with regard to impact on mechanical properties of the lung and gas exchange. The standard approach to administer surfactant is instillation via the endotracheal tube (ETT) in the mechanically ventilated infant with RDS. This allows rapid surfactant bolus application, resulting usually in a more homogenous surfactant distribution, compared to slow infusion of surfactant, as evidenced from animal studies.49,50,51 However, whether a plug forms coincidentally before the next inspiration, which is a prerequisite for a good surfactant distribution after bolus administration,50 cannot be anticipated. Surfactant obviously needs a few minutes to dissipate into the typical monolayer along bronchial and alveolar surfaces, which is essential for its physicochemical properties. However, an immediate change of resistance and the risk of disturbed blood pressure and heart rate, as well as bronchus obstruction, remain unsolved problems49,52,53,54; so, in individual cases slow surfactant infusion might be preferable.49 Against this background inhalation techniques continue to attract interest, in particular because intubation is not required.
Since mechanical ventilation is associated with barotrauma and increased risk for ventilator-associated infections, noninvasive modes to administer surfactant were sought to minimize need for endotracheal intubation or duration of mechanical ventilation.55,56
The INSURE procedure comprises intubation followed by surfactant administration and early extubation. This approach uses short acting sedatives for intubation allowing extubation to noninvasive respiratory support right after surfactant administration. Since the studies by Verder et al.55 this approach has been widely adopted, by which the period of mechanical ventilation is minimized. Reversal of sedation or use of very short acting sedatives allow for rapid return to spontaneous breathing.57 However, only about 30% of preterm infants below 32 weeks GA are successfully treated with the INSURE procedure, whereas two out of three patients require longer periods of ventilation or re-intubation, due to effect of sedatives, poor gas exchange despite continuous mechanical ventilation during the procedure, or exhaustion.58,59
More recently LISA was introduced, and this technique was adopted quickly into clinical practice.56,60 In this modification surfactant is delivered through a thin, flexible feeding tube or a catheter placed into the trachea during spontaneous breathing, often supported with CPAP, eliminating the need to intubate with an ETT. Usually little or no sedation is given for the procedure, which has been described as a rapid injection technique, but also as a slow infusion over 1&#;3&#;min.61 Depending on the risk of surfactant reflux due to the leak at the level of the larynx, a very slow application of surfactant may be preferred, and nonhomogenous distribution does not seem to be a problem with this technique.61 Also, coughing of the infant during the procedure may cause reflux into the pharynx and hamper deposition of the whole amount of surfactant in the lung.
Both newer modes of surfactant therapy have proven to reduce the duration of invasive mechanical ventilation. Several randomized trials showed an effectivity at least equivalent to the classical approach with intubation and mechanical ventilation.62,63 Inclusion of larger numbers of infants through meta-analyses suggests a reduction in BPD and mortality with the new modalities of surfactant administration.63 Therefore, combination of surfactant therapy and noninvasive respiratory support may be a valuable approach to further improve long-term outcomes.
Subgroup analysis of the NINSAPP trial, which compared invasive surfactant administration with the LISA technique, suggested that very immature infants may benefit less from the noninvasive approach compared to the subgroup of >24 completed weeks of GA.62 Also, the severity of RDS might influence the choice, by which mode surfactant is given. Further studies should try to unravel how to proceed in case of LISA or INSURE failure, defined for instance by persistent high oxygen demands.
Surfactant has been given into the pharynx before the first breath,64 via laryngeal mask65 or by nebulization66 either experimentally or in small trials. Deposition of a satisfactory dose is the main challenge hampering these approaches. However, with new technical developments, these techniques may play a role in the future.
Consistent with animal data human studies have clearly shown that antenatal corticosteroid (ANS) treatment has significant beneficial effects on the outcome of preterm infants, reducing incidence and severity of RDS, but also mortality as one of the most important effects.67 This reduced mortality is in part mediated by an improved lung function at the time of birth. Animal models have shown that ANS accelerate lung maturation by thinning of the walls between the alveolar and vascular compartment and by speeding up maturation of the surfactant producing type II pneumocytes.68 As a result lung volumes and mechanics are improved. Furthermore, ANS treatment enhances the effect of exogenous surfactant on these outcomes and on lung function.69 In summary, ANS together with surfactant independently, but also additively, reduce mortality, severity of RDS, and air leak of preterm infants. Mortality is reduced, but there is no effect on neurodevelopmental outcome, and rate of BPD is reduced only in single studies.
The most important effect of exogenous surfactant is lowering of the alveolar surface tension thereby improving lung volume, lung mechanics and gas exchange. However, the effect of exogenous surfactant on these outcomes may differ between patients, and several factors impacting the response to exogenous surfactant have been identified.
The timing of surfactant treatment after birth can also impact its efficacy. Several meta-analyses have shown that delaying surfactant treatment after birth will have a negative impact on its efficacy.70,71 It has been suggested that this difference in favor of early treatment may be explained by a more optimal distribution of surfactant in a still fluid-filled lung, and the lack of ventilator-induced lung injury accompanied by fluid and protein influx into the alveolar space. However, it is important to mention that these negative effects of delayed surfactant treatment have mainly been observed in trials using invasive mechanical ventilation as initial strategy for respiratory support after birth. Nowadays, many centers have adopted noninvasive ventilation as the primary mode postnatally, and studies have shown that delaying surfactant treatment under these circumstances does not have a negative effect on its efficacy, when compared with primary invasive respiratory support combined with early (prophylactic) surfactant treatment.70
Surfactant function can be impeded by several pathophysiologic conditions.
Secondary surfactant deficiency from surfactant inactivation may occur with aspiration syndrome, pulmonary hemorrhage, pneumonia or ARDS.
An aspiration syndrome may be due to ingestion of meconium,72 blood,73 milk74 or bile75 into the lung. Part of the deleterious effects of meconium aspiration syndrome is exerted by inactivation of alveolar surfactant and activation of severe inflammation causing pneumonitis.72
Blood components like hemoglobin, entering the lung either with sangineous amnion fluid or following pulmonary hemorrhage, rapidly inactivate surfactant causing secondary surfactant deficiency and severe decline in lung function.76 Lung lavage with diluted surfactant and subsequent refilling of the surfactant pool with an adequate dose of animal-derived surfactant can be performed to overcome serious respiratory compromise exerted by meconium77 or blood.78
Disturbance of surfactant homeostasis in the presence of chorioamnionitis or pneumonia results from inactivation of surfactant with leakage of plasma proteins into the airspaces and influx of inflammatory cells causing cytokine release and inflammation.79 A similar effect is part of the pathophysiologic cascade in ARDS. Surfactant is frequently needed in inflammation processes, like chorioamnionitis, pneumonia or ARDS. However, while the role of surfactant therapy is well established to improve gas exchange and reduce mortality in primary surfactant deficiency in the preterm infant, its role in surfactant inactivation through inflammation is less clear: response is more unpredictable and often slower; also repeated doses of surfactant may be needed.80
Mechanical ventilation of preterm infants is associated with volutrauma and hyperoxia, leading to lung damage. This triggers an inflammation process, which activates cellular response and release of cytokines and proteases, harbingers of BPD. This sequence of injury can be attenuated or even abrogated by surfactant administration.
Animal data suggest that large tidal volumes (Vt) delivered shortly after birth during respiratory support of preterm lambs have a negative impact on surfactant response.81 However, there are no data to support this in humans.
Animal studies have also shown that injurious invasive mechanical ventilation increases conversion of SA to LA surfactant, which leads to leakage of proteins into the alveolar space and reduces surfactant function. Applying so-called lung-protective ventilation strategies can attenuate this process.82 This observation may in part explain why several trials comparing high-frequency ventilation (HFV) to conventional mechanical ventilation (CMV) have shown that infants treated with (lung protective) HFV require less repeat treatments with surfactant, which may indirectly indicate a better preservation of the first surfactant dose.83
Lack of surfactant, due to premature birth, hampers constant lung expansion, so continuous distending pressure from intermittent mandatory ventilation (IMV) or CPAP and administration of exogenous surfactant is required.
A homogenous distribution across the whole compartment of terminal bronchioli and alveoli would be optimal; however, surfactant will not reach areas, which are filled with debris or are collapsed, so a certain distending pressure is required immediately before and after surfactant administration.
Unless surfactant is given via a side port of the ETT during continuous ventilation or CPAP, surfactant administration usually requires disconnection of the patient from the ventilator for a short period of time, during which alveoli will collapse. So a static distending pressure via ventilation bag to re-open the lung and facilitate distribution of surfactant into the periphery after disconnection may be advantageous.
Immediate increase in oxygenation, following surfactant administration, is probably the result of increased FRC, not of altered lung mechanics,84 so FiO2 is always the first parameter of ventilation, which can be reduced.
The subsequent ventilation most often requires increased peak inspiratory pressure (PIP) to yield at least minimum ventilation in the first minutes after surfactant treatment53,54 or to overcome the frequent phenomenon of total bronchial obstruction.54 This period of increased resistance requires a long inspiratory time, relatively long expiratory time, and thus a low frequency, which contrasts to findings from a model of excised rat lungs showing that higher frequencies in the range of 60/min improved homogenous distribution of surfactant to different lung lobes.85 In clinical practice change of pO2 and pCO2 will most often require an immediate intervention by intensification of ventilation.
Positive end-expiratory pressure (PEEP) must be high enough to keep alveoli open during expiration, and from the clinical perspective PIP must be high enough to yield visible chest expansions after surfactant administration.
To some extent ventilation modes with volume guarantee may help to overcome the problem of rapidly changing lung mechanics after surfactant, resulting in changing Vt, but PIP must be set high enough.54
Within a timeframe of about 30&#;60&#;min, compliance will increase and resistance will return to baseline.53 It is mandatory to notice this development by either watching thorax expansion, which can change rapidly, or to notice increasing Vt, if measured. A great and timely reduction of PIP and PEEP is then mandatory to avoid alveolar overdistension and extra-alveolar leakage. At this time point frequency can eventually be increased.
Surfactant administration while using HFV with the &#;open lung-concept&#; has also shown promising results to keep the lung open in surfactant deficiency; continuous distending pressure could be reduced,86 comparable to the effect during CMV, where FRC increases immediately and compliance increases after a short time.53
For effective and lung-protective ventilation in these most vulnerable preterm infants, the time-resolved mechanics of the inspiratory and expiratory part of the ventilation cycle should be taken into consideration. In this respect total bronchial and bronchiolar resistance and local bronchiolar and alveolar compliance are the most important determinants.
In animal and human studies surfactant administration leads to immediate changes in hemodynamics. It is speculated that surfactant might have a &#;pharmacological&#; effect causing vasodilation. In a dose-dependent manner mean arterial blood pressure decreases after surfactant, due to systemic vasodilation, but can be partly compensated by an increase in cardiac output. On the other hand, these effects are difficult to distinguish from effects resulting from the frequently observed increase in pCO2, leading in particular to cerebral vasodilation and a decrease of left-to-right-shunt across the PDA after increase of pulmonary vascular resistance. But there are also conflicting results regarding change of cerebral blood flow velocity and/or regional cerebral oxygenation immediately after surfactant and uncertainty about pulmonary arterial pressure and pulmonary blood flow. These parameters can be measured only indirectly, but differences in timing of measurement, surfactant dose and persistence of PDA may also lead to varying results. Alarming effects on hemodynamics at about 20&#;30&#;min after surfactant administration often are the result of a compromised venous return due to an overinflated lung, if PIP and PEEP are not reduced adequately.
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