FAQs: Recent Advances in Surfactant Therapy for Management of Neonatal RDS
Surfactant Therapy in Neonatal Respiratory Distress Syndrome (RDS)
What is the Recommendation for Giving Prophylactic Surfactant Therapy? What is the Ideal Time after Birth to Give Prophylactic Surfactant Therapy to Preterm Babies?
Prophylactic therapy should be given to babies less than 30 weeks of gestation. It should be given as soon as they are stable within a few minutes after intubation.
European Consensus Guidelines (2007) recommend that
- Prophylaxis (within 15 min of birth) should be given to almost all babies under 27 weeks' gestation.
- Prophylaxis should be considered for babies over 26 weeks but <30 weeks' gestation if intubation is required in the delivery suite or if the mother has not received prenatal corticosteroids (A).
(A-Grade of recommendation)
When is Early Rescue Surfactant Therapy Indicated?
Babies with RDS should receive rescue surfactant therapy as early as possible. There is evidence to suggest that early rescue therapy (within 2 hrs) is advantageous as it reduces risk of mortality and air leaks. For some reason, if surfactant is delayed to later than 24 hrs, still a single dose of surfactant may be beneficial.
What are the Criteria for Giving the Second Dote of Surfactant? How Many Repeat Doses Should be Given?
The repeat dose may be given if -
- The baby's condition deteriorates after an initial response. FiO2 cut off is usually 40%.
- It may be given earlier if baby's condition deteriorates and post surfactant X-ray does not show optimum improvement or it shows improvement only in right lung which may be due to surfactant entering only right bronchus.
The European consensus guidelines mention that a second, and sometimes a third dose of surfactant should be odministered if there is ongoing evidence of RDS such as a persistent oxygen requirement and need for mechanical ventilation or if over 50% oxygen is needed on CPAP at 6 cm H2O as this reduces pneumothorax and probably also mortality (A).
Retreotment criteria may differ with the preparation used. For Neosurf there is no minimum time interval recommended between 2 doses as recommended for some other surfactants. In clinical trials for Neosurf the decision to redose was taben based on need and not on arbitrary time point as this may leave some of the babies in distress.
(A-Grade of recommendation)
Which Surfactant is Better: Natural or Synthetic? Why?
Natural surfactants should be preferred over synthetic surfactants as they reduce pulmonary air leaks and mortality (A). Synthetic surfactants do not contain surfactant proteins B & C. Surfactant proteins B & C aid in adsorption of surfactant to alveolar surface facilitating rapid action of surfactant and inhibit inactivation of surfactant by plasma proteins in alveolar space.
(A-Grade of recommendation as per European consensus guidelines)
What should be the Optimum Dose of Surfactant in Neonatal RDS?
Dosage of the exogenous surfactants varies from 50 mg/kg to 200 mg/kg of phospholipids. The estimated pool size of alveolar surfactant in the full-term neonatal lung is about 100 mg/kg. Usually 100 mg/kg dose of phospholipids can cover the lung surface. There is some evidence to suggest that there is a dose response relationship with increasing dose of phospholipids. Generous dose aids to compensate for possible uneven distribution of the exogenous surfactant and to overcome inhibitory effects caused by vascular-to-alveolar leakage of plasma proteins in the immature lung.
How Early is the Positive Response Obtained after Surfactant Therapy in Babies with RDS?
Response is obtained immediately after surfactant therapy. With Neosurf improvement in lung compliance occurs within 5-30 minutes. Sometimes, it may occur even earlier. So it is important to monitor the baby closely and change the ventilator settings accordingly.
Can Surfactant Therapy be Given in a Setting Where Ventilator Facility is not Available but CPAP is available?
It is recommended that surfactant therapy should be given in a highly supervised clinical setting. The guidelines led by Fetus & Newborn Committee, Canodian Paediatric Society recommend that babies with gestation age <29 weeks may receive prophylactic surfactant therapy even outside the tertiary centre in the presence of a specialist. They may be then transferred to tertiary centre to ensure optimal outcomes. Also intubated babies with RDS may receive surfoctant therapy before transport to tertiary centre.
By using INSURE (Intubate-Surfactant-Extubate) technique, it may be possible to extubate babies with RDS, after surfactant administration and maintain them on CPAP. But babies with RDS may develop complications like pulmonary hoemorrhage, apnoea, air leaks etc., Hence, INSURE must be done in a centre where facilities for ventilation are available.
Also it should be noted that it is just not about ventilator; such babies need a certain level of medical nursing and infrastructural backup to tackle the problems effectively. In exceptional situations where transport to the level 3 center is not possible for various reasons one may tabe the risk of giving the surfactant on compassionate grounds after explaining all the risks involved to the parents.
Are there any Comparative Studies to Assess Outcomes of Nasal CPAP with or without Surfactant Therapy in Babies with RDS?
Verder and colleagues performed 2 studies to compare the benefits of giving surfactant therapy with CPAP over CPAP alone. Surfactant therapy was given by INSURE (Intubate-Surfactant-Extubate) technique. They concluded that preterm babies with moderate to severe RDS initially managed with nasal CPAP should be given a single dose of surfoctant at FiO2 of 0.35-0.4. This decreases the need for mechanical ventilation and reduces mortality. The outcome may be further improved by giving surfactant therapy even earlier.
At What Point of Time Should Antenatal Steroids be Given?
A single course of prenatal steroids should be given to all women at risk of preterm delivery (before 35 weeks' gestation) (A). Betamethasone is preferred over dexamethasone due to reduced associated risk of cystic periventricular leukomalacia. The recommended regimen is two doses of betamethsone 12 mg given intramusculariy 24 hrs apart. This should be given at least 24 hrs prior and not more than 7 days before delivery. If delivery is delayed beyond 7 days, no firm recommendations can be given regarding the second course of antenatal steroids. The most recent Cochrane systematic review does not recommend routine repeat courses of prenatal steroids.
(A-Grade of recommedation as per European consensus guidelines)
Is it Necessary to Give Surfactant to a Preterm Baby with CA Less than 30 Weeks, not Having Severe RDS and Easily Maintained on Nasal CPAP just to Replenish the Surfactant Pool? Can Intubation be Harmful Sometimes and Precipitate the Inflammatory Cascade?
In a baby with gestational age <30 weeks with moderate RDS who is put on CPAP, administration of a single dose of surfactant by INSURE (Intubate-Surfactant-Extubate) may help to decrease need for mechanical ventilation. A study done by Verder & colleagues showed that CPAP with early rescue therapy at FiO2 of 0.35 decreases the need for mechanical ventilation and mortality and concluded that surfactant therapy offered even earlier may be beneficial. Usually cutoff of FiO2 of 0.3 to 0.4 can be considered for surfactant therapy. Laryngoscopy and intubation may lead to changes in heart rate and oxygenation and airway trauma, but inflammatory cascade is not initiated by intubation. It is related to ventilation induced lung injury. After intubation baby should be provided with adequate PEEP in order to prevent atelectrauma. INSURE technique in fact will decrease need for mechanical ventilation.
Administration & Monitoring
Do You Find Double Outlet Endotracheal Tubes in India?
There are no double outlet tubes in India. But mechanical ventilation can be continued during administration of surfactant by using a Y connector or endotracheal tube with secondary lumen.
After Every Aliquot, is it Necessary to Push Saline in Order to Clear the Infant Feeding Tube off Surfactant?
Each aliquot should be instilled rapidly over 2-3 sec. After each aliquot is instilled, the infant should be ventilated manually for 30 seconds, using pressures sufficient to achieve good chest expansion before returning the infant to the ventilator. If the infant remains on mechanical ventilation during dosing, raise the pressure by 1 to 2 cm H2O, if necessary, to assist with emptying the endotracheal tube. It is not necessary to clear the infant feeding tube by pushing saline after each aliquot.
Some amount of reflux may occur during surfactant administration. This may subside just by ventilation. If not, PEEP can be increased by 1-2 cm of H2O.
Are there any Advantages of Giving Surfactant in Different Positions As 2-4 Aliquots?
The evidence suggests that giving surfactant in different positions as aliquots has no added benefits over single bolus method. Ideal is to give surfactant as a single bolus as rapidly as possible usually over 10 seconds in supine position. This aids in rapid and uniform distribution of surfactant reducing the risk of oxygen desaturation. The aliquot method may be used if the baby does not tolerate the bolus dose.
When Should an X-Ray Chest Be Taken Post-Surfactant Therapy?
If there is expected improvement in the oxygenation, you don't need to do an X-ray just by protocol. If the improvement is not as expected or if there is deterioration in clinical or blood gas parameters, one should consider X-ray of the chest.
How Long Should (ET) Endotracheal Tube Suctioning be Avoided After Surfactant Therapy?
ET tube suctioning in the ventilated neonate should be done when there is evidence of obstruction or presence of secretions on graphics or clinically. Endotracheal tube suctioning is avoided for 4 hrs post surfactant therapy, if there is no evidence of tube obstruction.
Can Surfactant be Given by Nebulization?
The recommendation for administration of exogenous surfactant is that it is to be administered by intratracheal instillation only after an endotracheal airway has been established. However many animal studies have been performed with surfactant therapy being administered by nebulization. In some of the studies nebulized natural surfactant improved gas exchange. But overall instilled surfactant has a reasonably homogeneous distribution, whereas nebulized surfactant has a less homogeneous distribution. The potential for nebulized surfactant therapy for respiratory distress syndrome (RDS) may be limited by the nonhomogeneous nature of ventilation in the preterm lung. Another disadvantage is that there may be loss of precious surfactant suspension in the delivery system of the ventilator or gas supply equipment. In one of the trial 34 spontaneously breathing newborns with respiratory distress syndrome (RDS) requiring nasal continuous positive airway pressure (CPAP) and an arterial-to-alveolar oxygen tension ratio (a/A PO2) of 0.15-0.22 were randomized to treatment with nebulized surfactant or to serve as controls, no beneficial effects of aerosolized surfactant were demonstrated, contrary to data from animal experiments.
Adverse Effects
What are the Adverse Effects of Surfactant Therapy? Is there any Systemic Toxicity?
Immediate risks of surfactant therapy include bradycardia and hypoxemia during instillation as well as blockage of endotracheal tube. There may be tachycardia due to agitation or apnoea. Surfactant therapy may increase risk of pulmonary hoemorrhage. Other complications which may occur are mainly related to the prematurity of neonates and to mechanical ventilation. These include intraventricular haemorrhage, pneumothorax, pulmonary interstitial emphysema, retinitis of prematurity, periventicular leukomalacia, necrotizing enterocolitis, pneumonia and chronic lung disease or bronchopulmonary dysplasia, patent ductus arteriosus etc.
Exogenous surfactant is cleared from the epithelial lining fluid (ELF) mainly by alveolar epithelial cells, although alveolar macrophages and the central airways may also contribute to clearance of the drug. Only small quantities of surfactant actually enter the blood stream. A significant fraction of surfactant is taken up, processed and secreted back into the alveolar space by type II alveolar cels. This process is termed recycling. Thus there is no risk of systemic toxicity. If for some reason overdosage occurs, there may be risk of airway obstruction.
Does Surfactant Therapy Increase Risk of Pulmonary Haemorrhage? What Should be the Management if a Baby Develops Sudden Onset Pulmonary Haemorrhage Immediately after Surfactant Therapy?
A meta-analysis of clinical trials with surfactant therapy showed that the risk of pulmonary haemorrhage increases slightly with surfactant therapy. Thrs increased risk is small compared with the documented benefits of surfactant therapy in respiratory distress syndrome. The management of pulmonary haemorrhage includes positive pressure ventilation and PEEP and correction of other factors like PH, hypovolemia, etc. If there is clinical deterioration, the baby may benefit from surfactant therapy irrespective of the cause of pulmonary haemorhage.
How Late can Pulmonary Haemorrhage Occur After Surfactant Instillation?
Pulmonary haemorrhage after surfactant therapy is generally related to a hemodynamically significant PDA (patent ductus arteriosus) which leads to sudden increase in left to right shunt due to improved lung mechanics. Also, it should be noted that there are many other risk factors for pulmonary haemorrhage in a ventilated preterm neonate (PDA is one of them) and it is generally difficult to pin point one of them as a culprit. Surfactant as a cause for pulmonary haemorrhage may be considered if within few hours upto a day of therapy, one gets blood in the endotracheal tube.
Does Surfactant Use Increase the Risk of Intraventricular Haemorrhage (IVH)?
Meta-analysis of 7 randomized trials showed that difference in incidence of IVH between surfactant and control group was in favour of surfactant therapy. In some of the trials the incidence of IVH was significantly lower in surfactant group.
What is the Incidence of Bronchopulmonary Dysplasia During Long Term Follow-Up of Cases Who Have Received Surfactant?
Combined analysis of 7 randomized trials which included neonates with RDS who received surfoctant either at birth or within 15 hrs of birth showed that incidence of bronchopulmonary dysplasia was 34 % as against 44 % incidence in the control group.
Neosurf
Between Neosurf & Bovine Minced Lung Extract Surfactant, Which One is Superior and Why?
Neosurf is bovine surfactant obtained by lung lavage. Bovine minced lung extract surfactant is modified natural surfactant obtained from mincing the lung tissue. DPPC, palmitic acid and tripalmitin are then added to specified concentrations. In the process of mincing the cellular components of the lung are added which makes Bovine minced surfactant more viscous. Also the presence of phospholipids from other cellular components of the lung makes this a modified surfactant with lower concentration of surfactant protein B&C.
Neosurf contains significantly more SP-B than Bovine minced lung extract surfactant which improves its surfactant qualities, and improves its resistance to inactivation by plasma proteins.
Neosurf has a lower ratio of small surfactant aggregate (SA) to large surfactant aggregate (LA) than Bovine minced lung extract surfactant. LA represent surface active component of surfactant and metabolic precursors of inactive SA. Lower SA/LA ratio is associated with a superior physiological response.
Neosurf is approximately eight times less viscous than Bovine minced lung extract surfactant. Using the Ostwald viscometer. Neosurf was found to have a viscosity of 4.5 times that of water, and Bovine minced lung extract surfactant had a viscosity of 33.3 times that of water. A more viscous material could lead to slower peripheral distribution of surfactant when instilled through the endotracheal tube, resulting in increases in PIP (Peak Inspiratory Pressure) and PaCO2, values due to airway obstruction. In a comparative study of Neosurf and Bovine minced lung extract surfactant in an animal model animals given instilled minced surfactant intratracheally had an acute deterioration in ventilator parameters compared with those treated with the instilledNeosurf.
Neosurf was compared with Bovine minced lung extract surfactant in infants with RDS in a study published by Lam et al. (Lam, 1995). The Neosurf group had a significantly improved oxygenation index throughout the 12-hour period after dosing compared to the other surfactant group. There was no difference in secondary outcomes, including mortality, ventilator days and occurrence of chronic lung disease. This may be attributed to smaller sample size The authors concluded that the infants with RDS responded favorably to both surfactants, but that Neosurf achieved a significantly faster clinical response in terms of oxygenation index.
Why is Dose of Neosurf Higher (5Ml/Kg) than Bovine Minced Lung Extract Surfactant (4ml/kg) when Each ml of Neosurf Contains 27mg of Phospholipids as Against Bovine Minced Lung Extract Surfactant Which Contains 25mg/ml of Phospholipids?
The recommended dose of Neosurf is 135 mg/kg of phospholipids or 5 ml/kg and for Bovine minced lung extract surfactant, it is 100 mg/kg of phospholipids or 4ml/kg. The dose of Neosurf is based on results of phase III trial with Neosurf. The surfactant pool size of a term baby is 100 mg/kg of phospholipids where as that of a preterm baby is 4-5 mg of phospholipids/kg. So to replenish this deficit adequate dose of surfactant is needed. Liberal dosage also compensates for possible uneven distribution of the exogenous surfactant and helps to overcome inhibitory effects caused by vascular-to-alveolar leakage of plasma proteins in the immature lung. There is some evidence to suggest that there is dose dependent improvement in response to a surfactant with increasing dose of phospholipids.
How Much Does Viscosity Affect the Action of the Surfactant? Which Factors Do Affect Viscosity? Why is the Viscosity of Neosurf Lower than Bovine Minced Lung Extract Surfactant?
Lower the viscosity, the more rapid is the distribution of surfactant to peripheral airways and less is the risk of airway obstruction. The viscosity of surfactant depends on the method of extraction. Minced extracts contain cellular components of lung tissue which increase viscosity.
Viscosity also depends on lipid content of surfactant. The surfactant preparations contain neutral lipids, disaturated lipids i.e. DPPC and polyunsaturated fatty acid containing phospholipids (PUFA-PL), plasmalogens and cholesterol. Viscosity is affected by the concentrations of plasmalogen, cholesterol and PUFA-PL in a surfactant.
Viscosity is also affected by concentration of surfactant associated protein B (SP-B).
Higher concentrations of plasmalogen, PUFA-PL and SP-B lower viscosity.
Viscosity of Neosurf as measured by viscometer is 8 times less than that of Bovine minced lung extract surfactant. Neosurf is obtained by lavage extraction as against Bovine minced lung extract surfactant which is obtained by mincing process. Neosurf contains higher concentration of surfactant protein B & C than Bovine minced lung extract surfactant In an animal study comparing Neosurf with Bovine minced lung extract surfactant, there was acute deterioration in ventilatory parameters with increase in PIP & PaCO2 with Bovine minced lung extract surfactant. This may be attributed to high viscosity of Bovine minced lung extract surfactant.
Is Neosurf Used for Prophylactic Surfactant Therapy in Canada?
Neosurf is used for prophylactic surfactant therapy in Canada.
Is Neosurf Being Used in Meconium Aspiration Syndrome? What is the Dose?
Ans, Neosurf is being used in management of meconium aspiration syndrome (MAS). Dose used in one of the open study was 100mg/kg of phospholipids. However definitive clinical trial has not been conducted withNeosurf in this indication. But doses upto 135mg/kg of phospholipids have been used in clinical practice.
If there any Risk of 'Mad Cow Disease' (BSE) with use of Bovine Surfactants?
Neosurf is not at risk of containing BSE (Bovine spongiform encephalopathy) prions and viruses. The manufacturer has a certificate from the 'European Directorate for the Quality of Medicines' that Neosurf does not have BSE prions based on how the raw material is collected and processed.
1. The age of the animals that are lavaged is less than 30 months. At that age, it is thought that BSE infertivity has not moved outside the brain tissue.
2. The lungs are considered a low source of BSE infectivity. In addition, for Neosurf production in particular, the lungs are washed and only the lung surfactant is collected not lung tissue.
3. Through a series of organic extractions, only the lipids and hydrophobic proteins are isolated and all hydrophilic proteins (which would include any prions) are removed.
4. Viruses: The product is terminally sterilized at 121ºC for 15 minutes, which will bill any viruses.
Other Indications
What are the Other Indications for Surfactant Therapy?
Surfactant therapy is being used in other indications like -
- Meconium aspiration syndrome
- Pulmonary hoemorrhage
- Pneumonia
- ARDS
What Is Role of Surfactant in Meconium Aspiration Syndrome (MAS)? What is the Recommended Dose?
The pathophysiology of MAS is related to mechanical obstruction of the airway and the inactivation of the surfactant by the meconium leading to pulmonary atelectasis. Thus, babies with MAS develop secondary surfactant deficiency. These babies are bom with normal/ near normal surfactant pool.
The guidelines led by the Fetus & Newborn Committee, Canadian Paediatric Society recommend that intubated infants with meconium aspiration syndrome requiring more than 50% oxygen should receive exogenous surfactant therapy (grade A recommendation).
Dose of surfactant given in these babies varies as per different unit protocols. Generally a dose of at least 50mg/kg phospholipid, rounded off to the nearest vial size is given (i.e. between 50 to 100 mg/kg).
If used in diluted form as a lavage, diluted surfactant solution may exerts a detergent effect to wash out the residual meconium from the airway.
What is the Role of Surfactant Therapy in Pneumonia?
Infection affects surfactant either directly through effects on surfactant phospholipids and proteins or indirectly through plasma protein leakage into the alveolus. In the study by Lotze et al, a subgroup analysis of 100 infants with sepsis and pneumonia showed that surfactant significantly improved ventilation and oxygenation and reduced the need for ECMO (extracorporeal membrane oxygenation). In infants with group B streptococcal pneumonia, surfactant improved ventilation but more surfactant was required than in a similar group of infants with RDS.
The guidelines led by the Fetus & Newborn Committee, Conadian Paediatric Society recommend that sick newborn infants with pneumonia and an oxygenation index greater than 15 should receive exogenous surfactant therapy (grade C recommendation).
What is the Role off Surfactant in Pulmonary Haemorrhage? What is the Dose?
Evidence suggests that surfactant therapy leads to slight increase in risk of pulmonary haemorrhage. This can be due to sudden improvement in lung mechanics with rapid improvement in oxygenation with rapid drop in pulmonary vascular resistance. This hyperoxia can be avoided by appropriate weaning after surf octant therapy.
But there is some evidence also to suggest that surfactant therapy improves oxygenation in infants with pulmonary hoemorrhage. This is because; hemoglobin inactivates the surfactant present in the lung thus causing surfactant deficiency. So replenishing surfactant pool may improve oxygenation. However, the first line therapy for pulmonary haemorrhoge is positive pressure ventilation, PEEP and improvement in fluid and acid-base status.
The guidelines led by the Fetus and Newborn Committee, Canadian Paediatric Society 2005 recommend that intubated newborn infants with pulmonary haemorrhage which leads to clinical deterioration should receive exogenous surfactant therapy as one aspect of clinical care (grade C recommendation).
In one of the pilot studies, the infants with pulmonary haemorrhage were given BLES (Neosurf) in the dosage of 100mg/kg of phospholipids. The primary diagnosis included RDS, MAS or isolated pulmonary haemorrhage. All neonates with RDS had received surfactant therapy prior to occurrence of pulmonary haemorrhage. There was Improvement in oxygenation index in all these infants with pulmonary haemorrhage after administration of surfactant irrespective of primary diagnosis.
Does Surfactant Therapy have any Role in Brochiolitis in Preterm Babies?
Abnormalities of pulmonary surfactant have been reported in infants with bronchiolitis. These amounted to a marked deficiency of SP-A and disaturated PC, both of which resolved as the disease improved. Functional activity of surfactant from these infants with bronchiolitis was less impaired but there may be a potential role for exogenous surfactant therapy. There has been one randomized controlled trial of a porcine-derived surfactant in infants with severe bronchiolitis. There were improvements in oxygenation and ventilator pressures from 1 and 3 hrs, respectively, in treated infants. All infants survived and those given surfactant had reduced time on the ventilator and shorter hospital admission. However randomized controlled trials are lacking in this area and routine use of surfactant in cases of bronchiolitis is not recommended. In selected cases of suspected secondary surfactant deficiency one may justify use of surfactant.
What is the Role of Surfactant Therapy in ARDS? Is there any Evidence For It's Use in ARDS?
For the surfactant therapy in ARDS, data from randomized, controlled trials are lacking. But it is evident from clinical experience that surfactant replacement which counter balances surfactant inactivation seems to improve oxygenation and lung function in many babies with ARDS without apparent negative side effects.
What is the Role Off Surfactant in Pulmonary Hypoplasia?
There are few case reports of prophylactic surfactant in pulmonary hypoplasia in cases of CDH (congenital diaphragmatic hernia) with survival benefit. However studies from humans do not show delay in surfactant maturation in fetuses with CDH. Systematic reviews do not support routine use of surfactant in this condition. The surfactant may be used in selected caves of term hypoplastic lungs if they are ventilated on high ventilator settings with high oxygen requirement.
Can Surfactant Therapy be Tried in Acute Asthma in Small Children by Aerosolization when there is Impending Respiratory Failure?
Studies with surfactant administration in patients with asthma have given contrasting results. Kurashima and coworkers found that the inhalation of a surfactant extract by adult patients during an asthma attack improved lung mechanics, but Oetomo and coworkers found no change in lung mechanics in children with asthma who inhaled a surfactant extract during a stable phase of their disease. Erpenbeck and coworkers found that pretreatment with the surfactant extract amplified the response to allergen exposure, increasing the concentrations of eosinophils, eotaxin, and IL-5 in lung lavage fluid and decreasing the concentration of interferon-r. So more research is needed before considering surfactant for the treatment of asthma.
Reference
1. AMJ Respir Crit Care Med 2004; 169: 550-551
2. AIDC 1991; 145:102-104
3. Biochimca et Biophysica Acta 1998; 1408; 346-361
4. BLES Monograph
5. J Appl Physiol 1996; 80:1156-1164
6. J Perinat Med 2007; 35:175-186
7. J Perinatol 2007; 27(9): 535-49
8. Paediatr Pulmonol, 2005; 39: 64-69
9. Paediatr Respir Rev 2003; 4:2-8
10. Pediatrics 1999; 103:1014-1018
11. PLoS Med 2007; 4(7): e237
