Respiratory distress syndrome (RDS) – the most common respiratory disorder in preterm neonates is the clinical expression of surfactant deficiency and its nonspecific histologic counterpart, hyaline membrane disease (HMD). However, some authors prefer the term surfactant deficiency disorder<xref ref-type="bibr" rid="bib001">1</xref>. According to the year 2003 report of National Neonatal Perinatal Database (NNPD), the incidence of RDS in our country was 1.2% of all live births <xref ref-type="bibr" rid="bib002">2</xref>. In a report from the NICHD Neonatal Research Network, Fanaroff and coworkers reported that 42% of infants between 500 and 1500 g were noted to have RDS, including 71% between 500 and 750 g, 54% between 751and 1000 g, 36% between 1001 and 1250 g, and 22% between 1251 and 1500 g<xref ref-type="bibr" rid="bib003">3</xref>.</sec><sec id="sec002"><title>Aetiopathogenesis

Journal of Neonatology

0971-2179

National Neonatology Forum

jn-21-2-004

REVIEW ARTICLE

Respiratory Distress Syndrome – Dilemmas in management

Suman Rao

Neonatal Unit, Department of Paediatrics, St. John's Medical College Hospital, Bangalore-560034.

*E-mail: raosumanv@rediffmail.com

4–62007

2129298

Respiratory distress syndrome (RDS) – the most common respiratory disorder in preterm neonates is the clinical expression of surfactant deficiency and its nonspecific histologic counterpart, hyaline membrane disease (HMD). However, some authors prefer the term surfactant deficiency disorder<xref ref-type="bibr" rid="bib001">1</xref>. According to the year 2003 report of National Neonatal Perinatal Database (NNPD), the incidence of RDS in our country was 1.2% of all live births <xref ref-type="bibr" rid="bib002">2</xref>. In a report from the NICHD Neonatal Research Network, Fanaroff and coworkers reported that 42% of infants between 500 and 1500 g were noted to have RDS, including 71% between 500 and 750 g, 54% between 751and 1000 g, 36% between 1001 and 1250 g, and 22% between 1251 and 1500 g<xref ref-type="bibr" rid="bib003">3</xref>.</sec><sec id="sec002"><title>Aetiopathogenesis

The aetiology of RDS is immaturity of the lungs, in particular of the surfactant-synthesizing systems. Surfactant, a complex surface-active lipoprotein containing primarily the phospholipids (90%) – dipalmitoylphosphatidylcholine (DPPC) and phosphatidylglycerol (PG) and proteins (10%) maintains the physical integrity of the normally expanded alveoli. Surfactant and surfactant proteins A, B, C, and D are produced by type II pneumocytes. The crucial role of surfactant proteins in RDS prevention is only understood recently. The previous axiom that intrauterine growth restriction (IUGR) is associated with increased pulmonary maturation and a decreased incidence of RDS has been challenged by recently published studies ⁴.

Boys, white infants, infants with asphyxia, infants of diabetic mothers, second of twin, have higher risk of RDS. Surfactant protein B deficiency (autosomal recessive) and mutations of ABCA3 gene are associated with fatal RDS³.

Clinical presentation

The diagnostic criteria for RDS were laid down before the era of neonatal intensive care.

These are:

A respiratory rate above 60/min

Grunting expiration

Indrawing of the sternum, intercostals spaces and lower ribs during inspiration

Cyanosis without oxygen

These signs must develop before the neonate is 6 hours old, and persist beyond 24 hours. The presence of apneic episodes at an early stage and the disappearance of grunting with increasing oxygen requirements are ominous signs. Pallor from anemia or peripheral vasoconstriction, murmur of patent ductus arteriosus (PDA), unilaterally decreased breath sounds are additional clinical features to be watched for.

The uncomplicated clinical course is characterized by a progressive worsening of symptoms with a peak severity by days 2 to 3 and onset of recovery by 72 hours. Surfactant therapy often greatly shortens this course. With complications such as air leaks, PDA, or bronchopulmonary dysplasia (BPD), recovery can be delayed for days, weeks or months. In the most severely affected patients, the transition from the recovery phase of RDS to BPD is clinically imperceptible. The diagnosis of HMD by NNPD requires all of the following three criteria²:

Preterm neonate

Respiratory distress having onset within 6 hours of birth

Amniotic fluid L/S ratio of <1.5, or negative gastric aspirate shake test, or X ray evidence. OR Autopsy evidence of HMD.

Investigations

The X-ray appearances depend on the severity of the disorder, with poorly inflated lungs being the cardinal feature⁵. In mild disease the lungs show fine homogeneous reticulogranular pattern (grade 1) but when more severe, widespread air bronchograms become visible (grade 2) followed by the development of confluent alveolar shadowing (grade 3) leading to a complete white-out of the lung fields with obscuring of the cardiac border in the most severe cases (grade 4). At birth, RDS can be predicted by the ‘shake test’ on gastric aspirates or measuring the lecithin/sphingomyelin ratio and phosphatidylglycerol (‘modified lung profile’) in lung effluents.

Management

Clinical innovations that have revolutionized the natural history of RDS include antenatal corticosteroid administration, surfactant replacement therapy, and increasingly sophisticated use of assisted ventilation. In addition, the application of the basic principles of neonatal care, such as thermoregulation, cardiovascular and nutritional support, treatment of early neonatal infection, and prevention of nosocomial infection, is fundamental to achieve the therapeutic objectives.

Prevention

Prevention of preterm births is not always possible. The single most important intervention to decrease the incidence of RDS is the antenatal administration of corticosteroids. A recent Cochrane meta-analysis has reiterated the magnitude of benefit of antenatal corticosteroids (Table 1)⁶: Table 1

Benefit of Antenatal Corticosteroids

	Relative risk	95% Confidence interval	No. of studies	No. of infants

Neonatal mortality	0.69	0.58 to 0.81	18	3956
RDS	0.66	0.59 to 0.73	21	4038
Cerebroventricular haemorrhage	0.54	0.43 to 0.69	13	2872
Necrotising enterocolitis	0.46	0.29 to 0.74	8	1675
Respiratory support, intensive care admissions	0.80	0.65 to 0.99	2	277
Syste mic infections in first 48 h	0.56	0.38 to 0.85	5	1319

Antenatal corticosteroid use is effective in women with premature rupture of membranes and pregnancy related hypertension syndromes. Treatment with antenatal corticosteroids does not increase the risk of death, chorioamnionitis or puerperal sepsis to the mother. The results of 30 year follow-up of the first and largest randomized controlled trial of antenatal corticosteroids have shown no adverse effect on cardiovascular risk, pulmonary function and psychological function.

The National Institute of Health (NIH) consensus conference statements on antenatal corticosteroid use recommend that all pregnant women should be considered eligible for a single course of corticosteroids during 24–34 weeks gestation⁷. The regimes recommended by the consensus conference are 12 mg of betamethasone intramuscularly for two doses 24 hours apart, or 6 mg of dexamethasone intramuscularly every 12 hours for four doses. What is however still a matter of debate is the benefit of incomplete course, multiple courses and the drug of choice.

Incomplete course of antenatal steroids

Many studies have found a definite benefit of an incomplete course of antenatal corticosteroids^8,9 - reduction in the need for vasopressors, the rate of intraventricular hemorrhage, and neonatal death in preterm neonates. Some authors have reported that one dose of antenatal steroids given 4–24 h before delivery was clinically comparable to the recommended schedule in surfactant-treated preterm infants <31 weeks¹⁰. Moreover, dosing betamethasone in 12-hour intervals may result in similar neonatal outcomes compared to the standard 24-hour regimen when delivery occurs within 48 hours of therapy initiation¹¹.

Multiple courses of antenatal steroids

NIH Consensus conference 2000 (7) recommended that repeat courses of antenatal corticosteroids should not be used outside of randomized controlled trials (RCTs) because there is insufficient evidence of safety or efficacy. This was based on several worrisome observations in animal models on interference with fetal growth (body growth, head growth, or individual organs growth) and neurodevelopmental deficits¹², few retrospective human studies ¹³ and early RCTs which failed to show any benefit¹⁴.

Not all reports of multiple corticosteroid courses are negative. Recent additions to the literature provide evidence supporting the use of repeat courses of antenatal steroids. Both human and animal studies offer evidence that repeat courses of corticosteroids improve neonatal pulmonary outcomes, especially for the infants delivered at earlier gestational ages¹⁵. RCTs in humans have shown that birth weight reduction was only seen in those infants treated with 4 or more courses of corticosteroids. In addition, the reduction in neonatal birth weight and head circumference normalized by the time of hospital discharge. Studies are ongoing to investigate the 24-month post delivery physical and neurodevelopmental outcomes in infants exposed to repeat courses of antenatal corticosteroids. Before the final word is out more RCTs are needed to determine the optimal number of courses of antenatal steroids to reduce the frequency of RDS without adversely affecting other neonatal outcomes.

Betamethasone Vs Dexamethasone

In view of the increased efficacy of betamethasone in experimental and clinical trials on mortality, memory and the evidence of increased risks of poor growth, periventricular leukomalacia and neurotoxicity with dexamethasone, it may be reasonable to prefer when possible betamethasone over dexamethasone¹⁶. The current recommendations from the NIH endorse either betamethasone or dexamethasone.

Other antenatal medications

Thyroid hormones are involved in the induction of surfactant synthesis. However, the antenatal administration of TRH has not proved beneficial. Antenatal aminophylline, opiates, ambroxol, betamimetics also have not improved neonatal lung function significantly.

In-utero transfer

In–utero transfer i.e. transport of pregnant women at risk of preterm labour to centers where appropriate skills are available for stabilization and ongoing respiratory support should be encouraged.

Surfactant

Two decades after Avery and Mead established the relationship between surfactant deficiency and RDS in preterm infants, exogenous surfactant was successfully administered to preterm infants with RDS by Fujiwara et al in Japan. Surfactant therapy is the most thoroughly evaluated therapy currently used in neonatal intensive care. It has been estimated that 80% of the decline in infant mortality rate between 1988 and 1990 can be attributed solely to the introduction of surfactant therapy, and this has substantially decreased the cost of care¹⁹. Surfactant preparations are of basically 3 types: (Table 2)

Natural surfactant (animal derived by either lung mince extract or by lung lavage extract)– phospholipids with surfactant proteins

Synthetic surfactant – only phospholipds

Newer surfactant –synthetic surfactants with synthetic peptides modeled on surfactant proteins, Aerosolized surfactants

Choice of surfactant

Both synthetic and natural surfactants are beneficial for prevention and treatment of RDS. Animal-derived surfactants lead to further reductions in mortality, a lower occurrence of pneumothorax, and faster weaning compared with synthetic surfactants²⁰. The newer synthetic peptide containing surfactants are at least as good as the natural surfactants and better than the older synthetic surfactants without surfactant proteins²¹.

Among the natural surfactants, Curosurf was found to have a more rapid onset of action and a significant decrease in neonatal mortality²². However, this advantage was when the dose of Curosurf was 200 mg/kg in comparison with 100 mg/kg of others. Most differences in effectiveness between natural surfactant preparations are short-lived. On the basis of currently available evidence, no preparation can clearly be considered superior to another with regard to morbidity and mortality. More data would be needed and future studies should include comparison of longterm outcome parameters. However, the clinical relevance of these differences is likely to be minimal; therefore, future studies should focus on more relevant aspects of surfactant therapy²³. Noninvasive surfactant instillation into the airways without the need for intubation is a highly appealing option for clinicians. Trials of aerosolized surfactants in neonates have documented safety but not efficacy convincingly and this mode of delivery needs to be further studies²⁴. Table 2

Main characteristics of surfactants used in neonates

Surfactant Family	Trade Name	Preparation	Protein	Phospholipd concentration	Dose

Synthetic	Exosurf	DPPC with 9% hexadecanol and 6% tyloxapol	No	13.5 mg/ml	5 ml/kg
	Surf act	DPPC	No	13.5 mg/ml	5 ml/kg
	Pumactant	DPPC, PG	No	40 mg/ml	1.2 ml/kg
Natural	Survanta (bovine)	DPPC, PG	Some SP-B and SP-C	25 mg/ml	4 ml/kg
	Curosurf (porcine)	DPPC, PG	SP-B and SP-C	80 mg/ml	2.5 ml/kg and 1.25 ml/kg
	Neosurf (BLES - bovine lipid extract surfactant)	DPPC, PG	SP-B and SP-C	27 mg/ml	5 ml/kg
	Infasurf (bovine)	DPPC, PG	SP-B and SP-C	35 mg/ml	3 ml/kg
	Alveofact (bovine)	DPPC, PG	SP-B and SP-C	40 mg/ml	1.2 ml/kg
Newer surfactants	Surfaxin	DPPC, POPG,	KL₄ peptide as SP-B (sinapultide)	30 mg/ml	5.8 ml/kg
	Venticute	DPPC, POPG	r SP-C	50 mg/ml	Not studied in neonates
	Aerozolized surfactants

Abbreviations: DPPC, dipalmitoylphosphatidylcholine; PG, phosphatidylglycerol; POPG, palmitoyloleylphosphatidylglycerol; SP-B, surfactant protein B;SP-C, surfactant protein C

Timing of surfactant

Surfactant may be given as:

Prophylactic therapy: soon after birth irrespective of the onset of respiratory distress

Early rescue therapy: within 2 hours of birth after onset of respiratory distress

Late rescue therapy: after 2 hours of birth

In reference to decreasing the incidence of air leaks and mortality, prophylactic therapy is better than early rescue which in turn is better than late rescue ^25,26. These trials were carried out in an era of low prenatal corticosteroid use and for this reason a lower gestation below which prophylactic surfactant can be recommended as a routine may be appropriate, perhaps <27 weeks. The benefits of prophylactic surfactant must be weighed against the fact that prophylaxis with surfactant will result in the treatment of a proportion of infants who do not require surfactant and will result in the intubation of a proportion of infants who otherwise would have not been intubated. The threshold for prophylactic surfactant may be extended to <30 weeks if intubation is required in the delivery room or if the mother has not received prenatal corticosteroids²⁷. Some have used tests such as the stable microbubble shake test on the gastric aspirates successfully to decide on the need for prophylaxis: newborns with < 25 microbubbles (MB)/mm received prophylactic surfactant²⁸.

Number of surfactant doses

A second, and sometimes a third dose of surfactant may be beneficial in reducing mortality and air leak syndromes. The criteria for repeating dosing may be either ‘low threshold’ (FiO₂ > 0.3, still requiring endotracheal intubation) or ‘high threshold’ (FiO₂ > 0.4, mean airway pressure >7 cm H₂O). The use of a higher threshold for re-treatment with surfactant appears to be as effective as a low threshold and can lead to significant savings in costs of the drug²⁹. We use FiO₂ > 0.4, still requiring endotracheal intubation as the criteria for a repeat dose of surfactant.

Method of administration

Most clinicians administer surfactant as either bolus instillation or fairly rapid instillation over one minute. Micro infusions results in non homogenous distribution. Administration via a dual lumen endotracheal tube without disconnection from mechanical ventilation is associated less bradycardia.. Keeping the chest in the horizontal position may result in the most even distribution of the surfactant in the two lungs³⁰. Antenatal administration as either in-utero amniotic instillation or oral administration has been reported but not well studied.

Ventilatory strategiesCPAP

Recognizing that the endotracheal tube ventilation may be one of the most important risk factors for BPD, the interest in continuous positive airway pressure (CPAP) and non invasive ventilation is renewed. In preterms with RDS, requiring some ventilatory support, CPAP is an attractive option as it supports ventilation with minimal damage to the lungs. Though prophylactic CPAP may not be beneficial³¹, early use of CPAP has been shown to reduce the need for mechanical ventilation³² and may possibly reduce the incidence of BPD³³. This is particularly true when early CPAP and surfactant therapy are used together. INSURE therapy (Intubate, surfactant and rapidly extubate to CPAP) has been shown to reduce the need for mechanical ventilation ³⁴. In our center – we start CPAP when the preterm baby's respiratory distress score exceeds 3 and/or FiO₂ requirement > 0.3. CPAP is definitely useful post extubation to prevent extubation failure in very low birth weight infants. The NNT (number needed to treat) with CPAP to prevent one extubation failure is only six³⁵.

Binasal prongs are superior to single nasal prongs. Nasal cannula can also be used to deliver CPAP, however, recognizing the risk of unknown uncontrolled pressure, the flow is recommended to be <2 l/min. The single most common difficulty with the use of nasal prongs or cannula is keeping them in proper position. Feeding is not a contra indication on CPAP, but routine placement of an orogastric tube to prevent ‘CPAP belly’ is required.

Non invasive ventilation (NIV)

NIV delivers positive pressure throughout the respiratory cycle with additional phasic increases in airway pressure, without the presence of an endotracheal tube. This additional pressure above CPAP may be synchronized with the patient's own efforts. – synchronized nasal intermittent positive pressure ventilation (SNIPPV). SNIPPV has been shown to reduce the work of breathing, the need for endotracheal intubation³⁷ and as a primary mode of ventilation has reduced the need for oxygen³⁸.

However a word of caution. Synchronized nasal ventilation can only be delivered by respirators with specific triggering devices like body surface sensors, such as an abdominal pressure capsule or special airflow sensor.

When to ventilate?

Mechanical ventilation for RDS is recommended if any of the following is present:

Clinical criteria - respiratory distress on CPAP, severe respiratory distress with shock or severe apnea And/or

ABG criteria - respiratory acidosis with a pH of <7.20 to 7.25 or severe hypoxemia with a PaO₂ < 50 to 60 despite a high FiO₂ (0.6 to 0.7) (often while on CPAP of upto 8)

Conventional ventilation

The initial strategy is to start with rapid rates 60/min, moderate PEEP (4–5 cm H₂O), low PIP (10–20 cm H₂O), Ti 0.3 to 0.4 and tidal volumes of 4–6 ml/kg. Rapid ventilator rates and short Ti are recommended because of the low pulmonary compliance and short time constant in neonatal RDS. These are associated with a lower incidence of air leaks. Rates rather than PIP should be increased for the target PaCO₂. Likewise, if hypocapneic, PIP rather than ventilator rate should be reduced first to decrease minute ventilation. Following surfactant administration, oxygenation improves rapidly because of an increase in functional residual capacity and is followed by a slower improvement in compliance. Appropriate and timely changes in ventilatory support is mandatory following surfactant administration. The changes in compliance can be visualized on the pulmonary graphics.

Although mechanical ventilation is lifesaving in infants with RDS, it may contribute to lung injury and subsequently to BPD. Permissive hypercapnia, permissive hypoxemia, minimal peak pressures, rapid rates, early therapeutic CPAP, and rapid extubation may help reduce ventilation induced lung injury (VILI) and possibly reduce BPD³⁹.

Oxygenation

Hyperoxia is a risk factor for BPD. The target PaO₂ is 50–70 mm Hg. Large trials evaluating the effect of oxygen on retinopathy failed to show any ophthalmologic effect, but liberal oxygen was associated with a higher incidence of oxygen dependency⁴⁰. The target SaO₂ is <93% and should not exceed 95%.

Permissive hypercapnia

Mild permissive hypercapnia where the target PaCO₂ is 45–55 mm Hg is safe and reduces the duration of ventilation⁴¹. However, PaCO₂ > 60 is a concern for its potential risk of altered cerebral blood flow and intra ventricular hemorrhage. Moreover, permissive hypercapnia has not been consistently shown to reduce BPD⁴².

Newer modes of ventilationPatient triggered ventilation

The technologic advancement of ventilators has provided a variety of new modalities, such as patient-triggered ventilation (PTV-assist control and synchronized intermittent mechanical ventilation) pressure support ventilation (PSV), and volumeguaranteed ventilation. Several RCTs have shown encouraging short-term benefits, such as fewer days on mechanical ventilation and less need for sedation. However, there is no evidence of any long term benefit in terms of survival or reduction in BPD⁴³.

PSV, one of the newest ventilatory modes, provides an inspiratory pressure boost during spontaneous breathing to overcome the imposed work of breathing. PSV achieves both inspiratory and expiratory synchrony. Currently, preliminary application of PSV to the neonatal population shows great promise. Applications include weaning in conjunction with SIMV, ventilator management of infants who have BPD and even as a primary management for RDS⁴⁴.

Volume ventilation

The debate of whether pressure or volume is a better target variable is ongoing⁴⁵. A meta-analysis of 4 studies has documented shorter duration of ventilation, reduction in air leaks and intraventricular hemorrhage with volume ventilation. However, no beneficial effect was seen on BPD or mortality. But this debate has made clinicians conscious of volumes and even in pressure modes, volume limit and volume guarantee are options on the newer ventilators which can limit volutrauma.

High frequency ventilation

High-frequency ventilation (HFV), a form of mechanical ventilation that uses small tidal volumes and extremely rapid ventilator rates, was received with great enthusiasm by neonatologists as a potential intervention to reduce BPD. However, after 20 years of data collection, this does not appear to be the case. Meta-analysis of 10 studies has shown no evidence for the elective use of HFV as the initial mode of ventilation to treat premature infants with RDS⁴⁶. The data are limited and the results are mixed as to whether high frequency jet ventilation (HFJV) may reduce the incidence of BPD⁴⁷. HFV as a rescue mode for severe pulmonary dysfunction in preterms requires more evaluation as the 2 previous studies were done in an era of limited surfactant and antenatal steroids use. However, the current literature does support the preferential use of HFV over CMV in conjunction with inhaled nitric oxide (iNO) to maximize oxygenation in hypoxemic respiratory failure. Concerns regarding central nervous system complications is still not totally resolved.

In summary, all types of mechanical ventilation are potentially injurious to the lung. A strategy for minimizing lung injury is to optimize lung volume whilst avoiding excessive tidal volumes and atelectasis. Strategy and technique are more important than mode of ventilation and the method that is most successful in one's own unit should be employed. All modes of ventilation can induce lung injury and should be limited to the shortest possible duration provided there is a reasonable chance of successful extubation.

Pharmacotherapy – beyond surfactantNitric oxide

Inhaled nitric oxide (iNO)– a selective pulmonary vasodilator improves oxygenation in preterm infants with severe RDS. The reason behind use of iNO in RDS, is that many infants have echocardiographic evidence of pulmonary hypertension. Nitric oxide may be a signaling molecule in parenchymal lung growth and animal studies have indicated that it may reduce lung injury and chronic lung disease⁴⁸. Several small trials have now evaluated acute responses to iNO in preterm infants and demonstrated significant improvement in oxygenation, but no differences in mortality. It's use in conjunction with CPAP too has been found to be beneficial⁴⁹. However, little is known about the potential adverse effects of iNO in preterm neonates. Several RCTs are currently underway.

Various other medications such as diuretics, postnatal thyroid hormone supplementation and antithrombin have not been found to be of any benefit. Certain other drugs, such as intravenous or inhaled ambroxol, require further evaluation.

Supportive therapy

Prevention and appropriate management of patent ductus arteriosus, fluid and electrolyte balance, appropriate antibiotics when needed are fundamental during management of RDS. Providing early and adequate calories, proteins and lipids is an important and integral part of management as this improves survival. Minimal enteral feeding should be started in stable babies with RDS as this will shorten duration of hospitalization. Early institution of intramuscular Vit A regimen has been found to be beneficial⁵⁸.

Outcome

A meta-analysis of 13 RCTs to review neuro-developmental outcome at 1 and 2 years of age following neonatal surfactant therapy has documented improved survival without an increase in subsequent morbidity at 1 and 2 years of age. Surfactant therapy was associated with a lower rate of mild disability at 1 year⁵⁰. In developing countries, despite facilities for respiratory care of newborn infants, RDS mortality rate and percentage of complications still remain high in comparison to the developed countries. The survival in RDS has varied from 25 to 84% in different centers in India. RDS contributes to 13.5% of neonatal mortality² in India. High initial FiO₂ >0.6, gestational age <34 weeks, birth weight <1500 g, air leak syndromes have been associated with higher mortality among babies ventilated for RDS. With more frequent use of surfactant and ventilation, chronic lung disease is also an emerging problem.

Future directions

Further development of synthetic surfactants to enhance their surface tension-lowering properties and capacity to withstand inactivation may increase future efficacy of surfactant therapy. This could further reduce the cost and make it affordable in India. Progress in surfactant administration, non invasive ventilation, strategies to minimize the potential lung damage by mechanical ventilation is awaited.

Conclusions

As highlighted in this review, substantial progress has been made in recent years in the management of RDS. The administration of antenatal steroids should be reiterated as even incomplete courses are beneficial. More than 25 years after the introduction of exogenous surfactant therapy, research around surfactant is still evolving. Surfactant remains a hallmark in the treatment of RDS, Efforts should be made to investigate the roles of NIV and alternative administration routes for surfactant in the treatment of preterm infants. Strategy of ventilation is more important than the mode used. Mechanical ventilation should be limited to the shortest duration possible.

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