INTRODUCTION — Respiratory distress syndrome (RDS), formerly known as hyaline membrane disease, is the major cause of respiratory distress in preterm infants.

The prevention, management, and complications of RDS in preterm infants will be reviewed here. The pathophysiology, clinical manifestations, and diagnosis of neonatal RDS are discussed separately. (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn".)

TERMINOLOGY

Prematurity — Different degrees of prematurity are defined by gestational age (GA), which is calculated from the first day of the mother's last period, or birth weight (BW). Data on bronchopulmonary dysplasia (BPD) is often based upon the following classification of preterm infants categorized by BW or GA (table 1).

Neonatal respiratory distress syndrome (RDS) — RDS, formerly known as hyaline membrane disease, is the major cause of respiratory distress in preterm infants. It is caused by deficiency of surfactant, the phospholipid mixture (predominantly desaturated palmitoyl phosphatidyl choline) that reduces alveolar surface tension, which decreases the pressure needed to keep the alveoli inflated and maintain alveolar stability. Infants with RDS are unable generate the inspiratory pressure needed to inflate alveolar units, resulting in the development of progressive and diffuse atelectasis. (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn", section on 'Pathophysiology' and "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn", section on 'Diagnosis'.)

CLINICAL APPROACH — The following sections detail our clinical approach in managing RDS in very preterm (VPT) infants (gestational age [GA] <32 weeks) who are at risk for RDS. Although this approach is based on the available literature, there remain significant gaps in our knowledge on how best to prevent and treat neonatal RDS. As a result, there is variability in the management of RDS in preterm infants among institutions. Our approach is consistent with recommendations from the 2014 American Academy of Pediatrics (AAP) policy statement regarding respiratory support in preterm infants at birth and a consensus approach based on expert opinions from the United Kingdom [1,2].

Goals and overview — RDS is a result of surfactant deficiency, which results in atelectasis, increased ventilation-perfusion mismatch, and potential lung injury due to a marked pulmonary inflammatory response (ie, bronchopulmonary dysplasia [BPD]). Therapeutic goals are:

●Preventive measures – Prevent or reduce the severity of neonatal RDS with the use of antenatal corticosteroid therapy and early administration of positive airway pressure.

●Management of RDS – Despite the use of preventive interventions, RDS still develops in a significant number of infants. Once the diagnosis of RDS has been established based on requiring oxygen supplementation with fraction of inspired oxygen (FiO₂) >0.3 to 0.4, management focuses on delivery of exogenous surfactant and respiratory support required for adequate oxygenation and ventilation while avoiding additional lung injury and complications (BPD).

●Supportive care – Supportive measures to optimize the neonate's metabolic and cardiorespiratory status as the infant transitions from the delivery room to the neonatal intensive care unit (NICU), thereby reducing oxygen consumption and energy expenditures.

Antenatal care — Antenatal corticosteroids (ACS) enhance fetal lung maturity with increased synthesis and release of surfactant, resulting in improved neonatal lung function. The efficacy and use of ACS in preterm infants GA<34 weeks are discussed in greater detail elsewhere. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on '23+0 to 33+6 weeks'.)

Initial management

Positive pressure — In our center, positive pressure is provided to all preterm infants (GA< 32 weeks) who are at risk for RDS to prevent atelectasis (algorithm 1) [1]. The choice of respiratory support is dependent on the infant's initial respiratory effort [1,3].

●For infants with a strong respiratory drive (ie, sustained regular respirations), noninvasive positive pressure is initially provided to prevent and reduce atelectasis. Nasal continuous positive airway pressure (nCPAP) and nasal intermittent positive pressure ventilation (NIPPV) are both reasonable options for noninvasive support. The choice among these is largely based upon cost and availability. While NIPPV may be modestly more effective than nCPAP in preventing intubation and respiratory morbidity, it requires a ventilator for administration, which makes it more costly and complex to use. For these reasons, we preferentially use nCPAP in our center. (See 'Noninvasive positive airway pressure' below.)

●Infants who are apneic or have poor respiratory effort (gasping) and/or a heart rate <100 beats per measure should be resuscitated with bag mask ventilation (BMV). Infants who do not respond to BMV require intubation and initiation of invasive mechanical ventilation. (See "Neonatal resuscitation in the delivery room", section on 'Apnea/gasping and heart rate <100 bpm'.)

Supplemental oxygen — Regardless of the type of respiratory support, supplemental oxygen is provided to maintain a targeted peripheral oxygen saturation (SpO₂) between 90 to 95 percent starting 10 minutes after delivery. However, additional interventions (eg, surfactant) are provided to avoid delivery of high oxygen concentration, which can cause lung injury. (See "Neonatal resuscitation in the delivery room", section on 'Pulse oximetry' and "Neonatal target oxygen levels for preterm infants", section on 'Oxygen target levels' and "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features", section on 'Oxygen toxicity'.)

Surfactant administration — Surfactant therapy is administered to infants who require FiO₂ >0.3 to 0.4 to maintain a saturation oxygen level (SpO₂) above 90 percent despite the use of nCPAP [4,5]. Surfactant has traditionally been instilled through an endotracheal tube after intubation. There is increasing use of less invasive techniques for surfactant administration to avoid the complications associated with endotracheal intubation and intermittent positive pressure ventilation. However, the choice of techniques varies amongst centers and amongst staff members within the same center, including at our institution. It is important for each center to determine the optimal delivery system dependent on clinical experience and availability of various modalities [5]. (See 'Surfactant administration technique' below.)

In our center:

●When endotracheal administration is used, surfactant is administered when FiO₂ ≥0.40 is needed to maintain SpO₂ above 90 percent.

Following surfactant therapy:

•Infants with a strong respiratory drive who maintain target oxygen SpO₂ with an FiO₂ <0.30 and a blood pH >7.25 are extubated and placed on either nCPAP or NIPPV. No additional doses of surfactant are administered.

•Infants who require oxygen supplementation with an FiO₂ ≥0.30 to maintain SpO₂ above 90 percent remain intubated and receive additional doses of surfactant.

●When less invasive measures are used, a lower threshold of FiO₂ ≥ 0.30 is used for surfactant administration. A second dose of surfactant is administered if the threshold FiO₂ remains ≥0.30.

Supportive care — General supportive care is provided to all preterm infants in the delivery room and as they are transitioned to and cared for in the neonatal intensive care unit. The following supportive care measures are focused on optimizing the infant's metabolic and cardiorespiratory status, thereby reducing oxygen consumption and energy expenditure.

●Thermal neutral environment – Infants should be maintained in a thermal neutral environment to minimize heat loss and maintain the core body temperature in a normal range, thereby reducing oxygen consumption and caloric needs. The ambient temperature should be selected to maintain an anterior abdominal skin temperature in the 36.5 to 37°C range. Rectal temperatures should be avoided in infants with RDS because of the greater risk of trauma or perforation associated with their use. As a result, abdominal temperatures are used to set the servo-controlling temperatures in incubators and in radiant warmers. (See "Short-term complications of the preterm infant", section on 'Hypothermia'.)

●Fluid management and avoidance of diuretics – Fluids should be adjusted to maintain a slightly negative water balance, as infants are born in a positive fluid state. Excessive fluid intake should be avoided as it is associated with patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and BPD [6]. (See "Fluid and electrolyte therapy in newborns".)

There is no evidence to support the routine use of diuretics (particularly furosemide) in preterm infants with RDS [7]. Diuretic use should be avoided because it often results in serum electrolyte abnormalities, especially hyponatremia and hypokalemia, due to urinary loss of sodium and potassium. Loop diuretics are also associated with nephrocalcinosis. (See "Fluid and electrolyte therapy in newborns", section on 'Electrolyte disorders' and "Nephrocalcinosis in neonates", section on 'Loop diuretics'.)

●Maintenance of a stable cardiovascular state – Cardiovascular management is focused on ensuring adequate perfusion for all patients. Systemic hypotension occurs commonly in the early stages of RDS. As a result, blood pressure should be frequently monitored noninvasively or continuously via intravascular catheter. However, intervention is not usually required for extremely low birth weight (ELBW) infants (BW <1000 g) with adequate perfusion. In contrast, infants with poor perfusion are in shock and require resuscitation to stabilize their hemodynamic state. (See "Assessment and management of low blood pressure in extremely preterm infants", section on 'Management approach' and "Neonatal shock: Etiology, clinical manifestations, and evaluation".)

●Caffeine – Early administration of caffeine therapy to increase respiratory drive for extremely preterm (EPT) infants (GA <28 weeks) as these patients universally will have apnea of prematurity and are at greatest risk for developing BPD. (See "Management of apnea of prematurity", section on 'Prophylactic use' and "Bronchopulmonary dysplasia: Prevention", section on 'Caffeine'.)

●Nutrition – The administration of early nutrition is important in the overall care of preterm infants. Energy needs must cover both metabolic expenditure (eg, resting metabolic rate and thermoregulation) and growth. The nutritional needs of preterm infants, especially very preterm (VPT) infants are often dependent upon parenteral nutrition (PN) during early postnatal life. (See "Parenteral nutrition in premature infants" and "Approach to enteral nutrition in the premature infant".)

Subsequent management of RDS — Despite the use of preventive and early intervention measures (antenatal corticosteroids, nCPAP or NIPPV, and surfactant administration), some preterm infants will have persistent respiratory disease, which may progress (manifested by increased work of breathing, increasing oxygen requirement, and classical chest radiographic findings (image 1)). For these patients, ongoing noninvasive respiratory support is directed towards ensuring adequate gas exchange. As previously discussed, nCPAP is the preferred modality for noninvasive respiratory support in our center (see 'Noninvasive positive airway pressure' below and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Choice of respiratory support and oxygen delivery system'). However, in some cases, mechanical ventilation is required when noninvasive support fails to provide adequate gas exchange.

Mechanical ventilation — Infants who have inadequate gas exchange or significant apnea despite efforts to maximize noninvasive support generally require intubation and invasive mechanical ventilation. The approach to mechanical ventilation in preterm neonates, including indications for initiating mechanical ventilation, is summarized in the table (table 2) and discussed in detail separately. (See "Approach to mechanical ventilation in very preterm neonates".)

SPECIFIC INTERVENTIONS

Noninvasive positive airway pressure — Noninvasive positive airway pressure, which prevents and reduces atelectasis, should be administered to all preterm infants with a gestational age (GA) <32 weeks who are at risk for RDS [1,8-14]. In our center, nasal continuous positive airway pressure (nCPAP) is the preferred device to provide positive airway pressure. Although data suggests NIPPV provides modest benefit over nCPAP as primary respiratory support, its widespread use is limited by cost concerns and availability due to NIPPV's requirement for a ventilator.

Nasal continuous positive airway pressure (nCPAP) — In preterm infants at risk for or with established RDS without respiratory failure, nCPAP is our preferred method to provide noninvasive positive pressure airway. This approach is consistent with the recommendations from the American Academy of Pediatrics (AAP), American Heart Association (AHA), International Liaison Committee on Resuscitation (ILOR) guidelines, and the European Consensus Guidelines [1,3,15,16]. (See 'Clinical approach' above and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Continuous positive airway pressure'.)

●CPAP versus invasive mechanical ventilation – Our preference for nCPAP over invasive mechanical ventilation as the initial modality for respiratory support in preterm neonates is supported by clinical trials and meta-analyses that have demonstrated reduced risk of bronchopulmonary dysplasia (BPD) and perhaps lower mortality with CPAP as compared with intubation and invasive mechanical ventilation (with or without surfactant administration) [13,14,17]. In a meta-analysis of three trials (2150 very preterm [VPT] neonates [GA <32 weeks]), prophylactic CPAP reduced the incidence of BPD at 36 weeks (relative risk [RR] 0.89, 95% CI 0.79-0.99) and there was a nonsignificant trend towards lower mortality in the CPAP group (RR 0.82, 95% CI 0.66-1.03) [17].

Follow-up studies at 18 to 22 months corrected age showed the group assigned to nCPAP compared with those assigned to intubation and surfactant had less respiratory morbidity and the groups had similar rates of death or neurodevelopmental impairment [18-20]. However, despite the use of CPAP, extremely preterm (gestational age <28 weeks) survivors remain at risk for impaired pulmonary function at eight years of age [21].

●CPAP versus supportive care – In infants with RDS, CPAP reduces mortality and the combined outcome of death or mechanical ventilation compared with supportive care with only supplemental oxygen. In a meta-analysis of five trials (322 neonates with RDS), CPAP reduced mortality and the use of assisted ventilation (typical RR 0.64, 95% CI 0.50-0.82) compared with spontaneous breathing with supplemental oxygen as necessary [12]. There was also a lower risk of mortality with CPAP (RR 0.53, 95% CI 0.34-0.83). The groups had similar risk for BPD (RR 1.04, 95% CI 0.35-3.13). Three out of the five trials were performed in the 1970s and the applicability to current practice is uncertain.

The benefit of prophylactic (early) use of CPAP surfactant administration versus supportive care appears to be more modest. In a meta-analysis of three trials (683 neonates), prophylactic CPAP reduced the need for surfactant compared with initial supportive care (RR 0.75, 95% CI 0.58-0.96) [17]. The incidence of BPD at 36 weeks was also lower in the CPAP group, but the finding was not statistically significant (RR 0.79, 95% CI 0.5-1.24). Mortality was similar in both groups (RR 1.04, 95% CI 0.6-1.9).

●CPAP following extubation – In our center, nCPAP is also used as respiratory support for infants with RDS who require intubation and are then extubated, as it reduces the incidence of adverse clinical events (apnea, respiratory acidosis, and increased oxygen requirements) and the need for reintubation.

Descriptions of nCPAP and other delivery system for infants with early RDS and postextubation are discussed separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Respiratory support and oxygen use post-delivery devices'.)

Nasal intermittent positive pressure ventilation — NIPPV is a delivery mode of positive pressure ventilation that augments nCPAP by delivering ventilator breaths via nasal prongs (or nasal mask). The available clinical trial data suggest that early use of NIPPV provides modest benefits compared with nCPAP as initial noninvasive respiratory support for preterm infants with RDS as well as postextubation. However, the trials were performed at centers experienced in using NIPPV and the findings may not be generalizable to other centers. In addition, because NIPPV requires a ventilator for administration, it is more costly and complex to use. For these reasons, many centers, including our own, preferentially use nCPAP.

●Primary respiratory support – NIPPV reduces the need for intubation compared with CPAP as illustrated by the following:

•In a meta-analysis of nine trials (950 neonates), NIPPV reduced the need for intubation compared with CPAP (24 versus 30 percent; relative risk [RR] 0.78, 95% CI 0.64-0.94) [22]. However, there was no statistical difference in outcomes between NIPPV and CPAP for mortality (6.3 versus 8.2; RR 0.77, 95% CI 0.51-1.17) and BPD (13 versus 17 percent; RR 0.78, 95% CI 0.58 to 1.06).

•A network meta-analysis that included 35 studies with 4078 infants reported NIPPV was the most effective primary respiratory support for infants with RDS as it was associated with the lowest risk of mechanical ventilation compared with CPAP and high-flow nasal cannulae [23].

●Postextubation respiratory support ‒ NIPPV compared with nCPAP has been reported to reduce extubation failure in preterm infants who required intubation and ventilation [24-29]. In a meta-analysis of 10 trials (1431 infants), infants assigned to NIPPV were less likely to fail extubation or need reintubation compared with those assigned to CPAP (RR 0.70, 95% CI 0.60-0.80) [29]. There was no difference between the two groups in regard to mortality or the risk of developing BPD or necrotizing enterocolitis (NEC). In addition, there was heterogeneity among the studies regarding the NIPPV device that was used and whether the delivery of NIPPV was synchronized or nonsynchronized.

A description of NIPPV is presented separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Nasal intermittent positive pressure ventilation'.)

High-flow nasal cannulae — Available data suggest high-flow nasal cannulae HFNC is not more beneficial as the primary therapy for neonatal RDS compared with nCPAP [30,31]. In addition, the delivered concentration of oxygen and pressure to the infant is highly variable with HFNC and difficult to monitor. As a result, we do not use HFNC as an initial measure to prevent or treat neonatal RDS. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'High-flow'.)

●Primary respiratory support – Two multicenter trials compared HFNC to nCPAP as primary respiratory support for preterm infants with the primary outcome of treatment failure within 72 hours of randomization defined as an infant receiving maximal support for either HFNC (gas flow at 8 L/min) or nCPAP (pressure of 8 cm Hg) and with one or more of the following criteria: intubation and mechanical ventilation, receiving fraction of inspired oxygen (FiO₂) ≥0.4, venous or arterial blood gas sample with a pH ≤7.2, or partial pressure of carbon dioxide (PaCO₂) >60 mmHg, and apnea episodes requiring positive pressure ventilation.

•In a multicenter trial of 564 preterm infants (GA >28 weeks) cared for in NICUs (level 3 neonatal care), patients with early respiratory distress randomly assigned to HFNC compared with those assigned to nCPAP for primary respiratory support had a higher treatment failure rate (25.5 versus 13.3 percent; risk difference [RD] 12.3 percent, 95% CI 5.8-18.7) [30]. However, the rate of intubation did not differ (15.5 and 11.5 percent; risk difference 3.9 percent, 95% CI -1.7 to 9.6), nor did the rate of adverse events. This trial was terminated early (564 patients recruited for a predetermined sample size of 750) when an interim predesignated analysis at 500-patient enrollment demonstrated a higher treatment failure rate for HFNC.

•In a multicenter trial of 754 preterm infants (GA ≥31 weeks) cared for in nontertiary special care nurseries (level 2 neonatal care), patients assigned to HFNC compared with those assigned to nCPAP for primary respiratory support had a higher treatment failure rate (20.5 versus 10.2 percent, RD 10.3 percent, 95% CI 5.2-15.4) [32]. However, the incidences of mechanical ventilation, transfer to a tertiary neonatal intensive care unit, and adverse events were similar between the groups.

●Postextubation – Data are inconsistent on whether HFNC is superior to nCPAP for respiratory support following extubation for preterm infants:

•In a meta-analysis of four studies (439 infant), preterm infants assigned to HFNC and nCPAP following extubation had similar rates of death, treatment failure, or reintubation [33]. Infants randomized to HFNC had less nasal trauma.

•Subsequent reports suggest HFNC was inferior to nCPAP postextubation:

-A multicenter clinical trial of preterm infants (GA <34 weeks) who received noninvasive ventilation following extubation reported a higher rate of treatment failure for the 176 infants assigned to HFNC versus 196 infants assigned to nCPAP or NIPPV (31 versus 16 percent, RD 14.9 percent, 95% CI 6.2-23.2) [34]. In this trial, treatment failure was defined as change to another respiratory mode of therapy within seven days of extubation based on FiO₂ ≥0.4, sustained pH <7.2, and pCO₂ >60 mmHg, and/or continued apnea for six hours requiring stimulation.

-A crossover study of 30 preterm infants (median GA of 27 weeks) undergoing their first extubation attempt reported longer respiratory pauses and need for higher FiO₂ when infants were placed on HFNC compared with when they were treated with nCPAP [35].

Surfactant therapy

Efficacy — Exogenous surfactant replacement therapy is effective in reducing RDS mortality and morbidity in preterm infants especially for extremely preterm infants (<28 weeks GA), who are at the greatest risk for RDS [36-41]. In clinical trials, surfactant therapy compared with placebo was associated with a lower incidence and severity of RDS and mortality and with a decreased rate of associated complications including BPD, pulmonary interstitial emphysema, and other pulmonary leak complications, such as pneumothorax [38,40-42]. In a meta-analysis of 10 trials (1469 neonates), treatment with natural surfactants reduced all-cause mortality compared with placebo or other control (19 versus 28 percent; RR 0.68, 95% CI 0.57-0.82) [43].

However, in a subsequent multicenter trial of 485 extremely preterm infants (GA ≤28 weeks) who were supported by CPAP and an FiO₂ 2 of ≥0.30 within six hours of birth, the primary outcome of death or BPD was not statistically different between the intervention (who received surfactant [poractant alfa] via a thin catheter [minimally invasive surfactant therapy; MIST]) and control groups (sham procedure without surfactant administration), but there was a trend favoring improved outcome in the surfactant group (43.6 versus 49.6 percent, RR 0.87, 95% CI 0.74-1.03) [44]. In analyses separating the two outcomes, the rate of death was similar (10 versus 7.8 percent, RR 1.27, 95% CI 0.63-2.57), but the risk of BPD was lower in the surfactant group (37.3 versus 45 percent, RR 0.83, 95% CI 0.7-0.98). MIST versus CPAP alone was also associated with better secondary outcomes including lower risk of need for intubation within 72 hours, shorter duration of mechanical ventilation and CPAP, and the lower risk of pneumothorax. Although the primary outcome was similar between the intervention and control groups, this may be due to limitation of sample size as the trial was closed early before the target enrollment goal of 606 patients was reached. The limitation of sample size may also have masked an effect on the separate components, especially mortality, which is much less prevalent than BPD.

When surfactant therapy is used, the following issues must be addressed [5]:

●Selection of surfactant preparation

●Indications for surfactant therapy

●Mode and timing of administration

Types of surfactant — Surfactant preparations include natural and synthetic surfactants. Although both types of surfactant preparations are effective, natural surfactants have been shown to be superior in clinical trials to synthetic preparations that did not contain protein B and C analogues [8,45,46]. In particular, the use of natural preparations was associated with lower inspired oxygen concentration and ventilator pressures, decreased mortality, and lower rate of RDS complications in preterm infants.

Natural surfactants derived from either bovine or porcine lungs are commercially available in the United States and Canada and the choice of surfactant is based on availability and institutional preference (table 3).

●Poractant alfa – Porcine lung minced extract

●Calfactant – Bovine lung lavage extract

●Beractant – Bovine lung minced extract

●Bovine lipid extract surfactant (BLES) – Bovine lung lavage extract

Natural surfactants are obtained by either animal lung lavage or by mincing animal lung tissue, and subsequently purified by lipid extraction that removes hydrophilic components, including hydrophilic surfactant proteins A and D. The purified lipid preparation retains surfactant proteins B and C, neutral lipids, and surface active phospholipids (PL) such as dipalmitoylphosphatidylcholine (DPPC). DPPC is the primary surface-active component that lowers alveolar surface tension.

The following data compare the effectiveness amongst the three natural preparations. In clinical practice, the choice of surfactant is based on availability and institutional preference.

●In a large observational study of 51,282 infants, similar outcomes were reported for three surfactant preparations (beractant, calfactant, and poractant alfa) for mortality and the risk of air leaks or BPD [47].

●In a meta-analysis that included 16 trials, direct comparisons were made between various surfactant preparations [48]. Similar outcomes of mortality and BPD were observed between bovine lung lavage and bovine minced lung surfactant extracts either in prophylactic trials (RR 1.02, 95% CI 0.89-1.17) or treatment trials (RR 0.95, 95% CI 0.86-1.06) [48]. Mortality prior to hospital discharge was higher in the bovine minced versus porcine minced lung surfactant extract groups (RR 1.44, 95% CI 1.04-2.00) and a lower risk of death or oxygen requirement at 36 weeks' postmenstrual age was also noted (RR 1.57, 95% CI 1.29-1.92). However, the benefit derived from the porcine preparation was only observed when given in a higher initial dose, and it was uncertain whether the observed benefit was due to the difference in the dose or source of extraction. Results were similar between bovine lung lavage compared with porcine minced lung surfactant (RR 1.4, 95% CI 0.51-3.87). There were no studies comparing bovine lung lavage to porcine lung lavage surfactant or porcine minced lung to porcine lung lavage surfactant.

●In contrast, another meta-analysis reported porcine and bovine minced surfactant extracts had similar rates of mortality (odds ratio [OR] 1.35 95% CI 0.98-1.86), BPD (OR 1.25, 95% CI 0.96-1.62), pneumothorax (OR 1.21, 95% CI 0.72-2.05), and air leak syndrome (OR 2.28, 95% CI 0.82-6.39) [49].

Although, the US Food and Drug Administration (FDA) approved the first synthetic peptide-containing surfactant (lucinactant) [50,51], it is no longer commercially available as the manufacturer has voluntarily discontinued production.

Indications — Our approach, which is consistent with the 2014 American Academy of Pediatrics (AAP), the European Consensus Guidelines (ECG) recommendations, and the Canadian Paediatric Society, is to administer surfactant to those with persistent respiratory distress (defined as requiring a fraction of inspired oxygen [FiO₂] >0.3 to 0.4 to maintain oxygen saturation above 90 percent) after a trial of positive airway pressure (algorithm 1) [1,5,8,15].

In a meta-analysis of six trials of early surfactant administered via endotracheal tube, a stratified analysis found that a lower threshold for FiO₂ <0.45 was associated with lower risk of BPD (RR 0.43, 95% CI 0.20-0.92) and air leak (RR 0.46, 95% CI 0.23-0.93) [52].

Additional doses of surfactant therapy are administered if the patient has a persistent requirement of an FiO₂ above a predetermined threshold, which varies based on the route of surfactant administration (see 'Surfactant administration technique' below). In the available clinical trials, repeated surfactant administration compared with a single dose decreased mortality and morbidity in infants <30 weeks gestation with RDS [36,53].

Timing — If surfactant therapy is used, it is most effective when given within the first two hours of life [5,36,54,55]. In a systematic review, late surfactant administration (2 hours after birth) was associated with increased risk lung injury, and a trend to increased risk of BPD and death [55]. However, the potential benefits of timely administration of surfactant must be balanced with adequate time for an initial trial of nCPAP.

Surfactant administration technique — The standard technique of surfactant administration has been endotracheal administration. Other less invasive measures have been introduced to reduce the complications associated with endotracheal administration and their use has expanded widely, especially in Europe. However, there remains variability on the techniques used for surfactant administration between centers, and between clinicians in a single center. Each center needs to determine how best to optimize delivery of surfactant based on the experience of the clinical staff and the availability of different delivery methods [5].

●Endotracheal administration – Endotracheal intubation has been the standard technique of surfactant administration. After intubation, surfactant is instilled through an end-hole catheter cut to a standard length of 8 cm or through a secondary lumen of a dual-lumen endotracheal tube. During administration, oxygen saturation needs to be monitored, as oxygen desaturation may occur. Following instillation, positive pressure ventilation is provided. Surfactant administration may be complicated by transient airway obstruction [8,56], inadvertent instillation into only one (typically right) main stem bronchus if the endotracheal tube is advanced too far in the airway, and other complications associated with intubation and mechanical ventilation (pulmonary injury, pulmonary air leak, and airway injury due to intubation. (See 'Endotracheal tube complications' below.)

●Less invasive measures – Due to the complications from the delivery of surfactant by intubation, minimal or less invasive administrative techniques have been developed and appear promising. These interventions include aerosolized/nebulized surfactant preparations, laryngeal mask airway-aided delivery of surfactant, pharyngeal instillation, and the use of thin intratracheal catheters [57-67].

There is a wide variation in MISTs used and patient selection [68-70]; however, the use of thin intratracheal catheter has been adopted by many centers including ours as it appears to be effective in delivering surfactant endotracheally without the complications associated with standard intubation.

•Thin intratracheal catheter administration – Systematic reviews of the literature of clinical trials reported that the use of thin catheter compared with the standard endotracheal intubation administration was associated with a lower rate of the composite outcome of death and BPD at 36 weeks, risk of BPD among survivors, need for mechanical ventilation within 72 hours of birth, or mechanical ventilation during the hospital stay [71-73].

-In a 2021 systematic review, delivery of surfactant through using thin catheter administration compared with standard intubation was associated with a lower risk of death and BPD at 36 weeks PMA (16 versus 26 percent, RR 0.59, 95% 0.48-0.73) based on 10 trials with 1324 neonates; intubation within the first 72 hours (23 versus 36 percent, RR 0.63, 95% CI 0.54-0.74) based on 12 trials with 1422 neonates [73].

-A second 2021 systematic review, which included many of the same clinical trials as the first meta-analysis, reported a trend for improved mortality using the thin catheter versus standard endotracheal administration (9.1 versus 12.1 percent, RR 0.75, 95% CI 0.56-1.00) based on 11 trials with 1478 neonates; and decreased rate of BPD (9.7 versus 16.4 percent, RR 0.5, 95% CI 0.46-0.75) based on 12 trials with 1831 neonates [74].

However, these results were limited by significant concerns for potential bias due to inadequate blinding, randomization, and allocation concealment leading to a downgrade of the quality of evidence.

Of note, one large multicenter trial did not show a benefit of surfactant therapy administered by thin catheter compared with sham procedure without surfactant administration as discussed above [44]. (See 'Efficacy' above.)

•Supraglottic administration – To avoid direct laryngoscopy, supraglottic airway strategies are being used to deliver surfactant including the use of laryngeal mask airway and aerosolized surfactant delivered through a nebulizer [67,75,76].

In a 2021 systematic review, a meta-analysis of 999 infants reported delivery of surfactant through nebulization with standard intubation reduced intubation rates 72 hours after birth (40 versus 53.2 percent, RR 0.73, 95% CI 0.63-0.84) [77]. However, this finding is limited by potential bias due to concerns of randomization, early termination, protocol deviations, and measuring and missing outcome data.

Although results are encouraging that less invasive administration of surfactant particularly the use of a thin catheter is a reasonable option, the quality of evidence remains moderate to low based on serious risk of bias (lack of adequate blinding, randomization, allocation concealment, and heterogeneity amongst studies) [73,78,79]. In addition, there is variation amongst practicing centers in techniques and patient selection [68-70]. Nevertheless, these data demonstrate that surfactant can be administered in a less invasive manner compared with standard endotracheal administration. However, it would be helpful if future research provides standardization of delivery. In addition, prior to routine adaption of a specific technique, each center needs to adequately train health care personnel to ensure adequate delivery of surfactant.

Inconclusive/ineffective therapies

Surfactant in combination with budesonide — Because of insufficient and inconsistent evidence, the combination of surfactant and budesonide cannot be recommended until there are more definitive data that show benefit that outweighs any adverse effect of the intervention.

●A 2017 systematic review that included two trials of very low birth weight (BW <1500 g) preterm infants with severe RDS requiring mechanical ventilation suggested that the combination of surfactant and budesonide (corticosteroid) reduced the incidence of BPD and the composite outcome of death and BPD [80]. There was no difference in mortality. However, there were several limitations including small number of patients and concern for bias as the studies were performed by the same group and there was incomplete blindness.

●In a small dose-escalation study of intubated extremely preterm infants (gestational age <28 weeks), the combination of budesonide and surfactant had no beneficial respiratory benefit at any dosing levels [81].

Inhaled nitric oxide — Data from clinical trials show that the use of inhaled nitric oxide (iNO) either as rescue or routine therapy is not beneficial in preterm infants with RDS in reducing mortality or the risk of BPD. As a result, we concur with the 2014 AAP clinical report and the ECG guidelines that iNO should not be used to treat preterm infants with RDS except in rare cases of pulmonary hypertension or hypoplasia [15,82].

An analysis from a retrospective study from the multicenter Pediatrix Medical Group of mechanically ventilated preterm infants born at 22 to 29 weeks gestation found no difference in mortality between patients who received iNO and those who did not [83]. In this cohort, iNO was associated with higher mortality among patients with RDS without a diagnosis of persistent pulmonary hypertension of the newborn (PPHN) after adjusting for confounding factors. In addition, iNO was not effective in a subanalysis of infants diagnosed with persistent pulmonary hypertension. As a result, we do not recommend iNO administration for extremely preterm infants (GA ≤28 weeks) with RDS. (See "Persistent pulmonary hypertension of the newborn".)

Evidence that iNO does not prevent BPD is discussed in greater detail separately. (See "Bronchopulmonary dysplasia: Prevention", section on 'Inhaled nitric oxide'.)

COMPLICATIONS — Therapy with exogenous surfactant and antenatal corticosteroids has lowered the mortality and morbidity associated with RDS [36-39]. Nevertheless, complications and deaths still persist. Some complications may occur as a consequence of therapeutic interventions including placement of arterial catheters, supplemental oxygen, positive pressure ventilation, and the use of endotracheal tubes.

Endotracheal tube complications — Adverse outcomes are common during neonatal endotracheal intubations [84]. Displacement or misplacement of the endotracheal tubes may occur. Endotracheal tube placement into a main stem (typically right-sided) bronchus is the most common complication, resulting in hyperinflation of the ventilated lung and atelectasis of the contralateral lung. The hyperinflation may contribute to air leak. (See "Pulmonary air leak in the newborn" and 'Pulmonary air leak' below.)

Other complications from intubation include subglottic stenosis [85]. Esophageal and pharyngeal perforations rarely occur and may be confined to the mediastinum or extend into the pleural cavity. (See "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia", section on 'Glottic and subglottic damage'.)

Pulmonary air leak — Pulmonary air leak is a complication of RDS that most commonly affects low birth weight infants (birth weight <1500 g). Air leaks are due to the rupture of an overdistended alveolus and may occur spontaneously or arise from positive pressure ventilation.

The clinical features, diagnosis, and management of each of these pulmonary air leak disorders are discussed elsewhere in the program. (See "Pulmonary air leak in the newborn".)

Bronchopulmonary dysplasia — Bronchopulmonary dysplasia (BPD) is the main chronic complication of RDS. Despite improvements in the management of RDS, the incidence of BPD is still substantial. The etiology of BPD is multifactorial. Inflammation, caused by volutrauma, barotrauma, oxygen toxicity, or infection, plays an important role in its development. This is compounded by the premature lung's structural and functional immaturity, including poorly developed airway support structures, surfactant deficiency, decreased compliance, underdeveloped antioxidant mechanisms, and inadequate fluid clearance.

The pathogenesis, clinical features, prevention, and management of bronchopulmonary dysplasia are discussed elsewhere. (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features" and "Bronchopulmonary dysplasia: Prevention" and "Bronchopulmonary dysplasia: Management".)

SUMMARY AND RECOMMENDATIONS

●Introduction and definition – Respiratory distress syndrome (RDS) is the major cause of respiratory distress in very preterm infants. It is a result of surfactant deficiency, which results in atelectasis, increased ventilation-perfusion mismatch, and potential lung injury due to a marked pulmonary inflammatory response. (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn", section on 'Pathophysiology'.)

●Antenatal corticosteroids – Pregnant women below 34 weeks gestation who are at high risk for preterm delivery should receive antenatal corticosteroids, as discussed in detail separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

●Initial respiratory support – The choice of initial respiratory support is dependent on the infant's respiratory effort (algorithm 1):

•Strong respiratory drive – For preterm infants <32 weeks gestational age (GA) with a strong respiratory drive, we recommend noninvasive positive airway pressure rather than intubation and invasive ventilation (Grade 1B). We also recommend noninvasive positive pressure rather than supportive care alone initially (Grade 1C). (See 'Positive pressure' above and 'Noninvasive positive airway pressure' above.)

We suggest either nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) rather than high-flow nasal cannula for initial noninvasive support (Grade 2C). The choice between nCPAP and NIPPV is largely based upon cost and availability. While NIPPV may be modestly more effective than nCPAP in preventing intubation and respiratory morbidity, it requires a ventilator for administration, which makes it more costly and complex to use. For these reasons, many centers, including our own, use nCPAP. (See 'Nasal continuous positive airway pressure (nCPAP)' above and 'Nasal intermittent positive pressure ventilation' above.)

•Apneic or poor respiratory effort – Infants who are apneic or have poor respiratory effort with a heart rate <100 beats per minute require resuscitation with bag mask ventilation (BMV) as discussed separately. Infants who do not respond to BMV require intubation and initiation of invasive ventilation. (See "Neonatal resuscitation in the delivery room", section on 'Apnea/gasping and heart rate <100 bpm'.)

●Surfactant – For neonates with an inadequate response to noninvasive respiratory support, we recommend surfactant rather than supportive interventions without surfactant (Grade 1B). We consider the response to noninvasive support inadequate if the neonate requires FiO₂ >0.3 to 0.4 to achieve target oxygen saturation >90 percent while receiving CPAP or NIPPV. (See 'Surfactant administration' above and 'Surfactant therapy' above.)

Natural surfactant preparations are commercially available (table 3) and the choice of surfactant is based on availability and institutional preference. (See 'Surfactant administration' above.)

●Supportive care – Supportive care is provided to optimize the neonate's metabolic and cardiorespiratory status, which reduce oxygen consumption and energy expenditures. This includes (see 'Supportive care' above):

•Maintenance of thermal neutral environment

•Optimal fluid balance with avoidance of fluid overload and diuretic therapy

•Maintenance of adequate perfusion

•Caffeine administration

•Early nutrition

●Subsequent management – Despite initial interventions and supportive care measures, subsequent therapy is needed for infants with persistent and sometimes progressive disease. (See 'Subsequent management of RDS' above.)

•For infants with strong respiratory drive adequately supported by noninvasive respiratory measures based on target gas exchange levels, support is gradually weaned if the neonate is able to maintain adequate oxygen saturation (ie, 90 to 95 percent). Target oxygen levels for preterm infants are discussed in detail separately. (See "Neonatal target oxygen levels for preterm infants".)

•Infants who have inadequate gas exchange or significant apnea despite efforts to maximize noninvasive support generally require intubation and invasive mechanical ventilation (MV). The approach to MV in preterm neonates is summarized in the table (table 2) and is discussed in detail separately.(See "Approach to mechanical ventilation in very preterm neonates".)

●Complications – Complications associated with RDS may arise because of disease severity or they may occur as a consequence of therapeutic interventions (eg, placement of arterial catheters and endotracheal tubes and use of supplemental and positive pressure ventilation. The most common complications include endotracheal tube complications (eg, misplaced endotracheal tube and subglottic stenosis), pulmonary air leak, and BPD. (See 'Complications' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen E Welty, MD, and Firas Saker, MD, FAAP, who contributed to an earlier version of this topic review.