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Respiratory distress syndrome (RDS) in preterm infants: Management

Respiratory distress syndrome (RDS) in preterm infants: Management
Literature review current through: Jan 2024.
This topic last updated: Nov 02, 2023.

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

The 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 "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis".)

The use of antenatal corticosteroid therapy for prevention of neonatal RDS is also discussed separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

TERMINOLOGY

Prematurity — Different degrees of prematurity are classifies by gestational age (GA), which is calculated from the first day of the mother's last period, or birth weight (BW), as summarized in the table (table 1).

Respiratory distress syndrome (RDS) — RDS, formerly known as hyaline membrane disease, is the major cause of respiratory distress in preterm infants. It is diagnosed clinically based upon onset of progressive respiratory insufficiency (eg, work of breathing, oxygen requirement) shortly after birth in a preterm infant, in conjunction with a characteristic chest radiograph (image 1). (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis", section on 'Diagnosis'.)

RDS is caused by deficiency of surfactant, the phospholipid mixture (predominantly desaturated palmitoyl phosphatidyl choline) that reduces alveolar surface tension. Inadequate surfactant activity results in high surface tension leading to instability of the lungs at end-expiration, low lung volume, and poor compliance. Infants with RDS are unable generate the inspiratory pressure needed to inflate alveolar units, resulting in the development of progressive and diffuse atelectasis. (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis", section on 'Pathophysiology'.)

CLINICAL APPROACH — The following sections detail our approach to the initial respiratory management of very preterm (VPT) infants (gestational age [GA] <32 weeks) who are at risk for RDS. Management and prevention of RDS includes:

Antenatal corticosteroids to reduce the risk of neonatal RDS and bronchopulmonary dysplasia (BPD). This is discussed separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

Early use of positive airway pressure to reduce the risk of BPD. (See 'Early positive pressure' below.)

Other 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. (See 'Supportive care' below.)

For neonates who require substantial respiratory support (ie, mechanical ventilation or requiring FiO2 [fraction of inspired oxygen] >0.3 to 0.4 on noninvasive support), initial management includes treatment with exogenous surfactant. (See 'Surfactant' below.)

Ongoing respiratory support is titrated to achieve adequate oxygenation and ventilation while minimizing further lung injury and complications such as BPD. (See 'Surfactant therapy' below and 'Subsequent management' below.)

There have been numerous clinical trials evaluating a wide range of interventions for neonates with or at risk for RDS. However, important uncertainties remain and there is variability in the management of RDS from center to center. Our approach described in the sections below is generally consistent with recommendations from the American Academy of Pediatrics (AAP) and other expert panels [1,2]. Links to these and other society guidelines are provided separately. (See 'Society guideline links' below.)

Initial management

Early positive pressure — In our center, we provide early positive pressure in all VPT infants since these neonates are at high risk for RDS (algorithm 1) [1]. The choice of respiratory support depends upon 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 more effective than nCPAP in preventing intubation and subsequent respiratory morbidity, it requires a ventilator for administration, which makes it more costly and complex to use. For these reasons, we preferentially use nCPAP for the initial mode of support in our center and reserve NIPPV for infants who fail nCPAP. (See 'Noninvasive positive airway pressure' below.)

Infants who are apneic or have poor respiratory effort (gasping) and/or a heart rate <100 beats per minute 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' and "Approach to mechanical ventilation in very preterm neonates".)

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. However, additional interventions (eg, surfactant) are provided to avoid the need for high FiO2, which can contribute to lung injury. (See "Neonatal target oxygen levels for preterm infants" and 'Surfactant therapy' below.)

Surfactant — Surfactant is administered to all intubated patients and to those with persistent hypoxemia after a trial of positive airway pressure (ie, those who require FiO2 >0.3 to 0.4 on noninvasive support to maintain SpO2 >90 percent) [4,5]. Traditionally, surfactant has been instilled through an endotracheal tube after intubation. Increasingly, minimally invasive surfactant therapy (MIST) techniques are used for surfactant administration in select patients to avoid the complications associated with endotracheal intubation. However, the choice of technique varies, as discussed below. (See 'Indications' below and 'Techniques for administration' below.)

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 NICU. The following supportive care measures are focused on optimizing the infant's metabolic and cardiorespiratory status.

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 "Overview of short-term complications in preterm infants", section on 'Hypothermia'.)

Maintaining hemodynamic stability – 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. Management of hemodynamic instability and low blood pressure is discussed separately. (See "Neonatal shock: Management" and "Assessment and management of low blood pressure in extremely preterm infants".)

Caffeine – In extremely preterm (EPT) infants (GA <28 weeks), initial management includes early administration of caffeine therapy to increase respiratory drive since these patients universally have apnea of prematurity and are at greatest risk for developing BPD. This is discussed separately. (See "Management of apnea of prematurity", 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. Nutrition support for preterm infants is discussed separately. (See "Parenteral nutrition in premature infants" and "Approach to enteral nutrition in the premature infant".)

Fluid balance – Fluids should be adjusted to maintain a neutral to slightly negative water balance, as infants are born in a positive fluid state. (See 'Fluid management' below and "Fluid and electrolyte therapy in newborns".)

Subsequent management

Ongoing respiratory support — For neonates with strong respiratory drive who have adequate gas exchange on noninvasive support, respiratory support is gradually weaned if the neonate is able to maintain adequate oxygenation (ie, SpO2 between 90 to 95 percent). (See "Neonatal target oxygen levels for preterm infants".)

However, despite the use of early supportive measures (eg, nCPAP, surfactant), some preterm neonates have persistent RDS, which may progress. This is generally manifested by increased work of breathing, increasing oxygen requirement, and classical chest radiographic findings (image 1). Patients with persistent or progressive RDS require ongoing respiratory support, which is titrated as needed to achieve adequate gas exchange.

For neonates with increased work of breathing and/or high oxygen requirement (ie, requiring FiO2 >0.4), nCPAP support can be increased up to 6 to 8 cm H2O. Occasionally, higher pressures may be used (up to 10 or 11 cm H2O). However, in most cases, if the neonate continues to have significant oxygen requirement and/or work of breathing despite optimizing nCPAP, we transition to NIPPV. (See 'Nasal continuous positive airway pressure (nCPAP)' below and 'Nasal intermittent positive pressure ventilation' below.)

Infants who have ongoing significant distress, ineffective breathing, inadequate gas exchange, and/or significant apnea despite optimizing noninvasive support generally require intubation and invasive mechanical ventilation. Indications for intubation and the approach to mechanical ventilation in VPT infants are summarized in the table (table 2) and discussed in detail separately. (See "Approach to mechanical ventilation in very preterm neonates".)

Post-extubation support — In our center, nCPAP is routinely used for respiratory support in infants with RDS who require intubation and are subsequently extubated. nCPAP reduces the risk of adverse clinical events following extubation (eg, apnea, respiratory acidosis, hypoxemia, and need for reintubation) [6]. NIPPV and high-flow nasal cannula (HFNC) are reasonable alternatives. (See 'Nasal continuous positive airway pressure (nCPAP)' below and 'Nasal intermittent positive pressure ventilation' below and 'High-flow nasal cannula' below.)

The efficacy of nCPAP in this setting is supported by randomized controlled trials carried out in the 1990s and early 2000s [6]. In a meta-analysis of eight trials (667 infants), reintubation rates were lower for infants extubated to nCPAP compared with those who were extubated to headbox oxygen (28 versus 47 percent; relative risk [RR] 0.59, 95% CI 0.48-0.72) [6].

Subsequent clinical trials have evaluated nCPAP relative to NIPPV and HFNC [7-15]:

CPAP versus NIPPV – In a meta-analysis of 19 trials (2738 infants), infants assigned to NIPPV less frequently required reintubation compared with those assigned to CPAP (27 versus 36 percent; RR 0.75, 95% CI 0.67-0.84) [12]. Other outcomes (including mortality, incidence of BPD, and necrotizing enterocolitis [NEC]) were similar in both groups. Though these data suggest that NIPPV provides modest benefit over nCPAP, we continue to prefer nCPAP because NIPPV requires a ventilator for administration, and it therefore is more costly and complex to use. We limit use of NIPPV in this setting to infants who fail nCPAP. (See 'Nasal intermittent positive pressure ventilation' below.)

CPAP versus HFNC – In a meta-analysis of four trials (698 infants), reintubation rates were similar in infants assigned to HFNC or nCPAP (16 versus 17 percent; RR 0.94, 95% CI 0.68-1.31) [6]. Mortality was similar in both groups. In a subsequent trial, more patients assigned to HFNC had treatment failure compared with those assigned to CPAP [14]. However, most neonates who failed HFNC were successfully managed with CPAP such that reintubation rates were similar in both arms (6 versus 9 percent, respectively). These data suggest that HFNC and nCPAP have comparable efficacy in this setting. We generally prefer nCPAP because there is greater experience with this modality in preterm neonates.

The optimal pressure level for nCPAP following extubation is uncertain. Findings from a trial of 93 infants suggest that high versus lower distending pressure (7 to 9 cm versus 4 to 6 cm H2O) was associated with a lower extubation failure rate and reintubation [16]. However, it remains uncertain whether increasing pressure levels for nCPAP would adversely affect cardiovascular function in preterm infants at risk for or with cardiovascular compromise.

Fluid management

Fluid balance – As previously discussed, fluids should be adjusted to maintain a neutral to 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 [17]. Our usual practice is to restrict total fluid intake to 130 to 140 mL/kg per day after the first week of life. However, the fluid status of the patient must be monitored frequently to avoid dehydration or overhydration as fluid needs widely vary in preterm infants due to differences in insensible fluid loss. Caloric intake and growth should be closely monitored. (See "Fluid and electrolyte therapy in newborns".)

The practice of using a modest fluid restriction in preterm neonates with RDS is supported by clinical trials and observational data [17-19]. In a meta-analysis of five trials, fluid restriction decreased the risk of NEC and hemodynamically significant PDA [17]. Rates of BPD were also lower in infants managed with modest fluid restriction, but the finding was not statistically significant (relative risk [RR] 0.85, 95% CI 0.63-1.14). All five trials reported that fluid restriction was associated with a postnatal weight loss, which may increase the risk of dehydration.

In a retrospective report of preterm infants (birth weight [BW] between 401 and 1000 g) from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network study, infants who either died or developed BPD had a higher fluid intake and a lower weight loss during the first 10 days after birth compared with those who survived without BPD [18]. Similarly, a retrospective single center Canadian study of EPT infants reported that a higher cumulative fluid balance at day 10 of life was associated with a higher risk of BPD and death [19].

Diuretic therapy – The available evidence does not support the routine use of diuretics in preterm infants with RDS [20]. Routine use of diuretics 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.

In our practice, use of diuretic therapy is limited to chronically ventilator-dependent infants with moderate to severe pulmonary impairment despite a trial of fluid restriction (130 to 140 mL/kg). In this setting, diuretic therapy is typically given as a trial; it is continued only if improvement is seen (as evidenced by the ability to reduce ventilatory support).

When the decision is made to use diuretic therapy, it typically consists of a trial of enteral furosemide (2 mg/kg per day) for three to five days. If the neonate's respiratory status does not improve, diuretic therapy is discontinued. If the patient improves, diuretic therapy is continued, typically with a thiazide diuretic (chlorothiazide or hydrochlorothiazide). Serum electrolytes should be measured one to two days after initiating diuretic therapy and after dose increases. During chronic therapy, electrolytes should be monitored at least weekly. Electrolyte supplements should be administered to compensate for increased urinary losses. (See "Fluid and electrolyte therapy in newborns", section on 'Hypokalemia'.)

Most of the available clinical trials evaluating routine use of diuretic therapy in preterm neonates were carried out in the 1970s to 1980s and the applicability to modern-day practice is questionable. Nevertheless, the available trial data suggest that routine diuretic therapy does not reduce mortality or rates of BPD [20].

The selective use of furosemide in this setting is supported by observational data. In a cohort of 37,693 preterm infants (GA <29 weeks), approximately half of whom received furosemide, greater exposure to furosemide correlated with decreased risk of BPD [21].

Use of diuretics in the management of infants with established BPD is discussed separately. (See "Bronchopulmonary dysplasia (BPD): Management and outcome", section on 'Diuretics'.)

SPECIFIC INTERVENTIONS

Noninvasive positive airway pressure — Noninvasive positive airway pressure, which prevents and reduces atelectasis, should be administered to all very preterm (VPT) infants (ie, gestational age [GA] <32 weeks) since these neonates are at high risk for RDS [1,22-28]. In our center, nasal continuous positive airway pressure (nCPAP) is the preferred modality for noninvasive support.

Nasal continuous positive airway pressure (nCPAP) — In preterm infants at risk for or with established RDS without respiratory failure, nCPAP is our preferred modality for noninvasive positive airway pressure. This approach is consistent with the recommendations from the American Academy of Pediatrics (AAP), American Heart Association (AHA), International Liaison Committee on Resuscitation (ILCOR) guidelines, and the European consensus guidelines [1-3,29]. (See 'Clinical approach' above and 'Society guideline links' below.)

The evidence supporting use of early CPAP in VPT neonates is discussed here. Additional details regarding nCPAP, including a description of different CPAP systems and initial settings, are provided separately. (See "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 VPT 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) [27,28,30]. In a meta-analysis of three trials (2150 VPT neonates), prophylactic CPAP reduced the incidence of BPD at 36 weeks (34 versus 38 percent; relative risk [RR] 0.89, 95% CI 0.80-0.99) [30]. Mortality was lower in the CPAP group (10 versus 13 percent) but the difference was not statistically significant (RR 0.82, 95% CI 0.66-1.03).

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 [31-33]. 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 [34].

CPAP versus supportive care in neonates with symptomatic RDS – In neonates with RDS who have signs of respiratory distress within the first 12 to 24 hours after birth, CPAP reduces mortality and the need for intubation and mechanical ventilation compared with supportive care with only supplemental oxygen. In a meta-analysis of five trials (322 neonates with RDS), CPAP reduced mortality (RR 0.53, 95% CI 0.34-0.83) and reduced the need for invasive MV (typical RR 0.72, 95% CI 0.54 to 0.96) compared with spontaneous breathing with supplemental oxygen as necessary [26]. The incidence of BPD among survivors was similar in both groups (RR 1.04, 95% CI 0.35-3.13). Three of the five trials were performed in the 1970s and the applicability to current practice is uncertain.

CPAP versus supportive care in asymptomatic at-risk neonates (prophylactic CPAP) – The benefit of early prophylactic CPAP (ie, initiated shortly after delivery regardless of whether the infant has signs of respiratory distress) appears to be more modest. In a meta-analysis of four trials (765 neonates), prophylactic CPAP reduced the need for surfactant compared with initial supportive care (23 versus 30 percent; RR 0.75, 95% CI 0.58-0.96) [30]. The incidence of BPD at 36 weeks was also lower in the CPAP group (10 versus 12 percent), but the difference was not statistically significant (RR 0.76, 95% CI 0.51-1.14). Mortality was similar in both groups (5 percent each).

Clinical trials performed in resource-limited settings have also demonstrated a benefit of early prophylactic CPAP. In a meta-analysis of two trials performed in resource-limited settings, delivery room CPAP reduced the need for intubation compared with supportive care with only supplemental oxygen (RR 0.73, 95% CI 0.56-0.96) [35]. In a separate meta-analysis of two observational studies from resource-limited settings, CPAP was associated with lower mortality compared with delivery room management without CPAP (RR 0.51, 95% CI 0.42-0.62) [35].  

CPAP versus NIPPV or HFNC – Studies comparing CPAP with nasal intermittent positive pressure ventilation (NIPPV) or high-flow nasal cannula (HFNC) are discussed below. (See 'Nasal intermittent positive pressure ventilation' below and 'High-flow nasal cannula' below.)

The evidence supporting use of CPAP following extubation is described above. (See 'Post-extubation support' above.)

Nasal intermittent positive pressure ventilation — NIPPV provides noninvasive respiratory support with phasic positive pressure ventilation (ie, higher pressure during inspiration, lower pressure during exhalation). It is delivered via nasal prongs or mask using a mechanical ventilator.

The available clinical trial evidence suggests that early NIPPV may reduce the need for intubation compared with early CPAP [36]. However, the trials have important limitations, as discussed below. In addition, widespread use of NIPPV routinely in all preterm neonates is generally not feasible since NIPPV requires a ventilator for administration and most centers do not have enough ventilators to support all preterm neonates in this manner. Moreover, most preterm neonates do not require the higher level of ventilatory support that NIPPV provides. For these reasons, many centers, including our own, preferentially use nCPAP for initial support in VPT neonates and reserve use of NIPPV for neonates who fail nCPAP. Routine use of early NIPPV is a reasonable alternative to our approach if resources are available to support such practice.

The evidence supporting use of NIPPV in VPT neonates is summarized here. Additional details regarding use of NIPPV in neonates are provided separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Nasal intermittent positive pressure ventilation'.)

In a meta-analysis of 16 trials (1848 neonates), early use of NIPPV reduced the need for intubation compared with early CPAP (15 versus 23 percent; RR 0.67, 95% CI 0.56-0.81) [36]. The incidence of BPD was modestly lower in the NIPPV group (11 versus 15 percent; RR 0.70, 95% CI 0.52 to 0.92); mortality rates were similar in both groups (7.1 versus 8.6; RR 0.82, 95% CI 0.62-1.10).

The meta-analysis was limited to studies in which patients were randomized to NIPPV or CPAP within six hours after birth [36]. As such, it included few patients from the largest trial evaluating this question (the NIPPV Study Group trial) [37]. The NIPPV Study Group trial randomly assigned 1007 extremely low birth weight (<1000 g) neonates to NIPPV or CPAP either for primary support or following extubation. There was no clear benefit of NIPPV in this trial; rates of BPD and mortality were similar in both groups. The inconsistency between this trial and other trials in the meta-analysis may be explained by differences in the study populations and/or the timing of starting NIPPV support.

An important limitation of the available trial data is that in most trials, neonates who were assigned to CPAP were not permitted to transition to NIPPV if they developed worsening respiratory compromise. This does not reflect practice in many NICUs where NIPPV is used as a rescue therapy for neonates who fail CPAP. Thus, while the clinical trials suggest that early use of NIPPV may reduce the need for intubation when compared with CPAP alone, it remains uncertain whether this approach is more effective than a strategy of initial CPAP with rescue NIPPV if necessary.

Another limitation of these data is that the trials were performed at centers experienced in using NIPPV and the findings may not be generalizable to other centers.

In a network meta-analysis of 35 randomized trials evaluating different types of noninvasive respiratory support for neonates with RDS (including NIPPV, CPAP, and HFNC), NIPPV was found to be the most effective modality for reducing the need for invasive mechanical ventilation [38].

Additional evidence evaluating use of NIPPV following extubation is described above. (See 'Post-extubation support' above.)

High-flow nasal cannula — HFNC delivers heated, humidified air at flow rates that are higher than standard low-flow nasal cannula. The flow rate and FiO2 are set by the clinician. Typical initial flow rates for neonates are 4 to 6 L/min up to maximum of 8 L/min. At these flow rates, the amount of positive airway pressure provided by HFNC ranges from 2 to 5 cm H2O, though it can vary substantially.

The evidence supporting use of HFNC in VPT neonates is summarized here. Additional details regarding use of HFNC in neonates are provided separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'High-flow nasal cannula'.)

The available data suggest that HFNC has similar efficacy compared with nCPAP for reducing the need for intubation when used as the primary mode of respiratory support for neonates with RDS [13,39,40]. An advantage of HFNC is that it is associated with a lower risk of nasal trauma. However, the main disadvantage is that the airway pressure delivered to the infant with HFNC is highly variable and difficult to monitor. As a result, we generally prefer nCPAP over HFNC for the initial mode of respiratory support in VPT neonates.

In a meta-analysis of nine trials (2042 neonates), intubation rates were similar in infants assigned to HFNC or CPAP (12 percent in both groups; RR 1.04, 95% CI 0.82-1.31) [13]. Both groups also had similar rates of BPD (3.7 versus 3.3 percent) and hospital mortality (1.8 versus 2.3 percent). Nasal trauma occurred less frequently in the HFNC group (6 versus 12 percent; RR 0.49, 95% CI 0.36-0.68).

Studies evaluating use of HFNC following extubation are described above. (See 'Post-extubation support' above.)

Mechanical ventilation — Indications for intubation and the approach to mechanical ventilation in VPT infants are summarized in the table (table 2) and discussed in detail separately. (See "Approach to mechanical ventilation in very preterm neonates".)

Surfactant therapy — Decisions regarding use of surfactant therapy in preterm neonates must address the following [5]:

Criteria for when to give it (see 'Indications' below)

Selection of surfactant product (see 'Specific surfactant agents' below)

Timing of administration (see 'Timing' below)

Technique for administration (see 'Techniques for administration' below)

Whether repeat doses are warranted (see 'Repeat doses' below)

Our approach outlined in the following sections is generally consistent with guidance from the American Academy of Pediatrics (AAP), the European consensus guidelines, the Canadian Paediatric Society, and other expert panels [2,5,22,41]. Links to these and other society guidelines are provided separately. (See 'Society guideline links' below.)

Indications — Surfactant is administered to all intubated patients and to those with persistent respiratory insufficiency after a trial of positive airway pressure (algorithm 1).

Neonates who require intubation for respiratory failure – Neonates with RDS who are intubated in the delivery room or early in the NICU course due to significant respiratory compromise should receive surfactant therapy, which is administered via endotracheal tube (ETT). (See 'Administration via ETT' below.)

Neonates who are managed with noninvasive ventilatory support – Different thresholds are used for surfactant therapy depending on the instillation technique (MIST [minimally invasive surfactant therapy] versus INSURE [INtubate, instill SURfactant, then Extubate to CPAP]). The choice of technique varies between centers and even between providers within the same center, as discussed below. (See 'Choice of technique' below.)

We suggest the following thresholds for each technique (algorithm 1):

If MIST will be used, our suggested threshold is a requirement of FiO2 ≥ 0.30 to maintain SpO2 >90 percent. (See 'Minimally invasive surfactant therapy (MIST)' below.)

If the INSURE technique will be used, our suggested threshold is a requirement of FiO2 ≥0.40 to maintain SpO2 >90 percent. (See 'Administration via ETT' below.)

Additional doses may be given depending upon the infant's response, as discussed below. (See 'Repeat doses' below.)

The practice of using these FiO2 thresholds for surfactant therapy is supported by a meta-analysis of five clinical trials in which neonates were randomized to early surfactant with rapid extubation to nCPAP versus later selective surfactant with ongoing mechanical ventilation [42]. Two of the trials used an FiO2 >0.45 as the threshold for surfactant administration, the other three trials used lower FiO2 thresholds. In subgroup analysis, the benefit of early surfactant therapy for reducing the incidence of BPD and pulmonary air leak was greater in trials that used a lower FiO2 threshold.

Timing — If surfactant therapy is used, it is most effective when given within the first two hours after birth [5,43-45]. In a meta-analysis of six trials, early surfactant administration (within two hours after birth) was associated with lower risk of BPD and pulmonary air leak compared with delayed administration (given after two hours) [45]. However, the potential benefits of timely administration of surfactant must be balanced with allowing adequate time for an initial trial of nCPAP.

Late administration of surfactant (ie, beyond seven days after birth) has been proposed as a potential intervention for ventilator-dependent preterm neonates with the rationale that transient surfactant dysfunction or deficiency may contribute to ongoing respiratory insufficiency in these neonates. However, we suggest not using this strategy since the available evidence does not support its efficacy [46-48]. In a multicenter trial (Trial of Late Surfactant [TOLSURF]), 511 EPT infants who remained ventilator-dependent at 7 to 14 days of age were randomized to late surfactant treatment or routine care without late surfactant. Both groups had similar rates of survival without BPD at 36 weeks PMA (31 versus 32 percent; RR 0.98; 95% CI 0.75-1.28) and at 40 weeks PMA (59 versus 54 percent, RR 1.08; 95% CI 0.92-1.27) [46]. Of note, all infants in this trial received inhaled nitric oxide (iNO), which is not a standard therapy in preterm infants with RDS, as discussed below. (See 'Inhaled nitric oxide' below.)

A follow-up report of the TOLSURF trial found that pulmonary morbidity at one year corrected age was similar in both groups [49].

Techniques for administration — The standard technique for surfactant administration has been endotracheal intubation and administration via ETT. Other less invasive techniques (ie, MIST) have been developed to reduce the complications associated with endotracheal intubation. Use of MIST has been expanding at many centers, but there remains considerable practice variation.

Choice of technique — In our center, we use the following approach to selecting a technique for surfactant administration:

For neonates who are likely to require ongoing mechanical ventilation (eg, extremely preterm neonates, neonates with significant apnea, neonates requiring moderate to high ventilatory support), surfactant is administered via ETT.

For more mature preterm neonates who meet criteria for surfactant therapy but are not expected to require ongoing mechanical ventilation, we generally prefer MIST over the INSURE technique (INtubate, instill SUrfactant, then Extubate).

However, the techniques used for surfactant administration vary between centers, and even between clinicians within 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]. In addition, prior to routine adaption of a specific technique, each center needs to ensure that health care personnel are adequately trained in the method.

Administration via ETT — 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 (see 'Adverse effects' below). Following instillation, positive pressure ventilation is provided.

For neonates requiring ongoing mechanical ventilation, the infant is placed on the ventilator following surfactant administration and ventilator settings are subsequently adjusted as needed to maintain adequate gas exchange. (See "Approach to mechanical ventilation in very preterm neonates".)

For neonates who do not have an ongoing requirement for mechanical ventilation (ie, more mature preterm infants with strong respiratory drive), some centers may use the INSURE technique. INSURE consists of endotracheal intubation and instillation of surfactant, followed by a brief period of bag ventilation, and then rapid extubation to nCPAP. As previously discussed, we generally prefer MIST over INSURE for neonates who do not require ongoing mechanical ventilation since MIST completely avoids bag ventilation and the available data suggest it may reduce the risk of BPD. (See 'Choice of technique' above.)

Minimally invasive surfactant therapy (MIST) — MIST (also called less invasive surfactant administration [LISA]) most commonly refers to surfactant administration via a thin intratracheal catheter. Other minimally invasive techniques include aerosolized/nebulized surfactant preparations, pharyngeal instillation, and laryngeal mask airway-aided delivery [50-60]. There is a wide variation in techniques used for MIST and in patient selection [61-63].

Thin intratracheal catheter administration – The best studied MIST technique is the use of thin intratracheal catheter. In this method, the neonate maintains spontaneous breathing on nCPAP while surfactant is gradually instilled in small aliquots through a thin catheter. This technique 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. In our center, we use this technique selectively in more mature preterm neonates who meet criteria for surfactant therapy but are not expected to require ongoing mechanical ventilation.

The efficacy of MIST via thin intratracheal catheter is supported by clinical trials and meta-analyses [64-67]. A 2021 systematic review and meta-analysis identified 16 trials comparing MIST via thin catheter versus surfactant administration via ETT [66]. Most trials used an INSURE technique as the control; two trials used endotracheal intubation with delayed extubation. MIST reduced the need for intubation during the first 72 hours (23 versus 36; RR 0.63, 0.54-0.74), reduced the incidence of BPD at 36 weeks PMA (10 versus 18 percent; RR 0.57, 95% CI 0.45-0.74), and reduced in-hospital mortality (8 versus 13 percent; RR 0.63, 95% CI 0.47-0.84). Similar findings were reported in a separate meta-analysis that included many of the same clinical trials [67]. However, the trials in these meta-analyses had important methodologic limitations (including small sample size, lack of blinding, selective reporting, and incomplete follow-up) which may have led to an overestimate the true effect.

In a subsequent large multicenter trial (OPTIMIST-A) published after the meta-analysis, MIST reduced the incidence of BPD in survivors at 36 weeks PMA compared with a sham procedure without surfactant administration (37 versus 45 percent; RR 0.83, 95% CI 0.7-0.98); though the trial did not detect a difference in hospital mortality (11.6 versus 8.2 percent; RR 1.41; 95% CI 0.73-2.7) [68]. A follow-up study of the OPTIMIST-A trial reported two-year outcomes for 400 of the 438 surviving infants (91 percent) from the original trial [69]. Fewer patients in the MIST group were hospitalized for respiratory illness in the first two years (25 versus 38 percent; RR 0.66 (95% CI 0.54-0.81) and parental/caregiver report of wheezing or breathing difficulty was less common in the MIST group (41 versus 54 percent; RR 0.76, 05% CI 0.63-0.90). Among patients who underwent complete neurodevelopmental assessment (n = 381), rates of neurodevelopmental impairment were similar in both groups (26 versus 28 percent; RR 0.94, 95% CI 0.71-1.25). There were five late deaths after discharge from the birth hospitalization (one on the MIST group, and four in the control group).

Taken together, the findings from the meta-analysis and OPTIMIST-A trial suggest that MIST improves short- and long-term pulmonary outcomes (ie, reduced need for intubation, reduced incidence of BPD, fewer respiratory illnesses during the first two years); however, these benefits may not translate into meaningful improvements in long-term neurodevelopmental outcomes. Nevertheless, we continue to use MIST via thin intratracheal catheter at our center in appropriate candidates (more mature preterm neonates who are not expected to require ongoing mechanical ventilation) given the demonstrated pulmonary benefits.

Other noninvasive techniques – Other noninvasive methods that are being used to deliver surfactant including the use of laryngeal mask airway and aerosolized surfactant delivered through a nebulizer [60,70,71].

In a 2021 meta-analysis of nine trials (999 infants), nebulized surfactant compared with standard intubation reduced intubation rates at 72 hours after birth (40 versus 53 percent, RR 0.73, 95% CI 0.63-0.84) [72]. However, this finding is limited by methodologic limitations of the trials, including lack of blinding, early termination, protocol deviations, and incomplete follow-up.

Repeat doses — Additional doses of surfactant are administered if the patient has a persistent oxygen requirement with an FiO2 ≥0.30:

For intubated neonates who require ongoing mechanical ventilation with an FiO2 ≥0.30 to maintain SpO2 >90 percent, up to three or four additional doses of surfactant can be given over 48 hours, no more frequently than every 12 hours.

For neonates who received the first dose via MIST and continue to require an FiO2 ≥0.30 to maintain SpO2 >90 percent, a second dose of surfactant is administered via MIST 12 hours after the first. If the neonate successfully weans to FiO2 <0.3, no additional doses of surfactant are necessary.

For patients who received the initial dose via the INSURE technique who are successfully extubated to CPAP and weaned to FiO2 <0.30, no additional doses of surfactant are necessary.

In the available clinical trials, repeated surfactant administration compared with a single dose decreased mortality and morbidity in infants <30 weeks gestation with RDS [43,73].

Adverse effects — Surfactant administration may be complicated by transient airway obstruction and associated desaturation and/or bradycardia [22,74]. Rare complications include pulmonary hemorrhage and pneumothorax [75]. If the ETT or tracheal catheter is not in the proper position, surfactant may inadvertently be instilled into only one lung (typically the right lung). This can result in a substantial difference between right-sided and left-sided lung compliance, which may contribute to risk of pulmonary air leak. (See "Pulmonary air leak in the newborn".)

Other adverse events can occur as a consequence of the intubation procedure itself. (See 'Complications of intubation' below.)

General efficacy — The efficacy of exogenous surfactant replacement therapy is supported by numerous clinical trials and meta-analyses which have demonstrated that surfactant reduces mortality and morbidity associated with RDS in preterm infants especially for extremely preterm infants (<28 weeks GA), who are at the greatest risk for RDS [43,68,76-80]. In clinical trials, surfactant therapy compared with placebo reduced the incidence and severity of RDS, mortality, and other associated complications including BPD, pulmonary interstitial emphysema, pneumothorax, and other pulmonary air leak complications [77,79-81]. 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) [82].

Specific surfactant agents — Surfactant agents include natural and synthetic surfactants. Both types of surfactants are effective, but in clinical trials, natural surfactants have been shown to be superior to synthetic preparations that do not contain protein B and C analogues [22,83,84]. In particular, the use of natural preparations was associated with lower ventilator requirements, 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 [85].

In a meta-analysis that included 16 trials, direct comparisons were made between various surfactant preparations [86]. 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) [86]. 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) [87].

Although, the US Food and Drug Administration (FDA) approved the first synthetic peptide-containing surfactant (lucinactant) [88,89], it is no longer commercially available as the manufacturer has voluntarily discontinued production.

Unproven and ineffective therapies

Surfactant in combination with budesonide — Data on the use of combination surfactant plus budesonide are limited. This therapy cannot be recommended until there are more definitive data establishing its safety and efficacy. The data supporting this intervention are discussed separately. (See "Postnatal use of glucocorticoids for prevention of bronchopulmonary dysplasia (BPD) in preterm infants", section on 'Intratracheal glucocorticoids'.)

Inhaled nitric oxide — The available clinical trial data suggest that the use of inhaled nitric oxide (iNO) either as rescue or routine therapy is not beneficial in preterm infants with RDS for reducing mortality or BPD. As a result, we concur with AAP guidance and other guidelines recommending that iNO not be used to treat preterm infants with RDS except in rare cases of pulmonary hypertension or hypoplasia [2,90].

The use of iNO in preterm neonates with RDS has been investigated in randomized trials and meta-analyses [91-102]. The available trials had considerable differences in study design (eg, dose, duration, early versus late administration of iNO, and severity of illness). A 2017 systematic review identified 17 trials evaluating iNO in preterm neonates and categorized them into three subgroups: trials examining routine use of iNO in preterm neonates (4 trials); trials examining early iNO use in preterm neonates with severe lung disease (10 trials); and trials examining later use of iNO in preterm neonates at high risk of BPD (3 trials) [101]. Meta-analyses of these trials did not detect a reduction in mortality in any subgroup (for routine use of iNO: RR 0.90, 95% CI 0.74-1.10; for early selective use: RR 1.02, 95% CI 0.89-1.18; for late selective use: RR 1.18, 95% CI 0.81-1.71). Similarly, the meta-analysis did not detect a reduction in rates of BPD at 36 weeks PMA in any subgroup (for routine use of iNO: RR 0.95, 95% CI 0.85-1.05; for early selective use: RR 0.89, 95% CI 0.76-1.04; for late selective use: RR 0.91, 95% CI 0.83-1.01).

Observational studies have reported similar findings with little to no difference in mortality between patients who received iNO compared with those who did not [103].

It is uncertain whether there is a subset of patients who may benefit from iNO. A patient-level meta-analysis of three trials involving preterm infants (GA <34 weeks) receiving respiratory support reported a significant subgroup effect according to race [102]. In this analysis, iNO reduced rates of BPD among Black infants (42 versus 57 percent; RR 0.88, 95% CI 0.8-0.98), but the effect in White infants was nonsignificant (61 versus 63 percent; RR 0.98, 95% CI 0.85-1.12). However, given the large number of subgroup analyses performed and the fact that the subgroup finding was not consistent across outcomes (ie, there was no apparent subgroup effect on mortality), it is likely that the difference according to race represents a spurious finding.

While iNO does not appear to be effective in the routine management of preterm neonates with RDS, it is a well-established treatment for term or late preterm infants with persistent pulmonary hypertension, as discussed separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Inhaled nitric oxide (iNO)'.)

COMPLICATIONS — Routine use of antenatal corticosteroids and surfactant therapy has lowered the mortality and morbidity associated with RDS [43,76-78]. Nevertheless, complications and deaths still persist. Complications may occur as a consequence of the lung disease itself or from therapeutic interventions such as positive pressure ventilation, intubation, and mechanical ventilation.

Complications of noninvasive ventilation — Noninvasive ventilation (including nasal continuous positive airway pressure [nCPAP], nasal intermittent positive pressure ventilation [NIPPV], high-flow nasal cannula [HFNC]) is generally well tolerated in preterm neonates and complications are uncommon. Potential complications include:

Nasal injury – Skin breakdown can occur from the pressure of the nasal interface. The risk is greater with nCPAP and NIPPV compared with HFNC [40]. Longer duration of positive pressure support also increases the risk.

Pneumothorax – All forms of positive pressure ventilation have the potential to cause pulmonary air leak. However, the risk associated with noninvasive support is generally less than with invasive mechanical ventilation. (See "Pulmonary air leak in the newborn", section on 'Risk factors'.)

Gastric distention – Theoretically, noninvasive positive pressure can cause the neonate to swallow more air which might lead to gastric distention and other gastrointestinal complications (eg, vomiting, feeding intolerance). However, in practice, noninvasive respiratory support using typical settings for RDS (eg, nCPAP of 5 to 7 cm H2O) has little impact on abdominal distention or feeding tolerance in most neonates [104]. Abdominal distention can occasionally occur with NIPPV, especially when high pressures are used.

Complications of noninvasive ventilation in pediatric patients are discussed in greater detail separately. (See "Noninvasive ventilation for acute and impending respiratory failure in children", section on 'Complications'.)

Complications of intubation — Adverse events are common during neonatal endotracheal intubation. This can range from minor transient desaturation and/or bradycardia to full cardiopulmonary arrest [105].

Preterm neonates are at substantially higher risk of experiencing displacement of the endotracheal tube (ETT) compared with larger term neonates and older infants. This can result in loss of the airway (self extubation) or mainstem intubation. ETT displacement into the mainstem bronchus (typically right-sided) is a particularly 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 laryngeal injury and subglottic stenosis [106]. 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, and management of bronchopulmonary dysplasia are discussed elsewhere. (See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis" and "Bronchopulmonary dysplasia (BPD): Management and outcome".)

Other complications — Other short- and long-term complications of preterm birth are discussed in separate topic reviews. (See "Overview of short-term complications in preterm infants" and "Overview of the long-term complications of preterm birth".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bronchopulmonary dysplasia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: When a baby is born premature (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition – Respiratory distress syndrome (RDS) is the major cause of respiratory distress in very preterm (VPT; gestational age [GA] <32 weeks) neonates. It is caused by surfactant deficiency and is manifested by progressive respiratory insufficiency (eg, work of breathing, oxygen requirement) shortly after birth in a preterm infant, in conjunction with a characteristic chest radiograph (image 1). (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis".)

Initial respiratory support for VPT neonates – The choice of initial respiratory support in VPT neonates depends upon the neonate's respiratory effort (algorithm 1):

Strong respiratory drive – For neonates with a strong respiratory drive, we recommend noninvasive positive airway pressure rather than supportive care alone initially and rather than proceeding directly to invasive mechanical ventilation (MV) (Grade 1B); we suggest nasal continuous positive airway pressure (nCPAP) for this purpose rather than other modalities (Grade 2C). Nasal intermittent positive pressure ventilation (NIPPV) and high-flow nasal cannula (HFNC) are reasonable alternatives. (See 'Early positive pressure' above and 'Noninvasive positive airway pressure' 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 MV. (See "Neonatal resuscitation in the delivery room", section on 'Apnea/gasping and heart rate <100 bpm' and "Approach to mechanical ventilation in very preterm neonates".)

Surfactant – For neonates requiring mechanical ventilation and those with persistent hypoxemia despite a trial of positive airway pressure, we recommend surfactant rather than supportive interventions without surfactant (Grade 1B). We define persistent hypoxemia as requiring FiO2 >0.3 to 0.4 on noninvasive support to maintain oxygen saturation >90 percent. Additional surfactant doses may be required if the neonate continues to have a significant oxygen requirement after the first dose. (See 'Surfactant therapy' above.)

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

Supportive care – Supportive care is provided to optimize the neonate's metabolic and cardiorespiratory status. This includes the following measures, which are discussed separately (see 'Supportive care' above):

Maintenance of thermal neutral environment (see "Overview of short-term complications in preterm infants", section on 'Hypothermia')

Optimal fluid balance with avoidance of fluid overload (see 'Fluid management' above and "Fluid and electrolyte therapy in newborns")

Hemodynamic support, if needed (see "Neonatal shock: Etiology, clinical manifestations, and evaluation" and "Assessment and management of low blood pressure in extremely preterm infants")

Caffeine therapy for neonates with clinically significant apnea and in all extremely preterm infants (GA <28 weeks) (see "Management of apnea of prematurity", section on 'Caffeine')

Early nutrition (see "Parenteral nutrition in premature infants" and "Approach to enteral nutrition in the premature infant")

Ongoing respiratory support – After providing initial supportive measures and surfactant (if indicated), ongoing respiratory support is titrated as needed to achieve adequate gas exchange. (See 'Subsequent management' above.)

For neonates with strong respiratory drive who have adequate gas exchange on noninvasive support, respiratory support is gradually weaned if the neonate is able to maintain adequate oxygen saturation (ie, 90 to 95 percent). (See 'Ongoing respiratory support' above and "Neonatal target oxygen levels for preterm infants".)

For neonates with increased work of breathing and/or high oxygen requirement (ie, requiring FiO2 >0.4), nCPAP support can be increased up to 6 to 8 cm H2O. If this is inadequate, the neonate can be transitioned to NIPPV. (See 'Nasal continuous positive airway pressure (nCPAP)' above and 'Nasal intermittent positive pressure ventilation' above.)

Neonates who have significant distress, ineffective breathing, inadequate gas exchange, and/or significant apnea despite optimizing noninvasive support generally require intubation and invasive mechanical ventilation. Indications for intubation and the approach to mechanical ventilation in VPT infants are summarized in the table (table 2) and discussed in detail separately. (See "Approach to mechanical ventilation in very preterm neonates".)

For neonates with RDS who require intubation and are subsequently extubated, we recommend routine use of noninvasive positive pressure following extubation rather than supportive care alone (Grade 1B); we suggest nCPAP for this purpose rather than other modalities (Grade 2C). NIPPV or HFNC are reasonable alternatives. (See 'Post-extubation support' above.)

Complications – Complications may occur as a consequence of the lung disease itself or from therapeutic interventions such as positive pressure ventilation, intubation, and mechanical ventilation. Bronchopulmonary dysplasia (BPD) is the main chronic complication of RDS. (See 'Complications' above and "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis".)

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.

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Topic 4997 Version 100.0

References

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