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Management of respiratory distress syndrome in preterm infants

Management of respiratory distress syndrome in preterm infants
Author:
Richard Martin, MD
Section Editor:
Joseph A Garcia-Prats, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Jul 2022. | This topic last updated: Apr 13, 2022.

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 "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn".)

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 "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn", 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 "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn", section on 'Pathophysiology'.)

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 (ACS) 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 corticosteroids — ACS therapy enhances fetal lung maturity with increased synthesis and release of surfactant, resulting in improved neonatal lung function. The use of ACS in pregnant individuals at risk for preterm delivery is discussed in greater detail separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

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 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 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'.)

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 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 — Surfactant therapy is administered to infants who require FiO2 >0.3 to 0.4 to maintain SpO2 >90 percent despite the use of nCPAP [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 to avoid the complications associated with endotracheal intubation. However, the choice of technique varies between centers and even between providers 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 '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 neonatal intensive care unit. 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 "Short-term complications of the preterm infant", section on 'Hypothermia'.)

Maintaining cardiovascular stability – Cardiovascular management is focused on ensuring adequate perfusion. 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 "Neonatal shock: Etiology, clinical manifestations, and evaluation" and "Assessment and management of low blood pressure in extremely preterm infants".)

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. 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. 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".)

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

Respiratory support — For infants 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 (ACS, nCPAP or NIPPV, and surfactant), some preterm infants will 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). 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. NIPPV is a reasonable option for neonates who fail CPAP. (See 'Nasal continuous positive airway pressure (nCPAP)' below and 'Nasal intermittent positive pressure ventilation' below.)

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 VPT infants, 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".)

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 (apnea, respiratory acidosis, and increased oxygen requirement) and the need for reintubation in this setting [6]. NIPPV and high-flow nasal cannula are reasonable alternatives. (See 'Nasal continuous positive airway pressure (nCPAP)' below and 'Nasal intermittent positive pressure ventilation' below and 'High-flow nasal cannulae' below.)

The efficacy of nCPAP in this setting is supported by several randomized controlled trials carried out in the 1990s and early 2000s [6]. In a meta-analysis of nine trials (726), nCPAP reduced the need for reintubation (27 versus 44 percent; relative risk [RR] 0.62, 95% CI 0.51-0.76).

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

In a meta-analysis of 10 trials (1431 infants), infants assigned to NIPPV were less likely to need reintubation compared with those assigned to CPAP (RR 0.70, 95% CI 0.60-0.80) [12]. Other outcomes (including mortality, incidence of BPD, and necrotizing enterocolitis [NEC]) were similar in both groups. There was considerable heterogeneity among the trials regarding the NIPPV device used and whether the delivery of NIPPV was synchronized or nonsynchronized. 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 CPAP. (See 'Nasal intermittent positive pressure ventilation' below.)

In a meta-analysis of four trials (439 infants), reintubation rates were similar in infants assigned to HFNC or nCPAP (15 versus 17 percent; RR 0.91, 95% CI 0.68-1.2); however, fewer patients in the HFNC group developed nasal trauma (25 versus 38 percent; RR 0.64, 95% CI 0.51-0.79) [13]. 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 the restrictive fluid restricted infants, 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 significant 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).

Typically, a trial of enteral furosemide is given for three to five days at 2 mg/kg per day. If the neonate’s respiratory status does not improve, diuretics are discontinued. If the patient improves, furosemide may be continued, or the diuretic is changed to a thiazide. If diuretic therapy is continued, ongoing and frequent monitoring of serum electrolyte status is required. Not infrequently, supplemental electrolytes, particularly potassium chloride, may be needed to maintain normal serum electrolytes. (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: Management", 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. Although NIPPV may provide modest benefit over nCPAP when used for primary respiratory support, its widespread use is limited by cost concerns and availability since NIPPV requires a ventilator for administration.

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 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 [1,3,29,30]. (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) [27,28,31]. 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 0.80-0.99) and there was a nonsignificant trend towards lower mortality in the CPAP group (RR 0.82, 95% CI 0.66-1.03) [31].

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 [32-34]. 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 [35].

CPAP versus supportive care – In infants with RDS, 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 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.

The trials in the above meta-analysis enrolled patients who developed signs of respiratory distress over the first 12 to 24 hours after birth. 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 (RR 0.75, 95% CI 0.58-0.96) [31]. The incidence of BPD at 36 weeks was also lower in the CPAP group, but the finding was not statistically significant (RR 0.76, 95% CI 0.51-1.14). Mortality was similar in both groups.

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) [36]. 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) [36].  

Additional details regarding use of nCPAP in neonates are provided separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Continuous positive airway pressure'.)

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.

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) [37]. There was a nonsignificant trend towards lower incidence of BPD in the NIPPV group (13 versus 17 percent; RR 0.78, 95% CI 0.58 to 1.06); mortality rates were similar in both groups (6.3 versus 8.2; RR 0.77, 95% CI 0.51-1.17).

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 [38].

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'.)

High-flow nasal cannulae — The available data suggest that HFNC has similar efficacy compared with nCPAP in reducing the need for intubation when used as the primary mode of respiratory support for neonates with RDS [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 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 nasal cannula'.)

In a multicenter randomized trial involving 564 preterm infants (GA >28 weeks) with early respiratory distress, patients assigned to HFNC for primary respiratory support had a higher rate of treatment failure compared with those assigned to nCPAP (26 versus 13 percent; risk difference [RD] 12.3 percent, 95% CI 5.8-18.7) [39]. However, most neonates who failed HFNC were successfully managed with nCPAP or NIPPV such that intubation rates were similar in both arms of the trial (16 versus 12 percent; RD 3.9 percent, 95% CI -1.7 to 9.6). Rates of other adverse events were also similar in both groups.

Similar findings were reported in another multicenter trial involving 754 preterm infants (GA ≥31 weeks) assigned to HFNC or nCPAP for primary respiratory support [41]. The treatment failure rate was higher in the HFNC group (20 versus 10 percent, RD 10.3 percent, 95% CI 5.2-15.4) [41]. However, intubation rates and other adverse events were similar between the groups.

Additional details regarding use of HFNC in neonates are provided separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Nasal intermittent positive pressure ventilation'.)

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)

Indications — Surfactant is administered to patients with persistent respiratory distress after a trial of positive airway pressure. The threshold used to determine the need for surfactant varies depending on the instillation technique used (endotracheal versus minimally invasive). The choice of technique varies between centers and even between providers within the same center. (See 'Techniques for administration' below.)

At out center, we use the following thresholds (algorithm 1):

The threshold used for endotracheal administration is a requirement of FiO2 ≥0.40 to maintain SpO2 >90 percent.

The threshold is used for minimally invasive surfactant therapy (MIST) is a requirement of FiO2 ≥ 0.30 to maintain SpO2 >90 percent.

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

Our approach is generally consistent with guidance from the American Academy of Pediatrics (AAP), the European Consensus Guidelines (ECG), and the Canadian Paediatric Society [1,5,22,29].

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 among 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 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]. 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.

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 [22,50], 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). (See 'Endotracheal tube complications' below.)

Minimally invasive surfactant therapy (MIST) – Due to the complications associated with endotracheal delivery, minimal or less invasive administrative techniques have been developed and appear promising. These interventions include thin intratracheal catheters, aerosolized/nebulized surfactant preparations, pharyngeal instillation, and laryngeal mask airway-aided delivery [51-61].

There is a wide variation in MIST techniques used and patient selection [62-64]; 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 – The efficacy of MIST via thin intratracheal catheter is supported by clinical trials and meta-analyses [65-68]. A 2021 systematic review and meta-analysis identified 16 trials comparing MIST via thin catheter versus surfactant administration via endotracheal intubation [67]. Most trials used an InSurE technique (Intubate, instill Surfactant, then Extubate) as the control; two trials used endotracheal intubation with delayed extubation. MIST reduced the need for intubation during the first 72 hours (23 verus 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). However, the certainty of these findings is limited since nearly all of the trials in the meta-analysis had important methodologic limitations, including small sample size, lack of blinding, selective reporting, and incomplete follow-up. Similar findings were reported in a separate meta-analysis that included many of the same clinical trials [68]. One large multicenter trial did not detect a mortality benefit of MIST compared with sham procedure without surfactant administration [69].

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 [61,70,71].

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.

The results from these trials are encouraging that MIST, particularly via a thin catheter, appears to be a safe and effective alternative to endotracheal instillation. However, the certainty of the evidence remains low because of the methodologic limitations of the trials, as previously described [67,73,74]. In addition, there is considerable variation amongst practicing centers in techniques and patient selection [62-64]. A priority for future research is to establish an optimal technique for delivery.

Repeat doses — Additional doses of surfactant therapy are administered if the patient has a persistent oxygen requirement with an FiO2 above a predetermined threshold, which varies based on the technique used for surfactant administration:

For neonates receiving endotracheal surfactant, the need for additional surfactant doses and ongoing mechanical ventilation is determined as follows:

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

Infants who require an FiO2 ≥0.30 to maintain SpO2 >90 percent remain intubated and receive additional doses of surfactant. Up to three or four doses can be given over 48 hours, no more frequently than every 12 hours.

For neonates receiving MIST, a second dose of surfactant is administered 12 hours after the first if the infant continues to require an FiO2 ≥0.30.

In the available clinical trials, repeated surfactant administration compared with a single dose decreased mortality and morbidity in infants <30 weeks gestation with RDS [43,75].

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 [43,69,76-80]. 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 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 natural surfactants have been shown to be superior to synthetic preparations that do not contain protein B and C analogues in clinical trials [22,83,84]. 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 [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.

Inconclusive/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 "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids", section on 'Intratracheal corticosteroids'.)

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 for reducing mortality or 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 [29,90].

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".)

COMPLICATIONS — Therapy with exogenous surfactant and antenatal corticosteroids has lowered the mortality and morbidity associated with RDS [43,76-78]. 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 [104]. 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 [105]. 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: Definition, pathogenesis, and clinical features" and "Bronchopulmonary dysplasia: Management".)

SUMMARY AND RECOMMENDATIONS

Introduction and definition – Respiratory distress syndrome (RDS) is the major cause of respiratory distress in very preterm neonates. It is caused by deficiency of surfactant, which results in atelectasis, increased ventilation-perfusion mismatch, and 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 – A key intervention for preventing RDS is administration of antenatal corticosteroid therapy in pregnant individuals who are at high risk for preterm delivery at <34 weeks gestation. This is 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 in neonates with RDS depends upon 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 supportive care alone initially and rather than proceeding directly to invasive mechanical ventilation (MV) (Grade 1B). (See 'Early 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 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 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 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, which reduce oxygen consumption and energy expenditures. This includes (see 'Supportive care' above):

Maintenance of thermal neutral environment (see "Short-term complications of the preterm infant", section on 'Hypothermia')

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

Maintenance of adequate perfusion (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")

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

For infants 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). 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.

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