Respiratory Distress Syndrome Treatment & Management

Updated: Jan 16, 2015
  • Author: Arun K Pramanik, MD, MBBS; Chief Editor: Ted Rosenkrantz, MD  more...
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Treatment

Approach Considerations

Promptly manage high-risk factors, such as diabetes, hypertension, incompetent cervix, and chorioamnionitis.

Delivery and resuscitation

A neonatologist experienced in the resuscitation and care of premature infants should attend the deliveries of fetuses born at less than 28 weeks' gestation. These neonates are at a high risk for maladaptation, which further inhibits surfactant production.

In the delivery room, nasal continuous positive airway pressure (CPAP) is often used in spontaneously breathing premature infants immediately after birth as a potential alternative to immediate intubation and surfactant replacement to minimize the severity of bronchopulmonary dysplasia (BPD). Several centers have reported success with the use of nasal bubble CPAP to decrease the complications associated with intubation and mechanical ventilation. [13, 14] By avoiding intubation, lung injury may be diminished. (See Table 1, below.)

Table 1. Meta-Analysis of Early Versus Delayed Surfactant Treatment of RDS (Open Table in a new window)

Outcome Number of



Trials



Relative Risk



(95% CI)



Relative Difference



(95% CI)



Pneumothorax 3 0.70 (0.59, 0.82) -5.2% (-7.5%, -2.9%)
Bronchopulmonary dysplasia (BPD) 3 0.97 (0.88, 1.06) -1.2% (-4.6%, 2.2%)
Mortality 4 0.87 (0.77, 0.99) -2.8% (-5.5%, 0.0%)
BPD or death 3 0.94 (0.88, 1.00) -3.7% (-7.2%, 0.0%)

 

In a study that evaluated the use and effectiveness of adjunctive therapies (surfactant administration, inhalation of nitric oxide [iNO], high-frequency oscillatory ventilation [HFOV], and extracorporeal membrane oxygenation [ECMO]) and newborn mortality from severe respiratory failure (respiratory distress syndrome, pneumonia sepsis, meconium aspiration syndrome, congenital diaphragmatic hernia) among 397 German infants, German investigators reported the following results [15] :

  • Surfactant: Administered to 77% of all newborns, with 71.6% efficacy
  • iNO: Administered to more than 40% of all infants, with improvement in every second case
  • HFOV: Used in every third newborn, 60% efficacy
  • ECMO: Used in 1 in 7 infants, with 80% survival rate
  • Overall mortality was 10.3%, with 29 infants who died without ECMO support (potentially contraindicated in 10; not transferred for ECMO in 19)

Transfer

Transfer the following patients to a tertiary care center:

  • Mothers with high-risk pregnancy
  • Mothers in premature labor
  • Newborn infants with respiratory failure
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Corticosteroids

Obstetricians with experience in fetal medicine should care for mothers whose infants are at an increased risk for respiratory distress syndrome, preferably at a tertiary perinatal center. Strategies to prevent premature birth include bed rest, tocolytics, antibiotics, and antenatal steroids. [16, 17, 18, 19, 20, 21, 22, 23]

One course of antenatal corticosteroids reduces the risk of respiratory distress syndrome and neonatal death. However, in a Canadian study of 1858 women at 25-32 weeks' gestation who remained undelivered after a single course of antenatal corticosteroids, multiple courses did not improve outcomes and were associated with decrease in weight, length, and head circumference at birth. [24]

In another trial, in which a single repeat dose of prenatal betamethasone treatment was given in women with imminent preterm birth before 34 weeks' gestation, the requirement for surfactant therapy was increased.

In contrast, however, several large clinical trials in which much higher fetal corticosteroid exposure occurred showed benefit, with less severe lung disease and no increased risks.

Another randomized, triple-blind clinical trial investigated the effectiveness of corticosteroids in reducing respiratory disorders in infants born at 34-36 weeks' gestation. The results found that while antenatal treatment with corticosteroids reduced the need for phototherapy for jaundice, it did not reduce the risk of respiratory disorders in newborn infants. [25]

The increased incidence of cerebral palsy found in a study by Wapner et al could be avoided by limiting retreatment to less than 4 weekly treatments. [26] Results from studies by Crowther and colleagues and Wapner and associates of multiple treatments with antenatal corticosteroids are not consistent with results from the alternative strategy (ie, a single treatment when delivery is imminent). [27] Nevertheless, these weekly retreatment trials demonstrated considerable safety for retreatment.

Corticosteroid treatment at recognition of a risk of preterm delivery is indicated. If the mother does not deliver within 1 week, retreatment may be considered; most perinatologists administer a single, 12-mg dose of betamethasone, rather than 2 doses.

Clinical judgment should be used about the risk for preterm delivery before any repeat dose is administered. If cervical dilation or signs of labor persist, a repeat dose may help. If the pregnancy appears to be at lower risk, retreatment may be deferred. Multiple retreatment (>4 times) may increase risk; however, the effect of corticosteroid retreatment for the risk of preterm delivery remains unclear.

In a recent study, among infants born at 23-25 weeks’ gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a low rate of death or neurodevelopmental impairment at 18-22 months. [28]

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Surfactant Replacement Therapy

The advent of surfactant therapy has reduced the mortality rate from respiratory distress syndrome by approximately 50%. [29, 30, 31, 32, 33]

Meta-analysis of clinical trials comparing early natural and synthetic surfactant therapy versus controls showed a decrease in air leaks. Meta-analysis of comparisons of early versus delayed selective treatment for neonatal respiratory distress syndrome suggested a decrease in pulmonary air leaks and chronic lung disease.

Early surfactant therapy in tiny neonates followed by rapid extubation to nasal continuous positive airway pressure (CPAP) decreased the need for and duration of mechanical ventilation and decreased the rate of pulmonary air leakage and 28-day mortality compared with selective surfactant therapy in respiratory distress syndrome followed by ventilation. Rates of pulmonary hemorrhage, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and bronchopulmonary dysplasia (BPD) did not differ between the groups.

Neonates with respiratory distress syndrome who require assisted ventilation with a fraction of inspiratory oxygen (FIO2) of more than 0.40 should receive intratracheal surfactant as soon as possible, preferably within 2 hours after birth.

Stevens et al, in a meta-analysis of 6 studies, concluded that administration of surfactant via transient intubation using a low treatment threshold (FIO2 < 0.45) is preferable to employing later, selective surfactant therapy using transient intubation and a higher threshold for study entry (FIO2 >0.45). [34, 35] Extremely premature neonates administered surfactant in the delivery room may have improvement in short-term outcomes and milder BPD.

Because surfactant protects the immature lungs, several investigators have recommended its prophylactic use after resuscitation in extremely premature neonates (< 27 weeks' gestation). In addition, pulmonary inflammation leads to leakage of proteins, inactivating the surfactant, damaging the surfactant phospholipids and fatty acids, affecting hydrolytic activity on surfactant proteins by proteolytic enzymes, and decreasing the synthesis of surfactant by type II cells after oxidant injury.

In developing countries, surfactant is not only expensive but is also unnecessary in most instances because more than 60% of premature infants do not have surfactant deficiency; the infants are intubated, with the resulting inherent risks. As an alternative, nasal bubble CPAP has been widely used in recent years to manage respiratory distress syndrome and apnea of prematurity. [36]

Dosage

Premature neonates with surfactant deficiency and respiratory distress syndrome have an alveolar pool of about 5mg/kg. Full-term animal models have pools of 50-100mg/kg. Recommended dosages of clinically available surfactant preparations are 50-200mg/kg, approximately the surfactant pool of term newborn lungs. Rapid bolus administration of surfactant after adequate lung recruitment with 3-4cm of positive end-expiratory pressure (PEEP) and adequate positive pressure may improve its homogeneous distribution.

Most neonates require 2 doses; however, as many as 4 doses, given at 6-hour to 12-hour intervals, were used in several clinical trials. If the patient rapidly improves after 1 dose, respiratory distress syndrome is unlikely. Conversely, in infants who have a poor or no response, patent ductus arteriosus (PDA), pneumonia, and complications of ventilation (air leak) should be excluded, especially before subsequent surfactant doses are given.

Surfactant comparisons

The ideal surfactant preparation to treat premature infants with respiratory distress syndrome and its sequelae has not been identified. [37, 38, 39, 40, 41, 42, 43, 44]

Lucinactant (Surfaxin), a KL4 polypeptide exogenous surfactant, was approved by the US Food and Drug Administration (FDA) in March 2012. Approval was based on the SELECT (Safety and Effectiveness of Lucinactant vs. Exosurf in a Clinical Trial) [45] and STAR (SURFAXIN Therapy Against RDS) [44] studies.

SELECT enrolled 1294 patients in a multinational, multicenter, randomized trial to demonstrate the safety and efficacy of lucinactant compared with colfosceril palmitate (Exosurf), which is no longer on the US market. Beractant (Survanta), an animal-derived surfactant that is a US market leader served as a reference arm. Key results from the SELECT trial can be summarized as follows [45] :

  • Lucinactant demonstrated a significant improvement in RDS related mortality profile through 14 days of life compared with beractant ( P ≤.001) and colfosceril palmitate ( P ≤.01)
  • No significant difference in improvement in RDS at 24 hours of life was observed compared with beractant
  • Lucinactant significantly ( P ≤.05) improved survival without BPD and overall incidence of BPD compared with colfosceril palmitate
  • Lucinactant treated infants required significantly fewer ( P ≤.05) reintubations compared with beractant
  • A pharmacoeconomic assessment of lucinactant demonstrated a reduction in total NICU days and patient days on ventilator compared with beractant

The STAR trial was a supportive, multinational, multicenter Phase 3 clinical trial enrolling 252 patients and was designed as a noninferiority trial comparing lucinactant with poractant alfa (Curosurf), a porcine (pig) derived surfactant and the leading surfactant used in Europe. Key results from the STAR trial can be summarized as follows [44] :

  • Lucinactant was noninferior to poractant alfa in survival without BPD
  • Survival profile through one year of life (corrected age) was significantly improved in lucinactant treated infants ( P ≤.05) compared with poractant alfa
  • Lucinactant treated infants required significantly fewer ( P ≤.05) reintubations compared with poractant alfa

However, these studies [46, 45] had several limitations. They were designed as "equivalent to the approved surfactant products" studies, presumably to satisfy product licensing requirements rather than to evaluate the role of various surfactant components. In one study, lucinactant was compared with colfosceril palmitate, which has been discontinued. The second study was halted halfway and was thus underpowered to establish equivalency of KL4 with poractant.

Most patients were enrolled in centers outside the United States experienced in conducting research. Data regarding the participation rate at each center and concerning the outcome range varied among the 55 and 22 centers in the 2 respective studies.

The dose of phospholipid ranged from 67.5-76 mg/kg, and the volume varied from 2.2-5.5 mL among the participating centers. This was apparently done for obtaining licensing requirements to compare with existing surfactant products. Furthermore, KL4 polypeptide does not lipid-associate as readily as SP-B and SP-C. Lucinactant forms a gel in its storage form and must be heated to 44ºC and shaken before administration and placed on a special heating block prior to administration. The metabolism reuptake of KL4 polypeptide by type II pneumocyte and its interaction with natural surfactant in these infants is unclear. Table 2 shows the source, composition, and dosages of several surfactant preparations.

Table 2. Surfactant Preparations: Type, Source, Composition, Dosages, and Other Information (Open Table in a new window)

Type Source Composition Dosing Comments
Beractant (Survanta) Bovine lung mince Dipalmitoyl phosphatidylcholine (DPPC), tripalmitin, SP-B < 0.5%, SP-C 99% of TP wt/wt 4mL/kg (100mg/kg), 1-4 doses every 6h Refrigerate
Surfactant-TA (Surfacten)
Bovactant (Alveofact) Bovine lung lavage 99% PL, 1% SP-B and SP-C 45mg/mL From the Federal Republic of Germany
Bovine lipid extract surfactant (bLES) Bovine lung lavage 75% phosphatidylcholine (PC) and 1% SP-B and SP-C 135mg/kg/dose (5mL/kg), 1-4 doses every 12h Canadian
Infasurf Calf lung lavage DPPC, tripalmitin, SP-B 290g/mL, SP-C 360g/mL 3mL/kg (105mg/kg), 1-4 doses every 6-12h 6mL vials, refrigerate
Calf lung surfactant extract (CLSE) Similar to Infasurf
Poractant alpha (Curosurf) Minced pig lung Phospholipids (DPPC, phosphatidylglycerol [PG]), neutral lipids, fatty acids; SP-B and SP-C; 80mg/mL of PL/mL [54mg PC (30.5mg DPPC and 1mg protein includes 0.3mg of SP-B)] Initially 2.5mL/kg (200mg/kg), followed by 1.25mL (100mg)/kg 1.5 and 3mL
Colfosceril palmitate (Exosurf) Synthetic 85% DPPC, 9% hexadecanol, 6% tyloxapol 5mL/kg (67.5mg/kg),



1-4 doses every 12h



No longer available; lyophilized, dissolve in 8mL
Lucinactant (Surfaxin) Synthetic Protein: KL4 (sinapultide) resembles SP-B; Phospholipids: DPPC, palmitoyloleoyl phosphatidylcholine (POPG) 175 mg/kg/dose phospholipid FDA-approved March 2012; warmed for 15min at 44°C on a heating block, followed by vigorous shaking until a uniform, free-flowing suspension forms
Artificial lung expanding compound (ALEC) Synthetic 70% DPPC, 30% unsaturated phosphatidylglycerol No data Discontinued

Clinical outcomes

Tables 3-7 summarize some complication assessments derived from a meta-analysis of several clinical trials of surfactants conducted worldwide. In the trials, fewer complications and more rapid improvement in infants’ respiratory status occurred with protein-containing natural surfactant than with synthetic surfactant. Currently marketed natural surfactants have various amounts of phospholipids (mostly desaturated phosphatidylcholine) and apoprotein B and C, but not apoprotein A and D. Apoprotein A and D may be important for host defense.

Table 3. Results of a Meta-Analysis of Separate Clinical Trials of the Treatment of Respiratory Distress Syndrome With Natural or Synthetic Surfactant Preparations (Open Table in a new window)

  Natural Surfactant Treatment Synthetic Surfactant Treatment
Outcome Number of Trials Relative Risk (95% Confidence Interval [CI])



Relative Difference (95% CI)



Number of Trials Relative Risk (95% CI)



Relative Difference (95% CI)



Pneumothorax 12 0.43 (0.35, 0.52)



-17% (-21%, -13%)



5 0.64 (0.55, 0.76)



-9% (-12%, -6%)



Bronchopulmonary dysplasia (BPD) 9 0.94 (0.72, 1.22)



-2% (-9%, 4%)



5 0.75 (0.61, 0.92)



-4% (-6%, -1%)



Mortality 12 0.68 (0.57, 0.80)



-9% (-13%, -5%)



6 0.73 (0.61, 0.88)



-5% (-7%, -2%)



BPD or death 10 0.76 (0.65, 0.90)



-14% (-21%, -7%)



4 0.73 (0.65, 0.83)



-8% (-11%, -5%)



Table 4. Results of a Meta-Analysis of Separate Clinical Trials of the Prophylactic Use of Natural or Synthetic Surfactant Preparations (Open Table in a new window)

  Natural Prophylaxis Synthetic Prophylaxis
Outcome Number of Trials Relative Risk (95% CI)



Relative Difference (95% CI)



Number of Trials Relative Risk (95% CI)



Relative Difference (95% CI)



Pneumothorax 8 0.35 (0.26, 0.49)



-13% (-20%, -11%)



6 0.67 (0.50, 0.90)



-5% (-9%, -2%)



BPD 7 0.93 (0.80, 1.07)



-4% (-9%, -3%)



4 1.06 (0.83, 1.36)



1% (-4%, 6%)



Mortality 7 0.60 (0.44, 0.83)



-7% (-12%, -3%)



7 0.70 (0.58, 0.85)



-7% (-11%, -3%)



BPD or death 7 0.84 (0.75, 0.93)



-10% (-16%, -4%)



4 0.80 (0.77, 1.03)



-4% (-10%, 1%)



Table 5. Results of a Meta-Analysis of Head-to-Head Trials With Natural Versus Synthetic Surfactants (Open Table in a new window)

Outcome Number of



Trials



Relative Risk



(95% CI)



Relative Difference



(95% CI)



Pneumothorax 5 0.68 (0.56, 0.83) -4.1% (-6.3%, -2.0%)
BPD 4 0.97 (0.88, 1.07) -1.2% (-5.4%, -2.9%)
Mortality 7 0.88 (0.76, 1.02) -2.2% (-4.7%, 0.4%)
BPD or death 2 0.94 (0.87, 1.01) -3.6% (-8.0%, 0.8%)

Table 6. Meta-Analysis of Clinical Trials Comparing Prophylactic Use of Surfactant Versus Rescue Treatment of Infants With Respiratory Distress Syndrome (Open Table in a new window)

Outcome Number of



Trials



Relative Risk



(95% CI)



Relative Difference



(95% CI)



Pneumothorax 6 0.62 (0.42, 0.89) -2.1% (-3.7%, -0.55)
BPD 7 0.95 (0.81, 1.11) -0.9% (-3.5%, 1.7%)
Mortality 6 0.59 (0.46, 0.76) -4.6% (-6.8%, -2.5%)
BPD or death 7 0.85 (0.76, 0.95) -4.5% (-7.4%, -1.5%)
Infants < 30 wk of gestation
Mortality 6 0.60 (0.47, 0.77) -6.5% (-9.6%, -3.4%)
BPD or death 7 0.86 (0.77, 0.96) -5.5% (-9.6%, -1.5%)

Table 7. Results of a Meta-Analysis of Clinical Trials to Compare Multiple Doses With a Single Dose of Surfactant (Open Table in a new window)

Outcome Number of



Trials



Relative Risk



(95% CI)



Relative Difference



(95% CI)



Pneumothorax 2 0.51 (0.30, 0.88) -8.7% (-15.4%, -2.0%)
BPD 1 1.10 (0.63, 1.93) 1.2% (-5.8%, 8.3%)
Mortality 2 0.63 (0.57, 1.11) -7.0% (-14%, 0%)
BPD or death 1 0.80 (0.57, 1.11) -6.6%, (-16.2%. 3%)
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Oxygenation and CPAP

Continuous positive airway pressure (CPAP) was introduced as the primary therapeutic modality when Gregory et al demonstrated a marked reduction in respiratory distress syndrome mortality. [47, 48, 49]

Oxygen was the primary therapeutic mode before the introduction of CPAP. Oxygen is administered via a hood or nasal canula or in the isolette to treat infants with mild respiratory distress syndrome or after discontinuation of CPAP or assisted ventilation. [50]

CPAP keeps the alveoli open at the end of expiration, decreasing the right-to-left pulmonary shunt. CPAP is often administered using nasal prongs. [51] In a Cochrane database review in which devices and pressure sources for administration of nasal CPAP were assessed, short, binasal prong devices were found to be more effective than single prongs and also reduced the rate of reintubation. [14]

A meta-analysis of studies on prophylactic use of nasal CPAP for preventing morbidity and mortality in very preterm infants concluded that intermittent positive pressure ventilation (IPPV) was not beneficial. [52]

In a retrospective, observational study of nasal CPAP in infants born at less than 27 weeks' gestation, the probability of an individual baby remaining on nasal CPAP was 66% on day 1 and 80% on day 2. [53]

A retrospective analysis of the first 48 hours in 225 infants of 23-28 weeks’ gestational age found that medical history and initial blood gas values could not adequately be used to predict the failure of nasal CPAP. [33]

In another trial, investigators found no reduction in death or bronchopulmonary dysplasia (BPD) with early nasal CPAP. In the study, 610 infants born at 25-28 weeks' gestation were randomly assigned to CPAP or intubation 5 minutes after birth, and their outcomes were assessed at age 28 days, at age 36 weeks, and before discharge. [54] The CPAP group had an increase in the incidence of pneumothorax (9% vs 3%) but also fewer days on ventilator, and fewer infants in the group received oxygen at age 28 days.

CPAP is an adjunct therapy given after surfactant if prolonged assisted ventilation is not required. Use of nasal CPAP after initial surfactant therapy has been successful in some infants. In a retrospective study, bubble nasal CPAP was successful in 76% of infants who weighed less than 1250 g and in 50% of infants who weighed less than 750 g. [55]

CPAP may be used after extubation in individuals with respiratory distress syndrome to prevent atelectasis and to prevent apnea in premature infants. A randomized, controlled trial compared postextubation bubble CPAP with infant flow driver CPAP in preterm infants with respiratory distress syndrome [13] ; although both were equally effective, bubble CPAP was associated with a significantly higher rate of successful extubation and reduced duration of CPAP in infants younger than age 14 days.

The goal of therapy for patients with respiratory distress syndrome is to maintain a pH of 7.25-7.4, a partial pressure of oxygen (PaO2) of 50-70mm Hg, and a carbon dioxide pressure (PCO2) of 40-65 mm Hg, depending on the infant's clinical status.

In a nonblinded, randomized, observational 4-period cross-over level 3 NICU study that compared bi-level nasal CPAP (bi-PAP) with conventional nasal CPAP in 20 newborns with persistent oxygen needs following recovery from respiratory distress syndrome, Lampland et al found that at similar mean airway pressures, bi-PAP did not improve CO 2 removal or oxygenation but did improve mean blood pressure, albeit without clinical significance. [56]

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Vapotherm

Vapotherm with heated and humidified, high-flow nasal canula (>2 L/min) has been used for respiratory support of neonates and to facilitate early extubation. [57] Neonatal units in the United States and the United Kingdom use Vapotherm as a means of providing respiratory support. This device allows the delivery of high flows of gas at body temperature with close to 100% relative humidity. [58]

Evidence suggests that Vapotherm may be an effective and well-tolerated method of providing babies with respiratory support. It has numerous advantages over therapies such as nasal continuous positive airway pressure (CPAP), including a reduction in the number of ventilator days and reduced nasal trauma. It may be better tolerated than other forms of noninvasive respiratory therapy.

Some evidence suggests that weight gain is improved using Vapotherm and that oral feeding can be introduced earlier. Further research is required, especially into the methods of weaning Vapotherm and, as with all neonatal treatments, the long-term effects.

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Assisted Ventilation

Kirby and deLemos introduced assisted ventilation several decades ago. [59] Assisted ventilation further decreased respiratory distress syndrome–related morbidity and mortality; however, early ventilators were associated with complications, such as air leaks, bronchopulmonary dysplasia (BPD; secondary to barotrauma or volutrauma), airway damage, and intraventricular hemorrhage.

See the video of assisted ventilation of the newborn, below.

Assisted ventilation newborn –Intubation and meconium aspiration. Video courtesy of Therese Canares, MD, and Jonathan Valente, MD, Rhode Island Hospital, Brown University.

Advances in microprocessor-based technology, transducers, and real-time monitoring have enabled patient-driven ventilator control and synchronization of mechanical ventilation with patient effort. The novelty of the newer ventilation techniques has generated controversies that remain to be resolved. Among these are signal detection and transduction, optimal volume delivery (ventilation modes), and weaning from mechanical ventilation.

Consider ventilation as a necessary physiologic support while the infant recovers from respiratory distress syndrome. Several investigators have suggested that permissive hypercapnia with arterial partial pressure of carbon dioxide (PaCO2) of 45-55mm Hg (with adequate lung volume) may facilitate weaning during recovery from respiratory distress syndrome. To minimize the complications of conventional intermittent mandatory ventilation, new ventilation techniques have been introduced, as described below.

Synchronous intermittent mandatory ventilation

Synchronous intermittent mandatory ventilation is a technique in which some of the patient's respirations are synchronized with breaths the ventilator delivers. [60] In a randomized, controlled trial, the incidence of BPD (defined as oxygen requirement at a corrected gestational age of 36 wk) was significantly reduced with this therapy compared with standard intermittent mandatory ventilation (47% vs 72%, respectively).

In another study, the duration of intubation was shortened and the need for oxygen was decreased with this strategy compared with conventional ventilation. The study involved neonates born at 28-34 weeks’ gestational age with respiratory distress syndrome who required surfactant, with early extubation to synchronous, intermittent positive-pressure ventilation

Assist-control ventilation and pressure-support ventilation

Assist-control ventilation has been suggested to improve outcomes. In a comparison of pressure-regulated volume control and the assist-control mode of ventilation from birth, the time to extubation was not altered in infants with respiratory distress syndrome.

Some physicians use pressure-support ventilation to wean infants who develop chronic lung changes. Further studies are required to evaluate its long-term benefits.

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High-Frequency Ventilation

With high-frequency ventilation (HFV), small tidal volumes (less than anatomic dead space) are usually delivered at rapid frequencies, thus eliminating the wide pressure swings seen with conventional ventilators. Conventional ventilators may deliver high or low tidal volumes (barotrauma or volutrauma), cause wide pressure swings, or cause cardiovascular compromise.

HFV was originally designed to treat patients with air leak. Many studies in animal models of respiratory distress syndrome demonstrated that HFV promoted uniform lung inflation, improved lung mechanics and gas exchange, and reduced exudative alveolar edema, air leak, and lung inflammation.

Adequate clinical trials controlled for resuscitation techniques, time and type of surfactant therapy, and similar strategies with the same types of HFV versus synchronous intermittent mandatory ventilation are awaited to evaluate short-term and long-term respiratory and neurologic outcomes.

HFV techniques involve a learning curve, and optimal ventilator strategies vary with the stage of respiratory distress syndrome.

High-frequency oscillatory ventilation

High-frequency oscillatory ventilation (HFOV) has a frequency range of 10-15Hz. Early in its use, high-HFOV was found to be clearly superior to conventional ventilation. In one clinical trial, prophylactic HFOV reduced chronic lung disease. [61]

Because expiration actively occurs, monitor patients for hypocarbia to prevent periventricular leukomalacia (PVL).]

Controlled trials of HFOV to reduce bronchopulmonary dysplasia (BPD) in infants with respiratory distress syndrome have been controversial. This is because of the varied types of ventilators used, varied learning curve by the users, time of lung recruitment, differences in surfactant treatment, and management of patent ductus arteriosus (PDA) and fluids.

The unfavorable outcome of HFOV in some studies has been attributed to (1) a low incidence of BPD with antenatal steroid use and, therefore, an inadequate sample size to detect a difference; (2) use of a suboptimal lung volume strategy in patients treated with HFOV; (3) definition of and differences in chorioamnionitis; and (4) differences in resuscitation techniques at birth.

High-frequency jet ventilation

The frequency range of this modality is 4-11Hz (usually 7Hz). High-frequency jet ventilation has to be used in tandem with conventional ventilation to provide positive end-expiratory pressure (PEEP) and sigh breaths. It decreases air leaks. Because the solenoid valves open intermittently to provide jet breaths, some neonatologists prefer to use high-frequency jet ventilation to treat infants with pulmonary air leaks.

High-frequency flow interrupter

The frequency range of this modality is 6-15Hz, with the advantages of a built-in conventional ventilator and an ability to provide sigh breaths. Its use is also associated with a decreased incidence of air leaks in infants with respiratory distress syndrome.

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Nitric Oxide

Although inhaled nitric oxide (iNO) is a safe and effective treatment for near-term and term newborn infants with pulmonary hypertension and hypoxic respiratory failure, its role in premature infants with respiratory distress is ill defined. [9, 62]

Inhaled NO has selective pulmonary vasodilation and, in premature infants, it may have a role in decreasing inflammation, reducing oxidative stress, and enhancing alveolarization and lung growth.

The effects of iNO in premature newborn infants with respiratory distress syndrome may be dependent on the timing, dose, and duration of iNO therapy and on the extent of the infant's lung disease. The results of several clinical trials are summarized in Table 8, below.

Table 8. Inhaled Nitric Oxide Therapy in Preterm Infants and Outcome Measures (Open Table in a new window)

Study Number Enrolled Mean



Gestational Age (wk)



Mean



Birth Weight (g)



Mean



Oxygen Index



Placebo



Death Rate



Therapy



Duration (d)



Maximum



Dose



% Change in Death/BPD
Kinsella et al [63] 80 27 1000 30 53% 7 5 ppm -15%
Schreiber et al [64] 201 27.2 970 10 22.5% 7 10 ppm -15%
Van Meurs et al [65] 420 26 839 22 44% 3 10 ppm -2%
Ballard et al [66] 587 26 760 7 6% 24 20 ppm -11%
Kinsella et al [67] 793 25 792 5 25% 14 5 ppm -4%

Some evidence suggests that low-dose iNO may be safe and effective for reducing the risk of death and bronchopulmonary dysplasia (BPD) for a subset of premature infants with a birth weight of less than 1000g (although the data represented in the first graph below shows no benefit for BPD in infants < 1000g).

Effects of early treatment of preterm infants with Effects of early treatment of preterm infants with low-dose inhaled nitric oxide (iNO) on bronchopulmonary dysplasia (BPD) incidence by birth weight strata. No difference in reduction was reported in infants weighing less than 1000 g (n = 129). Control = □; iNO = ■.
Effects of inhaled nitric oxide (iNO) survival wit Effects of inhaled nitric oxide (iNO) survival without bronchopulmonary dysplasia (BPD) for infants aged 7-21 days. iNO increased survival without BPD in infants who were treated before age 14 days (n = 727).

In addition, a neuroprotective effect of iNO has been demonstrated in large, randomized, clinical trials, although its exact relationship and mechanism of action are unclear.

Hintz et al reported no improvement in the neurodevelopmental outcome at a mean corrected age of 20 months in premature infants with a birth weight of less than 1500 g and severe respiratory failure enrolled in a randomized, controlled trial of iNO. [5] The investigators suggested that routine use of iNO in premature infants should be limited to research settings. However, they lost more than 50% of their patients to follow-up; therefore, interpretation of these results is difficult. (Results summarized in the graph below show a beneficial effect for iNO therapy on brain injury in infants < 1250g.)

Effects of early treatment with low-dose inhaled n Effects of early treatment with low-dose inhaled nitric oxide (iNO) on brain injury (ie, grade 3-4 intracranial hemorrhage [ICH], periventricular leukomalacia [PVL], ventriculomegaly) in premature infants according to birth weight strata. iNO reduced ultrasonography findings of brain injury for the overall group (n = 793), with the largest effect in the 750-g to 999-g group (n = 280). Control = □; iNO = ■.

In selected premature neonates born at less than 32 weeks' gestation with respiratory distress syndrome and hypoxic respiratory failure, low pulmonary blood flow, as determined with Doppler echocardiography, may be helpful in determining which patients are likely to benefit from iNO therapy.

However, a NIH Consensus Development Conference on “Inhaled Nitric Oxide Therapy for Premature Infants” held October 27-29, 2010 concluded the following:

  • “(1) Taken as a whole, the evidence does not support use of inhaled nitric oxide in early routine, early rescue, or later rescue regimens in the care of premature infants < 34 weeks gestation who require respiratory support.”
  • “(2) There are rare clinical situations, including pulmonary hypertension or hypoplasia, that have been inadequately studied in which inhaled nitric oxide may have benefit in infants < 34 weeks gestation. In such situations, clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties.”
  • “(3) Basic research and animal studies have contributed to important understandings of inhaled nitric oxide benefits on lung development and function in infants at high risk of bronchopulmonary dysplasia. These promising results have only partially been realized in clinical trials. Future research should seek to understand this gap.”
  • “(4) Predefined subgroup and post hoc analysis of previous trials showing potential benefits of inhaled nitric oxide have generated hypothesis for future research for clinical trials. Prior strategies shown to be ineffective are discouraged unless new evidence emerges. The positive results of one multicenter trial, which was characterized by later timing, higher dose, and longer duration of treatment, require confirmation. Future trials should attempt to quantify the individual effects of each of these treatment-related variables (timing, dose, and duration), ideally by randomizing them separately.”
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Supportive Therapy

Temperature regulation

Hypothermia increases oxygen consumption, further compromising neonates with respiratory distress syndrome who are born prematurely. Therefore, prevent hypothermia in neonates with respiratory distress syndrome during delivery, resuscitation, and transport. Care for these patients in a neutral thermal environment with the use of a double-walled incubator or radiant warmer.

Fluid, metabolic, and nutritional support

In infants with respiratory distress syndrome, initially administer 5% or 10% dextrose intravenously at a rate of 60-80 mL/kg/d. Closely monitor blood glucose (with Dextrostix testing), electrolytes, calcium, and phosphorous levels, as well as renal function and hydration (as determined by body weight and urine output), to prevent any imbalance.

Add calcium at birth to the initial IV fluid. IV sodium bicarbonate is often misused and is considered to be an unproven therapy. Electrolytes should be added as soon as the patient voids and as indicated by estimated serum electrolyte levels.

Gradually increase fluid intake to 120-140 mL/kg/d. Extremely premature infants occasionally require fluid intake of 200-300mL/kg or more because of insensible water loss occurring from their large body surfaces.

After the neonate is stable, IV nutrition with amino acids and lipid are commenced within 24-48 hours of birth. As soon as the patient can tolerate oral feedings, trophic feeding with small volumes (preferably breast milk) is commenced by using the orogastric tube to stimulate gut development. Gastric feedings are increased as tolerated, and IV nutritional support is decreased proportionately to maintain adequate fluid and calorie intake.

Data suggest that an adequate supply of macronutrients, micronutrients, vitamins, and antioxidants should be provided to maintain optimal lung, brain, eye, and somatic growth.

Circulation and anemia

Assess the baby's circulatory status by monitoring his or her heart rate, peripheral perfusion, and blood pressure. Administer blood or volume expanders, and use appropriate vasopressors to support circulation. Closely monitor blood withdrawn for laboratory tests in tiny patients and replace the blood with packed-cell transfusion when it reaches 10% of the patient's estimated blood volume or if the hematocrit level is less than 40-45%.

Anemia and blood loss can be minimized by using placental transfusion at delivery, by limiting blood loss with in vivo blood gas and electrolyte estimations, and by using erythropoietin with iron in extremely premature neonates.

Antibiotic administration

Start antibiotics in all infants who present with respiratory distress at birth after blood cultures, a complete blood count (CBC) with differential, and C-reactive protein levels are obtained. Discontinue antibiotics after 2-5 days if blood cultures are negative and if no maternal risk factors are found. Some neonatologists do not start antibiotics in infants whose mothers have received adequate antenatal care and have a recent negative cervix culture for beta-streptococci.

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Parent and Family Support

Parents often undergo much emotional and/or financial stress with the birth of a critically ill, premature baby with respiratory distress syndrome and its associated complications. The parents may feel guilty, they may be unable to relate to the neonate in the intensive care setting, and they may be anxious about their child's prognosis. In addition, the baby may be unable to provide adequate cues to arouse mothering. These factors interact to prevent maternal-infant bonding. Hence, adequate support must be provided to parents and other family members to prevent or minimize these problems.

Staff members (preferably a physician and a nurse) should keep the patient’s parents well informed by frequently talking to them, especially during the acute stage of respiratory distress syndrome. Encourage parents and assist them in frequently visiting their child. Explain the equipment and procedures to the parents, and encourage them to touch, feed, and care for their baby as soon as possible. Before the patient is discharged from the hospital, he or she is immunized, and follow-up care is arranged with a multidisciplinary team and coordinated by a pediatrician experienced in the care of problems of premature infants.

Familial psychopathology

Infants with respiratory distress syndrome are at increased risk for child abuse and failure to thrive; therefore, obtain home clearance in conjunction with a nurse and social worker before discharging the patient from the hospital. Encourage and document parental visits and the parent's interaction with the infant.

Advise parents to spend time with their infant with respiratory distress syndrome in a separate room before discharge, especially if the parents of an extremely premature infant are at high social risk (eg, teenagers).

Advise parents of infants who are discharged with oxygen and/or an apnea monitor, with a gastrostomy or a requirement for tube feeding, or with a tracheostomy or other special needs to spend time with their infants with respiratory distress syndrome in a separate room before discharge.

Physicians who are skilled in recognizing the problems encountered in these infants should be involved with their ongoing care because of the high risk of morbidity and mortality in infancy.

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