Approach Considerations
Several diagnoses may coexist with and complicate the course of respiratory distress syndrome, including the following:
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Pneumonia - Usually secondary to group B beta-hemolytic streptococci and often coexists with respiratory distress syndrome
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Metabolic problems - Eg, hypothermia, hypoglycemia
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Hematologic problems - Eg, anemia, polycythemia, jaundice
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Transient tachypnea of the newborn - Usually occurs in term or near-term neonates, often after cesarean delivery; the chest radiograph of an infant with transient tachypnea shows good lung expansion and, often, fluid in the horizontal fissure
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Aspiration syndromes - May result from aspiration of amniotic fluid, blood, or meconium; aspiration syndrome is observed in more mature infants and is differentiated by obtaining a history and by viewing the chest radiographs.
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Pulmonary air leaks - Eg, pneumothorax, interstitial emphysema, pneumomediastinum, pneumopericardium; in premature infants, these complications may be due to excessive positive-pressure ventilation (in rare cases, spontaneous pneumothorax may occur in large infants)
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Congenital anomalies of the lungs - Eg, diaphragmatic hernia, chylothorax, congenital cystic adenomatoid malformation of the lung, lobar emphysema, bronchogenic cyst, pulmonary sequestration
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Congenital anomalies of the heart
Congenital anomalies of the lungs and heart are uncommon in premature infants; these entities can be diagnosed on the basis of chest radiographic or echocardiographic findings. They coexist only rarely with respiratory distress syndrome.
Fetal lung maturity tests
Prediction of fetal lung maturity is derived by estimating the lecithin-to-sphingomyelin ratio and/or by testing for the presence of phosphatidylglycerol in the amniotic fluid obtained with amniocentesis.
Antenatal diagnosis of SP-B deficiency, a rare genetic disease, can also be antenatally diagnosed by analyzing the amniotic fluid; this diagnostic testing should be undertaken in previously affected siblings.
Procedures
Vascular access procedures
Vascular access procedures used in infants with respiratory distress syndrome include:
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Intravenous (IV) line placement
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Umbilical arterial catheterization
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Umbilical artery cut down
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Peripheral artery cannulation
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Umbilical venous catheterization
Other procedures
The following procedures may also be employed in infants with respiratory distress syndrome:
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Sedation, analgesia, or anesthesia whenever feasible
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Arterial puncture, venous puncture, and capillary blood sampling
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Tracheal intubation or tracheostomy
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Bronchoscopy
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Placement of thoracotomy tubes
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Placement of pericardial tubes
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Placement of gastric tubes
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Transfusion of blood, blood products, and exchange transfusion
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Lumbar puncture
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Suprapubic bladder aspiration and bladder catheterization
Blood Gases
Blood gases are usually obtained in respiratory distress syndrome, as clinically indicated, from an indwelling peripheral or central (umbilical) arterial catheter or by means of arterial puncture. In a multicenter study by Billman and colleagues, an in-line, ex-vivo, point-of-care monitor was shown to be reliable in critically ill neonates and infants. [12] It can be reliably used without adverse consequences associated with serial phlebotomy.
Blood gases show respiratory and metabolic acidosis along with hypoxia. Respiratory acidosis occurs because of alveolar atelectasis and/or overdistension of terminal airways. Metabolic acidosis is primarily lactic acidosis, which results from poor tissue perfusion and anaerobic metabolism.
Hypoxia occurs from right-to-left shunting of blood through the pulmonary vessels, patent ductus arteriosus (PDA), and/or patent foramen ovale.
Pulse Oximetry
Pulse oximetry is used as a noninvasive tool to monitor oxygen saturation, which should be maintained at 90-95%. However, it is unreliable for determining hyperoxia because of the flat-top portion of the S -shaped oxygen-hemoglobin dissociation curve. In the past, continuous, in-line arterial PaO2 monitoring and transcutaneous monitoring were used. Transcutaneous CO2 monitors should be used in infants with ongoing respiratory distress to monitor ventilation if it correlates with PaCO2.
Chest Radiography and Echocardiography
Chest radiography
Chest radiographs of a newborn infant with respiratory distress syndrome reveal bilateral, diffuse, reticular granular or ground-glass appearances; air bronchograms; and poor lung expansion. The prominent air bronchograms represent aerated bronchioles superimposed on a background of collapsed alveoli.
The cardiac silhouette may be normal or enlarged. Cardiomegaly may be the result of prenatal asphyxia, maternal diabetes, patent ductus arteriosus (PDA), an associated congenital heart anomaly, or simply poor lung expansion. These findings may be altered with early surfactant therapy and adequate mechanical ventilation. (See the image below.)
Chest radiographs in a premature infant with respiratory distress syndrome before and after surfactant treatment. Left: Initial radiograph shows poor lung expansion, air bronchogram, and reticular granular appearance. Right: Repeat chest radiograph obtained when the neonate is aged 3 hours and after surfactant therapy demonstrates marked improvement.
The radiologic findings of respiratory distress syndrome cannot be reliably differentiated from those of pneumonia, which is most commonly caused by group B beta-hemolytic streptococci. If the radiograph shows streaky opacities, the diagnosis of Ureaplasma or Mycoplasma pneumonia should be considered and confirmed by means of tracheal aspirate cultures grown in the appropriate medium.
Echocardiography
Echocardiographic evaluation is performed in selected infants to assist in diagnosing PDA and in determining the direction and degree of shunting on Doppler study. It is also useful in diagnosing pulmonary hypertension, assessing cardiac function, and excluding structural heart disease.
Pulmonary Mechanics Testing
Although pulmonary mechanics testing (PMT) has primarily been used as a research tool in the past, newer ventilators are equipped with PMT capabilities to assist the neonatologist in adequately managing the changing pulmonary course of premature newborn infants with respiratory distress syndrome.
Constant PMT may be helpful in preventing volutrauma due to alveolar and airway overdistension. Monitoring may also facilitate weaning the infant from the ventilator after surfactant therapy or in determining if the infant can be extubated. However, clinical studies of PMT to date have not proven its long-term outcome benefits in neonates with respiratory distress syndrome.
Infants with respiratory distress syndrome have substantially decreased lung compliance, with a range of 0.0005-0.0001 L/cm water. Therefore, for the same pressure gradient, the delivered tidal volume is reduced in premature infants with respiratory distress syndrome compared with healthy newborn infants.
Pulmonary compliance may considerably improve after surfactant administration. Hence, the patient's lung compliance and end-expiratory tidal volume should be monitored closely after surfactant therapy, and the peak inspiratory pressure should be adjusted accordingly.
The resistance (airway and tissues) may be normal or increased. The time constant and the corresponding pressure and volume equilibration are shortened. The anatomic dead space and the functional residual capacity are increased.
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Chest radiographs in a premature infant with respiratory distress syndrome before and after surfactant treatment. Left: Initial radiograph shows poor lung expansion, air bronchogram, and reticular granular appearance. Right: Repeat chest radiograph obtained when the neonate is aged 3 hours and after surfactant therapy demonstrates marked improvement.
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Microscopic appearance of lungs of an infant with respiratory distress syndrome. Hematoxylin and eosin stain shows hyaline membranes (pink areas).
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Schematic outlines the pathology of respiratory distress syndrome (RDS). Infants may recover completely or develop chronic lung damage, resulting in bronchopulmonary dysplasia (BPD). FiO2 = fraction of inspired oxygen; HMD = hyaline membrane disease; V/Q = ventilation perfusion.
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Bar chart demonstrates the composition of lung surfactant. About 1% of the 10% protein component comprises surfactant apoproteins; the remaining proteins are derived from alveolar exudate.
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Schematic show surfactant metabolism, with a single alveolus is shown and the location and movement of surfactant components. Surfactant components are synthesized from precursors in the endoplasmic reticulum and transported through the Golgi apparatus by multivesicular bodies. Components are ultimately packaged in lamellar bodies, which are intracellular storage granules for surfactant before its secretion. After secretion (exocytosis) into the liquid lining of the alveolus, surfactant phospholipids are organized into a complex lattice called tubular myelin. Tubular myelin is believed to generate the phospholipid that provides material for a monolayer at the air-liquid interface in the alveolus, which lowers surface tension. Surfactant phospholipids and proteins are subsequently taken back into type II cells, in the form of small vesicles, apparently by a specific pathway that involves endosomes, and then are transported for storage into lamellar bodies for recycling. Alveolar macrophages also take up some surfactant in the liquid layer. A single transit of the phospholipid components of surfactant through the alveolar lumen normally requires a few hours. The phospholipid in the lumen is taken back into type II cell and is reused 10 times before being degraded. Surfactant proteins are synthesized in polyribosomes and extensively modified in the endoplasmic reticulum, Golgi apparatus, and multivesicular bodies. Surfactant proteins are detected in lamellar bodies or secretory vesicles closely associated with lamellar bodies before they are secreted into the alveolus.
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Bottom curve reflects findings from lungs obtained at postmortem from an infant with hyaline membrane disease (HMD). Lungs with HMD require far more pressure than to achieve a given volume of inflation than do lungs obtained from an infant dying of a nonrespiratory cause. Arrows indicate inspiratory and expiratory limbs of the pressure-volume curves. Note the decreased lung compliance and increased critical opening and closing pressures, respectively, in the premature infant with HMD.
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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 = ■.
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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 = ■.
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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).
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Assisted ventilation newborn –Intubation and meconium aspiration. Video courtesy of Therese Canares, MD, and Jonathan Valente, MD, Rhode Island Hospital, Brown University.
Tables
- Table 1. Meta-Analysis of Early Versus Delayed Surfactant Treatment of RDS
- Table 2. Surfactant Preparations: Type, Source, Composition, Dosages, and Other Information
- Table 3. Results of a Meta-Analysis of Separate Clinical Trials of the Treatment of Respiratory Distress Syndrome With Natural or Synthetic Surfactant Preparations
- Table 4. Results of a Meta-Analysis of Separate Clinical Trials of the Prophylactic Use of Natural or Synthetic Surfactant Preparations
- Table 5. Results of a Meta-Analysis of Head-to-Head Trials With Natural Versus Synthetic Surfactants
- Table 6. Meta-Analysis of Clinical Trials Comparing Prophylactic Use of Surfactant Versus Rescue Treatment of Infants With Respiratory Distress Syndrome
- Table 7. Results of a Meta-Analysis of Clinical Trials to Compare Multiple Doses With a Single Dose of Surfactant
- Table 8. Inhaled Nitric Oxide Therapy in Preterm Infants and Outcome Measures
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%) |
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) |
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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 |
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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 |
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Natural Surfactant Treatment |
Synthetic Surfactant Treatment |
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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%) |
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Natural Prophylaxis |
Synthetic Prophylaxis |
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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%) |
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%) |
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 |
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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%) |
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%) |
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 [65] |
80 |
27 |
1000 |
30 |
53% |
7 |
5 ppm |
-15% |
Schreiber et al [66] |
201 |
27.2 |
970 |
10 |
22.5% |
7 |
10 ppm |
-15% |
Van Meurs et al [67] |
420 |
26 |
839 |
22 |
44% |
3 |
10 ppm |
-2% |
Ballard et al [68] |
587 |
26 |
760 |
7 |
6% |
24 |
20 ppm |
-11% |
Kinsella et al [69] |
793 |
25 |
792 |
5 |
25% |
14 |
5 ppm |
-4% |
