Diagnostic Considerations
Conditions to consider in the differential diagnosis of respiratory distress syndrome include the following:
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Metabolic problems
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Hematologic problems
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Pulmonary air leaks
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Congenital anomalies of the lungs
Differential Diagnoses
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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% |
