830 NEONATOLOGY

C. Infants with “asymptomatic” polycythemia have an increased risk for neurologic

sequelae, but normocythemic controls with the same perinatal histories have a
similarly increased risk.

Selected References
Dempsey EM, Barrington K. Short and long term outcomes following partial exchange trans-
fusion in the polycythaemic newborn: a systematic review. Arch Dis Child Fetal Neonatal
Td. 2006;91:F2—F6.
Dempsey EM, Barrington K. Crystalloid or colloid for partial exchange transfusion in neonatal
polycythemia: a systematic review and meta-analysis. Acta Paediatr. 2005;94:1650—1655.
Mercer JS, Vohr BR, McGrath MM, Padbury JF, Wallach M, Oh W. Delayed cord clamping in
very preterm infants reduces the incidence of intraventricular hemorrhage and late-onset
sepsis: a randomized, controlled trial. Pediatrics. 2006;117:1235—1242.
Morag I, Strauss T, Lubin D, Schushan-Eisen I, Kenet G, Kuint J. Restrictive management of
neonatal polycythemia. Am J Perinatol. 2011;2S:677—6S2.
Oh W. Timing of umbilical cord clamping at birth in full-term infants. JAMA. 2007;11:1257
— 1258.
Rosenkrantz TS. Polycythemia and hyperviscosity in the newborn. Semin Thromb Hemost.
2003:29:515—S27.
Seng YC, Rajadurai VS. Twin-twin transfusion syndrome: a five year review. Arch Dis Child
Fetal Neonatal Ed. 2000;83:F168—F170.

123Renal Failure, ACute (Acute Kidney Injury)

I. Definition. The term acute renal failure (ARF) has now been replaced with the term
acute kidney injury (AKI), and is now used to encompass mild renal dysfunction to
complete anuric kidney failure. In neonates, ARF/AKI is defined as a serum
creatinine
>1.5 mg/dL (132.6 mmol/L), regardless of age or urine output, with normal maternal
renal function. ARF/AKI can be anuric (absence of urinary output by 24—48 hours of
age), oliguric (urine output of <1.0 mL/kg), or nonoliguric (>1.0 mL/kg). ARF/AKI
can present with normal urinary output (seen in asphyxiated neonates). Normal urine
output is - 1—3 mL/kg/h with almost all infants voiding within 24 hours of birth. See
Table 68—1, page 467.
II. Incidence. In some studies, as many as 24% of neonatal intensive care unit (NICU)-
admitted neonates have some degree of renal failure. Prerenal is the most common
type in the neonate, which may be identified in up to 85%› of cases. Renal incidence
is 6-8% and postrenal 3-5*ñi.
III. Pathophysiology. The normal newborn kidney has poor concentrating ability (maxi-
mum specific gravity 1.025). Renal injury leads to problems with volume overload,
hyperkalemia, acidosis, hyperphosphatemia, and hypocalcemia. Postnatally
ARF/AKI is traditionally divided into 3 categories:
A. Prerenal failure is due to decreased renal blood flow/perfusion, which leads to a
decreased renal function in a normal kidney. Any condition that causes
inadequate renal perfusion can cause prerenal ARF/AKI. Common causes include
hemor- rhage, dehydration, septic shock, congestive heart failure, patent ductus
arterio- sus (PDA), and necrotizing enterocolitis (NEC). Other causes include
respiratory distress syndrome (RDS), hypoxia, congenital heart disease,
hypoalbuminemia,
123: RENAL FAILU RE, ACUTE (ACUTE KI DNEY INJU 831
RY)
perinatal asphyxia, extracorporeal membrane oxygenation/ extracorporeal life
sup- port (ECMO/ECLS), and hypotension. Medications in neonates that can
decrease renal blood flow include indomethacin, ibuprofen, angiotensin-
converting enzyme (ACE) inhibitors, and phenylephrine eye drops. Maternal
use of nonsteroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors, or
cyclooxygenase (COX)-2 inhibitors can also decrease renal blood flow.
B. Intrinsic renal failure refers to structural damage to the kidneys, which causes
renal tubular dysfunction. It includes acute tubular necrosis, congenital
anomalies, vascular lesions, and infections/toxins. Acute tubular necrosis
(ATN) is the most common cause, and it can be caused by prolonged poor
renal perfusion, ischemia or hypoxia, sepsis, cardiac surgery (blood product
transfusions), or nephrotoxins (aminoglycosides, NSAIDs, amphotericin b,
contrast agents, or acyclovir). Other causes include congenital anomalies (eg,
bilateral renal agenesis, polycystic kid- ney disease, congenital nephrotic
syndrome of the Finnish type, renal hypopla- sia/dysplasia), vascular lesions
(bilateral renal vein/artery thrombosis, cortical necrosis, disseminated
intravascular coagulation [DIC] ), infections (congenital: syphilis, toxoplasmosis;
candidiasis, pyelonephritis), exogenous toxins (uric acid nephropathy,
myoglobinuria, hemoglobinuria).
C. Postrenal/obstructive. All of the causes involve obstruction of urinary
outflow after the urine has been produced by the kidneys. The most common
cause in males is posterior urethral valves. Other causes include urethral
strictures, meatal stenosis, bilateral uteropelvic/vesical junction obstruction,
neurogenic bladder, large ureteroceles, blocked urinary drainage catheters,
megaureter, and prune belly syndrome. Rare causes in neonates include
extrinsic tumor compression of the bladder or ureters (sacrococcygeal
teratoma) or intrinsic obstruction (neph- rolithiasis, bilateral fungal bezoar).
IV. Risk factors. Include dehydration, sepsis, asphyxia, administration of
nephrotoxic drugs, prematurity, very low birthweight infants, congenital heart
disease undergoing cardiopulmonary bypass, and ECMO/ECLS. Maternal diabetes
may increase the risk for renal vein thrombosis and subsequent renal
insufficiency.
V. Clinical presentation
A. Decreased or absent urine output. Low or absent urine output is usually the
pre- senting problem. Virtually all infants void by 24 hours after birth (see
Chapter 68).
B. Family history. History of urinary tract disease in other family members;
history of oligohydramnios, which frequently accompanies urinary outflow
obstruction or severe renal dysplasia or agenesis; and maternal diabetes
should be obtained.
C. Physical examination
1. Abdominal mass may be due to a distended bladder, polycystic kidneys,
hydro- nephrosis, or tumors
2. Potter facies is associated with renal agenesis
3. Meningomyelocele is associated with neurogenic bladder
4. Pulmonary hypoplasia is due to severe oligohydramnios in utero
5. Urinary ascites may be seen with posterior urethral valves and severe
upper urinary tract obstruction
6. Prune belly syndrome. Hypoplasia of the abdominal wall musculature,
crypt- orchidism, and dilated upper urinary tracts
VI. Diagnosis
A. Urethral catheterization. Use a SF or 8F feeding tube to measure volume of
retained urine of monitor output (see Chapter 26).
B. Laboratory studies
1. Blood urea nitrogen (BUN) and creatinine
a. BUN. 15—20 mg/dL suggests dehydration or renal insufficiency.
b. Creatinine. Normal serum creatinine values are 0.8—1.0 mg/dL at 1
day, 0.7—0.8 mg/dL at 3 days, and <0.6 mg/dL by 7 days of life.
Higher values suggest renal disease except in low birthweight infants, in
whom a creatinine
832 NEONATOLOGY

Table 123—1. URIIiARY IIiDICES In THE 8E08ATE USED IB THE E¥ALIJATI0Ii OF ACUTE RE#AL
FAILURE/ACUTE KlDIiEY l/iJ8RY
Urinary Indices Prerenal Intrinsic
Urine osmolality (mosmoI/kg water) >400 <400
Urine sodium (mEq/L) f1 *19
Urine/plasma creatinine ratio 29 * 16 10 *4
Fractional excretion of s0dium (FeNa) (%) <2.5 >2.5
Renal failure index (RFI) <3.0 >3.0

level of <1.6 mg/dL is considered normal. (Rule of thumb: If the creatinine

doubles, then 50"% of the renal function has been lost.)
2. Urinary indices. (Table 123—1) A spot urine osmolality, serum and spot urine
sodium, and serum and urine creatinine are used to calculate the fractional
excretion of sodium (FeNa) and the renal failure index (RFI). These indices
are of limited value if measured while the effects of diuretics, such as
furosemide, are present.

Urine Na Plasma Cr
FENa = Urine Cr X Pl Na X
Urine Na X Serum Cr
Urine Cr

3. Complete blood count (CBC) and platelet count. May reveal thrombocyto-
penia, which is seen with sepsis or renal vein thrombosis.
4. Serum potassium. May be increased with renal insufficiency.
5. Urinalysis. May reveal hematuria (associated with renal vein thrombosis,
tumors, or DIC) or pyuria, suggesting urinary tract infection.
6. Biomarkers
a. Serum and urinary cystatic C levels. Used to calculate glomerular filtra-
tion rate
b. Plasma and urinary neutrophil gelatinase—associated lipocalin
(NGAL) levels.
c. Serum and urinary interleukin (IL)-18 levels.
d. Urinary albumin-to-creatinine ratio (ACR).
C. Diagnostic fluid challenge. If the patient does not have clinical volume overload or
congestive failure, give a fluid challenge. Administer normal saline or colloid
solution, 5-10 mL/kg as an intravenous bolus, and repeat once as needed. If there is
no response, give furosemide, 1 mg/kg IV. If there is still no increase in urine output,
obstruction above the level of the bladder must be ruled out by ultrasound
examination. If there is no evidence of obstruction, and the patient does not respond
to these maneuvers, the most likely cause of anuria or oliguria is intrinsic renal
failure.
D. Imaging studies
1. Abdominal ultrasonography. May identify hydronephrosis, dilated ureters,
abdominal masses, a distended bladder, or renal vein thrombosis.
2. Abdominal radiograph studies. May show spina bifida or an absent sacrum,
which may be associated with a neurogenic bladder. Displaced bowel loops
suggest the presence of a space-occupying mass.
3. Radionuclide scanning. May be used to assess function of renal
parenchymal, but is less accurate in neonates due to immature kidneys.
123: RENAL FAILU RE, ACUTE (ACUTE KI DNEY INJU RY) 833

VII. Management. See also Chapter his.

A. General management
1. Replace insensible fluid losses (preterm, 50-70 mL/kg/d; term, 30 mL/kg/d)
plus fluid output (urine and gastrointestinal tract).
2. Keep strict intake and output and frequent weights.
3. Monitor serum sodium and potassium levels frequently, and replace losses
cautiously as needed. Hyperkalemia may be lethal.
4. Restrict protein to <2 g/kg/d, and ensure adequate nonprotein caloric intake.
Breast milk or formulas such as Similar PM 60/40 are frequently used for
infants with renal failure.
5. Hyperphosphatemia and hypocalcemia frequently coexist, and phosphate
binders such as aluminum hydroxide, 50—150 mg/kg/d orally, should be used
to normalize phosphate. Once phosphate is normalized, calcium (with or with-
out vitamin D supplementation) is usually needed.
6. For tetany or convulsions, acute intravenous calcium replacement with 10*ñ›
calcium gluconate, 40 mg/kg, or 10% calcium chloride will increase the
serum calcium 1 mg/dL. Monitor ionized calcium.
7. Metabolic acidosis may require chronic oral bicarbonate supplementation.
Blood pressure should be monitored serially because these infants are always
at risk for chronic hypertension. Intravenous bicarbonate therapy should be
given if the pH is <7.25 or the serum bicarbonate (HCO,) is <12 mEq.

HCO deficit = (24 — observed) 0.5 X body weight (kg)

B. Definitive management
1. Prerenal failure. Treated by providing volume to increase and restore renal
perfusion and to treat the underlying cause.
2. Postrenal failure. Acute management involves bypassing the obstruction with
a bladder catheter or by percutaneous nephrostomy drainage, depending on
the level of the obstruction. Operative intervention with surgical repair may
be indicated to relieve obstruction. Urinary tract infection prophylaxis may be
indicated. Consult with pediatric urology.
3. Intrinsic renal disease. Stop or adjust doses of any nephrotoxic medications
if possible. Supportive therapy is indicated (see previous text). Diuretics
(furo- semide, 1—2 mg/kg/dose) may increase urine output and aid in fluid
manage- ment, but studies show that it does not improve the course of kidney
injury. Low-dose dopamine can increase renal perfus’ion. (Nofe: No studies
in neonates are reported, but studies in adults have shown it does not improve
survival.) Observe for hyponatremia, hyperkalemia, hyperphosphatemia,
hypocalcemia, and metabolic acidosis as they can occur frequently in intrinsic
renal disease. Follow blood pressure as hypertension can occur (more
common in renal artery/ venous thrombosis). Renal feeding formulas that
have a low renal solute and phosphorus should be considered. Pediatric
nephrology should be consulted.
4. Renal replacement therapy (peritoneal dialysis, hemodialysis, hemofiltra-
tion with or without dialysis). This is used if other measures fail. If
recovery of renal function is expected or if renal transplantation is
considered an option when the child is older, peritoneal dialysis is the
treatment most commonly used in the neonate.
VIII. Prognosis. The prognosis from ARF/AKI depends on the underlying cause or the
extent of damage. If renal disease is caused by toxins or acute tubular necrosis, renal
function may recover to some extent with time. Chronic renal failure may ensue as
neonates with ARF/AKI are at increased risk. Mortality and morbidity are increased
in newborns with multiorgan failure. Factors that increase mortality include
hypotension, need for mechanical ventilation, dialysis, use ofvasopressors,
hemodynamic instability, and multiorgan failure. Follow-up with monitoring of
urine, renal function, and blood pressure is necessary.
834 NEONATOLOGY

Selected References
Askenazi D, Koralkar R, Levitan EB, et al. Baseline values of candidate urine acute kidney
injury (AKI) biomarkers vary by gestational age in premature infants. Pediatr Res.
2011;70:302-306.
Askenazi DJ, Ambalavanan N, Goldstein SL. Acute kidney injury in critically ill newborns:
what do we know? What do we need to learn? Pediatr Nephrol. 2009;24:265-274.
Askenazi DJ, Ambalavanan N, Hamilton K, et al. Acute kidney injury and renal replacement
therapy independently predict mortality in neonatal and pediatric noncardiac patients
on extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2011;12:e1—e6.
Askenazi DJ, Montesanti A, Hunley H, et al. Urine biomarkers predict acute kidney injury and
mortality in very low birth weight infants. J Pediatr. 2011;159:907—912;e1.
Blinder JJ, Goldstein SL, Lee VV, et al. Congenital heart surgery in infants: effects of acute
kidney injury on outcomes. J Thorac Cardiovasc Surg. 2012;143:368—374.
Chua AN, Sar wal MMl. Acute renal failure management in the neonate. NeoReviews
200S;6;e369—e376.
Gadepalli SK, Selewski DT, Drongowski RA, Mychaliska GB. Acute kidney injury in
congeni- tal diaphragmatic hernia requiring extracorporeal life support: an insidious
problem. J Pediatr Surg. 2011;46:630-635.
Goldstein SL. Advances in pediatric renal replacement therapy for acute kidney injury. Scorn
Dial. 2011;24:187—191.
Jetton GJ, Askenazi DJ. Update on acute kidney injury in the neonate. Corr Opin Pediatr
2012 (Epub ahead of print).
Koralkar R, Ambalavanan N, Levitan EB, McGwin G, Goldstein S, Askenazi D. Acute
kidney injury reduces survival in very low birth weight infants. Pediatr Res.
2011;69:354-358.
Krawczeski CD, Woo JG, Wang Y, Bennett MR, Ma Q, Devarajan P. Neutrophil gelatinase-
associated lipocalin concentrations predict development of acute kidney injury
in neonates and children after cardiopulmonary bypass. J Pediatr. 2011;158: 1009—
1015;e 1.

124Respirat0ry Distress Syndr0me

I. Definition. Respiratory distress syndrome (RDS) was previously called hyaline

membrane disease. The Vermont Oxford Network definition for RDS requires that
babies have:
A. An arterial oxygen tension (Pao,) <50 mm Hg and central cyanosis in room
air, a requirement for supplemental oxygen to maintain Pao 2 >50 mm Hg, or a
requirement for supplemental oxygen to maintain a pulse oximeter saturation
over 85 */ .
B. A characteristic chest radiographic appearance (uniform reticulogranular pat- tern
to lung fields with or without low lung volumes and air bronchogram) within the
first 24 hours of life. The clinical course of the disease varies with the size of the
infant, severity of disease, use of surfactant replacement therapy, presence of
infection, degree of shunting of blood through the patent ductus arteriosus
(PDA), and whether or not assisted ventilation was initiated.
II. Incidence. Incidence of RDS is -91% at 23—25 weeks’ gestation, 88% at 26—27 weeks’
gestation, 74 */› at 25 —29 weeks’ gestation, and 52%› at 30—31 weeks’ gestation.
The incidence and severity of RDS are expected to decrease after the increase in use
124: RESPIRATORY DISTRESS SYNDROME 835

of antenatal steroids in recent years. After the introduction of exogenous surfactant,

the survival from RDS is at >90%›. During the surfactant era, RDS accounts for <6o/»
of all neonatal deaths.
III. Pathophysiology. Surfactant deficiency is the primary cause of RDS, often compli-
cated by an overly compliant chest wall. Both factors lead to progressive atelectasis
and failure to develop an effective functional residual capacity (FRC). Surfactant is a
surface-active material produced by airway epithelial cells called type II
pneumocytes. This cell line differentiates, and surfactant synthesis begins at 24-28
weeks’ gestation. Type II cells are sensitive to and decreased byasphyxial insults in
the perinatal period. The maturation of this cell line is delayed in the presence of fetal
hyperinsulinemia. The maturity of type II cells is enhanced by the administration of
antenatal corticosteroids and by chronic intrauterine stress such as pregnancy-induced
hypertension, intrauter- ine growth restriction, and twin gestation. Surfactant,
composed chiefly of phospho- lipid (75%) and protein (10%), is produced and stored
in the characteristic lamellar bodies of type II pneumocytes. This lipoprotein is
released into the airways, where it functions to decrease surface tension and maintain
alveolar expansion at physiologic pressures.
A. Lack of surfactant. In the absence of surfactant, the small airspaces collapse; each
expiration results in progressive atelectasis. Exudative proteinaceous material and
epithelial debris, resulting from progressive cellular damage, collect in the airway
and directly decrease total lung capacity. In pathologic specimens, this material
stains typically as eosinophilic hyaline membranes lining the alveolar spaces and
extending into small airways.
B. Presence of an overly compliant chest wall. In the presence of a chest wall with
weak structural support secondary to prematurity, the large negative pressures
generated to open the collapsed airways cause retraction and deformation of the
chest wall instead of inflation of the poorly compliant lungs.
C. Decreased intrathoracic pressure. The infant with RDS who is <30 weeks’
gesta- tional age often has immediate respiratory failure because of an inability to
gener- ate the intrathoracic pressure necessary to inflate the lungs without
surfactant.
D. Shunting. The presence or absence of a cardiovascular shunt through a PDA or
foramen ovale, or both, may change the presentation or course of the disease
process. Shortly after birth, the predominant shunting is right to left across the
foramen ovale into the left atrium, which may result in venous admixture and
worsening hypoxemia. After 18—24 hours, left-to-right shunting through the
PDA may become predominant as a result of falling pulmonary vascular
resistance, leading to pulmonary edema and impaired alveolar gas exchange.
Unfortunately, this usually occurs when the infant is starting to recover from RDS
and can be aggravated by surfactant replacement therapy.
IV. Risk factors. Table 124—1 lists factors that increase or decrease the risk of RDS.

Tabe 124—1. RISKFACTORSTMATINCREASEOR DEOREASETME

RISKOF RESPIRATORY DISTRESSSYNDROME
Increased Risk Decreased Risk
Prematurity P£0l0nged rupture 0f membranes
Male sex Femaesex
Fa u ilial predisposition Vaginal delivery
Cesarean delivery without Narcotic/cocaine
labor Perinatal asphyxia use Û0FtiC0StPf0idS
IŸÏ Mlti §l9 g9St üt i0FI
Thyroid h0rmone
Maternal diadetes Tocolytic agents
836 NEONATOLOGY

V. Clinical presentation
A. History. The infant is often preterm or has a history of asphyxia in the
perinatal period. Infants have some respiratory difficulty at birth, which
becomes progres- sively more severe. The classic worsening of the atelectasis
seen on chest radiograph and increasing oxygen requirement for these infants
have been greatly modified by the availability of exogenous surfactant therapy
and effective mechanical ventila- tory support.
B. Physical examination. The infant with RDS exhibits tachypnea, grunting, nasal
flaring, and retractions of the chest wall. The infant may have cyanosis in
room air. Grunting occurs when the infant partially closes the vocal cords to
prolong expiration and develop or maintain some FRC. This mechanism
actually improves alveolar ventilation. The retractions occur and increase as
the infant is forced to develop high transpulmonary pressure to reinflate
atelectatic air spaces.
VI. Diagnosis
A. Chest radiograph. An anteroposterior chest radiograph should be obtained for
all infants with respiratory distress of any duration. The typical radiographic
finding of RDS is a uniform reticulogranular pattern, referred to as a ground-
glass appear- ance, accompanied by peripheral air bronchograms (see Figure 11
—13). During the clinical course, sequential radiographs may reveal air leaks
secondary to mechani- cal ventilatory intervention as well as the onset of
changes compatible with bron- chopulmonary dysplasia/chronic lung disease
(BPD/CLD) (see Figure 11—17).
B. Laboratory studies
1. Blood gas sampling. Essential in the management of RDS. Usually,
intermittent arterial sampling is performed. Although there is no
consensus, most neona- tologists agree that arterial oxygen tensions of 50-
70 mm Hg and arterial carbon dioxide tensions of 45-60 mm Hg are
acceptable. Most would maintain the pH at or above 7.25 and the
arterial oxygen saturation at h5—93%. In addition, continuous
transcutaneous oxygen and carbon dioxide monitors or oxygen saturation
monitors, or both, are proving valuable in the minute-to-minute
monitoring of these infants.
2. Sepsis workup. A partial sepsis workup, including complete blood cell
count and blood culture, should be considered for each infant with a
diagnosis of RDS because early-onset sepsis (eg, infection with group B
$treptococcu5) can be indistinguishable from RDS on clinical grounds
alone.
3. Serum glucose levels. May be high or low initially and must be
monitored closely to assess the adequacy of dextrose infusion.
Hypoglycemia alone can lead to tachypnea and respiratory distress.
4. Serum electrolyte levels and calcium. Should be monitored every 12—24
hours for management of parenteral fluids. Hypocalcemia can contribute
to more respiratory symptoms and is common in sick, nonfed, preterm, or
asphyxiated infants.
C. Echocardiography. A valuable diagnostic tool in the evaluation of an infant
with hypoxemia and respiratory distress. It is used to confirm the diagnosis of
PDA as well as to document response to therapy. Significant congenital heart
disease can be excluded by this technique as well.
VII. Management
A. Prevention
1. Antenatal corticosteroids. Treatment with antenatal corticosteroids is
associ- ated with an overall reduction in neonatal death, RDS,
intraventricular hemor- rhage (IVH), necrotizing enterocolitis (NEC),
respiratory support, intensive care admissions, and systemic infections in
the first 48 hours of life. A single course of antenatal steroids is
recommended between 24 and 34 weeks of ges- tation to all women at
risk of preterm delivery within 7 days. A single course should be
administered to women with premature rupture of membranes before
32 weeks of gestation to reduce the risks of RDS, perinatal mortality, and
124: RESPIRATORY DISTRESS 837
SYNDROME
other morbidities. The efficacy of corticosteroid use at 32—33 completed
weeks for preterm prelabor rupture of membranes is unclear based on
current evi- dence, but treatment may be beneficial, especially if
pulmonary immaturity is documented. Antenatal corticosteroids should be
considered for threatened preterm birth at 22-23 weeks of gestation.
Antenatal corticosteroid exposure reduced improved survival of extremely
preterm infants. Antenatal treatment with corticosteroids at 34—36 weeks
of pregnancy has not reduced the risk of respiratory morbidity in
neonates. The optimal treatment to delivery interval is
>24 and <7 days after the start of steroid treatment. A second course
should be considered if the risk from RDS is felt to outweigh the
uncertainty about pos- sible long-term adverse effects. The recommended
glucocorticoid regimen con- sists of the administration to the mother of
two 12-mg doses of betamethasone given intramuscularly 24 hours apart.
Dexamethasone is not recommended because of increased risk for cystic
periventricular leukomalacia among very premature infants exposed to
the drug prenatally.
2. Preventive measures. Several preventive measures may improve the
survival of infants at risk for RDS and include antenatal
ultrasonography for more accurate assessment of gestational age and
fetal well being, continuous fetal monitoring to document fetal well-being
during labor or to signal the need for intervention when fetal distress is
discovered, tocolytic agents that prevent and treat preterm labor, and
assessment of fetal lung maturity before delivery (lecithin-to-sphingomyelin
ratio and phosphatidylglycerol; or amniotic fluid lamellar bodies, see
Chapter 1) to prevent iatrogenic prematurity.
B. Surfactant replacement. (See also Chapter S.) Now considered a standard of
care in the treatment of intubated infants with RDS. Since the late 1980s,
>30 random- ized clinical trials involving >6000 infants have been conducted.
Systematic reviews of these trials demonstrate that surfactant, whether used
prophylactically in the deliver y room or in the treatment of established
disease, leads to a significant decrease in the risk of pneumothorax and the
risk of death. These benefits were observed in both the trials of natural
surfactant extracts and synthetic surfactants. Prophylactic surfactant
replacement to prevent RDS in infants born at <31 weeks’ gestation has
reduced the risk of death or BPD/CLD but may result in some infants being
intubated and receiving treatment unnecessarily. A recent consensus state- ment
recommends surfactant prophylaxis (within 1ñ minutes of birth) to almost all
infants <26 weeks’ gestation. Prophylaxis should also be administered to all
preterm infants with RDS who require delivery-room intubation for
stabilization. Early rescue surfactant should be administered to preterm babies
with an evidence of RDS. The effect of surfactant therapy is better the earlier in
the course of RDS it is given. A second, sometimes a third dose of surfactant
should be administered in cases with ongoing evidence of RDS (ie, persistent
need of mechanical ventilation and oxygen supplementation).
Natural (derived from animal lungs) surfactant preparations are better
than synthetic (protein-free) at reducing pulmonary air leaks. Natural
surfactants are therefore the treatment of choice. Trials comparing natural
bovine surfactants, given prophylactically or as rescue therapy, have shown
similar outcomes. Trials comparing bovine and porcine-derived surfactants
have shown a more rapid im- provement in oxygenation in the latter. A better
survival has been demonstrated in a meta-analysis comparing a 200-mg/kg
dose of poractant alfa with 100 mg/kg of beractant, or 100 mg/kg poractant
alfa, for rescue treatment of moderate to se- vere RDS. Poractant alfa
treatment for RDS was in a retrospective study associated with a significantly
reduced likelihood of death, when compared with calfactant, and a trend
toward reduced mortality when compared with beractant.
Mechanical ventilation can be avoided by using the INSURE (Intubate-Surfac-
tant-Extubate to CPAP [continuous positive airway pressure]) technique when
surfactant is administered. This has reduced need for mechanical ventilation
and
838 NEONATOLOGY

development of BPD/CLD in randomized trials. Immediate (or early)

extubation to noninvasive respiratory support (CPAP or nasal intermittent
positive ventila- tion) following surfactant administration should be
considered in otherwise sta- bile infants.
Currently, long-term follow-up studies have not shown significant
differences between surfactant-treated patients and nontreated control
groups with regard to PDA, IVH, retinopathy of prematurity, NEC, and
BPD/CLD. Evidence exists that the length of stay on mechanical ventilation
and total ventilator days have been reduced with the use of surfactant at all
gestational age levels, even with the increase of extremely low birthweight
infants. A dramatic fall in deaths from RDS began in 1991. This probably
reflected the introduction of surfactant replacement therapy. In long-term
follow-up studies, no adverse effects attributable to surfac- tant therapy
have been identified.
C. Respiratory support
1. Endotracheal intubation and mechanical ventilation. Mainstays of therapy
for infants with RDS in whom apnea or hypoxemia with respiratory
acidosis develops. Mechanical ventilation (MV) modes include
conventional, such as intermittent positive pressure ventilation (IPPV), and
high-frequency oscilla- tory ventilation (HFOV). Ventilators with the
capacity to synchronize respira- tory effort may generate less inadvertent
airway pressure and lessen barotrauma. Ventilator settings should be
adjusted frequently to maintain the lowest pos- sible pressures and
inspired oxygen concentrations in an attempt to minimize damage to
parenchymal tissue. HFOV may be beneficial as a rescue therapy in
infants with respiratory failure on IPPV. Rescue HFOV reduces pulmonary
air leaks but is associated with an increased risk of IVH. Insufficient
evidence exists to recommend the routine use of HFOV instead of
conventional ventilation for preterm infants with lung disease. Hypocapnia is
associated with increased risks of BPD/CLD and periventricular leukomalacia
and should therefore be avoided. To minimize duration of MV, weaning
from MV should be started as soon as satisfactory gas exchange is
achieved. Caffeine should be routinely used for very preterm neonates with
RDS to augment extubation.
2. Continuous positive airway pressure (CPAP) and nasal synchronized inter-
mittent mandatory ventilation (SIMV). Nasal CPAP (NCPAP) or nasopha-
ryngeal CPAP (NPCPAP) can be used early to delay or prevent the need
for endotracheal intubation and mechanical ventilation. CPAP treatment is
rec- ommended to be started from birth in all infants at risk of RDS, as
those born at <30 weeks’ gestation. In this way some infants with RDS can
be managed without surfactant replacement. By not using surfactant,
however, the risk of pneumothorax is increased. Use of NCPAP or
NPCPAP on extubation after mechanical ventilation decreases the chance of
reintubation, when at least 5 cm H2O pressure is applied. Nasal SIMV is a
potentially useful way of augment- ing NCPAP. The ability to synchronize
the ventilator breaths with the infant’s own respiratory cycle has made
this mode of ventilation feasible. In 3 trials, nasal SIMV has reduced the
incidence of symptoms of extubation failure when compared with NCPAP.
Short binasal prongs should be used instead of a single prong.
3. Humidified high-flow nasal cannula system. This has been introduced to
neonatal respiratory care as a way to provide positive distending pressure,
even comparable to NCPAP, to a neonate with respiratory distress. It aims
to maxi- mize patient tolerance by using heated, humidified gas flow (ñ 1
L/min). Studies comparing high-flow nasal cannula with nasal SIMV for
RDS are going on.
4. Complications. Pulmonary air leaks, such as pneumothorax, pneumomediasti-
num, pneumopericardium, and pulmonary interstitial emphysema, may occur
(see Chapter S1). Chronic complications include respiratory problems such
as BPD/CLD (see Chapter 84) and tracheal stenosis.
124: RESPIRATORY DISTRESS SYNDROME 839

D. Fluid and nutritional support. In the very ill infant, it is possible to maintain
nutritional support with parenteral nutrition for an extended period. Full par-
enteral nutrition and minimal enteral feeding can be initiated on the first day of
life. Careful fluid balance should, however, be maintained. The specific needs of
preterm and term infants are becoming better understood, and the nutrient prepa-
rations available reflect this understanding (see Chapters 9 and 10).
E. Antibiotic therapy. Antibiotics that cover the most common neonatal infections
are usually begun initially.
F. Sedation. Commonly used to control ventilation in these sick infants. Morphine,
fentanyl, or lorazepam may be used for analgesia as well as sedation, but there
is significant controversy surrounding such treatment. Reported advantages of
treat- ment include improved ventilator synchrony and pulmonary function.
Decreased adverse long-term neurologic sequelae have been suggested.
Neuroendocrine responses to mechanical ventilation are alleviated by opioid
treatment, which may be beneficial in the long term. However, clinicians should
consider adverse effects of medication, especially opioids, including hypotension
with morphine and chest wall rigidity with fentanyl. Tolerance, dependence, and
withdrawal occur. In addi- tion, pharmacologic treatment does not decrease
adverse sequelae, at least in the short term. The most significant gaps in
knowledge include the inability to assess chronic pain in this population and the
long-term effects of treatment. Minimal handling to avoid pain is an important
means to decrease need for pain manage- ment in ventilated infants. Muscle
paralysis with pancuronium for infants with RDS remains controversial.
Sedation might be indicated for infants who “fight” the ventilator and exhale
during the inspiratory cycle of MV. This respiratory pattern may increase the
likelihood of complication such as air leak and therefore should be avoided.
Sedation of infants with fluctuating cerebral blood flow velocity theo- retically
decreases the risk of IVH. (See also Chapter 76.)
VIII. Outcome. Although the survival of infants with RDS has improved greatly, the survival
with or without respiratory and neurologic sequelae is highly dependent on birth-
weight and gestational age. Major morbidity (BPD/CLD, NEC, and severe IVH) and
poor postnatal growth remain high for the smallest infants.

Selected References
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Davis PG, Henderson-Smart DJ. Nasal continuous airway pressure immediately after
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