Fluid Management in Transient Tachypnea of the Newborn
Fluid Management in Transient Tachypnea of the Newborn
Transient tachypnea of the newborn (TTN) is a diagnosis given to infants born between 34 and
 42 weeks gestation who develop difficulty breathing during the first days of life when no
 specific cause of the breathing difficulty can be identified. Little is known about why some
 babies develop TTN, and there have not been many formal studies of the best way to take care
 of babies with this disease. Babies with TTN get better on their own within three to five
 days after birth, but may require extra oxygen to breath well.

 Most physicians believe that the symptoms of TTN are related to poor clearance of fluid from
 the newborn's lungs. Babies with TTN have extra fluid visible on chest x-ray. Diuretics,
 medicines that can help clear extra lung fluid in adults and in babies with extra lung fluid
 for other reasons, do not to help babies with TTN. Babies with TTN need intravenous fluids to
 be healthy because they breathe too fast to be able to eat. Breastfed babies only get a very
 small amount of fluid in the first few days of life, as it normally takes several days for a
 new mother to begin producing breastmilk. No one has yet examined whether giving babies with
 TTN an amount of fluid similar to the small amount they would receive if they could
 breastfeed would help them recover from TTN faster.

 In this study, the investigators compare whether giving newborns "standard" intravenous fluid
 or amounts of intravenous fluid more close to what a breastfed baby would receive speeds
 recovery in newborns with TTN.
1. Project Abstract Transient tachypnea of the newborn (TTN) is a self-limited respiratory
 distress syndrome of term and late pre-term neonates.1 Respiratory distress attributed
 to TTN requires management of otherwise healthy infants in an intensive care setting,
 thus increasing cost, and often length, of hospitalization as well as decreasing
 opportunity for parent-child bonding in the first days of life. Although hundreds of
 thousands of children are treated for TTN every year (over 250 in the Mount Sinai NICU
 in 2005 alone), little data underlie standard of care medical management. We are
 conducting a prospective study of neonates diagnosed with TTN to determine if changes in
 fluid management affects course of disease.

 2. Specific Aims To determine whether fluid restriction in the first 72 hours of life
 speeds resolution of respiratory distress in neonates diagnosed with TTN.

 3. Concise statement of Significance/Background Transient tachypnea of the newborn (TTN) is
 a self-limited respiratory distress syndrome of term and late pre-term neonates.1
 Newborns with TTN develop clinical signs of respiratory distress within the first hours
 after birth, in the absence of other pathology such as surfactant deficiency, infection,
 meconium aspiration, or anatomic cardiac or pulmonary anomaly. Signs of TTN include
 tachypnea (respiratory rate consistently > 60), subcostal, intercostals, and
 suprasternal retractions, nasal flaring, grunting, and hypoxia correctable with low FiO2
 supplemental oxygen (< 0.40) via conventional nasal cannula or continuous positive
 airway pressure (CPAP). The condition usually resolves with supportive care within 72
 hours without significant long-term adverse sequelae. Transient tachypnea of the newborn
 is associated with transient pulmonary edema diagnosed by typical chest x-ray findings.

 The traditional explanation for postnatal pulmonary edema is poor clearance of fluid
 from the fetal lungs in the perinatal period. Retained fluid leads to bronchioalveolar
 collapse with variable areas of hyperinflation and air trapping in the neonatal lung.
 The newborn compensates for this ventilation/perfusion mismatch with tachypnea and
 increased work of breathing, but often cannot completely compensate, becoming hypoxic
 through the period of fluid reabsorption.

 This pathophysiologic argument has been supported by the findings that brief or absent
 labor and short or absent time in the birth canal have been associated with TTN.2, 3 It
 has long been hypothesized that mechanical forces of labor and delivery work to
 "squeeze" edema away from air-exchange surfaces of the lung into the lymphatics. More
 recently, studies have demonstrated that immaturity of sodium ion channel transporters
 in the lung epithelium may play a more significant role in the failure of pulmonary
 fluid reabsorption than mechanical forces.4, 5 Data from animal models show that absent
 labor, such as found in scheduled Cesarean sections, may lead to delivery before the
 normal hormonally-mediated upregulation or activation of these sodium transporters
 occurs and thus may explain the increased likelihood of developing TTN seen in this
 patient cohort.

 Conditions that increase central venous pressure or decrease thoracic duct clearance
 have also been associated with TTN.6 Additionally, maternal diagnosis of asthma7 or
 gestational diabetes8 and male gender of the newborn9 have been associated with TTN,
 although the mechanism of these associations is incompletely understood. Although TTN is
 an exceedingly common cause of newborn morbidity, it is relatively understudied. Due to
 the low mortality of TTN there has been little interest in investigating either the
 range of pathologies underlying the clinical presentation of TTN or the evidence base
 behind the standard of care treatments of TTN. The high incidence of TTN and the
 significant increase in hospital care acuity and length of stay to otherwise healthy
 infants diagnosed with TTN, however, indicates a need for study.10 As the rate of
 Cesarean section and late pre-term delivery,11 as well as maternal morbidities such as
 asthma12 and gestational diabetes,13 rise it is particularly important to minimize the
 morbidity and cost of TTN. A better understanding of the pathogenesis of TTN and a
 thorough evaluation of current treatment strategies and their relationship to timely
 patient discharge is sorely needed.

 4. Concise statement of Preliminary Data (if available) No evidence base underlies current
 fluid management of neonates with TTN. Data exists demonstrating the inefficacy of loop
 diuretics as treatment for pulmonary fluid overload in newborns with TTN,14 but no
 systematic evaluation of intravenous fluid management exists. Exclusively breastfed
 babies typically have minimal fluid intake during the first four days of life as
 lactogenesis II (initial postpartum milk production) proceeds. Enteral intake by term
 infants begins at less than 100mL in the first day (equivalent to 40mL/kg for a 2.5kg
 neonate; this represents a term newborn at the 5th percentile or a 34 week gestational
 age newborn at the 70th percentile for weight) and increase gradually until milk
 production reaches sustenance levels, usually around the fourth day of life.15
 Regardless of gestational age, all neonates lose water weight during the first week of
 life during physiologic diuresis of extracellular fluid accumulated throughout
 gestation.16 Current management of both preterm and term neonates includes an effort to
 facilitate this physiologic diuresis by gradually increasing amounts of IV fluids until
 maintenance levels are reached between the third and fifth day of life. 17, 18

 5. Research Design and Methods In this study, we will conduct a prospective study of 68
 neonates born between 34 and 42 weeks gestation diagnosed with TTN and managed in the
 Mount Sinai Neonatal Intensive Care Unit (NICU). The study period will include the first
 three days (72 hours) of life. On admission to the NICU, parents will be consented for
 their child's inclusion in the study. If consent is given, the child will be randomized
 to "standard fluids" or "physiologic fluids" groups. "Standard fluids" refer to current
 standard clinical practice of IV fluid administration, not based on experimental
 evidence. "Physiologic fluids" refers to IV fluid amounts more similar to fluid volumes
 typically ingested during initiation of breastfeeding. Term infants assigned to the
 "standard fluids" group will be started on 60 mL/kg/day of glucose-containing
 intravenous fluids as is standard practice. Term infants assigned to the "physiologic
 fluids" group will be started on 40 mL/kg/day glucose-containing intravenous fluids.
 Late preterm infants (gestational age between 34 and 37 weeks) assigned to the "standard
 fluids" group will be started on 80 mL/kg/day of glucose-containing intravenous fluids
 as is standard practice. Late preterm infants (gestational age between 34 and 37 weeks)
 assigned to the "physiologic fluids" group will be started on 60 mL/kg/day
 glucose-containing intravenous fluids. For all groups, intravenous fluid rate will be
 increased by 20 mL/kg/day daily, as is current standard practice. Consistent with
 current standard management for newborns with respiratory distress, no infant will be
 allowed to take oral nutrition until respiratory distress abates. Newborns will be
 carefully monitored, and infants in the "physiologic fluid" group will be removed from
 the study and total daily fluids will be increased if they show signs of dehydration.
 Primary outcomes will be duration of respiratory distress, defined as respiratory rate
 consistently greater than 50 breaths/minute and oxygen saturation on room air
 consistently less than 95%. Secondary outcomes will be length of time to first oral feed
 and time to discharge from the intensive care unit.

 This research poses a minor increase over minimal risk for subjects enrolled in the
 intervention group. The anticipated risks include mild dehydration and/or hypoglycemia of
 neonates in the "physiologic fluid" intervention group. This risk is minor as all newborns in
 the NICU have urine output recorded every three hours, point-of-care glucose monitoring on
 admission and at least once every twelve hours thereafter, and serum electrolytes checked
 between 12 and 24 hours of life. If neonatal dehydration is noted as defined by urine output
 < 2mL/kg/hour over a twelve hour period, serum sodium < 130 mEq/L or > 150 mEq/L, weight loss
 of more than 10% of birth weight, or blood glucose by point-of-care testing of < 40 mg/dL,
 the child will be removed from the study and appropriate fluid resuscitation will be
 initiated. These guidelines for removal from the study are the same as or more conservative
 than criteria used for rehydration in clinical care, so long-term adverse sequelae of this
 level of brief mild dehydration or hypoglycemia are not expected.
Inclusion Criteria:

 1. Gestational age at birth 34 and 42 weeks of gestation

 2. Admission to the Mount Sinai NICU during the first 24 hours of life

 3. Diagnosis during the first 24 hours of life of transient tachypnea of the newborn

 Exclusion criteria:

 1. Gestational age at birth less than 34 weeks or greater than 42 weeks at birth

 2. No diagnosis of TTN made in the first 24 hours of life

 3. Additional infant diagnosis of major cardiac disease

 4. Additional infant diagnosis of major pulmonary disease other than TTN

 5. Additional infant diagnosis of meconium aspiration syndrome

 6. Additional infant diagnosis of major congenital anomaly with potential to affect
 respiratory status in the neonatal period

 7. Additional infant diagnosis of infectious disease process potentially affecting
 respiratory status in the neonatal period

 8. Observation of thick meconium in the amniotic fluid at delivery.

 9. Maternal diagnosis of chorioamnionitis or other infection of the uterus or fallopian
 tubes pre- or peri-partum.

 Criteria for removal from the study:

 (a) Additional infant diagnosis of major cardiac, pulmonary, or other disease process
 potentially affecting respiratory status in the neonatal period (i.e., infection, meconium
 aspiration, pneumothorax, congenital anomaly) present during the study period. (b) Positive
 test of infection (e.g. blood, CSF, or urine culture; viral DFA; microscopy) drawn from
 infant at any point during the study period. (c) Maternal diagnosis of chorioamnionitis or
 other infection of the uterus or fallopian tubes at any point during hospital stay. (d)
 Objective clinical signs of dehydration: (i) Newborn urine output less than 2 mL/kg/hr over
 a twelve hour period at any point during the study period. (ii) Newborn serum sodium less
 than 130 mEq/L or greater than 150 mEq/L at any point during the study period. (iii)
 Newborn weight loss >10% of birth weight at any point during the study period.

 (e) Newborn blood glucose by point-of-care testing of less than 40 mg/dL at any point
 during the study period. (f) Administration of exogenous surfactant at any point during the
 study period.