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Fluid Management in Transient Tachypnea of the Newborn

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ClinicalTrials.gov Identifier: NCT01225029
Recruitment Status : Completed
First Posted : October 20, 2010
Results First Posted : November 28, 2013
Last Update Posted : November 28, 2013
Sponsor:
Information provided by (Responsible Party):
Icahn School of Medicine at Mount Sinai

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Transient Tachypnea of the Newborn Other: Amount of total fluids Not Applicable

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Detailed Description:
  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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial of Fluid Management in Transient Tachypnea of the Newborn
Study Start Date : June 2008
Actual Primary Completion Date : September 2010
Actual Study Completion Date : September 2010


Arm Intervention/treatment
No Intervention: Standard Fluids
Term neonates receive total fluids of 60 mL/kg/day on day of life (DOL) 1. Preterm neonates receive total fluids of 80 mL/kg/day on DOL 1. Each group receives an extra 20 mL/kg/day daily until total fluids of 150 mL/kg/day are achieved.
Experimental: Restricted Fluids
Term neonates receive total fluids of 40 mL/kg/day on day of life (DOL) 1. Preterm neonates receive total fluids of 60 mL/kg/day on DOL 1. Each group receives an extra 20 mL/kg/day daily until total fluids of 150 mL/kg/day are achieved
Other: Amount of total fluids
Term neonates receive either total fluids of 60 mL/kg/day (standard) or 40 mL/kg/day (restricted) on day of life (DOL) 1. Preterm neonates receive total fluids of 80 mL/kg/day (standard) or 60 mL/kg/day (restricted) on DOL 1. Each group receives an extra 20 mL/kg/day daily until total fluids of 150 mL/kg/day are achieved.




Primary Outcome Measures :
  1. Duration of Respiratory Support [ Time Frame: every hour until patient stable without respiratory support, an average of approximately 55 hours and a maximum of 205 hours ]

Secondary Outcome Measures :
  1. Duration of ICU Admission [ Time Frame: every day until discharge, an average of approximately 8 days and a maximum of 12 days ]
  2. Time to First Enteral Feed [ Time Frame: hour until first enteral feed achieved, an average of approximately 40 hours and a maximum of 100 hours ]


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Ages Eligible for Study:   up to 24 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01225029


Locations
United States, New York
Mount Sinai School of Medicine
New York, New York, United States, 10029
Sponsors and Collaborators
Icahn School of Medicine at Mount Sinai
Investigators
Principal Investigator: Annemarie Stroustrup, MD, MPH Icahn School of Medicine at Mount Sinai

Additional Information:
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT01225029     History of Changes
Other Study ID Numbers: GCO 07-1069
First Posted: October 20, 2010    Key Record Dates
Results First Posted: November 28, 2013
Last Update Posted: November 28, 2013
Last Verified: September 2013

Keywords provided by Icahn School of Medicine at Mount Sinai:
premature birth
late preterm birth
respiratory distress of the newborn
Transient tachypnea of the newborn

Additional relevant MeSH terms:
Tachypnea
Transient Tachypnea of the Newborn
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Respiratory Distress Syndrome, Newborn
Lung Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases