Effect of Fluid restriction and Fluid balance targeting in early postnatal period on Respiratory Outcomes in Preterm infants born less than 29 weeks of Gestation. A Randomized Controlled Trial

Introduction:

Fluid balance in early postnatal period plays a very important role in extreme preterm infants. Higher fluid balance leads to pulmonary edema, impaired oxygenation and increased ventilatory requirements. Studies have shown positive fluid balance in first 14 days, early birth weight regain and requirement of diuretics aare associated with mortality and  increased mechanical ventilatory requirements.  Fluid restriction in early postnatal life has shown to decrease incidence of bronchopulmonary dysplasia and Patent ductus arteriosus. However definitve evidence of fluid restriction in extreme preterm is lacking. Hence we hypothesised that fluid restriction and fluid balance tagreting in the first 2-4 weeks of age could reduce the need and/or duration of ventilation.

Methods:

Study infants will be started on parenteral nutrition-at 100-110 ml/kg/day (less than 27 weeks), and 80 ml/kg/day (27 to 29 weeks). At 24 hrs, fluid increments in both groups will proceed as described in the intervention and comparator section. Total parenteral nutrition intake will be optimized in both groups starting at 40-45 Kcal/kg/day, 2g/kg/day of protein, lipids of 2g/kg/day to maximum of  80Kcal/kg/day, 3.5-4g/kg/day of protein and lipids of 4g/kg/day from TPN alone.

Additional fluid intake adjustments will be titrated according to the fluid balance on the given day.

Fluid balance (FB) will be estimated as daily weight minus birth weight divided by birth weight multiplied by 100.

In both groups, fluid adjustments (increase or decrease) besides the mandatory fluid intakes will be managed according to a FB chart that was designed based on average fluid balance over the first 2 weeks in large cohorts of extremely premature infants <29 weeks of gestation.

Non-restricted fluid group

Total fluid intake increase by 20 ml/kg/day Total fluid intake decrease by 20ml/kg/day
Day 2FB of -6 or lessFB of 0 or more
Day 3FB of -8 or lessFB of -2 or more
Day 4FB of -8 or lessFB of -3 or more
Day 5FB of -7 or lessFB of -1 or more
Day 6FB of -7 or lessFB of 1 or more
Day 7FB of -4 or lessFB of 5 or more
Day 8 FB of -3 or lessFB of 7 or more
Day 9FB of 0 or lessFB of 9 or more
Day 10FB of 1 or lessFB of 10 or more
Day 11FB of 2 or lessFB of 11 or more
Day 12FB of 4 or less FB of 13 or more
Day 13 FB of 5 or less FB of 15 or more
Day 14 FB of 6 or less FB of 17 or more

Restrictive fluid group

Total fluid intake increase by  20 ml/kg/day Total fluid intake decrease by 20 ml/kg/day
Day 2 FB of -10 or less FB of -1 or more
Day 3FB of -13 or lessFB of -3 or more
Day 4FB of -13 or lessFB of -4 or more
Day 5FB of -12 or lessFB of -2 or more
Day 6FB of -11 or lessFB of 0 or more
Day 7FB of -9 or lessFB of 2 or more
Day 8FB of -7 or lessFB of 2 or more
Day 9FB of -5 or lessFB of 4 or more
Day 10FB of -4 or lessFB of 6 or more
Day 11FB of -3 or lessFB of 7or more
Day 12FB of -2 or lessFB of 9 or more
Day 13FB of 0 or lessFB of 10 or more
Day 14FB of 0 or lessFB of 12 or more

Parenteral fluid intake will be increased beyond the maximum for each group (150 ml/kg/day in the restricted and 170ml/kg/day in the non-restricted group). In the presence of hypernatremia, sodium levels of 145 to 155 milliequivalent per litre, total fluid intake will be advanced by 10 to 20 ml/kg/day and for sodium levels above 155 milliequivalent per litre, total fluid intake will be advanced by 20 ml/kg/day.

Fluid restriction below 150 ml/kg/day considered in presence of cardiac dysfunction, pulmonary edema and Acute kidney injury (AKI).

Fluid management in the event of shock, oliguria (urine less than 1m/kg/hour) and severe hyponatremia will be according to discretion of treating clinicians.

these instances will be protocol deviations.

Feeding will be started as trophic feeds at 24 to 48 hours and advanced by 20- 25 ml/kg/day in SGA, 25-30 ml/kg/day for AGA infants and will reach the maximum intake of 170 ml/kg/day in RF group and 190ml/kg/day in NF group will be maintained until the completion of 4 weeks of postnatal age.

The feeds will be either MOM, PDHM until 33 weeks of gestation and postnatal weight of 1.5 kgs. Fortification will be started after a feed intake of 100-150ml/kg/day is achieved and preferably between 7-10 days whichever is earlier. Bovine based HMF will be used. TPN will be discontinued if the fluid rate is less than 1 ml/hour.

Primary outcome assessment:

Primary extubation criteria:

1. SPo2 > 92% for more than 80% of the time with Fio2 <35%

2. MAP < 8 cm of water

3. pH more than 7.25 and PaCO2 < 50 on capillary or arterial blood gas

Infants will be extubated to CPAP or NIPPV. If infant is reventilated within 48 h of primary extubation, the duration of primary ventilation will also include the period of reventialtion

Re-ventilation criteria:

1.Fio2 > 40% ( or >60%  after first month)

2 pH < 7.20 and PaCO2 >60 on capillary or arterial gas.

3.More than 1 apnoeic episode requiring IPPV in a 24 hour period or more than 3 apnoeic episodes needing tactile stimulation in one hour.

4. An urgent need for reintubation and mechanical ventilation, (shock, seizures or adverse effect from non-invasive ventilation such as pneumothorax or pneumoperitoneum) as determined by the treating neonatologist.

Infants that are hypoxic or acidotic on CPAP will be given a trial of NIPPV.

NIPPV criteria:

Starting at PIP of 16-18 cm of water, PEEP of 6-7 cm of water, inspiratory time of 0.4-0.5 seconds, respiratory rates of 40 per minute and increasing to maximum PIP of 22 -24 cm of water and PEEP of 8cm.

Sample size calculation

We estimated sample size using two sample means test (t test) assuming a common standard deviation in both groups.  By restricting fluid intake in first 2 weeks of age with aim to reduce positive fluid balance and maintaining a negative fluid balance, we expect reduction in duration of primary mechanical ventilation by atleast 2 days.

To test this hypothesis for a study power of 80% and two sided significance level of 0.05. A total sample size of 132 (66 in each group) will be required.