Research Article: Increased risk of refeeding syndrome–like hypophosphatemia with high initial amino acid intake in small-for-gestational-age, extremely-low-birthweight infants

Date Published: August 23, 2019

Publisher: Public Library of Science

Author(s): Se In Sung, Yun Sil Chang, Jin Hwa Choi, Yohan Ho, Jisook Kim, So Yoon Ahn, Won Soon Park, Olivier Baud.


Recent nutrition guidelines for extremely-low-birth-weight infants (ELBWIs) recommend implementation of high initial amino acid (AA) supplementation in parenteral nutrition.

We sought to evaluate the influence of AA intake on refeeding syndrome–like electrolyte disturbances including hypophosphatemia in ELBWIs.

Medical records of 142 ELBWIs were reviewed. Demographic, nutritional, outcome, and electrolyte data were compared between ELBWIs with initial low (1.5 g/kg/day) and high (3 g/kg/day) AA intake. Multivariate analysis was conducted to determine the odds ratio of hypophosphatemia with high AA intake and small-for-gestational-age (SGA) ELBWIs.

The incidence of hypophosphatemia and severe hypophosphatemia increased from 51% and 8% in period I to 59% and 20% in period II, respectively (p = 0.36 and < 0.01). Specifically, SGA ELBWIs showed higher incidence of hypophosphatemia than appropriate-for-gestational age (AGA) ELBWIs in period II, whereas there was no difference in period I. For severe hypophosphatemia, SGA ELBWIs presented a 27% incidence versus a 2% incidence in AGA ELBWIs, even with low initial AA intake. Despite no difference in phosphate intake between infants with and without hypophosphatemia, serum phosphate level reached a nadir at the sixth postnatal day and gradually recovered over the second week in infants with hypophosphatemia. In multivariate analyses, the odds ratios for severe hypophosphatemia were 3.6 and 6.6 with high AA intake and SGA status, respectively, with the highest being 18.0 with combined high AA intake and SGA status. In summary, high initial AA intake significantly increased the risk of refeeding syndrome–like electrolyte dysregulations including severe hypophosphatemia in ELBWIs. In SGA ELBWIs, the risk of electrolyte disturbance was significantly higher, even with low initial AA intake. Therefore, new tailored parenteral nutrition protocols starting with lower energy intake and a gradual increase over the first week may be warranted for application in high-risk SGA ELBWIs.

Partial Text

Early nutritional support including higher calories and greater protein intake in the first week of life for extremely-low-birthweight infants (ELBWIs) reduces mortality and the appearance of morbidities such as bronchopulmonary dysplasia and late-onset sepsis and improves neurodevelopmental outcome [1,2]. Recent ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition (PN) and Cochrane Database of Systematic Reviews on amino acid intake on PN in newborns recommend implementation of early aggressive nutrition composed of a PN regimen with high initial amino acid (AA) supplementation (2–3 g/kg/day) and initiation of early enteral trophic feeding soon after birth to limit cellular catabolism and promote extrauterine growth [3–7]. However, some clinical data suggest that electrolyte imbalances including hypophosphatemia, hypercalcemia, and hypokalemia might be triggered by early aggressive PN during the first week of life with high AA intake in ELBWIs [8–12]. Therefore, further studies are necessary to determine the safe and efficacious upper limits of initial energy and AA intake necessary to promote postnatal growth without toxicities in ELBWIs.

Data collection was approved by the Institutional Review Board (IRB) of Samsung Medical Center (SMC) in Seoul, Korea, which allowed for a waiver of informed consent requirements for this retrospective chart review (IRB no. SMC 2016-09-112).

Interruption of continuous placental nutritional flow after birth increases the risk of nutrient deficiency in ELBWIs. The recent ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric PN and also the recent Cochrane Database Systematic Reviews on amino acid supplementation on PN in newborns recommended initial amino acid supplementation with high AA (3g/kg/day) and energy intake [3,4]. The recent introduction of an early aggressive PN in ELBWIs has been shown to prevent early inadequate nutrition–induced metabolic disturbances such as hyperphosphatemia, hypocalcemia, nonoliguric hyperkalemia, and hypoglycemia by inhibiting cellular catabolism and promoting growth [9,20,21]. However, emerging evidence showed that early aggressive PN also facilitated refeeding syndrome–like electrolyte disturbances such as hypophosphatemia, hypercalcemia, hypokalemia, and hypomagnesemia, especially in SGA ELBWIs, at the end of first postnatal week.[9,10] Moreover, the incidence and extent of hypophosphatemia showed a significant association with AA intake amount in these infants [9–11]. In the present study, the difference of the incidence of hypophosphatemia (< 5 mg/dL) between period I and II did not reach statistical significance. This result might be probably due to the high incidence of mild hypophosphatemia in ELBWIs resulted from the cumulative deficit of postnatal phosphate supply. However, the incidence of severe hypophosphatemia (< 2.5 mg/dL) was significantly increased in period II compared with that in period I. The high amino acid intake, followed by transient hyperinsulinemia and accelerated cellular anabolism, increased the requirement of phosphate and other intracellular ions. Our results showed that the deficit of phosphate intake (estimated requirement–actual intake) during the first 5 days before the nadir of hypophosphatemia was higher in period II than in period I (2.6 ± 1.3 versus 4.0 ± 1.3 mM/kg/day, p < 0.01). Because there was no difference in the phosphate intake between the two periods, the increased cumulative deficit in period II might be a result of an increased estimated requirement of phosphate due to augmented AA anabolism. The lower phosphate supply since birth, combined with a scarce deposition of minerals in the bone and higher protein anabolism led to early hypophosphatemia, which was severe in the undernourished SGA infants. In the present study, high initial AA intake of 3 g/k/g/day increased the risk of refeeding syndrome-like electrolyte dysregulation in SGA ELBWIs. Moreover, the risk of severe hypophosphatemia (< 2.5mg/dL) was significantly higher even with a low initial AA intake of 1.5 g/kg/day in SGA (< 10th percentile) ELBWIs. A new tailored PN protocol starting with lower to intermediate AA (1.5–2.0 g/kg/day) and higher phosphate supply (Ca to P molar ratio of 1:1 or less), and gradually increasing the AA and phosphate intake over the first postnatal week might be necessary for high-risk SGA ELBWIs.   Source:


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