INVITED REVIEW
Biological Impact of Recent Guidelines on Parenteral Nutrition in Preterm Infants
Isabelle Guellec, yGe´raldine Gascoin, zAlain Beuchee, §Farid Boubred, jjPierre Tourneux, ô Duksha Ramful, #Elodie Zana-Taieb, and Olivier Baud
ABSTRACT Objectives: Recent guidelines for preterm neonates recommend early initiation of parenteral nutrition (PN) with high protein and relatively high caloric intake. This review considers whether these changes could influence homeostasis in very preterm infants during the first few postnatal weeks. Methods: This systematic review of relevant literature from searches of PubMed and recent guidelines was reviewed by investigators from several perinatal centers in France. Results: New recommendations for PN could be associated with metabolic acidosis via the increase in the amino acid ion gap, hyperchloremic acidosis, and ammonia acidosis. The introduction of high-intake amino acids soon after birth could induce hypophosphatemia and hypercalcemia, simulating a ‘‘repeat feeding–like syndrome’’ and could be prevented by the early intake of phosphorus, especially in preterm infants born after fetal growth restriction. Early high-dose amino acid infusions are relatively well tolerated in the preterm infant with regard to renal function. Additional studies, however, are warranted to determine markers of protein intolerance and to specify the optimal composition and amount of amino acid solutions. Conclusions: Optimal PN following new guidelines in very preterm infants, despite their demonstrated benefits on growth, may induce adverse effects on ionic homeostasis. Clinicians should implement appropriate monitoring to prevent and/or correct them. Key Words: high protein intake, homeostasis, parenteral nutrition, preterm infant
(JPGN 2015;61: 605–609)
T
he quality of parenteral nutrition (PN) in preterm infants has major effects on several outcomes including growth and neurocognitive development, and may induce metabolic and
Received January 29, 2015; accepted June 28, 2015. From the Neonatal and Pediatric Intensive Care Unit, CHU Armand Trousseau, Assistance Publique-Hoˆpitaux de Paris, Paris, the yNeonatal Intensive Care Unit, CHU Angers, Angers, the zNeonatal Intensive Care Unit, Poˆle Me´dico-Chirurgical de Pe´diatrie et de Ge´ne´tique Clinique, CHU Rennes, Rennes, the §Division of Neonatology, AP-HM, AixMarseille University, Marseille, the jjNeonatal Intensive Care Unit, Poˆle Femme Couple Enfant, CHU Amiens, Amiens, the ôNeonatal and Pediatric Intensive Care Unit, CHU Fe´lix Guyon, La Re´union, the #Neonatal Intensive Care Unit Port-Royal, Groupe Hospitalier Cochin-Broca-Hoˆtel Dieu, Assistance Publique-Hoˆpitaux de Paris, Paris, and the Neonatal Intensive Care Unit, Groupe Hospitalier Robert Debre´, Assistance Publique-Hoˆpitaux de Paris, Paris, France. Address correspondence and reprint requests to Olivier Baud, MD, PhD, Neonatal Intensive Care Unit, Hoˆpital Robert Debre´, 48 Blvd Se´rurier, F-75019 Paris, France (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000898
JPGN
Volume 61, Number 6, December 2015
What Is Known
The quality of parenteral nutrition has major effects on several outcomes in preterm neonates. Recent guidelines for the preterm neonate recommend early initiation/high-protein parenteral nutrition. These new guidelines may induce adverse effects on neonatal homeostasis.
What Is New
Revised parenteral nutrition composition may have several effects on ionic homeostasis. Clinicians should implement appropriate monitoring to prevent them. Future changes in guidelines for neonatal nutrition should be balanced with potential adverse effects.
cardiovascular diseases in adulthood (1–3). Because reports from neonatal intensive care units have shown that nutritional intake in preterm infants could be inadequate (4,5), clinical practice guidelines for the nutritional needs of preterm infants have been regularly revised by the Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Clinical Nutrition and Metabolism (6). Recent guidelines for the preterm neonate recommend early initiation of PN with high protein and relatively high caloric intake, especially following fetal growth restriction, to prevent extrauterine growth failure (7). The main purpose of the present review was to assess the influence of new guidelines for the parenteral needs of preterm infants on several biological disturbances observed during the first few postnatal weeks.
METHODS A systematic search of the published literature (PubMed) up to December 2014 was undertaken by investigators from perinatal centers in France, with an especial emphasis on PN and the implementation of these guidelines in French neonatal intensive care units. No ethical approval from the local institutional research board has been required for this review. This search identified the most recent reports focusing on the impact of revised PN composition on the main indicators of homeostasis in preterm infants. The following terms were used either alone or in combination: ‘‘parenteral nutrition,’’ ‘‘preterm,’’ ‘‘neonate,’’ ‘‘guidelines,’’ ‘‘homeostasis,’’ ‘‘fluid and electrolyte intake,’’ ‘‘fluid and electrolyte balance,’’ ‘‘protein intake,’’ ‘‘amino-acid supplementation,’’ ‘‘human,’’ and ‘‘animal.’’ We focused on articles published in
605
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Baud et al
JPGN
2005–2014 but included earlier publications when historically relevant or if the topic had not been adequately addressed in recent years. Articles selected were full-text, English-language papers. References cited in target articles were examined separately and were used to identify additional leads. This review is focused on the impact of early high amino acid, high caloric, and initial mean fluid intakes on biological disturbances frequently observed in preterm infants including hyperchloremic acidosis, metabolic acidosis other than hyperchloremic, elevated aminoacidemia blood urea and ammonia, hypophosphatemia, glucose tolerance, hyperkalemia, water balance and sodium intolerance, and lipid tolerance.
RESULTS/DISCUSSION One of the main characteristics of present guidelines for PN in preterm neonates is the introduction as soon as possible of high protein intake (1.5 g kg1 day1, and up to 4 g kg1 day1) (6), which could have a substantial impact on protein homeostasis and renal function. These disturbances were summarized in Table 1.
New Guidelines and the Risk of Hyperchloremic Acidosis The immaturity of the renal tubules observed in the preterm neonate mimics the situation in renal tubular acidosis (8). The substantial loss of sodium, which is therapeutically replaced with sodium chloride (salt) may exacerbate this phenomenon. An increase in the ratio of plasma chloride relative to sodium lowers the plasma strong ion difference and the pH (9). Hyperchloremia with a normal ion gap is also associated with low blood bicarbonate concentrations and the failure of urinary acidification. As a result of the excessive chloride intake, chloremia can reach concentrations >115 mmol/L, which is associated with metabolic acidosis (10). Another source of chloride is the amino acid mixture. Indeed, the metabolism of cationic amino acids (arginine, histidine, and lysine) releases an excess of protons (Hþ) and may cause hyperchloremic metabolic acidosis. The cation gap (cationic amino acids [anionic amino acids þ acetate]) may help to determine whether the amino acid mixture is well balanced or not. Heird et al (11) have shown that infants and children receiving amino acid mixtures with high titrable acidity do not become acidotic. Peters et al (12) recommend partially replacing chloride salt by acetate in parenteral perfusion. This reduces the incidence of hyperchloremia and leads to beneficial changes in acid-base status. The decrease in the base deficit, however, is accompanied by a rise in blood carbon dioxide tension (PaCO2) because of carbonic anhydrase activity. Phosphate intake also interferes with acid-base homeostasis affecting the renal regulation of plasma bicarbonate. PN-related factors associated with metabolic acidosis are sodium, chloride intakes in preterm infants (13).
New Guidelines and the Risk of Metabolic Acidosis Other Than Hyperchloremic If serum albumin is low, the anion gap in commonly used to estimate the presence of excess unmeasured inorganic and organic anions such as ketones, and pyruvate or pyroglutamic acid (14). Jadhav et al (15) have shown that the dose or duration of parenteral amino acid and cysteine administration does not seem to affect arterial acidosis. Metabolic acidosis, however, unrelated to the anion gap is commonly seen in premature children between days 3 and 5 after birth. Balancing cysteine hydrochloride with an equimolar amount of base (acetate) could be an option to prevent
606
Volume 61, Number 6, December 2015
metabolic acidosis and promote nitrogen accretion in very preterm infants. Both adults and neonates must excrete acid generated by metabolism in the form of ammonia and titrable acid. In the preterm infant, the activity of glutaminase, the key enzyme leading to ammonia production, in the kidney is lower, and the renal content of glutamine as a substrate is also low (16). Although no significant changes in ammonia concentration have been observed in response to glutamine supplementation (17), Sato et al (18) have suggested that the low urinary excretion rate of ammonium (NH4þ) could be a major cause of metabolic acidosis in the neonatal period. Indeed, neonates need to excrete 2 or 3 times more acids than adults (2–3 mEq kg1 j1) because of their higher protein intake and bone accretion (19). New recommendations for PN could be associated with metabolic acidosis via the increase in the amino acid ion gap, hyperchloremic acidosis, and ammonia acidosis.
New Guidelines and the Risk of Elevated Aminoacidemia, Blood Urea, and Ammonia High protein intake soon after birth (3–4 g kg1 day1) as part of optimal PN is believed to induce metabolic disturbances in preterm infants. This assumption is based on reports from the early 1970s of azotemia and metabolic acidosis in infants who received protein hydrolysate solutions or the first generation of synthetic crystalline amino acid solutions (12). Since the 1990s, multiple studies have demonstrated that high protein intake (1.0–2.5 g kg1 day1) with more recently developed parenteral amino acid preparations can not only reverse a negative nitrogen balance in preterm infants but is also relatively safe for preterm infants (20). Elevated blood urea is often interpreted as a sign of an infant’s intolerance to amino acids, especially when it exceeds 10 mmol/L. The relation between plasma urea concentrations and amino acid intake, however, in preterm infants is still unclear. Indeed, some clinical trials with early amino acid infusions up to 3.5 g/kg on the first day of life have found no increase in plasma urea levels, and a poor correlation between plasma urea nitrogen and protein intake (21). In contrast, others have reported significantly higher plasma urea concentrations in infants receiving between 2 and 3.6 g kg1 day1 of amino acids on the first day of life (15,22–25). Rising blood urea levels, however, do not necessarily mean intolerance to amino acids but rather reflect the oxidation of amino acids, as seen in utero. Moreover, blood urea concentrations depend on hydration status, renal function, gestational age, and acuteness of illness, and there is limited information as to safe blood urea levels in preterm infants. Therefore, using urea levels as a monitoring tool for protein tolerance remains questionable. In several studies, plasma ammonia concentrations have been shown to remain in the normal range in preterm infants receiving modern amino acid mixtures early in life (20). Blanco et al (23) have reported elevated ammonia concentrations (ranging from 97 to 123 mmol/L), mostly in extremely preterm infants with very high plasma urea concentrations (>20 mmol/L). Excessive aminoacidemia has been reported in preterm infants receiving early high amino acid intake compared with healthy term newborns (26,27). Other reports, however, do not confirm these data (20,24,26). In particular, Thureen et al (26) have demonstrated that 3 g kg1 day1 beginning on the first day of life is safe and associated with plasma amino acid concentrations remarkably similar to those of second and third trimester fetuses. Altogether, there is increasing evidence that early high-dose amino acid infusions are relatively well tolerated in the preterm infant with regard to metabolism and renal function. Additional www.jpgn.org
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 61, Number 6, December 2015
Parenteral Nutrition and Homeostasis
TABLE 1. Main ESPGHAN and ESPEN recommendations regarding PN and potential concerns related to these new guidelines Guideline points Early high amino acid intake
Biological disturbances
Points to consider
Arginine-, histidine-, and lysine-related release of Hþ: hyperchloremic metabolic acidosis Low glutaminase activity: ammonia acidosis Cysteine hydrochloride imbalance: increased amino acid anion gap Positive potassium balance: hyper or hypokalemia Hypophosphatemia
Early high caloric intake
Hyperglycemia related to glucose intolerance (especially in growth-restricted and very immature infants) Hypertriglyceridemia related to lipid infusion
Initial mean fluid intake
Extremely low glomerular filtration rate High insensible water loss within the first days of life
Adjust plasma chloride/sodium ratio Repeat measurements and adjust sodium and phosphate intake Consider balancing cysteine hydrochloride with equimolar amounts of base (acetate) Repeat measurements and adjust potassium intake Adjust phosphorus intake according to serum concentrations and protein and calcium intake Repeat capillary blood glucose measurements; consider insulin therapy if needed Repeat measurements of triglycerides and cholesterol, and adjust lipid intake to fat oxidation capability Repeat sodium measurements and adjust water intake
ESPEN ¼ European Society for Clinical Nutrition and Metabolism; ESPGHAN ¼ European Society of Paediatric Gastroenterology, Hepatology, and Nutrition; PN ¼ parenteral nutrition.
studies, however, are warranted to determine markers of protein intolerance and to specify the optimal composition and amount of amino acid solutions, especially in the very immature preterm infant and following fetal growth restriction.
The early introduction of amino acids through PN soon after birth could be completed by the early intake of phosphorus, especially in preterm infants born following fetal growth restriction because they are the main determinants of cellular growth.
New Guidelines and the Risk of Hypophosphatemia
Impact of New Guidelines on Glucose Tolerance
During the first few days of life, PN in very preterm infants can be associated with important metabolic disturbances, particularly hypophosphatemia and hypercalcemia, simulating a ‘‘repeat feeding–like syndrome’’ observed after intense nutritional deprivation (28,29). These disturbances are closely related to the suboptimal availability of nutrients after the disruption of placental feeding. Indeed, amino acid and energy supply through PN maintains the cell in an anabolic state and promotes the uptake of phosphorus, which forms part of the composition of nucleic acids, ATP, and the cell membrane. This high phosphorus consumption by the cell in the growing newborn causes a decrease in its plasma concentrations. If the phosphorus intake is not adequate to cope with these cellular requirements, the bone acts as a mineral reservoir and releases phosphorus into the circulation to maintain its plasma concentrations. It simultaneously releases calcium into the extracellular space, leading to hypercalcemia and hypercalciuria. A formula to calculate phosphorus needs has recently been elaborated from a prospective observational study (29):
After birth, continuous transplacental transfer of glucose is interrupted. Maintaining normal glucose concentrations that match those of the normally growing fetus is important for neurodevelopment (27). Glucose is the main energy source for the neonate receiving PN. To ensure that preterm infants receive adequate amounts of glucose, especially for brain energy supply, it should initially be delivered at the hepatic glucose production rate of 6 to 8 mg kg1 min1. Glucose levels need to be monitored regularly with the initiation of PN because preterm infants are at risk of developing hyperglycemia. Indeed, defective islet b cell processing of proinsulin, peripheral resistance to insulin, and persistent hepatic glucose production during parenteral glucose infusion are likely responsible for PN-related hyperglycemia, especially in growthrestricted and very immature infants (31). In addition to careful monitoring of serum glucose level in PN-fed preterm infants, exogenous insulin infusion is efficient and may be used with caution. Paradoxically, low plasma tyrosine levels associated with an increase in insulin-treated hyperglycemia have been recently reported (32). Early higher amino acid intake significantly increases insulin plasma concentration and could therefore decrease glucose intolerance (26).
Ph needed ¼ Ca intake/2.15 þ (amino acid intake 1.3) 0.8 12.3, where indicates mg kg1 day1 and indicates g kg1 day1. Repeated measurement of serum phosphate is essential in the first week of life to adjust phosphorus supplementation to optimize mineralization and extrauterine growth. Hypophosphatemia is defined as a serum phosphate level 7 mmol/L in any infant, although hypokalemia
Biological Impact of Recent Guidelines on Parenteral Nutrition in Preterm Infants
Isabelle Guellec, yGe´raldine Gascoin, zAlain Beuchee, §Farid Boubred, jjPierre Tourneux, ô Duksha Ramful, #Elodie Zana-Taieb, and Olivier Baud
ABSTRACT Objectives: Recent guidelines for preterm neonates recommend early initiation of parenteral nutrition (PN) with high protein and relatively high caloric intake. This review considers whether these changes could influence homeostasis in very preterm infants during the first few postnatal weeks. Methods: This systematic review of relevant literature from searches of PubMed and recent guidelines was reviewed by investigators from several perinatal centers in France. Results: New recommendations for PN could be associated with metabolic acidosis via the increase in the amino acid ion gap, hyperchloremic acidosis, and ammonia acidosis. The introduction of high-intake amino acids soon after birth could induce hypophosphatemia and hypercalcemia, simulating a ‘‘repeat feeding–like syndrome’’ and could be prevented by the early intake of phosphorus, especially in preterm infants born after fetal growth restriction. Early high-dose amino acid infusions are relatively well tolerated in the preterm infant with regard to renal function. Additional studies, however, are warranted to determine markers of protein intolerance and to specify the optimal composition and amount of amino acid solutions. Conclusions: Optimal PN following new guidelines in very preterm infants, despite their demonstrated benefits on growth, may induce adverse effects on ionic homeostasis. Clinicians should implement appropriate monitoring to prevent and/or correct them. Key Words: high protein intake, homeostasis, parenteral nutrition, preterm infant
(JPGN 2015;61: 605–609)
T
he quality of parenteral nutrition (PN) in preterm infants has major effects on several outcomes including growth and neurocognitive development, and may induce metabolic and
Received January 29, 2015; accepted June 28, 2015. From the Neonatal and Pediatric Intensive Care Unit, CHU Armand Trousseau, Assistance Publique-Hoˆpitaux de Paris, Paris, the yNeonatal Intensive Care Unit, CHU Angers, Angers, the zNeonatal Intensive Care Unit, Poˆle Me´dico-Chirurgical de Pe´diatrie et de Ge´ne´tique Clinique, CHU Rennes, Rennes, the §Division of Neonatology, AP-HM, AixMarseille University, Marseille, the jjNeonatal Intensive Care Unit, Poˆle Femme Couple Enfant, CHU Amiens, Amiens, the ôNeonatal and Pediatric Intensive Care Unit, CHU Fe´lix Guyon, La Re´union, the #Neonatal Intensive Care Unit Port-Royal, Groupe Hospitalier Cochin-Broca-Hoˆtel Dieu, Assistance Publique-Hoˆpitaux de Paris, Paris, and the Neonatal Intensive Care Unit, Groupe Hospitalier Robert Debre´, Assistance Publique-Hoˆpitaux de Paris, Paris, France. Address correspondence and reprint requests to Olivier Baud, MD, PhD, Neonatal Intensive Care Unit, Hoˆpital Robert Debre´, 48 Blvd Se´rurier, F-75019 Paris, France (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000898
JPGN
Volume 61, Number 6, December 2015
What Is Known
The quality of parenteral nutrition has major effects on several outcomes in preterm neonates. Recent guidelines for the preterm neonate recommend early initiation/high-protein parenteral nutrition. These new guidelines may induce adverse effects on neonatal homeostasis.
What Is New
Revised parenteral nutrition composition may have several effects on ionic homeostasis. Clinicians should implement appropriate monitoring to prevent them. Future changes in guidelines for neonatal nutrition should be balanced with potential adverse effects.
cardiovascular diseases in adulthood (1–3). Because reports from neonatal intensive care units have shown that nutritional intake in preterm infants could be inadequate (4,5), clinical practice guidelines for the nutritional needs of preterm infants have been regularly revised by the Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Clinical Nutrition and Metabolism (6). Recent guidelines for the preterm neonate recommend early initiation of PN with high protein and relatively high caloric intake, especially following fetal growth restriction, to prevent extrauterine growth failure (7). The main purpose of the present review was to assess the influence of new guidelines for the parenteral needs of preterm infants on several biological disturbances observed during the first few postnatal weeks.
METHODS A systematic search of the published literature (PubMed) up to December 2014 was undertaken by investigators from perinatal centers in France, with an especial emphasis on PN and the implementation of these guidelines in French neonatal intensive care units. No ethical approval from the local institutional research board has been required for this review. This search identified the most recent reports focusing on the impact of revised PN composition on the main indicators of homeostasis in preterm infants. The following terms were used either alone or in combination: ‘‘parenteral nutrition,’’ ‘‘preterm,’’ ‘‘neonate,’’ ‘‘guidelines,’’ ‘‘homeostasis,’’ ‘‘fluid and electrolyte intake,’’ ‘‘fluid and electrolyte balance,’’ ‘‘protein intake,’’ ‘‘amino-acid supplementation,’’ ‘‘human,’’ and ‘‘animal.’’ We focused on articles published in
605
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Baud et al
JPGN
2005–2014 but included earlier publications when historically relevant or if the topic had not been adequately addressed in recent years. Articles selected were full-text, English-language papers. References cited in target articles were examined separately and were used to identify additional leads. This review is focused on the impact of early high amino acid, high caloric, and initial mean fluid intakes on biological disturbances frequently observed in preterm infants including hyperchloremic acidosis, metabolic acidosis other than hyperchloremic, elevated aminoacidemia blood urea and ammonia, hypophosphatemia, glucose tolerance, hyperkalemia, water balance and sodium intolerance, and lipid tolerance.
RESULTS/DISCUSSION One of the main characteristics of present guidelines for PN in preterm neonates is the introduction as soon as possible of high protein intake (1.5 g kg1 day1, and up to 4 g kg1 day1) (6), which could have a substantial impact on protein homeostasis and renal function. These disturbances were summarized in Table 1.
New Guidelines and the Risk of Hyperchloremic Acidosis The immaturity of the renal tubules observed in the preterm neonate mimics the situation in renal tubular acidosis (8). The substantial loss of sodium, which is therapeutically replaced with sodium chloride (salt) may exacerbate this phenomenon. An increase in the ratio of plasma chloride relative to sodium lowers the plasma strong ion difference and the pH (9). Hyperchloremia with a normal ion gap is also associated with low blood bicarbonate concentrations and the failure of urinary acidification. As a result of the excessive chloride intake, chloremia can reach concentrations >115 mmol/L, which is associated with metabolic acidosis (10). Another source of chloride is the amino acid mixture. Indeed, the metabolism of cationic amino acids (arginine, histidine, and lysine) releases an excess of protons (Hþ) and may cause hyperchloremic metabolic acidosis. The cation gap (cationic amino acids [anionic amino acids þ acetate]) may help to determine whether the amino acid mixture is well balanced or not. Heird et al (11) have shown that infants and children receiving amino acid mixtures with high titrable acidity do not become acidotic. Peters et al (12) recommend partially replacing chloride salt by acetate in parenteral perfusion. This reduces the incidence of hyperchloremia and leads to beneficial changes in acid-base status. The decrease in the base deficit, however, is accompanied by a rise in blood carbon dioxide tension (PaCO2) because of carbonic anhydrase activity. Phosphate intake also interferes with acid-base homeostasis affecting the renal regulation of plasma bicarbonate. PN-related factors associated with metabolic acidosis are sodium, chloride intakes in preterm infants (13).
New Guidelines and the Risk of Metabolic Acidosis Other Than Hyperchloremic If serum albumin is low, the anion gap in commonly used to estimate the presence of excess unmeasured inorganic and organic anions such as ketones, and pyruvate or pyroglutamic acid (14). Jadhav et al (15) have shown that the dose or duration of parenteral amino acid and cysteine administration does not seem to affect arterial acidosis. Metabolic acidosis, however, unrelated to the anion gap is commonly seen in premature children between days 3 and 5 after birth. Balancing cysteine hydrochloride with an equimolar amount of base (acetate) could be an option to prevent
606
Volume 61, Number 6, December 2015
metabolic acidosis and promote nitrogen accretion in very preterm infants. Both adults and neonates must excrete acid generated by metabolism in the form of ammonia and titrable acid. In the preterm infant, the activity of glutaminase, the key enzyme leading to ammonia production, in the kidney is lower, and the renal content of glutamine as a substrate is also low (16). Although no significant changes in ammonia concentration have been observed in response to glutamine supplementation (17), Sato et al (18) have suggested that the low urinary excretion rate of ammonium (NH4þ) could be a major cause of metabolic acidosis in the neonatal period. Indeed, neonates need to excrete 2 or 3 times more acids than adults (2–3 mEq kg1 j1) because of their higher protein intake and bone accretion (19). New recommendations for PN could be associated with metabolic acidosis via the increase in the amino acid ion gap, hyperchloremic acidosis, and ammonia acidosis.
New Guidelines and the Risk of Elevated Aminoacidemia, Blood Urea, and Ammonia High protein intake soon after birth (3–4 g kg1 day1) as part of optimal PN is believed to induce metabolic disturbances in preterm infants. This assumption is based on reports from the early 1970s of azotemia and metabolic acidosis in infants who received protein hydrolysate solutions or the first generation of synthetic crystalline amino acid solutions (12). Since the 1990s, multiple studies have demonstrated that high protein intake (1.0–2.5 g kg1 day1) with more recently developed parenteral amino acid preparations can not only reverse a negative nitrogen balance in preterm infants but is also relatively safe for preterm infants (20). Elevated blood urea is often interpreted as a sign of an infant’s intolerance to amino acids, especially when it exceeds 10 mmol/L. The relation between plasma urea concentrations and amino acid intake, however, in preterm infants is still unclear. Indeed, some clinical trials with early amino acid infusions up to 3.5 g/kg on the first day of life have found no increase in plasma urea levels, and a poor correlation between plasma urea nitrogen and protein intake (21). In contrast, others have reported significantly higher plasma urea concentrations in infants receiving between 2 and 3.6 g kg1 day1 of amino acids on the first day of life (15,22–25). Rising blood urea levels, however, do not necessarily mean intolerance to amino acids but rather reflect the oxidation of amino acids, as seen in utero. Moreover, blood urea concentrations depend on hydration status, renal function, gestational age, and acuteness of illness, and there is limited information as to safe blood urea levels in preterm infants. Therefore, using urea levels as a monitoring tool for protein tolerance remains questionable. In several studies, plasma ammonia concentrations have been shown to remain in the normal range in preterm infants receiving modern amino acid mixtures early in life (20). Blanco et al (23) have reported elevated ammonia concentrations (ranging from 97 to 123 mmol/L), mostly in extremely preterm infants with very high plasma urea concentrations (>20 mmol/L). Excessive aminoacidemia has been reported in preterm infants receiving early high amino acid intake compared with healthy term newborns (26,27). Other reports, however, do not confirm these data (20,24,26). In particular, Thureen et al (26) have demonstrated that 3 g kg1 day1 beginning on the first day of life is safe and associated with plasma amino acid concentrations remarkably similar to those of second and third trimester fetuses. Altogether, there is increasing evidence that early high-dose amino acid infusions are relatively well tolerated in the preterm infant with regard to metabolism and renal function. Additional www.jpgn.org
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 61, Number 6, December 2015
Parenteral Nutrition and Homeostasis
TABLE 1. Main ESPGHAN and ESPEN recommendations regarding PN and potential concerns related to these new guidelines Guideline points Early high amino acid intake
Biological disturbances
Points to consider
Arginine-, histidine-, and lysine-related release of Hþ: hyperchloremic metabolic acidosis Low glutaminase activity: ammonia acidosis Cysteine hydrochloride imbalance: increased amino acid anion gap Positive potassium balance: hyper or hypokalemia Hypophosphatemia
Early high caloric intake
Hyperglycemia related to glucose intolerance (especially in growth-restricted and very immature infants) Hypertriglyceridemia related to lipid infusion
Initial mean fluid intake
Extremely low glomerular filtration rate High insensible water loss within the first days of life
Adjust plasma chloride/sodium ratio Repeat measurements and adjust sodium and phosphate intake Consider balancing cysteine hydrochloride with equimolar amounts of base (acetate) Repeat measurements and adjust potassium intake Adjust phosphorus intake according to serum concentrations and protein and calcium intake Repeat capillary blood glucose measurements; consider insulin therapy if needed Repeat measurements of triglycerides and cholesterol, and adjust lipid intake to fat oxidation capability Repeat sodium measurements and adjust water intake
ESPEN ¼ European Society for Clinical Nutrition and Metabolism; ESPGHAN ¼ European Society of Paediatric Gastroenterology, Hepatology, and Nutrition; PN ¼ parenteral nutrition.
studies, however, are warranted to determine markers of protein intolerance and to specify the optimal composition and amount of amino acid solutions, especially in the very immature preterm infant and following fetal growth restriction.
The early introduction of amino acids through PN soon after birth could be completed by the early intake of phosphorus, especially in preterm infants born following fetal growth restriction because they are the main determinants of cellular growth.
New Guidelines and the Risk of Hypophosphatemia
Impact of New Guidelines on Glucose Tolerance
During the first few days of life, PN in very preterm infants can be associated with important metabolic disturbances, particularly hypophosphatemia and hypercalcemia, simulating a ‘‘repeat feeding–like syndrome’’ observed after intense nutritional deprivation (28,29). These disturbances are closely related to the suboptimal availability of nutrients after the disruption of placental feeding. Indeed, amino acid and energy supply through PN maintains the cell in an anabolic state and promotes the uptake of phosphorus, which forms part of the composition of nucleic acids, ATP, and the cell membrane. This high phosphorus consumption by the cell in the growing newborn causes a decrease in its plasma concentrations. If the phosphorus intake is not adequate to cope with these cellular requirements, the bone acts as a mineral reservoir and releases phosphorus into the circulation to maintain its plasma concentrations. It simultaneously releases calcium into the extracellular space, leading to hypercalcemia and hypercalciuria. A formula to calculate phosphorus needs has recently been elaborated from a prospective observational study (29):
After birth, continuous transplacental transfer of glucose is interrupted. Maintaining normal glucose concentrations that match those of the normally growing fetus is important for neurodevelopment (27). Glucose is the main energy source for the neonate receiving PN. To ensure that preterm infants receive adequate amounts of glucose, especially for brain energy supply, it should initially be delivered at the hepatic glucose production rate of 6 to 8 mg kg1 min1. Glucose levels need to be monitored regularly with the initiation of PN because preterm infants are at risk of developing hyperglycemia. Indeed, defective islet b cell processing of proinsulin, peripheral resistance to insulin, and persistent hepatic glucose production during parenteral glucose infusion are likely responsible for PN-related hyperglycemia, especially in growthrestricted and very immature infants (31). In addition to careful monitoring of serum glucose level in PN-fed preterm infants, exogenous insulin infusion is efficient and may be used with caution. Paradoxically, low plasma tyrosine levels associated with an increase in insulin-treated hyperglycemia have been recently reported (32). Early higher amino acid intake significantly increases insulin plasma concentration and could therefore decrease glucose intolerance (26).
Ph needed ¼ Ca intake/2.15 þ (amino acid intake 1.3) 0.8 12.3, where indicates mg kg1 day1 and indicates g kg1 day1. Repeated measurement of serum phosphate is essential in the first week of life to adjust phosphorus supplementation to optimize mineralization and extrauterine growth. Hypophosphatemia is defined as a serum phosphate level 7 mmol/L in any infant, although hypokalemia
