Parenteral Amino Acid and Metabolic Acidosis in Premature InfantsFrom the Schwartz Center for Metabolism and Nutrition and Department of Pediatrics, Case Western Reserve University, MetroHealth Medical Center, Cleveland, Ohio Correspondence: Satish C. Kalhan, MBBS, FRCP, Department of Gastroenterology and Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. Electronic mail may be sent to sck{at}case.edu.
Background: Aggressive parenteral nutrition (PN) including amino
acids is recommended for low-birth-weight infants to prevent energy and
protein deficit. Their impact on acid-base homeostasis has not been examined.
Methods: We investigated the impact of dose and duration of
parenteral amino acids, with cysteine, on acid-base parameters in 122
low-birth-weight infants. Premature infants Low-birth-weight infants, although born appropriate for gestational age, consistently show postnatal growth restriction.1–3 Postnatal growth failure in premature infants has been attributed to protein and energy deficits accruing over the duration of the hospital stay.4 Therefore, greater emphasis has been placed on early aggressive nutrition care of these infants in order to prevent postnatal growth retardation. A number of investigators have suggested that parenteral nutrition (PN) should be initiated as early after birth as possible and that parenteral amino acids be administered at 3–3.5 g/kg/d in order to mimic protein accretion during fetal life.5–12 Only a few studies have examined the safety of early and aggressive administration of parenteral amino acids to low-birth-weight infants. A recent publication by te Braake et al11 showed that prematurely born infants tolerated PN containing 2.4 g/kg/d of amino acids initiated soon after birth, without any significant change in acid-base status. In their study, the amount of parenteral amino acids provided was lower than the current recommendation,8 and acid-base parameters were only monitored once a day. The impact of other factors affecting the acid-base status in premature infants was not explored. We examined the dose-response relationship between duration—short (5 hour), extended (24 hour), and prolonged (3–5 days)—and dose—1.5–3.0 g/kg/d—of parenteral amino acids on changes in acid-base parameters in premature infants. In addition, we examined the effect of acuity of illness and clinical morbidities on the above parameters, specifically in relation to age at initiation of PN. Data in the literature13 had shown that balanced (cation = anion) amino acid mixtures, because they are ionically balanced, do not cause acidosis in vivo. Therefore, we hypothesized that changes in acid-base status in premature infants will be the consequence of associated clinical morbidities, and that early initiation of parenteral amino acids will not affect their acid-base status.
The present study was prompted by an anonymous complaint to the institutional review board (IRB), insinuating high incidence of "perceived acidosis" with early parenteral administration of amino acids at 3 g/kg/d. Prospectively obtained laboratory data from our published14–16 and unpublished physiologic studies of glutamine metabolism and that obtained from chart review of a matched case-control group were examined. The impact of duration (5 hours, 24 hours, and 3–5 days) of parenteral amino acids at 1.5–3 g/kg/d on acid-base homeostasis was evaluated.
Subjects and Study Design
All decisions regarding clinical management, IV fluids, glucose, Intralipid, electrolytes, minerals, and trace elements in the PN, ventilatory support, use of vasopressor, etc were made by the primary physician, irrespective of participation of infants in the study protocols.
Data Collection The frequency of laboratory tests including the arterial blood gases was decided by the primary physician according to the clinical status of the infants. Generally, infants had their arterial blood gases monitored every 2–4 hours. Only arterial blood gas data (pH, PaCO2, PaO2) obtained daily during the first week after birth were collected. Venous and capillary blood gas parameters were not included in the data collection. Serum electrolytes and blood urea nitrogen were obtained daily starting on the second day after birth as per clinical practice. Anion gap [(Na + K) – (Cl + HCO3)] was calculated from the data of serum electrolytes. Blood ammonia levels were determined only in study subjects receiving 3 g/kg/d of parenteral amino acids.
Statistical Analysis
Clinical characteristics of infants enrolled in the previously reported studies14–16 are summarized in Table I. Birth weight, gestational age, and the score of neonatal acute physiology (SNAP), an indicator of severity of acute illness, were not different among infants recruited in different study protocols. All infants lost approximately 10% of their weight during the first 5 days after birth. The impact of amino acid load 1.5 g/kg/d vs 3.0 g/kg/d for a short (5-hour) extended (24-hour), and for a prolonged period (3–5 days) on acid-base parameters is displayed in Table III. An increase in parenteral amino acids to 3.0 g/kg/d for a shorter or an extended duration had no significant impact on pH. Similarly, infusion of amino acids at 3.0 g/kg/d for a prolonged period had no effect on arterial pH. Arterial PaCO2, serum chloride and bicarbonate, anion gap, and blood urea nitrogen were not different between the study groups. The concentration of blood ammonia was within the normal range in infants receiving 3.0 g/kg/d amino acids.
We recruited 21 infants between 0 and 72 hours after birth to examine the effect of 3–5 days of parenteral amino acids (3 g/kg/d) with or without supplemental glutamine on glutamine and whole body protein metabolism (unpublished data). Their clinical characteristics, along with matched case controls, are shown in Table II. Birth weight, gestational age, SNAP score, magnitude of weight loss, and age when the tracer isotope studies were performed in the "completed" group were similar to our previous studies. Premature infants who were "withdrawn" from the study protocol for clinical reasons had lower birth weight (p < .05), lower gestational age (p < .05), and their weight loss during the first 5 days after birth was significantly higher (p < .05) compared with those who completed the study. There was no significant difference in birth weight, gestational age, and SNAP score between withdrawn infants and those in the matched controls. Infants who were withdrawn had greater prevalence of PDA (70%), had large PDA according to the echocardiography findings, and 5/7 (71%) infants underwent surgical ligation for PDA. In addition, these infants required ventilator support for a prolonged period (p < .01) and had significantly higher weight loss (p < .05) during the first 5 days after birth. As per the study protocol, infants in the study group received a higher amount of amino acid load and consequently a higher amount of cysteine added to the parenteral amino acid solution (Table II). Sequential change in acid-base parameters during the first 5 days after birth in the study group and matched controls is shown in Table IV. Because there were no differences in acid-base parameters among those who completed and those who were withdrawn from the study, the data were combined. Acid-base parameters obtained after the infant was withdrawn from the study were not included in the analysis. Infants included in the study showed a progressive decline in arterial pH, with nadir on day 5 after birth. Infants in the withdrawn group also showed a decrease in pH with age; however, the lowest pH was evident earlier (ie, on the third day after birth). Infants matched for birth weight and gestational age (controls) and receiving lower doses of parenteral amino acids, as ordered by their primary care providers, also demonstrated a similar change in arterial pH with postnatal age. There were no differences in PaCO2, serum bicarbonate, serum chloride, and anion gap within and between the groups.
The concentration of blood urea nitrogen on day 5 was higher in infants included in the study (31 ± 17 mg/dL) compared with controls (15 ± 10 mg/dL; p < .05). However, blood urea nitrogen levels increased starting on day 2 (p < .01) in infants in the withdrawn group. There was no change in serum sodium levels with advancing postnatal age. IV fluids were increased in all the groups during the first 5 days after birth. There were no significant differences in total volume of IV fluids administered between the groups. Because a lower pH was evident at an earlier postnatal age in the withdrawn and control groups, we examined a number of clinical factors contributing to metabolic acidosis (Table II). Infants who were withdrawn had large PDA; nearly two-thirds of these infants underwent surgical ligation and had significantly greater weight loss during the first 3 days after birth (p < .05). Analysis of individual cases revealed that the nadir in pH corresponded to the diagnosis of large PDA and the use of bicarbonate to treat acidosis. In order to identify potential factor(s) contributing to metabolic acidosis, we have constructed a model with pH on days 3 and 4 as dependent variable and incorporated all the factors that could potentially cause metabolic acidosis preceding days 3–4 as independent variables. Gestational age, large PDA, and weight loss accounted for 65% of variance in pH.
We show that all very-LBW infants developed acidosis (pH <7.25) between days 3 and 5 after birth. Infants with moderate to large PDA developed acidosis earlier. The diagnosis of PDA coincided with higher blood urea nitrogen. A lower pH correlated with gestational age, large PDA, and the magnitude of weight loss during the first 72 hours after birth. Importantly, the dose or duration of parenteral amino acid and cysteine did not seem to affect arterial pH (acidosis). Defects in urinary acidification, together with a number of other factors such as infections, hypotension, inappropriate administration of IV fluids, higher insensible water losses, and decreased tissue perfusion, contribute to metabolic acidosis in premature infants. In such a complex situation, it is difficult to ascertain whether parenteral amino acids worsen metabolic acidosis in premature infants. In this study, we examined the interaction between a number of factors to identify the potential contributors to acidosis, specifically, the impact of dose and duration of parenteral amino acids. Infants included in the present study received crystalline amino acid solution (10% TrophaAmine; Braun Medical Inc, Irvine, CA), providing a mixture of essential and nonessential amino acids, as well as taurine and a soluble form of tyrosine, N-acetyl-D-tyrosine. The majority were nonsalt amino acids, except lysine and cysteine, which were added, respectively, as acetate and hydrochloride salt. Although the titratable acidity, the amount of blood buffers consumed in vivo to titrate the infusate (pH 5.5) to a normal blood pH, was not determined in infants, Heird and colleagues13 showed that infants and children receiving amino acid mixtures with high titratable acidity did not become acidotic. Their data suggest that metabolism of cationic amino acids and resulting release of excess protons (H+) may cause hyperchloremic metabolic acidosis, if it is not balanced by an equal proportion of metabolizable anionic amino acids. Thus, determination of cationic gap (cationic amino acids – anionic amino acids + acetate) may assist in determining whether there is an imbalance in the amino acid mixture. TrophAmine is a balanced amino acid solution containing 156 mmol/L of cationic amino acids (arginine, histidine, and lysine) and 155 mmol/L of anionic amino acids (glutamic acid and aspartate) plus acetate. Thus, the metabolic acidosis observed in the LBW infants could not be attributed to the "balanced" amino acid mixture administered.
Infants in the present study demonstrated a normal anion-gap
metabolic acidosis with advancing postnatal age (nadir on days 4–5). Few
limited studies have examined the reasons for such a metabolic acidosis. Sato
and colleagues18
showed that low-birth-weight infants have a higher urinary pH, higher
fractional excretion of bicarbonate, and most importantly lower urinary
ammonium excretion rate persisting even on days 4–6 after birth. They
suggested that insufficiency of ammonium excretion was the main cause of
metabolic acidosis in the early neonatal
period.18 The
reported pH in their study on days 4–6 (
Metabolic acidosis in the present study occurred independent of the amount
and duration of amino acids infusions and the dose of supplemental cysteine,
suggesting that factors other than parenteral amino acids contribute to the
development of acidosis. A recent study has shown that administration of 2.4
g/kg/d of amino acids was safe and did not result in changes in acid-base
parameters.11 Our
data are robust in that we determined the dose-response relationship, examined
sequential changes in blood gas and serum electrolytes in response to a higher
(currently recommended) dose of parenteral amino acid for a prolonged period,
and examined the impact of cysteine load and other comorbidities. We observed
that infants with large PDA developed acidosis early (day 3), had
significantly lower arterial pH, were given IV bicarbonate to treat acidosis,
and required ionotropic drugs to maintain normal blood pressure (withdrawn
group: Table II). PDA becomes
clinically manifest with improvement in pulmonary compliance. The associated
"ductal steal" affects blood flow to vital organs, resulting in
hypoperfusion.19
Onset of early acidosis coinciding with the diagnosis of PDA and higher
concentration of blood urea nitrogen in the withdrawn group suggest renal
hypoperfusion. We speculate that in premature infants, renal tubular
immaturity, hypoperfusion, and hypotension, accompanied by clinical
interventions used to treat PDA, may have resulted in a decrease in pH at an
earlier postnatal age. Our model confirmed that gestational age, weight loss,
possibly as a result of restriction of IV fluids, and PDA accounted for a
large majority ( The present study underscores the complexities involved in identifying the cause of metabolic acidosis in a rapidly changing clinical situation (ie, the preterm neonate in the intensive care unit). Because blood pH is a labile parameter influenced by clinical state and confounding complications (PDA, hypovolemia, etc) and equally important clinical interventions, it is difficult to identify the cause of change in pH. In fact, the investigating committee appointed by the IRB found it difficult to manage the large amount of clinical and laboratory data obtained in these studies and resolved to identify acidosis according to administration of bicarbonate by the clinician. They were not able to attribute bicarbonate administration to any identifiable clinical parameters. Only by performing a case-control analysis could we show that low-birth-weight infants develop relative metabolic acidosis in the first few days after birth irrespective of the amount of parenteral amino acids administered. We conclude that non–anion gap metabolic acidosis is common in premature infants. Early recognition and management of PDA, prevention of excess water losses in conjunction with judicious fluid and electrolyte management, and balancing cysteine hydrochloride with an equimolar amount of base (acetate) could prevent metabolic acidosis. Such a strategy will result in provision of an optimal amount of parenteral amino acids to promote nitrogen accretion in LBW infants. These studies were supported by a grant from the National Institute of Child Health and Human Development (RO1-HD042152). The secretarial assistance of Mrs Joyce Nolan is gratefully appreciated. Received for publication May 2, 2006. Accepted for publication February 23, 2007.
Journal of Parenteral and Enteral Nutrition, Vol. 31, No. 4,
278-283 (2007)
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32 weeks, 
17% of birth weight)
when compared with infants without PDA. Gestational age, weight loss, and
patent ductus arteriosus accounted for 65% of variance in acidosis.
Conclusions: Low-birth-weight infants develop metabolic acidosis
between 2 and 5 days after birth, irrespective of dose and duration of
parenteral amino acid administration. Careful management of parenteral fluids
and comorbidities may lower the incidence of acidosis and promote protein
accretion. 
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MATERIALS AND METHODS
RESULTS