Locust bean gum safety in neonates and young infants: An integrated review of the toxicological database and clinical evidence

Locust bean gum (LBG) is a galactomannan polysaccharide used as thickener in infant formulas with the therapeutic aim to treat uncomplicated gastroesophageal reflux (GER). Since its use in young infants below 12 weeks of age is not explicitly covered by the current scientific concept of the derivation of health based guidance values, the present integrated safety review aimed to compile all the relevant preclinical toxicological studies and to combine them with substantial evidence gathered from the clinical paediatric use as part of the weight of evidence supporting the safety in young infants below 12 weeks of age. LBG was demonstrated to have very low toxicity in preclinical studies mainly resulting from its indigestible nature leading to negligible systemic bioavailability and only possibly influencing tolerance. A standard therapeutic level of 0.5 g/100 mL in thickened infant formula is shown to confer a sufficiently protective Margin of Safety. LBG was not associated with any adverse toxic or nutritional effects in healthy term infants, while there are limited case-reports of possible adverse effects in preterms receiving the thickener inappropriately. Altogether, it can be concluded that LBG is safe for its intended therapeutic use in term-born infants to treat uncomplicated regurgitation from birth onwards.     

Diagnostic value of simultaneous non-invasive continuous,ambulatory finger blood pressure and electrocardiogram monitoring in a patient with hypertrophic obstructive cardiomyopathy

BACKGROUND: The pathophysiology of hypertrophic obstructive cardiomyopathy (HOCM) is complex and heterogeneous, and it may be difficult to disentangle the various pathophysiologic properties leading to complaints. OBJECTIVES: To elucidate the sequence of acute pathophysiologic changes leading to complaints in a patient with HOCM. METHODS: Cardiopres measurements [the combination of non-invasive, continuous finger artery blood pressure monitoring, and three-lead electrocardiogram (ECG) recordings] were performed during physiologic, supine exercise--before and after replacement of metoprolol by verapamil. Within 24 h of the Cardiopres measurement standard Doppler echocardiography was performed. Finger artery pressure wave was analysed using Beatscope software (BMI-TNO, Amsterdam, The Netherlands), ST analysis was performed with H-Scribe (Mortara Instrument, Bilt, The Netherlands). RESULTS: Exercise under metoprolol: finger BP decreased from 130/65 mmHg to 90/60 mmHg, heart rate increased from 65 bpm to 100 bpm and ST analysis revealed significant ST depression in all leads. The occurrence of ST depression preceded the hypotension. Echocardiography showed a dynamic gradient of 70 mmHg. Exercise under verapamil: the patient had less complaints, BP increased from 125/60 mmHg to 165/65 mmHg, heart rate increased from 75 bpm to 107 bpm and ST analysis showed no ST depression > 1 mm. Echocardiography showed no change. CONCLUSIONS: The use of the Cardiopres during a physiological stimulus showed improvement in exercise capacity in a patient with HOCM, while the standard test, stress-echocardiography, showed no correlation with clinical status. The Cardiopres is a useful diagnostic and research tool, allowing non-invasive, ambulatory monitoring of blood pressure and ECG changes.     

Protein nutrition of the neonate

The period of growth and development between birth and weaning is crucial for the long-term well-being of the organism. Protein deposition is very rapid, is achieved with a high nutritional efficiency, and is accompanied by marked differences in the growth rates of individual tissues and a series of maturational processes. These important aspects of development occur while the neonate is consuming a single and highly-specific food source, milk. Surprisingly, although there is a clear relationship between the nutrient density of milk and the growth rate of its recipient, this relationship does not apply to the overall amino acid composition of mixed milk proteins. Some amino acids, notably glycine and arginine, are supplied in milk in quantities that are much less than the needs of the neonate. The milk-fed neonate is therefore capable of carrying out a tightly-regulated transfer of N from amino acids in excess to those that are deficient. The rapid growth of the neonate is supported by a high rate of tissue protein synthesis. This process appears to be activated by the consumption of the first meals of colostrum. Recent research has identified that skeletal muscle and the brain are specifically responsive to an unidentified factor in colostrum. Following the initial anabolic response the rate of protein synthesis in some tissues, notably muscle, falls from birth to weaning. This decrease reflects a progressively smaller anabolic response to nutrient intake, which not only involves an overall fall in the capacity for protein synthesis, but also in responses to insulin and amino acids. The study of growth and protein metabolism, and their regulation in the neonate is not only important for pediatrics, but may provide important pointers to more general aspects of regulation that could be applied to the nutrition of the mature animal.     

A careful course of action in a conflict regarding useful treatment of a newborn infant with severe brain damage

In a newborn female infant, it was concluded that severe perinatal asphyxia had caused such extensive cerebral damage that further medical treatment was useless. Based on their religious beliefs, the parents disagreed, despite the fact that the requested second opinions supported the conclusion of the medical staff. Since the parents persisted, a period of inurement was agreed upon during which reanimation would be performed if necessary. After several months, there was no change in the attitude of the parents towards the policy not to reanimate, even though it was clear that there was no improvement whatsoever in the patient's neurological status, while everyone agreed that she showed signs of increased suffering. The decision regarding the determination of a situation in which further medical treatment was useless was re-evaluated carefully. In a legal procedure started by the parents, the judge supported the decision of the attending physicians. In order to prevent the parents from taking their child home, in which case a situation could arise in which she would be deprived of adequate sedation or analgesia, which the attending physicians were obliged to provide, the Dutch Child Protection Council was consulted and the parents were deprived of their parental authority. Ultimately, the patient died suddenly due to respiratory and circulatory arrest without another situation in which reanimation might have been indicated.     

Continuous stroke volume monitoring by modelling flow from non-invasive measurement of arterial pressure in humans under orthostatic stress.

The relationship between aortic flow and pressure is described by a three-element model of the arterial input impedance, including continuous correction for variations in the diameter and the compliance of the aorta (Modelflow). We computed the aortic flow from arterial pressure by this model, and evaluated whether, under orthostatic stress, flow may be derived from both an invasive and a non-invasive determination of arterial pressure. In 10 young adults, Modelflow stroke volume (MFSV) was computed from both intra-brachial arterial pressure (IAP) and non-invasive finger pressure (FINAP) measurements. For comparison, a computer-controlled series of four thermodilution estimates (thermodilution-determined stroke volume; TDSV) were averaged for the following positions: supine, standing, head-down tilt at 20 degrees (HDT20) and head-up tilt at 30 degrees and 70 degrees (HUT30 and HUT70 respectively). Data from one subject were discarded due to malfunctioning thermodilution injections. A total of 155 recordings from 160 series were available for comparison. The supine TDSV of 113+/-13 ml (mean+/-S.D.) dropped by 40% to 68+/-14 ml during standing, by 24% to 86+/-12 ml during HUT30, and by 51% to 55+/-15 ml during HUT70. During HDT20, TDSV was 114+/-13 ml. MFSV for IAP underestimated TDSV during HDT20 (-6+/-6 ml; P<0.05), but that for FINAP did not (-4+/-7 ml; not significant). For HUT70 and standing, MFSV for IAP overestimated TDSV by 11+/-10 ml (HUT70; P<0.01) and 12+/-9 ml (standing; P<0.01). However, the offset of MFSV for FINAP was not significant for either HUT70 (3+/-8 ml) or standing (3+/-9 ml). In conclusion, due to orthostasis, changes in the aortic transmural pressure may lead to an offset in MFSV from IAP. However, Modelflow correctly calculated aortic flow from non-invasively determined finger pressure during orthostasis.     

Splanchnic metabolism of ingested amino acids in neonates

PURPOSE OF REVIEW: Neonates typically show rapid growth. Nutrient absorption in the neonatal period is higher than during any other time in life so as to meet the requirements for this rapid growth. Generally, nutrients are administered enterally, and in the past the gut was considered to absorb and digest these nutrients without major metabolism. Recent animal and human work has, however, revealed that the intestine and other splanchnic tissues contribute significantly to whole-body metabolism, and have their own specific functions. This review focuses on these observations. RECENT FINDINGS: The splanchnic tissues take up greatly different proportions of each of the amino acids, ranging from 80-100% for threonine and several nonessential amino acids to 15-30% for lysine. The metabolic fates of the utilized substrates differ as well. Some are predominantly used for constitutive protein synthesis, others for energy generation or for formation of (glyco-)proteins that are secreted into the lumen. Glucose appears to be the major contributor to energy generation, but amino acids are important as well. SUMMARY: Both animal and human studies have shown that the intestine uses substantial amounts of dietary amino acids. This has several implications for the nutritional needs of infants to maintain growth, especially during times of inadequate enteral nutrition.     

Albumin synthesis in premature neonates is stimulated by parenterally administered amino acids during the first days of life

BACKGROUND: We recently showed that parenteral administration of amino acids to premature infants immediately after birth is safe and results in a positive nitrogen balance and increased whole-body protein synthesis. However, we did not determine organ-specific effects; albumin, produced by the liver, is an important protein, but its concentration is often low in premature neonates during the first few days after birth. OBJECTIVE: The objective of the study was to test the hypothesis that the fractional and absolute albumin synthesis rates would increase with the administration of amino acids after birth, even at low nonprotein energy intake. DESIGN: Premature infants (<1500 g birth weight), who were on ventilation, received from birth onward either glucose only (control group, n = 7) or glucose and 2.4 g amino acid kg(-1) d(-1) (intervention group, n = 8). On postnatal day 2, all infants received a primed continuous infusion of [1-(13)C]leucine, and mass spectrometry techniques were used to determine the incorporation of the leucine into albumin. Results are expressed as medians and 25th and 75th percentiles. RESULTS: Albumin fractional synthesis rates in the intervention group were significantly higher than those in the control group [22.9% (17.6-28.0%)/d and 12.6% (11.0-19.4%)/d, respectively; P = 0.029]. Likewise, the albumin absolute synthesis rates in the intervention group were significantly higher than those in the control group [228 (187-289) mg kg(-1) d(-1) and 168 (118-203) mg kg(-1) d(-1), respectively; P = 0.030]. CONCLUSION: Amino acid administration increases albumin synthesis rates in premature neonates even at a low energy intake.     

The gut takes nearly all: threonine kinetics in infants

BACKGROUND: Threonine is an essential amino acid that is abundantly present in intestinally produced glycoproteins. Animal studies show that intestinal first-pass threonine metabolism is high, particularly during a restricted enteral protein intake. OBJECTIVE: The objective of the study was to quantify intestinal first-pass threonine metabolism in preterm infants during full enteral feeding and during restricted enteral intake. DESIGN: Eight preterm infants (x +/- SD birth weight: 1.1 +/- 0.1 kg; gestational age: 29 +/- 2 wk) were studied during 2 periods. During period A, 40% of total intake was administered enterally and 60% was administered parenterally. Total threonine intake was 58 +/- 6 micromol kg(-1) h(-1). During period B, the infants received full enteral feeding, and the total threonine intake was 63 +/- 6 micromol kg(-1) h(-1). Dual stable-isotope tracer techniques were used to assess splanchnic and whole-body threonine kinetics. RESULTS: The fractional first-pass threonine uptake by the intestine was remarkably high in both periods: 82 +/- 6% during partial enteral feeding and 70 +/- 6% during full enteral feeding. Net threonine retention was not affected by the route of feeding. CONCLUSION: In preterm infants, the splanchnic tissues extract a very large amount of the dietary threonine intake, which indicates a high obligatory visceral need for threonine, presumably for the purposes of synthesis.     

Adaptive regulation of intestinal lysine metabolism

The metabolism of dietary essential amino acids by the gut has a direct effect on their systemic availability and potentially limits growth. We demonstrate that, in neonatal pigs bearing portal and arterial catheters and fed a diet containing 23% protein [high protein (HP) diet], more than half the intake of essential amino acids is metabolized by the portal-drained viscera (PDV). Intraduodenal or i.v. infusions of [U-(13)C]-lysine were used to measure the appearance across and the use of the tracer by the PDV. In HP-fed pigs, lysine use by the PDV was derived almost entirely from the arterial input. In these animals, the small amount of dietary lysine used in first pass was oxidized almost entirely. Even so, intestinal lysine oxidation (24 micromol/kg per h) accounted for one-third of whole-body lysine oxidation (77 micromol/kg per h). Total lysine use by the PDV was not affected by low protein (LP) feeding (HP, 213 micromol/kg per h; LP,186 micromol/kg per h). In LP-fed pigs, the use of lysine by the PDV accounted for more than 75% of its intake. In contrast to HP feeding, both dietary and arterial lysines were used by the PDV of LP-fed pigs in nearly equal amounts. Intestinal lysine oxidation was suppressed completely. We conclude that the PDV are key organs with respect to amino acid metabolism and that the intestines use a disproportionately large amount of the dietary supply of amino acids during protein restriction.