Plasma and tissue levels of lipids, fatty acids and plasma carnitine in neonates receiving a new fat emulsion

This study was undertaken to compare Intralipid® with a new fat emulsion containing gamma-linolenic acid and carnitine, named Pediatric Fat Emulsion 4501, in neonates with regard to lipid and carnitine metabolism over a short period of total parenteral nutrition. There were 10 neonates in each group and they tolerated the total parenteral nutrition well. In spite of the gamma-linolenic acid supplementation in the new emulsion, arachidonic acid decreased significantly in plasma lipid esters and adipose tissue in both groups after 5 d of treatment. Also, there was a decrease in plasma docosahexaenoic acid which was more pronounced in the treatment group. The relative percentage values of linoleic and linolenic acids in adipose tissue were increased, indicating that newborns have a rapid accretion of fatty acids. Plasma triglycerides were effectively cleared during the periods without fat infusion. In the group that received Pediatric Fat Emulsion 4501 the means of both free and total plasma carnitine concentrations increased significantly, whereas they tended to decrease in the Intralipid® group.     

Effect of carnitine on lipid metabolism in the neonate. II. Carnitine addition to lipid infusion during prolonged total parenteral nutrition

The effect of carnitine administration on lipid metabolism and carnitine and acylcarnitine plasma values of newborn infants, given total parenteral nutrition for the first 7 days of life, was studied during a 4-hour infusion of Intralipid. An increase in plasma concentrations of total carnitine, free carnitine, and short-chain and long-chain acylcarnitine was found, but no significant change in triglycerides, free fatty acids, glycerol, or beta-hydroxybutyrate plasma values was noted, as compared with values obtained without carnitine administration. Moreover, the low free carnitine and short-chain and long-chain acylcarnitine plasma levels found in newborn infants after 7 days of total parenteral nutrition did not seem to impair the utilization of infused lipids. The results support the concept that the relation between the carnitine pool and lipid metabolism can be influenced by intravenous glucose infusion. Low carnitine plasma concentrations do not necessarily signify a depletion of body carnitine, and sufficient tissue carnitine concentrations can probably maintain good lipid utilization for an extended period.     

Carnitine deficiency in premature infants receiving total parenteral nutrition: effect of L-carnitine supplementation

To investigate whether L-carnitine supplementation may correct nutritional carnitine deficiency and associated metabolic disturbances in premature infants receiving total parenteral nutrition, an intravenous fat tolerance test (1 gm/kg Intralipid over four hours) was performed in 29 premature infants 6 to 10 days of age (15 receiving carnitine supplement 10 mg/kg . day L-carnitine IV, and 14 receiving no supplement). Total carnitine plasma values were normal or slightly elevated in supplemented but decreased in nonsupplemented infants. In both groups, fat infusion resulted in an increase in plasma concentrations of triglycerides, free fatty acids, D-beta-hydroxybutyrate, and short-chain and long-chain acylcarnitine, but total carnitine values did not change. After fat infusion, the free fatty acids/D-beta-hydroxybutyrate ratios were lower and the increase of acylcarnitine greater in supplemented infants of 29 to 33 weeks' gestation than in nonsupplemented infants of the same gestational age. This study provides evidence that premature infants of less than 34 weeks' gestation requiring total parenteral nutrition develop nutritional carnitine deficiency with impaired fatty acid oxidation and ketogenesis. Carnitine supplementation improves this metabolic disturbance.     

Postheparin plasma lipases and carnitine in infants during parenteral nutrition

Lipoprotein lipase is the rate-limiting factor for hydrolyzing triglycerides to glycerol and fatty acids. Carnitine is a cofactor in the transport of long-chain fatty acids through the mitochondrial membrane for oxidation. To assess these determinants of fat utilization during total parenteral nutrition, lipoprotein and hepatic lipase activities and carnitine concentrations of nine newborn infants, operated on because of gastrointestinal anomalies during the first day of life, were measured with specific methods. Total parenteral nutrition was built up in 3 days whereafter the infants received 3 g/kg of fat at a constant rate of infusion for 24 h/day. Lipoprotein lipase activity of post-heparin plasma increased from 14 to 35 mumol free fatty acids/ml/h during parenteral nutrition whereas hepatic lipase activity remained unchanged at 40 mumol free fatty acids/ml/h. Serum free carnitine and acylcarnitine levels decreased significantly during parenteral nutrition; urinary excretion of carnitine decreased also. In addition, serum cholesterol and phospholipids increased markedly during parenteral nutrition whereas serum triglycerides, free fatty acids, and blood beta-hydroxybutyrate remained unchanged. Serum apolipoprotein A-I concentrations were unaltered, apolipoprotein A-II underwent a transient increase, and apolipoprotein B increased monotonically during parenteral nutrition. The results suggest that under the present circumstances neither lipoprotein lipase activity nor carnitine resources are rate-limiting for the utilization of fat in newborn infants during total parenteral nutrition.     

多种油脂肪乳在超低出生体重儿中应用的疗效分析

目的 分析多种油脂肪乳(SMOF)在超低出生体重(ELBW)儿中应用的疗效.方法 回顾性选取2018年1月1日至2020年7月30日收治的ELBW儿49例为研究对象,入院时日龄≤14 d,接受胃肠外营养时间>14 d.根据应用的脂肪乳剂种类,分为SMOF组(n=26)和中长链脂肪乳(MCT/LCT)组(n=23),比较...     

Carnitine supplementation and ketogenesis by small-for-date neonates on medium-and long-chain fatty acid formulae

Carnitine is a key molecule in energy production from various substrates. Although it is generally believed that it plays no role in the metabolism of medium-chain triglycerides, quite a few data exist to the contrary. In the present study we investigated the effect of carnitine on ketogenesis in small-for-date neonates fed formulae of equal caloric value and fat content that was predominantly long-chain triglycerides or medium-chain triglycerides (46% of total fat). According to our results there was a statistically significant interaction between carnitine and the chain length of the administered fat with respect to ketone production. Increased ketogenesis was only shown by the neonates receiving medium-chain triglycerides and carnitine. Our results provide further evidence for the involvement of carnitine in medium-chain triglyceride metabolism.     

Enhanced lipid utilization in infants receiving oral L-carnitine during long-term parenteral nutrition

Fourteen infants requiring long-term total parenteral nutrition but able to tolerate small quantities of enteral feedings were randomized into carnitine treatment and placebo control groups. All infants had received nutritional support devoid of carnitine. Plasma carnitine levels and observed plasma lipid indices were not different before supplementation. Under standardized, steady-state conditions, 0.5 g/kg fat emulsion (intralipid) was administered intravenously over 2 hours both before and after infants received 7 days of continuous nasogastric or gastric tube L-carnitine (50 mumol/kg/day) or placebo. Plasma triglyceride, free fatty acid, acetoacetate, beta-hydroxybutyrate, and carnitine concentrations were observed at 0 (start of lipid infusion), 2, and 4 hours for pre- and post-treatment periods, and in addition at 6 and 8 hours after carnitine supplementation. Infants receiving carnitine had significantly greater beta-hydroxybutyrate plasma concentrations (P less than 0.05) and carnitine (P less than 0.001) at 0, 2, 4, 6, and 8 hours, and greater plasma acetoacetate concentrations (P less than 0.05) at 2, 4, 6, and 8 hours, compared with controls. Twenty-four-hour urinary carnitine excretion was very low for both groups before supplementation; after supplementation, excretion was higher (P less than 0.05) in the carnitine group. No significant differences were found between groups for plasma triglyceride or free fatty acid concentrations at any observation period. This study demonstrated enhanced fatty acid oxidation, as evidenced by increased ketogenesis, with L-carnitine supplementation in infants receiving long-term total parenteral nutrition.     

Tolerance of mixed lipid emulsion in neonates: effect of concentration.

AIMS: To compare the effect of concentration of a mixed lipid emulsion (50:50 medium chain triglyceride/long chain triglyceride) (MCT/LCT) on lipid tolerance in neonates. METHODS: A prospective randomised controlled trial of 75 neonates requiring prolonged parenteral nutrition was conducted in the neonatal intensive care units of the Royal Maternity Hospital, Belfast, and the Waveney Hospital, Ballymena. Thirty eight infants received 10% and 37 20% lipid emulsion. Infants were randomly assigned to groups at the start of parenteral nutrition and studied if they required seven or more days of this. Lipid tolerance was assessed by twice weekly measurements of plasma triglyceride and cholesterol concentrations and weekly measurement of non-esterified fatty acids and beta hydroxy butyrate. Anthropometry was carried out weekly. RESULTS: The mean cholesterol in the 10% group was significantly higher within the first seven days of the study compared with the 20% group (3.5 vs 2.87 mmol/l), and continued to rise over the study period in contrast to the 20% group. A similar pattern was observed with the triglyceride concentrations. There was no significant difference in non-esterified fatty acids, beta hydroxy butyrate, or growth between the two groups. CONCLUSION: Sick neonates show better biochemical tolerance to 20% MCT/LCT emulsion than to 10% emulsion.     

Impairment of lipid emulsion metabolism associated with carnitine insufficiency in premature infants

Carnitine status and its relation to lipid metabolism were determined in 11 premature infants (less than 34 weeks of gestation) receiving parenteral nutrition. Intravenous administration of lipid emulsion increased serum concentrations of free fatty acids at 2, 4, and 8 h after infusion. Despite this increase, serum levels of ketone bodies remained low, reaching only 40 to 45% of levels in full-term infants receiving enteral feeds. In premature infants, levels of plasma total and free carnitine were about half those in full-term infants and were not altered by lipid infusion. The results indicate limited potential for lipid emulsion as a source of energy in premature infants, possibly because carnitine insufficiency restricts fatty acid oxidation.     

Neonatal Parenteral Nutrition with a Fat Emulsion Containing Medium Chain Triglycerides

ABSTRACT. Fifty-one newborn infants requiring parenteral nutrition were randomly assigned to receive a 50% medium chain triglyceride/50% long chain triglyceride lipid emulsion or the conventional 100% long chain triglyceride emulsion. Fat was administered daily for 20 hours, to a maximum of 3 g/kg/day. Plasma triglycerides, cholesterol, free fatty acids, ketones, glucose and capillary blood gases were monitored daily up to the sixth day of fat infusion. There were no significant differences in mean plasma triglycerides and free fatty acids between the two groups. No cases of hyperketonaemia were detected in the infants studied. Hyperglycaemic episodes were detected with similar frequency in both groups. The group who received the emulsion containing medium chain triglycerides had significantly lower mean plasma cholesterol values during the study. After 6 days of intravenous fat administration mean plasma cholesterol was more than 100% higher in the group which received the conventional emulsion. Differences in cholesterol content between the emulsions and a cholesterol lowering effect of medium chain triglycerides are possible explanations for these findings.     

The metabolic effects of two different lipid emulsions used in parenterally fed premature infants--a randomized comparative study

Objective

To compare the effects of two different lipid emulsions, based on soybean oil and olive oil respectively on plasma lipid concentrations and acylcarnitine profile of very low birth weight infants.

Design

Randomized comparative study.

Patients and methods

Forty very low birth weight infants, ≤ 32 weeks of gestational age and receiving at least 40% of the calorie taken by parenteral nutrition from lipid solution at 14th day of life were evaluated. Group I (n = 20) received soybean oil based lipid emulsion (Intralipid®) and Group II (n = 20) received olive oil based lipid emulsion (Clinoleic®).

Main outcome measures

Plasma lipid concentrations and acylcarnitine profile were assessed.

Results

Triglyceride, cholesterol, high and low density lipoprotein levels, liver function tests were similar between two groups whereas very low density lipoprotein level was statistically lower in Group I (p < 0.05). Free carnitine levels were 15.73 ± 10.67 in Group I and 34.25 ± 22.18 μM in Group II (p = 0.012) and hexanoyl carnitine levels 2.18 ± 2.10 in Group I and 0.38 ± 0.12 μM in Group II, respectively (p = 0.005). Plasma medium chain acylcarnitine levels were significantly higher in Group I.

Conclusions

Low levels of very low density lipoprotein in Group I may be a way of hemostasis to keep the serum triglyceride within normal levels. Lower free carnitine levels in soybean oil-based group is the result of carnitine need during the mitochondrial transport of long chain fatty acids. In Group I, due to the inefficient transport of medium chain fatty acids into the mitochondria, medium chain acylcarnitines accumulate in plasma. This may be the reason of lower carnitine levels in Group I. We suggest that higher levels of hexanoyl carnitine, reflecting defective mitochondrial transport of hexanoyl which leads immunsupression, may be the cause of higher sepsis risk in Group I.     

Neonatal parenteral nutrition with a fat emulsion containing medium chain triglycerides

Fifty-one newborn infants requiring parenteral nutrition were randomly assigned to receive a 50% medium chain triglyceride/50% long chain triglyceride lipid emulsion or the conventional 100% long chain triglyceride emulsion. Fat was administered daily for 20 hours, to a maximum of 3 g/kg/day. Plasma triglycerides, cholesterol, free fatty acids, ketones, glucose and capillary blood gases were monitored daily up to the sixth day of fat infusion. There were no significant differences in mean plasma triglycerides and free fatty acids between the two groups. No cases of hyperketonaemia were detected in the infants studied. Hyperglycaemic episodes were detected with similar frequency in both groups. The group who received the emulsion containing medium chain triglycerides had significantly lower mean plasma cholesterol values during the study. After 6 days of intravenous fat administration mean plasma cholesterol was more than 100% higher in the group which received the conventional emulsion. Differences in cholesterol content between the emulsions and a cholesterol lowering effect of medium chain triglycerides are possible explanations for these findings.     

Use of intravenous lipid and hyperbilirubinemia in the first week.

Serum triglycerides, free fatty acids, unconjugated bilirubin, and albumin were evaluated in 40 neonates receiving 0.5-3.5 g/kg/day of a 50/50 soybean-safflower lipid emulsion infused during 18 h. The purpose of the study was to evaluate lipid tolerance and unconjugated hyperbilirubinemia according to our total parenteral nutrition protocol, which initiates lipid on postnatal day 4. Mean serum triglycerides and free fatty acids were within the range of prelipid infusion values at all dosages, and no statistically significant differences were noted between very-low-birth-weight neonates and those greater than 1,500 g birth weight. Mean free fatty acid:albumin molar ratio was less than 1.0 at all dosages and no individual patient values exceeded a ratio of 3.0. Mean peak serum unconjugated bilirubin of 5.8 mg/dl on postnatal day 3 was stable or fell the next 10 days of lipid-inclusive total parenteral nutrition. Initiating intravenous lipid on the 4th postnatal day at 0.5 g/kg/day and increasing at 0.5 g/kg/day increments at the end of the 1st postnatal week appears to be tolerated well. However, 5% of serum triglyceride levels exceeded 200 mg/dl. Therefore, in view of the unpredictability of a given patient's tolerance to lipid infusion, there should be monitoring for lipemia.     

Low blood and plasma carnitine levels in children receiving long-term parenteral nutrition

Total and free carnitine and acylcarnitine concentrations were analyzed in whole blood and plasma in 12 children with a mean age of 68.4 +/- 42.9 months who had received carnitine-free total parenteral nutrition (TPN) for an average of 4 years. The purpose of the study was to see if the children had become carnitine deficient and, if so, whether this correlated with poor lipid clearance. Compared to controls, the TPN-dependent children had significantly decreased concentrations of total and free carnitine in blood (26.6 +/- 9.4 (SD) mumols/L vs. 43.3 +/- 9.1 mumols/L, p less than 0.001, and 17.1 +/- 7.7 mumols/L vs. 35.2 +/- 8.1 mumols/L, p less than 0.001, respectively). Similar results were found in plasma (total carnitine of 19.0 +/- 8.0 mumols/L vs. 41.9 +/- 5.2 mumols/L, p less than 0.001, and free carnitine of 15.7 +/- 7.3 mumols/L vs. 36.1 +/- 5.2 mumols/L, p less than 0.001, respectively). The acylcarnitine concentration in plasma was decreased in the TPN children (3.3 +/- 1.5 mumols/L vs. 5.8 +/- 3.0 mumols/L, p less than 0.01) compared to controls. Despite the low carnitine concentrations, serum triglyceride levels and serum free fatty acid levels were within the normal range. There was no correlation between carnitine concentrations in plasma and serum triglyceride and free fatty acid levels. Our data show that children receiving carnitine-free TPN for many years developed markedly decreased concentrations of carnitine in blood and plasma. However, no adverse effects of the low carnitine levels were found on triglyceride and free fatty acid metabolism under stable conditions.     

Postnatal changes in neonatal acylcarnitine profile

++Electrospray-tandem mass spectrometry represents a powerful method for detection of inborn errors of fatty acid metabolism. In the present study, it was used to examine neonatal carnitine metabolism, which reflects fatty acid metabolism. In 70 healthy neonates, blood samples were taken from the umbilical cord and by heel-stick puncture in full-term neonates on postnatal d 5. Cord blood specimens were also obtained from 15 preterm and 10 small-for-gestational-age infants. Acylcarnitine concentrations were measured in dried blood spots by electrospray tandem mass spectrometry. Compared with cord blood, the levels of nearly all acylcarnitine species were significantly higher on the postnatal d 5, whereas free carnitine remained unchanged. Total acylcarnitine/free carnitine-ratio increased, whereas the free carnitine/total carnitine-ratio (0.54 +/- 0.05; p < 0.01) further decreased. A reduced availability of free carnitine in the early neonatal period may affect fatty acid oxidation and thus be of potential pathophysiological relevance under conditions with higher energy demands, e.g. in sepsis. Cord blood concentrations of free carnitine, total carnitine, and total acylcarnitines were strongly related to birth weight (p < 0.01). Lower umbilical artery pH, i.e. mild hypoxia, caused accumulation of mainly long-chain acylcarnitines. This implicates that long-chain acylcarnitines could serve as a parameter of perinatal asphyxia.     

Metabolic studies of carnitine in a child with propionic acidemia

Carnitine metabolism was studied in a 7-y-old boy with propionic acidemia due to an almost total deficiency of propionyl-CoA carboxylase. The initial diagnosis was made at 3 wk of age followed by numerous episodes of metabolic acidosis despite a low-content branch-chain amino acid diet containing supplemental biotin. Although clinically stable and in a nonacidotic state, the plasma concentration of total carnitine was normal (38.9 microM; normal = 46 +/- 10, mean +/- SD, n = 30) whereas free carnitine was decreased (5.7 microM; normal = 37 +/- 8) and short-chain acylcarnitines were increased (28.6 microM; normal = 5.7 +/- 3.5). Skeletal muscle and liver specimens obtained at open biopsy had low total and free carnitine contents and increased ratio of short-chain acylcarnitines to free carnitine. Short-chain acylcarnitine content was low in liver but increased in skeletal muscle. The liver contained fatty vacuoles, enlarged mitochondria with paracrystalline inclusions, and numerous peroxisomes whereas the skeletal muscle also had lipid vacuoles and an increase in number and size of mitochondria. A carnitine challenge test (100 mg L-carnitine/kg body wt via a gastrostomy tube) resulted in a peak plasma carnitine concentration at 120 min. With maintenance therapy of 100 mg L-carnitine/kg/day the plasma free carnitine remained relatively low, the plasma glycine concentration decreased, and urinary acylcarnitine excretion increased. This study demonstrates that the alterations in carnitine and its derivatives observed in plasma and urine reflect the same type of altered distribution in tissue and provides further data on the effects of L-carnitine therapy.     

Blood levels of total carnitine and lipid utilization with and without carnitine supplementation in newborn infants

Postnatal changes of the plasma carnitine level were compared in orally and parenterally fed newborn infants. As expected, in contrast to the increasing plasma level of carnitine in infants fed with human milk, a gradual and significant fall was observed during parenteral feeding. Next, the effect of carnitine supplementation on the elimination rate of an Intralipid load was tested. The increased disappearance rate of triglycerides associated with the exogenously administered carnitine suggested an increased lipid utilization during the carnitine supplemented period of parenteral nutrition.     

Tissue carnitine homeostasis in very-long-chain acyl-CoA dehydrogenase-deficient mice

Deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD) is the most common long-chain fatty acid oxidation defect and presents with heterogeneous clinical manifestations. Accumulation of long-chain acylcarnitines and deficiency of free carnitine have often been proposed to play an important role in disease pathogenesis. The VLCAD-deficient mouse exhibits similar clinical and biochemical phenotypes to those observed in humans and, therefore, represents an excellent model to study VLCAD deficiency. We measured carnitine and acylcarnitine profiles in liver, skeletal muscle (SkM), bile, and blood from VLCAD knock-out mice and controls under nonstressed and various stress conditions. Carnitine and acylcarnitines were extracted from body fluids with methanol and from tissues with acetonitrile, respectively, and were analyzed as their butyl esters using electrospray ionization tandem mass spectrometry. Fasting combined with a cold challenge for 8 h significantly induced liver long-chain acylcarnitine and free carnitine production. Acylcarnitines in SkM predominantly accumulated during exercise with a concomitant decrease of free carnitine. Changes in blood free carnitine did not correlate with carnitine homeostasis in liver and SkM. Our results demonstrate different tissue-specific long-chain acylcarnitine profiles in response to various stressors, which may be of importance with respect to the heterogeneous clinical manifestations of VLCAD deficiency in humans. Furthermore, we conclude that carnitine biosynthesis in the liver seems sufficiently active to maintain liver carnitine levels during increased demand. Our data suggest that carnitine supplementation in long-chain beta-oxidation defects may not be required, and blood carnitine concentrations do not reflect tissue carnitine homeostasis.     

Carnitine status of children receiving long-term total parenteral nutrition: a longitudinal prospective study.

Nine children receiving carnitine-free total parenteral nutrition for 7.2 +/- 2.6 years since birth were prospectively studied for 3 years. Plasma values of total and free carnitine were 50% lower than those of age-matched healthy control subjects (p less than 0.02) but did not decrease further during the 3-year period. No significant abnormalities in free fatty acids, triglycerides, or cholesterol were found. The mean levels of alanine and aspartate aminotransferases and of alkaline phosphatase were slightly increased (p less than 0.02) at the initiation of the study but remained in the same range 3 years later. The low plasma carnitine values appeared to be without clinical consequence after 10 years of carnitine-free total parenteral nutrition.     

Safflower oil emulsion administration during parenteral nutrition in the preterm infant. 2. Effect on triglyceride and free fatty acid levels

During a study to evaluate the effect of a safflower oil emulsion on essential fatty acid status during parenteral nutrition, we also measured plasma triglycerides and plasma free fatty acids (FFA) in a group of preterm infants. Subjects received 0.34 g/kg (group 1) or 0.68 g/kg (group 2) of lipid daily for 5 days. Essential fatty acid status remained normal in both groups, but the changes in plasma triglycerides were greater (p less than 0.025), and hypertriglyceridemia was somewhat more common (p = 0.06) in group 2 than in group 1. Plasma FFA did not differ in either treatment group. However, postinfusion FFA were greater (p less than 0.05) and FFA uptake was less (p less than 0.05) in infants at less than 32 than at 32-34 weeks gestation, but in no instance did postinfusion FFA exceed an FFA/albumin ratio of 6:1. In addition, triglyceride and FFA uptake did not improve during the study, but the changes in plasma triglycerides and FFA were greater (p less than 0.05) at the end than at the beginning of the study.