Parenteral use of medium-chain triglycerides: A reappraisal

NUTRITIONm -I-HE

APPLIED

INTERNATIONAL AND BASIC

JOURNAL NUTRITIONAL

OF SCIENCES

Number 4

April 1996

Volume 12

CURRENT

CONCEPTS

IN CLINICAL

NUTRITION

New Horizons in Nutritional Biochemistry and Metabolism: Part VII

GUEST EDITOR: DAVID P. KATZ, PhD From the Department of Anesthesiology, Montejiore Medical Center and The Albert Einstein College of Medicine, Bronx, New York, USA

Parenteral Use of Medium-Chain Triglycerides: A Reappraisal HARRY

ULRICH,

MD, STEPHEN MCCARTHY PASTORES, MD, DAVID P. KATZ, AND VLADIMIR KVETAN, MD

PHD,

From the Division of Critical Care Medicine, Department of Anesthesiology, Montejiore Medical Center and The Albert Einstein College of Medicine, Bronx, New York, USA Date accepted:

INTRODUCTION

Intravenous fat emulsions (IVFE) , although originally designed as a means of preventing or ameliorating essential fatty acid deficiency, are now routinely used as a primary source of calories.’ The commercially available IVFE contain long-chain triglycerides (LCT) derived from either soybean or safflower oil and phospholipids from either egg yolk or soy.’ Lipid emulsions have been designed in the model of the chylomicron, with a triglyceride core and a surface layer of phospholipids.’ This

Correspondence 10467. USA.

to: H. Ulrich,

MD; Division

Nutrition 12:231-238, 1996 OElsevier Science Inc. 1996 Printed in the USA. All rights reserved.

of Critical

Care Medicine;

15 March 1996

results in lipid emulsions containing two different particle populations that consist of triglyceride-rich and phospholipid-rich particles. Metabolism of lipid emulsions involves both these types of particles (Fig. 1) . There have been several concerns expressed over the continued use of the seed-derived oils, which are enriched with linoleic acid (18:2n-6), an essential fatty acid. Experimental evidence suggests that high concentrations of n-6 polyunsaturated fatty acids may have negative side effects that include inhibition of neutrophi13 and macrophage function4 impairment of the reticuloendothelial system

Department

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of Anesthesiology,

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Medical

Center,

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0899-9007/96/$15.00 PII: SO899-9007(96)00089-5

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USE OF MEDIUM CHAIN TRIGLYCERIDES

(RES ) 5-8 and decreased rate of clearance in sepsis.’ Although this may not pose a problem for the stable patient receiving parenteral nutrition, it is apparent that the stressed immunocompromised patient could be disadvantaged by a metabolic fuel with this profile. Medium-chain triglycerides (MCT) have been long promised as an alternative IV calorie source with a metabolic profile that would offer some advantages to the compromised patient. Although there is much theory and experimental data and some human data, the question remains whether there is a need for MCT as part of our IV armamentarium. The objective of this review is to critically evaluate the evidence associated with the use of MCT as an IV fat, in its many forms, which include physical mixtures and structured lipids.“-‘* The question remains whether there is sufficient proof to warrant the cost associated with development and subsequent use of IVFE containing MCT relative to its purported benefit. STRUCTURE,BIOCHBMISTRYAND METABOLISMOF MCT

MCT are triacylglycerols that contain saturated fatty acids of 6- 12 carbon atoms I3 and are derived primarily from fractionated coconut and palm kernel oils.9*‘3MCT possess several unique physical, chemical and structural characteristics that make them a more desirable substrate than LCT for enteral and parenteral nutrition. MCT are approximately 100 times more water soluble than LCT l3 and are more rapidly hydrolyzed and absorbed from the intestinal lumen because they do not require the presence of bile and pancreatic lipase. These fatty acids are transported directly into the blood to the liver via the portal vein and extrahepatic organs. The half-life of MCT in plasma is around 17 min compared with 33 min for LCT.9.‘4*15When given parenterally, MCT are not stored in adipose tissuei6*” and do not accumulate in the liver. More importantly, MCT do not promote synthesis of eicosanoids (prostaglandins, thromboxanes and leukotrienes) nor serve as precursors for oxygen free-radical production, both of which may adversely affect RES function and amplify systemic inflammatory responses, especially in the critically ill. ‘* Finally, MCT have a thermogenie effect due to their more efficient oxidation and a decreased likelihood of being stored when compared with an equivalent amount of LCT and have protein sparing effects at least equal to LCT.19 MCT are more readily oxidized than LCT since they do not require the carnitine transport system for mitochondrial entry (Fig. 2). 2,20-26Their oxidation is also less affected by glucose and insulin than is the oxidation of LCT. Ordinarily, fatty acids are taken up from the plasma and activated on the outer mitochondrial membrane, where they are catalyzed by acyl CoA synthetase to form long-chain acyl CoA molecules. The latter do not readily traverse the inner mitochondrial membrane and therefore require carnitine, a zwitterionic compound formed from lysine. Inside the mitochondrial matrix, the acyl CoA molecules undergo a series of reactions, including oxidation by flavin adenine dinucleotide, hydration, oxidation by NAD+ and thiolysis by CoA, to generate FADH2, NADH and acetyl CoA. Five high-energy phosphate bonds, which can be converted to ATP, are synthesized for each of the first seven acetyl CoA molecules formed by this beta-oxidation of, for example, pahnitate.* Acetyl CoA enters the tricarboxylic citric acid (TCA) cycle (Krebs cycle), depending on the appropriate balance of fat and carbohydrate degradation. In the citric acid cycle, complete oxidation of acetyl CoA to carbon dioxide and water yields 12 more high-energy phosphate bonds for each molecule of acetyl CoA. If fat breakdown predominates, acetyl CoA in the liver undergoes a different metabolic fate, since the concentration of oxaloacetate, the major substrate required by acetyl CoA to enter the TCA cycle, is decreased when carbohydrate

FIG. 1. Intravascularmetabolism of lipid emulsions. This involves both triglyceride-rich (TG) and phospholipid-rich (PL) particles. Note the formation of phospholipid-free cholesterol (FC) complexes. Also note the competition of liposomes for lipoprotein lipase (LPL) and the speculated potential competition of exogenous remnants for binding to the low-density lipoprotein (LDL) receptors. CE = cholesteryl ester, HDL = high-density lipoprotein, FFA = free fatty acids. (Modified from Carper&r YA. Intravascular metabolism of fat emulsions: the Arvid Wretlind Lecture.,ASPEN 1988. Clin Nutr 1989;8: 115

is unavailable or improperly used.’ In starvation and in diabetes, oxaloacetate is used to form glucose and is thus unavailable for condensation with acetyl CoA. Under these conditions, acetyl CoA is diverted to the formation of ketone bodies, acetoacetate and D-3-hydroxybutyrate (Fig. 3). The latter two molecules, along with acetone, can serve as important alternate fuel substrates and partially replace the need for glucose oxidation. Because of their ketogenic effects, MCT are of limited usefulness in patients with diabetes mellitus and in clinical conditions where acidosis or ketosis is a major problem.L’3*27-M Metabolism of the phospholipid-rich component of lipid emusions can interfere with lipid and lipoprotein metabolism.* Such interference includes depletion of free cholesterol from membranes of cells in contact with the circulating phospholipids (e.g., erythrocytes) and prevention of the binding of lowdensity lipoproteins (LDL) to their specific receptors, leading to the accumulation of LDL.* Work by Carpentier et al.” on long-term administration of fat emulsions suggests that the addition of MCT to LCT emulsions may prevent these changes. MCT have had a broad area of application in enteral nutrition, particularly in conditions associated with impairment of ordinary fat digestion, absorption or lymphatic transport and are discussed elsewhere.‘3*32-” MCT is formulated for parenteral nutrition.” in physical mixtures or as a component of structured lipids. Physical mixtures are lipid emulsions characterized by partial replacement of LCT with MCT, on a percentage basis. Structured lipids are synthetic compounds made up of both

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TRIGLYCERIDES L.C.T.I

I

M.C.T. LIPOPROTEIN LIPASE I MCFA

LEFA

ACETYL

I

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MITOCHONORION

HEPATOCYTE

1 I

ET0 NES

CoA-

I

t

4

FIG. 2. Intracellular (hepatocyte) metabolism of MCT and LCT. MCT does not require carnitine for transport into the mitochondria of the hepatocyte. TCA = citric acid cycle, CoA = coenzyme-A, MCFA = medium-chain fatty acid, LCFA = long-chain fatty acid. (From Den-

nison et a1.43with permission.) medium and long-chain fatty acids bound on the same glycerol molecule in a predetermined proportion to form a structured triglyceride.‘0-‘2 These “designer lipids” provide fuel as well as meet essential fatty acids (EFA) requirements. At the present time, physical mixtures are commercially available only in Europe, and structured lipids are not commercially available. In this article, we present the experimental and clinical studies of MCT-based fat emulsions, with emphasis on their therapeutic potential for nutritional support in hospitalized patients.

emulsions on nitrogen balance have shown conflicting res~lts.*‘*~~-~~ Dennison et al., 43in a randomized crossover trial of critically ill surgical patients, compared two IVFE, one with LCT and the other containing MCT/LCT (5050 by wt) . They reported significant improvement in nitrogen balance among the patients who received the MCT/LCT mixture compared with those who received LCT. Dawes et al.& similarly demonstrated improved nitrogen balance with a lipid emulsion containing MCT in perioperative surgical patients. More recently, Jiang et al.45 studied 12 perioperative patients and 6 healthy volunteers who were randomly assigned to receive parenteral nutrition with MCT (10% Lipofundin, 5050, B. Braun Inc., Melsungen, Germany) or LCT emulsion (10% Endolipid, B. Braun Inc., France) .4sMeasurement of arterial and venous concentration differences across the forearm showed that the uptake of triglycerides was significantly improved with MCT administration. There was also a trend toward improved nitrogen balance in the MCT group and less weight loss in the postoperative period. They postulated that the improvement in nitrogen economy may be associated with the increased ketone and insulin levels associated with MCT administration. Other studies have failed to show any significant improvement in nitrogen balance in patients receiving MCT.39-42 In a randomized study of 24 patients with severe head trauma receiving total parenteral nutrition (TPN) with either LCT or MCT/LCT (50:50), Calon et al.” demonstrated no difference in nitrogen balance between the two treated groups. However, thyroxine-binding -prealbumin concentrations increased significantly in the patients who received the MCT/LCT mixture, suggesting that the MCT might have a beneficial effect on visceral protein metabolism after head trauma. Effects of MCT on Immune Function. To assess the influence of a lipid source on immune function, studies have focused on the RES .s.6*9The RES is composed primarily of macrophages and other cells in the liver, lung, spleen and bone marrow, responsible for the phagocytosis of microorganisms and particulate matter in the bloodstream, as well as in the production of numerous inflammatory mediators (including cytokines, oxyLIPID

MCT: EXPERIMENTAL AND CLINICAL EVIDENCE

/-

\

MC1

Experimental Studies The theoretical basis for the utility of MCT-containing lipid emulsions focuses on experimental studies on effects on nitrogen balance, liver and immune function. A summary of these effects are listed in Table I. These studies demonstrated that MCT in physical mixtures or structured lipid formulas cause less fatty acid deposition in the liver, improve nitrogen balance and interfere less with the RES than their LCT counterparts. Clinical Studies Evidence for the clinical utility of MCT-containing lipid emulsions is summarized in Table II and is discussed below in relevant clinical sections. Effects on Nitrogen Balance. Major catabolic stresses, such as trauma or sepsis, lead to an accelerated breakdown of muscle proteins, increased nitrogen excretion and negative nitrogen balance.‘6v36-3*LCT-based fat emulsions serve as essential nonglucose fuel that provides energy so that amino acids can be used for protein synthesis and not as a caloric source.38 It has been proposed that MCT, because of its rapid and rather complete oxidation, may have protein-sparing effects at least as good if not better, than that of LCT. However, human studies on the effects of MCT-based fat

I

LIPOPROTEIN LIPASE

LCT 1 LCFA

MCFA

MUSCLE

ADIPOSE . VITAL

ORGANS

TISSUE

OXIDISED IN PER I PHERAL TISSUES

FIG. 3. Hepatic lipid metabolism. MCFA are more frequently converted to ketones than LCFA; MCFA can be used directly by muscle; MCFA do not require very-low-density lipoproteins (VLDL) for transport; MCFA are only minimally (if at all) re-esterified into triglycerides and deposited as adipose tissue. MCFA = medium-chain fatty acid, LCFA = long-chain fatty acid. (From Dennison et al!’ with permission.)

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TABLE I. SUMMARY OF SELECTED REPORTED EFFECTS OF MCT AS OBSERVED IN ANIMAL STUDIES Type of study

Findings

Author

Liver function

Less deposition of fatty acids in liver with MCT/LCT TPN containing MCT may be superior in animals after hepatectomy LCT superior to MCI in liver regeneration after hepatecomy in rats Nonstressed rats had worse N-balance with MCWLCT vs. LCT No beneficial effect of MCT/LCT vs. LCT on negative nitrogen balance in stressed rats

Stein et a1.64(1984) Mitsuyoshi et al.” (1990) Nakagama et al.79 (1991) Stein et al.M (1984) Mok et alI9 (1984) Maiz et al.” (1984) Fried et alz6 (1990) Stein et als” (1986)

Nitrogen balance

Nonstressed animal model revealed evidence for decreased protein metabolism in animals given MCT Higher nitrogen balance noted with enteral feeding with SL SL given as TPN can spare nitrogen

Immune function

IV LCT impairs function of RES and improved with MCI or SL

Beaufrere” (1985) Teo et al.“’ (1989) DeMichele et alI2 (1988) Yamazaki et al a’(1984) Mok et ali9 (1984) Maiz et al.” (1984) Sobrado et al5 (1985) Hamawy et al6 (1985)

SL = structured lipids, MCT = medium-chain triglycerides, LCT = long-chain triglycerides, RES = reticuloendothelial system, TPN = total parer&ml nutrition.

TABLE II. SUMMARY OF SELECTED REPORTED EFFECTS OF MCT AS OBSERVED IN CLINICAL STUDIES Focus of study Nitrogen balance

Protein metabolism Liver function

RES

Ketonemia Immune system

Respiratory system Metabolic rate Cardiac surgery

Findings Parenteml MCT/LCT associated with improved nitrogen balance in the stressed patient Substantial but not significant improvement in nitrogen balance with MCDLCT No difference in nitrogen balance with MCT/LCT in stressed patients MCT cleared mom efficiently than LCT by forearm muscles and its use trends toward improved nitrogen balance Increased prealbumin in stressed patients given MCDLCT Plasma bilirubin significantly higher with LCT vs. MCWLCT Ultrasound of liver revealed increased fatty infiltration with LCT vs. MCT/LCT Metabolism of MCIXCT not impaired in the cirrhotic

Rapid infusion of MCT/LCT did not inhibit RES Higher levels of ketones in patients receiving MCDLCT MCT/LCI emulsions show less inhibition of activated lymphocytes MCT has deleterious effects on the function of neutrophils (in vitro) Elevated TNF production seen with LCT not seen with MCIXCT No deterioration in oxygenation seen with MCT/LCT MCT causes increased thermogenesis No adverse cardiopulmonary or metabolic effects with MCI/ LCT

TNF = tumor necrosis factor, MCI = medium-chain triglycerides, RES = reticuloendothelial system.

Author Dennison et al!’ (1988) Ball*’ (1993) Hatton et al.@’(1990) Bal14’(1991) Clarke et al.@ (1987) Crowe et al.39(1985) Jiang et al.” (1993) Calon et al.” (1990) Bal14’(1991) Baldermann (1991) Fan et al.” (1992) Muller et a16’(1992) Drum1 et al.@ (1995) Jensen et al.’ (1990) Ball” (1993) Sedman et al4 (1990) Bellinati-Peres et al.” (1993) Gogos et al?’ (1994) Radermacher et al.‘* (1992) Mascioli et al.59(1991) Fiaccadori et al.‘5 (1994)

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gen free-radicals and eicosanoids) during injury or infection. In addition to its crucial role in host defense, the RES participates in the clearance of fat. The effects of LCT emulsions on RES function in humans have been well documented.5~7~8Similar to the results observed in animals, human studies have demonstrated that LCT emulsions depress RES function and increase susceptibility to infectious complications8 The reported adverse effects of LCT emulsions on immune function include mechanical blockade of the RES, interference with T and B lymphocyte function (particularly cytokine production), neutrophil and macrophage function, immunoglobulin synthesis and impairment of in vitro complement synthesis.47-49 These effects have been attributed to alterations in arachidonic acid metabolism, interference with cell membrane enzyme activity and alterations in membrane fluidity.4 It is important to note that earlier studies suggesting immune suppression caused by LCT emulsions were performed with infusions of LCT at high and clinically irrelevant doses.’ More recent clinical and experimental studies have demonstrated that alterations in RES function caused by lipid emulsions, in general, are clearly related to the quantity, quality and rate of lipid administration.’ Ota et al.” reported no significant alterations in immune function in animals during IV. administration of Intmlipid, an LCT-based emulsion. MCT-based fat emulsions have been shown to support host bactericidal capacity and improve RES function. Physical mixtures of MCT and LCT have been shown to downregulate eicosanoid synthesis and production of tumor necrosis factor, a potent proinflammatory cytokine, synthesized by human mononuclear cells and other immune cells during injury and infection.” Jensen et al.’ studied the effects of parenteral infusion of LCT and MCT on RES function in humans as measured by the rate of clearance of 99technetium sulfur colloid (TSC). Eight patients were given a standard LCT emulsion (Travamulsion 20%, Clintec, Deerfield, IL) infused as a continuous threein-one admixture over 24 h for each of the 3 days after baseline TSC clearance determination. Another nine patients received the same amount of fat as an MCT/LCT (75%:25%) emulsion (Clintec, Deerlield, IL) infused intermittently over 10 h during the same 3-day period. All patients received continuous parenteral nutrition comprised of protein, 1.5 g - kg-’ * d-r, and dextrose, 4.5 g. kg-’ *d-l. These investigators demonstrated no significant impairment of TX clearance with either continuous LCT administration or intermittent MCT/LCT infusion. They concluded that the provision of fat principally as MCT may allow for rapid metabolic use without RES dysfunction. Similarly, administration of continuous LCT in a three-in-one admixture allows adequate metabolism and avoids potential risk of excessive infusion rates. Bellinati-Peres et al.‘* demonstrated several deleterious effects of MCT on neutrophil function. In their in vitro study, neutrophil from healthy adult male volunteers were assessed after incubation with lipid emulsions containing either LCT, MCT or an MCT/LCT (50:50) mixture. They demonstrated that MCT-treated neutrophils had reduced chemotactic and phagocytic properties and decreased production of oxygen free radicals, whereas those incubated with LCT did not show any significant alteration of these functions. CLINICAL APPLICATIONS

OF MCT

Respiratory Illness Lipid-based nutritional support is generally recommended for patients with acute or chronic respiratory insufficiency, since oxidation of lipids results in substantially lower carbon dioxide production and minute ventilation compared with car-

235 bohydrate oxidation. However, several experimental and clinical studies have demonstrated transient deleterious effects associated with IVFE based solely on LCT in patients with respiratory insufficiency, including hypoxemia associated with increases in pulmonary venous admixture (shunt) and pulmonary artery pressures.53-55 It has been postulated that these abnormalities are due to the increased production of prostaglandins (e.g., prostacyclin) and thromboxanes from linoleic acid.S5.56The vasodilatatory prostaglandins worsen hypoxemia by reversing the reflex hypoxic vasoconstriction that occurs with lung disease, thus causing an increase in the intrapulmonary right to left shunt, whereas certain thromboxanes (e.g., thromboxane B2) exert potent vasocontrictive effects on the pulmonary vascular bed that can have consequences on pulmonary gas exchange as well. MCT-based fat emulsions may be advantageous in patients with respiratory failure because they do not influence eicosanoid synthesis and availability. In a study of nine mechanically ventilated septic patients. Radermacher et al.‘* demonstrated no significant alterations in systemic or pulmonary hemodynamics and ventilation/perfusion ratios (using the multiple inert gas elimination technique) with the use of a parenteral MCT/LCT (50:50) mixture. The authors concluded that the more rapid oxidation of MCT and limited synthesis of eicosanoids might be helpful in minimizing the deleterious effects on pulmonary hemodynamics and gas exchange parameters observed with conventional LCT-based emulsions. Similarly, Ball and White,57 in a crossover study, investigated the metabolic effects of lO%MCT/ lO%LCT (Lipofundin MCT/LCT, B. Braun, Inc. Melsungen) and a conventional LCT emulsion (20% LCT, Lipofundin S) in 16 critically ill ventilated patients. The MCT/ LCT infusion was well tolerated and was associated with higher concentrations of insulin and nonesterified fatty acids and ketone bodies in plasma compared with that of the LCT infusion. Furthermore, there were no adverse pulmonary consequences related to the MCT/LCT infusion. Due to its rapid rate of oxidation, MCT-based infusions may cause increased thermogenesis associated with increased oxygen consumption and increased carbon dioxide production.58S9 However, this phenomenon occurs without an increase in body temperature and is not associated with either changes in systemic oxygen delivery or worsening of nitrogen balance in humans.” Recently, Chassard et al.,@’in a prospective, randomized, crossover trial, evaluated the effects of TPN containing MCT or LCT on oxygen consumption and pulmonary gas exchange in six mechanically ventilated patients. Oxygen consumption (VO,), CO* production and minute ventilation were measured by indirect calorimetry. They reported that MCT caused an increase in metabolic rate (increased Vo2) when infused over a short period (8 h). The authors recommended that postoperative or intensive care unit patients with diminished pulmonary reserve should receive infusions of MCT over 24 hr to help avoid adverse respiratory effects. Liver Disease Liver disease is associated with profound alterations in lipid metabolism.6’-m In cases of acute hepatocellular injury, plasma high-density lipoprotein levels decrease and plasma cholesterol and triglyceride levels increase. Similarly, patients with chronic hepatic failure have increased plasma concentrations and turnover of free fatty acids associated with a reduction in fat stores.66The increased oxidation of fatty acids is thought to be caused by an activation of lipolysis in a state of limited availability of glucose, because of a decreased hepatic glycogen content as a consequence of impaired hepatic gluconeogenesis.66 In the past, the use of parenteral lipids were not recom-

PARENTERAL mended for patients with severe hepatic dysfunction. It was thought that in patients with severely compromised liver function (e.g., cirrhosis), lipids are not used adequately and efficiently cleared, which might further impair hepatic metabolism and Kupffer cell function. Furthermore, lipids may augment hepatic encephalopathy by replacing tryptophan from its binding to albumin, due to the increase in circulating fatty acids.66*67Patients with severe liver dysfunction have reduced synthesis of albumin, carnitine, hepatic triglyceride lipase, phospholipase, lecithin cholesterol acyltransferase and of apoprotein C-II, which is required for lipoprotein lipase activity.68-70 Thus, lipid emulsions containing both MCT and LCT were proposed as an ideal source of fat for these patients since they would meet the increased requirements for fatty acids and provide essential fatty acids for their depleted stores. Furthermore, because MCT are cleared rapidly from the bloodstream and metabolized independent of camitine, they potentially cause lesser impairment of Kupffer cell function. Finally, by providing readily oxidized fat, MCT may cause a reduction in hepatic side effects during parenteral nutrition (cholestasis, steatosis, fatty liver), characteristics that might be important for patients with cirrhosis. Investigation of ‘the elimination of lipid emulsions in patients with liver cirrhosis showed conflicting results: two studies demonstrated normal or decreased clearance and one study reported increased clearance. Muscaritoli et aL6* in a study of 10 patients with compensated liver cirrhosis, demonstrated impaired metabolic clearance of LCT associated with low hepatic synthesis of apoprotein C-II.68 Fan and Wong7’ performed an IV fat-tolerance test on 28 patients with cirrhosis and nine normal volunteers to determine the clearance rate of Lipofundin MCT 20%, which contains a physical mixture of equal portions of MCT and LCT. They reported that the clearance of the MCT/LCT mixture in cirrhotic patients were comparable with that of the healthy control subjects. Muller et a16’compared the elimination of LCT versus MCT-containing emulsions in cirrhotic patients using indirect calorimetry to assess rates of lipid oxidation. They demonstrated no differences in lipid oxidation rates and substrate-induced thermogenesis with either type of lipid emulsions. Mote recently, Druml et al.@ analyzed the elimination and hydrolysis of two lipid emulsions containing either LCT or MCT/LCT (50:50 by wt) in eight patients with chronic hepatic failure and in six healthy control patients. In their study, the clearance of both LCT and MCT/LCT were comparable in patients with chronic hepatic failure with that of healthy subjects, and the rise in plasma triglycerides and release of free fatty acids was identical. They concluded that at clinically relevant infusion rates, the elimination and hydrolysis of lVFE containing LCT or MCT/LCT are not impaired in patients with chronic hepatic failure. Fatty infiltration of the liver with cholestasis is a common complication of TPN. The etiology of this complication has not been firmly established. It has been postulated that MCT may have a protective effect on liver function and the gut barrier function due to their rapid and efficient oxidative metabolism and production of ketone bodies.66 In addition, the balanced EFA pattern maintained in membrane phospholipids during prolonged administration of MCT with LCT (as with physical mixtures and structured lipids) may positively impact cell functions? Baldermann et al.63 evaluated 14 patients requiring TPN by ultrasonogmphy to compare liver size and gray-scale value (a measure of fatty infiltration) before and after 7 days of TPN. Seven patients were randomly given a LCT emulsion (Intralipid lo%, Fa. Pfrimmer), whereas the other seven received a MCT/ LCT physical mixture (Lipofundin MCT lo%, Fa. Braun Melsungen, Germany). There were no changes in liver size and grayscale value in the MCT/LCT group, whereas both parameters

USE OF MEDIUM CHAIN TRIGLYCERIDES

showed a significant increase in the patients who received LCT. They concluded that TPN, administered with a physical mixture of MCT/LCT as fat components, can reduce the risk of hepatic dysfunction and cholestasis during parenteral nutrition. Sepsis and Critically Ill Patients In sepsis, fat metabolism is charactetized by increased oxidation of all fatty acids, regardless of chain length.” Despite the increase in fat oxidation, ketone body synthesis is decreased In addition, critically ill septic patients have decreased camitine store? and develop insulin resistance. Triglyceride clearance from the plasma decreases with the development of hepatic failure associated with sepsis-induced multiple organ failure (MOF) .73The progression of MOF is characterized by the loss of the ability to oxidize both fat and glucose. Hyperglycemia, hyperlipidemia and an increase in the respiratory quotient ensue as glucose becomes the preferred fuel, accompanied by a fall in resting energy expenditure.” However, in septic patients, the administration of exogenous glucose is unable to inhibit the increased mobilization of peripheral fat stores and a substantial part of the delivered glucose is stored as glycogen rather than used. MCT-based fat emulsions have theoretical advantages in septic and critically ill patients ‘because they do not require camitine for entry into mitochondtia and thus are rapidly and more efficiently oxidized. To date, there have been limited studies undertaken in critically ill and septic patients to assess the advantages of lipid emulsions wntaining MCf. In a study of 20 critically ill patients, Ball” reported increased ketone and glycerol concentrations, improved nitrogen balance and no apparent adverse effects in patients who received 500 ml 20% Lipofundin, a physical mixture containing 100 g/L MCT and 100 g/L LCT, compared with those patients who received a conventional LCT emulsion (20% Lipofundin S). Similarly, Fiaccadori et al:’ recently mported no adverse cardiopuhnonary or metabolic effects with infusion of 20% Lipofundin in 12 cardiac surgical patients evaluated in the early postoperative period after mitral valve replacement. They concluded that IVFE wntaining both MCT and LCT could represent a source of rapidly metabolized substrates in this patient population. SUMMARY

Over the last two decades, the clinical use of intravenous fat emulsions for the nutritional support of hospitalized patients has become routine. During this time long-chain triglycerides (LCT) derived from soybean and/or safflower oils were the exclusive lipid source for these emulsions, providing both a safe calorically dense alternative to dextrose and essential fatty acids needed for biologic membranes and the maintenance of immune function. During the past decade, the availability of novel experimental triglycerides for pare&ml use has generated interest in the use of these substrates for nutritional and metabolic support. Medium-chain triglycerides (MCT), long advocated as a superior substrate for parenteral use, possess many unique physiccchemical and metabolic properties that make them theoretically advantageous over their LCT wunterparts. Although not yet approved in the United States, preparations containing MCT have been widely available in Europe. Intravenous MCT preparations, either as physical mixtures or structuted lipids, have been used clinically in patients with immunosuppresion, critical illness, liver and pulmonary disease and in premature infants. Despite great promise, the clinical data comparing the efficacy of MCT-based lipid emulsions to their LCf counterparts has been equivocal. This may be due in part to the limited nature of the published clinical trials. Measures of efficacy for patenteral or enteral nutritional products has taken on new meaning, in light of the mported experience using immunomodulatory nutrients.7697Current concerns about cost of medical care and resource use warrant careful deliberation about

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the utility of any new and expensive therapy. Until clinical data can fulfill expectations dekd from animal studies, it is difficult to advocate the general use of Mm-based lipid emulsions. Future

clinical studies with Mm-based emulsions should have clear outcome objectives sufficient to prove their theorized metabolic superiOrity.

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USE OF MEDIUM CHAIN TRIGLYCERIDES

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Part I appeared in Nutrition 1992:8:3 11 Part II appeared in Nutrition 1993:9:113 Part III appeared in Nutrition 1993:9:495 Part IV appeared in Nutrition 1994:10:385 Part V appeared in Nutrition 1995:11:255 Part VI appeared in Nutrition 1995: 11:725 Part VIII will appear in an upcoming issue of Nutrition.