Clinical Science (1989) 76, 165-170
165
Metabolic effects of intravenous medium- and long-chain
triacylglycerols in critically ill patients
M. J. BALL
AND
K. WHITE
Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford, U.K.
(Received 29 March 1988; accepted 13 June 1988)
SUMMARY
1. The metabolic effects of an intravenous lipid emulsion containing medium-chain triacylglycerols (MCT)
and long-chain triacylglycerols (LCT) were studied in 16
critically ill, ventilated patients. The effects were compared in a cross-over study with those of a conventional
emulsion containing only LCT.
2. The lipid was well tolerated but the metabolic
effects of the MCT/LCT infusion differed from those of
the LCT infusion.
3. The major differences were a 60% higher insulin
concentration and a significantly greater increase in the
plasma concentrations of non-esterified fatty acids during
MCT/LCT infusion than during LCT infusion. The mean
rise in plasma ketone concentration was also higher
during MTC/LCT infusion, although this did not reach
statistical significance.
Key words: intravenous lipid, medium-chain triacylglycerols.
Abbreviations: LCT, long-chain triacylglycerols; MCT,
medium-chain triacylglycerols; NEFA, non-esterified
fatty acids.
INTRODUCTION
Severely ill patients may require parenteral nutrition and
they often have high energy requirements. The provision
of large quantities of glucose may result in hyperglycaemia and excess CO 2 production. Lipid emulsions are
often used to supply part of the non-protein calories.
Several studies have indicated that the rate of oxidation of
exogenous lipids is increased in stressed, septic patients
[1], although it may be reduced in some very severely ill
septic patients when oxidative metabolism becomes
impaired [2].
Correspondence: Dr M. J. Ball, Department of Clinical
Biochemistry, Level 4, John Radcliffe Hospital, Oxford, Oxon
OX3 9DU, UK
The lipid emulsions in current use contain long-chain
triacylglycerols (LCT) with fatty acid chain lengths of
16-20 carbon atoms. Entry of these long-chain fatty acids
into the mitochondria for oxidative metabolism depends
on esterification with carnitine. The acetyl-CoA subsequently formed by p-oxidation can enter the tricarboxylic
acid cycle or be metabolized to ketones in the liver.
Lipolysis increases in conditions of moderate stress
and starvation, and plasma ketone levels frequently rise,
but in critically ill patients they may remain low. This may
be due to increased tissue utilization or reduced ketogenesis and this remains controversial [3]. Infusions of
ketones can decrease nitrogen excretion [4],which is often
very high in severely ill patients, but large quantities cannot
be administered safely. Short-chain triacylglycerols,
although ketogenic, are toxic [5]. Medium-chain triacylglycerols (MCT) are also ketogenic [6] and have potential
benefits over LCT. MCT are utilized readily, as storage is
very limited [7] and the fatty acids are metabolized more
rapidly than long-chain fatty acids in animals [8] and in
humans [9]. Medium-chain fatty acids can also enter the
mitochondria by mechanisms largely independent of
carnitine, which may be important if carnitine stores
become depleted as may occur in some severely ill, malnourished patients. Medium-chain fatty acids of some
lipids have, however, produced adverse effects [10]. This
study investigates the effects of a new intravenous emulsion containing MCT on plasma concentrations of lipids,
glucose and hormones, and compares them with those of
LCT in severely ill patients.
METHODS
Patients
Sixteen critically ill patients were studied. These
patients (11 male, five female) were aged between 16 and
70 years and required intermittent positive pressure
ventilation and intensive care after major trauma or
gastrointestinal surgery. All patients were studied at least
48 h after surgery. Ethical permission was obtained from
M. J. Ball and K. White
166
Table 1. Patient data
Patient no.
Sex
Weight
(kg)
1
2
3
4
5
6
7
8
9
10
M
F
72
II
M
M
M
68
12
13
14
15
16
F
F
F
M
M
M
M
M
F
M
M
58
70
61
34
61
76
80
60
59
72
69
62
67
72
Condition
APACHE II score
Broncho-pleural fistula
Road accident: multiple injuries
Oesophagogastrectomy
Oesophagectomy, malnutrition
Road accident: multiple injuries
Oesophagogastrectomy
Road accident: multiple injuries
Hemicolectomy, wound dehiscence
Polyarteritis
Road accident: chestinjuries
Aorticvalve and lungsurgery
Toxic megacolon, septicaemia
Road accident: multiple injuries
Majorintestinal surgery, septicaemia
Hemicolectomy
Majorgastrointestinal surgery
8
9
7
9
4
5
7
16
19
13
8
7
6
13
7
9
the Central Oxford Region Ethical Commitee. The
patient data are given in Table 1. Four patients had experienced major trauma, 10 were post-operative (seven
had undergone major gastrointestinal surgery) and two
had severe acute respiratory disorders. The severity of
their disease was assessed using the APACHE II system
[11]. All patients were catabolic with a negative nitrogen
balance and a high glucagon/insulin ratio, and had
received less than 1500 kJ/24 h, usually as glucose, in the
previous 2 days.
Protocol
A randomized cross-over design was used with the two
lipids being administered to each patient within a 16 h
period to minimize the influence of disease processes and
alteration in clinical condition. Patients were randomly
allocated, according to a random number sequence, to
receive either 20% LCT (Lipofundin S; B. Braun,
Melsungen) or 10% MCT/lO% LCT (Lipofundin MCT/
LCT; B. Braun) as the first emulsion. Lipofundin MCT/
LCT contains 46% fatty acids of chain length C 6-C IO, and
54% C I 6 and CIM' Lipofundin LCT contains 99% C l 6 and
CIM' The lipid was given at a rate of 3.5 mg min -1 kg- 1
body weight for 3.5 h. After an interval of 5-8 h the
second lipid emulsion was infused. n-Glucose (0.45 mg
min -I kg- I body weight) was infused simultaneously via
another line. Blood samples were taken from an indwelling arterial cannula before each infusion, at 2, 3 and 3.5 h
and 10,20,40,60 and 120 min after infusion. Pulse rate,
electrocardiograph, blood pressure and temperature were
continuously monitored.
subtracted from the triacylglycerol result. Non-esterified
fatty acids (NEFA) were measured enzymatically using
acyl-CoA synthetase [12] which measures fatty acids of
various chain lengths. {3-Hydroxybutyrate and acetoacetate were measured enzymatically using {3-hydroxybutyrate dehydrogenase on specimens deproteinized by
perchloric acid [13]. Plasma insulin concentration was
measured by radioimmunoassay using charcoal separation [14]. Specimens for glucagon analysis were collected
into Trasylol, and glucagon, cortisol and growth hormone
were measured by double-antibody radioimmunoassay.
The concentration of each metabolite and the difference
from the pre-infusion value was calculated at various time
points.
Statistics
Statistical analysis was performed using the two-tailed
Wilcoxon paired signed-rank test and the Spearman rank
correlation [15].
RESULTS
Clinical effects
Continual physiological monitoring did not reveal any
specific adverse effects on cardiac function or body temperature attributable to the MCT infusion. The mean (SD)
change in pulse rate and systolic blood pressure was + 2.4
(7.8) beats/min on LCT and 4.6 (9.7) beats/min on MCT/
LCT and +0.3 (1.5) kPa on LCT and 0.9 (2) kPa on
MCT/LCT, respectively.
Metabolites
Analytical methods
Plasma glucose was measured using a Beckman glucose
oxidase analyser on specimens collected into fluoride/
oxalate. Plasma triacylglycerols were measured enzymatically, using a kit from Sigma Chemical Co. Glycerol was
measured independently by an enzymatic method and
The plasma concentration of ketone bodies, triacylglycerol and NEFA rose during both lipid infusions. Triacylglycerol levels appeared to reach a steady state after 3 h
infusion. There was no statistically significant difference
in the rise or fall in plasma triacylglycerol concentration
comparing the two lipid infusions (Fig. 1). Logarithmic
Intravenous medium-chain triacylglycerols
plots of the triacylglycerol concentration against time
after infusion revealed marked interpatient difference in
'clearance' with apparent first-order kinetics in some but
'mixed-order kinetics in others. For each individual
patient, however, the pattern appeared similar with the
two lipid preparations. Two very stressed septic patients
with baseline plasma triacylglycerol levels greater than 4
mmol/l and markedly raised levels (> 8 mmolfl) during
infusion of both lipids, showed a similar slow rate of fall of
less than 0.5 mmol h - 1 1- I after discontinuation of the
infusion.
The peak plasma NEFA concentration sometimes
occurred after the infusion was discontinued. The rise in
plasma NEFA concentration was significantly higher on
MCT/LCT at several time points (P<0.05 at 3 h, 3.5 h
and 20 min after infusion, Fig. 2). The mean rise in
plasma ketone concentration was higher with MCT/LCT
infusion than with LCT infusion [mean MCT/LCT 0.47
(SD 0.29); mean LCT 0.44 (SD 0.31)] but was not statistically significant (P=0.06), and differed little between
septic and non-septic patients (Fig. 3).
of clinical problems. The rate of lipid infusion was chosen
because it approximated to the routine clinical practice on
the intensive care unit where 500 ml of lipid is usually
infused over 8 h. The glucose infusion rate was chosen to
Lipid infusion
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The plasma concentrations of glucagon, growth
hormone and cortisol were )lot significantly affected by
either emulsion (Table 2), but the plasma glucose and
insulin concentrations were significantly higher after
MCT/LCT infusion than after LCT infusion (P= 0.03,
P< 0.01, respectively). The insulin/glucagon molar ratio
was thus considerably higher in patients receiving MCT/
LCT, but did not correlate significantly with plasma
glucose concentrations (rank correlation coefficient,
rs = 0.5 ).
2
0
3
Time (h)
5
4
6
Fig. 2. Plasma concentrations of NEFA in patients receiving infusion of MCT/LCT (0---0) or LCT (.
.).
Values shown are medians with 25th and 75th centiles.
Statistical significance (Wilcoxon paired signed-rank test):
*'P<0.05 compared withLCT.
(a)
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DISCUSSION
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Fig. 1. Plasma concentrations of triacylglycerol in patients
receiving infusion of MCT/LCT (0---0) or LCT
(.
.). Values shown are medians with 25th and 75th
centiles.
o
Baseline
End of infusion
Baseline
End of infusion
Fig. 3. Plasma concentrations of total ketones (acetoacetate plus p-hydroxybutyrate) before and at the end of
infusion of MCT/LCT (a) or LCT (b) in patients with
bacteriologically confirmed sepsis (--) and with no
obvious septic complications (- - --'-).
M. J. Ball and K. White
168
Table 2. Plasma concentrations of glucose and hormones before and after lipid infusion
Results are means±sEM (n= 16). Statistical significance (Wilcoxon paired signed-rank test):
«r« 0.05; tP<O.Ol compared with MCT/LCT.
MCT/LCT
LCT
Glucose concentration (rnmol/l)
Before infusion
End of infusion
2 h after infusion
6.7 ±OA
7.7±OA
7.9±0.7
7.0±OA
7.1 ±OA*
7.1 ±0.5
Insulin concentration (rn-units/I)
Before infusion
After infusion
16.7±2.9
26.5 ± 3.9
16.8±2.6
16.2 ±3.0t
Glucagon concentration (ng/I)
Before infusion
After infusion
567 ± 86
592 ± 70
719±200
600±96
Cortisol concentration (nrnol/l)
Before infusion
After infusion
696± 144
751±174
729± 148
673 ± 97
4.7 ± 1.2
4.9 ± 1.2
4.3 ± 1.3
3.0±0.6
Growth hormone concentration (m-units/l)
Before infusion
After infusion
provide little glucose, but to be sufficient to act as a
solvent for certain drugs and to maintain the patency of
the line.
Triacylglycerols
The rise in plasma triacylglycerol concentration was
similar during the two infusions, despite the greater
number of moles of triacylglycerol supplied by MCT/LCT
when equivalent weights of triacylglycerol were given (the
molecular mass of MCT/LCT triacylglycerols is 646 Da
and of LCT is 825 Da). The interpatient differences in triacylglycerol clearance indicated marked variation in
metabolism which was probably related to the patients'
clinical condition. It was relatively independent of the
type of lipid. Persistent hyperlipidaemia may have adverse
effects on leucocyte function [16] and interferes with
laboratory analyses [17]. The data from these patients did
not suggest that the use of MCT/LCT affected the
problem of hypertriglyceridaemia in particular patients.
NEFA and ketones
The significantly greater increase in plasma NEFA
concentration during MCT/LCT infusion probably
reflects an increased production, which may reflect the
greater number of moles of triacylglycerol infused and
available for hydrolysis, or a difference in the action of
lipases. The change in plasma ketone concentration varied
between 0.1 and 0.7 mmol/l but was not significantly
greater with MCT/LCT. Levels did, however, fall rapidly
after infusion, indicating prompt tissue utilization. Thus
any increased production could have been masked by
tissue utilization. Whether patients were septic or not did
not appear to have a marked effect on the changes in
plasma ketone levels.
Glucose and insulin
The rise in plasma glucose concentration during MCT/
LCT infusion may result from diminished utilization by
peripheral tissues. Other metabolic fuels such as NEFA
and ketones present at relatively high concentration may
be used instead and despite the fall over the 2 h after infusion they may still be high enough after 2 h to provide
energy and reduce the utilization of glucose. Acetoacetate
has long been known to suppress glucose oxidation in
heart muscle [18]. Glycerol, which is present in increased
quantities in MCT/LCT, can also be utilized in gluconeogenesis, and can be a valuable energy source [19]. Oral
MCT may cause hypoglycaemia [20] or hyperglycaemia
[21], but this involves the additional effects of gastrointestinal hormones and transport in the portal system. In normal volunteers the plasma glucose has been reported to
rise slightly. The rise in plasma glucose seen in our
patients during MCT/LCT infusion would not be
expected to cause clinical problems, although it may
necessitate additional monitoring.
Higher insulin levels during MCT/LCT infusion may
result from this increased plasma glucose concentration,
but may be related to other factors such as small changes
in NEFA or ketones. Insulin levels rise when intravenous
short-chain fatty acids are administered to rodents [22].
Perfusion of the rat pancreas with octanoate plus glucose
causes a greater release of insulin than does glucose alone,
indicating a possible direct effect of MCFA on the islet
j3-cells[23]. Such an effect, plus a slight increase in ketone
production from MCFA could explain higher plasma
insulin levels. This would then be expected to have effects
on the metabolism of glucose, protein and the lipid itself.
However, despite the higher insulin/glucagon ratio,
plasma glucose concentrations remained above preinfusion values for at least 2 h after the infusion. Insulin
decreases 3-hydroxybutyrate production from [14C]octa-
Intravenous medium-chain triacylglycerols
noic acid [24] and this could explain higher NEFA but
similar ketone concentrations during MCT/LCT infusion.
The use of an isotope-labelled MCT/LCT preparation
would have allowed the measurement of metabolic fluxes
but no inexpensive preparation suitable for human use
was available.
There are few published reports of the effects of intravenous MCT-containing emulsions in man. Sailer &
Muller [25] infused a 10% lipid emulsion containing 75%
MCT in 10 healthy volunteers at 0.12 g h-\ body weight
kg- 1 and found significantly higher plasma levels of f3hydroxybutyrate and a smaller increase in triacylglycerols
than with LCT. In contrast to our findings, no significant
changes in serum glucose or insulin were seen. This was
also the finding of Crowe et al. [26] in perioperative
patients, although the lipid infusion rate was much slower
than in our study. In the study by Eckart et al. [27] of
short-term infusions in a few intensive care unit patients
plasma glucose did rise, but plasma insulin levels were not
documented. This difference between healthy and intensive care unit patients may reflect the differences in insulin levels and tissue response which occur in many
critically ill patients [28]. The patients studied were very
ill, and their baseline concentrations of cortisol, glucose
and insulin higher than healthy individuals. It is also likely
that they had raised catecholamines. All these factors will
influence the handling of infused lipid.
Preliminary studies indicate MCT may improve protein sparing [29] and its metabolism is relatively independent of carnitine. This and the rapid rise in NEFA and
ketone levels suggest an emulsion containing MCT may
be a valuable energy source for critically ill patients. The
anabolic effects of the increased plasma insulin levels may
also be advantageous in catabolic patients if nutritional
support is adequate. Administration of insulin plus
glucose can counteract the negative nitrogen balance and
catabolism of severe injury and infection [30], an effect
apparently primarily due to the insulin [31]. No adverse
physiological effects of the MCT emulsion were observed
in these critically ill patients and there appear possible
benefits which warrant further study.
ACKNOWLEDGMENTS
We are grateful for the assistance of Dr Andrew Grant
and for the support of the intensive care unit staff. Mr B.
Smith performed the glucagon analyses. B. Braun, Melsungen, ER.G. kindly supplied the lipid emulsions.
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