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Use of a mixture of medium-chain triglycerides and long-chaintriglycerides versus long-chain triglycerides in critically ill surgical patients: a randomized prospective double-blind study
Clinical Nutrition (1998) 17:23-29 © Harcourt Brace & Co. Ltd 1998
Use of a mixture of medium-chain triglycerides and longchain triglycerides versus long-chain triglycerides in critically ill surgical patients: a randomized prospective double-blind study R. J. NIJVELDT, A. M. TAN, H. A. PRINS, D. DE JONG, G. L. VAN RIJ, R. I. C. WESDORP and P. A. M. VAN LEEUWEN Department of Surgery, Free University Hospital, Amsterdam, The Netherlands (Correspondence to P. A. M. van L, Department of Surgery, Free University Hospital, PO Box 7057 1007 MB Amsterdam, The Netherlands) A b s t r a c t - - T w e n t y critically-ill surgical patients who needed total parenteral nutrition were randomly
enrolled in a double-blind study comparing two intravenous fat emulsions: one containing a mixture of 50% medium-chain triglycerides and 50% long-chain triglycerides and another containing 100% longchain triglycerides. The purpose of this study was to investigate metabolic and biochemical differences between both emulsions with special reference to liver enzymes. After a baseline period of 24 h with only glucose and NaCI infusion, the lipid emulsion was added continuously during 24 h over 5 days. The parenteral nutrition was administered in mixture bags containing amino-acids, glucose and lipids together. Two-thirds of the non-protein calories were administered as glucose 40% and one third as either long-chain triglycerides or a mixture of medium-chain triglycerides and long-chain triglycerides. The total amount of non-protein calories received was the measured energy expenditure during the baseline period plus 10% and was fixed during the study. Plasma substrate concentrations, energy expenditure, and nitrogen balance were determined and arterial blood samples were taken. No toxic effects or complications attributable to one of the two emulsions were observed. There was no significant difference in energy expenditure, nitrogen balance, liver function tests, carnitine, transferrin, pre-albumin, albumin, cholesterol, triglycerides and free fatty acids. The only parameter that showed a different pattern of reaction between the two emulsions was serum bilirubin concentration. In this study no evidence of any advantageous effect of a mixture of medium-chain triglycerides and long-chain triglycerides was seen. Key words: Parenteral nutrition; Lipid emulsion; Critical illness; Triglycefides; Phospholipids; Cholesterol; Lipoproteins
contain a mixture of MCT and LCT to provide both rapidly and slowly metabolized fuels as well as essential fatty acids. No conclusive evidence has been obtained from the few studies done in critically-ill patients who should benefit most from the MCT emulsions (25-29), although some indicate a greater net fat oxidation (25), less free fatty acid (FFA) re-esterification (25), higher FFA (26), higher insulin concentration (26) a decreased whole body lipolysis (25), a protein sparing effect with a more positive nitrogen balance (27, 28, 30-34) and higher ketones (28). This prospective randomized double-blind study was designed in order to examine the metabolic and biochemical effects of infusing a mixture of MCT and LCT compared to LCT into critically-ill surgical patients.
Introduction
In order to supply energy to a patient with parenteral nutrition for more than 5 days lipids are essential as a caloric source (1, 2). They supply energy and essential fatty acids in a small volume. The conventional fat emulsion contains long-chain triglycerides (LCTs) with chain lengths of 16-20 carbon atoms. Though generally considered safe LCT emulsions have been associated with fatty infiltration of tissues, slow clearance from blood circulation, hypertriglyceridemia, impaired immune functions and interference with the reticuloendothelial system (3-5). The newer medium-chain triglyceride (MCT) containing emulsions are supposed to be a more efficient source of energy. MCTs are cleared more rapidly from the circulation (6-12), oxidized efficiently (12-16) and stored in the adipose tissue and liver in a limited fashion (17-19). They can enter the mitochondfia relative independently from the carnitine transport system (20, 21) and should interfere less with the reticuloendothelial system (22, 23). Further more MCTs are ketogenic (24) and could be useful as an energy source in the critically-ill hypermetabolic patient. Medium-chain emulsions have been developed that
Material and methods Patients
Twenty critically-ill patients were enrolled in this doubleblind randomized study (8 female, 12 male). The clinical details of the population are given in the Table. Patients in the surgical intensive care unit were included when at least 5 days of ventilatory support was necessary and administration of total parenteral nutrition (TPN) was needed on clinical grounds. Patients met at least three of the four 23
24 USE OF A MIXTURE OF MEDIUM-CHAIN TRIGLYCERIDES AND LONG-CHAIN TRIGLYCERIDES
Table Clinical details of study population on day 0. Age, sex, diagnosis, APACHE II and sepsis care in the two study populations (MCT/LCT versus LCT) with mean -+ SEM. Age
Sex
Diagnosis
APACHE II
Sepsis score
MCT/LCT n=12 72 71 65 51 35 46 16 62 72 75 31 76
M M F M F M F F F F M M
perforated gastric ulcer, abscesses ruptured aneurysma aortae abdominalis car accident, multiple injuries, ARDS car accident, multiple injuries, pneumonia fall from 15 m, multiple injuries pancreatitis, abdominal abscesses fall from 10 m, ARDS, partial liver resection gastric resection, anastomosis leakage car accident, multiple injuries pancreatitis, fistula car accident, multiple injuries ruptured aneurysma aortae abdominalis
25 24 22 18 16 22 20 25 19 19 15 22
11 3 16 11 5 24 13 13 6 17 16 17
21±3.3
13±6.3
25 22 24 28 20 18 28 20
11 15 10 16 12 19 8 20
22 _+3.3
14 _+4.2
56 + 20 LCT n=8 47 54 63 75 27 34 70 49
M F F M F M M M
fall from 15 m, multiple injuries, ARDS perforated diverticulitis, pneumonia multiple abdominal abscesses e.c.i. perforated gastric ulcer, abscesses, gastrocutaneous fistula multiple gunshot wounds abdomen, ARDS multiple gunshot wounds thorax, pneumonia ruptured aneurysma aortae abdominalis multiple stabwounds thorax, pneumonia
52 ± 16.7
criteria of sepsis (temperature > 38.0°C, leucocyte count > 15"109, positive blood culture or a clear septic focus). Patients with severe hepatocellular or renal insufficiency were excluded from the trial. Finally, the patients who entered the study were randomly distributed into two groups. Pathology varied, but both groups were comparable for age, weight, length, acute physiologic and chronic health evaluation (APACHE II) (34) and sepsis score (35). The study was approved by the local ethical committee.
puter) was used. This open device system measures oxygen consumption (VO2), carbon dioxide production (VCO2) and flow by using a gas dilution system. Respiratory quotient (RQ), EE and substrate oxidation were automatically calculated according to Weir (36) and Frayn (37) equations. The equations are as follows:
Procedure
where UN is urinary nitrogen excretion (g/day).
When the patients were estimated to be eligible for the study, a baseline period of 24 h (day 0) was started. During this period.patients received i.v. infusion of glucose 2.5% and NaC1 0.45% only and 24 h energy expenditure (EE) measurement by indirect calorimetry was commenced. After randomization, the parenteral nutrition was administered in mixture bags containing amino acids, glucose and lipids together. Two-thirds of the non-protein calories were administered as glucose 40% and one third as either LCT (Intralipid 20%, Kabi Vitrum, Amsterdam) or MCT 50%/ LCT 50% (Lipofundin 20%, Braun, Amsterdam). The total amount of non-protein calories received was the measured EE during baseline plus 10% and was fixed during the study. Nitrogen/calorie ratio was 1:140. Trace elements, vitamins and electrolytes were added to the mixture in standard concentrations and adjusted when necessary. Patients received nutrition in 24 h during 5 days.
*Carbohydrate utilization (g/day) = 1.44 ([4.12 * VCO2] -
Fat utilization (g/day) is multiplied by 9.46 to calculate fat utilization (kcal/day).
Indirect calorimetry An indirect calorimeter (Datex Deltatrac metabolic com-
*Carbohydrate utilization (g/day) = 1.44 ([1.36"VO2] [0.157 - V C O 2 ] ) - 7 . 4 6 ( U N )
*EE(kcal/day)
=
1.44([3.827"VO2]
+ [1.233"VCO2])
-
1.994(UN)
[2.91" VO2]) - 2.56(UN)
Carbohydrate utilization (g/day) is multiplied by 4.18 to calculate carbohydrate utilization (kcal/day). *Fat utilization (g/day) = 1.44 ([1.69 * VO2] - [1.69" VCO2]) - 1.92(UN)
*Protein utilization (g/day) = 6.25(UN) Protein utilization (g/day) is multiplied by 4.32 to calculate protein utilization (kcal/day). If the fat utilization calculation yields a negative value and the RQ is very near to 1.0, fat synthesis is implied and the following alternative equations are employed:
CLINICAL NUTRITION
*Fat utilization (g/day) = 1.44 ([1.67"VO2]) - ([1.67"VO2]) + 1.92(UN)
Blood samples and analyses Blood samples were taken immediately before the start of the lipid infusion and then daily at 06:00 from an indwelling arterial catheter. The blood samples were cooled and centrifuged at the time of sampling. Urine was collected over 24 h and nitrogen excretion was determined by the modified Kjeldahl technique. Enzymatically measured were plasma concentrations of cholesterol (CHOD-PAP, Boehringer Mannheim/Hitachi), triglycerides (GPO-PAP, Boehringer Mannheim/Hitachi) and free fatty acids (ACS-ACOD, Wako/NEFA C). Transferrin, pre-albumin, albumin, c-reactive protein, alpha-1-acid glycoprotein were determined by the immunonephelometric method on a Beckman analyser. Bilirubin was measured by the Jendrassik method (38) and free carnitine in serum by the colorimetric method of Pearson et al (39) after deproteinisation according to Rodriguez-Segade et al (40). Creatinine, urea, alkaline phosphatase (ALP), gammaglutamyl transferase (gamma-GT), alanin-aminotransferase (GPT), aspartate aminotransferase (GOT), hydroxybutyrate and c-reactive protein (CRP) were determined using standard tests on a Boehringer Mannheim/Hitachi 747 analyser. Daily nitrogen balance was calculated from the difference between intake of nitrogen as amino acid and excretion of urinary nitrogen because there was no fecal output in the critically-ill patients. Fluctuations in daily blood urea nitrogen were also accounted for when calculating the differences in daily urea production and excretion.
Statistical methods Values are expressed as mean _+ SEM and the threshold of significance was at 5%. Student t test was used to compare results between the two groups. The Student paired t test was used to compare results within the same group. Because of the limited number of patients comparisons between the two groups were also performed using nonparametic statistics (Mann-Whitney U test).
25
During the study period there was no difference in mean temperature (MCT/LCT 37.4 _+ 1.0, LCT 37.9 _+ 1.0), mean pulse rate, mean blood pressure, mean arterial blood gasses, mean length of days on the ventilator (MCT/LCT 13.8 + 2.9, LCT 17.4 _+ 3.0) or ventilator related parameters (mean PEEP: MCT/LCT 6.6 _+ 1.3, LCT 5.5 _+ 1.2, mean FiO2: MCT/LCT 39.8 + 2.5, LCT 39.0 _+ 3.5), incidence of new infections, positive blood cultures, mean APACHE II-score or mean sepsis score. Two patients on MCT/LCT and one with LCT only ultimately died of causes not directly related to the trial.
Metabolic and biochemical effects We observed a rise in mean EE (kcal/day) during the study period in both groups (mean rise/day MCT/LCT + 47 + 156, LCT +103 _+ 539) without any significant differences between the two groups (Fig. 1). Also a rise was observed in RQ and VO2. There was, however, a great individual variability and no significant differences were observed. No difference was observed in fat, carbohydrate and protein utilization (Figs 2 4 ) . After one day with the fat emulsion, nitrogen balance improved significantly in both groups EE DATEX 25OO 2000
15oo .~ 1000 500 0
I~ 0
1
~[m
I
2
m
3
~ 4
5
day
Fig. 1 Energy expenditure (kcal/day) measured by Datex Deltatrac metabolic computer in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+SEM.
Fat oxidation
Results
Patients
1200 ] 1000 [
Finally, the results were obtained from 20 patients, all of them completed the minimum period of 5 days on TPN. The clinical details are given in Table 1. The groups are well matched for age (MCT/LCT age median: 52 _+ 16.7 range: 34-75, LCT age median: 56 -+ 20.0 range: 16-76). Both groups were also comparable for weight, length, body mass index, APACHE II-score and sepsis score (Table 1).
800 / 600
..
We observed no toxic effects or complications attributable to either of the two fat emulsions.
LCT
200 I 0
Clinical effects
+
4O0
1
I 2
I 3
I 4
I 5
day Fig. 2 Fat oxidation (kcal/day) calculated according to Weir (36) and Frayn (37) equations in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+SEM.
I
26 USE OF A MIXTUREOF MEDIUM-CHAINTRIGLYCERIDESAND LONG-CHAINTRIGLYCERIDES
Substrate oxidation MCTILCT prot 24% cho '!.4% fat 32% Fig. 3 Mean substrate oxidation (days 2-5) with MCT/LCT (%), calculated according to Weir (36) and Frayn (37) equations. (prot = protein utilization, fat = fat utilization, cho = carbohydrate utilization).
( M C T / L C T P < 0.001, L C T P = 0.02), but during the study nitrogen balance r e m a i n e d n e g a t i v e and s h o w e d no difference b e t w e e n the two groups (Fig. 5). S e r u m concentrations o f creatinine, transferrin, prealbumin, albumin and a l p h a - l - a c i d g l y c o p r o t e i n r e m a i n e d stable during lipid infusion and there w e r e no differences b e t w e e n the lipids. T h e r e was a non-significant difference in m e a n serum carnitine concentration (nmol/1) on day 0 ( M C T / L C T 47.0 _+ 19.1, L C T 32.8 _+ 12.5 P = 0.08) and during lipid infusion s e r u m carnitine concentration r e m a i n e d higher on M C T / L C T with significant results (Fig. 6). H o w e v e r , serum levels o f carnitine r e m a i n e d relatively stable in both groups and no significant difference b e t w e e n day 0 and day 5 was found. L e v e l s of G P T , G O T , A L P , g a m m a - G T (Fig. 7) tended to rise during the study with no differences b e t w e e n the lipids. T h e only parameter that s h o w e d a different pattern o f reaction with the two kinds of nutrition was serum bilirubin concentration (pmol/1) (Fig. 8). T h e r e was a decrease in s e r u m concentration in the M C T / L C T group (mean fall/
Substrate oxidation LeT prot 21%
)cho 39%
Camitine
60 5O 40
t
o 30 E 2O
MCT/LCT LCT
10 0 0
fat 40%
1
2
5
Fig. 6 Camitine concentration serum (nmol/1) in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+SEM. Significant differences on days 1-5. *P < 0.05 (difference between MCT/LCT and LCT].
gamma-GT
nitrogen balance 1
4
day
Fig. 4 Mean substrate oxidation (days 2-5) with LCT (%), calculated according to Weir (36) and Frayn (37) equations. (prot = protein utilization, fat = fat utilization, cho = carbohydrate utilization).
0
3
2
day
3
4
5
160
10
140
5
120 100
.~ ~.
0 -5
• MCT/LCT BLCT
.~
-10
40 20
-15
0
-20
Fig. 5 Nitrogen balance (g/24 h) calculated from nitrogen intake and urinary output, corrected for a rise in serum urea nitrogen in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+SEM.
NMCT/LCT
80 60
BLCT
o
..,-
,~
~
~
~,
day Fig. 7 Gamma-glutamyltransferase (gamma-GT) concentration (Lift) in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean -+ SEM.
CLINICAL NUTRITION
Bilirubin
160 140 _
120
~100o80 60 "r=
IIMCT/LCT LCT
40 2O 0 0
1
2
3
4
5
day Fig. 8 Bilirubin concentration serum (micromol/l) in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+ SEM.
CRP
2oo 250
_
- - .0- - - M C T / L C T
150
LCT
50 -I. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I 0
1 0
I 1
I 2
I 3
I 4
I 5
day Fig. 9 C-Reactive protein (CRP) concentration (rag/l) in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean + SEM.
day - 6.15 _+ 18.9) and an increase with LCT only (mean rise/day +9.19 _+ 20.1), due to large standard deviations this was not significantly different either. Levels of hydroxybutyrate (mmol/1) were elevated on day 0 (MCT/LCT 0.06 _+0.09, LCT 0.05 _+0.05), suggesting mild ketonaemia, but after one day on lipids levels fell and remained stable during the study period (mean hydroxy-butyrate MCT/LCT 0.04 _+0.07, LCT 0.02 _+0.02). Triglyceride and FFA levels showed no reaction and remained stable during the study with no significant differences. Cholesterol (mmol/1) level showed a tendency to rise in both groups (mean rise/day MCT/LCT +0.05 _+0.31, mean rise/day LCT +0.11 _+ 0.53). C-reactive protein concentration fell during the lipid infusion similarly in both groups (Fig. 9). Comparisons between the two groups performed using non-parametric statistics gave the same results.
Discussion
The evaluation of these data is complicated by the heterogenity of the patients and their pathology resulting in a
27
large inter-patient variety. However, this group of patients presents a genuine group population of critically-ill patients. In order to obtain an objective parameter to compare the state of illness in both groups the APACHE II-score was used and combined with a sepsis score. Groups did not differ statistically concerning these scores and there were also no differences in baseline values collected on day 0. The amount of published reports of the effect of MCT containing fat emulsions in this kind of population are very limited with small numbers of patients. Some of them suggest that MCT/LCT emulsions are a more effective source of energy; however, their conclusions are mainly based on theoretical grounds. Some advantages of MCT like decreased interference with RES (22, 23), decreased storage of in adipose tissue (17, 18) and ketogenic properties might not be present in MCT/LCT. Investigators demonstrated advantageous effects of MCT/LCT in rats, healthy subjects and stable patients like a more rapid clearance (6-12) and a more effective oxidation (12-16). The few studies done in critically-ill patients also suggest possible advantages of MCT/LCT mixtures but some of these contain contradictory results and no conclusive evidence has been obtained. After rapid elimination and oxidation of the MCT in a physical mixture a delayed utilization of LCT could be present. The efficacy of the mixture would then depend on LCT metabolism and its limits. This could possibly explain the contradictory results in others studies. Energy expenditure and oxygen consumption did not tend to rise more with MCT/LCT in our study, contradicting the thermogenic effect suggested by others (41). This study showed a nonsignificantly higher net fat oxidation on LCT during 4 of the 5 days of the study in contrast to the results reported by Jeevanandam et al (25) who describe a greater net fat oxidation with MCT75%/LCT25% in four patients. Nitrogen balance has been reported to be more positive (30-34) and the same with MCT containing fat emulsions. In this study a less negative nitrogen balance was seen after 1 day with the fat infusion, but there were no differences between the two groups. The only variable in the study that showed a different pattern was serum bilirubin concentration, which has been reported before (42-44) and might be an expression of different liver function. The effect of the carnifine independency of MCT-metabolism as an advantageous characteristic remains to be discussed. Medium-chain fatty acids do not need carnitine to be transported across the mitochondrial membrane (21), but this does not mean that carnitine is not used for MCT metabolism (45, 46). Carnitine deficiency in critically-ill patients has been described (47-49), but a wide range of normal values has been reported (50). If that wide range of normal values was applied to this population, only one patient (LCT group) with a depressed carnitine concentration (10.4 nmol/ml on day 2) was present. No significant difference was observed in patients with carnitine concentrations below 40 nmol/1 (threshold of depression mentioned by other authors [49] on either nutritional regime). Carnitine plays a role in nutritional state and metabolism (20, 51), but it may not be the limiting factor in lipid utilization in
28 USE OF A MIXTUREOF MEDIUM-CHAINTRIGLYCERIDESAND LONG-CHAINTRIGLYCERIDES critically-ill patients. D e s p i t e the fact that fat o x i d a t i o n is an o b l i g a t e p a t h w a y o f m e t a b o l i s m in i n j u r e d and septic patients, there is a limit in lipid utilization that has b e e n o b s e r v e d after i n f u s i o n o f L C T - f a t . T h e h o p e that M C T / L C T lipid e m u l s i o n s m i g h t s o l v e this p r o b l e m is still b a s e d o n t h e o r e t i c a l g r o u n d s and has n o t b e e n p r o v e d in large studies. In this study no e v i d e n c e o f any a d v a n t a g e o u s e f f e c t o f a m i x t u r e o f M C T and L C T w a s seen; h o w e v e r , also no d i s a d v a n t a g e has b e e n o b s e r v e d . W e s u g g e s t fat m e t a b o l i s m r e m a i n s i m p a i r e d in critically-ill patients either d u e to a limit in fat utilization as a w h o l e or due to i m p a i r e d L C T c l e a r a n c e a n d oxidation. I f the latter is the c a s e structured lipids d e v e l o p e d b y B a b a y a n (52, 53) m i g h t o f f e r a w a y to o p t i m i z e fat utilization in the critically-ill patient.
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18. Zurier R B, Campbell R G, Hashim S A, Van ltallie T B. Enrichement of depot fat with odd and even numbered medium-chain fatty acids. Am J Physiol 1967; 212:291-294 19. Pomposelli J J, Moldawer L L, Palombo J D et al. Short term administration of parenteral ghicose-lipid mixtures improves protein kinetics in portocaval shunted rats. Gastroenterology 1986; 91: 469-486 20. Tan R C, Yoshimura N N. Carnitine metabolism and its application in parenteral nutrition. Journal of Parenteral and Enteral Nutrition 1980; 4:469-486 21. McGarry J D, Robles-Valdes C, Foster D W. Role of carnitine in hepatic ketogenesis. Proc Natl Acad Sci USA 1975; 72:4385-4388 22. Hamawy K J, Moldawer L L, Georgieff Met al. The effect of lipid emulsions on reticuloendothelial system function in the injured animal. Journal of Parenteral and Enteral Nutrition 1985; 9:559-656 23. Sobrado J, Moldawer L L, Pomposelli J J, Mascioli E A, Babayon V K, Blackburn G L. Lipid emulsions and reticuloendothelial system function in healthy and burned guinea-pigs. Am J Clin Nntr 1985; 42:855-863 24. Bach A C, Babayon V K. Medium chain triglycerides: an update. Am J Clin Nutr 1982; 36:950-962 25. Jeevanandam M, Holaday N J, Voss T, Buier R, Petersen S R. Efficacy of a mixture of medium-chain triglycerides (75%) and longchain triglycerides (25%) fat emulsions in the nutritional management of multiple-trauma patients. Nutrition 1995; 11:275-284 26. Ball M J, White K. Metabolic effects of intravenous medium- and long-chain triacylglycerols in critically ill patients• Clin Sci 1989; 76:165-170 27. Jiang Z M, Zhang S Z, Wang X R, Yang N F, Zhu Y, Wilmore D. Comparison of medium-chain and long-chain triglycerides in surgical patients. Ann Surg 1993; 217:175-184 28. Ball M J. Parenteral nutrition in the critically ill: use of a medium chain triglyceride emulsion. Intensive Care Med 1993; 19:89-95 29. M011erT F, Mt~llerA, Bachem M G, Lange H. Immediate metabolic effects of different nutritional regimens in critically ill medical patients. Intensive Care Med 1995; 21:561-566 30. Ball M J, Sear J W. Intravenous feeding with medium chain triglycerides: effect on bloodgasses and the complement system in critically ill patients. Anesthesia 1986; 41:423-426 31. Bach A C, Guirand M, Gibanlt J Pet al. Medium chain triglycerides in septic patients on parenteral nutrition. Clinical Nutrition 1988; 7:157-163 32. Bach A C, Frey A, Lutz O. Clinical and experimental effects of medium-chain-triglyceride-based fat emulsions. A review. Clinical Nutrition 1989; 8:223-235 33. Dawes R F H, Royle G T, Dennison A R, Crowe P J, Ball M J. Metabolic studies of a lipid emulsion containing medium chain triglyceride in perioperative and total parenterat nutrition infusions. World J Surg 1984; 10:38-46 34. Knans W, Draper E, Wagner D, Zimmerman J. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13:818-829 35. Elebute E A, Stoner H B. The grading of sepsis. Br J Surg 1983; 70:29-31 36. Weir J B. New methods for calculation of metabolic rate with special reference to protein metabolism. J Physiol 1949; t09:1 37. Frayn K N. Calculation of substrate oxidation in vivo from gaseous exchange. J Appl Physiol 1983; 55:628-634 38. Jendrassik L, GrafB. Bilirubin. Biochemische Zeitung 1938; 297:81 39. Pearson D J, Tubbs P K, Chase J F A. Carnitine and acylcarnitine. In: Bergmeijer H U (ed). Methods of ezymafic analysis; 2rid ed. New York: Academic Press 1974; 4:t762-1764 40. Rodriguez-Segade S, de la Pena C A, Pazi J M, Del Rio R. Determination of L-carnitine in serum and implementation on the ABA-100 and centrifichem 600. Clin Chem 1985; 131:754-757 41. Weisman C, Chiolero R, Gill K et al. The thermogenic effect of intravenously administered medium-chain triglycerides. In: Garrow J S, Halliday D (eds). Substrate and Energy Metabolism. London: Libbey 1985:24 42. Dennison A R, Ball M J, Hands Let al. Total parenterai nutrition using conventional and medium chain triglycerides: effect on liver function tests, complement and nitrogen balance. Journal of Parenteral and Euteral Nutrition 1988; 12:15-19 43. Clarck P J, Ball M J, Hands Jet al. Use of a lipid containing medium chain triglycerides in patients receiving TPN: a randomized prospective trial. Br J Surg 1987; 74:701-704 44. Harrel D, Rubin M, Naor Net al. Neonatal jaundice effect of lipid
CLINICAL NUTRITION 29
45.
46. 47. 48.
infusion with different triglyceride cores, LCT vs MCT/LCT. Clinical Nutrition 1989; 8 (suppl) Groot P H E, Hulsman W C. The activation and oxidation of octanoate and palmitate by rat skeletal muscle mitochondria. Biochim Biophys Acta 1973; 316:124-135 Otto D A. Relationship of the ATP/ADP ratio to the site of octanoate activation. J Biol Chem 1984; 259:5490-5494 Border J, Burns G, Rumph C. Carnitine levels in severe infection and starvation. Surgery 1970; 68:175-179 Worthley L I, Fishlock R C, Snoswell A M. Carnitine deficiency with hyperbilirubinemia, generalized skeletal muscle weakness and reactive hypoglycemia in a patient on long term TPN: Treatment with iv L-carnitine. Journal of Parenteral and Enteral Nutrition 1983; 7:176-180
Submission date: 8 April 1997 Accepted: 7 November 1997
49. Nanni G, Pittiruti M, Giovanni I e t al. Plasma carnitine levels and carnitine excretion during sepsis. Journal of Parenteral and Enteral Nutrition 1985; 9:483-490 50. Lambert M E, Shirpley K, Holbrook I, Faragher E B, Irving M D. Serumcarnitine levels in normal individuals. Journal of Parenteral and Enteral Nutrition 1988; 12:143-146 51. Fritz I B. Carnitine and its role in fatty acid metabolism. Adv Lipid Res 1963; 1:285-334 52. Babayan V K. Medium chain triglycerides and structured lipids. Lipids 1987; 22:417-420 53. Hyltander A, Sandstr6m R, Lundholm K. Metabolic effects of structured triglycerides in humans. Nutrition in Clinical Practice 1995; 10:91-97
Use of a mixture of medium-chain triglycerides and longchain triglycerides versus long-chain triglycerides in critically ill surgical patients: a randomized prospective double-blind study R. J. NIJVELDT, A. M. TAN, H. A. PRINS, D. DE JONG, G. L. VAN RIJ, R. I. C. WESDORP and P. A. M. VAN LEEUWEN Department of Surgery, Free University Hospital, Amsterdam, The Netherlands (Correspondence to P. A. M. van L, Department of Surgery, Free University Hospital, PO Box 7057 1007 MB Amsterdam, The Netherlands) A b s t r a c t - - T w e n t y critically-ill surgical patients who needed total parenteral nutrition were randomly
enrolled in a double-blind study comparing two intravenous fat emulsions: one containing a mixture of 50% medium-chain triglycerides and 50% long-chain triglycerides and another containing 100% longchain triglycerides. The purpose of this study was to investigate metabolic and biochemical differences between both emulsions with special reference to liver enzymes. After a baseline period of 24 h with only glucose and NaCI infusion, the lipid emulsion was added continuously during 24 h over 5 days. The parenteral nutrition was administered in mixture bags containing amino-acids, glucose and lipids together. Two-thirds of the non-protein calories were administered as glucose 40% and one third as either long-chain triglycerides or a mixture of medium-chain triglycerides and long-chain triglycerides. The total amount of non-protein calories received was the measured energy expenditure during the baseline period plus 10% and was fixed during the study. Plasma substrate concentrations, energy expenditure, and nitrogen balance were determined and arterial blood samples were taken. No toxic effects or complications attributable to one of the two emulsions were observed. There was no significant difference in energy expenditure, nitrogen balance, liver function tests, carnitine, transferrin, pre-albumin, albumin, cholesterol, triglycerides and free fatty acids. The only parameter that showed a different pattern of reaction between the two emulsions was serum bilirubin concentration. In this study no evidence of any advantageous effect of a mixture of medium-chain triglycerides and long-chain triglycerides was seen. Key words: Parenteral nutrition; Lipid emulsion; Critical illness; Triglycefides; Phospholipids; Cholesterol; Lipoproteins
contain a mixture of MCT and LCT to provide both rapidly and slowly metabolized fuels as well as essential fatty acids. No conclusive evidence has been obtained from the few studies done in critically-ill patients who should benefit most from the MCT emulsions (25-29), although some indicate a greater net fat oxidation (25), less free fatty acid (FFA) re-esterification (25), higher FFA (26), higher insulin concentration (26) a decreased whole body lipolysis (25), a protein sparing effect with a more positive nitrogen balance (27, 28, 30-34) and higher ketones (28). This prospective randomized double-blind study was designed in order to examine the metabolic and biochemical effects of infusing a mixture of MCT and LCT compared to LCT into critically-ill surgical patients.
Introduction
In order to supply energy to a patient with parenteral nutrition for more than 5 days lipids are essential as a caloric source (1, 2). They supply energy and essential fatty acids in a small volume. The conventional fat emulsion contains long-chain triglycerides (LCTs) with chain lengths of 16-20 carbon atoms. Though generally considered safe LCT emulsions have been associated with fatty infiltration of tissues, slow clearance from blood circulation, hypertriglyceridemia, impaired immune functions and interference with the reticuloendothelial system (3-5). The newer medium-chain triglyceride (MCT) containing emulsions are supposed to be a more efficient source of energy. MCTs are cleared more rapidly from the circulation (6-12), oxidized efficiently (12-16) and stored in the adipose tissue and liver in a limited fashion (17-19). They can enter the mitochondfia relative independently from the carnitine transport system (20, 21) and should interfere less with the reticuloendothelial system (22, 23). Further more MCTs are ketogenic (24) and could be useful as an energy source in the critically-ill hypermetabolic patient. Medium-chain emulsions have been developed that
Material and methods Patients
Twenty critically-ill patients were enrolled in this doubleblind randomized study (8 female, 12 male). The clinical details of the population are given in the Table. Patients in the surgical intensive care unit were included when at least 5 days of ventilatory support was necessary and administration of total parenteral nutrition (TPN) was needed on clinical grounds. Patients met at least three of the four 23
24 USE OF A MIXTURE OF MEDIUM-CHAIN TRIGLYCERIDES AND LONG-CHAIN TRIGLYCERIDES
Table Clinical details of study population on day 0. Age, sex, diagnosis, APACHE II and sepsis care in the two study populations (MCT/LCT versus LCT) with mean -+ SEM. Age
Sex
Diagnosis
APACHE II
Sepsis score
MCT/LCT n=12 72 71 65 51 35 46 16 62 72 75 31 76
M M F M F M F F F F M M
perforated gastric ulcer, abscesses ruptured aneurysma aortae abdominalis car accident, multiple injuries, ARDS car accident, multiple injuries, pneumonia fall from 15 m, multiple injuries pancreatitis, abdominal abscesses fall from 10 m, ARDS, partial liver resection gastric resection, anastomosis leakage car accident, multiple injuries pancreatitis, fistula car accident, multiple injuries ruptured aneurysma aortae abdominalis
25 24 22 18 16 22 20 25 19 19 15 22
11 3 16 11 5 24 13 13 6 17 16 17
21±3.3
13±6.3
25 22 24 28 20 18 28 20
11 15 10 16 12 19 8 20
22 _+3.3
14 _+4.2
56 + 20 LCT n=8 47 54 63 75 27 34 70 49
M F F M F M M M
fall from 15 m, multiple injuries, ARDS perforated diverticulitis, pneumonia multiple abdominal abscesses e.c.i. perforated gastric ulcer, abscesses, gastrocutaneous fistula multiple gunshot wounds abdomen, ARDS multiple gunshot wounds thorax, pneumonia ruptured aneurysma aortae abdominalis multiple stabwounds thorax, pneumonia
52 ± 16.7
criteria of sepsis (temperature > 38.0°C, leucocyte count > 15"109, positive blood culture or a clear septic focus). Patients with severe hepatocellular or renal insufficiency were excluded from the trial. Finally, the patients who entered the study were randomly distributed into two groups. Pathology varied, but both groups were comparable for age, weight, length, acute physiologic and chronic health evaluation (APACHE II) (34) and sepsis score (35). The study was approved by the local ethical committee.
puter) was used. This open device system measures oxygen consumption (VO2), carbon dioxide production (VCO2) and flow by using a gas dilution system. Respiratory quotient (RQ), EE and substrate oxidation were automatically calculated according to Weir (36) and Frayn (37) equations. The equations are as follows:
Procedure
where UN is urinary nitrogen excretion (g/day).
When the patients were estimated to be eligible for the study, a baseline period of 24 h (day 0) was started. During this period.patients received i.v. infusion of glucose 2.5% and NaC1 0.45% only and 24 h energy expenditure (EE) measurement by indirect calorimetry was commenced. After randomization, the parenteral nutrition was administered in mixture bags containing amino acids, glucose and lipids together. Two-thirds of the non-protein calories were administered as glucose 40% and one third as either LCT (Intralipid 20%, Kabi Vitrum, Amsterdam) or MCT 50%/ LCT 50% (Lipofundin 20%, Braun, Amsterdam). The total amount of non-protein calories received was the measured EE during baseline plus 10% and was fixed during the study. Nitrogen/calorie ratio was 1:140. Trace elements, vitamins and electrolytes were added to the mixture in standard concentrations and adjusted when necessary. Patients received nutrition in 24 h during 5 days.
*Carbohydrate utilization (g/day) = 1.44 ([4.12 * VCO2] -
Fat utilization (g/day) is multiplied by 9.46 to calculate fat utilization (kcal/day).
Indirect calorimetry An indirect calorimeter (Datex Deltatrac metabolic com-
*Carbohydrate utilization (g/day) = 1.44 ([1.36"VO2] [0.157 - V C O 2 ] ) - 7 . 4 6 ( U N )
*EE(kcal/day)
=
1.44([3.827"VO2]
+ [1.233"VCO2])
-
1.994(UN)
[2.91" VO2]) - 2.56(UN)
Carbohydrate utilization (g/day) is multiplied by 4.18 to calculate carbohydrate utilization (kcal/day). *Fat utilization (g/day) = 1.44 ([1.69 * VO2] - [1.69" VCO2]) - 1.92(UN)
*Protein utilization (g/day) = 6.25(UN) Protein utilization (g/day) is multiplied by 4.32 to calculate protein utilization (kcal/day). If the fat utilization calculation yields a negative value and the RQ is very near to 1.0, fat synthesis is implied and the following alternative equations are employed:
CLINICAL NUTRITION
*Fat utilization (g/day) = 1.44 ([1.67"VO2]) - ([1.67"VO2]) + 1.92(UN)
Blood samples and analyses Blood samples were taken immediately before the start of the lipid infusion and then daily at 06:00 from an indwelling arterial catheter. The blood samples were cooled and centrifuged at the time of sampling. Urine was collected over 24 h and nitrogen excretion was determined by the modified Kjeldahl technique. Enzymatically measured were plasma concentrations of cholesterol (CHOD-PAP, Boehringer Mannheim/Hitachi), triglycerides (GPO-PAP, Boehringer Mannheim/Hitachi) and free fatty acids (ACS-ACOD, Wako/NEFA C). Transferrin, pre-albumin, albumin, c-reactive protein, alpha-1-acid glycoprotein were determined by the immunonephelometric method on a Beckman analyser. Bilirubin was measured by the Jendrassik method (38) and free carnitine in serum by the colorimetric method of Pearson et al (39) after deproteinisation according to Rodriguez-Segade et al (40). Creatinine, urea, alkaline phosphatase (ALP), gammaglutamyl transferase (gamma-GT), alanin-aminotransferase (GPT), aspartate aminotransferase (GOT), hydroxybutyrate and c-reactive protein (CRP) were determined using standard tests on a Boehringer Mannheim/Hitachi 747 analyser. Daily nitrogen balance was calculated from the difference between intake of nitrogen as amino acid and excretion of urinary nitrogen because there was no fecal output in the critically-ill patients. Fluctuations in daily blood urea nitrogen were also accounted for when calculating the differences in daily urea production and excretion.
Statistical methods Values are expressed as mean _+ SEM and the threshold of significance was at 5%. Student t test was used to compare results between the two groups. The Student paired t test was used to compare results within the same group. Because of the limited number of patients comparisons between the two groups were also performed using nonparametic statistics (Mann-Whitney U test).
25
During the study period there was no difference in mean temperature (MCT/LCT 37.4 _+ 1.0, LCT 37.9 _+ 1.0), mean pulse rate, mean blood pressure, mean arterial blood gasses, mean length of days on the ventilator (MCT/LCT 13.8 + 2.9, LCT 17.4 _+ 3.0) or ventilator related parameters (mean PEEP: MCT/LCT 6.6 _+ 1.3, LCT 5.5 _+ 1.2, mean FiO2: MCT/LCT 39.8 + 2.5, LCT 39.0 _+ 3.5), incidence of new infections, positive blood cultures, mean APACHE II-score or mean sepsis score. Two patients on MCT/LCT and one with LCT only ultimately died of causes not directly related to the trial.
Metabolic and biochemical effects We observed a rise in mean EE (kcal/day) during the study period in both groups (mean rise/day MCT/LCT + 47 + 156, LCT +103 _+ 539) without any significant differences between the two groups (Fig. 1). Also a rise was observed in RQ and VO2. There was, however, a great individual variability and no significant differences were observed. No difference was observed in fat, carbohydrate and protein utilization (Figs 2 4 ) . After one day with the fat emulsion, nitrogen balance improved significantly in both groups EE DATEX 25OO 2000
15oo .~ 1000 500 0
I~ 0
1
~[m
I
2
m
3
~ 4
5
day
Fig. 1 Energy expenditure (kcal/day) measured by Datex Deltatrac metabolic computer in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+SEM.
Fat oxidation
Results
Patients
1200 ] 1000 [
Finally, the results were obtained from 20 patients, all of them completed the minimum period of 5 days on TPN. The clinical details are given in Table 1. The groups are well matched for age (MCT/LCT age median: 52 _+ 16.7 range: 34-75, LCT age median: 56 -+ 20.0 range: 16-76). Both groups were also comparable for weight, length, body mass index, APACHE II-score and sepsis score (Table 1).
800 / 600
..
We observed no toxic effects or complications attributable to either of the two fat emulsions.
LCT
200 I 0
Clinical effects
+
4O0
1
I 2
I 3
I 4
I 5
day Fig. 2 Fat oxidation (kcal/day) calculated according to Weir (36) and Frayn (37) equations in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+SEM.
I
26 USE OF A MIXTUREOF MEDIUM-CHAINTRIGLYCERIDESAND LONG-CHAINTRIGLYCERIDES
Substrate oxidation MCTILCT prot 24% cho '!.4% fat 32% Fig. 3 Mean substrate oxidation (days 2-5) with MCT/LCT (%), calculated according to Weir (36) and Frayn (37) equations. (prot = protein utilization, fat = fat utilization, cho = carbohydrate utilization).
( M C T / L C T P < 0.001, L C T P = 0.02), but during the study nitrogen balance r e m a i n e d n e g a t i v e and s h o w e d no difference b e t w e e n the two groups (Fig. 5). S e r u m concentrations o f creatinine, transferrin, prealbumin, albumin and a l p h a - l - a c i d g l y c o p r o t e i n r e m a i n e d stable during lipid infusion and there w e r e no differences b e t w e e n the lipids. T h e r e was a non-significant difference in m e a n serum carnitine concentration (nmol/1) on day 0 ( M C T / L C T 47.0 _+ 19.1, L C T 32.8 _+ 12.5 P = 0.08) and during lipid infusion s e r u m carnitine concentration r e m a i n e d higher on M C T / L C T with significant results (Fig. 6). H o w e v e r , serum levels o f carnitine r e m a i n e d relatively stable in both groups and no significant difference b e t w e e n day 0 and day 5 was found. L e v e l s of G P T , G O T , A L P , g a m m a - G T (Fig. 7) tended to rise during the study with no differences b e t w e e n the lipids. T h e only parameter that s h o w e d a different pattern o f reaction with the two kinds of nutrition was serum bilirubin concentration (pmol/1) (Fig. 8). T h e r e was a decrease in s e r u m concentration in the M C T / L C T group (mean fall/
Substrate oxidation LeT prot 21%
)cho 39%
Camitine
60 5O 40
t
o 30 E 2O
MCT/LCT LCT
10 0 0
fat 40%
1
2
5
Fig. 6 Camitine concentration serum (nmol/1) in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+SEM. Significant differences on days 1-5. *P < 0.05 (difference between MCT/LCT and LCT].
gamma-GT
nitrogen balance 1
4
day
Fig. 4 Mean substrate oxidation (days 2-5) with LCT (%), calculated according to Weir (36) and Frayn (37) equations. (prot = protein utilization, fat = fat utilization, cho = carbohydrate utilization).
0
3
2
day
3
4
5
160
10
140
5
120 100
.~ ~.
0 -5
• MCT/LCT BLCT
.~
-10
40 20
-15
0
-20
Fig. 5 Nitrogen balance (g/24 h) calculated from nitrogen intake and urinary output, corrected for a rise in serum urea nitrogen in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+SEM.
NMCT/LCT
80 60
BLCT
o
..,-
,~
~
~
~,
day Fig. 7 Gamma-glutamyltransferase (gamma-GT) concentration (Lift) in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean -+ SEM.
CLINICAL NUTRITION
Bilirubin
160 140 _
120
~100o80 60 "r=
IIMCT/LCT LCT
40 2O 0 0
1
2
3
4
5
day Fig. 8 Bilirubin concentration serum (micromol/l) in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean _+ SEM.
CRP
2oo 250
_
- - .0- - - M C T / L C T
150
LCT
50 -I. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I 0
1 0
I 1
I 2
I 3
I 4
I 5
day Fig. 9 C-Reactive protein (CRP) concentration (rag/l) in the two study populations (MCT/LCT versus LCT) on days 0-5. Data are expressed as mean + SEM.
day - 6.15 _+ 18.9) and an increase with LCT only (mean rise/day +9.19 _+ 20.1), due to large standard deviations this was not significantly different either. Levels of hydroxybutyrate (mmol/1) were elevated on day 0 (MCT/LCT 0.06 _+0.09, LCT 0.05 _+0.05), suggesting mild ketonaemia, but after one day on lipids levels fell and remained stable during the study period (mean hydroxy-butyrate MCT/LCT 0.04 _+0.07, LCT 0.02 _+0.02). Triglyceride and FFA levels showed no reaction and remained stable during the study with no significant differences. Cholesterol (mmol/1) level showed a tendency to rise in both groups (mean rise/day MCT/LCT +0.05 _+0.31, mean rise/day LCT +0.11 _+ 0.53). C-reactive protein concentration fell during the lipid infusion similarly in both groups (Fig. 9). Comparisons between the two groups performed using non-parametric statistics gave the same results.
Discussion
The evaluation of these data is complicated by the heterogenity of the patients and their pathology resulting in a
27
large inter-patient variety. However, this group of patients presents a genuine group population of critically-ill patients. In order to obtain an objective parameter to compare the state of illness in both groups the APACHE II-score was used and combined with a sepsis score. Groups did not differ statistically concerning these scores and there were also no differences in baseline values collected on day 0. The amount of published reports of the effect of MCT containing fat emulsions in this kind of population are very limited with small numbers of patients. Some of them suggest that MCT/LCT emulsions are a more effective source of energy; however, their conclusions are mainly based on theoretical grounds. Some advantages of MCT like decreased interference with RES (22, 23), decreased storage of in adipose tissue (17, 18) and ketogenic properties might not be present in MCT/LCT. Investigators demonstrated advantageous effects of MCT/LCT in rats, healthy subjects and stable patients like a more rapid clearance (6-12) and a more effective oxidation (12-16). The few studies done in critically-ill patients also suggest possible advantages of MCT/LCT mixtures but some of these contain contradictory results and no conclusive evidence has been obtained. After rapid elimination and oxidation of the MCT in a physical mixture a delayed utilization of LCT could be present. The efficacy of the mixture would then depend on LCT metabolism and its limits. This could possibly explain the contradictory results in others studies. Energy expenditure and oxygen consumption did not tend to rise more with MCT/LCT in our study, contradicting the thermogenic effect suggested by others (41). This study showed a nonsignificantly higher net fat oxidation on LCT during 4 of the 5 days of the study in contrast to the results reported by Jeevanandam et al (25) who describe a greater net fat oxidation with MCT75%/LCT25% in four patients. Nitrogen balance has been reported to be more positive (30-34) and the same with MCT containing fat emulsions. In this study a less negative nitrogen balance was seen after 1 day with the fat infusion, but there were no differences between the two groups. The only variable in the study that showed a different pattern was serum bilirubin concentration, which has been reported before (42-44) and might be an expression of different liver function. The effect of the carnifine independency of MCT-metabolism as an advantageous characteristic remains to be discussed. Medium-chain fatty acids do not need carnitine to be transported across the mitochondrial membrane (21), but this does not mean that carnitine is not used for MCT metabolism (45, 46). Carnitine deficiency in critically-ill patients has been described (47-49), but a wide range of normal values has been reported (50). If that wide range of normal values was applied to this population, only one patient (LCT group) with a depressed carnitine concentration (10.4 nmol/ml on day 2) was present. No significant difference was observed in patients with carnitine concentrations below 40 nmol/1 (threshold of depression mentioned by other authors [49] on either nutritional regime). Carnitine plays a role in nutritional state and metabolism (20, 51), but it may not be the limiting factor in lipid utilization in
28 USE OF A MIXTUREOF MEDIUM-CHAINTRIGLYCERIDESAND LONG-CHAINTRIGLYCERIDES critically-ill patients. D e s p i t e the fact that fat o x i d a t i o n is an o b l i g a t e p a t h w a y o f m e t a b o l i s m in i n j u r e d and septic patients, there is a limit in lipid utilization that has b e e n o b s e r v e d after i n f u s i o n o f L C T - f a t . T h e h o p e that M C T / L C T lipid e m u l s i o n s m i g h t s o l v e this p r o b l e m is still b a s e d o n t h e o r e t i c a l g r o u n d s and has n o t b e e n p r o v e d in large studies. In this study no e v i d e n c e o f any a d v a n t a g e o u s e f f e c t o f a m i x t u r e o f M C T and L C T w a s seen; h o w e v e r , also no d i s a d v a n t a g e has b e e n o b s e r v e d . W e s u g g e s t fat m e t a b o l i s m r e m a i n s i m p a i r e d in critically-ill patients either d u e to a limit in fat utilization as a w h o l e or due to i m p a i r e d L C T c l e a r a n c e a n d oxidation. I f the latter is the c a s e structured lipids d e v e l o p e d b y B a b a y a n (52, 53) m i g h t o f f e r a w a y to o p t i m i z e fat utilization in the critically-ill patient.
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Submission date: 8 April 1997 Accepted: 7 November 1997
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