CLINICAL NUTRITION (1987) 6: 227-232 , Longman Group C!K Ltd

Fructose as an Alternative to Glucose as an Energy Source During Intravenous Feeding

N. D. Carr, E. Gowland, P. F. Schofield and D. E. F. Tweedle

Teaching Unit Five (Department of Surgery) Withington Hospital, West Didsbury, Manchester M20 8LR UK (Reprint requests to D.E.F. T.)

ABSTRACT The metabolic effects of infusing an amino-acid solution with either a 24”& solution of glucose or a 24%* solution of glucose and fructrose have been investigated in 10 patients who underwent elective surgery for cola-rectal carcinoma.

The serum concentrations of all measured biochemical indices and the plasma venous concentrations of individual amino-acids were similar during the infusion of glucose and the mixture of glucose and fructose. Statistically significant increases in the serum concentrations of urea, creatinine and glucose and statistically significant decreases in the serum concentrations of uric acid and bilirubin were observed during infusion of both energy substrates. A persistent increase in the plasma venous concentrations of all amino-acids was observed throughout the period of intravenous feeding.

Glycosuria occurred during the infusion of both energy substrates, but the urinary loss of glucose during the infusion of glucose was statistically significantly greater than that during the infusion of glucose and fructose.

It is concluded that at these rates of infusion fructose has no advantages or disadvantages over glucose as a source of non-protein energy during intravenous feeding in this type of patient.

INTRODUCTION

Following the introduction of intravenous amino-acid

solutions it soon became apparent that protein sparing

was improved when these solutions were infused simul- taneously with a source of non-protein energy [l]. Glucose, being a naturally occurring monosaccharide which is metabolised by all tissues would seem to be a

logical choice of energy substrate, but a number of objections have been raised concerning its use for intra-

venous feeding. Hypertonic solutions must be infused in order to administer sufficient energy and exogenous insulin is required to prevent hyperglycaemia with sub- sequent urinary loss of glucose or hyperosmolar syn- dromes [Z]. By contrast, it has been suggested that

fructose does not have these advantages [3,4], that its metabolism is independent of insulin [5] and is there- fore more efficient as a source of carbohydrate than glu- cose, particularly during the phase of insulin resistance following surgery or trauma. Furthermore, it has been claimed tht 200/b solutions (0.33 g/kg/h) of glucose can be infused in post-operative patients without excessive hyperglycaemia, glycosuria or the need for exogenous insulin [6].

The purpose of the present study was to investigate the metabolic effects of infusing amino-acid solutions

with solutions of glucose alone or a mixture of glucose

and fructose with particular reference to these claims.

PATIENTS &METHODS

Patients

Five male and five female patients were studied, all of whom had undergone elective surgery for cola-rectal carcinoma. The age range was 4&-81 years and the mean pre-operative body weight was 69.3 kg.

Methods

The patients were allocated at random to either group 1 or group 2. On the day of operation all patients received electrolyte solutions, plasma expander or blood as indi- cated clinically. No more than 1.5 1 of 59+, Dextrose solution was infused during this time. Intravenous feeding was begun on the morning of the first post- operative day. The content of the solutions is shown in Tables 1 and 2.

227

228 FRUCTOSE AS AN ALTERNATIVE TO GLUCOSE AS AN ENERGY SOURCE DURING INTRAVENOUS FEEDING

Table 1 Composition of Sugar Solutions

Glucose & Glucose Fructose

(glucovenous (combivenous 240,~) 240,)

Volume (1) 1 1 Glucose (g/l) 240 120 Fructose (g/l) 120 Sodium (mmol/l) 25 20 Potassium (mmol/l) 20 20 Calcium (mmol/l) 8 5 Magnesium (pmol/l) 5 5 Zinc (mmol/l) 5 Chloride (rmnol/l) 50 50

* Fresenius Pharma.

Table 2 Composition of Amino-acid Solution (aminosteril 109b R’)*

Amino-acids

Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophane Valine

Arginine Histidine

Cystine Alanine Serine Proline Tyrosine Glycine

Electrolytes

Sodium Potassium Magnesium Phosphate Acetate

* Fresenius Pharma.

Concentration 8/l

6.40 10.75 7.09 4.62 4.57 5.15 1.83 7.09

6.40 4.14

0.38 7.16 9.03

16.19 5.49 4.14

Concentration (mmol/l)

60 60

5 60 10

During the period of intravenous feeding, both the nitrogen and energy source were infused concurrently into a central vein via the ante-cubital or subclavian route. Oral intake was restricted to water only during this time and blood and urine samples were collected

daily. Patients in group 1 received 11 of amino-acid solu-

tion (14.43 g nitrogen/l) and 2 1 of a 24% glucose solu- tion (240 g glucose/l). This regimen was continued until the morning of the 4th post-operative day when 2 1

of a mixture of glucose and fructose (120 g glucose +

120 g fructose/l) was substituted for the glucose solu- tion and feeding continued for a further 3 days. Patients

in group 2 received exactly the same solutions but in the reverse order. By following this different sequence of infusion in the two groups any bias induced by the

proximity to the day of operation should have been excluded.

When this study was planned it was decided to give

insulin as infrequently as possible as it is the require- ment for infusion of insulin that deters many clinicians

from using hypertonic solutions of glucose. Accord- ingly we elected to give insulin only when the blood

glucose concentration reached 15 mmol/l. We wish to emphasise that this concentration is higher than the

upper limit that we consider to be acceptable in our

normal practice and was chosen as the extreme upper limit that we and our colleagues considered to be acceptable under any circumstance. Blood glucose esti-

mations were performed three times each day in all

patients during the 6 days of parenteral feeding. In those patients who required control of their hypergly-

caemia, soluble insulin (5-10 units intravenously) was administered every hour until the blood glucose con- centration fell to within the acceptable range. The haemoglobin concentration, white cell count and the

serum concentrations and urinary excretion of many

biochemical substances were measured daily during the

study (Tables 3,4,5 and 6).

Statistical analysis

Each of the serum and urinary indices were assessed

separately using a repeated measure analysis of vari- ance. This technique provided information on both the

effect of infusion and the order of infusion. Significant

differences in the analyses of variance were examined in detail using the Tukey multiple comparison test.

RESULTS

There were no statistically significant differences in the mean daily serum concentration or urinary excretion of the measured biochemical indices with respect to which carbohydrate substrate was infused first.

Serum indices

Serum concentrations of urea, creatinine and glucose showed a statistically significant increase during the in- fusion of glucose and the mixture of glucose and fruc- tose. By contrast the serum concentrations of uric acid and bilirubin decreased significantly during infusion of both energy substrates. There were no statistically sig-

CLINICAL NUTRITION 229

Table 3 Serum Indices During Intravenous Feeding With Glucose And Glucose and Fructose (mean 5 s.d.)

Pre-operative Glucose Glucose and Fructose

Sodium (mmol/l) 13t3.0+4.5 134.0f 3.9 135.0* 2.6 Potassium (mmol/l) 3.91 f 0.40 4.0910.38 4.04 i 0.44 jCh1oride (mmol/l) 103.0f5.1 97.0 f 3.7 lOO.Ort6.1 tBicarbonate (mmol/l) 23.2f4.3 28.2 f 6.4 25.8 f 7.2 *Urea (mmol/l) 4.83 f 1.85 6.19f 1.50 6.75 * 2.16 *Creatinine (mmol/l) 0.090f0.017 0.071 fO.O1O 0.072 f 0.013 Osmolality (mOsm/kg) 300.0& 17.1 297.0f 13.8 297.0f 7.4 Calcium (mmol/l) 2.14rtO.10 2.09&00.13 2.11 kO.08 Phosphate (mmol/l) l.Of0.18 1.02 f 0.26 0.90*0.26 *Glucose (mmol/l) 8.25 f 2.32 14.07 i 5.60 12.64+4.64 *Uric acid (mmol/l) 0.311 f 0.075 0.117*0.043 0.127+ 0.038 Cholesterol (mmol/l) 4.61 f 3.14 3.18+0.64 3.20i0.76 Total protein (gjl) 58.4 zt 4.4 56.9rt4.3 56.5 & 5.8 Albumin (g/l) 33.7 f 3.5 30.7 * 3.5 30.6 & 3.5 Globulin (g/l) 24.7 f 3.6 26.1 f 3.0 25.4 f 3.5 l Bilirubin (mmol/l) 20.4f 14.5 10.9f6.9 11.4*6.8 Alkaline phosphatase (IV/l) 71.8+9.9 80.01t 19.9 78.9h28.5 Aspartate aminotransferase (IV/l) 25.4 & 14.9 31.9f 14.6 34.2 * 24.7 Lactate (mmol/l) 1.23 f 0.29 1.93f0.94 1.96+ 1.16 Pyruvate (umol/l) 98.1 + 37.8 146.4i41.7 136.0+23.9

* Statistically significant differences between pre-study period and both infusion periods (p ~0.05) t Statistically significant differences between pre-study period and infusion of glucose only (p <0.05).

Table 4 Plasma Venous Concentrations of Individual Amino-acids During Intravenous Feeding With Glucose And Glucose and Fructose. (mean * s.d.)

Pre-operative Glucose Glucose and Fructose

Asparagine 14.9 i 3.8 17.8 zt 6.8 17.6zt6.8 Threonine 141.9&71.2 198.1 z+z 103.3 268.0f 125.8 Serine 117.5+32.2 160.6& 111.5 159.9 + 76.7 Proline 205.9* 147.1 480.9 f 222.1 505.2 + 323.3 Glycine 204.4f 49.2 199.4f 110.2 220.8 f 82.2 Alanine 303.9* 122.3 351.0f 114.9 347.0& 103.3 Valine 254.9 + 64.6 297.3 f 150.3 375.9f 153.1 Methionine 27.4+ 11.5 89.6 f 67.3 98.7f 112.1 Isoleucine 76.6f 17.7 121.1 f 105.1 97.2f44.1 Leucine 147.5zk42.0 220.2 i 170.8 185.7f84.2 Tyrosine 59.9i 17.4 67.9 i 16.7 72.1 i 16.7 Phenylalanine 57.8 f 12.4 100.7f 42.5 93.6 z!z 32.8 Omithine 90.2 f 39.6 92.0f31.2 105.4f51.4 Lysine 187.7 * 44.4 194.9f93.3 212.0 f 79.4 Histidine 67.5 zt 13.9 72.6 i 39.3 70.6f25.1 Arginine 57.21t21.5 74.3zt 36.6 80.2f33.0

nificant differences in the serum concentrations of lac- tate, pyruvate and phosphate between the pre-study period and either infusion period (Table 3).

There was no difference between the concentrations of individual amino-acids during infusion of glucose alone when compared with infusion of glucose and fructose (Table 4). After operation, but before infusion began, the concentration of the majority of the amino- acids fell except for valine, isoleucine, leucine and tyro- sine which remained the same and phenylalanine which increased (Table 5). It is evident from Table 5 that

following that start of intravenous feeding there was a persistent increase in the concentrations of all the amino-acids measured until the infusion was ceased after 6 days. Although the concentrations of alanine, arginine, glycine, histidine, leucine and lysine in- creased, their concentrations did not exceed normal fasting levels. By contrast, the concentrations of aspartic acid, isoleucine, phenylalanine, serine, tyrosine and valine exceeded the upper limit of the normal range of fasting concentrations, but the excesses were not great. However, the concentrations of proline in par-

230 FRUCTOSE AS AN ALTERNATIVE TO GLUCOSE AS AN ENERGY SOURCE DURING INTRAVENOUS FEEDING

Table 5 Plasma Venous Concentrations of Individual Amino-acids Before, During and After Intravenous Feeding (mean f s.d.)

Asparagine Threonine Serine Proline Glycine Alanine Valine Methionine Isoleucine Leucine Tyrosine Phenylalanine Ornithine Lysine Histidine Arginine

Pre-operative Post-operative

14.9 + 3.8 11.9f3.4 143.1 + 70.8 72.8 f 25.2 116.6zk31.6 63.3f 16.0 201.1 f 144.1 109.1 k49.1 204.7 f 49.2 137.3 + 36.9 303.6f 122.3 219.7 f 87.6 254.8* 64.6 254.4f67.1

27.3f 11.5 18.8f8.1 76.5 f 17.7 65.0f31.4

147.3f42.9 139.8f62.1 59.9f 17.4 64.2f 18.1 57.8 + 12.4 66.3 f 15.4 90.2 f 39.6 56.1 f 23.9

187.8f44.4 127.3 zt 44.3 67.5 f 13.9 57.9* 11.6 51.6f28.1 33.8f 11.3

Day 4

16.6k4.4 162.7 f 98.5 113.2f 70.2 385.6 * 220.7 168.7 rt 74.9 306.2 f 82.9 327.2+ 155.6

85.1 i 116.5 75.9 f 50.2

152.8f97.1 69.5 f 17.3 89.6f 33.5 92.4% 54.6

177.9 f 86.7 64.0 f 23.9 55.1 f 19.6

Day 7 Normal range

18.8 * 8.3 413 304.0 k 92.1 87-175 207.3f92.1 80-188 644.1 f201.7 122-231 251.5rt98.6 145-416 397.5f111.3 228409 389.7f 83.8 141-369 102.7 zk 58.7 1540 142.4*91.2 44-134 253.1 f 148.1 79-344

70.5 k 16.4 32-66 104.7 + 40.7 30-90 105.Ozt25.3 30-152 229.0 f 78.8 115-321

79.2 f 38.4 54-150 90.8f28.7 51-154

Table 6 Urinary Indices During Intravenous Feeding With Glucose And Glucose and Fructose (mean f s.d.)

Pre-operative Glucose Glucose and Fructose

*Volume (I/d) 1.40 f 0.62 2.69f0.86 2.52 f 0.86 Sodium (mmoljd) 167.0 * 97.5 156.Ok81.8 168.0f89.1 Potassium (mmoljd) 68.0 f 29.9 74.5 f 15.6 75.4f 26.9 *Urea (mmoljd) 207.0 f 79.0 361.01171.4 475.0f 125.4 Creatinine (mmoljd) lO.Of2.6 9.5 f 2.9 10.1 f2.8 Osmolality (mOsm/kg) 579.2 f 79.9 627.3 f 191.3 607.6 * 179.8 Uric Acid (mmol/d) 2.72 f 0.87 3.25f 1.41 3.64rt 1.42 *tGlucose (mmol/d) 9.0f8.5 269.5 I!Z 118.4 117.0zt83.5 Fructose (mmol/d) 13.7 f 12.6 *Nitrogen (g/d) 7.2 f 2.8 12.6f6.0 16.4f4.4

* Statisically significant differences between pre-study period and both infusion periods (p < 0.05). t Significant difference between each infusion period (p < 0.05).

titular and, to a lesser extent, those of threonine and methiomne were definitely excessive.

Urinary indices

The mean volume of urine excreted during each in- fusion period was significantly greater than that observed in the pre-study period. Although glycosuria was observed during the infusion of both energy sub- strates, a significantly greater loss of glucose occurred during the infusion of glucose when compared with that observed during the infusion of the combined solution (Table 6). The urinary osmolality was similar during the infusion of either substrate. Non-metabolised fruc- tose contributed to the osmolar load during the infusion of the combined solution (Table 6). Nitrogen balance was achieved by eight of out ten patients during the in- fusion of glucose, and six out of ten patients during the infusion of the mixture of glucose and fructose.

Insulin requirements

The number of occasions when the blood glucose con- centration exceeded 15 mmol/l did not differ signifi-

cantly during each infusion period (Table 7).

DISCUSSION

The removal of infused fructose by the liver and its initial phosphorylation by the enzyme fructokinase to fructose-l-phosphate occurs rapidly and independently of insulin [5, 71. These observations have led to the suggestion that fructose may be more effectively handled than glucose by stressed patients and provide an ideal substrate for intravenous feeding [S-lo].

After phosphorylation, fructose-l-phosphate is further metabolised via D-glyceraldehyde to either glu- cose or pyruvate and lactate [5]. Using infusions of 14 C labelled fructose in rats it has been shown that most of

CLINICAL NUTRITION 231

Table 7 Number of Episodes When Blood Glucose Concentration > 15 mmol/l.

Patient Glucose Glucose and Fructose

WD AL

;y GS Lw* PE TK

;z*

Total

1 1 3 2 2 1 1 1 1 2 1 2 2 1 1

12 11

* These three patients required insulin regularly during the infusion of glucose and the mixture of glucose and fructose to control hyperglycaemia.

the radioactivity appears in the animal’s plasma glucose [Ill, but the relative proportion of infused fructose

which is converted to glucose in stressed post-operative

patients in uncertain. Hessov [12] observed less hyperglycaemia during the short term intravenous ad-

ministration of 0.5 g/kg/h of fructose to post-operative patients than with similar quantities of glucose and con-

cluded that only small amounts of fructose were con- verted to glucose in this situation. These results contrast with those of Vinay et al [13] who demon-

strated that blood glucose concentration was not

reduced in a group of surgical patients who received a

mixture of O.l5g/kg/h of fructose and 0.45g/kg/h of glucose when compared with patients who received 0.6g/kg/h of glucose only. The findings from the

present study confirm that unacceptable hyperglycaemia may result from prolonged infusion of 0.15 g/kg/h fructose in the post-operative period. Moreover, this

glucose requires insulin for its peripheral utilisation and hence a reduction in the amount of insulin required

to control hyperglycaemia during the infusion of the

mixture of glucose and fructose was not apparent in the present series of patients. However, we do not consider the need for insulin to be a nuisance during intravenous feeding as it affords control over excessive metabolism

of glucose and aids the cellular uptake of amino-acids and their incorporation into protein [ 141. The utilisa- tion of fructose is uncontrolled and infusion at rates

greater than 0.5 g/kg/h may produce lactic acidosis [ 15, 161. An increase in the plasma concentration of lactate did not occur with the lower rate of infusion of fructose employed in this study. The concurrent infusion of amino-acids has been shown to afford protection against lactic acidosis during fructose administration [ 171 and this may provide another explanation for the absence of this complication in the present series of patients. Uric acidaemia due to an increase in the break-

down of purine nucleotides has also been described

during infusion of fructose [ 151. It is of interest that

patients in this study showed a significant decrease in

the serum concentration of uric acid. The three-fold in- crease in clearance of uric acid during the infusion of

either substrate was probably responsible for this unex-

pected finding. Hypophosphataemia may complicate intravenous

feeding when hypertonic solutions of glucose or fruc-

tose are used as the sole source of non-protein energy [ 121. However, Vinay et al [ 131 observed a decrease in

the seurm concentration of inorganic phosphate during

the administration of fructose which was not seen dur-

ing the infusion of glucose. These authors attributed this change to the sequestration of inorganic phosphate in tissues actively metabolising fructose. The provision

of adequate exogenous phosphate prevented the devel- opment of hypophosphataemia with either substrate in

our study. The concentrations of the amino-acids immediately

before operation are within previously published ranges

in healthy individuals after an overnight fast [ 181. Pre-

vious studies of the effect of operation upon venous

plasma free amino-acids showed that in general the mean post-operative levels were lower than the pre- operative concentrations but that the concentration of

phenylanine increases [ 191. In the liver of healthy indi-

viduals phenylalanine is hydroxylated to tyrosine and it has been suggested that in periods of metabolic stress,

the efficiency of this pathway may be impaired, with

consequent accumulation of phenylalanine. Similar changes have been noted in patients with severe battle wounds [20], following sand-fly fever [21] and in

patients with post-operative sepsis [22]. Consequently,

in periods of metabolic stress, tyrosine and perhaps other amino-acids may be considered to be ‘essential’ (i.e., cannot be synthesised at the required rate and

should be included in the diet).

The changes in the concentration of the plasma free

amino-acids after operation may be due to a variety of factors including alteration in intake, changes in hydra- tion and changes in metabolism induced by anaesthesia and surgery [19]. The changes in the concentrations

due to alterations in metabolism may reflect both changes in protein synthesis and protein catabolism [23]. Because of these features, caution must be advised

in using concentrations of plasma amino-acids alone in assessing the ideal composition of solutions of amino acids for particular patients. However, if the concentra- tions are grossly abnormal, some conclusions may be drawn. In the present study there was a persistent in- crease in the plasma venous concentrations of all amino-acids during the period of intravenous feeding and it may be inferred that the total quantity of amino- acids infused was slightly excessive. Only the concen-

232 FRUCTOSE AS AN ALTERNATIVE TO GLUCOSE AS AN ENERGY SOURCE DURING INTRAVENOUS FEEDING

trations of proline, threonine and methionine greatly exceeded the upper limit of the normal range and we

feel that the quantities of these amino-acids in the solu- tion used in this study be reduced. A comparison

between the plasma venous concentrations of these

amino-acids during the period of feeding and those of

normal fasting suggests that the reduction in the con- centration of proline, threonine and methionine could

be made good by an increase in the concentrations of

arginine and histidine. Although the plasma concentra-

tions of some of the amino-acids became abnormal dur-

ing intravenous feeding, the abnormalities were less

than those that have been observed in other studies in

which amino-acids were infused alone [ 181 or, as here,

with a source of non-protein energy [24].The solutions

infused in these other studies, [ 18,241 like this solution

have been in clinical use for many years and many thou-

sands of patients have benefitted without any apparent

deleterious effect from major alterations in plasma amino-acid concentrations. It is apparent that during the last two decades more thought has been given to

intravenous amino-acid requirements and that manu-

facturers have modified their solutions so that the major excesses and deficiencies of the earlier solutions are now

uncommon. However, it would appear from this and other studies that minor modifications may still be required to ensure optimal utilisation particularly in

patients with altered metabolism.

ACKNOWLEDGEMENTS

The authors wish to thank the Department of Biochemistry, University Hospital of South Manchester for analysing the blood and urine samples from the patients included in this study, and Fresenius Pharmaceuticals who kindly provided the intravenous feeding solutions used in this investigations.

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Submission date: 14 April 1985. Accepted: 12 April 1987

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v41

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