Nitrogen Balancein the Post-Operative Patient Receiving Parenteral Nutrition A. C. AMEs AND A. THoMAS Neath General Hospital, Neath, Glamorganshire

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1 Ann. c/in. Biochem. 9 (1972) 135 Nitrogen Balancein the Post-Operative Patient Receiving Parenteral Nutrition A. C. AMEs AND A. THoMAS Neath General Hospital, Neath, Glamorganshire Nitrogen balance was measured in patients receiving balanced parenteral nutrition, most of whom were recovering from major surgery involving the alimentary tract. Their pre-operative nutritional status was found to be an important factor in relation to the nitrogen balance that was induced. Positive nitrogen balance did not occur in patients with little or no pre-operative weight loss, but when the weight loss was more than 6 kg. positive or very small negative nitrogen balances were readily induced. The urine creatine/creatinine ratio which is an indirect index of muscle metabolic activity can be used to anticipate the nitrogen balance that may be achieved in a post-operative patient receiving parenteral nutrition. The value of parenteral nutrition in minimising the post-operative nitrogen deficit and reducing or reversing the catabolism of body protein and fat which results from starvation, stress or tissue trauma is well established (Holden, Krieger, Levey, and Abbott, 1957; Lawson, 1965; Larsen and Brockner, 1966; Johnston, Marino, and Stevens, 1966). Unfortunately it is not always possible to obtain a positive nitrogen balance in traumatised or postoperative patients who are given calories and amino-acid nitrogen intravenously when oral or tube feeding is contra-indicated. Several factors, briefly outlined, may be responsible for this. It is important that individual patient's calorie and nitrogen requirements are correctly assessed and satisfied, but these can be greatly increased in those with extensive trauma, burns or severe in- could be established subsequently by parenteral nutrition. In this investigation surgical patients were studied to see whether there was a relationship between their pre-operative nutritional status and post-operative nitrogen balance when they received balanced parenteral nutrition. The 24 h urine creatine/creatinine ratio was also measured before and during parenteral nutrition. This was to investigate the possibility that the creatine/creatinine ratio, which is an indirect index of the metabolic activity of skeletal muscle, would reflect changes in the nitrogen balance. PATIENTS Twenty-six unselected patients who were admitted fection (Peaston, 1967). In these so called 'hyper- to the general surgical wards for routine or catabolic' states catabolism is excessive and gluco- emergency surgery were investigated. There were 22 neogenesis from tissue protein is increased which men and 4 women whose ages ranged from often leads to the development of large nitrogen years. Twenty-four required some form of major deficits. There must also be an adequate intake of gastrointestinal surgery ranging from pharyngosodium and potassium if positive nitrogen balance laryngectomy to proctocolectomy. The other two is to be established (McCance, 1936; Beal, Frost, patients suffering from dysphagia and cachexia due and Smith, 1953). It has been suggested (peaston, to carcinoma of the pharynx and oesophageal 1968) that positive nitrogen balance was less likely stricture, were admitted for intravenous nutrition to occur with synthetic dl-amino acids than with prior to operation. Normal oral or intraduodenal the slightly better utilised I-amino acids in casein feeding was contraindicated in all the posthydrolysates, but this is controversial. operative patients and they received parenteral Abbott and Albertsen (1963) while investigating nutrition which commenced the day after operathe effect of starvation and surgery on metabolism tion. found that well-nourished individuals had a larger The patients were weighed on admission. Their nitrogen deficit than undernourished subjects. pre-operative weight loss, if any, was taken as the Johnston et al. (1966) found the normal catabolic difference from their normal body weight, which was response to trauma failed to occur in malnourished obtained from out-patient records in many cases. subjects and doubted the value of parenteral nu- They were divided arbitrarily into two groups. trition in their pre- and post-operative care. These Patients who had lost less than 6 kg were allocated observations suggest that the nutritional state of to Group J, and those with a greater weight loss, to a patient before operation or trauma might have Group II. There were 13 patients in each group. a definite influence on the nitrogen balance that Eleven patients in Group II and three in Group I 135

136 were below their ideal weight, derived from standard tables. The weight losses recorded by patients in Group IT were variable ranging from 8-25 kg.

2 136 were below their ideal weight, derived from standard tables. The weight losses recorded by patients in Group IT were variable ranging from 8-25 kg. Some had experienced a slow progressive loss of weight over a year or more, while others had a rapid acute loss of weight over a period of weeks or months. Parenteral nutrition Synthetic dl-amino acids were the source of amino-acid nitrogen and provided g nitrogen/l (Trophysan Cone. 10). The main calorie sources were 30% Sorbitol which provided 1200 cal/i and cottonseed oil fat emulsion which provided 1240 cal/l (Lipiphysan 10%). (Trophysan, Sorbitol and Lipiphysan from Servier Laboratories Ltd., Harrow, London.) The solutions were given in combination through a 'Y' connector via a polythene catheter (lntracath Bard Davol Ltd.), usually introduced into the cephalic vein. The minimum daily nitrogen (145 mg/kg body weight) and calorie (27 cal/kg body weight) requirements of each patient, recommended by AIlen and Lee (1969) were covered and often exceeded in all but a few patients who developed congestive cardiac failure or oliguria, which temporarily restricted the volume of infused fluid. Those patients with hypercatabolic complications received larger nitrogen and calorie intakes to cover their increased requirements, within the limitations imposed by their ability to handle the increased fluid volume. In the majority of patients, approximately 20% of the total calorie intake was given as fat emulsion. Patients were maintained in sodium, potassium, calcium and magnesium balance by adding supplements of '5xnormal' saline (this contains 770 mm sodium chloride/f) potassium chloride (20 g/loo ml), calcium gluconate (10 g/loo ml) and magnesium sulphate (10 g/loo ml) to the aqueous parenteral solutions. The amounts given were based on a daily assessment of losses of these ions in the urine, gastric aspirates and other drainage or fistula fluids. METHODS During the period of parenteral nutrition, continuous 24 h urine samples, preserved with toluene, were collected from each patient, together with any gastric aspirate, fistula fluid or faecal material. Total nitrogen, urea, creatine, creatinine, sodium, potassium, calcium and magnesium were measured daily in each urine with routine estimations of urea and these electrolytes in serum. When necessary, the total nitrogen in faeces and otherfluids was measured to obtain complete nitrogen balances. In those patients developing uraemia post-operatively, the nitrogen retention was calculated and the appropriate adjustment made to the nitrogen balance (Allen and Lee, 1969). Urine creatine/creatinine ratios were measured prior to operation in the patients admitted for routine surgery, to establish baseline or control values, and during the infusion period. Twenty-four hour urine creatine/creatinine ratios were also measured in the following groups of individuals to establish normal ranges: 1. Normal ambulant men. 2. Male patients either pre-operative or recovering from minor surgery (cystoscopy, herniorrhaphy, etc.), on a normal diet. 3. Male patients recovering from major surgery (gastrectomy, colectomy, etc.) but receiving intravenous dextrose and saline. Total nitrogen was measured by the micro Kjeldahl method using a Markham apparatus and urine creatine, creatinine and urea by standard TechniconAutoAnalyzer methods (Wootton, 1964}. REsULTS 24 h urine creatine/creatinine ratios: Control groups Figure 1 shows the ratios found in normal individuals and patients classified into minor and major post-operative groups. There is a statistically significant difference between the means in each of the three groups. Nitrogen balances and 24 h urine creatine/creatinine ratios in Groups I and II: Tables 1 and 2 present the clinical information of the patients forming both Groups together with details of their parenteral nutrition. The nitrogen balances and urine creatine/creatinine ratios for each patient are reported as mean values for the period during which parenteral nutrition was given. All patients in Group I had a negative nitrogen balance, the nitrogen deficit ranging from g/day. It must be emphasised that the negative nitrogen balances would probably have been much greater without parenteral nutrition. In Group II, eight patients achieved a positive nitrogen balance, while four others had a small nitrogen deficit ofless than 1.5 g/day. There were five patients in Group I who clinically had some additional post-operative hypercatabolic complication like bronchopneumonia, peritonitis or septicaemia which exaggerated the nitrogen deficit.

3 o & 0.7'- i u !; i 0.5 tj! : 0.4 ::z: Pre-opera.llve or Ma.jor poslminor Norma.l post- operqtive QmbulQ/1t 0r,erQtlve (norma.l IintrQvenous dell dextrdse sqline) I- I- 0.8I- p.<o,ooi - 0.3I- o. 1 n p.«o,ool Fig h urine creatine: creatinine ratios In three cootrol groups. It should be noted, however, that hypercatabolic complications did not prevent a positive nitrogen balance in three of the four patients in Group II. There was a statistically significant difference between the means of the nitrogen balances in Group I and II. There was a statistically significant difference between the means of the urine creatine/creatinine ratios in Groups I and II as shown in Table 3. Figure 2 indicates that this was due solely to a lower excretion of creatine in Group II, with values expressed in mg/kg body weight. There was a statistically significant difference in the actual creatine excretion in both Groups, but the creatinine excretion was similar and not significantly different. Parenteral nutrition was not observed to reduce urine creatine/creatinine ratios in Group II patients for they were invariably found to have low ratios in the control pre-operative period. The majority of patients in Group I had a low basal ratio preoperatively which increased after operation. In a few,...: t.:l '0... l:l.s..... ;it.. -s::, "t:.. l:! 9- """1Cl : ;j ;it -5 ::l I::, ] '" d u ',c I::.Q v,!3 '- -, i Nu l:! u:, ' i E 8-9! J: g8 '8 ;j ni 1... f;j ]0 Jl CJ 5 '3 rho 'I:: /:1 '':: I:: f-o 11'8 1::.,S! '':: &11 '>: ni 'I:: :sl -l:!.0 I 1,g a 8...,.ci.!:l s.. ;.,- Cl 'O'iiii O'-..\oll...: 1Xl"'" < zn::: :g iss 5n::: n: l;;; c::ic::ic::ic::ic::ic::ic::ic::ic::ic::ic::ic::ic::i t"'-o\l.n'l'lc\r'f").-4not"'-...-livo\ '" "'..o"'..;o\r..:m...:"'..; I I I I I I I I I I I I I tn'='fii'f:"f:' "'-""'-"''-''''''-''''-'''-'''''''''... '-''''''-'''-'''... "" OOIClN "''''''''':gicl''''' :!:::oo

4 Table 2. Details ofparenteralnutrition, nitrogen balance and CN/CNINE ratios in patients with pre-operative weight loss greater than 6 kg (Group II). ee w GROUP II: Pre-operative weight loss greater than 6 kg Age Body Infused Calories Total Mean nitrogen Mean 24 h weight nitrogen infused calories/g balance urine creatine/ (kg) (mg/kg (kg nitrogen (g/day) creatinine ratio b.wt/day) b.wt/day) (7) Cholecystjejunostomy--arcinoma of pancreas (5) Total gastreetomy---an:inoma of stomach" (6) Gastroenterostomy-ischaemia ofjejunum" (12) Dysphagia--arcinoma pharynx (4) Ileostomy-intestinal obstruction (5) Proctocolectomy-Crohn's disease" (3) Gastrojejunostomy-<:arcinoma of stomach (4) Partial gastrectomy-duodenal ulcer (6) Pre-operative-carcinoma of stomach (4) Acute pancreatitis-marsupialisation of pseudo cyst (4) Total gastrectomy-c-carcinoma of stomach" (10) POS1 oesophageetomy stricture-dysphagia (3) Ileal resection-crohn's disease Hypercatabolic n -''0 S"g"[ET -.8 ",ne' a l} S.1ll... a I;J (D' OQ...,... _.::s [0" _oc::cu=.;::t ::r - 5' :$10- o' S '" =:s '< nn... el ::s :: c n::s2'::r 'G' if 0!i!-n::!.'O '0 a _::s a., _.'0 n _. I:l- o'il! e: fj _. E; g 5' ap. e, '<Ill-- _ n c '" :::I n P-g-:$1 0'-':$1 S.=:s :$1 "' :::I 'tl III _. ::r -el ::rn::;-o I;: u. n., =:;e ::S=:SOQ:$1 =:s.. II s ::+"0 n!" ::1. Ra::S n "' :::ig"noq::s ll::., 'R s c'oe.gqsa.. alll a no i (ii" 2 (i"::t. ::to == ::s S;"P"9-. 2ae:g., cs- III.'" '" :::l a:$1 -:$1:$1 n' '0 on, 8. OQ _. if el el.. n II Q S- """""... =:s II ::l 2 0' -...I C s l;- o:[::;-" I+g III S s III... ::l c2w2 5g"go.n iii g"& -!" a s.g '" it(.l: ::I ::I!='!=' e 0'1 0'1 o ::r 5 S. 6 -'::1 I' C"t( l: + I R 0,..._. 10 1lQ::; -0 Cl-1lQ.ell'...,::1 o-i S(5"::l 'I::I C 1:Ie: c:li!ll... 1' C" W. '? liq ;: '51 s "'5- " 8. E' o 0 o l:i =g r: r: "0"0 Co :I ;;;- f =- ;'1Il =!' l;o- C ::s..,.., :::::!; ::l!=- o 0 'l; s ira "' e ;0-", <' c" ai: eg l l :I S.c" e ;! = =- 00 Iil et OijEl... :!. "'... =g v «:IS" s. go. "'''' '" '" is'... '"... :I I:l get 6" I'> g Co ::r!i! ii "'''' -e l: " :>. 10 :,...., " o b "'''' l I I D I I -I :0:: :.., '" :0:: id o I I t lal3.0", cg: ;r 10 c:... '" c;> I.., - 5' n a :;- 0.., r: 0.., r: 5' -!l c;> e,i" a -I r: '.., = " v 0 I I

5 139 previous day's excretion an estimate is obtained of the amount of nitrogen that should be infused to maintain nitrogen balance. DISCUSSION It was assumed that the recent changes in body weight ofthe patients investigated were an indication of their pre-operative nutritional status. The arbitrary division of patients into two groups based on a weight loss of less or greater than 6 kg is open to criticism, but its selection separated two contrasting groups of patients when their nitrogen balances and urine creatine/creatinine ratios were considered. This investigation demonstrated that in spite of adequate parenteral nutrition, it was difficult to induce a positive nitrogen balance in well-nourished patients, and in some cases increasing the amount of infused amino-acid nitrogen only resulted in an increased excretion of urine urea with little effect, if any, on the nitrogen balance. This suggests that gluconeogenesis persists in these individuals who preferentially utilise their own body protein rather than an exogenous source to satisfy their energy requirements. It appears that there must be an optimal nitrogen requirement. If this is exceeded there is inefficient utilisation of the excess nitrogen which is promptly excreted. In contrast, the majority of malnourished patients in Group II who were subject to similar operative trauma readily achieved a positive nitrogen balance. They appeared to have an avidity for exogenous nitrogen and calories which they utilised more efficiently and this was demonstrated by an immediate anabolic response to parenteral nutrition. Considering the short duration of the majority of the parenteral infusions it would not be expected that this anabolic effect would manifest as weight gain by any patient. However, two patients infused for day periods increased their body weight by 2 kg and 3 kg respectively. It is interesting that positive nitrogen balance was induced even in three patients with hypercatabolic complications. A possible explanation is that adaptive enzyme changes occur in the liver of man during malnutrition which increase the incorporation of amino-acids into protein, but decrease their deamination for the synthesis of urea (Waterlow. 1968). This may be the underlying mechanism of the increased economy of amino acid utilisation which is part of the normal response to a reduction in protein intake. An interesting finding, not reported here, which is the subject of further investigations, was that patients in Group I had consistently higher losses of potassium in the urine when compared with those in Group II. The lower urine potassium excretion in Group IT could be related indirectly to the enhanced cellular anabolism of this group with consequent retention of potassium, while the larger losses in Group I could be due to progressive cellular catabolism. The urine creatine/creatinine ratios in the three control groups (Fig. I), confirm that in conditions where there is recumbency with muscle wasting or trauma, there is an increase in creatine excretion and the normal ratio which is < is exceeded. In the semi-starved surgical patients who received dextrose and saline only, there was an even greater increase in the meanratio, although there was a wide scatter of values about the mean. The increased creatine/creatinine ratios in Group I subjects are also the result of an increase in creatine excretion relative to the urinary excretion of creatinine, which is similar in Groups I and II. These patients suffer a catabolic response to trauma which is confirmed by their negative nitrogen balances and the creatinuria is consistent with either a creatine 'leak' or a reduced uptake of creatine from the circulation by muscle cells in a catabolic phase. Paradoxically, the malnourished patients in Group II who had lost weight prior to surgery did not have as high a creatine/creatinine ratio as might have been expected. This might be due either to an enhanced uptake by or a diminished 'leak' ofcreatine from muscle cells in an intense anabolic phase. Results from this study suggest that a postoperative patient with a urine creatine/creatinine ratio of < 0.20 can be expected to develop a positive nitrogen balance provided parenteral nutrition is adequate. Higher ratios should not deter any efforts to maintain a parenteral nutrition regime, for although positive nitrogen balances may not be attained, this treatment will greatly diminish the large nitrogen deficits that would otherwise develop. We wish to thank Mr. L. John and Mr. E. H. Jones for permission to investigate their patients; the nursing staff and surgical residents for their co-operation; the staff of the biochemistry department for their technical assistance, and Servier Laboratories Ltd., who provided the Trophysan, Lipiphysan and Sorbitol. REFERENCES Abbott, W. E., Albertsen, K. The effect of starvation, infection and injury on the metabolic processes and body composition. Ann. N. Y. Acad. Sci. 110(1963) 941. Allen, P. C., Lee, H. A. A Clinical Guide to Intravenous Nutrition. Blackwell Scientific Publications, Oxford, Beal,J. M., Frost, B. M., Smith,J. L. 'Influenceof calories and potassium intake on nitrogen retention in man. Ann. Surg. 138 (1953) 842.

6 140 Holden, W. D., Krieger, H., Levey, S., Abbott, W. E. The effect of nutrition on nitrogen balance in the surgical patient. Ann. Surg. 146 (1957) 563. Johnston, I. D. A., Marino, J. D. Stevens, J. Z. The effect of intravenous feeding on the balances of nitrogen, sodium and potassium after operation. Brit. J. Surg. 53 (1966) 885. Larsen, V., Brockner, J. Nitrogen balance and operative stress. Acta. Chir. Scand. Suppl, 343 (1965) 191. Lawson, L. J. Parenteral nutrition in surgery. Brit. J. Surg. 5Z (1965) 795. McCance, R. A. Experimental sodium chloride deficiency in man. Proc. Roy. Soc. Land. Ser. B. 119 (1936) 245. Peaston, M. J. T. Maintenance of metabolism during intensive patient care. Postgrad. Med. J. 43 (1967) 317. Peaston, M. J. T. A comparison of hydrolysed L- and synthesised DL- amino acids for complete parenteral nutrition. C/in. Pharm. Therap, 9, (1968) 61. Waterlow, J. C. Observation on the mechanism of adaptation to low protein intakes. Lancet, 2 (1968) Wootton, I. D. P. Microanalysis in Medical Biochemistry. J. and A. Churchill Ltd., 4th Ed., 1964.

Portsmouth, Hants. the true needs. Furthermore, the high cost of intravenous nutrition makes it that more important

Portsmouth, Hants. the true needs. Furthermore, the high cost of intravenous nutrition makes it that more important Postgraduate Medical Journal (July 1975) 51, 441-445. A method of determining daily nitrogen requirements H. A. LEE B.Sc., M.B., B.S., F.R.C.P. T. F. HARTLEY B.Sc., Ph.D. Department of Nephrology, University