Bolus intravenous infusion of amino acids or lipids does not stimulate gallbladder contraction in neonates on total parenteral nutrition

Bolus Intravenous Infusion of Amino Acids or Lipids Does Not Stimulate Gallbladder Contraction in Neonates on Total Parenteral Nutrition By

Simon

Phelps,

Evelyn Dykes, and Agostino London, England

Be&ground/Purpose; Stimulation of gallbladder contractIon in patients receiving total parenteral nutrition (TPN) may be beneficial in preventing cholestatic jaundice associated with TPN. Bolus intravenous administration of either amino acids or fat promotes gallbladder contraction in normal adult volunteers after a period of starvation. This phenomenon has not been investigated in patients receiving continuous TPN. The aim of this study was to test the hypothesis that bolus intravenous infusion of amino acids or fat produces gallbladder contraction in neonates receiving TPN.

were made minutes for

before 1 hour.

Pierro

starting

the

bolus

infusion

and

every

15

Res&s: The volume of the gallbladder before bolus intravenous infusion was not significantly different between experiments (median, 985; range, 603 to 1,802 mm3). These volumes are consistent with an enlarged and atonic gallbladder as previously reported in infants receiving parenteral nutrition. In all experiments there was no significant decrease in gallbladder volume after bolus infusion of either amino acids or fat.

Methods: Twenty-eight studies of gallbladder contraction were performed in 18 neonates receiving continuous TPN (median weight, 2.3 kg; range, 1.3 to 7.3; gestational age, 37 weeks; range, 28 to 40; age, 6.5 days; range, 2 to 180). Different types of experiments were performed: (1) bolus intravenous infusion of amino acid or fat for 60 minutes at twice the normal infusion rate; (2) bolus intravenous infusion of amino acid or fat for 15 minutes at four times the normal infusion rate. Gallbladder volume was measured by real-time ultrasonography by a single investigator. Measurements

Conc/usions: Contrary to their effects in adults, bolus infusions of amino acids or fat did not induce gallbladder contraction in neonates on TPN. This may have been because of lack of starvation in the neonates and/or the effect of continuous glucose infusion. J Pediatr Surg 33:817-820. Copyright 0 1998 by WI?. Sawders Company.

INCE ITS FIRST successful use in a neonate in 1968, total parenteral nutrition (TPN), has become essential for the growth and survival of infants who are unable to be fed enteral1y.l Cholestasis associated with TPN, first recognized in 197 1, has been reported in 7% to 84% of infants on TPN.l Although the hepatic abnormalities are largely reversible with restoration of enteral feeds, in some infants, these progress to cirrhosis and liver failure. The etiology of cholestasis associated with TPN remains unclear but is certainly multifactorial. Prematurity, sepsis, and lack of enteral feeds are recognized as predisposing factors. In neonates on TPN the gallbladder is signiiicantly dilated compared with enterally fed infants and does not contract.3 Several studies in human neonates have shown that cholecystokinin may be used both to treat and to prevent cholestasis associated with TPN.‘-7 In humans this hormone is a potent stimulant of gallbladder contraction, which suggests that this disorder may be prevented by promotion of gallbladder contractility. Experiments in fasting adult volunteers have demonstrated that (1) the administration of intravenous bolus

infusions of amino acids at rates equal to and greater than 125 mg/kg/h (normal rate in TPN is 65 mg/kg/h) stimulates dose-dependent gallbladder contraction,8.9 (2) intravenous infusions of lipids also promotes gallbladder emptying.lO The aim of this study was to test the hypothesis that intravenous bolus infusions of amino acids or lipids stimulate gallbladder contraction and emptying in the human neonate.

S

huma/

ofPediatric

%rgery,Vol33,

No 6 (June),

7998: pp 817.8XI

INDEX WORDS: Cholestasis, der, neonates, amino acids,

MATERIALS Twenty-eight ing intravenous

parenteral lipids.

AND

nutrition,

gallblad-

METHODS

studies were performed in 18 newborn infants receivnutrition. Infants were considered eligible for the study

From The ChildreFz k Hospitcd, Lewwham, and The Insti&te of Child Health and Great Ormond Street Hospitul for Children, London, England. Presented at the 29th Annual Meeting of the Canadian Associahon of Paediatric Surgeons, BanfJ Alberta, Canada, October 3-6, 1997. Address reprint requests to Agostino f’lerro, MD, FRCS, Reader und Consultant m Paediatric Surgery, The Institute of Child Health and Great Ormond Street Hosprtal for Children2 30 Guilford St, London WCIN IEH England. Copyright 0 I998 by WB. Saunders Campany 0022-3448/98/3306-0002.$03.00/0

817

818

PHELPS,

Table 1. Patient

DYKES,

AND

PIERRO

Demographics Experiment

A

A Fat

Amino Aads

Patients

6

B Amino Acids

3

6

B Fat

6

Studies GestatIonal age bvkj Weight (kg)

13 37.5 (35-40) 2.78 (I .98-3.48)

3 31 .o (30-33 5) 1.8 (1.3-2.36)

6 38 (32-40) 3.41 (2-7.3)

6 35.8 (27.5-40) 2.13 (1.89-3.98)

Conceptional

38.2 (35.4-40.7)

34.5 (31.4-36.1) -

40.9 (35.7-60.4)

39.1 (35.2-41.3)

NOTE.

aga bvk)

Data are expressed

as median

with

range

in parentheses.

tf they were less than 6 months old. hemodynamically stable, normoglycemtc. not receiving opiates, and had not received enteral feeding for at least 48 hours. At the time of the study. patients were receiving either 10% dextrose with added electrolytes, or standard TPN, which included carbohydrate, amino acids, fat. electrolytes, vitamins. and trace elements. Intravenous nutrients were administered continuously by precision infusion pumps (Neo.Mate IVAC 565; San Diego. CA). Gallbladder volume was measured after a bolus intravenous infusion of amino acids or fat. The same amino acid solution (Vaminolact, Pharmacia and Uplohn, Milton Keynes. UK) and lipid emulsion (Intralipid 20%, Pharmacia and Upjohn) were used for the bolus infusion in all patients studied. Four experiments were carried out. In experiment “A ammo acids” (six patients, 13 studies) the infants received a bolus mtravenous infusion of amino acids at twice the normal infusion rate (210 mg/kgih) over 1 hour. In experiment ‘*A fat” (three patients, three studies) the infants received a bolus intravenous infusion of fat at twice the normal infusion rate (250 mg/kg/h) over 1 hour. In experiment “B amino acids” (six patients, six studies) the infants received a rapid intravenous infusion of amino acids at four times the normal mfusion rate (420 mg/kg/h) over 15 minutes. In experiment “B fat” (six patients, six studies) the infants received a rapid intravenous infusion of fat at four times the normal infusion rate (500 mg/kg/h) over 15 minutes. Vital signs such as respuatoq rate. heart rate, and body core temperature were monitored every 10 minutes during and immediately after the bolus infnsion of amino acids and fat. Three patients underwent more than one experiment.

Measurement of Gallbladder Volume Gallbladder volume was measured by a single investigator (S.P.) using real-time ultrasound scan with a 5 MHz transducer (Hitachi, Japan, Model EUB-405). The maximum length (L). and two crosssectional diameters (Wl, W2) were each measured three times, and a mean value in milhmetres was calculated for each parameter. Gallbladder volume was calculated using the ellipsoid formulaii: Gallbladder

volume

(mm3)

Experiments

0

15

= n/6

X L X Wi

X W2.

A

30 45 time (min)

In both phases of the study, gallbladder volume was measured lust before the bolus and thereafter at 15 minute intervals for 1 hour. The smdy protocol was approved by the ethics committees in both participating hospitals and by informed written consent obtained from the parents of suitable neonates.

Statistical Analysis Analyzed variables are expressed as median and range. Comparisons between the groups were made with the Mann-Whitney U test. Comparisons of gallbladder volume within the groups were made using the Wilcoxon’s matched-pairs signed-rank test. Differences were considered significant at the P < .05 level. The data were analyzed using the SPSS-PC+ V 3.1 program (Microsoft Corporation; Chicago, IL).

RESULTS

The subjects in the four experiments were comparable with respect to indication for intravenous feeding, which included gut dysfunction caused by congenital intestinal abnormalities (seven patients), prematurity (six patients), and necrotising enterocolitis (five patients). There was no significant difference in weight, gestational age, and conceptional age between the four groups of patients (Table 1). The median gallbladder volume before bolus infusion was 897.8 mm3 (range, 603 to 1,485) in experiment A amino acids, 1,242.O mm3 (range, 1,194 to 1,430) in experiment A fat, 989.0 mm3 (range, 700 to 1,802) in experiment B amino acids, and 936.0 mm3 (range, 669 to 1,275) in experiment B fat. There was no significant difference among the four experiments in these baseline gallbladder volumes (Fig 1). This demonstrates that the gallbladder volume in newborn infants receiving TPN is Experiments

80

0

15

30 45 time (min)

B

80

Fig 1. Effect of bolus intravenous infusion of amino acids (@I and fat (0) on gallbladder volume. lTme 0 rapresents baseline immediately before bolus infusion. In experiments A the subjects received an infusion of amino acid or lipid for 1 hour from time 0 at twice their standard rates. In experiments B these nutrients wara given at four times their usual rates for 15 minutes from time 0. Data ara axmessed as median.

TPN

AND

GALLBLADDER

CONTRACTION

839

significantly larger than the volume measured in newborn infants receiving normal enteral feeding (250 mm3).3 There was no effect of bolus intravenous infusion in any experiment on recorded vital signs. Moreover, none of the patients studied showed any clinical sign of distress during and immediately after the bolus infusion. Gallbladder volume did not decrease significantly after the intravenous infusion of either amino acid or lipid given at twice normal TPN rate over 1 hour (experiments A, Fig 1). Similarly, gallbladder emptying was not stimulated by the rapid infusion (15 minutes) of these two nutrients at four times TPN rates (experiments B, Fig 1). DISCUSSION

Stimulation of gallbladder contraction in patients receiving TPN may be beneficial in preventing cholestatic jaundice associated with this form of nutrition. Prophylactic administration of cholecystokinin to infants on intravenous nutrition is thought to be helpful in reducing its severity before enteral nutrition can be started.’ Moreover. in fasting adults it has been shown that intravenous bolus infusion of amino acids or lipids may stimulate gallbladder emptying.s-lo However the effect of bolus intravenous infusion of these nutrients on gallbladder volume has not been investigated in infants. To our knowledge this is the first time that gallbladder contractility has been investigated in patients receiving bolus administration of nutrients during intravenous feeding. Until recently, no studies had been made of gallbladder contractility in infants either on enteral or parenteral nutrition. However, it has now been established that the neonatal gallbladder starts to contract within 15 minutes of an enteral bolus feed, attains a maximum contraction index of 49.5% by 30 minutes, and regains its baseline volume by 90 minutes.3 Furthermore, dynamic ultrasonography studies in newborn infants receiving TPN have shown that the gallbladder is four times larger than in enterally fed infants and does not contract. This study confirms these previous findings that the median resting gallbladder volume in parenterally fed infants is approximately 1,000 mm.3 Our study failed to demonstrate a contraction of the gallbladder after bolus intravenous infusion of either amino acids or fat. Our observations are surprisingly at variance with those from adult volunteer studies. Nealon et al8 showed that intravenous bolus administration of amino acids at a rate of 240 and 600 mg/kg/h for 1 hour

produced a significant reduction in gallbladder volume to 32% and 23% of fasting volume, respectively. Our chosen rates of bolus infusion were comparable. In our study, the infusion at four times the normal rate was given for only 15 minutes to avoid the risks of fluid overload and acid-base disturbances. The adult data* show that after 15 minutes bolus infusion the gallbladder volume is already reduced to 50% of its fasting volume. The reason for the discrepancy between our results and those in adult volunteers may be because of differences in study design. In the adult studies the subjects had been starved overnight before the bolus intravenous infusion and were not receiving any other intravenous fluids. In contrast, in our study, the infants continued to receive either 10% dextrose or standard TPN solution before the bolus infusion to avoid the risk of hypoglycaemia. It has been demonstrated in adults that elevating the blood glucose level to 15 mmol/L abolishes gallbladder contraction induced by an amino acid infusion of 250 mg/kgfh.lz Furthermore, in another experiment the same investigators showed that a blood glucose level of 8 mmolL attenuated gallbladder response to a cholecystokinin infusion.13 Although none of the infants in this study were hyperglycemic, the glucose in their maintenance fluids may have been sufficient to suppress the expected gallbladder contraction. The existing evidence for a positive effect of intravenous lipid infusions on gallbladder emptying in adults is less consistent than that for amino acids. In one adult study, infusion of lipid at 100 mg/kg/h caused a small (20% of fasting volume) gallbladder contraction after 15 minutes, which reached a maximal contraction of 36% by 35 minutes.‘O Infusion rates in our studies were 250 and 500 mg/kg/h and therefore should have produced a measurable gallbladder contraction. In agreement with our observations, De Boer et alI4 observed that the gallbladder volume remained static during a 90-minute infusion of lipids at approximately 280 mg/kg/h. From the evidence available, it seems unlikely that bolus lipid infusion will be capable of inducing gallbladder emptying in infants on TPN. The lack of contraction after bolus infusion of amino acids merits further investigation. It is possible that brief interruption of intravenous glucose administration before the bolus amino acids infusion may result in a significant gallbladder contraction.

REFERENCES 1 Wihnore DW. Dudrick SJI Ccowth and development of an infant receiving all nuhients exclusively by vein. JAMA203:860-864, 1968 2, Quigley EMM, Marsh MN, Shaffer .I, et al: Hepatobihary Complications of Total Parenteral Nutrition. Gastroenterology 104:286301,1993

3. Jawaheer G. Pierro A, LIoyd D. et al: Gallbladder contractihty in neonates’ Effects of parenteral and enteral feeding. Arch DIS Child 72:F200-F202, 1995 4. Schwartz JB, Merritt RJ, Rosenthal P, et al: Ceruletlde to treat neonatal cholestasis. Lancet May 28:1219-1220, 1988

PHELPS,

5. Rintala RJ. Lindahl H, Pohjavuori M: Total parenteral nutritionassociated cholestasis m surgical neonates may be reversed by mtravenous cholecystokinin: A preliminary report. .I Pediatr Surg 30:827-830, 1995 6. Teitelbaum DH, Han-Markey T, Schumacher RE: Treatment of parenteral nutrition-associated cholestasis with cholecystokininoctapepttde. .I Pediatr Surg 30:1082-1085, 1995 7. Teitelbaum DH, Han-Markey T, Drongowskt RA, et al: Use of cholecystokinin to prevent the development of parentera nutritioi~associated cholestasis. J Parenter Enter NuuVol21:100-103, 1997 8. Nealon NH, Upp JR, Alexander RW, et al: Intravenous amino acids stimulate human gallbladder emptying and hormone release. Am J Physiol259:Gl73-8, 1990 9. Zoh G, Ballinger A, Healy J, et al: Promotion of gallbladder emptying by intravenous ammo acids. Lancet 341:1240-1241,1993

DYKES,

AND

PIERRO

10. Kalfarentzos F, Vagenas C, Michail A, et al: Gallbladder contraction after administration of intravenous amino acids and triacylglycerols in humans. Nutrition 7:347-349, 1991 11. Dodds WJ, Groh WJ, Darweesh RMA, et al: Sonographic measurement of gallbladder volume. Am J Radio1 145: 1009-loll,1985 12. De Boer SY, Masclee AAM, Lam WF, et al: Effect of intravenous glucose on intravenous amino acid-induced gallbladder contraction and CCK secretion. Dig Dis Set 39:268-273, 1994 13. De Boer SY, Masclee AAM, Jebbink hyperglycaemia on gallbladder contraction in humans. Gut 34:1128-1132, 1993

MCW. et al: Effect of acute induced by cholecystokinin

14. De Boer SY. Masclee AAM. Jebbink MCW. et al: Effect intravenous fat on cholecystokinin secretion and gallbladder motility man J Parenter Enter Nutr 16:16-19, 1992

of in