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The comparative effects of abrupt vs. stepwise discontinuation of TPN in rats
Physiology&Behavior,Vol. 52, pp. 591-595, 1992
0031-9384/92 $5.00 + .00 Copyright © 1992 Pergamon Press Ltd.
Printed in the USA.
The Comparative Effects of Abrupt vs. Stepwise Discontinuation of TPN in Rats GYORGY
B O D O K Y , A N T O N I O C. C A M P O S , Z H O N G - J I N Y A N G , D A V I D C. H I T C H A N D M I C H A E L M. M E G U I D l
Surgical Metabolism & Nutrition Laboratory, Department of Surgery, University Hospital, S U N Y Health Science Center, Syracuse, N Y R e c e i v e d 13 J a n u a r y 1992 BODOKY, G., A. C. CAMPOS, Z.-J. YANG, D. C. HITCH AND M. M. MEGUID. The comparative effects of abrupt vs. stepwise discontinuation of TPN in rats. PHYSIOL BEHAV 52(3) 591-595, 1992.--The comparative effects of discontinuing total parenteral nutrition (TPN: caloric ratio of glucose:fat:amino acid = 50:30:20) abruptly or in a stepwise manner on spontaneous food intake were investigated in two studies. Study 1: In 16 rats, TPN was given for 4 days, then stopped abruptly in eight rats. In the other eight rats, TPN was tapered; they received TPN at 75%, 50%, and 25% of their mean daily energy requirements per day for 3 consecutive days, and then switched to normal saline. Total parenteral nutrition induced a significant 60% reduction in spontaneous food intake (SFI) in both groups during the first TPN day. After 4 days of TPN, an 80% decrease in SFI had occurred in both groups. Resumption of SFI was significantly sooner in the abruptly-stopping group than in the stepwise-stopping group. But, in the latter group, there was a significantly greater cumulative caloric intake during the entire study. Study 2: In 32 rats, TPN providing either 100%, 50%, or 25% of their mean daily caloric requirements was given to three groups each of eight rats, for 3 days, then abruptly changed to normal saline; control rats received normal saline throughout. The TPN-induced decrease in SFI was proportional to the caloric density of the solution infused. Three days of 100%, 50%, or 25% TPN infusion led to an approximate 85%, 60%, or 35% decrease in SFI, respectively. Spontaneous food intake recovery was independent of the caloric density of TPN. Taken together, data show that tapering TPN: i) does not result in a compensatory increase in SFI, ii) leads to a delay in attaining adequate oral energy intake independent of TPN, and iii) leads to a greater cumulative energy intake during the time to full SFI recovery. Parenteral nutrition
Food intake
Resumption of food intake
IN surgical practice total parenteral nutrition (TPN) is most often initiated to provide prompt intravenous nutritional support, not only for the malnourished patient (15,16), but also after an operation when a significant delay is anticipated in the resumption of adequate oral intake (9,17). During the postoperative recovery of a patient receiving TPN, oral intake is begun and encouraged. However, patients often neither resume eating as promptly as anticipated nor consume the expected a m o u n t of food. This p h e n o m e n o n has been observed with T P N in adult patients (11-13,26), in both neonates and infants (28), and in normal volunteers (6), and is thought to be due to a relative lack of interest in food induced by TPN. Furthermore, this phenomenon has been repeatedly observed in animals (18,31). To stimulate appetite and hasten resumption of adequate oral intake while ensuring an appropriate total energy intake during the period that the patient does not eat sufficiently, T P N is c o m m o n l y tapered, i.e., discontinued in a stepwise fashion. However, whether tapering T P N enhances the resumption of adequate oral intake has not been demonstrated. In the present study, using an established and a well-studied rat T P N model, different amounts of T P N were given. Total
Cessation of TPN
parenteral nutrition was then stopped either abruptly or in a stepwise manner to evaluate the assumption inherent in the clinical practice that tapering T P N enhances spontaneous food intake (SFI). METHOD
Animals and Surgical Procedures Young, male Fischer 344 rats (Charles River, Inc., Wilmington, MA) with a purchase weight of 260-290 g were housed individually in holding cages for acclimatization to the constant study surroundings of 12-h light/dark cycle (0600 to 1800), room temperature of 26 + 1 °C, and 45% relative humidity. The rats were allowed free access to water and coarsely ground Purina rat chow. Rats that appeared healthy and demonstrated normal weight gain and normal food intake were studied. Rats were anesthetized by intraperitoneal injection of 3% chloral hydrate (30 mg/100 g body weight) and the right internal jugular vein was cannulated as previously described (18). The cannula was exteriorized at the nape of the neck via a subcutaneous tunnel, and the catheter was protected by a weighted spring and swivel
Requests for reprints should be addressed to Michael M. Meguid, M.D., Ph.D., Department of Surgery, University Hospital, SUNY Health Science Center, 750 East Adams Street, Syracuse, NY 13210.
591
592 device (Instech Corp., Plymouth Meeting, PA) that was sutured to the skin at the neck exit site and afforded the rats easy access to rat chow and water, and allowed normal sleeping posture. Catheter patency was maintained by the constant 3 ml/h infusion of normal saline with a calibrated Imed 960 volumetric infusion pump (Imed Corp., San Diego, CA). After catheter insertion, the rats were placed into their individual metabolic cages (Nalgene Metabolic Cage, American Scientific Products, Baxter Health Care, Edison, NJ). Because of the presence of the catheter and its protective spring and swivel device, rats were weighed only before catheter placement and after the study when the catheter had been removed.
BODOKY ET AL. same physiological fuel value as oral chow. The sum of the oral and intravenous energy constituted total energy intake. When the total energy intake exceeded the 100% level, it was expressed as positive energy intake. A negative energy intake was a deficit relative to the 100% level.
Statistical Analysis Intragroup changes were determined using ANOVA test, with a post hoc Student's t-test used to compare between groups. Data are expressed as mean +_ SE. RESULTS
Experimental Design The studies were approved by the Committee for the Humane Use of Animals, University Hospital, SUNY Health Sciences Center at Syracuse. Two serial studies were done infusing normal saline and then TPN.
Study l Sixteen rats received normal saline for an initial 10 days after catheter placement. After SFI had stabilized, TPN- 100 (providing 100% of the rat's mean daily energy requirements) was infused continuously at 3 ml/h for days 11-14. On day 15, the rats were randomized into two groups, each of eight rats, depending on how TPN was stopped: abruptly-stopping group, in which TPN100 was abruptly stopped and replaced by normal saline, and stepwise-stopping group, in which rats received TPN-75 on day 15, TPN-50 on day 16, TPN-25 on day 17, and on day 18 normal saline for one day. Each TPN solution provided either 75%, 50%, or 25% of the rat's mean daily energy requirements. All infusions were given at 3 ml/h. Daily SFI was measured, and daily energy intakes were determined.
Study 1 The initial and final body weights of rats in the abruptlystopping group and the stepwise-stopping group were 280 + 4.7 g and 286 + 6.5 g, and 272 + 2.9 g and 278 ___2.4 g, respectively. There were no significant differences in initial and final body weights between the two groups. Four days of TPN decreased SFI significantly in all rats (Fig. 1). The maximum effect of TPN on decreasing SFI in both groups occurred in the first 24 h, when about 60% of SFI suppression occurred. During the next 3 TPN days, further but smaller decreases occurred, resulting in an 80% reduction in SFI. Spontaneous food intake was not completely inhibited by TPN in either group of rats. Consequently, total energy intake was increased in each rat. On day 14, rats were randomized as described in the Methods section. When, in the abruptly-stopping group, TPN was stopped and replaced by normal saline, SFI increased rapidly and by larger increments than in the stepwise-stopping
24
Study 2
22
Thirty-two study rats with internal jugular cannulas received normal saline during the recovery period following cannulation and were randomized into three TPN groups and one control group, each of eight rats. Total parenteral nutrition provided either 100% (TPN-100), 50% (TPN-50), or 25% (TPN-25) of the rat's mean daily energy requirements and was infused at 3 m l / h for days 11-13. After day 13, each TPN solution was abruptly stopped and replaced by normal saline at 3 ml/h and continued until day 18. The control group received normal saline at 3 ml/h from day 1 to 18. Spontaneous food intake was measured daily in each group.
20
Rat Chow and Total Parenteral Nutrition (TPN) Formulab Chow #5008 was used (Ralston Purina, St. Louis, MO). One g of chow provides 0.97 kJ (4.2 kcal) of gross energy. Its physiological fuel value is 0.81 kJ/g (3.5 kcal/g) (2). Daily SFI in male adult Fischer 344 rats varies between 12 to 15 g; mean daily energy requirement is 11 kJ (48 kcal). The sterile pyrogen-free TPN solution contained 10.7% w/v dextrose, 2.2% w/v lipids as IntralipidR, and 3.8% w/v balanced crystalline amino acids as NovamineR (Kabi Vitrum, Inc., Alameda, CA). It provided 12.2 kJ (53 kcal/day at 212 kcal/kg rat body weight), the 100% energy equivalent of mean daily oral intake. Solutions of TPN providing a varying percent of the rat's daily energy requirements were used. The energy ratio of glucose to fat to amino acid was 50:30:20. Total parenteral nutrition100 provides 12.2 kJ (53 kcal) of gross energy. Considering the metabolisable energy in TPN is 90%, then TPN provides the
i
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FIG. 1. Spontaneous food intake (SFI) in both groups was significantly depressed, not totally abolished, when TPN was administered. Stopping TPN abruptly led to a rapid SFI increase and larger increments than in the stepwise-stoppinggroup; SFI reached pre-TPN level within 4 days. In the stepwise-stoppinggroup, TPN-100 was replaced by TPN-75, TPN50, and TPN-25 on days 15, 16, and 17, respectively.Spontaneous food intake increased but at a slower rate, each daily incremental SFI rise being significantlylower than its corresponding level with the abruptlystopping group. During the last SFI recovery day, when TPN-25 was replaced by normal saline, a more rapid increase in SFI occurred. The final mean SFI level was still significantlylower than pre-TPN level.
A B R U P T VS. STEPWISE D I S C O N T I N U A T I O N O F T P N
group, as shown in Fig. 1, and reached pre-TPN level within 4 days. In contrast, when in the stepwise-stopping group TPN100 was replaced by TPN-75, TPN-50, and TPN-25 on days 15, 16, and 17, respectively, SFI increased, also as s h o w n in Fig. 1, but at a slower rate, each level being significantly lower than its corresponding level with the abruptly-stopping group. During the last SFI recovery day, w h e n TPN-25 was replaced by normal saline, a m o r e rapid increase in SFI occurred, but the final m e a n SFI level was still significantly lower than pre-TPN level, reaching only 80% o f this level. Since T P N did not completely abolish food intake, a cumulative positive energy intake occurred in both the abruptlyand the stepwise-stopping groups. As shown in Table 1, during the 4 days o f TPN-100 total energy intake in the abruptly- and in the stepwise-stopping groups was 60.1 _+ 1.6 kJ (261.1 + 7.1 kcal) and 60.0 + 1.2 kJ (260.7 + 5.0 kcal), respectively. Discontinuing T P N either abruptly or in a stepwise m a n n e r led to a negative energy intake because rats did not resume eating promptly. Thus, cumulative total energy intake during the 4 days after TPN-100 was stopped abruptly was 33.0 _+ 2.5 kJ (143.3 + 10.8 kcal). By comparison, it was 36.3 + 2.6 kJ (157.7 _+ 11.5 kcal) w h e n T P N was tapered stepwise. The difference between these two cumulative total energy intakes was not significant. The difference between the cumulative 8-day total energy intake o f the two groups, 93.0 _+ 4.1 kJ vs. 96.2 + 2.6 kJ (404.4 _+ 17.9 vs. 418.4 _+ 11.5 kcal), also was not significant.
Study 2 The initial and final body weights o f rats in the TPN-100 group were 285.0 + 2.5 g a n d 290.0 + 3.0 g; TPN-50 group were 283.8 + 1.8 g and 302.5 + 8.8 g; and TPN-25 group were 275.6 _+ 1.5 g and 285.6 _+ 5.2 g. In the control group, the initial and final body weights were 279.0 _+ 4.3 g and 30.40 _+ 2.1 g. There were no significant differences between initial and final body weights in the four groups. As shown in Fig. 2, control rats on normal saline continued to eat at a relatively stable level (range 14.5 to 15.5 g) during
593
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8
10
12
14
16
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Days
FIG. 2. Total parenteral nutrition decreased SFI proportional to the amount infused. After TPN was stopped, the duration in the recovery of SFI was the same, although only with TPN-100 was energy intake maintained.
the study, which did not differ significantly from day to day. During the infusion of TPN-100, TPN-50, or TPN-25, SFI decreased in each group. The greatest absolute decrease in each group also occurred during the first T P N day by 59%, 31%, and 31%, respectively. The nadir occurred usually on the third day, w h e n the reduction in SFI was by 92% and 59% in TPN-100 and TPN-50 groups, respectively. The rate o f fall and the degree o f suppression in SFI were proportional to the a m o u n t o f infused energy. During TPN, rats in all groups c o n t i n u e d to c o n s u m e s o m e chow, thereby increasing their total energy intake above the a m o u n t infused in the TPN. After day 13, the infusion o f
TABLE1 MEAN TOTAL ENERGY INTAKE (TEl; ~) DURING AND A~ER TPN Study TPN-100 Day
11
12
SFI Recovery 13
14
15
16
17
18
Abruptly-stoppinggroup (n = 8) Daily energy intake kcal
TPN-100 + PO
Normal Saline + PO
16.4 ± 0.4* 15.0 ± 0.1 14.6 ± 0.5 14.0 + 0.6 71.4 ± 1.8" 65.4 ± 0.5 63,3 ± 2.3 61.0 ± 2.5 Cumulative TEl = 60.1 ± 1.6 kJ (261.1 ± 7.1 kcal)
4.7 + 1.0 7.6 -± 0.6 9.4 + 0.6 11.3 ± 0.3 20.4 ± 4.3 33.1 ± 2.8 40.8 ± 2.3 49.0 ± 1.4 Cumulative TEl - 33.0 ± 2.5 kJ (143.3 - 10.8 kcal)
Cumulative 8-day TEl = 93.0 ± 4.1 kJ (404.4 ± 17.9 (kcal) Stepwise-stoppinggroup (n = 8) TPN-100 + PO Daily energy intake kcal
16.9 + 0.3 15.0 + 0.3 13.8 _+0.3 14.2 + 0.3 73.6 ± 1.1 65.4 ± 1.1 60.0 ± 1.4 61.7 + 1.4 Cumulative TEI= 60.0 ± 1.2 kJ (260.7 ± 5.0 kcal)
TPN-75 + PO
TPN-50 + PO
TNP-25 + PO
NS + PO
11.1 -+ 0.5 9.2 ± 0.8 7.7 ± 0.7 8.2 _+0.5 48.1 ± 2.3 40.2 + 3.7 33.6 ± 3.2 35.8 ± 2.3 Cumulative TEl = 36.3 ± 2.6 kJ (157.7 ± 11.5 kcal)
Cumulative 8-day TEI = 96.2 + 3.8 kJ (418.4 + 16.4 kcal) PO = per os. * During days 1 t-14, TPN-100 contributed 12.2 El/day (53 kcal/day), representing the 100% energy equivalent of daily mean oral intake.
594
BODOKY ET AL.
TPN was abruptly stopped and switched to normal saline in all rats. The resumption of SFI was equal in the three groups and resulted in a gradual increase in SFI, reaching pre-TPN level in each group by day 17. Only in the TPN-25 group did SF! rise slightly above the pre-TPN infusion amount on day 17. The cumulative total daily energy intakes during the infusion of the three different TPN levels and during their subsequent respective normal saline SFI recovery periods show that when TPN-100 was given for 3 days, the cumulative total energy intake was 47.3 _+ 0.8 kJ (205.7 + 3.5 kcal). With TPN-50 and TPN25 it was 38.6 _+ 0.7 kJ (167.7 + 7.3 kcal) and 33.2 _+ 1.0 kJ (144.4 _+ 4.2 kcal). Replacing the TPN solution with normal saline led to a gradual rise in the amount eaten per day, resulting in cumulative 4-day total energy intakes of 35.9 + 2.3 kJ (156.1 + 10.1 kcal), 30.8 + 1.7 kJ (134.1 _+ 7.3 kcal), and 42.9 + 2.2 kJ (186.4 + 9.4 kcal), respectively, in the three groups. The cumulative total energy intake for the 7 days for the three groups was 83.2 _+ 2.0 kJ (361.8 + 8.8), 69.4 _+ 4.8 kJ (301.8 _+ 20.7 kcal), and 76.1 -+ 2.8 kJ (330.8 -+ 12.3 kcal) per day, respectively. DISCUSSION In our study, the continuous infusion of TPN for 3 or 4 days, whether providing 100%, 50%, or 25% of the rat's daily mean oral energy intake, depressed SH in a time- and dose-related manner, as previously reported by us (7,22,33). Similar results were also reported by us even when TPN-100 or TPN-25 was continuously infused for 9 days (4) or when TPN- 100 was infused over 12 h for 9 days (32). These observations are also similar to the phenomenon observed with TPN in adult patients ( 11-13,26) and infants (28). To determine whether tapering TPN enhances SFI recovery, two studies were done. In the first study, the concept of tapering TPN, as is commonly done in clinical practice, was tested to determine if this influenced the SH resumption and whether tapering TPN resulted in the maintenance of an adequate total energy intake during the period when the rat did not eat sufficient amounts to sustain itself, independent of TPN. Compared to the control group, whose TPN was stopped abruptly, tapering TPN resulted in a slower SFI recovery because the TPN continued to inhibit SFI to some degree, so that 4 days later SFI was only 80% of control. Thus, tapering TPN does not result in a compensatory increase in appetite and leads to a delay in attaining an adequate energy intake, independent of TPN. But, cumulative energy balance was greater. The infusion of TPN, even at a lower concentration, continues to provide energy, thereby maintaining an adequate energy intake. In the second study, the question examined was whether the energy density of the TPN solution had an influence on SFI recovery. Our data show that when TPN was stopped abruptly, a resumption of SFI occurred independent of the energy density of the antecedent TPN infusion and to an equal degree in all three groups without delay, increased rapidly on a daily basis, and reached pre-TPN oral energy intake levels within 4 days. Thus, the speed of SFI recovery is independent of the energy density of the previously infused TPN solution. Furthermore, the higher the energy density of the TPN, the greater the overall energy intake during the time until full SFI recovery occurs. Taken together our data suggest that tapering TPN: a. does not stimulate an increase in SFI, b. leads to a delay in attaining adequate energy intake independent of TPN, and c. leads to a greater cumulative energy intake during the time to full SFI recovery.
Although findings from rat studies may not exactly apply to humans, these data, taken together with our data in patients on starting TPN (17), do serve as a guide to two potential clinical strategies until data from man becomes available: 1. Ifa patient is well nourished, has a functioning gastrointestinal tract, and rapid resumption of oral intake is desired and assured, then stopping TPN abruptly is indicated. 2. If, however, a patient is malnourished and the function of the gastrointestinal tract is not assured, then gradually tapering TPN in a stepwise fashion would ensure the optimal maintenance of energy intake pending the establishment of adequate oral intake. The avoidance of rebound hypocalcemia is another reason frequently cited as to why TPN should be tapered in clinical practice. However, it has been reported in postoperative patients that serum glucose and insulin levels had returned to normal baseline within 2 h of acute discontinuation of TPN without any symptoms or signs of hypoglycemia (29). Thus, prevention of hypoglycemia is no longer considered a reason to taper TPN. Furthermore, in many institutions using the mixed fuel 3-in-1 TPN admixture (glucose and fat and crystalline amino acids), the fear of rebound hypoglycemia is now only of historic interest (3,5,10,14,20) because rebound hypoglycemia does not occur when TPN is stopped abruptly, primarily because the fat emulsion stimulates glucagon and its hepatic gluconeogenic effects counteract that of hyperinsulinemia, thereby preventing hypoglycemia. A similar decrease in SFI has also been observed when rats are fed enterally via a stomach tube (8,21,24). When, however, the gastrointestinal tract is used, a compensatory energy reduction occurs so that the total energy intake more precisely reflects the usual daily energy intake. In contrast, when nutrients are infused parenterally, total daily energy intake increases because of a failure to adequately compensate for the nutrient intake by a corresponding reduction in SFI (1,18,19,30). These data strongly suggest that gastrointestinal signals also play an important role in initiating satiety due to these nutrients. The regulation of SFI involves feedback signals reflecting the status of short-term energy balance, as recently reviewed (27). In this study, 3 or 4 days of TPN providing 100% equivalent of rat's daily energy requirement did not completely abolish oral food intake. The extra energy is stored as glycogen and triglyceride in the liver, and as triglycerides in fat cells. It is postulated that the increase in energy storage is sensed by feeding regulatory centers primarily in the liver (25) and brain (23). When TPN is stopped abruptly, rats start eating by initially consuming less because of the positive energy balance. When TPN is stopped via tapering technique, the full resumption of oral intake is delayed because the drive to eat, i.e., appetite, is continuously depressed by the further nutrient infusions. At present it remains unclear whether the rat regulates shortterm energy balance, i.e., moment-to-moment food intake, from the blood level of some unknown factor (nutrients or hormones), or whether it is regulated by the cumulative energy balance as fat stores. It is also unclear as to whether man has an effective appestat that controls SFI in the manner similar to rats. Until these factors are more clearly elucidated, the extent to which postoperative TPN should be titrated in order to achieve maximal oral intake, once TPN tapering is started, remains clouded. However, this work clearly shows two features to be relevant to the human postoperative situation: 1. infusion of TPN, even at one-quarter of the daily energy needs, does depress SFI, and
A B R U P T VS. STEPWISE D I S C O N T I N U A T I O N O F T P N
2. even though T P N administration providing 100% of energy needs leads to virtual cessation of oral intake, sudden withdrawal of T P N is followed by eventual resumption of full oral intake. The delay in complete SFI recovery after stopping T P N abruptly is similar whether the T P N solution provides 25%, 50%, or 100% of the energy needs. But, only the stepwise tapering of T P N
595
ensures the maintenance of adequate energy balance until oral intake levels are once more considered adequate. ACKNOWLEDGEMENT We thank Mrs. Darlene Thompson for editorial assistance and William G. Hammond, M.D., for continued counsel and advice. Work presented in this paper is supported in part by the Hendricks Fund for Medical Research, account #930258, Syracuse, NY.
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Printed in the USA.
The Comparative Effects of Abrupt vs. Stepwise Discontinuation of TPN in Rats GYORGY
B O D O K Y , A N T O N I O C. C A M P O S , Z H O N G - J I N Y A N G , D A V I D C. H I T C H A N D M I C H A E L M. M E G U I D l
Surgical Metabolism & Nutrition Laboratory, Department of Surgery, University Hospital, S U N Y Health Science Center, Syracuse, N Y R e c e i v e d 13 J a n u a r y 1992 BODOKY, G., A. C. CAMPOS, Z.-J. YANG, D. C. HITCH AND M. M. MEGUID. The comparative effects of abrupt vs. stepwise discontinuation of TPN in rats. PHYSIOL BEHAV 52(3) 591-595, 1992.--The comparative effects of discontinuing total parenteral nutrition (TPN: caloric ratio of glucose:fat:amino acid = 50:30:20) abruptly or in a stepwise manner on spontaneous food intake were investigated in two studies. Study 1: In 16 rats, TPN was given for 4 days, then stopped abruptly in eight rats. In the other eight rats, TPN was tapered; they received TPN at 75%, 50%, and 25% of their mean daily energy requirements per day for 3 consecutive days, and then switched to normal saline. Total parenteral nutrition induced a significant 60% reduction in spontaneous food intake (SFI) in both groups during the first TPN day. After 4 days of TPN, an 80% decrease in SFI had occurred in both groups. Resumption of SFI was significantly sooner in the abruptly-stopping group than in the stepwise-stopping group. But, in the latter group, there was a significantly greater cumulative caloric intake during the entire study. Study 2: In 32 rats, TPN providing either 100%, 50%, or 25% of their mean daily caloric requirements was given to three groups each of eight rats, for 3 days, then abruptly changed to normal saline; control rats received normal saline throughout. The TPN-induced decrease in SFI was proportional to the caloric density of the solution infused. Three days of 100%, 50%, or 25% TPN infusion led to an approximate 85%, 60%, or 35% decrease in SFI, respectively. Spontaneous food intake recovery was independent of the caloric density of TPN. Taken together, data show that tapering TPN: i) does not result in a compensatory increase in SFI, ii) leads to a delay in attaining adequate oral energy intake independent of TPN, and iii) leads to a greater cumulative energy intake during the time to full SFI recovery. Parenteral nutrition
Food intake
Resumption of food intake
IN surgical practice total parenteral nutrition (TPN) is most often initiated to provide prompt intravenous nutritional support, not only for the malnourished patient (15,16), but also after an operation when a significant delay is anticipated in the resumption of adequate oral intake (9,17). During the postoperative recovery of a patient receiving TPN, oral intake is begun and encouraged. However, patients often neither resume eating as promptly as anticipated nor consume the expected a m o u n t of food. This p h e n o m e n o n has been observed with T P N in adult patients (11-13,26), in both neonates and infants (28), and in normal volunteers (6), and is thought to be due to a relative lack of interest in food induced by TPN. Furthermore, this phenomenon has been repeatedly observed in animals (18,31). To stimulate appetite and hasten resumption of adequate oral intake while ensuring an appropriate total energy intake during the period that the patient does not eat sufficiently, T P N is c o m m o n l y tapered, i.e., discontinued in a stepwise fashion. However, whether tapering T P N enhances the resumption of adequate oral intake has not been demonstrated. In the present study, using an established and a well-studied rat T P N model, different amounts of T P N were given. Total
Cessation of TPN
parenteral nutrition was then stopped either abruptly or in a stepwise manner to evaluate the assumption inherent in the clinical practice that tapering T P N enhances spontaneous food intake (SFI). METHOD
Animals and Surgical Procedures Young, male Fischer 344 rats (Charles River, Inc., Wilmington, MA) with a purchase weight of 260-290 g were housed individually in holding cages for acclimatization to the constant study surroundings of 12-h light/dark cycle (0600 to 1800), room temperature of 26 + 1 °C, and 45% relative humidity. The rats were allowed free access to water and coarsely ground Purina rat chow. Rats that appeared healthy and demonstrated normal weight gain and normal food intake were studied. Rats were anesthetized by intraperitoneal injection of 3% chloral hydrate (30 mg/100 g body weight) and the right internal jugular vein was cannulated as previously described (18). The cannula was exteriorized at the nape of the neck via a subcutaneous tunnel, and the catheter was protected by a weighted spring and swivel
Requests for reprints should be addressed to Michael M. Meguid, M.D., Ph.D., Department of Surgery, University Hospital, SUNY Health Science Center, 750 East Adams Street, Syracuse, NY 13210.
591
592 device (Instech Corp., Plymouth Meeting, PA) that was sutured to the skin at the neck exit site and afforded the rats easy access to rat chow and water, and allowed normal sleeping posture. Catheter patency was maintained by the constant 3 ml/h infusion of normal saline with a calibrated Imed 960 volumetric infusion pump (Imed Corp., San Diego, CA). After catheter insertion, the rats were placed into their individual metabolic cages (Nalgene Metabolic Cage, American Scientific Products, Baxter Health Care, Edison, NJ). Because of the presence of the catheter and its protective spring and swivel device, rats were weighed only before catheter placement and after the study when the catheter had been removed.
BODOKY ET AL. same physiological fuel value as oral chow. The sum of the oral and intravenous energy constituted total energy intake. When the total energy intake exceeded the 100% level, it was expressed as positive energy intake. A negative energy intake was a deficit relative to the 100% level.
Statistical Analysis Intragroup changes were determined using ANOVA test, with a post hoc Student's t-test used to compare between groups. Data are expressed as mean +_ SE. RESULTS
Experimental Design The studies were approved by the Committee for the Humane Use of Animals, University Hospital, SUNY Health Sciences Center at Syracuse. Two serial studies were done infusing normal saline and then TPN.
Study l Sixteen rats received normal saline for an initial 10 days after catheter placement. After SFI had stabilized, TPN- 100 (providing 100% of the rat's mean daily energy requirements) was infused continuously at 3 ml/h for days 11-14. On day 15, the rats were randomized into two groups, each of eight rats, depending on how TPN was stopped: abruptly-stopping group, in which TPN100 was abruptly stopped and replaced by normal saline, and stepwise-stopping group, in which rats received TPN-75 on day 15, TPN-50 on day 16, TPN-25 on day 17, and on day 18 normal saline for one day. Each TPN solution provided either 75%, 50%, or 25% of the rat's mean daily energy requirements. All infusions were given at 3 ml/h. Daily SFI was measured, and daily energy intakes were determined.
Study 1 The initial and final body weights of rats in the abruptlystopping group and the stepwise-stopping group were 280 + 4.7 g and 286 + 6.5 g, and 272 + 2.9 g and 278 ___2.4 g, respectively. There were no significant differences in initial and final body weights between the two groups. Four days of TPN decreased SFI significantly in all rats (Fig. 1). The maximum effect of TPN on decreasing SFI in both groups occurred in the first 24 h, when about 60% of SFI suppression occurred. During the next 3 TPN days, further but smaller decreases occurred, resulting in an 80% reduction in SFI. Spontaneous food intake was not completely inhibited by TPN in either group of rats. Consequently, total energy intake was increased in each rat. On day 14, rats were randomized as described in the Methods section. When, in the abruptly-stopping group, TPN was stopped and replaced by normal saline, SFI increased rapidly and by larger increments than in the stepwise-stopping
24
Study 2
22
Thirty-two study rats with internal jugular cannulas received normal saline during the recovery period following cannulation and were randomized into three TPN groups and one control group, each of eight rats. Total parenteral nutrition provided either 100% (TPN-100), 50% (TPN-50), or 25% (TPN-25) of the rat's mean daily energy requirements and was infused at 3 m l / h for days 11-13. After day 13, each TPN solution was abruptly stopped and replaced by normal saline at 3 ml/h and continued until day 18. The control group received normal saline at 3 ml/h from day 1 to 18. Spontaneous food intake was measured daily in each group.
20
Rat Chow and Total Parenteral Nutrition (TPN) Formulab Chow #5008 was used (Ralston Purina, St. Louis, MO). One g of chow provides 0.97 kJ (4.2 kcal) of gross energy. Its physiological fuel value is 0.81 kJ/g (3.5 kcal/g) (2). Daily SFI in male adult Fischer 344 rats varies between 12 to 15 g; mean daily energy requirement is 11 kJ (48 kcal). The sterile pyrogen-free TPN solution contained 10.7% w/v dextrose, 2.2% w/v lipids as IntralipidR, and 3.8% w/v balanced crystalline amino acids as NovamineR (Kabi Vitrum, Inc., Alameda, CA). It provided 12.2 kJ (53 kcal/day at 212 kcal/kg rat body weight), the 100% energy equivalent of mean daily oral intake. Solutions of TPN providing a varying percent of the rat's daily energy requirements were used. The energy ratio of glucose to fat to amino acid was 50:30:20. Total parenteral nutrition100 provides 12.2 kJ (53 kcal) of gross energy. Considering the metabolisable energy in TPN is 90%, then TPN provides the
i
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DAYS
FIG. 1. Spontaneous food intake (SFI) in both groups was significantly depressed, not totally abolished, when TPN was administered. Stopping TPN abruptly led to a rapid SFI increase and larger increments than in the stepwise-stoppinggroup; SFI reached pre-TPN level within 4 days. In the stepwise-stoppinggroup, TPN-100 was replaced by TPN-75, TPN50, and TPN-25 on days 15, 16, and 17, respectively.Spontaneous food intake increased but at a slower rate, each daily incremental SFI rise being significantlylower than its corresponding level with the abruptlystopping group. During the last SFI recovery day, when TPN-25 was replaced by normal saline, a more rapid increase in SFI occurred. The final mean SFI level was still significantlylower than pre-TPN level.
A B R U P T VS. STEPWISE D I S C O N T I N U A T I O N O F T P N
group, as shown in Fig. 1, and reached pre-TPN level within 4 days. In contrast, when in the stepwise-stopping group TPN100 was replaced by TPN-75, TPN-50, and TPN-25 on days 15, 16, and 17, respectively, SFI increased, also as s h o w n in Fig. 1, but at a slower rate, each level being significantly lower than its corresponding level with the abruptly-stopping group. During the last SFI recovery day, w h e n TPN-25 was replaced by normal saline, a m o r e rapid increase in SFI occurred, but the final m e a n SFI level was still significantly lower than pre-TPN level, reaching only 80% o f this level. Since T P N did not completely abolish food intake, a cumulative positive energy intake occurred in both the abruptlyand the stepwise-stopping groups. As shown in Table 1, during the 4 days o f TPN-100 total energy intake in the abruptly- and in the stepwise-stopping groups was 60.1 _+ 1.6 kJ (261.1 + 7.1 kcal) and 60.0 + 1.2 kJ (260.7 + 5.0 kcal), respectively. Discontinuing T P N either abruptly or in a stepwise m a n n e r led to a negative energy intake because rats did not resume eating promptly. Thus, cumulative total energy intake during the 4 days after TPN-100 was stopped abruptly was 33.0 _+ 2.5 kJ (143.3 + 10.8 kcal). By comparison, it was 36.3 + 2.6 kJ (157.7 _+ 11.5 kcal) w h e n T P N was tapered stepwise. The difference between these two cumulative total energy intakes was not significant. The difference between the cumulative 8-day total energy intake o f the two groups, 93.0 _+ 4.1 kJ vs. 96.2 + 2.6 kJ (404.4 _+ 17.9 vs. 418.4 _+ 11.5 kcal), also was not significant.
Study 2 The initial and final body weights o f rats in the TPN-100 group were 285.0 + 2.5 g a n d 290.0 + 3.0 g; TPN-50 group were 283.8 + 1.8 g and 302.5 + 8.8 g; and TPN-25 group were 275.6 _+ 1.5 g and 285.6 _+ 5.2 g. In the control group, the initial and final body weights were 279.0 _+ 4.3 g and 30.40 _+ 2.1 g. There were no significant differences between initial and final body weights in the four groups. As shown in Fig. 2, control rats on normal saline continued to eat at a relatively stable level (range 14.5 to 15.5 g) during
593
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8
10
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Days
FIG. 2. Total parenteral nutrition decreased SFI proportional to the amount infused. After TPN was stopped, the duration in the recovery of SFI was the same, although only with TPN-100 was energy intake maintained.
the study, which did not differ significantly from day to day. During the infusion of TPN-100, TPN-50, or TPN-25, SFI decreased in each group. The greatest absolute decrease in each group also occurred during the first T P N day by 59%, 31%, and 31%, respectively. The nadir occurred usually on the third day, w h e n the reduction in SFI was by 92% and 59% in TPN-100 and TPN-50 groups, respectively. The rate o f fall and the degree o f suppression in SFI were proportional to the a m o u n t o f infused energy. During TPN, rats in all groups c o n t i n u e d to c o n s u m e s o m e chow, thereby increasing their total energy intake above the a m o u n t infused in the TPN. After day 13, the infusion o f
TABLE1 MEAN TOTAL ENERGY INTAKE (TEl; ~) DURING AND A~ER TPN Study TPN-100 Day
11
12
SFI Recovery 13
14
15
16
17
18
Abruptly-stoppinggroup (n = 8) Daily energy intake kcal
TPN-100 + PO
Normal Saline + PO
16.4 ± 0.4* 15.0 ± 0.1 14.6 ± 0.5 14.0 + 0.6 71.4 ± 1.8" 65.4 ± 0.5 63,3 ± 2.3 61.0 ± 2.5 Cumulative TEl = 60.1 ± 1.6 kJ (261.1 ± 7.1 kcal)
4.7 + 1.0 7.6 -± 0.6 9.4 + 0.6 11.3 ± 0.3 20.4 ± 4.3 33.1 ± 2.8 40.8 ± 2.3 49.0 ± 1.4 Cumulative TEl - 33.0 ± 2.5 kJ (143.3 - 10.8 kcal)
Cumulative 8-day TEl = 93.0 ± 4.1 kJ (404.4 ± 17.9 (kcal) Stepwise-stoppinggroup (n = 8) TPN-100 + PO Daily energy intake kcal
16.9 + 0.3 15.0 + 0.3 13.8 _+0.3 14.2 + 0.3 73.6 ± 1.1 65.4 ± 1.1 60.0 ± 1.4 61.7 + 1.4 Cumulative TEI= 60.0 ± 1.2 kJ (260.7 ± 5.0 kcal)
TPN-75 + PO
TPN-50 + PO
TNP-25 + PO
NS + PO
11.1 -+ 0.5 9.2 ± 0.8 7.7 ± 0.7 8.2 _+0.5 48.1 ± 2.3 40.2 + 3.7 33.6 ± 3.2 35.8 ± 2.3 Cumulative TEl = 36.3 ± 2.6 kJ (157.7 ± 11.5 kcal)
Cumulative 8-day TEI = 96.2 + 3.8 kJ (418.4 + 16.4 kcal) PO = per os. * During days 1 t-14, TPN-100 contributed 12.2 El/day (53 kcal/day), representing the 100% energy equivalent of daily mean oral intake.
594
BODOKY ET AL.
TPN was abruptly stopped and switched to normal saline in all rats. The resumption of SFI was equal in the three groups and resulted in a gradual increase in SFI, reaching pre-TPN level in each group by day 17. Only in the TPN-25 group did SF! rise slightly above the pre-TPN infusion amount on day 17. The cumulative total daily energy intakes during the infusion of the three different TPN levels and during their subsequent respective normal saline SFI recovery periods show that when TPN-100 was given for 3 days, the cumulative total energy intake was 47.3 _+ 0.8 kJ (205.7 + 3.5 kcal). With TPN-50 and TPN25 it was 38.6 _+ 0.7 kJ (167.7 + 7.3 kcal) and 33.2 _+ 1.0 kJ (144.4 _+ 4.2 kcal). Replacing the TPN solution with normal saline led to a gradual rise in the amount eaten per day, resulting in cumulative 4-day total energy intakes of 35.9 + 2.3 kJ (156.1 + 10.1 kcal), 30.8 + 1.7 kJ (134.1 _+ 7.3 kcal), and 42.9 + 2.2 kJ (186.4 + 9.4 kcal), respectively, in the three groups. The cumulative total energy intake for the 7 days for the three groups was 83.2 _+ 2.0 kJ (361.8 + 8.8), 69.4 _+ 4.8 kJ (301.8 _+ 20.7 kcal), and 76.1 -+ 2.8 kJ (330.8 -+ 12.3 kcal) per day, respectively. DISCUSSION In our study, the continuous infusion of TPN for 3 or 4 days, whether providing 100%, 50%, or 25% of the rat's daily mean oral energy intake, depressed SH in a time- and dose-related manner, as previously reported by us (7,22,33). Similar results were also reported by us even when TPN-100 or TPN-25 was continuously infused for 9 days (4) or when TPN- 100 was infused over 12 h for 9 days (32). These observations are also similar to the phenomenon observed with TPN in adult patients ( 11-13,26) and infants (28). To determine whether tapering TPN enhances SFI recovery, two studies were done. In the first study, the concept of tapering TPN, as is commonly done in clinical practice, was tested to determine if this influenced the SH resumption and whether tapering TPN resulted in the maintenance of an adequate total energy intake during the period when the rat did not eat sufficient amounts to sustain itself, independent of TPN. Compared to the control group, whose TPN was stopped abruptly, tapering TPN resulted in a slower SFI recovery because the TPN continued to inhibit SFI to some degree, so that 4 days later SFI was only 80% of control. Thus, tapering TPN does not result in a compensatory increase in appetite and leads to a delay in attaining an adequate energy intake, independent of TPN. But, cumulative energy balance was greater. The infusion of TPN, even at a lower concentration, continues to provide energy, thereby maintaining an adequate energy intake. In the second study, the question examined was whether the energy density of the TPN solution had an influence on SFI recovery. Our data show that when TPN was stopped abruptly, a resumption of SFI occurred independent of the energy density of the antecedent TPN infusion and to an equal degree in all three groups without delay, increased rapidly on a daily basis, and reached pre-TPN oral energy intake levels within 4 days. Thus, the speed of SFI recovery is independent of the energy density of the previously infused TPN solution. Furthermore, the higher the energy density of the TPN, the greater the overall energy intake during the time until full SFI recovery occurs. Taken together our data suggest that tapering TPN: a. does not stimulate an increase in SFI, b. leads to a delay in attaining adequate energy intake independent of TPN, and c. leads to a greater cumulative energy intake during the time to full SFI recovery.
Although findings from rat studies may not exactly apply to humans, these data, taken together with our data in patients on starting TPN (17), do serve as a guide to two potential clinical strategies until data from man becomes available: 1. Ifa patient is well nourished, has a functioning gastrointestinal tract, and rapid resumption of oral intake is desired and assured, then stopping TPN abruptly is indicated. 2. If, however, a patient is malnourished and the function of the gastrointestinal tract is not assured, then gradually tapering TPN in a stepwise fashion would ensure the optimal maintenance of energy intake pending the establishment of adequate oral intake. The avoidance of rebound hypocalcemia is another reason frequently cited as to why TPN should be tapered in clinical practice. However, it has been reported in postoperative patients that serum glucose and insulin levels had returned to normal baseline within 2 h of acute discontinuation of TPN without any symptoms or signs of hypoglycemia (29). Thus, prevention of hypoglycemia is no longer considered a reason to taper TPN. Furthermore, in many institutions using the mixed fuel 3-in-1 TPN admixture (glucose and fat and crystalline amino acids), the fear of rebound hypoglycemia is now only of historic interest (3,5,10,14,20) because rebound hypoglycemia does not occur when TPN is stopped abruptly, primarily because the fat emulsion stimulates glucagon and its hepatic gluconeogenic effects counteract that of hyperinsulinemia, thereby preventing hypoglycemia. A similar decrease in SFI has also been observed when rats are fed enterally via a stomach tube (8,21,24). When, however, the gastrointestinal tract is used, a compensatory energy reduction occurs so that the total energy intake more precisely reflects the usual daily energy intake. In contrast, when nutrients are infused parenterally, total daily energy intake increases because of a failure to adequately compensate for the nutrient intake by a corresponding reduction in SFI (1,18,19,30). These data strongly suggest that gastrointestinal signals also play an important role in initiating satiety due to these nutrients. The regulation of SFI involves feedback signals reflecting the status of short-term energy balance, as recently reviewed (27). In this study, 3 or 4 days of TPN providing 100% equivalent of rat's daily energy requirement did not completely abolish oral food intake. The extra energy is stored as glycogen and triglyceride in the liver, and as triglycerides in fat cells. It is postulated that the increase in energy storage is sensed by feeding regulatory centers primarily in the liver (25) and brain (23). When TPN is stopped abruptly, rats start eating by initially consuming less because of the positive energy balance. When TPN is stopped via tapering technique, the full resumption of oral intake is delayed because the drive to eat, i.e., appetite, is continuously depressed by the further nutrient infusions. At present it remains unclear whether the rat regulates shortterm energy balance, i.e., moment-to-moment food intake, from the blood level of some unknown factor (nutrients or hormones), or whether it is regulated by the cumulative energy balance as fat stores. It is also unclear as to whether man has an effective appestat that controls SFI in the manner similar to rats. Until these factors are more clearly elucidated, the extent to which postoperative TPN should be titrated in order to achieve maximal oral intake, once TPN tapering is started, remains clouded. However, this work clearly shows two features to be relevant to the human postoperative situation: 1. infusion of TPN, even at one-quarter of the daily energy needs, does depress SFI, and
A B R U P T VS. STEPWISE D I S C O N T I N U A T I O N O F T P N
2. even though T P N administration providing 100% of energy needs leads to virtual cessation of oral intake, sudden withdrawal of T P N is followed by eventual resumption of full oral intake. The delay in complete SFI recovery after stopping T P N abruptly is similar whether the T P N solution provides 25%, 50%, or 100% of the energy needs. But, only the stepwise tapering of T P N
595
ensures the maintenance of adequate energy balance until oral intake levels are once more considered adequate. ACKNOWLEDGEMENT We thank Mrs. Darlene Thompson for editorial assistance and William G. Hammond, M.D., for continued counsel and advice. Work presented in this paper is supported in part by the Hendricks Fund for Medical Research, account #930258, Syracuse, NY.
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