Effects of Enterul and Paren teral Nutrition on Appetite in Monkeys
Abstract: Varied clinical observations of the presence of either hunger or anorexia during intragastric or intravenous alimentation have led to the. current experiments. Nine rhesus monkeys (Macaca mulatta) were involved in studies of the long-term effects of enteral and parenteral nutrition on appetite as assessed by feeding behavior and gastric motility. The monkeys received either intragastric infusions of glucose or a complete liquid diet, or intravenous infusions of glucose or glucose/amino acid solutions. Oral intake was accurately adjusted to account for the calories administered by the intragastric route. Oral intake was also reduced in a calorically equivalent amount to account for the calories received during intravenous glucose. When glucose/amino acid solutions were administered parenterally, adjustments were less accurate, with resultant overeating and weight gain in some monkeys during parenteral nutrition, followed by prolonged suppression of appetite after cessation of the infusions. Further studies of the effects of varied compositions of parenteral nutrition, and varied methods of weaning from infusions, are indicated.
Barbara Wafike Hansen, Ph.D. Cynthia H. DeSomery, M.N.
Patricia Kribbs Hagedorn, B.S. Lynne W. Kalnusy, B.S.
Frorri the Departtwits of Pliysiology arid Biophysics, a i d Physiological h‘ursir ig, at id R egior ial Primate R esearcli Center, Uri iversity of IVa’asliinglori, Seattle, Ll’asliitigtoii, and Departtmrit of Physiology, arid School of Niirsirig, University of Alicliigari, Ariri Arbor, hlichigari. Dr. ffartseii is Assochre Professor, Scliools of A’itrsiiig aiid hledicine, Departrn erit of PIi~siologyarid Biophysics, Uriirersity of IVasliirigtori; Captairi DeSoiriery is wit11 the US.Army: hIs. ffagedoni is a stirderit. Scliool of Deritistty. Uriiversity of Washirigtoti; atid’hls. Kalriasy is a Researcli Associate, University of Washirigtoti. Reqirests for reptitits slrould be addressed to Barbara Walike Ifariseti, Pli.D., A14120 Medical Scierice Building, Uriiversity of hlicliigari, Aiiri Arbor, Alicliigari 48109. I
Patients receiving either total parenteral nutrition (TPN) or enteral nutrition vary in their reports of either hunger or anorexia during these infusions; Such clinical observations led to the present series of experiments & i c h addressed the following specific questions: ’ 1. \%at happens to appetite and the regulation of food intake during intragastric or intravenous nutrition? 2. Do parenteral or enteral infusions have a calorie-forcalorie effect in suppressing oral intake, or are there differential effects which relate t o the specific type of in fusate? 3. Do reports of “hunger” by patients receiving nutrient infusions have clinical significance as possible indicators of inadequate nutritional provision? . 4. What is the optimal means of weaning-a patient from parenteral nutrition? Is there a resid,ual effect of TPN which persists &hen levels of. infusion are decreased . ... or stopped and when food is reintroduced? Studies in animals and h m a n s have occasionally addressed these questions; howeQer, the methods used have rarely made posiible extrapolation of findings to the clinical setthg. The earliest studies were of brief duration, and were carried out primarily on rats or dogs. These studies generally ‘concluded that re‘gulation of food intake continued during enteial ‘or ‘parenteral nuithion but with diminished accuracy leading to either under: or. overfeedOther early studies were aimed’at altering blood glucose or other blood chemistry values iri order to’ileter- . ..
MONKEYS
Fig. I : Monkey iii pninate chair. Camas dress worn by monkey is attached to middle tier of chair and prevents tire monkey from removing the canrrirlas or strain gauge wires which exit from the abdominal wall between the second mid third tiers of tire chair.
mine the role of circulating substrate levels on ingestive Levels of intravenous caloric infusion in these studies were minimal and were maintained only for brief periods. Early studies of amino acid infusions in humans7f8 and in rats4 were complicated by symptoms of nausea and vomiting. Thus, to date, no studies have provided definitive answers to the above questions. The results of two studies in humans are important to the present experiments. In 1971, Grinker et a19 administered glucose intravenously and found a reduction in “hunger” as reported by her volunteers, but no effect on subsequent food intake. In the only study of hunger and satiety in humans during total parenteral nutrition, Jordan et all obtained reports of hunger in 24 of the 32 patients in his first study. They found n o relationship between these reports of hunger and the amount or duration of total parenteral nutrition or the degree of weight loss. The same report goes on to describe the more detailed study of 18 additional patients, all of whom experienced weight loss p r i o r to the initiation of total parenteral nutrition (X = 15.2 percent loss of body weight). All had various diseases of the gastrointestinal tract which differed in severity. Sixteen of these 1 8 patients reported some experience of hunger during total parenteral nutrition. At maximum caloric infusion levels, hunger was not uniformly suppressed. Only half of the patients reported an increase in hunger as the calories were tapered off, and many reported
fullness and satiety, which prevented adequate oral intake during and following the reintroduction of food. The findings of Jordan et a1 indicate the need for further study in order to better understand the effects of parenteral and entcral nutrition on hunger and appetite. Studies of humans, however, are greatly complicated by the following conditions: 1. hlost patients have sustained significant weight losses prior to the start of such infusions, and even after weight gain it is difficult to determine at what optimal weight a patient should be maintained. 2. Data collection is confounded by the prior and/or concurrent disease condition which may produce continuing symptoms or memories of the effects of oral ingestion on those symptoms. 3. Levels of nutrient infusion cannot be readily manipulated for experimental purposes because patients’ clinical needs must not be compromised. 4. The only measure of hunger which is generally available in the clinical setting is the patient’s own statement of hunger and his subjective rating of its in tensity. In order to avoid the above listed complications involved in studies of humans, monkeys were selected as subjects in the present series of experiments. The monkeys were stable in body weight and free of disease. The nature, route, and levels of nutrient infusions were varied, and their effects on appetite were assessed by changes in oral intake and gastric motility. METHOD Nine male rhesus monkeys (hlacaca mulatta) weighing five to seven kg were chronically restrained in three-tiered primate chairs for the duration of these studies. hlonkeys were surgically implanted with silastic central venous cannulas, generally via the jugular vein, and silastic intragastric cannulas which were used for parenteral or enteral infusions. In addition, four monkeys had strain gauges’ sutured to the stomach wall in order to measure gastric motility. The chair restraint system prevented the dislodging of these implants, while permitting significant movement of trunk, arms and legs (Fig. 1). All monkeys were completely adapted to the experimental situation and were eating normally and maintaining body weight prior to the initiation of intragastric or intravenous infusions. Each monkey had a complete liquid diet (Ensure) available eight hours per day throughout the experiments. The diet was delivered by means of a sucking activated automated pump system’ * wluch permitted complete and accurate recording and analysis of food intake. Simultaneously and in parallel, gastric motility was recorded. Analysis of gastric motility included the calculation of a motility index which combined the frequency and amplitude of gastric contractions. Intragastric infusions tested were: (1) controls: n o infusion or water or normal saline in volumes equivalent to
IIANSEN ET AL
nutrient infusions amounts; (2) 20 percent dextrose; and (3) 1 kcal/cc SirniZuc. Intravenous infusions used were (1) controls: no infusion or normal saline; (2) 2 0 percent dextrose; and (3) parenteral nutrition solutions including 25 percent dextrose and 5 percent modified protein hydrolysate* and 25 percent dextrose and 4.2 percent crystalline amino acids.? Rate of delivery of infusions was pump controlled.
0Oral Intake Monkey 72099 500r
ZooloDextrose IG
/JJJJl 1 KCOI Sirnitac IG
RESULTS Eight monkeys were studied during intragastric infusions and six during intravenous infusions (representative data from each group are presented.) At the initiation of each new infusion type or level, a minimum of three days was considered an adaptation period and these data were not included in the analyses. Occasionally this adaptation period was extended until the monkey exhibited stable feeding behavior. All infusions were maintained for a minimum of seven days a t a constant level, and most infusions continued for ten days t o two weeks before each change in level or type of infusate. The actual duration of each infusion period was varied between monkeys as their rate of adaptation differed. In these experiments, an attempt was made to reach a stable ingestion state at each infusion level, where oral intake was neither increasing nor decreasing, so that the accuracy of compensation for intragastric or intravenous infusions could be assessed and comparisons made. Figure 2 illustrates the mean caloric intake of monkey No. 72099 during nine periods of stable feeding behavior. The intragastric ’infusion of normal saline, dextrose equivalent t o 10 and 2 0 percent of baseline caloric intake, and Sintilac in amounts equivalent t o 10,30, and 50 percent of baseline oral intake had n o significant effect on total caloric intake. All monkeys adjusted their oral caloric intake appropriately in order to maintain a relatively stable nutrient level. Similar findings were apparent for monkeys in whom relatively low levels of intravenous glucose infusion were carried out. Figure 3 illustrates the adjustment of oral intake of monkey No. 72272 during three levels of intravenous glucose, each maintained for a minimum of two weeks. The infusion levels were selected to be equivalent to 10, 20, and 30 percent of baseline caloric intake. As during intragastric glucose, intravenous glucose had a calorie-forcalorie suppressing effect on oral intake and food intake was closely adjusted to total caloric need. In contrast, initial findings utilizing amino acid/glucose infusions raise the possibility of unique effects of total parenteral nutrition on oral intake and appetite. Figure 4 illustrates the baseline intake of monkey No. 73285 during saline infusion prior to the initiation of the amino acid/ *Hiprotigen, hlcGaw Laboratories. fFrea,nitie Ire hlcGaw Laboratories.
INFUSION PERIODS OF 17 DAYS Fig. 2: Effects of intragastric infisiorl of dextrose or Similac on oral intake (monkey No. 72099). Dextrose infirsion atnouiits were selected to be equiraletit to 10 and 20 percent of baseline oral caloric intake indicated by the colltmns labeled “no IG.” Similac iiifusioris were sekcted to be equivalctit to 10, 30, and 50 percent of baseline intake. Each bar represetits the mean f S.D. for a p e i . . d of sereti days or more.
Monkey 72272 20% Dextrose IV
-
a
Oral Intake
T
i
INFUSION PERIODS OF 2 14 DAYS Fig. 3: Effects of ititravenoils blfirsior1 of dextrose on oral intake (tnorikey No. 72272). Dextrose was infused at levels of 10, 20, and 30 percent of baseline calories for periods of I4 to 21 duys.
h1ONIEYS
glucose solution, and during subsequent periods where total p a r e n t e d nutrition levels were maintained at 30, 60, 90, and 100 percent of baseline caloric intake. It is in~mediately apparent that the total caloric intake of this monkey was significantly higher during levels of 30 to 60 percent intravenous Caloric infusions. In fact, oraZ intake did not differ significantly from baseline (control) levels during either the 30 percent or 60 percent infusions. With an infusion equivalent to 90 percent of needed calories, oral intake decreased but not sufficiently to accurately compensate for the intravenous caloric infusion. Oral intake decreased to near zero only when 100 percent of baseline calories were infused intravenously. A small amount of oral intake continued over the following three-week period, during wl~ich the parenteral infusion level was maintained at 100 percent. In order to determine the effect of total parenteral nutri-
tion on appetite following tlus prolonged period of intravenous nutrition, the infusion was stopped and feeding bellavior and body weight were followed until they returned to normal. Figure 5 illustrates the significant sustained suppression of oral intake following total p a r e n t e d nutrition, and the gradual reduction in body weight to approximately pre-infusion levels. At this point, it is not possible to ascertain whether this suppression of feeding behavior was due to (a) an elevated body weight achieved during the early phase of parenteral nutrition, or (b) to a specific effect of total parenteral nutrition on appetite. The effect of total parenteral nutrition on gastric motility was analyzed in detail for monkey No. 73285. High amplitude gastric contractions generally occur only during fasting in the monkey. We have recorded these large amplitude contractions by means of a nasogastric cannula in
Monkey 73285
F
u+
Infused 0 Oral
700
-r:
5.4
J5.0
600 Mean pre -operative 500 . caloric intake '
w -
8 400 -I a
300 200
I00 BASELINE 30 60 90 100 % (Saline Infusion) LEVEL OF PARENTERAL NUTRITION Fig. 4: Effects of iritrarciious ariiiiro acidlglircose irifirsiori on oral iritake (rrior~keyNo. 73285). Each bar iudicates tlic caloric iritake for one day. TPiVIevels were selccted t o be cqtriralcnt to 30, 60,90, and 100 perce~!tof baselirie oral irirake. Intake during adapfatiori periods betrveeii Iewls are riot slio,r.ri.
IIANSEN ET AL
Monkey 73285
591-
3
400
c
pre -operative caloric intake
_________---
20 24 DAYS AFTER STOPPING PARENTERAL NUTRITION 1
Fig. 5: Oral iiitake arid body rveiglit followiriga proloiiged period of V I V (monkey No. 73285). This period followed tlie irifirsioiiperiod slio~c.iiiii Fig.4.
human volunteers, and have found that these contractions are frequently associated with reports of “hunger pangs” or hunger sensations referred to the epigastric region. Figure 6 illustrates variations in tlie motility index over time. The largest symbols indicate the presence of the large “hunger type” motility patterns. A significant change in gastric motility pattern takes place as levels of parenteral nutrition are increased. At the 100 percent level almost all large amplitude motility is suppressed. A low level pattern of activity becomes apparent tluoughout the 24 hours and no large amplitude fasting-type activity is seen during the post-midnight hours. During times in which oral intake was significant (compare to Figure 4), motility was completely suppressed during and immediately foUowing the eight-hour feeding period. Not all animals responded similarly to total parenteral nutrition. However, at tlus time, we cannot specify die causes of any differences. It is evident to us that many more studies involving variations in the nunlbers of calories infused and the ratios of carbohydrate, fat, and protein are needed in order to ,clarify the specific effects on appetite and to produce clinically applicable prescriptions for the optimal manipulation of parenteral nutrition.
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CONCLUSIONS
REFERENCES
Normal monkeys regulate their oral intake very precisely to account for the calories provided by glucose intravenously, or by glucose or complete liquid diets intragastricdy. Thus, none of these appears to have an effect on appetite beyond the caloric load. By contrast, total parenteral nutrition does not have this consistent and predictable effect. Oral intake during and following p a r e n t e d infusions containing amino acids and glucose appears to be less precisely controlled. During levels of p a r e n t e d nutrition of less than the body caloric requirements, some monkeys overate and showed accelerated weight gain. At levels designed to meet or exceed the caloric needs, the monkeys’ oral intakes were usually close to zero. However, at all times the monkeys continued to nibble or ingest small amounts of food. Following the cessation of total p a r e n t e d nutrition, appetite was suppressed for one to three weeks before normal intake was resumed. Gastric motility during total parenteral nutrition changes very significantly in pattern, amplitude and time of occurrence of contractions. The large amplitude contractions associated with sensations of hunger pangs in humans appear to be completely absent when total caloric needs are being met by total parenteral nutrition. There is no doubt that further studies of both monkeys and humans in relation to the effects of various parenteral nutrition solutions on appetite and gastric motility are needed to give greater understanding of patient complaints of anorexia or hunger and as a basis for the weaning process from total parenteral nutrition. We have only begun to answer. the questions posed at the beginning of this study.
1. Janowitz 11, Grossman All: Effect of parented administration of glucose and protein hydrolysate on food intake in the rat. Am J Physiol 155:28-32, 1948. 2.Epstein A, TeiteIbaum P: Regulation of food intake in the absence of taste, smell and other oropharyngeal senution. J Comp Physiol Psych 55:753-759, 1962. 3.hiook D: Oral and postingestional determinants of intake of various solutions in rats with esophageal fistulas. J Comp Physiol Psych 56:645-659.1963. 4.Adair ER, hliller NE, Booth DA: Effects of continuous intravenous infusion of nutritive substances on consummatory behavior in rats. Comm Behav Biol2:25-37, 1968. 5.Mayer J: Reguhtion of energy intake and body weight: the glucostatic theory and the lipostatic hypothesis. Ann NY AcaP Sci 63:1543,1955. 6.Baile CA, Zinn W, hlayer J: Feeding behavior of monkeys: glucose utilization rate and site of glucose entry. Physiol Behav 6:537-541,1971. 7.Smyth CJ, Lasichak AG, Levey S: The effect of orally and intravenously administered amino acid mixtures on voluntary food consumption in normal men. J Clin Invest 26:439445, 1946. 8.hIellinkoff Shl, hankland hi, Boyle D et al: Relationship between serum amino acid concentration and fluctuations in appetite. J Appl Physiol8:535-538,1956. 9.Grinker J, Cohn C, Iiirsh J: The effect of intravenous administration of glucose, saline and mannitol on meal regulation in normal weight human subjects. Comm Behav Biol6:203-208, 1971. 10.Jordan HA, hloses €1, hIacFayden BV et al: Hunger and satiety in humans during parenteral hyperalimentation. Psychosom hied 36:144-155,1974. ll.\Veisbrodt NW, Wiley JN, Overholt BF et al: A relation between gastroduodenal muscle contractions and gastric emptying. Gut 10~543-548,1969. 12.Walike BC, Campbell DJ, Hillman RA: A liquid diet feeder for monkeys. J Appl Physiol31:946-947,1971.
Abstract: Varied clinical observations of the presence of either hunger or anorexia during intragastric or intravenous alimentation have led to the. current experiments. Nine rhesus monkeys (Macaca mulatta) were involved in studies of the long-term effects of enteral and parenteral nutrition on appetite as assessed by feeding behavior and gastric motility. The monkeys received either intragastric infusions of glucose or a complete liquid diet, or intravenous infusions of glucose or glucose/amino acid solutions. Oral intake was accurately adjusted to account for the calories administered by the intragastric route. Oral intake was also reduced in a calorically equivalent amount to account for the calories received during intravenous glucose. When glucose/amino acid solutions were administered parenterally, adjustments were less accurate, with resultant overeating and weight gain in some monkeys during parenteral nutrition, followed by prolonged suppression of appetite after cessation of the infusions. Further studies of the effects of varied compositions of parenteral nutrition, and varied methods of weaning from infusions, are indicated.
Barbara Wafike Hansen, Ph.D. Cynthia H. DeSomery, M.N.
Patricia Kribbs Hagedorn, B.S. Lynne W. Kalnusy, B.S.
Frorri the Departtwits of Pliysiology arid Biophysics, a i d Physiological h‘ursir ig, at id R egior ial Primate R esearcli Center, Uri iversity of IVa’asliinglori, Seattle, Ll’asliitigtoii, and Departtmrit of Physiology, arid School of Niirsirig, University of Alicliigari, Ariri Arbor, hlichigari. Dr. ffartseii is Assochre Professor, Scliools of A’itrsiiig aiid hledicine, Departrn erit of PIi~siologyarid Biophysics, Uriirersity of IVasliirigtori; Captairi DeSoiriery is wit11 the US.Army: hIs. ffagedoni is a stirderit. Scliool of Deritistty. Uriiversity of Washirigtoti; atid’hls. Kalriasy is a Researcli Associate, University of Washirigtoti. Reqirests for reptitits slrould be addressed to Barbara Walike Ifariseti, Pli.D., A14120 Medical Scierice Building, Uriiversity of hlicliigari, Aiiri Arbor, Alicliigari 48109. I
Patients receiving either total parenteral nutrition (TPN) or enteral nutrition vary in their reports of either hunger or anorexia during these infusions; Such clinical observations led to the present series of experiments & i c h addressed the following specific questions: ’ 1. \%at happens to appetite and the regulation of food intake during intragastric or intravenous nutrition? 2. Do parenteral or enteral infusions have a calorie-forcalorie effect in suppressing oral intake, or are there differential effects which relate t o the specific type of in fusate? 3. Do reports of “hunger” by patients receiving nutrient infusions have clinical significance as possible indicators of inadequate nutritional provision? . 4. What is the optimal means of weaning-a patient from parenteral nutrition? Is there a resid,ual effect of TPN which persists &hen levels of. infusion are decreased . ... or stopped and when food is reintroduced? Studies in animals and h m a n s have occasionally addressed these questions; howeQer, the methods used have rarely made posiible extrapolation of findings to the clinical setthg. The earliest studies were of brief duration, and were carried out primarily on rats or dogs. These studies generally ‘concluded that re‘gulation of food intake continued during enteial ‘or ‘parenteral nuithion but with diminished accuracy leading to either under: or. overfeedOther early studies were aimed’at altering blood glucose or other blood chemistry values iri order to’ileter- . ..
MONKEYS
Fig. I : Monkey iii pninate chair. Camas dress worn by monkey is attached to middle tier of chair and prevents tire monkey from removing the canrrirlas or strain gauge wires which exit from the abdominal wall between the second mid third tiers of tire chair.
mine the role of circulating substrate levels on ingestive Levels of intravenous caloric infusion in these studies were minimal and were maintained only for brief periods. Early studies of amino acid infusions in humans7f8 and in rats4 were complicated by symptoms of nausea and vomiting. Thus, to date, no studies have provided definitive answers to the above questions. The results of two studies in humans are important to the present experiments. In 1971, Grinker et a19 administered glucose intravenously and found a reduction in “hunger” as reported by her volunteers, but no effect on subsequent food intake. In the only study of hunger and satiety in humans during total parenteral nutrition, Jordan et all obtained reports of hunger in 24 of the 32 patients in his first study. They found n o relationship between these reports of hunger and the amount or duration of total parenteral nutrition or the degree of weight loss. The same report goes on to describe the more detailed study of 18 additional patients, all of whom experienced weight loss p r i o r to the initiation of total parenteral nutrition (X = 15.2 percent loss of body weight). All had various diseases of the gastrointestinal tract which differed in severity. Sixteen of these 1 8 patients reported some experience of hunger during total parenteral nutrition. At maximum caloric infusion levels, hunger was not uniformly suppressed. Only half of the patients reported an increase in hunger as the calories were tapered off, and many reported
fullness and satiety, which prevented adequate oral intake during and following the reintroduction of food. The findings of Jordan et a1 indicate the need for further study in order to better understand the effects of parenteral and entcral nutrition on hunger and appetite. Studies of humans, however, are greatly complicated by the following conditions: 1. hlost patients have sustained significant weight losses prior to the start of such infusions, and even after weight gain it is difficult to determine at what optimal weight a patient should be maintained. 2. Data collection is confounded by the prior and/or concurrent disease condition which may produce continuing symptoms or memories of the effects of oral ingestion on those symptoms. 3. Levels of nutrient infusion cannot be readily manipulated for experimental purposes because patients’ clinical needs must not be compromised. 4. The only measure of hunger which is generally available in the clinical setting is the patient’s own statement of hunger and his subjective rating of its in tensity. In order to avoid the above listed complications involved in studies of humans, monkeys were selected as subjects in the present series of experiments. The monkeys were stable in body weight and free of disease. The nature, route, and levels of nutrient infusions were varied, and their effects on appetite were assessed by changes in oral intake and gastric motility. METHOD Nine male rhesus monkeys (hlacaca mulatta) weighing five to seven kg were chronically restrained in three-tiered primate chairs for the duration of these studies. hlonkeys were surgically implanted with silastic central venous cannulas, generally via the jugular vein, and silastic intragastric cannulas which were used for parenteral or enteral infusions. In addition, four monkeys had strain gauges’ sutured to the stomach wall in order to measure gastric motility. The chair restraint system prevented the dislodging of these implants, while permitting significant movement of trunk, arms and legs (Fig. 1). All monkeys were completely adapted to the experimental situation and were eating normally and maintaining body weight prior to the initiation of intragastric or intravenous infusions. Each monkey had a complete liquid diet (Ensure) available eight hours per day throughout the experiments. The diet was delivered by means of a sucking activated automated pump system’ * wluch permitted complete and accurate recording and analysis of food intake. Simultaneously and in parallel, gastric motility was recorded. Analysis of gastric motility included the calculation of a motility index which combined the frequency and amplitude of gastric contractions. Intragastric infusions tested were: (1) controls: n o infusion or water or normal saline in volumes equivalent to
IIANSEN ET AL
nutrient infusions amounts; (2) 20 percent dextrose; and (3) 1 kcal/cc SirniZuc. Intravenous infusions used were (1) controls: no infusion or normal saline; (2) 2 0 percent dextrose; and (3) parenteral nutrition solutions including 25 percent dextrose and 5 percent modified protein hydrolysate* and 25 percent dextrose and 4.2 percent crystalline amino acids.? Rate of delivery of infusions was pump controlled.
0Oral Intake Monkey 72099 500r
ZooloDextrose IG
/JJJJl 1 KCOI Sirnitac IG
RESULTS Eight monkeys were studied during intragastric infusions and six during intravenous infusions (representative data from each group are presented.) At the initiation of each new infusion type or level, a minimum of three days was considered an adaptation period and these data were not included in the analyses. Occasionally this adaptation period was extended until the monkey exhibited stable feeding behavior. All infusions were maintained for a minimum of seven days a t a constant level, and most infusions continued for ten days t o two weeks before each change in level or type of infusate. The actual duration of each infusion period was varied between monkeys as their rate of adaptation differed. In these experiments, an attempt was made to reach a stable ingestion state at each infusion level, where oral intake was neither increasing nor decreasing, so that the accuracy of compensation for intragastric or intravenous infusions could be assessed and comparisons made. Figure 2 illustrates the mean caloric intake of monkey No. 72099 during nine periods of stable feeding behavior. The intragastric ’infusion of normal saline, dextrose equivalent t o 10 and 2 0 percent of baseline caloric intake, and Sintilac in amounts equivalent t o 10,30, and 50 percent of baseline oral intake had n o significant effect on total caloric intake. All monkeys adjusted their oral caloric intake appropriately in order to maintain a relatively stable nutrient level. Similar findings were apparent for monkeys in whom relatively low levels of intravenous glucose infusion were carried out. Figure 3 illustrates the adjustment of oral intake of monkey No. 72272 during three levels of intravenous glucose, each maintained for a minimum of two weeks. The infusion levels were selected to be equivalent to 10, 20, and 30 percent of baseline caloric intake. As during intragastric glucose, intravenous glucose had a calorie-forcalorie suppressing effect on oral intake and food intake was closely adjusted to total caloric need. In contrast, initial findings utilizing amino acid/glucose infusions raise the possibility of unique effects of total parenteral nutrition on oral intake and appetite. Figure 4 illustrates the baseline intake of monkey No. 73285 during saline infusion prior to the initiation of the amino acid/ *Hiprotigen, hlcGaw Laboratories. fFrea,nitie Ire hlcGaw Laboratories.
INFUSION PERIODS OF 17 DAYS Fig. 2: Effects of intragastric infisiorl of dextrose or Similac on oral intake (monkey No. 72099). Dextrose infirsion atnouiits were selected to be equiraletit to 10 and 20 percent of baseline oral caloric intake indicated by the colltmns labeled “no IG.” Similac iiifusioris were sekcted to be equivalctit to 10, 30, and 50 percent of baseline intake. Each bar represetits the mean f S.D. for a p e i . . d of sereti days or more.
Monkey 72272 20% Dextrose IV
-
a
Oral Intake
T
i
INFUSION PERIODS OF 2 14 DAYS Fig. 3: Effects of ititravenoils blfirsior1 of dextrose on oral intake (tnorikey No. 72272). Dextrose was infused at levels of 10, 20, and 30 percent of baseline calories for periods of I4 to 21 duys.
h1ONIEYS
glucose solution, and during subsequent periods where total p a r e n t e d nutrition levels were maintained at 30, 60, 90, and 100 percent of baseline caloric intake. It is in~mediately apparent that the total caloric intake of this monkey was significantly higher during levels of 30 to 60 percent intravenous Caloric infusions. In fact, oraZ intake did not differ significantly from baseline (control) levels during either the 30 percent or 60 percent infusions. With an infusion equivalent to 90 percent of needed calories, oral intake decreased but not sufficiently to accurately compensate for the intravenous caloric infusion. Oral intake decreased to near zero only when 100 percent of baseline calories were infused intravenously. A small amount of oral intake continued over the following three-week period, during wl~ich the parenteral infusion level was maintained at 100 percent. In order to determine the effect of total parenteral nutri-
tion on appetite following tlus prolonged period of intravenous nutrition, the infusion was stopped and feeding bellavior and body weight were followed until they returned to normal. Figure 5 illustrates the significant sustained suppression of oral intake following total p a r e n t e d nutrition, and the gradual reduction in body weight to approximately pre-infusion levels. At this point, it is not possible to ascertain whether this suppression of feeding behavior was due to (a) an elevated body weight achieved during the early phase of parenteral nutrition, or (b) to a specific effect of total parenteral nutrition on appetite. The effect of total parenteral nutrition on gastric motility was analyzed in detail for monkey No. 73285. High amplitude gastric contractions generally occur only during fasting in the monkey. We have recorded these large amplitude contractions by means of a nasogastric cannula in
Monkey 73285
F
u+
Infused 0 Oral
700
-r:
5.4
J5.0
600 Mean pre -operative 500 . caloric intake '
w -
8 400 -I a
300 200
I00 BASELINE 30 60 90 100 % (Saline Infusion) LEVEL OF PARENTERAL NUTRITION Fig. 4: Effects of iritrarciious ariiiiro acidlglircose irifirsiori on oral iritake (rrior~keyNo. 73285). Each bar iudicates tlic caloric iritake for one day. TPiVIevels were selccted t o be cqtriralcnt to 30, 60,90, and 100 perce~!tof baselirie oral irirake. Intake during adapfatiori periods betrveeii Iewls are riot slio,r.ri.
IIANSEN ET AL
Monkey 73285
591-
3
400
c
pre -operative caloric intake
_________---
20 24 DAYS AFTER STOPPING PARENTERAL NUTRITION 1
Fig. 5: Oral iiitake arid body rveiglit followiriga proloiiged period of V I V (monkey No. 73285). This period followed tlie irifirsioiiperiod slio~c.iiiii Fig.4.
human volunteers, and have found that these contractions are frequently associated with reports of “hunger pangs” or hunger sensations referred to the epigastric region. Figure 6 illustrates variations in tlie motility index over time. The largest symbols indicate the presence of the large “hunger type” motility patterns. A significant change in gastric motility pattern takes place as levels of parenteral nutrition are increased. At the 100 percent level almost all large amplitude motility is suppressed. A low level pattern of activity becomes apparent tluoughout the 24 hours and no large amplitude fasting-type activity is seen during the post-midnight hours. During times in which oral intake was significant (compare to Figure 4), motility was completely suppressed during and immediately foUowing the eight-hour feeding period. Not all animals responded similarly to total parenteral nutrition. However, at tlus time, we cannot specify die causes of any differences. It is evident to us that many more studies involving variations in the nunlbers of calories infused and the ratios of carbohydrate, fat, and protein are needed in order to ,clarify the specific effects on appetite and to produce clinically applicable prescriptions for the optimal manipulation of parenteral nutrition.
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CONCLUSIONS
REFERENCES
Normal monkeys regulate their oral intake very precisely to account for the calories provided by glucose intravenously, or by glucose or complete liquid diets intragastricdy. Thus, none of these appears to have an effect on appetite beyond the caloric load. By contrast, total parenteral nutrition does not have this consistent and predictable effect. Oral intake during and following p a r e n t e d infusions containing amino acids and glucose appears to be less precisely controlled. During levels of p a r e n t e d nutrition of less than the body caloric requirements, some monkeys overate and showed accelerated weight gain. At levels designed to meet or exceed the caloric needs, the monkeys’ oral intakes were usually close to zero. However, at all times the monkeys continued to nibble or ingest small amounts of food. Following the cessation of total p a r e n t e d nutrition, appetite was suppressed for one to three weeks before normal intake was resumed. Gastric motility during total parenteral nutrition changes very significantly in pattern, amplitude and time of occurrence of contractions. The large amplitude contractions associated with sensations of hunger pangs in humans appear to be completely absent when total caloric needs are being met by total parenteral nutrition. There is no doubt that further studies of both monkeys and humans in relation to the effects of various parenteral nutrition solutions on appetite and gastric motility are needed to give greater understanding of patient complaints of anorexia or hunger and as a basis for the weaning process from total parenteral nutrition. We have only begun to answer. the questions posed at the beginning of this study.
1. Janowitz 11, Grossman All: Effect of parented administration of glucose and protein hydrolysate on food intake in the rat. Am J Physiol 155:28-32, 1948. 2.Epstein A, TeiteIbaum P: Regulation of food intake in the absence of taste, smell and other oropharyngeal senution. J Comp Physiol Psych 55:753-759, 1962. 3.hiook D: Oral and postingestional determinants of intake of various solutions in rats with esophageal fistulas. J Comp Physiol Psych 56:645-659.1963. 4.Adair ER, hliller NE, Booth DA: Effects of continuous intravenous infusion of nutritive substances on consummatory behavior in rats. Comm Behav Biol2:25-37, 1968. 5.Mayer J: Reguhtion of energy intake and body weight: the glucostatic theory and the lipostatic hypothesis. Ann NY AcaP Sci 63:1543,1955. 6.Baile CA, Zinn W, hlayer J: Feeding behavior of monkeys: glucose utilization rate and site of glucose entry. Physiol Behav 6:537-541,1971. 7.Smyth CJ, Lasichak AG, Levey S: The effect of orally and intravenously administered amino acid mixtures on voluntary food consumption in normal men. J Clin Invest 26:439445, 1946. 8.hIellinkoff Shl, hankland hi, Boyle D et al: Relationship between serum amino acid concentration and fluctuations in appetite. J Appl Physiol8:535-538,1956. 9.Grinker J, Cohn C, Iiirsh J: The effect of intravenous administration of glucose, saline and mannitol on meal regulation in normal weight human subjects. Comm Behav Biol6:203-208, 1971. 10.Jordan HA, hloses €1, hIacFayden BV et al: Hunger and satiety in humans during parenteral hyperalimentation. Psychosom hied 36:144-155,1974. ll.\Veisbrodt NW, Wiley JN, Overholt BF et al: A relation between gastroduodenal muscle contractions and gastric emptying. Gut 10~543-548,1969. 12.Walike BC, Campbell DJ, Hillman RA: A liquid diet feeder for monkeys. J Appl Physiol31:946-947,1971.
