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A new method of study of upper gastrointestinal transit time and secretion in ileostomy patients Dowell, Anthony James 1982

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A NEW METHOD OF STUDY OF UPPER GASTROINTESTINAL TRANSIT TIME AND SECRET ION IN ILEOSTOMY PATIENTS by Anthony James Dowcll M.B., B.S. U n i v e r s i t y of London, 1970 Thesis submitted i n p a r t i a l f u l f i l m e n t the requirements of the degree of Master of Science i n the Department of Surgery We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA (3) May, 1982 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of Su&Atsfi-Y The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date ZHtr^ cJ^<T DE-6 (3/81) I ABSTRACT There i s a need f o r a simple, safe, reproducible and non-invasive method for studying upper g a s t r o i n t e s t i n a l m o t i l i t y i n humans. Ex i s t i n g methods, measuring e l e c t r i c a l contractions and intraluminal pressure changes have l i m i t a t i o n s i n t h e i r c o r r e l a t i o n with the physiology of what i s a c t u a l l y happening to ingested food. T r a n s i t time has been suggested as a more physiologic means of studying gut m o t i l i t y ; therefore a method was developed to measure t r a n s i t time and secretory changes i n response to ingested l i q u i d s , using ileostomy patients. 2.5 gm of polyethylene g l y c o l (PEG) was added to 500 ml of normal s a l i n e , and given o r a l l y to volunteers with ileostomies. The ileostomy e f f l u e n t was c o l l e c t e d f o r 2 hours i n 10 minute a l i q u o t s . PEG assay was performed by the turbidimetric method of Hyden, using Malawer's modification with an emulsifier. The following were measured: most rapid, mode, median, mean and t o t a l t r a n s i t t imes. A study was then performed to determine i f d i f f e r e n t foodstuffs -carbohydrate, f a t , and protein - produce measurable changes i n t r a n s i t time. 2.5 gm of PEG was added to 500 ml of (a) 90 ml Lipomul i n 410 ml normal saline (b) 5% dextrose (c) 100 ml of Travasol 10% i n 400 ml d i s t i l l e d water. The volumes were chosen to produce isoosmolar test feeds. Validating studies showed s a t i s f a c t o r y r e p r o d u c i b i l i t y and i n d i v i d u a l v a r i a t i o n (r = 0.68 f o r volume recovery, r = 0.69 for PEG recovery, p = < 0.5) II The recovery pattern of a tes t feed of 500 ml normal saline was found to follow a skew d i s t r i b u t i o n , with mode, median and mean t r a n s i t times a l l d i f f e r e n t . The most reproducible and e a s i l y measured, was mode, or peak, t r a n s i t time (average 40 minutes f o r volume and PEG recovery). S i g n i f i c a n t delays i n a l l t r a n s i t times were found (p = <5 0.01) using each of the test feeds: (a) f o r Lipomul a peak volume recovery of 60 minutes and PEG recovery of 70 minutes; (b) f o r 5% dextrose a peak volume recovery of 90 minutes and PEG recovery of 90 minutes; (c) with Travasol, n e g l i g i b l e amounts of ileostomy output were obtained over 2 hours. The most rapid t r a n s i t time was co n s i s t e n t l y less than 10 minutes, as measured by PEG appearance from the ileostomy. This i s f a r less than previously described by standard methods, but i s i n accordance with t r a n s i t times measured to the i l e o c a e c a l valve i n int a c t g a s t r o i n t e s t i n a l tracts using the recently-introduced breath hydrogen method following lactulose ingestion. Comparison of t o t a l volume recovery with t o t a l PEG recovery over 2 hours indicates whether net absorption or secretion has occurred: (a) with normal s a l i n e a volume recovery of 62% and PEG recovery of 48% indicates net secretion; (b) with Lipomul a volume recovery of 66% and PEG recovery of 58% also indicates net secretion, with no s i g n i f i c a n t d i f f e r e n c e from normal s a l i n e (p = < 0.05); (c) with 5% dextrose a volume recovery of 4% and PEG recovery of 13% indicates net absorption, s i g n i f i c a n t l y d i f f e r e n t from normal s a l i n e (p = < 0.01); (d) for Travasol a volume recovery of 1% and PEG recovery of 1% indicates no net absorption or secretion, but confirms the above finding of a very large delay i n t r a n s i t time. I l l These studies have shown that i s o t o n i c solutions of normal s a l i n e , glucose, f a t and protein r e s u l t i n widely d i f f e r e n t peak t r a n s i t times i n ileostomy patients. They also r e s u l t i n widely d i f f e r e n t f l u i d outputs from the ileostomy due to net absorption or secretion. These differences have not been described before. IV LIST OF FIGURES Figure 1 Diagram of Slow Waves i n the small i n t e s t i n e Figure 2 Showing how Slow Waves and Action Potentials contribute to i n t e s t i n a l contractions Figure 3 Recovery of 500 ml o r a l normal sa l i n e from ileostomy Figure 4 Recovery of 2.5 gm dose polyethylene g l y c o l (PEG) i n 500 ml of normal s a l i n e Figure 5a Individual r e p r o d u c i b i l i t y . Recovery of 500 ml normal sa l i n e from ileostomy i n one patient on two occasions Figure 5b Individual r e p r o d u c i b i l i t y . Recovery of 500 ml normal saline from ileostomy i n one patient on three occasions Figure 6 R e p r o d u c i b i l i t y of method. A plo t of volume recovery f o r one te s t against a second test on a d i f f e r e n t day, using logarithmic transformations Figure 7 The volume and PEG recoveries following 500 ml o r a l doses of normal s a l i n e , glucose and lipomul Figure 8 The percentage recovery of volume and PEG from the ileostomy i n response to test feeds of 500 ml normal s a l i n e , Lipomul and glucose (5% dextrose), showing net f l u i d absorption with s a l i n e and glucose, and net secretion with lipomul V Figure 9 Serum hormone responses to 500 ml o r a l s a l i n e , glucose and 1ipomul Figure 10 Showing a normal d i s t r i b u t i o n and a skew d i s t r i b u t i o n Figure 11 Volume and PEG recovery with 500 ml normal sa l i n e + 2.5 gm PEG i n patient with reversed i l e a l segment and short bowel syndrome Figure 12 Volume recovery from Figure 11 compared to controls Figure 13 Polyethylene g l y c o l standard curve at o p t i c a l density 650 mu VI LIST OF TABLES Table 1 Percentage recovery from ileostomy of 500 ml of various test feeds Table 2 E l e c t r o l y t e composition of ileostomy f l u i d following various test feeds, and following GIP i n f u s i o n Table 3 Volume recovery of 500 ml o r a l normal saline Table 4 Recovery of 2.5 gm PEG i n 500 ml normal s a l i n e Table 5 R e p r o d u c i b i l i t y of method. Volume recovery data Table 6 Reprodu c i b i l i t y of method. PEG recovery data Table 7 Volume recovery (ml) a f t e r 500 ml o r a l lipomul i n saline Table 8 PEG recovery (mg) a f t e r 500 ml o r a l lipomul i n s a l i n e Table 9 ' Volume recovery (ml) a f t e r 500 ml o r a l glucose Table 10 PEG recovery (mg) a f t e r 500 ml o r a l glucose Table 11 Volume (ml) and PEG (mg) recovery of 500 ml Dextrose i n saline + 2.5 gm PEG Table 12 Volume recovery (ml) of 500 ml water + 2.5 gm PEG VII Table 13 Volume (ml) and PEG (mg) recovery a f t e r 100 ml Travasol + 400 ml water + 2.5 gm PEG Table 14 Recovery of 500 ml normal s a l i n e + 2.5 gm PEG and GIP i n f u s i o n 0.8 u units/kg Table 15 ' O p t i c a l d e n s i t i e s f o r PEG Standard curve VIII CONTENTS Page ABSTRACT I LIST OF FIGURES IV LIST OF TABLES VI INTRODUCTION AND REVIEW OF LITERATURE 1 In t e s t i n a l M o t i l i t y 1 Tran s i t Time 4 Markers 5 Known Tra n s i t Times 6 Factors A f f e c t i n g Transit Time 7 Ga s t r o i n t e s t i n a l Hormones and Secretion 8 PURPOSE OF STUDY 11 MATERIALS AND METHODS 12 Co l l e c t i o n of Specimens 13 P i l o t Studies - Study 1 14 - Study 2 14 - Study 3 14 Test feeds 15 Polyethylene Glycol Assay 16 S t a t i s t i c s 18 RESULTS Controls, R e p r o d u c i b i l i t y : P i l o t Studies 19 Eff e c t of Test Feeds 20 (a) Transit 20 (b) Secretion 21 (c) E l e c t r o l y t e Composition 22 (d) Hormonal Responses 23 DISCUSSION V a l i d i t y of Method 24 Advantages and Disadvantages 26 Possible Sources of Erro r 27 Ef f e c t of Test Feeds 29 SUMMARY 30 CLINICAL APPLICATIONS OF METHOD 32 FURTHER WORK 33 ACKNOWLEDGEMENTS 34 FIGURES 35-46 TABLES 47-61 BIBLIOGRAPHY 62-65 INTRODUCTION Because of the r e l a t i v e i n a c c e s s i b i l i t y of the small bowel for i n v e s t i g a t i o n , and also perhaps because of the r e l a t i v e r a r i t y of diseases a f f e c t i n g i t , l i t t l e i s known about the physiology of small bowel function. The main areas of study have been m o t i l i t y and t r a n s i t time. I n t e s t i n a l M o t i l i t y " M o t i l i t y " has been i n t e n s i v e l y investigated by methods measuring e l e c t r i c a l a c t i v i t y and mechanical contractions (1). The electrophysiology of small bowel a c t i v i t y has been characterized into a Basic E l e c t r i c a l Rhythm (B.E.R. or "slow waves" Figure 1), not d i r e c t l y i n i t i a t i n g contraction, but determining i t s d i s t r i b u t i o n and frequency, as a pacemaker, and Action Potentials ("Spikes" Figure 2), associated with smooth muscle contraction (2,3). I n t e s t i n a l contractions have been separated into 4 patterns - Segmental, Sequential, P e r i s t a l t i c Rushes, and Retrograde (1). Measurement of intraluminal pressure using water f i l l e d balloons, open-tipped f l u i d - f i l l e d catheters connected to external transducers (4), and radiotelemetering devices, has shown 4 basic types of contraction, based on pressure and duration. Each contributes to the o v e r a l l pattern of contraction (5). Attempts have been made to r e l a t e these observations to the progress of chyme (1,6). None of these studies however, have been very rewarding i n the basic understanding of the physiology and pathophysiology of i n t e s t i n a l function (7). The modifying influences on m o t i l i t y have been studied i n d e t a i l , namely the autonomic nervous system, chemicals, and hormones (1). Cholinergic parasympathetic nerves stimulate smooth muscle and f a c i l i t a t e contraction, whilst adrenergic and noradrenergic a c t i v i t y i n h i b i t s contraction. There i s also a d e f i n i t e pathway, v i a the thalamus and hypothalamus, whereby external s t i m u l i that evoke an emotional response can -2-Scl i rm. i iu i r p i r * . r m . » l inn of sin** flow MHVT m ' lon* in I hi duodenum and uppr i jejunum M n u » « v r v H a i r Imni * lix. u> disiul lo A . un j ( ik disl.il lo B A ruinni i in limr l>.i*.r t t r i o i d r d v i m u l l * n r o u » - l ) ' l u p i r t r n l loi A H nnd ( 1 hr / » < y « r m * of » l i > « »* .!*.«••• in nil i n i r r IIH'I it Ihr snnir and o sjid Ii* hr "pU*\r locked " Mo**rvei. M Infv in p l m » r hchind A and ( b f\ in pli.ivr hrliinri H 1 tif fiftuw /HI' o l e p i n c n i e d t -y llir di.tfnnxl dn i i rd linr FIGURE 1 : ' D i a g r a m o f S l o w Waves i n the s m a l l i n t e s t i n e ( f r o m B o c k u s H L , e d . G a s t r o e n t e r o l o g y , 3 rd e d . ) 7ypr U'tivr* Slow. w;ivrv (HF.RI / Slow toilvcv / Aclion pnu-nlia! / Muscle I'nnimciion 1 onci ludinnl muscle liiyer Ci tc i i lur muscle C i r c u l a i muscle DiH use Sequence ofi-leciricHl iiclivily of smooth muscle which results in muscle conlr.iciion. ELECTRODES Longitudinal: b I my. ELECTRODES .I/ML . . i. , » 6 E l e c t r i c a l a c t i v i t y a n d p r c s ! - > u r e t e c o r d o d f r o m t h e d u o d e n u m o f a n u n a n c s t h e t i ^ e d d o g A t nn nnHint o p e r -a t i o n , t h e d u o d e n u m w a s b r o u g h t o u t t h r o u g h t h r a b d o m i -n a l w a l l a n d c o v e r e d b y a s k i n H a p i o t h a t It l o r m e d a p o r m a n e n l h a n d l e - l i k e l o o p E l e c t r i c a l r e c o r d i n g m a d * f r o m n p e d l e e l e c t i o d e s I n s e r t e d i n t o t h e m u s c l e t h r o u g h t h e B k i n ; p r e s s u r e w a s r o c o r d e d b y n i e n n s o l a n o p e n - t i p c a t h e l o r i n s e r t e d t h r o u g h a I h i n - w a l l n d h y p o d n m i c nnndle 1 h r d n g w » n g i v e n m n r p h i n * b y | l n w I n l i » v r ' u m » i n j r C l n » n 1 f i r I n f t h u l l p t t h p i n < n d i i h i > w » 1ht» b » » l c ^ I r f t i n ul r h y t h m w l l h kumr n p l k i n p P u m MH r t m : • e h t r f c t p l k » * i n p t p i k i n p A t t h o m i d d l e (>t t h e IM o t d t p l k l n p t » i - c o " » p | p n % -t < m g t * d a n d t h r u - Ik n < o i t r a p o i f t l i n g l n ( tt>h.r I n I n l n t U i m i -n » l p t i ' \ f c u i » {I i u ' n IUM V , * f a f A m J I ' h y n n l T\)\ i ' M FIGURE 2 Showing how Slow Waves and A c t i o n P o t e n t i a l s c o n t r i b u t e t o i n t e s t i n a l c o n t r a c t i o n s ( f r o m B o c k u s H L , e d . G a s t r o e n t e r o l o g y , 3rd c d . ) -3-influence the autonomic nervous system, and hence i n t e s t i n a l a c t i v i t y (8,9,10). Serotonin (5HT) may have a physiologic role i n p e r i s t a l s i s , possibly by stimulating ganglia, s e n s i t i z i n g smooth muscle to the actions of acetylcholine, and s e n s i t i z i n g stretch receptors i n the mucosa, lowering t h e i r threshold (11,12). In the f a s t i n g state, the human small i n t e s t i n e shows only minimal motor a c t i v i t y . A f t e r a meal i s eaten and food enters the duodenum, the motor a c t i v i t y of the i n t e s t i n e increases markedly (12). The function of t h i s a c t i v i t y i s to mix the food thoroughly with the d i g e s t i v e j u i c e s (effected mainly by segmenting contractions), and to transport the mixing and digesting contents of the i n t e s t i n e onward from the duodenum (effected by both segmenting and p e r i s t a l t i c contractions). In general (13), the motor and e l e c t r i c a l a c t i v i t i e s of small i n t e s t i n a l muscle are increased by c h o l e c y s t o k i n i n - l i k e peptides (cholecystokinin -pancreozymin, and g a s t r i n ) and also prostaglandin-E, and decreased by s e c r e t i n - l i k e peptides, with the possible exception (14) of vasoactive i n t e s t i n a l peptide (VIP). The following table summarizes current thinking: Stimulate small bowel contractions I n h i b i t contractions Cholecystokinin Secretin Gastrin M o t i l i n VIP Glucagon Speed small bowel t r a n s i t Slow Tr a n s i t Cholecystokinin VIP M o t i l i n Glucagon (Aft e r Thomas PA. World J Surg. Nov 79) -4-None of these actions have been demonstrated p h y s i o l o g i c a l . What i s known i s : (1) c y c l i c bursts of gastroduodenal contractions that occur during f a s t i n g are accompanied by increased plasma m o t i l i n l e v e l s . (2) contractions c h a r a c t e r i s t i c of the fed state are copied by exogenous administration of g a s t r i n and CCK. The e f f e c t of GIP on small bowel m o t i l i t y has not been investigated. The e f f e c t of intravenous cholecystokinin i s both rapid and s t r i k i n g , and considerably more marked than the e f f e c t of g a s t r i n . A l l regions of the small i n t e s t i n e appear to behave i n the same way, with the exception of the second part of the duodenum, adjacent to the sphincter of Oddi, which relaxes i n response to cholecystokinin. The increased motor a c t i v i t y produced by cholecystokinin i s accompanied by a corresponding decrease i n the time taken by the contents of the small i n t e s t i n e to reach the colon (12). T r a n s i t Time Tra n s i t time has been examined less than other aspects of g a s t r o i n t e s t i n a l m o t i l i t y , but may represent a more ph y s i o l o g i c a l assessment of what i s a c t u a l l y happening to ingested foods. Borgstrom i n 1958 described a method f o r analyzing the digestion and absorption process, by sampling chyme at d i f f e r e n t l e v e l s of the i n t e s t i n a l tract through holes i n p o l y v i n y l tubing, under conditions very c l o s e l y resembling the physiologic state (15). Longstreth has since confirmed that the presence of a transpyloric tube does not a l t e r g a s t r i c m o t i l i t y , secretory or hormonal responses (16). A reference substance, polyethylene g l y c o l , was incorporated as a marker into test meals, and the appearance time, volume and composition measured by a s p i r a t i o n of samples at i n t e r v a l s along the i n t e s t i n e . Developments of t h i s o r i g i n a l technique have led to the dye d i l u t i o n method, marker washout technique, and the use of markers for perfusion studies to measure absorption from or secretion into the lumen (17). Small bowel t r a n s i t , flow rates and peak v e l o c i t i e s can be measured. -5-Markers A v a r i e t y of markers i s a v a i l a b l e , the c r i t e r i a being that they should be i n e r t , non-absorbable, mix uniformly, r e a d i l y assayed, and completely recoverable (18). In the r a d i o l o g i c a l method, barium sulphate i s the usual marker, and s i m i l a r l y vegetable dyes such as carmine red are easy to detect (19), but measure only the head and t a i l of a stream. Barium may also give a f a l s e l y short time, and i t s t r a n s i t time related to that of normally ingested substances remains to be established. Colored beads, non-digested seeds, such as sesame, and radiopaque p e l l e t s are u s e f u l , mainly f o r mouth-to-anus t r a n s i t time (19). Chemical markers, such as polyethylene g l y c o l and chromium sesquioxide, give consistent recoveries (20) and , depending to some extent on the homogenicity of the i n t e s t i n a l contents (21), d i s t r i b u t e evenly under normal conditions and accurately measure t r a n s i t time (22,23). Isotopic variants are also a v a i l a b l e , with the advantage of easy assay by scintiscanning (24). Markers can be given as a bolus (dye d i l u t i o n ) or i n t e r m i t t e n t l y (marker washout) or continuous i n f u s i o n (perfusion studies). The measurement of breath hydrogen following l a c t u l o s e ingestion was introduced recently by L e v i t t (25) and i s being increasingly used. Polyethylene g l y c o l (PEG) i s commonly used as a non-absorbable volume marker i n i n t e s t i n a l perfusion and flow studies. It has been assumed that PEG does not a f f e c t water and e l e c t r o l y t e movement, but recent studies have shown (27) a progressive reduction i n water and e l e c t r o l y t e absorption i n the jejunum and ileum with increasing concentrations of PEG i n the perfusing f l u i d . It seems that t h i s most l i k e l y r e s u l t s from an osmotic e f f e c t rather than an i n h i b i t i o n of active absorption or stimulation of secretion, as the e f f e c t i s mainly seen at PEG concentrations above 5 gm/litre. -6-Known Transit Times Most a v a i l a b l e information has been derived from barium studies. These measure the most rapid t r a n s i t time, from the moment g a s t r i c emptying s t a r t s , to the a r r i v a l of the head of the column at the i l e o - c e c a l valve. These show a large v a r i a t i o n i n normal subjects, with a range 15 min - 5 hours i n 315 subjects, mean 84 min., reported by Kim (28). Texter found a range of 2-3 hours (29). Marine-Fiol reported a range of 2 1/2 - 6 hours i n 49 normals (30). In a c l a s s i c study, Lonnerblad found a mean t r a n s i t time of 178 minutes i n 108 subjects (31). These studies also showed poor r e p r o d u c i b i l i t y i n a given subject: Lonnerblad found an average 66 minute diffe r e n c e from the 1st measurement i n 35 repeat studies. This mean standard deviation f o r a sing l e determination could be 1 hour. Burkett has stated i t i s the t o t a l time ingested material i n contact with the bowel wall that i s important (32), and therefore records t o t a l t r a n s i t time -usually measured as the time f o r a l l ingested p e l l e t s to be passed. Other workers measure mean t r a n s i t time (33), expressed as sum tm sum m where t = ingestion to recovery time of samples m = amount of marker i n sample Bond and L e v i t t have shown a t r a n s i t time average of 72 minutes (range 25-118) f o r 10 gm. of Lactulose, using polyethylene g l y c o l as a marker (25). Individual r e p r o d u c i b i l i t y they found + 14%. They were, however, using a c o l l e c t i n g tube extending down the e n t i r e length of the small bowel to c o l l e c t i l e a l samples, and t h i s may not represent a p h y s i o l o g i c a l s i t u a t i o n . It i s known that the volume and composition of ileostomy f l u i d d i f f e r s from that passing the normal i l e o - c e c a l valve (33). Soergel and Hogan however, - 7 -have s t u d i e d t r a n s i t t i m e i n i l e o s t o m y p a t i e n t s u s i n g p o l y e t h y l e n e g l y c o l as a m a r k e r and f o u n d a mean t r a n s i t t i m e o f 1 1/2 h o u r s , s i m i l a r t o t h a t o b t a i n e d f o r s m a l l b o w e l i n i n t a c t g a s t r o i n t e s t i n a l t r a c t s ( 2 2 ) . F a c t o r s A f f e c t i n g T r a n s i t Time T r a n s i t t i m e i s t h e p r o d u c t o f a v a r i e t y o f c o n d i t i o n s o f m o t o r a c t i v i t y o f t he gu t and p h y s i c a l s t a t e o f t he f o o d . U s i n g b a r i u m , G o l d e n has s t a t e d t h a t most r a p i d t r a n s i t t i m e i s n o t i n f l u e n c e d by the r a t e o f e m p t y i n g o f t he s tomach (34). Weigen c o n f i r m e d t h i s i n dogs (35), and L o n n e r b l a d ' s s t u d i e s i n humans a l s o showed no a p p r e c i a b l e change i n s tomach e m p t y i n g t i m e w i t h r e s p e c t t o t r a n s i t t i m e . He a l s o found t h a t e m o t i o n a l f a c t o r s ( f r i g h t , a p p r e h e n s i o n ) c o u l d n o t be shown t o m a r k e d l y i n f l u e n c e t r a n s i t t i m e . M e e r o f f s t a t e s t h a t g a s t r i c e m p t y i n g a p p e a r s t o be r e g u l a t e d by o s m o l a l i t y o f d u o d e n a l c o n t e n t s . O s t i c k has s t u d i e d the e f f e c t o f c o n s i s t e n c y o f f o o d on g a s t r i c e m p t y i n g ( 3 6 ) , and B e n n e t t has shown s t i m u l a t i o n o f i n t e s t i n a l p r o p u l s i o n by l o w e r e d i n t r a l u m i n a l pH ( 3 7 ) . The p o s s i b i l i t y o f " s t r e a m i n g " i n t h e g a s t r o i n t e s t i n a l t r a c t has been r a i s e d by s e v e r a l a u t h o r s . S t r e a m i n g o c c u r s i f t h e r e i s a d i f f e r e n t i a l f l o w r a t e be tween t h e s o l i d and l i q u i d phase s o f t h e gu t c o n t e n t s . F i n d l a y c o n c l u d e d t h a t s t r e a m i n g does n o t o c c u r i n n o r m a l s u b j e c t s ( 2 1 ) . W a l l e r has s u g g e s t e d c o l o n i c t r a n s i t , r a t h e r t h a n g a s t r i c e m p t y i n g o r s m a l l b o w e l t r a n s i t t i m e , d e t e r m i n e s o v e r a l l t r a n s i t t i m e , a t l e a s t i n p a t i e n t s w i t h g r o s s a b n o r m a l i t i e s o f t o t a l t r a n s i t t i m e - c o n s t i p a t i o n and d i a r r h e a ( 2 6 ) . H a r v e r y h o w e v e r , s t a t e s t h a t t h e o r d e r l y a s s i m i l a t i o n o f a m e a l i s i n l a r g e p a r t dependen t upon o p t i m a l r a t e s o f g a s t r i c e m p t y i n g and o f s m a l l b o w e l t r a n s i t , and t h a t changes i n m o t o r a c t i v i t y a f t e r f o o d , s e e n a t a l l l e v e l s o f t h e g a s t r o e n t e s t i n a l t r a c t , a r e m a r k e d l y i n f l u e n c e d by g a s t r o i n t e s t i n a l hormones ( 1 0 ) . -8-G a s t r o i n t e s t i n a l Hormones and Secretion In 1938 Nasset reported that c e r t a i n extracts of i n t e s t i n a l mucosa stimulate i n t e s t i n a l s ecretion (38). He named the active p r i n c i p l e " e nterocrinin". In addition to the three recognized g a s t r o i n t e s t i n a l hormones, s e c r e t i n , g a s t r i n and cholecystokinin, there are a large number of what might be c a l l e d candidate hormones. Of the three well known hormones, only g a s t r i n (and pentagastrin) stimulates i n t e s t i n a l secretion. Glucagon, a pancreatic i s l e t hormone, also stimulates (39). Two other peptides, vasoactive i n t e s t i n a l peptide (VIP) and g a s t r i c i n h i b i t o r y peptide (GIP) have also been shown to stimulate small gut secretion (39,40,41,42,43,44). The e f f e c t of these peptides on gut secretion has been shown to be s i m i l a r to that of c y c l i c AMP, stimulation of the adenyl cyclase system being the l i k e l y f i n a l common path f o r a l l known stimulants, including cholera toxin and prostaglandins (45). Excessive secretion from the gut i s a well known pathological phenomenon, best i l l u s t r a t e d by cholera. Rates of f l u i d s ecretion s i m i l a r to those produced by cholera toxin have been produced i n response to several gut peptides (39,46,47). As i n cholera, the protein content of these secretions i s low, i n d i c a t i n g that mucosal i n t e g r i t y has been maintained, unlike the secretion r e s u l t i n g from increased i n t e r s t i t i a l hydrostatic pressure. The p o s s i b i l i t y has been raised that cholera toxin acts at least i n part by releasing one of the gut peptides (53). Some pancreatic i s l e t - c e l l tumors are known to produce VIP, causing depressed g a s t r i c secretion and watery diarrhea. A d i f f e r e n t explanation, based on the same observations, would be to regard the small bowel not as an organ which receives some 2 l i t r e s of g a s t r i c and -9-d i g e s t i v e secretions into i t s proximal end each day and passes 1 l i t r e d i s t a l l y through the i l e o c a e c a l valve, but as an organ i n active f l u x , analagous to the kidney. I f , say, 50 l i t r e s of i n t e s t i n a l secretions were produced d a i l y , and 49 l i t r e s a c t i v e l y resorbed, through a c y c l i c AMP-mediated mechamism, the net r e s u l t would be the same. Profound changes could then be brought about by any interference with c y c l i c AMP. It i s possible that cholera toxin, and also the peptides increasing net secretion, may act by blocking the cyclic-AMP mechamism. Conversely, potentiation of the resorptive mechanism would produce a decrease i n net secretion. GIP was i s o l a t e d from a side f r a c t i o n obtained during the p u r i f i c a t i o n of cholecystokinin - pancreozymin by Brown i n Vancouver (48,49). It i s a candidate f o r the t h e o r e t i c a l hormone "enterogastrone", suggested o r i g i n a l l y by Kosaka and Lim, which i s l i b e r a t e d by f a t or i t s digestion products and which i n h i b i t s g a s t r i c secretion and m o t i l i t y . In addition to an i n h i b i t o r y e f f e c t on acid secretion, GIP has been shown to be i n i n s u l i n o t r o p i c , potentiating i n s u l i n release to an intravenous infusion of glucose, and improving glucose tolerance i n man (44,50). Thus GIP has been shown to have at least 3 diverse e f f e c t s : the i n h i b i t i o n of g a s t r i c a c i d secretion and m o t i l i t y (enterogastrone e f f e c t ) , release of i n s u l i n ( i n c r e t i n e f f e c t ) , and stimulation of i n t e s t i n a l secretion (enterocrinin e f f e c t ) . The physiologic s i g n i f i c a n c e of the e n t e r o c r i n i n e f f e c t of GIP i s s t i l l uncertain. Helman and Barbezat have shown (40,41), using a t r i p l e lumen tube j e j u n a l perfusion technique that during GIP i n f u s i o n there i s a net reduction i n sodium, potassium and bicarbonate absorption, and that chloride f l u x i s switched from absorption to secretion. They conclude that GIP induces secretion from the small bowel. -10-Recent work has shown that p h y s i o l o g i c a l l e v e l s of GIP probably do not cause s i g n i f i c a n t i n h i b i t i o n of g a s t r i c acid or pepsin secretion i n humans (52), and that i t s p r i n c i p l e e f f e c t would seem to be i n s u l i n o t r o p i c . Bloom has i n fact suggested that the a l t e r n a t i v e t i t l e of "Glucose-dependent Insulinotropic Peptide" ( s t i l l GIP) i s preferable (53). The e f f e c t of G-I hormones can be investigated by administration, or by provoking t h e i r p h y s i o l o g i c a l release. In humans, the l a t t e r i s obviously preferable. Cleator and Gourlay i n Vancouver have shown that o r a l ingestion of food substances, i n p a r t i c u l a r glucose and f a t , provoke the release of GIP (54). This has recently been confirmed by Williams (55), who has shown that only glucose of the common dietary sugars produces a strong stimulation, and that only t r i g l y c e r i d e i n the form of corn o i l , rather than i n d i v i d u a l f a t t y acids, causes GIP release. Thomas has demonstrated weak stimulation of GIP secretion by intraduodenal amino acids (56). This i s not confirmed i n Williams' recent study. -11-PURPOSE OF STUDY There i s a need f o r a simple technique which r e l i a b l y r e f l e c t s the t r a n s i t time of ingested foodstuffs i n the small bowel, and which i s p r a c t i c a l , safe, reproducible and, therefore suitable as an experimental model for i n v e s t i g a t i o n of the c o n t r o l of gut m o t i l i t y . The objectives i n t h i s work are to develop and validate such a method i n ileostomy patients, and then to use i t i n patients with established ileostomies to determine the influence of various f l u i d s and primary foodstuffs on upper g a s t r o i n t e s t i n a l t r a n s i t and secretion, and t h e i r possible r e l a t i o n s h i p to GIP. A study was designed to show i f the o r a l ingestion of foodstuffs calculated to provoke hormone release, and s p e c i f i c a l l y GIP, produce measurable changes i n small bowel m o t i l i t y , measured by t r a n s i t time, and in secretion. -12-MATERIALS AND METHODS Patients were selected from those attending the Stoma C l i n i c at St. Paul's Hospital, Vancouver, who had long standing ileostomies as a r e s u l t of u l c e r a t i v e c o l i t i s , and were i n good health, with normally functioning ileostomies. This was done with the help of the United Ostomy Association, and informed consent was obtained from the patient and family physician. The study was approved by the University of B.C. Medical Screening Committee f o r research involving" human subjects. There were a t o t a l of 9 patients, 5 female and 4 male, with an age range of from 23-63 years. A l l had had s a t i s f a c t o r y stomas for at least 5 years (range 5-17 years). This provided patients with normal small bowel, e a s i l y accessible f o r study. -13-COLLECTION OF ILEOSTOMY'FLUID I n i t i a l l y , attempts were made to c o l l e c t the ileostomy e f f l u e n t d i r e c t l y from the ileostomy. The stoma appliance was removed, and a red rubber catheter inserted into the stoma. A f t e r a number of accidents and s p i l l a g e s , and also f i n d i n g that a catheter placed i n an ileostomy which i s functioning i s r a p i d l y extruded anyway, i t was found that simply c o l l e c t i n g d i r e c t l y from the stoma bag was s a t i s f a c t o r y . The volunteer emptied the stoma bag immediately before each experiment, then l e f t i t open and emptying into a 250 ml. Pyrex glass beaker. F l u i d specimens were c o l l e c t e d by dependent drainage, poured into a 100 ml measuring cylinder, the volume measured and then pooled a f t e r a 5 ml aliquot had been taken for subsequent PEG analysis. - 1 4 -PILOT STUDIES  S t u d y 1 An i n i t i a l s e r i e s o f t e s t s u s i n g v a r i o u s vo lumes o f n o r m a l s a l i n e ( 2 0 0 c c , 300 c c , 500 c c , 750 c c and 1000 c c ) i n 4 v o l u n t e e r s , f a s t e d o v e r n i g h t , we re p e r f o r m e d t o a s c e r t a i n t h e vo lume o f f l u i d r e q u i r e d to e n s u r e a c o n t i n u o u s l y m e a s u r a b l e i l e o s t o m y o u t p u t f o r a t l e a s t 2 h o u r s , the p e r i o d c h o s e n d u r i n g w h i c h t h e h o r m o n a l r e s p o n s e s t o t h e f e e d s w o u l d o c c u r . No t a l l v o l u m t e e r s were s t u d i e d a t a l l v o l u m e s . The t e s t vo lume was d runk c o n t i n u o u s l y , i n l e s s t h a n 2 m i n u t e s . 500 m l was s e l e c t e d as s u i t a b l e , m e a s u r a b l e a l i q u o t s b e i n g o b t a i n a b l e a t 10 m i n u t e i n t e r v a l s , and p e r s i s t i n g f o r 2 h o u r s . Volumes l e s s t h a n 500 m l d i d n o t p r o d u c e p r e d i c t a b l e r e s p o n s e s , i n some c a s e s t h e i l e o s t o m y n o t f u n c t i o n i n g a t a l l d u r i n g the t e s t p e r i o d , and vo lumes o v e r 500 m l were d i f f i c u l t f o r some v o l u n t e e r s t o d r i n k c o n t i n u o u s l y . S t u d y 2 V a r i o u s amounts o f P o l y e t h y l e n e G l y c o l (PEG) were added t o t h e t e s t f eeds i n the same 4 v o l u m t e e r s ( 2 . 5 gm, 5 gm, 10 gm, and 15 gm) t o p r o d u c e c o n c e n t r a t i o n s o f f r o m 500 m g / d l t o 1500 m g / d l , t o d e t e r m i n e t h e amount t o be added t o p r o d u c e a PEG l e v e l above 200 m g / d l i n the i l e o s t o m y o u t p u t , t he t h r e s h o l d f o r a c c u r a t e a n a l y s i s ( s e e u n d e r PEG a n a l y s i s ) . Not a l l t e s t vo lumes were s t u d i e d a t a l l PEG c o n c e n t r a t i o n s . 2 . 5 gm PEG p e r 500 m l was s e l e c t e d , a c o n c e n t r a t i o n o f 500 m g / d l . Carmine Red (300 mg) was i n i t i a l l y added t o a l l f e e d s , t o a c t as a v i s u a l m a r k e r o f t h e most r a p i d and t o t a l t r a n s i t t i m e s so t h a t some i n d i c a t i o n c o u l d be g a t h e r e d o f when PEG m i g h t be a p p e a r i n g , f o r subsequen t a n a l y s i s , and a l s o as a s o l i d phase m a r k e r , t o a s s e s s p o s s i b l e " s t r e a m i n g " . S t u d y 3 I n d i v i d u a l v a r i a t i o n u n d e r s t a n d a r d c o n d i t i o n s , t h a t i s r e p r o d u c i b i l i t y , was t h e n a s s e s s e d i n a t o t a l o f 4 p a t i e n t s , m e a s u r i n g volume and PEG r e c o v e r i e s o f 500 m l n o r m a l s a l i n e on a t l e a s t 2 o c c a s i o n s , on d i f f e r e n t d a y s . -15-TEST FEEDS Six ileostomy patients were given test meals of : 1. 500 cc 5% dextrose 2. 500 cc normal sa l i n e 3. 90 cc Lipomul + 410 cc normal s a l i n e A l l feeds were isoosmolar and constant pH (7.4) by measurement i n St. Paul's Hospital c l i n i c a l laboratory. Test meals were l a b e l l e d with 2.5 gm polyethylene g l y c o l 4000 (500 mg/dl). An IV drip with normal saline was established i n the forearm, and 5 ml blood samples were taken at F, 5', 10', 20', 30', 45', 60', 90' and 120' and aliquoted for GIP, glucose and i n s u l i n . Benzamidine (50 u moles/ml) was added to GIP aliquots as a preservative. Ileostomy e f f l u e n t following the test meal was c o l l e c t e d every 10 minutes, the volume recorded, and the sample pooled a f t e r an aliquot was taken for l a t e r PEG analysis. An aliquot of the pooled effluent c o l l e c t e d over the test period was sent to the St. Paul's c l i n i c a l laboratory f o r e l e c t r o l y t e measurement. By comparison of the o p i t i c a l d e n s i t i e s of the treated PEG samples to a set of standards, a measurement of the concentration of PEG i n mg/dl was made. This value m u l t i p l i e d by the volume of that p a r t i c u l a r sample gives the actual amount of PEG i n that sample. It i s therefore possible to know how much of the 2.5 gm i n i t i a l l y given i s recovered over the test period. This recovery of PEG, expressed as a percentage of the amount given i n the test feed, can then be compared to the volume recovery of the same feed, and an i n d i c a t i o n i s then obtained as to whether net absorption or secretion has occurred. Further studies were l a t e r added i n 3 patients using: 4. 500 cc 31/3% dextrose/saline 0.3% 5. 500 cc d i s t i l l e d water 6. 500 cc normal sa l i n e + 2 tablespoons bran 7. 100 cc 10% Travasol + 400 cc d i s t i l l e d water. The study design was the same as above. -16-PEG ASSAY PEG analysis i s performed according to the method of Sidney J Malawer (52). This method involves the development of an oil-in-water emulsion of PEG when exposed to t r i c h l o r o a c e t i c acid i n the presence of barium ions. The oil-i n - w a t e r emulsion i s s t a b i l i z e d by the addition of an emulsifying agent, gum arabic. This produces a stable and prolonged peak of maximum t u r b i d i t y . An i n i t i a l Ba (OH)^ - ZnSO^ - BaCl^ p r e c i p i t a t i o n / f i l t r a t i o n step serves to remove protein and sulfates ( i n t e r f e r i n g substances) from the reaction mixture. A standard curve of PEG concentrations ranging from 200 - 1100 mg/100 ml gives a l i n e a r r e l a t i o n s h i p with the o p t i c a l density at 650 mu and therefore affords determination of the unknown PEG concentrations to the nearest mg per 100 ml (Figure 13 and Table 15). Duplicate determinations were performed on a l l standards and samples. Standard solutions of PEG (Polyethylene Glycol 4000, Union Carbine Corporation, New York. Average molecular weight 3000-3700) were prepared freshly each morning f o r a sing l e day's experiments. A single l o t number of PEG was used throughout t h i s study. \ -17-To 50 ml. Erlenmeyer flasks containing 1 ml of d i s t i l l e d water (for the blank), a 1 ml PEG standard solution, or gut j u i c e sample with PEG concentrations designed to be between 300 and 1100 mg per 100 ml, the following were added: 10 ml of water 1 ml of 10% (w/v) BaCl^ anhydrons 2 ml of 0.3 N Ba (0H) 2 These were mixed by s w i r l i n g a f t e r each a d d i t i o n 2 ml of 5% 2nS0. . 7H.0 4 2 The f l a s k s were then capped with parafilm and shaken vigorously. The flasks are then l e f t to stand at room temperature f o r 10 minutes, and then the contents f i l t e r e d through double thickness Whatman no. 42 f i l t e r paper. 1 ml aliquots of the f i l t r a t e s are transferred to 16 by 150 mm test tubes, 3 ml of gum arabic s o l u t i o n (Acacia Gum Arabic , U.S.P. powder. Fisher S c i e n t i f i c Co. Cat. No. 9-85) i s added and mixed by gentle a g i t a t i o n . 4 ml of 30% t r i c h l o r o a c e t i c acid (TCA) containing 5% (w/v) BaC^ anhydrous, are added by pipette, the tubes capped with parafilm, and mixed by i n v e r t i n g 5 t imes. This TCA reagent i s added to the samples sequentially and each mixed immediately. Sixty to ninety minutes l a t e r , the o p t i c a l densities of the samples are read against the blank i n standard 4 ml, 10 mm l i g h t path absorption c e l l s , using a Pye Unicam Spectrophotometer set at 650 mu and a s l i t width of 0.04 mm. A standard curve i s constructed and the unknown samples are read from t h i s graph to the nearest mg per 100 ml. With t h i s procedure, the f i n a l reaction mixture (8 ml) contains 0.19 to 0.69 mg of PEG i f the o r i g i n a l samples contained 300 to 1100 mg per 100 ml. -18-STATISTICS Standard s t a t i s t i c a l methods are employed, with data c o l l e c t e d s u i t a b l e for analysis by paired t - t e s t . Values are recorded as mean - S.E.M. Regression analysis was used to plo t c o r r e l a t i o n c o e f f i c i e n t s of control and r e p r o d u c i b i l i t y experiments using a logarithmic transformation. Detailed c a l c u l a t i o n s were according to Bailey NTJ: S t a t i s t i c a l methods i n Biology, The English U n i v e r s i t i e s Press, London, 1974. -19-RESULTS P i l o t Studies : Controls and Reproducibility  Study 1 Oral doses of 200 ml and 300 ml of normal saline produced n e g l i g i b l e ileostomy outputs, varying between 0 and 5 ml per 10 minute i n t e r v a l . 500 ml produced a r e l i a b l e and predictable response i n a l l i n d i v i d u a l s tested, with a peak recovery at 40 minutes, returning to basal l e v e l s within 2 hours (Figure 3). Volumes greater than 500 ml produced the same recovery pattern, but the 10 minute aliquots became much larger (up to 390 ml) and rather unmanageable, and the volunteers had some d i f f i c u l t y drinking the volume continuously. Study 2 It was found that addition of 2.5 gm of PEG to 500 ml of test feed (500 mg%) resulted i n s a t i s f a c t o r y l e v e l s f o r analysis, above 200 mg% i n the ileostomy output. PEG analysis of the specimens c o l l e c t e d i n Study 1 showed the same pattern for PEG recovery as f o r volume recovery (Figure 4), the s t r i k i n g f i n d i n g being that measurable quantities of PEG appeared i n a l l cases i n the f i r s t aliquot, c o l l e c t e d at 10 minutes. This i s considerably f a s t e r than the most rapid t r a n s i t times reported so f a r by other methods. Use of carmine red was discontinued a f t e r an i n i t i a l 3 studies i n which the volunteers were inconvenienced by i t s continuing appearance i n ileostomy e f f l u e n t f or at least 24 hours. It i n i t i a l l y appeared i n less than 10 minutes i n a l l 3 volunteers. Study 3 Individual r e p r o d u c i b i l i t y proved s a t i s f a c t o r y (Figures 3 and 4 showing re a d i l y i d e n t i f i a b l e recovery patterns with acceptible S.E.M. values). T y p i c a l i n d i v i d u a l r e s u l t s are shown i n Figures 5a and 5b. The r e p r o d u c i b i l i t y of the method was tested with a regression analysis of pooled data, using logarithmic transformations of volume and PEG values (Figure 6). Correlation c o e f f i c i e n t s were 0.68 for volume recovery and 0.69 for PEG recovery, acceptible values for b i o l o g i c a l data of t h i s sort, the s t a t i s t i c a l s i g n i f i c a n c e being p = < .05. 20-EFFECTS OF TEST FEEDS (a) Transit A s t r i k i n g delay i n the peak volume recovery (90 min) and PEG recovery (90 min) was shown i n response to 500 ml of 5% glucose, and also i n response to 500 ml s a l i n e containing 90 ml of Lipomul, which produced a peak volume recovery at 60 min. and PEG recovery at 70 min (Figure 7). Detailed r e s u l t s are presented i n Tables 7 - 10. These are s i g n i f i c a n t changes (P = < .01). -21-(b) Secretion Large changes are seen when percentage recovery of volume and PEG over the 2 hours c o l l e c t i n g period are calculated (Table 1). These are presented as Histograms i n Figure 8. There i s no s i g n i f i c a n t d i f f e r e n c e between the PEG recovery f o r sa l i n e and Lipomul - 62% and 58% (p = > .0,5), but a s i g n i f i c a n t difference (p = < .05) between volume recoveries - 249 ml f o r sal i n e (48%) and 323 ml f o r Lipomul (66%). This indicates net f l u i d absorption with sali n e , and net f l u i d secretion with Lipomul. The most dramatic, and unexpected, finding was with 500 ml of 5% glucose, where average volume recovery was just 21 ml at 2 hours (4%), and PEG recovery was 13%. (p = < .01). This indicates a very large net f l u i d absorption. In f a c t , i n 2 of the 6 patients tested, there was no recordable output at a l l from the stoma f o r the 2 hour period. The p o s s i b i l i t y of PEG absorption also has to be considered with these r e s u l t s . A f t e r t h i s part of the study was completed and the results apparent, a further 3 tests were performed i n the same patients using isoosmolar glucose i n saline and 500 ml of d i s t i l l e d water. N e g l i g i b l e amounts of ileostomy output were obtained over 2 hours (Tables 11 and 12), containing minimal PEG. A further 3 studies were done using an issosmolar protein solution, 100 ml of 10% Travasol i n 400 ml water, and minimal volume and PEG recoveries obtained over 2 hours (Table 13). -22-(c) E l e c t r o l y t e Composition Analysis of the t o t a l volumes c o l l e c t e d over 2 hours for e l e c t r o l y t e s i s shown i n Table 2. This shows a net secretion of potassium with a saline test feed, and a larger net secretion with glucose or Lipomul. There i s net secretion of chloride i n response to saline and no change with Lipomul. There i s net secretion of sodium i n response to Lipomul when compared to s a l i n e . Secretion of sodium and chloride i n response to dextrose cannot be assessed because of the small volume of the samples, and could not be measured with dextrose i n s a l i n e or protein because no samples could be obtained. -23-(d) Hormonal Responses These are shown i n Figure 9. GIP, sugar and i n s u l i n l e v e l s were unchanged a f t e r normal saline ingestion, as expected. Sugar and i n s u l i n l e v e l s were unchanged a f t e r Lipomul, but GIP increased to expected l e v e l s , although rather slower than expected. This may be related to the use for radioimmunoassay of an early antiserum, GP01. GIP, sugar and i n s u l i n l e v e l s increased to expected values a f t e r o r a l glucose. -24-DISCUSSION V a l i d i t y of Method This series of studies has shown that the method proposed for studying upper g a s t r o i n t e s t i n a l t r a n s i t time i n humans, using ileostomy patients, i s safe, simple, reporducible and subject to acceptable i n d i v i d u a l v a r i a t i o n . The use of PEG 4000 as a Liquid-phase marker has been shown to co n s i s t e n t l y and reproducibly match the recovery of volume i n co n t r o l studies using o r a l normal s a l i n e . This work shows that the recovery of volume and chemical markers following an o r a l s a l i n e load from an ileostomy follows a skew d i s t r i b u t i o n . Therefore, mode, median and mean t r a n s i t times w i l l a l l be d i f f e r e n t (Figure 10). Previous studies of small bowel t r a n s i t time have reported: (a) most rapid t r a n s i t time: f o r barium a range of 15 min - 6 hours, standard deviation 1 hour (31) and f o r PEG i n lactose an average of 72 min with a range of 20 - 120 min and a r e p r o d u c i b i l i t y of + 14% (25). (b) mean t r a n s i t time: 90 min f o r PEG i n s a l i n e (22) (c) t o t a l t r a n s i t time (18), which i s probably best suited f o r measurement of mouth-to-anus t r a n s i t . This method conveniently provides a measurement of a l l these, and also allows mode and median values to be assessed. Measureable amounts of PEG have always been present i n the f i r s t 10 minute sample, thus the most rapid t r a n s i t time by t h i s method i s consistently less than 10 minutes, and gives no useful comparitive data. This i n i t s e l f i s considered an important fi n d i n g i n that most rapid t r a n s i t times f o r small bowel t h i s short have not generally been described before, although s i m i l a r figures have been obtained by L e v i t t using the expired-breath measurement technique (25), an i n d i r e c t method. The reasons f o r this variance from the l i t e r a t u r e may include: 1) most rapid t r a n s i t times have not been measured -25-before i n ileostomy patients 2) most rapid t r a n s i t times have previously been measured by other methods - such as with barium, radiotelemetering capsules and with long transpyloric j e j u n a l tubes. The most reproducible and e a s i l y measured single value i s mode or peak t r a n s i t time. It i s e a s i l y i d e n t i f i e d by inspection of the volume recovery data, i s confirmed by subsequent analysis of PEG marker and i s subject to l i t t l e enough i n d i v i d u a l v a r i a t i o n to make changes easy to detect. Peak t r a n s i t time has not been used before i n studies of i n t e s t i n a l m o t i l i t y . Most work c u r r e n t l y published using PEG as a marker employs Hyden's o r i g i n a l method of Turbidimetric analysis, published i n 1955 i n a rather inaccessible journal (58). It took nearly a year to obtain a copy of this a r t i c l e through standard U n i v e r s i t y of B.C. l i b r a r y procedures. A modification, using an e m u l s i f i e r , which s i m p l i f i e s the technique considerably by prolonging the stable phase of the emulsion, was published by Malawer i n 1967 (57), but does not seem to have received a t t e n t i o n . This modification has provided extremely accurate extimation of PEG i n our laboratory, c o r r e l a t i o n c o e f f i c i e n t s of standard plots being of the order of 0.997, and deserves wider use. The dose l e v e l of PEG used i n th i s study was below the minimum l e v e l found to possibly exert an osmotic e f f e c t on absorption i n the small bowel (27). -26-Advantages and Disadvantages The advantages of a human model for studies of i n t e s t i n a l physiology are r e a d i l y apparent: there i s not the problem of whether the animal model r e f l e c t s the human s i t u a t i o n . As already discussed, most information on small bowel function has been obtained e i t h e r i n d i r e c t l y , or by rather unphysiologic means: long nasogastric tubes have been passed into the small bowel, often with balloons i n f l a t e d , and the information obtained i n d i r e c t l y by pefusion methods. The model used i n t h i s study provides a d i r e c t method of studying the small bowel, using what i s e f f e c t i v e l y a terminal f i s t u l a . In some ways th i s i s reminiscent of the early studies on g a s t r i c secretion, using subjects with g a s t r i c f i s t u l a e . This method seems very s u i t a b l e f o r the modalities under study, namely t r a n s i t time and secretion. A number of disadvantages of using a human model were also rapidly apparent during these i n v e s t i g a t i o n s , despite the enthusiastic cooperation of the volunteers at a l l times. It was p r a c t i c a b l e to perform only one test per day, as the subjects fasted overnight, and thus only 3 or 4 per week, with i n e v i t a b l e cancellations due to i l l n e s s , missed appointments, and problems with equipment and supplies. The work therefore proceeded much more slowly than other work i n the department using animals. There were problems i n the number of volunteers i n c o l l e c t i n g the required blood samples, due to poor peripheral veins which had been used repeatedly during h o s p i t a l admissions, and 14 experiments had to be repeated or were incomplete because of t h i s . Possible Sources of E r r o r These can be considered under two categories; error inherent i n the model, and errors i n measurement. The differences between the f l u i d emerging from an ileostomy and that passing a normal i l e o c e c a l valve have to be considered when in t e r p r e t i n g data on secretion (33). With regard to m o t i l i t y , s i m i l a r mean t r a n s i t times have been observed from ileostomies as f o r small bowel i n i n t a c t g a s t r o i n t e s t i n a l tracts (21), but the absence of the i l e o c e c a l valve may possibly have an e f f e c t on t r a n s i t . Also, the absence of a colon i n these patients has to be noted. Seal and Debas have shown (57) that the colon may well be the source of hormonal factors a f f e c t i n g at least g a s t r i c secretion. It i s possible these hormones may also have an e f f e c t on small bowel. None of the patients i n t h i s study had any d i f f i c u l t y taking the test feeds i n a reproducible manner, i n less than two minutes steady drinking. The method of c o l l e c t i n g samples was simple and provided volumes of ileostomy f l u i d of betweem 3 and 90 ml at 10 minute i n t e r v a l s , measured to the nearest 1 ml. The r e p r o d u c i b i l i t y figures already quoted support that methods of measurement were accurate f o r b i o l o g i c a l specimens of this s o r t . The c o r r e l a t i o n c o e f f i c i e n t s quoted for our standard plots for PEG analysis (0.997) confirm that a n a l y t i c a l error i s extremely u n l i k e l y . The main aim of t h i s study has been to gather information on small bowel function: i n the model used, mouth-to-ileostomy t r a n s i t time has been measured. The test feeds were designed to a l l be equivalent, as f a r as known physical factors a f f e c t i n g g a s t r i c emptying are concerned, such as composition ( L i q u i d ) , volume, osmolality, pH. In order to eliminate possible v a r i a t i o n s i n g a s t r i c emptying rate and to obtain a pure measure of small bowel t r a n s i t time, the o r i g i n a l protocol c a l l e d f or a further series of tests to be done, i n s t i l l i n g the test feeds d i r e c t l y into the duodenum v i a a nasogastric tube passed through the pylorus. This proved not possible within the time -28-a v a i l a b l e , due to lack of volunteers w i l l i n g to comply. A subsequent inv e s t i g a t o r s i m i l a r l y was not able to perform these studies. A simpler method of measuring the e f f e c t of these test feeds on g a s t r i c emptying time has been devised (see further work). A further consideration i s that t h i s method, measuring mouth-to-ileostomy t r a n s i t time, may also be affected by other enteric secretions, including s a l i v a , acid, mucons, b i l e , pancreatic j u i c e , and succus entericus. The measurements obtained therefore w i l l r e f l e c t the net e f f e c t of a l l these, l e s s any absorption. The data obtained on secretion w i l l also be the net e f f e c t of a l l these. E f f e c t of Test Feeds This study has shown that o r a l ingestion of isotonic solutions of normal sa l i n e , f a t , glucose and protein r e s u l t i n widely d i f f e r e n t t r a n s i t times i n ileostomy patients. They also r e s u l t i n widely d i f f e r e n t f l u i d outputs due to net absorption or secretion. These differences have not been described before. The test feeds were chosen to p h y s i o l o g i c a l l y provoke the release of c e r t a i n g a s t r o i n t e s t i n a l hormones, G.I.P. i n p a r t i c u l a r . The cause of these a l t e r a t i o n s i n t r a n s i t time and net f l u i d output may be due to the release of g a s t r o i n t e s t i n a l hormones. -30-SUMMARY This study was designed to v a l i d a t e a new method of studying upper g a s t r o i n t e s t i n a l t r a n s i t time and secretion i n humans, using ileostomy patients, and Polyethylene Glycol (PEG) as a marker. We have confirmed the accuracy of Malawer's modification, using an emulsifier, of Hyden's turbidimetric method of analysis of PEG. We have found that, i n a co n t r o l s i t u a t i o n , the recovery of PEG co n s i s t e n t l y and reproducibly matches the volume recovery of a test feed of normal sa l i n e from an ileostomy. It also matches the recovery of various foodstuffs given as test feeds, and provides an i n d i c a t i o n as to whether net absorption or secretion has occurred. In the s i t u a t i o n of net f l u i d absorption i n response to a p a r t i c u l a r foodstuff, such as glucose, the profound disappearance also of PEG from recovered samples must r a i s e the p o s s i b i l i t y of absorption also of PEG: previously, PEG has been thought a non-absorbed marker. We have found that the recovery pattern of a control test feed follows a skew d i s t r i b u t i o n : therefore, the mode, median and average t r a n s i t times w i l l a l l be d i f f e r e n t . Previous studies of small bowel t r a n s i t time have reported variously most rapid t r a n s i t time, mean t r a n s i t time, aor t o t a l t r a n s i t time. This method conveniently provides a measure of a l l of them. We have found that the most reproducible and e a s i l y measured i s mode, or peak t r a n s i t time. This i s r e a d i l y i d e n t i f i e d by inspection of volume recovery data, and i s confirmed by PEG analysis of samples, and i s subject to l i t t l e i n d i v i d u a l v a r i a t i o n under standard or test conditions. The most rapid t r a n s i t time, by th i s method, measured by PEG recovery from the ileostomy, i s cons i s t e n t l y less than 10 minutes, f a r less than previously reported by other methods. We have shown that isotomic solutions of normal salin e , glucose, f a t and protein r e s u l t i n widely d i f f e r e n t peak t r a n s i t times i n ileostomy patients. They also r e s u l t i n widely d i f f e r e n t f l u i d outputs from the ileostomy due to -31-net absorption or secretion. These differences have not been described before. Further work includes i n v e s t i g a t i o n of whether these a l t e r a t i o n s i n t r a n s i t time and net f l u i d output are related to the release of g a s t r o i n t e s t i n a l hormones. -32-CLTNICAL APPLICATIONS OF METHOD Now that the method has been established and validated, and the observations made of the response to the various test feeds, a number of c l i n i c a l a pplications have become apparent: A patient with an ileostomy and short bowel syndrome due to small bowel resection, who was successfully treated with a reversed j e j u n a l segment, has been studied and t r a n s i t times measured i n response to normal s a l i n e . The recovery pattern f o r volume and PEG i s most i n t e r e s t i n g , and follows a biphasic pattern, with the second peak being s t r i k i n g l y larger (Figure 11). If this recovery pattern i s compared to normal controls (Figure 12), one notes that the i n i t i a l peaks coincide at 30 minutes, and that at 60 minutes, the time of the second peak i n the study subject, there i s a suggestion of a minor peak, or "hump" on the control curve. This could possibly be due to a reserv o i r e f f e c t i n the normal small bowel, which acts to spread out volume t r a n s i t by distending and e f f e c t i v e l y "ballooning", and t h i s e f f e c t might be absent i n a short bowel subject. Patients with Koch-pouch "continent ileostomies" are being studied with respect to t r a n s i t time and secretion. Patients with ileostomies who catch influenza often become profoundly i l l with uncontrollable diarrhea, dehydration and e l e c t r o l y t e imbalance. We have treated several such patients with o r a l doses of 50% glucose and have observed a dramatic diminution i n ileostomy output to almost normal l e v e l s . A temporary diminution i n output has been achieved i n a patient with severe chronic ileostomy diarrhea, and also a d i m i n i t i o n i n the temporary diarrhea which follows refashioning of an ileostomy stoma. These empirical findings can now be studied further using t h i s method. -33-FURTHER WORK Dietary f i b r e i s known to exert a profound influence on g a s t r o i n t e s t i n a l t r a n s i t time, and i t s main e f f e c t has been presumed to be on the large bowel. The e f f e c t of bran on the small bowel i s being assessed with t h i s technique. So f a r , i n three volunteers, no di f f e r e n c e has been found i n any of the types of t r a n s i t time, measured by volume or PEG recovery, using bran i n normal s a l i n e , when compared to controls with normal sa l i n e only. The t r a n s i t and secretory response to standard test feeds of normal saline i s being studied during i n f u s i o n of selected peptide hormones, commencing with GIP. This i s to f i n d out i f any of the observed e f f e c t i n response to lipomul and glucose can be ascribed to release of known hormones. Results are incomplete, due to problems with GIP supply and subsequently with GIP assay, but 3 tests have been performed so f a r (Table 14), giving a standard 500 ml of normal s a l i n e o r a l l y a f t e r an intravenous i n f u s i o n of GIP has been established, designed to produce a ph y s i o l o g i c a l l e v e l of GIP i n the systemic c i r c u l a t i o n . These have shown no s i g n i f i c a n t change so f a r i n peak or any other t r a n s i t time by volume or PEG recovery (p =>0.05). Total volume recovery averages 55% (controls with o r a l s a l i n e alone 48%), and t o t a l PEG recovery averages 65% (controls 62%), no s i g n i f i c a n t d i fference, and ind i c a t i n g a net secretion that i s not s i g n i f i c a n t l y d i f f e r e n t from c o n t r o l experiments without GIP. E l e c t r o l y t e l e v e l s i n the t o t a l volume of ileostomy f l u i d recovered average exactly the same as control experiments with o r a l s a l i n e and no GIP in f u s i o n - Na 139, K 5.1, Cl 121 (Table 14). These preliminary findings would suggest that GIP has no e f f e c t on small bowel m o t i l i t y as measured by t r a n s i t time, and has no e f f e c t on net secretion over a 2 hour period as measured by t h i s d i r e c t method. -34-ACKNOWLEDGEMENTS This work was c a r r i e d out i n a research year during residency t r a i n i n g i n General Surgery, under the d i r e c t i o n of Dr. Iain Cleator, Director of the Ga s t r o i n t e s t i n a l C l i n i c at St. Paul's Hospital, Vancouver, to whom I am very g r a t e f u l f o r much help and encouragement. Dr. Akira Nakayasu, an M.Sc. student from Kyoto, Japan, provided much stimulating discussion. Radioimmunoassay of peptide hormones was done by Miss Nicola O'Connor, who also established our assay f o r polyethylene g l y c o l . Her successor i n the G.I. C l i n i c , Mr. Douglas Burget gave constant help during the analysis and w r i t i n g up of the data, and p a r t i c u l a r l y with s t a t i s t i c a l i n t e r p r e t a t i o n . - 3 6 -FIGURE 5a Individual r e p r o d u c i b i l i t y . Recovery of 500 m] normal s a l i n e from ileostomy in one patient on two occasions. FIGURE 5b I n d i v i d u a l r e p r o d u c i b i l i t y . R e c o v e r y o f 500 n i l n o r m a l s a l i n e f rom i l e o s t o m y i n one p a t i e n t on t h r e e o c c a s i o n s . FIGURE 6 Rep r o d u c i b i l i t y of method. A plot of volume. recovery f o r one test against a second test on a d i f f e r e n t day, using logarithmic transformations. 400 -i 300 t ime , minutes = s a l i n e 0 "C = g I ucose i pomuI 200 PEG recovery mg 100 0 FIGURE 7 =8 —1 120 - 4 1 -1 0 0 given recovered g iven recovered given recovered 80 J 60 i 4 0 J vo I 20 J 0 J 500 PEG vo f 48$ 249 PEG 62% vo 500 PEG vo I 66$ 323 PEG 5 8 2 vo 500 PEG vol PEG 21 13? ml no rmaI s a l i n e i pomuI glucose FIGURE 8 The percentage recovery of volume and PEG from the ileostomy i n response to te s t feeds of 5 0 0 ml normal s a l i n e , lipomul and glucose (5% dextrose), showing net f l u i d absorption with s a l i n e and glucose, and net secr e t i o n with lipomul. -42-> •« = sa I I ne 20 40 60 80 100 120 t i me, mi n u t o s FIGURE 9 Serum hormone responses to 500 ml o r a l s a l i n e , glucose and lipomul ' - 4 3 -FREQUENCY MODE = MEDIAN = MEAN FREQUENCY MODE j MEAN MEDIAN FIGURE 10 Showing a Normal d i s t r i b u t i o n (above), and a Skew d i s t r i b u t i o n (below): mode = most frequent value median - arithmetic midpoint mean = average value (from Hays WL, Basic S t a t i s t i c s , 1967) -44-Figure 12 Volume recovery from controls (n = 6). Figure 11 compared to -46-600 800 1000 1200 PEG mg/100 ml Polyethylene g l y c o l standard curve at o p t i c a l density 650 mu. -47-• TEST'FEED MEAN % S .E.M. SALINE volume PEG 62.2 48.4 6.8 5.1 LIPOMUL volume PEG 66.4 58 3.6 5.2 DEXTROSE DEX/SALINE volume PEG volume PEG 4.2 12.8 1 1 2.3 8.7 PROTEIN volume PEG Table 1 Percentage recovery from ileostomy of 500 ml of various test feeds. -48-n SODIUM POTASSIUM CHLORIDE TEST FEED  SALINE 9 141 5.1 121 SALINE + GIP 3 139 5.1 121 LIPOMUL 6 143 5.9 107 DEXTROSE 6 127 5.9 63 DEX/SALINE 3 -PROTEIN 3 -Table 2 E l e c t r o l y t e composition of ileostomy f l u i d following various test feeds, and following GIP infusion. - 4 9 -S U B J E C T , VOLUME Time M i n u t e s 1 2 3 4 5 6 7 8 9 10 11 12 MEAN S . D . S . E . 10 40 30 0 0 30 0 • 0 0 0 , 0 0 18 9 . 0 8 14 .87 4 .12 20 40 50 0 60 50 7 0 16 0 4 48 24 2 3 . 0 0 23 .32 6 .47 30 60 90 90 50 80 3 0 55 33 53 99 77 62. 23 3 7 . 4 3 10 .38 40 70 80 110 90 20 0 33 50 73 76 81 64 72 .77 4 8 . 3 2 13.4 50 55 30 20 5 0 22 31 40 . 52 98 9 58 3 4 . 6 9 2 6 . 5 6 7 .37 60 15 15 0 5 5 54 52 5 42 33 12 20 2 0 . 5 4 18 .57 5 .15 70 5 5 5 5 3 16 37 T 21 7 22 15 12 .15 9 .84 2 .73 80 3 2 5 5 5 4 14 1 1 20 1 4 5 .00 5 .73 1.59 90 2 3 0 5 3 0 5 1 2 1 2 2 2 . 00 1 .68 . 4 7 100 5 3 0 2 1 2 1 0 2 1 0 1 1 .38 1.45 .4 110 5 2 10 1 1 0 1 0 2 1 1 1 1 .92 2 .75 . 7 6 120 2 1 5 2 1 4 0 0 0 1 1 2 1 .46 1.56 .43 TOTAL 2 4 2 . 0 7 8 . 3 0 % 4 8 . 4 4 1 5 . 4 4 5.1 T a b l e 3 V o l u m e - r e c o v e r y o f 500 ml o r a l n o r m a l s a l i n e ( see a l s o F i g u r e 3 ) . -50-SUBJECT, PEG mg Test Minutes 1 2 3 4 5 6 7 8 9 MEAN S.D. S.E.M 10 0 0 27 28 0 , 0 0 0 0 6.11 12.13 4.04 20 3 107 50 166 0 6 0 23 0 39.44 59.24 19.75 30 68 467 303 406 401 2 0 216 50 212.6 188.0 62. 67 40 308 552 365 138 799 0 90 308 413 330.3 245.4 82.8 50 572 78 455 0 136 58 407 304 406 268.4 205.1 68.3 60 208 122 233 12 39 267 394 42 440 195.3 155.5 52 70 51 322 224 7 39 109 321 75 289 160.8 130.4 43 80 153 16 78 12 0 37 45 11 42 43.78 47.33 16 90 7 33 41 8 0 0 59 10 0 17.56 21.48 7 100 7 0 20 7 0 25 7 0 28 10.44 11.04 3.6 110 7 19 20 7 0 0 8 0 45 11. 78 14.58 4.6 120 7 19 40 7 0 33 0 0 0 11.78 15.41 5 o t a l 1369 1764 2002 1117 1532 495 1300 988 1888 1384 478.0 66 81 88 52 77 27 53 40 76 62.22 20.50 6.8 Table 4 Recovery of 2.5 gm PEG i n 500 ml normal s a l i n e (see also Figure 4) SUBJECT 1 SUBJECT 2 SUBJECT 3 SUBJECT 4 Test : 1 Test 2 Test 1 Test 2 Test 1 Test 2 Test 1 • Test 2 Vol Log Vol Log Vol Log Vol Log Vol Log Vol Log Vol Log Vol Log 10 30 1.477 0 0 0 0 0 0 0 0 0 0 18 1.255 0 0 20 50 1.699 48 1.618 60 1.778 0 0 0 0 4 0.602 24 1.380 0 0 30 80 1.903 99 1.996 50 1.699 90 1.954 0 0 53 1.724 77 1.886 33 1.519 40 20 1.301 81 1.908 90 1.954 110 2.041 33 1.519 76 1.881 64 1.806 73 1.863 50 0 0 9 0.954 5 0.699 20 1.301 31 1.491 98 I. 991 58 1.763 52 1.716 Time 60 5 0.699 12 1.079 5 0.699 0 0 52 1. 716 33 1.519 20 1.301 42 1.623 Minutes 70 3 0.477 22 1.342 5 0.699 5 0.699 37 1.568 7 0.845 15 1.176 21 1.322 80 5 0.699 1 0 5 0.699 5 0.699 14 1.146 20 1.301 4 0.602 1 0 90 3 0.477 2 0.301 5 0.699 0 0 5 0.699 1 0 2 0.301 2 0.301 100 1 0 0 0 2 0.301 0 0 1 0 1 0 1 0 2 0.301 110 1 0 1 0 1 0 10 1.000 1 0 1 0 1 0 2 0.301 120 1 0 1 0 2 0.301 5 0.699 0 0 1 0 2 0.301 0 0 r = .6107 MR/MC = .6755 p = 0.05 TABLE 5 Reproducibility of method Volume recovery f o r one test using 500 ml normal saline against a second test on a d i f f e r e n t day, with logarithmic transformations (See also Figure 6) -52-Subject 1 Subject 2 Subject 3 Test 1 Test 2 Test 1 Test 2 Test 1 Test 2 Time PEG Log PEG Log PEG Log PEG Log PEG Log PEG Log 10 0 0 0 0 27 1.43. 0 0 0 0 28 1.447 20 3 0.477 0 0 50 1.699 0 0 107 2.029 116 2.220 30 68. 1.832 0 • 0 303 2.481 50 1.699 467 2.669 406 2. 609 40 308 2.489 90 1.954 365 2.562 413 2. 616 552 2.743 138 2.140 50 572 2.757 407 2.610 455 2.658 406 2.609 78 1.892 0 0 60 208 2.318 394 2.596 233 2.367 440 2.643 122 2.086 12 1.079 70 51 1.708 321 2.507 224 2.350 289 2.461 322 2.521 7 0.845 80 153 2.185 45 1.653 78 1.892 42 1.623 16 1.204 12 1.079 90 7 0.845 59 1.771 41 1.613 0 0 33 1.519 8 0.903 100 7 .0.845 7 0.845 20 1.301 28 1.447 0 0 7 0.845 110 7 0.845 8 0.903 20 1.301 45 1.653 19 1.279 7 0.845 120 7 0.845 0 0 40 1.602 0 0 19 1.279 7 0.845 r = .5734 MR/MC = .6883 p = 0.05 TABLE 6 -. R e p r o d u c i b i l i t y of method. PEG recovery f o r one t e s t , using 500 ml. normal s a l i n e , against a second test on a d i f f e r e n t day, with logarithmic transformations. (See also Figure 6) -53-SUBJEGT Time 1 2 3 4 5 MEAN S.D. S.E.M. 10 0 6 0 16 0 4.40 6.99 3.13 20 0 23 0 23 0 9.20 12.60 5.63 30 0 63 23 4 0 18.00 26.90 12.03 40 60 97 24 2 39 44.40 36.24 16.21 50 49 74 76 1 78 55.60 32.72 14.63 60 25 21 27 77 57 41.40 24.51 10.96 70 70 49 20 67 85 58.20 24.89 11.13 80 4 6 25 65 34 26.80 24.83 11.1 90 44 7 41 27 26 29.00 14. 71 6.58 100 19 5 7 16 12 11.80 5.89 2. 63 110 15 10 15 11 14 13.00 2.35 1.05 120 37 28 12 9 10 19.20 12.60 5.63 TOTAL 355 318 270 389 323 331 44.42 % 71 64 54 78 65 66.4 8.91 3.6 TABLE 7 Volume recovery (ml) a f t e r 500 ml o r a l lipomul i n salin e . (See also Figure 7) -54-SUBJECT 3 4 5 MEAN S.D. 10 0 13 0 5 0 3.60 5.68 20 0 19 0 25 0 8.80 12.24 30 0 3 15 133 0 30.20 57.80 40 21 2 16 415 161 123.0 175.6 50 46 1 168 617 193 205.0 244.0 60 37 80 91 231 122 112.2 73.06 70 102 73 131 513 494 262.8 221.2 80 76 105 217 51 26 95.00 74.23 90 92 118 415 50 418 218.6 182.3 100 51 142 80 34 116 84.60 44. 70 110 86 161 205 54 74 116.0 64.14 120 82 155 200 104 151 138.0 46.35 TOTAL 627 537 1126 2338 2129 1351 839.0 % 25 21 50 100 94 58 37.36 15.2 TABLE 8 PEG recovery (mg) a f t e r 500 ml or a l lipomul i n sa l i n e (See also Figure 7) -55-SUBJECT TTME 1 2 3 4 5 MEAN S.D. S.E.M. 10 0 3 0 5 6 2.80 2.77 1.24 20 0 1 0 12 0 2.60 5.27 2.46 30 0 0 0 1 2 0.60 0.89 0.4 40 0 5 0 1 0 1.20 2.17 0.97 50 0 3 0 0 0 0.60 1.34 0.6 60 0 3 0 0 3 1.20 1.64 0. 73 70 0 10 0 0 0 2.00 4.47 2.0 80 0 6 0 0 0 1.20 2.68 1.2 90 0 18 0 0 0 3.60 8.05 3.6 100 0 13 0 0 0 2.60 5.81 2.6 110 0 3 0 1 5 1.80 2.17 0.97 120 0 3 0 0 0 0.60 1.34 0.6 TOTAL 0 68 0 20 16 20.80 27.91 % 0 14 0 4 3 4.20 5.76 2.3 TABLE 9 Volume recovery (ml) a f t e r 500 ml o r a l glucose. (See also Figure 7) -56-SUBJECT TIME 1 2 3 4 5 MEAN S.D. 10 0 2 0 3 2 1.40 1.34 20 0 1 0 6 0 1.40 2.61 30 0 0 0 1 1 3.40 0.55 40 0 3 0 1 0 0.80 1.30 50 0 3 0 0 0 0.60 1.34 60 0 3 0 0 0 0.60 1.34 70 0 32 0 0 1 6.60 14.21 80 0 72 0 0 0 14.40 32.20 90 0 444 0 0 0 88.80 198.6 100 0 332 0 0 0 66.40 148.5 110 0 ' 69 0 1 0 14.00 30.75 120 0 65 0 0 2 ' 13.40 28.86 TOTAL 0 1494 0 10 6 302.0 666.4 % 0 60 0 1 3 12.80 26.41 10.7 TABLE 10 PEG recovery (mg) a f t e r 500 ml or a l glucose. (See also Figure 7) -57-SUBJECT 1 2 3 TIME VOL PEG VOL PEG VOL PEG 10 0 0 0 0 0 0 20 0 0 0 0 0 0 30 0 0 0 0 0 0 40 0 0 0 0 0 0 50 0 0 0 0 0 0 60 0 0 0 0 0 0 70 0 0 0 0 0 0 80 0 0 0 0 0 0 90 0 0 1 .02 0 0 100 0 0 0 0 2 .02 110 0 0 0 0 0 0 120 0 0 0 0 1 .02 TABLE 11 Volume (ml) and PEG (mg) recovery of 500 ml 3 1/3% Dextrose: 0.3% sa l i n e and 2.5 gm PEG. -58-SUBJECT TLME MINUTES • 1 2 3 10 0 0 0 20 0 0 0 30 0 0 0 40 0 0 0 50 0 0 0 60 12 0 0 70 0 0 0 80 0 0 0 90 0 5 0 100 0 0 1 110 0 0 0 129 4 0 0 TABLE 12 Volume recovery (ml) of 500 ml water + 2.5 gm PEG. -59-SUBJECT 1 • 2 3 TIME VOL PEG VOL PEG VOL PEG 10 0 0 0 0 0 0 20 0 0 0 0 0 0 30 0 0 0 0 0 0 40 0 0 0 0 0 0 50 0 0 0 0 0 0 60 0 0 0 0 0 0 70 0 0 0 0 0 0 80 1 .02 0 0 0 0 90 0 0 0 0 . 0 0 100 2 .02 0 0 0 0 110 3 .02 0 0 0 0 120 0 0 0 0 1 .02 TABLE 13 Volume (ml) and PEG (mg) recovery a f t e r 100 ml 10% Travasol + 400 ml water + 2.5 gm PEG. -60-SUBJECT 1 2 3 TIME VOL(ml) PEG VOL (ml) PEG VOL(ml) PEG 10 0 0 0 0 43 86 20 0 0 3 3 76 220 30 14 18 0 0 79 387 40 81 340 4 4 95 732 50 11 70 40 104 56 465 60 27 206 99 505 4 44 70 27 202 60 462 6 72 80 54 407 24 192 3 36 90 2) 20 5 44 1) 24 100 1) 1) 27 1) 110 0 0 2) 0 0 120 0 0 0 0 0 0 TOTAL 217 1317 238 1341 364 2066 % 43 59 48 54 73 82 Na 140 139 139 K 5.4 5.4 4.6 Cl 111 122 130 Averages : Volume recovery 55% PEG recovery 65% Na 139 : K 5.1 : Cl 121 TABLE 14 Recovery of 500 ml normal sa l i n e with 2.5 PEG and GIP in f u s i o n 0.8 u units/kg. -61-PEG mg/100 m l P . 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