Br. J. clin. Pharmac. (1990), 29, 703-708
Inter- and intrasubject variability of gastric emptying in healthy volunteers measured by scintigraphy and paracetamol absorption 0. U. PETRING' & H. FLACHS2 'Department of Anaesthesia, Department of Clinical Physiology and Nuclear Medicine and 2Department of Clinical Chemistry, Rigshospitalet, Copenhagen 0. DK-2100 Denmark
1 Inter- and intrasubject variability in the gastric emptying of semisolids and liquids was measured by scintigraphic emptying of radionuclide-labelled semisolid and from paracetamol absorption in ten healthy volunteers of both sexes. 2 The intrasubject variability was not statistically significant for any of scintigraphic or paracetamol absorption parameters. 3 The intersubject variation was significant for all scintigraphic and paracetamol absorption parameters. 4 In women, the gastric emptying rate of semisolid decreased linearly during the menstrual cycle. 5 The lag period and paracetamol absorption parameters were unrelated to the day of the menstrual cycle day. 6 There was no statistically significant relationship between scintigraphic and paracetamol absorption parameters.
Keywords gastric emptying variability radionuclide scintigraphy paracetamol absorption semisolids liquids Introduction Radionuclide-based measurements of gastric emptying are widely used in clinical and investigative medicine. However, few studies have addressed the reproducibility of the method within and between individuals (Brophy et al., 1986; Collins et al., 1983). Investigations of the effect of gender on gastric emptying have given conflicting results (Datz et al., 1987; Horowitz et al., 1984) and in many studies the possible influence of gender or menstrual cycle on gastric emptying is not considered. In previous studies of gastric emptying in both sexes we observed large differences in emptying rates of a Tc-99m labelled semisolid meal within and between subjects on separate study days (Petring et al., 1986; Petring, 1989).
Initial changes in the plasma concentration of paracetamol given orally have previously been shown to reflect the rate of gastric emptying of liquids as determined by an In-113m DTPA chelate scintiscanning technique (Clements et al., 1978), and paracetamol absorption has been used in several studies of the gastric emptying of liquids (Nimmo, 1984). In healthy volunteers no relationship was found between paracetamol absorption and scintigraphic measurement of gastric emptying of semisolids (Petring et al., 1986). The principal aim of the present study was to determine the extent of inter- and intrasubject variability in the gastric emptying of semisolids and liquids using scintigraphic measurements
Correspondence: Dr Oscar Ulf Petring, Department of Anaesthesia, Rigshospitalet, Copenhagen 0, DK-2100 Denmark
703
704
0. U. Petring & H. Flachs
and paracetamol absorption. A second aim was to assess any effect of the menstrual cycle on the rate of gastric emptying. Methods The study protocol was approved by the Regional Ethics Committee and informed consent was obtained from each subject. Ten healthy subjects, five women and five men (aged 27-36 years, weight range 55-87 kg) were studied, each on four occasions separated by 1 week. None of the females was taking an oral contraceptive. All gastric emptying studies were conducted at 08.30 h. After an overnight fast for a minimum of 8 hours the volunteers sat while eating a semisolid meal comprising 30 g oatmeal, 5 g sugar, 100 ml of cold milk and paracetamol powder 20 mg kg-1 uniformly mixed with 37 MBq of Tc99m Chelex-100 resin (Petring et al., 1986). To control the extent of mastication, the subjects had to eat the semisolid meal within 10 min. Immediately after the meal, with the subjects in the supine position, gastric emptying was studied in the anterior projection using a gammacamera with low energy parallel-hole colimator (Maxi 500, G.E.) on line to computer system (gamma 11, D.E.C., Maynard, M.A.). The stomach was outlined using an irregular region of interest (ROI) in sequential 5 min images and the activity curve from this region was calculated over the period of the study after correction for decay of the Tc-99m marker. Lag period, defined as the period of time between ingestion of the meal and the appearance of the isotope outside the gastric region of interest (Camilleri et al., 1985) was determined from an ROI over the intestine. Gastric emptying determined scintigraphically was expressed by the following parameters: Ego = percentage of initial counts in the stomach region at 90 min and Lag (min) = duration of lag period. Venous blood samples were withdrawn from an indwelling cannula before ingestion of the meal and at 10 min intervals thereafter up to 90 min. The serum was separated and stored at -20° C until assay for paracetamol by Fluorescence Polarization Immunoassay (TDX Acetaminophen, Abbott Laboratories, North Chicago, USA). The relative standard deviation of this assay was 4% (x = 58 ,umol I-1), and the recovery of paracetamol in blank plasma was 102 ± 0.9%. Gastric emptying determined by paracetamol absorption was expressed by the following parameters: Cmax (,umol I-1) = maximum serum paracetamol concentration; tmax (min) = time to reach maximum serum para-
cetamol concentration, and AUC (,mol 1-1 min) = area under the serum paracetamol concentration-time curve from 0-90 min. All days in the menstrual cycle were counted from the first day of menstrual bleeding (day 1).
Statistics Analysis of variance was used to determine inter- and intrasubject variability. Linear regression analysis with individual (categorical) and menstrual cycle day as explanatory variables was used to test the relationship between gastric emptying in female volunteers and menstrual cycle day. To compare the gastric emptying of semisolids and liquids, scintigraphic and paracetamol absorption parameters were assessed by correlation coefficients and analysis of variance. In all comparisons differences were taken as significant if P < 0.05.
Results
The individual values of scintigraphic and paracetamol absorption parameters on the four occasions are shown in Table 1. The gastric emptying of semisolid was characterized by a lag period of variable duration followed by a linear emptying in all subjects. Intrasubject variability was not statistically significant for any of the scintigraphic or paracetamol absorption parameters (Table 2). The largest intrasubject differences in Ego noted on the four experimental occasions were 15% in a male volunteer (subject 1) and 18% in a female volunteer (subject 7). Intersubject variability was significant for all parameters (Table 2). The largest intersubject difference in Ego noted on the four experimental occasions was 39% (subjects 6 and 8). A comparison of scintigraphic and paracetamol parameters in men and women showed no significant differences between the sexes (P > 0.1). In women, a linear correlation was noted between Ego and menstrual cycle day (P = 0.01), i.e. gastric emptying of semisolid decreased towards the onset of menstruation (Figure 1). The duration of the lag period, and the parameters of paracetamol absorption were unrelated to the menstrual cycle day. There was no statistically significant relationship between scintigraphic and paracetamol absorption parameters (Table 3). Discussion In the present study intrasubject variation of gastric emptying of semisolids and liquids
Gastric emptying by scintigraphy and paracetamol absorption Table 1 Individual values of scintigraphic and paracetamol absorption parameters on four separate occasions (m = male, f = female)
Subject
Ego
Lag
Cm=
1(m)
73 58 62 64 67 61 60 59 74 64 67 64 53 51 47 53 58 55 51 51 44 56 59 42 45 45 49 63 79 81 65 67 52 54
5 10 5 10 20 10 15
59 77 95 85 76 71 72 77 60 48 58 57 51 46 65 62 46 62 47 54 112 79 75 91 55 35 54 42 54 55 73 60 50 47 33 59 53 37 42 43
2(m)
3(m)
4(m)
5(m)
6(f)
7(f)
8(f)
9(f)
60 57 46 63 49 61
10(f)
MCD
=
10 5 5 5 5 15 15 15 20 30 5 30 30 10 20 5 5 5 5 10 5 20 25 15 10 10 5 15 10 15 5 20 10
tm
AUC MCD
70 20 10 10 40 40 30 20 20 20 40 20 70 90 50 40 80 90 10 60 40 60 20 30 40 30 40 80 50 30 40 30 60
5880 5530 5750 5610 5000 4975 5015 5535 3355 3565 3845 3445 2715 2580 3725 4390 2920 4760 3635 3830 7290 5645 5520 5505 3735 2650 3655 2445 3560 3785 4605 3880 3530
90 30 60 60 90 80 90
2675 2125 3435 3545 2075 2205 2575
13 20 27 6 2 9 16 23 20 27 7 13 6 13 20 27 17 24 3 10
menstrual cycle day.
Scintigraphic parameters: Ego (%) = percentage of initial counts in the stomach region at 90 min and Lag (min) = duration of lag period. Paracetamol absorption parameters: Cma,, (,umol 1-1) = maximum serum paracetamol concentration; tmax (min) = time to reach maximum serum paracetamol concentration; AUC (,umol 1-1 min) = area under serum paracetamol concentration-time curve from 0-90 min.
705
0. U. Petring & H. Flachs
706
Table 2 Assessment of reproducibility using analysis of variance
Intrasubject P MS
Intersubject P MS
(%)
Scintigraphic parameters*
Ego Lag Paracetamol absorption parameters*
Cmax tmax AUC
NS NS
39 35
0.0001 0.003
250 39
66 53
NS NS NS
101 445
0.0001 0.013 0.0001
940 1299 5610214
74 47 82
374661
% = % of the observed variability explained by intersubject differences. MS = Mean square of the corresponding sum of squares divided by the degrees of freedom (\/Mi- = standard deviation). NS = not significant (P > 0.1). * See explanation in Table 1. Table 3 Correlation coefficients and P values (analysis of variance) between the scintigraphic and paracetamol absorption parameters (see explanation in Table 1)
Cmax
tmax
rr= -0.05, P= 0.76 r= -0.16, P= 0.34 r = -0.13, P= 0.41 r = 0.07, P = 0.67
Ego Lag
AUC r= 0.02, P= 0.92 r = -0.12, P = 0.48
(135 g) with a total caloric value of only 771 kJ
90
E 75
0
o
D
.°
(184 kcal)
cn
° C' 60 .E a) 45
^ *
D
Zs
0
* D L.
(
I0
20
30
Menstrual cycle day Figure 1 T'he % of semisolid emptied at 90 mn in female voluinteers 6(), 7(E), 8(o), 9(o) and 10(A) in relation t(o the day of their menstrual cycle day (slope = 0.655, P = 0.0001). determine(d scintigraphically and by paracetamol absorptioni was not significant compared with the variatii on between the subjects. It is genterally assumed that the scintigraphic determina tion of gastric emptying of either liquids or solids is accompanied by significant inter- and intrasubject variation (Brophy et al., 1986). ThI e insignificant intrasubject variability in our studly could be explained by use of a small semisolid test meal of approximately 115 ml
(Petring et al., 1986). The variability
of gastric emptying of semisolids is similar to that found by Collins et al. (1983) who used a dual isotope technique with an attenuation correction ~~~~from a lateral image of the stomach. However, the differences in radionuclide markers, meal *composition and detection techniques complicate any comparison of results obtained in different studies. The use of an anteriorly placed gamma camera alone in measurements of gastric empty-
ing can result in inaccurate estimations of the gastric emptying rate and lag period. This error appears proportional to the size and composition of the test meal (Akkermans et al., 1984; Fahey et al., 1989). Furthermore, it is shown that when only one gamma camera is available, the most accurate emptying patterns can be obtained from the anterior view, since the actual emptying rate closely parallels the emptying rate of the mean curve (Akkermans et al., 1984). In an attempt to minimize the need for correction for tissue attenuation we have used a small volume semisolid test meal of approximately 115 ml (Petring et al., 1986) and the lag period was determined by generation of time-activity curves over the intestine. As a result, the lag
Gastric emptying by scintigraphy and paracetamol absorption period could be measured even when only anterior detection was used. There is disagreement as to the existence of such a lag period (Christian etal., 1983; Collins etal., 1988). In the present study the emptying pattern of semisolid and the filling curve of the intestine confirmed the existence of a lag period with a significant intersubject variation in its extent (Petring, 1989). Intrasubject variation in the lag period was, however, not significant. This suggests that the lag period is subject-specific and uninfluenced by the initial emotional stress of being a volunteer. Our findings confirm a lack of any relationship between the scintigraphic measurement of gastric emptying of semisolids and paracetamol absorption representing gastric emptying of liquids (Petring et al., 1986). This accords with the results of Heading et al. (1976) who showed that, in normal subjects, simultaneously ingested liquid and digestible solid food emptied from stomach at different rates and according to different patterns. However, when a solid and a caloric liquid meal are consumed together, the rate and pattern of gastric emptying is modified by each component (Maddox et al., 1989). The assessment of the influence of semisolid on the gastric emptying of simultaneously ingested paracetamol needs to be investigated. Studies of the effect of gender on gastric emptying have yielded conflicting results. Some have found similar gastric emptying rates in men and women (Horowitz et al., 1984), while others have found that the gastric emptying of both solids and liquids was slower in women (Datz et al., 1987; Hutson et al., 1989). In the present study the differences in gastric emptying of semi-
707
solids or liquids between women and men were smaller than the differences between the subjects. Gill et al. (1987) found that during the luteal phase of the menstrual cycle, emptying of the solid-phase marker was significantly slower than during the follicular phase, but that emptying of the liquid-phase marker was not significantly different during the two phases of the menstrual cycle. In contrast, using a dual isotope radionuclide technique, Horowitz et al. (1985) found no difference in the gastric emptying rates of solids and liquids during the two phases of the menstrual cycle. In the present study the gastric emptying of semisolids in women serving as their own controls decreased linearly during the menstrual cycle towards the luteal phase, whereas emptying of the liquid phase was unchanged. The mechanism of alteration in gastric emptying of semisolids during the menstrual cycle is not known. However, the concept that sex steroids exert effects on gastric emptying has gained considerable support (Datz et al., 1987; Hutson et al., 1989) and it appears that gastric emptying of solids correlates with serum concentrations of progesterone (Gill et al., 1987). Unfortunately, in the present study biochemical markers of the stage of the menstrual cycle were not measured. However, all of the females had a regular menstrual cycle and none was taking birth control pills. This study was supported by a grant from the Danish Medical Research Council, and by the Professor, dr.med. Bj0rn Ibsen Foundation. Statistical analysis was supported by the Danish Medical Research Council.
References Akkermans, L. M. A., Jacobs, F., Smout, A. J. P. M. & Oei, H. Y. (1984). Radionuclide measurement of normal and disturbed gastric motility. Scand. J. Gastroenterol., 19 (Suppl. 96), 19-26. Brophy, C. M., Moore, J. G., Christian, P. E., Egger, M. J. & Taylor, A. T. (1986). Variability of gastric emptying measurements in man employing standardized radiolabeled meals. Dig. Dis. Sci., 31, 799-806. Camilleri, M., Malagelada, J-R., Brown, M. L., Becker, G. & Zinsmeister, A. R. (1985). Relation between antral motility and gastric emptying of solids and liquids in humans. Am. J. Physiol., 249,
G580-G585. Christian, P. E., Datz, F. L., Sorenson, J. A. & Taylor, A. (1983). Technical factors in gastric emptying studies. J. nucl. Med., 24, 264-268. Clements, J. A., Heading, R. C., Nimmo, W. S. &
Prescott, L. F. (1978). Kinetics of acetaminophen absorption and gastric emptying in man. Clin. Pharmac. Ther., 24, 420-431. Collins, P. J., Horowitz, M., Cook, D. J., Harding, P. E. & Shearman, D. J. C. (1983). Gastric emptying in normal subjects-a reproducible technique using a single scintillation camera and computer system. Gut, 24, 1117-1125. Collins, P. J., Horowitz, M. & Chatterton, B. E. (1988). Proximal, distal and total stomach emptying of a digestible solid meal in normal subjects. Br. J. Radiol., 61, 12-18. Datz, F. L., Christian, P. E. & Moore, J. (1987). Gender-related differences in gastric emptying. J. nucl. Med., 28, 1204-1207. Fahey, F. H., Ziessman, H. A., Collen, M. J. & Eggli, D. F. (1989). Left anterior oblique projection and peak-to-scatter ratio for attenuation compensation
708
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of gastric emptying studies. J. nucl. Med., 30, 233239. Gill, R. C., Murphy, P. D., Hooper, H. R., Bowes, K. L. & Kingma, Y. J. (1987). Effect of the menstrual cycle on gastric emptying. Digestion, 36, 168-174. Heading, R. C., Tothill, P., McLoughlin, G. P. & Shearman, D. J. C. (1976). Gastric emptying rate measurement in man. A double isotope scanning technique for simultaneous study of liquid and solid components of a meal. Gastroenterology, 71, 45-50. Horowitz, M., Maddern, G. J., Chatterton, B. E., Collins, P. J., Harding, P. E. & Shearman, D. J. C. (1984). Changes in gastric emptying rates with age. Clin. Sci., 67, 213-218. Horowitz, M., Maddern, G. J., Chatterton, B. E., Collins, P. J., Petrucco, 0. M., Seamark, R. & Shearman, D. J. C. (1985). The normal menstrual cycle has no effect on gastric emptying. Br. J. Obstet. Gynaecol., 92, 743-746.
Hutson, W. R., Roehrkasse, R. L. & Wald, A. (1989). Influence of gender and menopause on gastric emptying and motility. Gastroenterology, 96, 1117. Maddox, A., Horowitz, M., Bochner, M., Wishart, J., Collins, P. & Shearman, D. (1989). Relationships between gastric emptying of solid and caloric liquid meals. J. nucl. Med., 30, 887. Nimmo, W. S. (1984). Effect of anaesthesia on gastric motility and emptying. Br. J. Anaesth., 56, 29-36. Petring, 0. U. (1989). The effect of oxytocin on basal and pethidine-induced delayed gastric emptying. Br. J. clin. Pharmac., 28, 409-413. Petring, 0. U., Adelh0j, B., Ibsen, M. & Poulsen, H. E. (1986). The relationship between gastric emptying of semisolids and paracetamol absorption. Br. J. clin. Pharmac., 22, 659-662.
(Received 27 November 1989, accepted 5 January 1990)
Inter- and intrasubject variability of gastric emptying in healthy volunteers measured by scintigraphy and paracetamol absorption 0. U. PETRING' & H. FLACHS2 'Department of Anaesthesia, Department of Clinical Physiology and Nuclear Medicine and 2Department of Clinical Chemistry, Rigshospitalet, Copenhagen 0. DK-2100 Denmark
1 Inter- and intrasubject variability in the gastric emptying of semisolids and liquids was measured by scintigraphic emptying of radionuclide-labelled semisolid and from paracetamol absorption in ten healthy volunteers of both sexes. 2 The intrasubject variability was not statistically significant for any of scintigraphic or paracetamol absorption parameters. 3 The intersubject variation was significant for all scintigraphic and paracetamol absorption parameters. 4 In women, the gastric emptying rate of semisolid decreased linearly during the menstrual cycle. 5 The lag period and paracetamol absorption parameters were unrelated to the day of the menstrual cycle day. 6 There was no statistically significant relationship between scintigraphic and paracetamol absorption parameters.
Keywords gastric emptying variability radionuclide scintigraphy paracetamol absorption semisolids liquids Introduction Radionuclide-based measurements of gastric emptying are widely used in clinical and investigative medicine. However, few studies have addressed the reproducibility of the method within and between individuals (Brophy et al., 1986; Collins et al., 1983). Investigations of the effect of gender on gastric emptying have given conflicting results (Datz et al., 1987; Horowitz et al., 1984) and in many studies the possible influence of gender or menstrual cycle on gastric emptying is not considered. In previous studies of gastric emptying in both sexes we observed large differences in emptying rates of a Tc-99m labelled semisolid meal within and between subjects on separate study days (Petring et al., 1986; Petring, 1989).
Initial changes in the plasma concentration of paracetamol given orally have previously been shown to reflect the rate of gastric emptying of liquids as determined by an In-113m DTPA chelate scintiscanning technique (Clements et al., 1978), and paracetamol absorption has been used in several studies of the gastric emptying of liquids (Nimmo, 1984). In healthy volunteers no relationship was found between paracetamol absorption and scintigraphic measurement of gastric emptying of semisolids (Petring et al., 1986). The principal aim of the present study was to determine the extent of inter- and intrasubject variability in the gastric emptying of semisolids and liquids using scintigraphic measurements
Correspondence: Dr Oscar Ulf Petring, Department of Anaesthesia, Rigshospitalet, Copenhagen 0, DK-2100 Denmark
703
704
0. U. Petring & H. Flachs
and paracetamol absorption. A second aim was to assess any effect of the menstrual cycle on the rate of gastric emptying. Methods The study protocol was approved by the Regional Ethics Committee and informed consent was obtained from each subject. Ten healthy subjects, five women and five men (aged 27-36 years, weight range 55-87 kg) were studied, each on four occasions separated by 1 week. None of the females was taking an oral contraceptive. All gastric emptying studies were conducted at 08.30 h. After an overnight fast for a minimum of 8 hours the volunteers sat while eating a semisolid meal comprising 30 g oatmeal, 5 g sugar, 100 ml of cold milk and paracetamol powder 20 mg kg-1 uniformly mixed with 37 MBq of Tc99m Chelex-100 resin (Petring et al., 1986). To control the extent of mastication, the subjects had to eat the semisolid meal within 10 min. Immediately after the meal, with the subjects in the supine position, gastric emptying was studied in the anterior projection using a gammacamera with low energy parallel-hole colimator (Maxi 500, G.E.) on line to computer system (gamma 11, D.E.C., Maynard, M.A.). The stomach was outlined using an irregular region of interest (ROI) in sequential 5 min images and the activity curve from this region was calculated over the period of the study after correction for decay of the Tc-99m marker. Lag period, defined as the period of time between ingestion of the meal and the appearance of the isotope outside the gastric region of interest (Camilleri et al., 1985) was determined from an ROI over the intestine. Gastric emptying determined scintigraphically was expressed by the following parameters: Ego = percentage of initial counts in the stomach region at 90 min and Lag (min) = duration of lag period. Venous blood samples were withdrawn from an indwelling cannula before ingestion of the meal and at 10 min intervals thereafter up to 90 min. The serum was separated and stored at -20° C until assay for paracetamol by Fluorescence Polarization Immunoassay (TDX Acetaminophen, Abbott Laboratories, North Chicago, USA). The relative standard deviation of this assay was 4% (x = 58 ,umol I-1), and the recovery of paracetamol in blank plasma was 102 ± 0.9%. Gastric emptying determined by paracetamol absorption was expressed by the following parameters: Cmax (,umol I-1) = maximum serum paracetamol concentration; tmax (min) = time to reach maximum serum para-
cetamol concentration, and AUC (,mol 1-1 min) = area under the serum paracetamol concentration-time curve from 0-90 min. All days in the menstrual cycle were counted from the first day of menstrual bleeding (day 1).
Statistics Analysis of variance was used to determine inter- and intrasubject variability. Linear regression analysis with individual (categorical) and menstrual cycle day as explanatory variables was used to test the relationship between gastric emptying in female volunteers and menstrual cycle day. To compare the gastric emptying of semisolids and liquids, scintigraphic and paracetamol absorption parameters were assessed by correlation coefficients and analysis of variance. In all comparisons differences were taken as significant if P < 0.05.
Results
The individual values of scintigraphic and paracetamol absorption parameters on the four occasions are shown in Table 1. The gastric emptying of semisolid was characterized by a lag period of variable duration followed by a linear emptying in all subjects. Intrasubject variability was not statistically significant for any of the scintigraphic or paracetamol absorption parameters (Table 2). The largest intrasubject differences in Ego noted on the four experimental occasions were 15% in a male volunteer (subject 1) and 18% in a female volunteer (subject 7). Intersubject variability was significant for all parameters (Table 2). The largest intersubject difference in Ego noted on the four experimental occasions was 39% (subjects 6 and 8). A comparison of scintigraphic and paracetamol parameters in men and women showed no significant differences between the sexes (P > 0.1). In women, a linear correlation was noted between Ego and menstrual cycle day (P = 0.01), i.e. gastric emptying of semisolid decreased towards the onset of menstruation (Figure 1). The duration of the lag period, and the parameters of paracetamol absorption were unrelated to the menstrual cycle day. There was no statistically significant relationship between scintigraphic and paracetamol absorption parameters (Table 3). Discussion In the present study intrasubject variation of gastric emptying of semisolids and liquids
Gastric emptying by scintigraphy and paracetamol absorption Table 1 Individual values of scintigraphic and paracetamol absorption parameters on four separate occasions (m = male, f = female)
Subject
Ego
Lag
Cm=
1(m)
73 58 62 64 67 61 60 59 74 64 67 64 53 51 47 53 58 55 51 51 44 56 59 42 45 45 49 63 79 81 65 67 52 54
5 10 5 10 20 10 15
59 77 95 85 76 71 72 77 60 48 58 57 51 46 65 62 46 62 47 54 112 79 75 91 55 35 54 42 54 55 73 60 50 47 33 59 53 37 42 43
2(m)
3(m)
4(m)
5(m)
6(f)
7(f)
8(f)
9(f)
60 57 46 63 49 61
10(f)
MCD
=
10 5 5 5 5 15 15 15 20 30 5 30 30 10 20 5 5 5 5 10 5 20 25 15 10 10 5 15 10 15 5 20 10
tm
AUC MCD
70 20 10 10 40 40 30 20 20 20 40 20 70 90 50 40 80 90 10 60 40 60 20 30 40 30 40 80 50 30 40 30 60
5880 5530 5750 5610 5000 4975 5015 5535 3355 3565 3845 3445 2715 2580 3725 4390 2920 4760 3635 3830 7290 5645 5520 5505 3735 2650 3655 2445 3560 3785 4605 3880 3530
90 30 60 60 90 80 90
2675 2125 3435 3545 2075 2205 2575
13 20 27 6 2 9 16 23 20 27 7 13 6 13 20 27 17 24 3 10
menstrual cycle day.
Scintigraphic parameters: Ego (%) = percentage of initial counts in the stomach region at 90 min and Lag (min) = duration of lag period. Paracetamol absorption parameters: Cma,, (,umol 1-1) = maximum serum paracetamol concentration; tmax (min) = time to reach maximum serum paracetamol concentration; AUC (,umol 1-1 min) = area under serum paracetamol concentration-time curve from 0-90 min.
705
0. U. Petring & H. Flachs
706
Table 2 Assessment of reproducibility using analysis of variance
Intrasubject P MS
Intersubject P MS
(%)
Scintigraphic parameters*
Ego Lag Paracetamol absorption parameters*
Cmax tmax AUC
NS NS
39 35
0.0001 0.003
250 39
66 53
NS NS NS
101 445
0.0001 0.013 0.0001
940 1299 5610214
74 47 82
374661
% = % of the observed variability explained by intersubject differences. MS = Mean square of the corresponding sum of squares divided by the degrees of freedom (\/Mi- = standard deviation). NS = not significant (P > 0.1). * See explanation in Table 1. Table 3 Correlation coefficients and P values (analysis of variance) between the scintigraphic and paracetamol absorption parameters (see explanation in Table 1)
Cmax
tmax
rr= -0.05, P= 0.76 r= -0.16, P= 0.34 r = -0.13, P= 0.41 r = 0.07, P = 0.67
Ego Lag
AUC r= 0.02, P= 0.92 r = -0.12, P = 0.48
(135 g) with a total caloric value of only 771 kJ
90
E 75
0
o
D
.°
(184 kcal)
cn
° C' 60 .E a) 45
^ *
D
Zs
0
* D L.
(
I0
20
30
Menstrual cycle day Figure 1 T'he % of semisolid emptied at 90 mn in female voluinteers 6(), 7(E), 8(o), 9(o) and 10(A) in relation t(o the day of their menstrual cycle day (slope = 0.655, P = 0.0001). determine(d scintigraphically and by paracetamol absorptioni was not significant compared with the variatii on between the subjects. It is genterally assumed that the scintigraphic determina tion of gastric emptying of either liquids or solids is accompanied by significant inter- and intrasubject variation (Brophy et al., 1986). ThI e insignificant intrasubject variability in our studly could be explained by use of a small semisolid test meal of approximately 115 ml
(Petring et al., 1986). The variability
of gastric emptying of semisolids is similar to that found by Collins et al. (1983) who used a dual isotope technique with an attenuation correction ~~~~from a lateral image of the stomach. However, the differences in radionuclide markers, meal *composition and detection techniques complicate any comparison of results obtained in different studies. The use of an anteriorly placed gamma camera alone in measurements of gastric empty-
ing can result in inaccurate estimations of the gastric emptying rate and lag period. This error appears proportional to the size and composition of the test meal (Akkermans et al., 1984; Fahey et al., 1989). Furthermore, it is shown that when only one gamma camera is available, the most accurate emptying patterns can be obtained from the anterior view, since the actual emptying rate closely parallels the emptying rate of the mean curve (Akkermans et al., 1984). In an attempt to minimize the need for correction for tissue attenuation we have used a small volume semisolid test meal of approximately 115 ml (Petring et al., 1986) and the lag period was determined by generation of time-activity curves over the intestine. As a result, the lag
Gastric emptying by scintigraphy and paracetamol absorption period could be measured even when only anterior detection was used. There is disagreement as to the existence of such a lag period (Christian etal., 1983; Collins etal., 1988). In the present study the emptying pattern of semisolid and the filling curve of the intestine confirmed the existence of a lag period with a significant intersubject variation in its extent (Petring, 1989). Intrasubject variation in the lag period was, however, not significant. This suggests that the lag period is subject-specific and uninfluenced by the initial emotional stress of being a volunteer. Our findings confirm a lack of any relationship between the scintigraphic measurement of gastric emptying of semisolids and paracetamol absorption representing gastric emptying of liquids (Petring et al., 1986). This accords with the results of Heading et al. (1976) who showed that, in normal subjects, simultaneously ingested liquid and digestible solid food emptied from stomach at different rates and according to different patterns. However, when a solid and a caloric liquid meal are consumed together, the rate and pattern of gastric emptying is modified by each component (Maddox et al., 1989). The assessment of the influence of semisolid on the gastric emptying of simultaneously ingested paracetamol needs to be investigated. Studies of the effect of gender on gastric emptying have yielded conflicting results. Some have found similar gastric emptying rates in men and women (Horowitz et al., 1984), while others have found that the gastric emptying of both solids and liquids was slower in women (Datz et al., 1987; Hutson et al., 1989). In the present study the differences in gastric emptying of semi-
707
solids or liquids between women and men were smaller than the differences between the subjects. Gill et al. (1987) found that during the luteal phase of the menstrual cycle, emptying of the solid-phase marker was significantly slower than during the follicular phase, but that emptying of the liquid-phase marker was not significantly different during the two phases of the menstrual cycle. In contrast, using a dual isotope radionuclide technique, Horowitz et al. (1985) found no difference in the gastric emptying rates of solids and liquids during the two phases of the menstrual cycle. In the present study the gastric emptying of semisolids in women serving as their own controls decreased linearly during the menstrual cycle towards the luteal phase, whereas emptying of the liquid phase was unchanged. The mechanism of alteration in gastric emptying of semisolids during the menstrual cycle is not known. However, the concept that sex steroids exert effects on gastric emptying has gained considerable support (Datz et al., 1987; Hutson et al., 1989) and it appears that gastric emptying of solids correlates with serum concentrations of progesterone (Gill et al., 1987). Unfortunately, in the present study biochemical markers of the stage of the menstrual cycle were not measured. However, all of the females had a regular menstrual cycle and none was taking birth control pills. This study was supported by a grant from the Danish Medical Research Council, and by the Professor, dr.med. Bj0rn Ibsen Foundation. Statistical analysis was supported by the Danish Medical Research Council.
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(Received 27 November 1989, accepted 5 January 1990)
