GASTROINTESTINAL MOTILITY AND GASTRIC ph AND EMPTYING FOLLOWING INGESTION OF DIAZEPAM

Transcription

1 Br. J. Anaesth. (1988), 61, GASTROINTESTINAL MOTILITY AND GASTRIC ph AND EMPTYING FOLLOWING INGESTION OF DIAZEPAM B. A. SCHURIZEK, K. KRAGLUND, F. ANDREASEN, L. V. JENSEN AND B. JUHL Premedcaton wth benzodazepnes by mouth s used wdely and s not usually assocated wth an ncreased rsk of pulmonary aspraton [1]. Prevous studes have shown a decrease n the volume and acdty of the stomach contents after ngeston of dazepam [2,3]. Several factors nfluence the absorpton of drugs admnstered by mouth, ncludng gastrontestnal actvty [4-6]. Ths study was undertaken to nvestgate the effects of dazepam on antroduodenal motlty, gastrc ph and gastrc emptyng rate. SUBJECTS AND METHODS Ten healthy volunteers (seven men and three women, aged yr) wthout gastrontestnal symptoms partcpated n the study. None was a regular user of any drugs and no medcaton was taken n the week precedng each of the two study days, whch were 8-14 days apart. All subjects fasted overnght before and durng the nvestgatons. Informed consent was obtaned from all ndvduals before the studes, whch were approved by the local Ethcs Commttee. Antroduodenal motlty was recorded usng a sx-lumen polyvnylchlorde tube wth an external dameter of 4.7 mm (GIMK-14R7-250 A, Wllam Cook Europe AS) [7]. Each lumen had an nternal dameter of 0.7 mm and a sde-hole openng sted at varous dstances from the tp. The manometrc assembly, complete wth ph BlRGITTE ASMIN SCHURIZEK, M.D. ; KARSTEN KRAGLUND, M.D.; LARS VINTER JENSEN, M.D.; BENT JUHL, M.D.; Department of Anaesthesology and Surgcal Gastroenterology, Unversty Hosptal of Aarhus, DK-8000 Aarhus C, Denmark. FREDERIK ANDREASEN, M.D., Insttute of Pharmacology, Unversty of Aarhus, Denmark. Accepted for Publcaton: March 25, Correspondence to B.A. S. SUMMARY The effects of dazepam on antroduodenal motlty, gastrc ph and gastrc emptyng rate were nvestgated n 10 volunteers. Gastrc emptyng was assessed usng paracetamol absorpton and antroduodenal motlty and ph by means of a perfused multlumen tube. On the frst study day, the volunteers receved paracetamol n phase I after the occurrence of one complete nterdgestve motlty complex (IDMC). was gven on the second study day at the begnnng of the frst phase I and paracetamol was gven one IDMC later. The rate of absorpton correlated wth motlty (P < 0.03). Some volunteers were fast absorbers on the frst study day and slow on the second, ndcatng that absorpton rate s not constant, but dependent on gastroduodenal motlty. tended to ncrease the gastrc emptyng rate and enhanced the ampltude of contractons and the motlty ndex durng phase II (P<0.02). Gastrc ph ncreased after ngeston of dazepam (? < 0.05). electrode, was passed through a nostrl and placed, under fluoroscopc control, so that the tp of the tube was near to the lgament of Tretz. Sde openngs at 2, 18, 26, 34 and 42 cm from the tp of the tube were arranged so that two were placed n the gastrc antrum (Al proxmal, and A2 dstal) and three n the duodenum (Dl, D2 and D3). The lumna were perfused contnuously wth dstlled water at a rate of 0.2 ml mn" 1 per channel, utlzng a pressure nfusor. Intralumnal pressure was measured by stran gauge transducers (Gould-Statham) and recorded on a multchannel paper chart recorder (Mngograf 805, Semens Elema). A ph mcroelectrode (GK 2801-C, Radometer,

2 GASTRIC EMPTYING 713 Phase II Phase III Phase I Antrum 1 Antrum 2 Duodenum Duodenum 2 L f50 mm Hg Duodenum 3 V p o H J 5mln FIG. 1. Antroduodenal motlty n the fastng stage followng dazepam. Al proxmal and A2 dstal antrum, Dl proxmal, D2 mddle and D3 dstal duodenum. Copenhagen) was passed through one lumen and attached to the sde of the manometrc catheter between the two antral recordng stes. The ph electrode was calbrated wth commercal buffer solutons (ph 4.01 and 1.09). Gastrc antral ph was dsplayed contnuously on a ph-meter (Radometer, Copenhagen) and recorded on the paper chart recorder. All measurements were recorded also va an nterface on a multchannel tape recorder (TEAC xr-510), for later data compresson and analyss. The rate of gastrc emptyng was assessed by paracetamol absorpton after oral ngeston [8-10]. All the nvestgatons commenced at 7 a.m. and the subjects remaned supne throughout the nvestgatons. Paracetamol was admnstered after one complete nterdgestve motlty complex (IDMC) mmedately after the second phase III on the frst study day. An IDMC was denned as the motlty pattern from the begnnng of one phase III to the begnnng of the next (fg. 1) [11]. Each ndvdual receved paracetamol 20 mg kg" 1 (medan mg kg" 1 ) as Panodl tablets, gven as a combnaton of whole and half 500-mg tablets, wth 40 ml of water. was gven mmedately after the frst phase III on the second study day. Each ndvdual receved dazepam 0.25 mg kg" 1 ( mg kg" 1 ) as Stesold tablets, gven as whole and half 5- or 10-mg tablets wth 40 ml of water. One IDMC later, paracetamol 20 mg kg" 1 was admnstered after the second phase III. Blood samples were taken at 15, 30, 60,90, 120 and 180 mn after ngeston of paracetamol on both study days. Antroduodenal motlty and gastrc ph were measured contnuously untl the last blood sample had been taken. Data analyss The recordngs of motlty were assessed manually and each phase of the IDMC was dentfed and assessed separately [11]. The duraton of the quescent phase I was noted. Phase II, whch s characterzed by persstent rregular contractons, was assessed for duraton, frequency and ampltude of contractons and the motlty ndex (frequency x ampltude) calculated. Each phase II was dvded nto 5-mn ntervals for assessment of frequency and average ampltude of contracton at each recordng ste. Phase III of the IDMC was defned as a coordnated burst of actvty propagated caudad. Each phase III was assessed for ts duraton at each ste, frequency, velocty of propagaton

3 714 BRITISH JOURNAL OF ANAESTHESIA (cm mn l ) and ampltude of contracton. " Incomplete" phase III perods, denned as those wth only antral or duodenal components, were also noted. Serum paracetamol concentratons were measured by hgh pressure lqud chromatography [12]. Paracetamol absorpton was assessed from serum concentratons at each samplng tme, the peak paracetamol concentraton (Cmax), the tme to reach the peak (rmax) and the area under the serum concentraton curves (AUC) for each of the study days and correlated wth the pattern of motlty. The motlty data for each phase of the IDMC and ph wth and wthout dazepam were pooled and compared for each of the study days. The medan of the hghest and lowest antral ph was calculated for each 5-mn epoch. Statstcal analyss Statstcal analyss was carred out wth the Mann-Whtney, Kruskall-Walls, Fsher's exact and Spearman rank sum tests. Values are gven as medans wth range or quartle spans, or both. P < 0.05 was consdered sgnfcant. RESULTS Twenty-fve IDMC (two to four n each subject) were observed on the frst study day durng the recordng perod, whch was a medan of 279 ( ) mn. Thrty IDMC (two to four n each subject) were observed on the second study day followng ngeston of dazepam. Recordng tme was a medan of 250 ( ) mn. The cycle duraton vared consderably both between and wthn subjects and wth and wthout dazepam. Table I shows the duraton of IDMC and the duraton of the phases I, II and III after ngeston of paracetamol on the frst and second study days. No sgnfcant dfference was found between the study perods I 16- I t 2-0 I -I A1 A2 D1 D2 D3 I I FIG. 2. Frequency of contractons durng phase II on the control day (open columns) and followng dazepam (crosshatched columns). Values are medans (#) wth quartle spans (-) and range. Phase II motlty and ph dd not alter the frequency of antral or duodenal contractons (fg. 2), but ncreased the ampltude of contracton n the gastrc antrum and the proxmal duodenum (fg. 3). The motlty ndex ncreased n both antrum and duodenum (fg. 4). A narrow range of ph values was observed n the control study followng paracetamol, the medan (range) of de lowest and hghest values beng 1.4 ( ) and 2.4 ( ), respectvely. reduced the secreton of acd by the TABLE I. Duraton (mn) of IDMC and phases I, II and III n the dazepam. Medan values (range) control perod and followng n IDMC Phase I Phase II Phase III (47-161) 68 (37-113) 20 (7-53) 19 (5-J5) 49 (20-133) 38 (3-135) 6.5 (4-13) 7.5 (3-15.5)

4 GASTRIC EMPTYING n E J 60- o -a a o o * T * T A1 A2 D1 D2 D3 FIG. 3. Ampltude of contracton durng phase II n the control perod and after dazepam. Values are medans wth quartle spans. *P < 0.05 compared wth control. x 240 ' T r [Ml I - ± 120- L 80- stomach, the medan (range) values beng 2.1 ( ) and 2.9 ( ), respectvely (P < 0.01). Phase III motlty and ph dd not affect the frequency of occurrence of phase III of the IDMC. After ngeston of paracetamol, 19 phase III perods were recorded on the frst study day and 23 on the second. Twenty-three per cent of the phase III perods were complete wth antral actvty on the o T ; * < < _ f I - - A1 A2 D1 D2 D3 FIG. 4. Motlty ndex durng phase II n the control perod and after dazepam. Values are medans wth quartle spans. *P < 0.05 compared wth control. control day, compared wth 43.8% followng dazepam. The medan duraton of phase III at all measurng stes was longer both wth and wthout dazepam when an antral component was present (table II) (P < 0.01). The duraton ncreased at the dstal measurement stes. The frequency and ampltude of contracton dd not dffer between the two study days (table III). The velocty of propagaton followng dazepam * _L TABLE II. Duraton (mtt) of phase 111 (wth ( + ) and wthout ( ) antral actvty) n control measurements and followng dazepam. Medan values (range). *P < 0.01 compared wth phases wthout antral actvty + antral antral + antral antral Antral actvty Al A2 Duodenal phase III Dl D2 D3 2.2 ( ) 1.0 ( ) 1.4 ( ) 5.1 ( ) 6.4* ( ) 1.1 ( ) 3.5 ( ) ) 3.2 ( ) 2.3 ( ) 3.0 ( ) 7.1* ( ) 7.4* ( ) 0.5 ( ) 4.8 ( ) 5.3 ( )

5 716 BRITISH JOURNAL OF ANAESTHESIA TABLE III. Frequency of contractons (mn' 1 ) and ampltudes (mm Hg) of contractons durng phase III at antral (AI, AT) and duodenal (Dl, D2, D3) stes. Medan values (range) Frequency Ampltude Antral Al A2 Duodenal Dl D2 D3 3.4 ( ) 3.5 ( ) 9.1 ( ) 11.6 ( ) 11.6 ( ) 3.4 ( ) 3.6 ( ) 9.9 ( ) 11.2 ( ) 11.6 ( ) 26.3 ( ) 30.0 ( ) 39.9 ( ) 28.9 ( ) 41.9 ( ) 35.4 ( ) 51.6 ( ) 32.6 ( ) 35.4 ( ) 44.3 ( ) o ^ 18-1 a 16- I 14- CD CD CO CO a. concn c 1 2 " 00 I y y 0 1 Tme (h) FIG. 5. Absorpton curves for paracetamol wth and wthout dazepam. O = measurements; = after dazepam. Values are medans wth range. 1 r 1, was unchanged n the gastrc antrum and proxmal duodenum, but decreased n the dstal duodenum (table IV) (P < 0.05). The ph values durng phase III were ncreased followng dazepam, the medan lowest and hghest values (range) n the control perod beng 1.4 ( ) and 3.4 ( ), respectvely (P < 0.01) followng dazepam. Gastrc emptyng Paracetamol was gven a medan of 95 (58-175) mn after dazepam. The absorpton curves for the ( ) and 1.8 ( ), respectvely, and 2.5 two study days are shown n fgure 5. The rate of

6 GASTRIC EMPTYING 717 TABLE IV. Velocty of propagaton (cm mn ') of the contracton wave durng phase III at antral (A2) and duodenal (Dl, D2, D3) stes. Medan values (range). *P < 0.05 compared wth control Recordng ste Al A2 Dl D2 D ( ) 9.7 ( ) 9.9( ) 9.1 ( ) 10.6 ( ) 10.6 ( ) 10.6 ( ) 6.5* ( ) rmax for the three groups are shown n table V. Only two of the volunteers had the same pattern of absorpton durng the two study days. The number of fast, medum and slow absorbers dd not change followng dazepam. The patterns of absorpton correlated wth the patterns of motlty on both study days (fg. 6) (P < 0.03 and P < 0.02). The characterstcs of the motlty pattern durng phase II are shown n table VI. The duraton of phase II was longer n the group of medum absorbers than n the group of fast absorbers (P < 0.01). TABLE V. Tme (Xmax) (mn) to reach peak concentraton (Cmax) (fg ml' 1 ) of paracetamol n fast, medum and slow absorbers of paracetamol. Medan values (range) Fast Medum Slow rmax or or Cmax 20.0 ( ) 20.3 ( ) 20.3 ( ) 14.6 ( ) 10.2 ( ) 4.9 ( ) TABLE VI. Phase II characterstcs (medan (range)) for the fast, medum and slow absorbers. + = Present; = absent. Motlty ndex = frequency x ampltude *P < 0.01 compared wth fast absorbers Fast Medum Slow Duraton (mn) Antral component 44 (33-60) + 34 (26-41) + 123* (80-133) + 102* (70-170) + 52 (20-83) 42 (31-70) Motlty ndex Al 233 ( ) 265 ( ) 95 (20-265) 305 ( ) gastrc emptyng dd not dffer sgnfcantly between the two study days, but gastrc emptyng tended to ncrease followng dazepam (P at 15 mn and P = at 30 mn for serum concentratons of paracetamol). No paracetamol was absorbed durng phase I. Three patterns of absorpton were seen on both study days. One group were fast absorbers, another medum and the thrd slow. Cmax and 0 0 DISCUSSION Many drugs alter the rate of gastrc emptyng, ether by an effect on smooth muscle or by nfluencng the release of gastrontestnal hormones whch modulate gastrontestnal actvty. There are few studes n man that demonstrate the magntude and sgnfcance of these effects [6,13]. s used wdely as a tranqullzer and as a premedcant before anaesthesa, and s absorbed better after oral than after.m. admnstraton, the same dose gvng hgher peak concentratons [14,15]. Paracetamol was admnstered approxmately 1.5 h after the dazepam, when the plasma concentraton should have been close to ts peak value [16]. The treatments were not gven n random order, so that the presence of normal antroduodenal motlty could be ensured n each volunteer before proceedng to the study proper. There s no reason to presume that ths would have nfluenced the results. The actons of dazepam on antroduodenal motlty are probably medated by ts actons on hgher regulatory structures n the central nervous system through the cholnergc vagal fbres whch enhance contractons [7,17]. The acdty of the stomach contents was reduced followng dazepam, probably through a smlar mechansm. Serum paracetamol concentratons were used n ths study as an ndex of gastrc emptyng rate. Paracetamol has often been used as a model for absorpton studes as t s a weak acd (pat a 9.5) and s largely un-onzed n the stomach. It s not absorbed from the stomach, but s absorbed rapdly from the small ntestne and ts rate of absorpton s an ndrect measure of gastrc emptyng [8]. No paracetamol was absorbed durng phase I, and the admnstraton of the drugs wth water dd not tself provoke any contractons.

7 718 BRITISH JOURNAL OF ANAESTHESIA > O L A1 ndex 60 mn FIG. 6. Relatonshp between the AUC for paracetamol 60 mn after ngeston and the motlty ndex at pont Al (I Al ndex) at the same tme. O = measurements; # = after dazepam. Correlaton by Spearman test: control Rho P = 0.023; dazepam Rho P = tended to accelerate the rate of gastrc emptyng, probably by ncreasng the strength of contractons durng phase II. The rapdty of paracetamol absorpton depended partly upon the occurrence of antral actvty and partly upon the duraton of phase II. The occurrence of antral contractons ncreased towards the end of phase II and the rate of absorpton ncreased accordngly. It was noted that some volunteers were fast absorbers on the frst study day and slow on the second. It would appear that the pattern of absorpton s not constant, but vares n parallel wth the pattern of antroduodenal motlty. We conclude that dazepam ncreases the ampltude of contractons and the motlty ndex durng phase II of the IDMC and reduces the acdty of the stomach contents. ACKNOWLEDGEMENTS We are grateful to Lars Rybro, M.D., for hs valuable advce and help wth the statstcal analyss. REFERENCES Rsbo A, Schmdt JF. Peroral dazepam compared wth parenteral morphnescopolamne wth regard to gastrc content. Ada Anaeslhesologca Scandnavca 1983; 27: Hjortsoe E, Mondorf T. Does oral premedcaton ncrease the rsk of gastrc aspraton? A study to compare the effect of dazepam gven orally and ntramuscularly on the volume and acdty of gastrc asprate. Ada Anaeslhesologca Scandnavca 1982; 26: Brnbaum D, Karmell F, Tefera M. The effect of dazepam on human gastrc secreton. Gut 1971; 12: Kelly AK. Motlty of the stomach and the gastroduodenal juncton. In: Johnson LR, ed. Physology of the Gastrontestnal Tract. New York: Raven Press, 1981; Kellow JE, Borody TJ, Phllps SJ, Tucker RL, Haddad AC. Human nterdgestve motlty: varatons n patterns from esophagus to colon. Gastroenterology 1986; 91: Nmmo WS. Drugs, dseases and altered gastrc emptyng. Clncal Pharmacoknetcs 1976; 1: Malagelada JR. Basc aspects n performng gastrontestnal manometry. In: Malagelada JR, Cameller M, Stanghelln V, eds. Manometrc Dagnoss of Gastrontestnal Motlty Dsorders. New York: Theme, 1986; Headng RC, Nmmo WS, Prescott LF, Tothll P. The dependence of paracetamol absorpton on the rate of gastrc emptyng. Brtsh Journal of Pharmacology 1973; 47: Nmmo WS, Headng RC, Wlson J, Tothll P, Prescott LF. Inhbton of gastrc emptyng and drug absorpton by narcotc analgescs. Brtsh Journal of Clncal Pharmacology 1975; 2: Todd JG, Nmmo WS. Effect of premedcaton on drug absorpton and gastrc emptyng. Brtsh Journal of Anaesthesa 1983; 55: Scratcherd T, Grundy D. The physology of ntestnal motlty and secreton. Brtsh Journal of Anaesthesa 1984; 56: 3-18.

8 GASTRIC EMPTYING Prescott LF. Gas-lqud chromatographc estmaton of paracetamol. Journal of Pharmacologcal Pharmacology 1971; 23: Nmmo WS. Effect of anaesthesa on gastrc motlty and emptyng. Brtsh Journal of Anaesthesa 1984; 56: Assaf RAE, Dundee JW, Gamble JAS. The nfluence of the route of admnstraton on clncal acton of dazepam. Anaesthesa 1975; 30: Gamble JAS, Dundee JW, Assaf RAE. Plasma dazepam levels after sngle dose oral and ntramuscular admnstraton. Anaesthesa 1975; 30: Thompson DG, Rchelson E, Malagelada JR. Pertubaton of gastrc emptyng and duodenal motlty through the central nervous system. Gastroenterology 1982; 83: Stanhelnn V, Malagelada JR, Znmester AR. Effect of opate and adrenergc blockers on gut motor response to centrally actng stmul. Gastroenterology 1984; 85: