362

Reduction

of transmural oesophageal metoclopramide

In nineteen patients with portal hypertensiw endusccopically by direct puncture

and cesophageal

variceal pressure by

varices, transmural

of the varices before and after intravenous

varicea! blood pressure was detwmined

administration

of ‘20 ntg metocloprsmide

or

placebo. No change in pressure was observed after placebo (mean difference -1.3 + 24.5%, N.S.), however, metaciopramide reduced the pressure by 17.6 f 18.6% (p = 0.02). Our results suggest that metoclopramide may be beneficial for the prevention or treatmen? of variceal haemorrhage.

In patients with portal hypertension, blood is drained from the portal vein territory to the oesophqeal vaices via submucosal vcssetc in close contact to the lower oerophageal sphincter (1). A drug-induced increase in sptxwter tone may be expected to compress these vessels and lead t(> a reduction in blood flow or pressure in the oesophageal var:ces. Sir..s tix zrygos vein coI!scts blood from the oesophageal vatices. the effect an aqgus flow of substances which increase lcwer oesophageal sphincter tone has been prewvuriy investigated. The resuin of these studtes, however, are cuotradictoty (L3.4). Clmical sil;dies on the effect of these drugs on the short-term outcome in patients with blwding writes bavc aba pro&xed epirocni results (5.6). To dare, no conrxlled evaluation of the effen nf these +xtances on the variceal blood pressure has been published. Blood pressure in ocjophageal varices may play a role in the pathogenesia of varicea: b&ding. Reduction of pressurn may reduce the bleeding rate or arrest active bleeding (7).

The aim of the present study was to investigate whethtr metoclopramide, a drug which increases lower oesophageal sphincter tone, would reduce variceal pressure.

Between August 1987 and December 1989,SO patients with patal hyperteusion and suspected oesophageal varices, who had not been previously treated with sclerarberapy or@-blockers were rehrred to the Endoscopy Unit of the Department of Medicine II, Klinikom Grosshadern for assessment of variceal pressure and included in the present study. Immediately before the ondoscopic procedure, patients were blindly randomized to receive either placeba (II = 24) OTmetoclopnmide (n = 26). However, 31 of these patients (14 in the placebo and 17 in the mew clopramide group) were excluded before the code was broken, ix., while tte observers were still unaware whether the patients had received metoclopramide orplacebo. Exclusion was due either to absence of varices (n =

363 5) or because pressure recordings before or after Er’ gadrninistratlor were unsatisfactory accordin? to the c-iteria defined below (n = 26). Satisfactory pressure recordings were obtained in 19 patients (placebo n = 10; metoctopramide n = 9). who wete included in tire final aoaiyjis. Patient characteristics are give” in Table 1. The varin pressure measurenent was approved by the ethical committee of the med;cal faculty of the University of Mtmich and informed consent was obtained from all patients. Determination of trr-lsmural msophagesl variceal pressure was carried out before sclerotherapy as previously described (9). For measurement of intravariceat pressure, a xlerotherapy needle (outer diameter 0.7 mm) connected to a Teflon tube (outer diameter 1.5 mm) and

tuations both in the oedophagus and the vadx for et least

perfused with 0.6 mllmin Hz0 using a low compliance capillary pump system (MUI Scientific, Canada) was passed through the biopsy channel of a” endoscope (Olympus GIF K2). The varix was punctured with thn ttood!e 5 tn above the gastrooesophageal junction The correct position of the needle in the vessel was identified

All measorement~ were petformed in the slightly sedated patient (IO mg diazepam i.v, before introdactio” of the endascope). N-Butyl scopolamine, a drug whtch tepresses oesophageal peristalsis was not administered, since it is known to affect the lower oesophageal sphincter tone. Cefotaxime (2 g Lv.) and tobrsmycine (80 mg I.Y.) were administered 10 min before the introduction of the

by the typical respiration-dependent

pressure fluctuations

15 s or during at least three r’spirarory cycles (see Fig. 1) before and after drug administration. Transmural vadceal pressures were calculated as the difference between vatiteal and oesophageal lumwal ?reseures (Fig measured by electromechanical transducers and a Sensor Medics R611 Dynograph recorder. Immediately after determination of basal wriceal pussure. patients received either an i.v. bolus of 20 sg metockipramide (n = 9) orrrlme (n = IO). The adoscope W=P the” withdraw”. Fifteen. mi” after drug injection ins mdoscope was remtroduced and a second meawiement of varicaal pressure .*a~ performed 20 min after drug injection.

sumwere

I) ores.

(Fig. 1). Oesophsgeal luminal pressure was recorded simuitaneourly (Fig. 1) via a similar Teflon tube attached :o the o”ter surface of !he endoawpe and perfused as above. Calibrations of the perfusion system were performed before each session by raising the needle to varying hcigh’; in 10 cot steps between 11-40 cm H,O. A satisfactory pres-

endoscope for prophylaxis of bacteremla. To prevent bleeding from the puncture site, the sckrotherapy needle was withdraw” after each varix pressure measurement and the tip of the endoscope advanced into the stomach and kept in this position for 2 min. No bleeding or septic events related to the endoscopic procedure ?yere ob-

wre recording

served in ow patients.

was defined

as stable, horizontal

tracings with typical respiration-dependert

pressure

pressure

flucThe results are expressed as means f S.D. Intraindividual pressure changes before and after drug administration were evaluated by the paired t-test. Presxxe changes after metoclopramide were compared to those after saline by analysis of variance. p valuer < 0.05 (two-tailed) were ccnsideredstatistically significant.

There were no significant differences between patients who received me.oclopramide end those -ho :z-eivcd z: line with regard to sex, age, aetiology of penal bypeztension, liver function. presence of ascites, bleeding history and endoscopic criteria (Table 1j. changes in the baseline oesnphageal luminal pressure observed after administra:ion of placebo (+0.2 t 2.2 cm H,O) wex not significantly different from those observed after administration of metoclopramide (-0.5 + 3.3 cm H>O). Transmuml variceaf pressure HBS not affected by &xehn !hefore 24.1 + 8.4 cm H,O. after 23.7 + 9.7 cm

.

H,O, N.S., Fig. 2). However.

aft& the admi”istntio”

of

364 TARLC

dent of the mctoclopramide

I

group (-16.9

cm H,O).

was due to a large change of intravascular sure (-19.2

and -19.7

cm H,O,

?i?t?rtnc~s :ou!d be fwnd patients in comparison

respectively).

of portal

ascites (absent in both), (diameter

byperrension

cirrhosis, Child

A

endoscapic appearance

of vatices >5

mm, red c&w

sign present) and change in mean arterial drug administration

of these

tc, the other patients (see Tables 1

and 2) with respeci 10 drtiology

of !heir writes

No clear

in the characteristics

and scvcritv of liver disease (alcoholic in both),

This

variceal pres-

pressure after

(-3 and -8 mm Hp. respectively).

Dlood pressure and heart rate were not significantly fluenced by metoclopramide

in-

or placebo (Table 2).

Discussion In the present controlled pramide on transmural

study, the effect of metoclo-

oesophageal variceal pressure was

investigated in patients with portal hypertension. sessment of drug-induced

The as-

changes did not lead to compli-

cations in our patients. In nine patients obtained metoclopramide

it decreased significantly

(before 29.0 f

tration,

in whom satisfactory

variable

but significant

53cmH~O,after23.9+6.3cmH,O,p=O.O2,Fig.2).A

variceal pressure (-17.6

decrease in pressure was observed in three of ten patients

no comparable

receiving placebo, pramide

metoclopramide -1.3

but in all patients

(D < 0.01).

? 24.5%

and placebo b

receiving metoclo-

The mean changes in pressure afier were -17.6

= 0.06 metaclapramide

f

18.6%

and

vs. placebo).

f

!n more than ha!f of the patients no satisfactory sure recordings were obtained tracing can be easily identified pressure fluctuations

cm H,O)

the analysis. The

lier studies (9,10),

to be

pres-

so that they had to be ex-

cluded from

Ircm m the piacebo group (-15.6

Since

or the endorcopic manipulation.

0.2, N.S.).

variceal pressure occurred

of transmural

were observed.

patients receiving saline, these results are unlikely due to the premeditation

the basal pressure in either group (r = 0.2, N.S. and I =

As is evident from Fig. 2, a large and unexpected reduc-

reductions

18.6%)

were

adminis-

pressure changes were evident in the ten

The pressure changes did not correlate with the height of

tion in rransmural

recordings

both before and af?cr metoclopramide

typical

variceal

pressure

by resFiration.dep~ndent

(see Fig. 1). In contrast to our ear-

in the present trial we did not use sco-

in one pa.

polamine 10 reduce oesophageal peristalsis since thir drug

and in one pa-

may reduce the oesophageal sphincter tone and hence antagonise the effeci of metoclopramide. er, that

reliable

when peristaltic pressure. In ordtr

recordings

cannot

It appears, howevalways be obtained

waves are superimposed to eliminate

a potential

on the V.&X selection bias,

the exclusion of these patients was performed

Mean

ar,eria,

before the

“canrare

code ~‘8s broken. i.e.. under double-blind conditions. The large. unexpected variations of variccal pressure ob served in two of the included patients (one in the placebo group and one in the mctoc’opramide group) barl no c!sa; explanation, could however be due to influences of the eridoscop~ proccourc on the measurements. Theoretically, both systemic and local effects could be responsible for the reduction of rransmurat variceat pressue following metoclopramido administration. Systemic haemodynamic effects could not be demonstrated in the present study in accordance with a previous report (2). Furthermore, portal pressure was not influenced by metoclopramide (2). Thus the action of this drug is probably restricted to the variceal hemodynamics itself. The metoclopramide

dogage applied in the prcscnt trial

has been shown to increase lower ocsophagcal sphincter tone more than Z-fold 20 min after i.v. injection

in normal subiccts (11). Tbe sphincter response is probably nor altered m cirrhotic patients (3). lnmaoesnphageal variccs ale kd from the portal vein territory via small sribmucosal veins, which arc in close contact with the mux dar strw turcs of the lower oesophageal sphincter (1). An elevatian of sphincter tone may be expected to compress these veins and thus increase the vascular resistance between the portal vein territory and the oesopbageal writes. This ~~~c~~!d rewlt in a decrease in variccal blood flow and in a corresponding decrease in intravascular vcriceal pres-

ancc with p:~vious portographic wdies which showed a reduction of variccal blood flow after administration of ~inous ruhwmces whtch increase lower oesaphageal sphincter prcwure (12,13). Tbc effect of these substances on azygos blood ftow has also been studied. One study reponcd a rcducnon of qgos blood flow by metoclapramide or domperidone (2). However. for domperidone this has not beer: substantiated (3). Azygor blood flow is a measure of hoth intraoesophageal tori pcrioewphagea! collateral flow. However, since the submucous veins at the level of the lower oesophageal sphincter supply the intraoesophageal varices, only the intraoesophageal varix blood tlow is subject to alterations in the sphincter tone. Haemodynamic alterations induced by an increase in spi%ucr tone would therefore be mmc apparent in transmural vanceal prcssu~a than in azygos blooddlow. In a previous noncontrolled study. pentagastrin. a drug, which increases the oceophagcal sphincter tone to a greater extent than metcclopramide, was shown to rcduce variceat pressure (5). The same study also reporied the clinical efficacy of mrtuclopramide in arresting acute variccal bleeding. Our data are in accordance with this report and suggest that a possible beneficial action of metoclopramidc indeed may be due to a decrease in variccal pressure.

sure. It is noteworthy that in our patients oesophageal luminal pressure did not change after administration of mc-

Acknowledgements

toclo?ramide. mihis was not surprising since metwlopramide increases ocsophagcal luminal pressttrc only at the site of the sphincter. However, in order to oblain reference pressure values for asscsstttcnt of transmural varicccl prcsstucs, aesophageal luminal pressure wcs mcasured ct the site of varix puncture, i.e., proximal to the lo-

This study was suppatcd by a giant from the WilhelmSander-Foundation. Federal Republic of Germany. We arc indebted to the stcff of the endoscopy unit for their help. Revision of the English text by Mm Karen Moss is gr.,tefctly scknowledged.

cation of the lower oesophsgeal sphincter. Thus, sincr oesophageal huninal pressure did not change, the observed reduction of rransmurcl variceal pressure was due to a reduction in intravascular variceal pressure in our patients. The results

of the present investigation

are in accord-

During the review process of the present trial another study (Digestion 1990; 47: 56-M)) was published showing a t5.7% reduction of variceal pressure IO min after metoclopramide (IO mg i.v.) in cirrhotic pattents.

slatin does not rcdrcc ncrophageal wti;cal pressurein liver cirrhotic%Cmr 1988;29: 153-6. II Cohen S. Morris DW, Schnen HJ. DiMarino Al. The effect of ar’l and mlmvcnouc mcmcloprom~dron human tower orrophq:sl sphinclcrprcrrurc. Gastroenterology1976; 70: 484-7. 12 Lunderquis! A. Alwmork A. Ciullrtrund P. e! sl. Pharmacologic ildlucnce on csophngesl variccs. Cardiovarc lntcrvcm Radmt 19Rl: 6: 65-71