Inhibition of Gastric Acid Secretion in Man by the Transcranial Application of Low Intensity Pulsed Current

GASTROENTEROLOGY 69:359-363, 1975 Copy right© 1975 by The Williams & Wilk ins Co.

Vol. 69. No.2 Printed in U.S.A.

INHIBITION OF GASTRIC ACID SECRETION IN MAN BY THE TRANSCRANIAL APPLICATION OF LOW INTENSITY PULSED CURRENT GARY S. Ko·nEn , EnNEST KALBFLEISCH , PH .D.

0.

HENSCIIEL ,

M .D.,

WALTP.H

J.

Hoc;AN ,

M.D.,

ANI> JouN H.

The M edical Collef?e of Wiscon.~in, Department of Anesthesiolo~-:y , Department of Gastroenterolo~-:y, and Biostatistics Unit, Departm ent of Preventive Medicin e, Veterans Administration Ho spital, Milwauk ee -Wood , Wisconsin

This study was conducted to determine the effectiveness of transcranial electrotherapy (TCE) in reducing gastric secretion in man. TCE has been proposed as a therapeutic modality which induces a relaxed psychological state by the application of low intensity diffuse electrical current and has been purported by Soviet investigators to be beneficial in the treatment of peptic ulcers. Secretion rates were monitored in adult male volunteers by a method of intragastric titration utilizing a pH-sens itive telemetry capsule. In one study 5 subjects had their basal secretion rates monitored before, during, and after the application of TCE at ~raduated current intensities. A threshold of inhibition was observed for currents of 0.9 rna and greater. In a second study, 12 subjects had histamine-stimulated maximum acid output determined for control and during TCE application. Gastric acid secretion was reduced by an average of 30% when 1-ma TCE was applied, with individual reductions ranging from 5.7rYt, to 53.2%. Since the application of relatively high TCE currents may produce discomfort in some subjects, a third study was conducted to determine whether the inhibition might not merely be the result of nonspecific noxious stimuli. For this study the electrical connections to the TCE electrodes were altered so that the same uncomfortable sensation was produced on the forehead , but no current was actually applied transcranially. This "placebo" TCE produced no reduction in the maximal acid output of 6 volunteers, but when the currents were applied transcranially, the gastric acid secretion was reduced by an average of 27 % below control values. Transcranial electrotherapy (TCE) reportedly induces a relaxed psychological state by the application of low intensity diffuse electrical current . This form of therapy is widely used in Soviet clinics for the treatment of disturbances having a psychiatric or psychosomatic component. The Russian word for the therapy, "elektroson, " is translated as electrosleep. This Received May 10, 1974. Accepted March 21, 1975. Address requests for reprints to: Mr. Gary S. Kotter, The Medical College of Wisconsin , Veterans Administra tion Hospit a l, 5000 West National Avenue, Milwaukee-Wood, Wisconsin IJ319:l :lG~J

has caused a good deal of misunderstanding since patients do not necessarily sleep during treatment. The more appropriate term, transcranial electrotherapy, will be used in this paper, although "cerebral electrotherapy" and "electrotherapeutic sleep" are synonymous terms which have been used by other authors . Various researchers in the U.S .S. R have reported using TCE in programs of combined therapy for treating peptic ulcers. ~-o~ They concluded that TCE is effective hut were unable to correlate the patient's improvement to any decrease in the gastric

360

KOTTER ET AL.

secretion levels which were determined before and after the course of therapy. However, there is evidence of reduced gastric output in animals during the time electrical current is actually applied. 5 This investigation has attempted to determine the effectiveness of TCE in reducing gastric acid secretion in man. Materials and Methods Gastric acid secretion was monitored by the "Telefunken-Heidelberg" radiotelemetry system utilizing the method of intragastric titration originally developed by Noller. 6 The system is comprised of a pH-sensitive telemetry capsule measuring 20 by 7 mm , a multidirectional belt antenna , and a combined receiver-recorder. The capsule is activated by immersion in saline and calibrated by placing it in buffer solutions of pH 1 and pH 7 which are heated to 37°C . A small hole is provided for attachment of a string to aid in positioning and maintaining the capsule in the dependent position after ingestion. When rechecked after completion of the day's study, all capsules had drifted less than ± 0.5 pH. Figure 1 is an example of the method of intragastric titration which will aid in explaining the determination of gastric acid secretion. Following the establishment of a base line pH, a titrating dose of NaHC0 3 is given and the pH rises. As the stomach secretes acid, the pH falls until the basal pH level is reached. Gastric acid in milliequivalents per hr is calculated as the titrating dosage divided by the time necessary to regain base line {t) . For example, if the titrating dosage is 1 mEq, and the alkali test time (t) is 12 min (0.2 hr) , the rate of secretion is 5 mEq .H + per hr. TCE currents were supplied by an Electrodorm I which was modified to operate from batteries to eliminate any possible hazard from the 120-v AC line. The current is applied through electrodes fixed in place across the pH

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FIG . 1. Exampl e of recorder strip showing intragastric titration curves.

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head by Velcro straps. The two pairs of elec· trodes (frontal-negative and occipital-positive) make contact with the skin by means of salinesaturated pads. The output of this device is aD C biased rectangular wave. In all studies, the frequency and pulse duration were held constant at 100 Hz and 1 msec, respectively. The average current intensity was incrementally increased from 0.1 to 1.5 rna on successive test days durin g the first study to determine what relationship, if any, existed between the current level and the basal gastric secretion rates. In subsequent studies, the current was set to 1 rna on the basis of the results of the first study. The subjects were all adult males who ranged in age from 23 to 58 yea rs. The testing procedure and purpose of the invest igation were explained to each volunteer and informed consents were obtained . Testing began at 8:00 AM with the subjects having fasted overnight. During the tes t the volunteers were recumbent with their heads slightly elevated and were perm itted to read, work crosswork puzzles, etc. In the first study, after ingestion of the previously calibrated capsule, the participants were given an oral dose of 1 mEq of sodium bicarbonate. Subsequent doses were adjusted so that the alkali test time was approximately 10 min . After 1 hr, the TCE electrodes were put in place and left on for 3 hr ; monitoring was continued for an additional 3 hr after this period. The initial test day was a control in which no current was passed through the electrodes . Dur· ing the second, the mean current level was set to 0.1 rna. The current level was increased in increments of 0.2 rna on subsequent test days until the 1.5-ma level was reached . The final session was again a control with no current passing through the electrodes. In the second study, eac h subject underwent two tests in which his maximal acid output (MAO) was deterined using the augmented hi sta mine test of Kay, 7 with diphenhydramine hydrochloride (Benadryl) being given 1h hr before the histamine acid phosphate injection (0.4 mg per kg of body weight) . In both sessions, the TCE electrodes were applied in the same manner . On a randomized basis no current was passed through the elecrodes during one of the studies , whereas a mean current of 1 rna was applied during the other . Since the inhibition of gastric secretion is related to noxious sti muli in a nons pecific way, a third study was conducted to determine whether the observed inhibition was act ually caused by the passage of current or merely the discomfort associated with the current . It

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ELECTROTHERAPY AND GASTRIC AClD SECRET[()N

should be pointed out that with the type of current used (DC biased rectangular waves, 100 Hz, 1 msec) and careful application of the electrodes, there is usually an awareness of the current, but no discomfort up to a range from 0.5 to 1.0 rna. Current levels greater than this can cause a degree of discomfort which will vary widely between subjects . The discomfort associ ated with high levels of TCE is characterized by sensations of tightness and pressure on the forehead. In order to simulate these sensations, the electrical connections to the electrodes were altered so that the current was passed only between the two frontal electrodes and not transcranially. For this study 6 volunteers each underwent tests to determine their MAO for control, "placebo" TCE, and active TCE of 1 rna. As in the second study the order of these tests was randomized.

Results To examine for a current level at which a significant reduction in basal gastric acid secretion is observed, analysis of variance mean square statistics and associated P levels corresponding to each possible current "breakpoint" were determined for each of the first 3-hr (active TCE) and second 3-hr (post-TCE) sessions. The results indicate a maximum breakpoint at 0.8 rna (P < 0.01), whereas no breakpoint is indicated for the post-TCE data . This means that TCE currents of 0.9 rna and greater caused a significant reduction below control values in basal gastric acid secretion (fig. 2). Figure 3 shows the average change in basal gastric acid secretion for the 5 subjects during the 0.9-ma test. Additional analysis indicates that there was no significant difference between the initial and final control test days. The results of the second study are summarized in table 1 which shows the control MAO, the MAO during TCE application of 1 ma, and the reduction expressed in terms of milliequivalents .H+ per hr and per cent. The 12 subjects experienced highly significant reductions (P < 0.01) in their MAO's that ranged from 5.7 to 53.2%. The average was 30%, which represents a reduction of 8.6 ± 2.2 SEM mEq .H + per hr. The results of the third study, which are shown in table 2, list the results of the histamine-stimulated MAO tests under

three conditions . The first and third columns represent the control and active TCE (1 rna) outputs, respectively. The second column lists the results of the placebo TCE

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F1<:. 3. Chan~e in basal gastric acid secretion rate during application of 0 .9 rna of Transcranial electrotherapy (mean values ± sE). T AHL~; 1. Inhibitory effect of tra,.~cranial electrotherapy (TCE) on histamine-stimulated uastric acid secretion Subject

Control

TCE

Reduction

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Reduction %

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14.:l 14.4 16.4 19.5 20.0 23.0 27.8 29.5 39.2 40.9 42.0 60.0

12.8 12.3 12.1 14.7 17.8 21.7 18.7 24.2 17.9 24.7 29.0 38.0

1.5 2.1 4.3 4.8 2.2 1.3 9.1 5.3 2U 16.2 13.0 22.0

10.5 14.6 26. 2 24.6 11.0 5 .7 32.7 18.0 53.2 39.6 30.9 36.7

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KOTTER ET AL.

362

2. Effects of placebo and active transcranial ele ctrotherapy (TCE) on histamine-stimulated J!astric acid se cre tion

TABLE

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ActiveTCE

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Control

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16.9 25.2 37.7 22.6 20.9 28.7

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tests in which current was applied only across the frontal electrodes. Analysis indicates that there is no significant difference between the control and placebo results , but that active TCE did cause an average reduction of 27 .3% with individual reductions ranging from 6.3 to 46.5%. Figure 4 portrays the combined results of the second and third studies. It compares the results of the histamine-stimulated MAO tests during placebo (P) and active TCE of 1 rna (A) relative to the control MAO (C). The corresponding simple linear regression equations are: Placebo (0 rna TCE) regression equation: p = - 3.7 + 1.11 c Active (1 rna TCE) regression requation : A = 5.8 + 0.502 C

Statistical testing of the null hypothesis of no change in MAO (slope = 1, intercept = 0) shows that the placebo regression coefficients do not show significant differences (P < 0.5 for the slope, P < 0.4 for the intercept); thus, there is no evidence against the relationship P = C. Similar testing showed that the active (1 rna TCE) equation is significantly different than the A = C no change conjecture of the null hypothesis (?< 0.001 for the slope, P < 0.02 for the intercept). The 1 rna TCE regression equation shows that an average MAO of 13.3 mEq .H+ per hr can be expected when the control MAO is 15 mEq .H+ per hr (a reduction of 11.3%), whereas an average MAO of 28.4 mEq. H+ per hr will result for a control MAO of 45 mEq .H+ per hr (a reduction of 36.9%). The shaded

Vol . 69 , No.2

area about the 1 rna TCE regression line in figure 4 depicts 95% confidence limits for future maximal acid outputs during 1-ma TCE for the given range of control MAO.

Discussion The results of all three studies indicate that TCE can cause a highly significant reduction in both basal and histamine stimulated gastric acid output. Unfortunately, the telemetry method does not permit determination of whether this reduction is in acid volume, concentration, or both. However, Reigel et a!. 5 reported a reduction in both acid volume and acid concentration during TCE application in their study of the stump tail macque. From figure 2 it can be seen that there is increased inhibition at the higher current intensities. However, virtually every subject will experience some degree of discomfort at these elevated levels. It was for this reason that a mean current level of 1 rna was chosen for the histamine-stimulated studies . The average reductions of 30% in the second study and 27 .3% in the third study are consistent with the reduction experienced at 1 rna in the first study of basal gastric secretion. The finding that there was no significant difference between the initial and final control session is in agreement with the 50 o PLACEBO cDr:tA TCE I •

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ELECTROTHERAPY AND UASTU/C ACff) SECRETION

conclusion of the Soviet investigators. There is no permanent reduction in gastric secretion due to repeated TCE applica tions. The inhibitory action of TCE becomes effective within 15 to 30 min after onset and disappears within the same period upon cessation of the current (see fig. 3). This suggests that a neurohumoral inhibitory mechanism may be at work as proposed by Reigel et a\. 8 • 9 However, it should be noted that the " inhibitor" has only been demonstrated in monkeys at the much higher current levels needed to produce unresponsiveness (electroanesthesia). Whether this temporary reduction in gastric acid secretion would be of any benefit in the treatment peptic ulcer disease is unknown. Some of the confusion associated with the misnomer "electrosleep" is the result of studies conducted on blindfolded patients in a quiet room. There is an obvious tendency to sleep under these circumstances whether or not TCE is applied. However, in the 7 -hr study of basal secretions where patients were frequently interrupted to drink the bicarbonate titrating solution, there was little sleeping. The inhibitory effect of TCE is therefore clearly not dependent on the patient's state of wakefulness. The method of intragastric titration utilizing a telemetry capsule has been compared with the direct gastric aspiration technique with correlation coefficients ranging from 0.63 to 0.89. 10 ' 13 The over-all coefficient of variation for two or more maximal histamine tests utilizing the nasogastric tube was reported as approximately 10% by Sircus, 14 whereas a variation of 12% was reported by Stavney et al. 11 using the telemetry method. Although TCE has been used for nearly 25 years in the U.S .S. R., it has only recently been a subject of interest to the Western world. Whether TCE has any efficacy as a therapeutic modality has not been determined and will depend on the results of carefully controlled clinical stud-

ies as well as further investigation in to the underlying mech a nisms. REFERENCES l. Bulatov PK, Hul' PI: Elcktroson i Elcktroancstez iya (Eiektronarkoz). Moscow, 19GG, p :2492!12

2. Pervomayskiy BY, Scmenko IF , Mikhaylov a TN. et al: Elcktroson i Elcktroanesteziya (l~l c kt ronarkoz). Moscow, 1966 , p 2f:i:l - 2S!i 3. Pclcshchuk AP, R e h enok YN, Nyrtseva Yl: Elcktroson i Elekt roanesteziya (El ect ronarkoz). Moscow, 19G6 , p 2!i6-2fiR 4. Krupitskaya VS : Elcktroson: Elcktroancsteziyn (Elekt ronarkoz). Moscow, 19Gfi, p 2!i9 - 2GO !i. Rei gel DH, Dallma nn DE, Chri stman NT, et al: Physiological effects of electro! herapcu t ic currents in the primate and man. Proceedings of the Second International Symposium on Electrotherapeutic Slee p and Electroanesthesia, Craz. Austria, 19fi9 6. Noll er HG: Res ul ts of exa minations of stomach function with the e ndoradio capsule. Fortsch Med 80::lS1 , WG2

7. Kay AW: Effects of large doses of histamine on gastric sec retion of H C 1: a n augmented hist.a rn inc test. Rr Med ,J 2:77, 19!i:l 8. Reigel DH, La rso n S.J, Sances A .Jr: Effect of limb ic system st imulation and elect.roa ncs t hesia upon gastric secret ion . Gast roent.erology f>fi : 1 192 , 19G9

9. Reigel, DH , Har boriak ,J,J , Larson S.J, ct al: The effect of clectroan es thesia on gastric acid secret ion. Proceedings of the Second Internal ion a I Sym posium on Electrotherapeutic Sleep and Electroancsthesia, Graz, Austria, WG!J 10 . Connell AM , Wate rs TE: Assess ment of gastric func tion by pH telemetering ca psu le. L a nc et 2:227-2:10, 1964

11. Stavney SL, Hami lton T, Sircus W, et al : Evaluation of t he pH-sensitive telemetering ca psule in the est im at ion of gastric sec retory capacity. Am ,J Dig Dis 11:10, 1966 12 . McAlha ny VA, Ya rborough DR, Weidner MG, et al: Evaluation o f pH telemetry in the clinical study of gastric phys iology . Am Surg :lfi: 12, 1969 13 . Andres MR, Bingham JR: Tubel ess gastric a nalys is with radio-telemetering pill (Heidelberg capsule). Can Med Assoc J 102:1087-1089, 1970 14. Sircus WJ: The ap pli cat ion of the " maximal" histamine test of gastric secretion to problems of peptic ul cer surgery. J R Coil Surg Edinh 4: 1fi:l, 19!i9