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Gastric secretory response to pressure on vagal nuclei
Gastric Secretory Response to Pressure on Vagal Nuclei
L. Norton, MD, Denver, Colorado E. Fuchs, MD, Denver, Colorado B. Eiseman, MD, Denver, Colorado
Severe head injury is frequently associated with gastric acid hypersecretion and gastrointestinal ulceration [1,2]. Cushing’s ulcer differs from other forms of stress ulcer in being uniquely associated with gastric hypersecretion [3,4]. Mechanisms responsible for this hyperacidity are unclear, but vagal transmission is probable in light of the blocking action of anticholinergic agents [5]. Cushing [6] hypothesized the presence in the diencephalon of a parasympathetic center capable of stimulating vagal nuclei to induce vagal hyperactivity [6]. Vagally stimulated gastric hypersecretion might thus be secondary to pressure effects on the hypothalamus. This study, in contrast to that of Cushing, indicates that direct pressure on the floor of the fourth ventricle above efferent vagal nuclei is capable of stimulating gastric hypersecretion independent of hypothalamic control. Methods Sixteen mongrel dogs, 25 to 39 kg in weight, were studied for basal gastric acid secretion under anesthesia after preparation with simple gastrostomy (four animals), innervated [Pavlov] gastric pouch (four animals), or pyloric fistula (eight animals). The dogs were anesthetized with sodium pentobarbital, 30 mg/kg given intravenously; they were then intubated and artificial respiration was carried out. During basal secretory studies, the pulse rate, blood pressure (via arterial catheter), central venous pressure, ~02, pCOs, and arterial pH were monitored at intervals of thirty to sixty minutes. From the Department of Surgery, University of Colorado Medical School and Denver General Hospital, Denver, Colorado. This work was supported by grants from the US Public Health Service and the John Hartford Foundation. Reprint reqUeStS should be addressed to Dr Ben Eiseman, Department of Surgery, Denver General Hospital, West 8th and Cherokee, Denver, Colorado 80204. Presented at the Twelfth Annual Meeting of the Society for Surgery of the Alimentary Tract, Atlantic City, New Jersey, June 19 and 20. 1971.
Volume 123, January 1972
Gastrostomy. In four dogs, a simple gastric fistula was maintained by means of a plastic cannula. Craniotomy for placement of a balloon catheter in the fourth ventricle was performed immediately after gastrostomy. After intervals of three to eight days, during which basal gastric acid secretion under anesthesia was measured, the inlying ventricular balloon was inflated and the stimulated gastric secretion collected. Pavlov Pouch. An innervated pouch was constructed from the body of the stomach at the greater curvature in four dogs. Integrity of the double mucosal barrier between pouch and gastric lumen was confirmed at one week by failure to recover ingested methylene blue in pouch secretions. Two to sixteen days later the animals were anesthetized for collection of basal gastric secretion. Craniotomy was performed immediately thereafter followed by measurement of stimulated secretion. Pyloric Fistula. In eight dogs, the gastroduodenal junction was divided, the proximal duodenum closed, and the pylorus sutured to the skin of the abdomen to create a total gastric pouch. In two of these dogs complete truncal vagotomy was performed at the time of laparotomy. After twenty-four hours, during which fluids and electrolytes were given parenterally, all animals were anesthetized for gastric secretory studies before and after craniotomy and fourth ventricle pressure stimulation. Gastric Analysis. For basal and stimulated acid secretory studies the anesthetized prone animal was positioned to allow optimal gravity drainage of gastric secretions through a flanged size 26 F catheter inserted into the gastric stoma or connected to the indwelling plastic cannula. Before collections, the stomach or pouch was irrigated with normal saline solution, aspirated, and allowed to drain for thirty secreminutes or longer. Both basal and stimulated
13
Norton, Fuchs, and Eiseman
tions were collected in thirty minute samples for periods of three hours each. Volume and pH of each sample were measured using an Instrumentation Laboratory pH meter. Total acid in each specimen was determined by neutralization with O.lN sodium hydroxide to pH 7.4. Acid concentration in milliequivalents per liter was multiplied by volume in liters to calculate the amount of HCl collected in one half hour. With the dog in prone posiCraniotomy Technic. tion, unchanged after collection of basal gastric secretions, a muscle-splitting incision was made in the dorsal part of the neck to expose the occipital skull and proximal cervical spine. Through a burr hole placed caudad to the external occipital protuberance, the posterior cranial fossa was entered. After incising dura and arachnoid, the cerebellar vermis was retracted superiorly to open the entrance to the fourth ventricle.
Figure 1. By refracting the vermis of the cerebellum a balloon catheter could be inserted into the fourth ventricle of the dog.
A size 8 F Foley catheter, shortened by 1 cm at the tip, was inserted into the ventricle until the tip lodged in the sylvian aqueduct and the balloon (3 cc capacity) lay entirely within the ventricle. (Figure 1.) Small amounts of cerebrospinal fluid drained from the aqueduct through the catheter to decompress the ventricular system. The catheter was secured to the edge of the cranial defect by a suture. Position of the balloon was confirmed after each experiment by autopsy or skull roentgenogram after balloon inflation with 2 cc sodium diatrizoate (Hypaquem). (Figure 2.)
Figure 2. After stimulation, position of the balloon fourth ventricle was confirmed by x-ray studies.
14
in the
Immediately after placement of the catheter in Pavlov pouch and pyloric fistula dogs and at the beginning of the test period in dogs with gastrostomy, the balloon was inflated with 2 cc of saline solution. Earlier autopsy studies showed that the fourth ventricle of a 40 kg dog is filled with less than half this volume. While monitoring of vital signs and blood gases continued at intervals of one to thirty minutes, half hour samples of stimulated gastric secretion were collected and analyzed as described. Animals were then sacrificed except in experiment 3, in which the balloon was deflated after three hours and reinflated twenty-four hours later. In experiment 11, a dog prepared with a pyloric fistula, the balloon was deflated after ninety minutes, allowed to remain empty for thirty minutes, and then reinflated with 3 cc of saline solution. Two experiments were performed on Cordectomy. dogs with pyloric fistula (experiments 13 and ‘14) to eliminate the effects of simultaneous sympathetic stimulation of respiratory and cardiovascular systems which might contribute to gastric hypersecretion. After craniotomy, but before balloon inflation, the cervical spinal cord was transected at C%-Ck, sparing the anterior spinal artery.
The American Journal of Surgery
Gastric Secretion and Pressure on Vagal Nuclei
PYLORIC
Results
I
In animals with intact spinal cords, balloon inflation caused immediate truncal hyperextension (opisthotonos), nystagmus, and mydriasis. These signs disappeared within one hour, even with continued balloon inflation. A typical response of vital signs to pressure stimulation is shown in Figure 3. In all cases, arterial pressure soared instantly, often exceeding recordable levels (400 mm Hg), but fell to low levels (50 mm Hg) within fifteen minutes. Pulse rate also increased rapidly (over 200 beats per minute) but gradually returned to control values within three hours. Central venous pressure rose precipitously with stimulation and remained variably elevated. In the two animals having cord transection hypertension and tachycardia did not occur with balloon inflation. (Figure 4.) Blood pressure fell slowly to hypotensive levels within thirty minutes and thereafter was controlled in normal range by intermittent infusion of epinephrine. Pulse rate decreased slightly while central venous pressure rose to thrice normal values. Blood gases and arterial pH generally were unaltered by balloon inflation in dogs with intact spinal cords. Values of pOz and pH decreased slightly with hypotension in cordectomized animals. Gastrostomy. Four dogs were stimulated by balloon inflation at three, four, seven, and eight days after craniotomy and balloon placement. In the interval between craniotomy and inflation, the animals’ neurologic status varied between alertness and semicoma. Only one dog (experiment 3) was able to walk and eat. The others required intravenous feeding. All dogs with gastrostomy responded to stimulation by increasing gastric acid secretion. Three showed increases in the first thirty minutes of 344, 359 and 875 per cent, respectively, compared to average basal thirty minute secretion. (Table I.) Figure 5 illustrates a typical response. The fourth dog (experiment 2) showed only slight increase in acidity in the first half hour but increases of 300 per cent and 410 per cent in the second and third collection periods, respectively. In the dog not sacrificed after initial testing (experiment 3), reinflation of the balloon after twenty-four hours increased acid levels in the first half hour by 454 per cent compared to average control values. Pavlov Pouch. Four animals showed maximal increases in acid secretion after fourth ventricle stimulation of 950, 2233, 712, and 467 per cent, respectively. (Table I.) A representative secretory pattern is shown in Figure 6. In three dogs hypersecretion occurred within the first hour whereas in the fourth (experiment 7) half hour acid secretion increased from
Volume123.January1972
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Figure 3. Response of vital signs to balloon inflation in a noncordectomized dog. Blood pressure, pulse, and central venous pressure rose instantly.
204 per cent initially to 712 per cent at two and one half hours. Pyloric Fistula. Four dogs with intact spinal cords had immediate increase of acid secretion by 260, 270, 281, and 1150 per cent. (Table I.) Hypersecretion occurred during the first thirty minutes with subsequent values in low or normal range. Figure 7 depicts the secretory pattern in experiment 11. Reinflation of the balloon after thirty minutes of deflation in this animal caused no secondary increase in acid secretion. The two animals with pyloric fistula and cordectomy had an increase of acid secretion of 956 per cent and 300 per cent, respectively, in the first thirty minutes. The secretory response of one is shown in Figure 8. Vagotomy. Two dogs prepared with truncal vagotomy and pyloric fistula showed no increase in gastric acid secretion after fourth ventricle pressure stimulation. The response of one dog is shown in Figure 9.
PYLORIC
FISTULA-CORDECTOMY
200.
-16
t 150.
-12
I" E 100. E 50.
I
I 1
2
3
4
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Figure 4. Response of vital signs to balloon inflation in a cordectomized dog. Marked hypertension and tachycardia did not occur.
15
Norton, Fuchs, and Eiseman
TABLE I
Comparison of Mean Thirty Minute Basal Secretion Values to Gastric Acid Secretion in First Thirtv Minutes after Stimilation and Maximal &imulated Secretion in Any Thirty Minute Period during Three Hour Tesi
_
Mean 30 Minute Basal HCI
First 30 Minute Test HCI
Increase*
Maximal 30 Minute Test HCI
Maximal Increase
Experiment
Preparation
(mE@
(mEq)
(%I
(mEq)
(%I
1 2 3 4 5 6 7 8 9 10 11 12 13t
Gastrostomy Gastrostomy Gastrostomy Gastrostomy Pavlov Pavlov Pavlov Pavlov Pyloric fistula Pyloric fistula Pyloric fistula Pyloric fistula Pyloric fistula Pyloric fistula
.45 .40 .37 .20 .lO .15 .24 .12 .50 .50 .18 .32
2.00
344 80 359 a75 900 100 204 467 260 270 1150 281 956 300
2.00 2.05 1.70 1.95 1.05 3.50 1.95 .68 1.80 1 .a5 2.25 1.22 1.90 1.76
344 410 359 875 950 2233 712 467 260 270 1150 281 956 300
14t
.72 1.70 1.95 1 .oo .30 .73 .68 1.80 1.85 2.25 1.22 1.90 1.76 -_
.ia .44
*Mean increase %, 468. t Cord transection.
GASTROSTOMY
t8 -6
-L .4
mEq
pH
7,
_e--
t2
e--
*_--
i
i
j
4
5
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Comments
Figure 5. Secretory pattern of dog with gastrostomy (experiment 3). Acid secretion increased 359 per cent in the first half hour compared to average basal values. PAVLOV POUCH
8
2.0
6
m Eq. 1.0
4 PH 2
1
2
3
4
5
HOURS Figure 6. Secretory pattern of dog with Pavlov pouch (experiment 5). Maximal increase in acid secretion (950 per cent) occurred in the second collection period.
16
Such failure for hypersecretion to occur in dogs after vagotomy is in contrast to results in fourteen nonvagotomized dogs in which mean increase in acid secretion in the first thirty minutes after fourth ventricle pressure stimulation was 468 per cent. If maximal stimulated thirty minute secretion, occurring at any time during three hours, is compared to average basal values, the mean increase was 683 per cent. Although gastric pH tended to decrease with hypersecretion in nonvagotomized dogs, the relationship was less constant than anticipated and quite minimal in dogs in experiments 2, 3,9, and 10.
Since Rokitansky’s observation in 1841 [7] that gastric ulceration may follow intracranial disease, investigators have sought to localize central neural control of gastric acid secretion. Their technics of measuring gastric acid and creating brain lesions have varied widely in reliability [8]. Two areas of the brain of special interest are the hypothalamus and the limbic system. Porter, Movius, and French [9] showed that gastric pH decreases when the anterior hypothalamus of monkeys is electrically stimulated. Ridley and Brooks [IO] more accurately localized control of acid secretion by demonstrating basal hypersecretion in hyperphagic rats with ventromedial hypothalamic lesions. Electrical stimulation of the limbic systems also increases volume and acidity of gastric secretion [II, 121. Integration of the hypothalamus, the limbic system, and even the cortex in the central neural control of gastric secretion is likely. Higher levels of the autonomic nervous system, acting through diffusely
The American Journal of Surgery
Gastric
projecting efferent fibers, tend to inhibit medullary or local mechanisms involved in basal secretion [13]. Direct stimulation of vagal nuclei would be expected to increase gastric acidity. Conventional neurophysiologic technics of ablation or stimulation are more difficult to apply to the medulla than to the diencephalon. Effects on adjacent sympathetic centers, which influence cardiovascular and respiratory systems, may mask the precise role of vagal nuclei. Pressure stimuli in the fourth ventricle, previously unreported, are not exempt from this criticism unless combined with high sympathectomy to eliminate sympathetic response. In the dog, efferent central vagal nuclei are divided into ventral and dorsal groups. The latter are located in the floor of the fourth ventricle. Kerr and Preshaw [14] have shown that vagal stimulation of gastric acid results from discharge of the dorsal efferent nuclei. Increased pressure within the fourth ventricle would be readily transmitted to these nuclei. Our experimental model demonstrates that gastric acid hypersecretion results from direct pressure stimulation of vagal nuclei. The balloon is separated from higher autonomic centers such as the hypothalamus and limbic system by at least 3 cm, and concurrent pressure on these structures is unlikely. Absence of hypersecretion in vagotomized animals is evidence that the fourth ventricle pressure response is mediated via the vagus nerves. The brevity of hypersecretion in these experiments is puzzling. It may be due to pressure ischemia and exhaustion of dorsal motor nuclei beneath the balloon. Deflating the balloon after ninety minutes and reinflating it one half hour later (experiment ll), however, did not produce a second rise in acid levels. Fatigue of the vagal mechanism of acid secretion has been postulated [15] but this phenomenon would not be expected within one hour. Gastric inhibition of acid secretion by antral mechanisms is also an unlikely explanation since the “exhaustion” of secretion was seen in the dogs with Pavlov pouches as well as in those with pyloric fistula. Pentobarbital anesthesia is known to decrease histamine-stimulated gastric secretion in dogs [16]. Effects of pentobarbital on canine basal secretion are less well defined but the fact that both control and test acid values in these studies were obtained using identical anesthesia would tend to minimize error of this sort. The dynamics of increasing intracranial pressure are poorly understood. Supratentorial pressure transmitted to higher autonomic centers alone might initially diminish gastric secretion by increasing inhibition of medullary centers. Infratentorial pressure would be transmitted directly to vagal nuclei in the
Volume 123, January 1972
Secretion
and Pressure
PYLORIC
on Vagal Nuclei
FISTULA
I 20.
8
1.5.
6
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--.* pH
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4 PH
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2
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7. Secretory pattern of dog with pyloric f&u/a (experiment 11). A transient increase (1,150 per cent) in acid secretion followed balloon inflation. Reinflation of the balloon at hour 5 after thirty minutes deflation caused no secondary increase in acid secretion.
PYLORIC
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---\
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Figure 8. Secretory pattern in dog with pyloric fistula with transected spinal cord (experiment 13). Acid secretion increased by 956 per cent in the first half hour.
PYLORIC
FISTULA-VAGOTOMY
2.0.
-8
1.5.
-6
mEq. l.O*
HOURS
Figure 9. Secretory pattern in dog with pyloric fistula and vagotomy. No increase in gastric acid secretion followed pressure stimulation.
17
Norton, Fuchs, and Eiseman
floor of the fourth ventricle and should produce earlier and greater gastric hypersecretion. This would explain Cushing’s impression that gastrointestinal ulcers are most frequent with posterior fossa surgery [6] and the report of Watts and Clark [I] that acid secretion is highest in decerebrate patients. We previously reported gastric hyperacidity in nondecerebrate patients with severe head injury [2]. The increased intracranial pressure in these patients presumably is transmitted from the cerebrum through the brain stem to medullary vagal nuclei. Whether additional stimulation of the dorsal vagal nuclei due to pressure on the anterior hypothalamus plays a role in the hyperacidity of head injury is unknown. It is of theoretical and practical interest to define more accurately the various causes of stress ulcer. Cushing’s ulcer is uniquely identifiable by virtue of acid hypersecretion. The ability of vagal-blocking drugs to interrupt this hypersecretion suggested the need to further define the neural pathways involved. The current experiments localize at least one stimuIatory center as being in the floor of the fourth ventricle wherein lie the vagal nuclei and suggest that intracranial pressure applied directly to these nuclei may be of etiologic significance in Cushing’s ulcer. Summary
1. Inlying balloon pressure on the floor of the fourth ventricle produced an immediate, transient increase (mean 468 per cent in first thirty minutes) in gastric acid secretion in fourteen dogs. 2. Cervical spinal cord transection obliterated sympathetic response to balloon inflation but did not alter hypersecretion in two dogs. 3. Hypersecretion did not occur in two vagotomized dogs. 4. Gastric acid hypersecretion after severe head injury may be due to direct pressure stimulation of
18
vagal nuclei rather than to hypothalamic stimulation, as suggested by Cushing.
mediated
References 1. Watts CC, Clark K: Gastric acidity in the comatose patient. J Neorosurg 30: 107, 1969. 2. Norton L, Greer J, Eiseman B: Gastric secretory response to head injury. Arch Surg 101: 200, 1970. 3. Dragstedt LR, Ragins H, Dragstedt LR: Stress and duodenal ulcer. Ann Surg 144: 450, 1956. 4. O’Neill JA: The influence of thermal burns on gastric acid secretion. Surgery 67: 267, 1970. 5. Watts C, Clark K: Effects of an anticholinergic drug on gastric acid secretion in the comatose patient. Surg Gynec Obstet 130: 61, 1970. 6. Cushing H: Peptic ulcer and the interbrain. Surg Gynec Obstef 55: l( ! 932. 7. Rokitansky C: Handbuch der Pathologischen Anatomie, 1841-46. vol 3, p 40. (Swaine WE, tr.) Philadelphia, Blanchard and Lea, 1855. 8. Davis RA, Brooks FP: Experimental peptic ulcer associated with lesions or stimulation of the central nervous system. Surg Gynec Obstef 116: 307, 1963. 9. Porter RW, Movius HJ, French JD: Hypothalamic influences on hydrochloric acid secretion in the stomach. Surgery 33: 875. 1953. 10. Ridley PT, Brooks FP: Alterations in gastric secretion following hypothalamic lesions producing hyperphagia. Amer J Physiol209: 319, 1965. 11. Sen RN, Anand BK: Effect of electrical stimulation of the limbic system of brain (“visceral brain”) on gastric secretory activity and ulceration. lndian J Med Res 45: 515,1957. 12. Shealy CN, Peele TL: Studies on amygdaloid nucleus of the cat. J Neurophysiol20: 125, 1957. 13. Brooks FP: Central neural control of acid secretion. Handbook of Physiology, sect 6, Alimentary Canal, vol 2, Secretion. (Heidal W, ed.) Washington, American Physiological Society, 1967. function of the dorsal 14. Kerr FW, Preshaw RM: Secretomotor motor nucleus of the vagus. J Physiol (London) 205: 405, 1969. 15. Orahood RC, Eisenberg MM: The importance of the vagal release of gastrin in vagal mechanism fatigue. Gastroenterology (abstr) 60: 703, 1971. 16. Mason R: Anesthesia and stimulated gastric secretion. Gastroenterology (abstr) 60: 695, 1971.
The American Journal of Surgery
L. Norton, MD, Denver, Colorado E. Fuchs, MD, Denver, Colorado B. Eiseman, MD, Denver, Colorado
Severe head injury is frequently associated with gastric acid hypersecretion and gastrointestinal ulceration [1,2]. Cushing’s ulcer differs from other forms of stress ulcer in being uniquely associated with gastric hypersecretion [3,4]. Mechanisms responsible for this hyperacidity are unclear, but vagal transmission is probable in light of the blocking action of anticholinergic agents [5]. Cushing [6] hypothesized the presence in the diencephalon of a parasympathetic center capable of stimulating vagal nuclei to induce vagal hyperactivity [6]. Vagally stimulated gastric hypersecretion might thus be secondary to pressure effects on the hypothalamus. This study, in contrast to that of Cushing, indicates that direct pressure on the floor of the fourth ventricle above efferent vagal nuclei is capable of stimulating gastric hypersecretion independent of hypothalamic control. Methods Sixteen mongrel dogs, 25 to 39 kg in weight, were studied for basal gastric acid secretion under anesthesia after preparation with simple gastrostomy (four animals), innervated [Pavlov] gastric pouch (four animals), or pyloric fistula (eight animals). The dogs were anesthetized with sodium pentobarbital, 30 mg/kg given intravenously; they were then intubated and artificial respiration was carried out. During basal secretory studies, the pulse rate, blood pressure (via arterial catheter), central venous pressure, ~02, pCOs, and arterial pH were monitored at intervals of thirty to sixty minutes. From the Department of Surgery, University of Colorado Medical School and Denver General Hospital, Denver, Colorado. This work was supported by grants from the US Public Health Service and the John Hartford Foundation. Reprint reqUeStS should be addressed to Dr Ben Eiseman, Department of Surgery, Denver General Hospital, West 8th and Cherokee, Denver, Colorado 80204. Presented at the Twelfth Annual Meeting of the Society for Surgery of the Alimentary Tract, Atlantic City, New Jersey, June 19 and 20. 1971.
Volume 123, January 1972
Gastrostomy. In four dogs, a simple gastric fistula was maintained by means of a plastic cannula. Craniotomy for placement of a balloon catheter in the fourth ventricle was performed immediately after gastrostomy. After intervals of three to eight days, during which basal gastric acid secretion under anesthesia was measured, the inlying ventricular balloon was inflated and the stimulated gastric secretion collected. Pavlov Pouch. An innervated pouch was constructed from the body of the stomach at the greater curvature in four dogs. Integrity of the double mucosal barrier between pouch and gastric lumen was confirmed at one week by failure to recover ingested methylene blue in pouch secretions. Two to sixteen days later the animals were anesthetized for collection of basal gastric secretion. Craniotomy was performed immediately thereafter followed by measurement of stimulated secretion. Pyloric Fistula. In eight dogs, the gastroduodenal junction was divided, the proximal duodenum closed, and the pylorus sutured to the skin of the abdomen to create a total gastric pouch. In two of these dogs complete truncal vagotomy was performed at the time of laparotomy. After twenty-four hours, during which fluids and electrolytes were given parenterally, all animals were anesthetized for gastric secretory studies before and after craniotomy and fourth ventricle pressure stimulation. Gastric Analysis. For basal and stimulated acid secretory studies the anesthetized prone animal was positioned to allow optimal gravity drainage of gastric secretions through a flanged size 26 F catheter inserted into the gastric stoma or connected to the indwelling plastic cannula. Before collections, the stomach or pouch was irrigated with normal saline solution, aspirated, and allowed to drain for thirty secreminutes or longer. Both basal and stimulated
13
Norton, Fuchs, and Eiseman
tions were collected in thirty minute samples for periods of three hours each. Volume and pH of each sample were measured using an Instrumentation Laboratory pH meter. Total acid in each specimen was determined by neutralization with O.lN sodium hydroxide to pH 7.4. Acid concentration in milliequivalents per liter was multiplied by volume in liters to calculate the amount of HCl collected in one half hour. With the dog in prone posiCraniotomy Technic. tion, unchanged after collection of basal gastric secretions, a muscle-splitting incision was made in the dorsal part of the neck to expose the occipital skull and proximal cervical spine. Through a burr hole placed caudad to the external occipital protuberance, the posterior cranial fossa was entered. After incising dura and arachnoid, the cerebellar vermis was retracted superiorly to open the entrance to the fourth ventricle.
Figure 1. By refracting the vermis of the cerebellum a balloon catheter could be inserted into the fourth ventricle of the dog.
A size 8 F Foley catheter, shortened by 1 cm at the tip, was inserted into the ventricle until the tip lodged in the sylvian aqueduct and the balloon (3 cc capacity) lay entirely within the ventricle. (Figure 1.) Small amounts of cerebrospinal fluid drained from the aqueduct through the catheter to decompress the ventricular system. The catheter was secured to the edge of the cranial defect by a suture. Position of the balloon was confirmed after each experiment by autopsy or skull roentgenogram after balloon inflation with 2 cc sodium diatrizoate (Hypaquem). (Figure 2.)
Figure 2. After stimulation, position of the balloon fourth ventricle was confirmed by x-ray studies.
14
in the
Immediately after placement of the catheter in Pavlov pouch and pyloric fistula dogs and at the beginning of the test period in dogs with gastrostomy, the balloon was inflated with 2 cc of saline solution. Earlier autopsy studies showed that the fourth ventricle of a 40 kg dog is filled with less than half this volume. While monitoring of vital signs and blood gases continued at intervals of one to thirty minutes, half hour samples of stimulated gastric secretion were collected and analyzed as described. Animals were then sacrificed except in experiment 3, in which the balloon was deflated after three hours and reinflated twenty-four hours later. In experiment 11, a dog prepared with a pyloric fistula, the balloon was deflated after ninety minutes, allowed to remain empty for thirty minutes, and then reinflated with 3 cc of saline solution. Two experiments were performed on Cordectomy. dogs with pyloric fistula (experiments 13 and ‘14) to eliminate the effects of simultaneous sympathetic stimulation of respiratory and cardiovascular systems which might contribute to gastric hypersecretion. After craniotomy, but before balloon inflation, the cervical spinal cord was transected at C%-Ck, sparing the anterior spinal artery.
The American Journal of Surgery
Gastric Secretion and Pressure on Vagal Nuclei
PYLORIC
Results
I
In animals with intact spinal cords, balloon inflation caused immediate truncal hyperextension (opisthotonos), nystagmus, and mydriasis. These signs disappeared within one hour, even with continued balloon inflation. A typical response of vital signs to pressure stimulation is shown in Figure 3. In all cases, arterial pressure soared instantly, often exceeding recordable levels (400 mm Hg), but fell to low levels (50 mm Hg) within fifteen minutes. Pulse rate also increased rapidly (over 200 beats per minute) but gradually returned to control values within three hours. Central venous pressure rose precipitously with stimulation and remained variably elevated. In the two animals having cord transection hypertension and tachycardia did not occur with balloon inflation. (Figure 4.) Blood pressure fell slowly to hypotensive levels within thirty minutes and thereafter was controlled in normal range by intermittent infusion of epinephrine. Pulse rate decreased slightly while central venous pressure rose to thrice normal values. Blood gases and arterial pH generally were unaltered by balloon inflation in dogs with intact spinal cords. Values of pOz and pH decreased slightly with hypotension in cordectomized animals. Gastrostomy. Four dogs were stimulated by balloon inflation at three, four, seven, and eight days after craniotomy and balloon placement. In the interval between craniotomy and inflation, the animals’ neurologic status varied between alertness and semicoma. Only one dog (experiment 3) was able to walk and eat. The others required intravenous feeding. All dogs with gastrostomy responded to stimulation by increasing gastric acid secretion. Three showed increases in the first thirty minutes of 344, 359 and 875 per cent, respectively, compared to average basal thirty minute secretion. (Table I.) Figure 5 illustrates a typical response. The fourth dog (experiment 2) showed only slight increase in acidity in the first half hour but increases of 300 per cent and 410 per cent in the second and third collection periods, respectively. In the dog not sacrificed after initial testing (experiment 3), reinflation of the balloon after twenty-four hours increased acid levels in the first half hour by 454 per cent compared to average control values. Pavlov Pouch. Four animals showed maximal increases in acid secretion after fourth ventricle stimulation of 950, 2233, 712, and 467 per cent, respectively. (Table I.) A representative secretory pattern is shown in Figure 6. In three dogs hypersecretion occurred within the first hour whereas in the fourth (experiment 7) half hour acid secretion increased from
Volume123.January1972
FISTULA
n -16
200.
I* *,_
150.
'
a
-12 '.
A, x.0
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I ,
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CVP __--____-_-__-
i
i
I
j
i
j
HOURS
Figure 3. Response of vital signs to balloon inflation in a noncordectomized dog. Blood pressure, pulse, and central venous pressure rose instantly.
204 per cent initially to 712 per cent at two and one half hours. Pyloric Fistula. Four dogs with intact spinal cords had immediate increase of acid secretion by 260, 270, 281, and 1150 per cent. (Table I.) Hypersecretion occurred during the first thirty minutes with subsequent values in low or normal range. Figure 7 depicts the secretory pattern in experiment 11. Reinflation of the balloon after thirty minutes of deflation in this animal caused no secondary increase in acid secretion. The two animals with pyloric fistula and cordectomy had an increase of acid secretion of 956 per cent and 300 per cent, respectively, in the first thirty minutes. The secretory response of one is shown in Figure 8. Vagotomy. Two dogs prepared with truncal vagotomy and pyloric fistula showed no increase in gastric acid secretion after fourth ventricle pressure stimulation. The response of one dog is shown in Figure 9.
PYLORIC
FISTULA-CORDECTOMY
200.
-16
t 150.
-12
I" E 100. E 50.
I
I 1
2
3
4
5
HOURS
Figure 4. Response of vital signs to balloon inflation in a cordectomized dog. Marked hypertension and tachycardia did not occur.
15
Norton, Fuchs, and Eiseman
TABLE I
Comparison of Mean Thirty Minute Basal Secretion Values to Gastric Acid Secretion in First Thirtv Minutes after Stimilation and Maximal &imulated Secretion in Any Thirty Minute Period during Three Hour Tesi
_
Mean 30 Minute Basal HCI
First 30 Minute Test HCI
Increase*
Maximal 30 Minute Test HCI
Maximal Increase
Experiment
Preparation
(mE@
(mEq)
(%I
(mEq)
(%I
1 2 3 4 5 6 7 8 9 10 11 12 13t
Gastrostomy Gastrostomy Gastrostomy Gastrostomy Pavlov Pavlov Pavlov Pavlov Pyloric fistula Pyloric fistula Pyloric fistula Pyloric fistula Pyloric fistula Pyloric fistula
.45 .40 .37 .20 .lO .15 .24 .12 .50 .50 .18 .32
2.00
344 80 359 a75 900 100 204 467 260 270 1150 281 956 300
2.00 2.05 1.70 1.95 1.05 3.50 1.95 .68 1.80 1 .a5 2.25 1.22 1.90 1.76
344 410 359 875 950 2233 712 467 260 270 1150 281 956 300
14t
.72 1.70 1.95 1 .oo .30 .73 .68 1.80 1.85 2.25 1.22 1.90 1.76 -_
.ia .44
*Mean increase %, 468. t Cord transection.
GASTROSTOMY
t8 -6
-L .4
mEq
pH
7,
_e--
t2
e--
*_--
i
i
j
4
5
HOURS
Comments
Figure 5. Secretory pattern of dog with gastrostomy (experiment 3). Acid secretion increased 359 per cent in the first half hour compared to average basal values. PAVLOV POUCH
8
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HOURS Figure 6. Secretory pattern of dog with Pavlov pouch (experiment 5). Maximal increase in acid secretion (950 per cent) occurred in the second collection period.
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Such failure for hypersecretion to occur in dogs after vagotomy is in contrast to results in fourteen nonvagotomized dogs in which mean increase in acid secretion in the first thirty minutes after fourth ventricle pressure stimulation was 468 per cent. If maximal stimulated thirty minute secretion, occurring at any time during three hours, is compared to average basal values, the mean increase was 683 per cent. Although gastric pH tended to decrease with hypersecretion in nonvagotomized dogs, the relationship was less constant than anticipated and quite minimal in dogs in experiments 2, 3,9, and 10.
Since Rokitansky’s observation in 1841 [7] that gastric ulceration may follow intracranial disease, investigators have sought to localize central neural control of gastric acid secretion. Their technics of measuring gastric acid and creating brain lesions have varied widely in reliability [8]. Two areas of the brain of special interest are the hypothalamus and the limbic system. Porter, Movius, and French [9] showed that gastric pH decreases when the anterior hypothalamus of monkeys is electrically stimulated. Ridley and Brooks [IO] more accurately localized control of acid secretion by demonstrating basal hypersecretion in hyperphagic rats with ventromedial hypothalamic lesions. Electrical stimulation of the limbic systems also increases volume and acidity of gastric secretion [II, 121. Integration of the hypothalamus, the limbic system, and even the cortex in the central neural control of gastric secretion is likely. Higher levels of the autonomic nervous system, acting through diffusely
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Gastric
projecting efferent fibers, tend to inhibit medullary or local mechanisms involved in basal secretion [13]. Direct stimulation of vagal nuclei would be expected to increase gastric acidity. Conventional neurophysiologic technics of ablation or stimulation are more difficult to apply to the medulla than to the diencephalon. Effects on adjacent sympathetic centers, which influence cardiovascular and respiratory systems, may mask the precise role of vagal nuclei. Pressure stimuli in the fourth ventricle, previously unreported, are not exempt from this criticism unless combined with high sympathectomy to eliminate sympathetic response. In the dog, efferent central vagal nuclei are divided into ventral and dorsal groups. The latter are located in the floor of the fourth ventricle. Kerr and Preshaw [14] have shown that vagal stimulation of gastric acid results from discharge of the dorsal efferent nuclei. Increased pressure within the fourth ventricle would be readily transmitted to these nuclei. Our experimental model demonstrates that gastric acid hypersecretion results from direct pressure stimulation of vagal nuclei. The balloon is separated from higher autonomic centers such as the hypothalamus and limbic system by at least 3 cm, and concurrent pressure on these structures is unlikely. Absence of hypersecretion in vagotomized animals is evidence that the fourth ventricle pressure response is mediated via the vagus nerves. The brevity of hypersecretion in these experiments is puzzling. It may be due to pressure ischemia and exhaustion of dorsal motor nuclei beneath the balloon. Deflating the balloon after ninety minutes and reinflating it one half hour later (experiment ll), however, did not produce a second rise in acid levels. Fatigue of the vagal mechanism of acid secretion has been postulated [15] but this phenomenon would not be expected within one hour. Gastric inhibition of acid secretion by antral mechanisms is also an unlikely explanation since the “exhaustion” of secretion was seen in the dogs with Pavlov pouches as well as in those with pyloric fistula. Pentobarbital anesthesia is known to decrease histamine-stimulated gastric secretion in dogs [16]. Effects of pentobarbital on canine basal secretion are less well defined but the fact that both control and test acid values in these studies were obtained using identical anesthesia would tend to minimize error of this sort. The dynamics of increasing intracranial pressure are poorly understood. Supratentorial pressure transmitted to higher autonomic centers alone might initially diminish gastric secretion by increasing inhibition of medullary centers. Infratentorial pressure would be transmitted directly to vagal nuclei in the
Volume 123, January 1972
Secretion
and Pressure
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7. Secretory pattern of dog with pyloric f&u/a (experiment 11). A transient increase (1,150 per cent) in acid secretion followed balloon inflation. Reinflation of the balloon at hour 5 after thirty minutes deflation caused no secondary increase in acid secretion.
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Figure 8. Secretory pattern in dog with pyloric fistula with transected spinal cord (experiment 13). Acid secretion increased by 956 per cent in the first half hour.
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Figure 9. Secretory pattern in dog with pyloric fistula and vagotomy. No increase in gastric acid secretion followed pressure stimulation.
17
Norton, Fuchs, and Eiseman
floor of the fourth ventricle and should produce earlier and greater gastric hypersecretion. This would explain Cushing’s impression that gastrointestinal ulcers are most frequent with posterior fossa surgery [6] and the report of Watts and Clark [I] that acid secretion is highest in decerebrate patients. We previously reported gastric hyperacidity in nondecerebrate patients with severe head injury [2]. The increased intracranial pressure in these patients presumably is transmitted from the cerebrum through the brain stem to medullary vagal nuclei. Whether additional stimulation of the dorsal vagal nuclei due to pressure on the anterior hypothalamus plays a role in the hyperacidity of head injury is unknown. It is of theoretical and practical interest to define more accurately the various causes of stress ulcer. Cushing’s ulcer is uniquely identifiable by virtue of acid hypersecretion. The ability of vagal-blocking drugs to interrupt this hypersecretion suggested the need to further define the neural pathways involved. The current experiments localize at least one stimuIatory center as being in the floor of the fourth ventricle wherein lie the vagal nuclei and suggest that intracranial pressure applied directly to these nuclei may be of etiologic significance in Cushing’s ulcer. Summary
1. Inlying balloon pressure on the floor of the fourth ventricle produced an immediate, transient increase (mean 468 per cent in first thirty minutes) in gastric acid secretion in fourteen dogs. 2. Cervical spinal cord transection obliterated sympathetic response to balloon inflation but did not alter hypersecretion in two dogs. 3. Hypersecretion did not occur in two vagotomized dogs. 4. Gastric acid hypersecretion after severe head injury may be due to direct pressure stimulation of
18
vagal nuclei rather than to hypothalamic stimulation, as suggested by Cushing.
mediated
References 1. Watts CC, Clark K: Gastric acidity in the comatose patient. J Neorosurg 30: 107, 1969. 2. Norton L, Greer J, Eiseman B: Gastric secretory response to head injury. Arch Surg 101: 200, 1970. 3. Dragstedt LR, Ragins H, Dragstedt LR: Stress and duodenal ulcer. Ann Surg 144: 450, 1956. 4. O’Neill JA: The influence of thermal burns on gastric acid secretion. Surgery 67: 267, 1970. 5. Watts C, Clark K: Effects of an anticholinergic drug on gastric acid secretion in the comatose patient. Surg Gynec Obstet 130: 61, 1970. 6. Cushing H: Peptic ulcer and the interbrain. Surg Gynec Obstef 55: l( ! 932. 7. Rokitansky C: Handbuch der Pathologischen Anatomie, 1841-46. vol 3, p 40. (Swaine WE, tr.) Philadelphia, Blanchard and Lea, 1855. 8. Davis RA, Brooks FP: Experimental peptic ulcer associated with lesions or stimulation of the central nervous system. Surg Gynec Obstef 116: 307, 1963. 9. Porter RW, Movius HJ, French JD: Hypothalamic influences on hydrochloric acid secretion in the stomach. Surgery 33: 875. 1953. 10. Ridley PT, Brooks FP: Alterations in gastric secretion following hypothalamic lesions producing hyperphagia. Amer J Physiol209: 319, 1965. 11. Sen RN, Anand BK: Effect of electrical stimulation of the limbic system of brain (“visceral brain”) on gastric secretory activity and ulceration. lndian J Med Res 45: 515,1957. 12. Shealy CN, Peele TL: Studies on amygdaloid nucleus of the cat. J Neurophysiol20: 125, 1957. 13. Brooks FP: Central neural control of acid secretion. Handbook of Physiology, sect 6, Alimentary Canal, vol 2, Secretion. (Heidal W, ed.) Washington, American Physiological Society, 1967. function of the dorsal 14. Kerr FW, Preshaw RM: Secretomotor motor nucleus of the vagus. J Physiol (London) 205: 405, 1969. 15. Orahood RC, Eisenberg MM: The importance of the vagal release of gastrin in vagal mechanism fatigue. Gastroenterology (abstr) 60: 703, 1971. 16. Mason R: Anesthesia and stimulated gastric secretion. Gastroenterology (abstr) 60: 695, 1971.
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