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 Table of Contents  
CASE REPORT
Year : 2016  |  Volume : 3  |  Issue : 4  |  Page : 191-198

Effect of midazolam on gastric secretion and stress-induced gastric ulceration in male albino rats


1 Physiolgy Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 Anaesthesia and Intensive Care Unit, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt

Date of Submission14-May-2016
Date of Acceptance26-Jul-2016
Date of Web Publication16-Dec-2016

Correspondence Address:
Soad Sayed El-Gaby
Department of Anesthesiology and Intensive Care, Faculty of Medicine, Al Azhar University for Girls, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2356-9115.195876

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  Abstract 

The term ‘benzodiazepine’ refers to a distinct chemical structure. Benzodiazepines are now used for testing acute anxiety states, and also as a premedication before surgery. Although diazepam is the prototype of benzodiazepine, midazolam is more potent. As peptic ulcers are now being diagnosed more often in school children, and because preanaesthetic management is difficult for children, the use of preoperative sedatives may help to diminish anxiety, minimize psychological trauma and improve the quality of anaesthesia. Midazolam is often used as a preoperative sedative, and during procedures such as endoscopy, where anaesthesia is not required. There is no available data about the effect of various doses of midazolam on gastric secretion and on restraint-induced gastric ulcers in rats. Therefore, the aim of the present study was to study the effect of 0.5, 1 and 2.5 mg/kg of midazolam on gastric secretion and on immobilization-induced gastric stress ulcers in rats. This study was conducted on 48 rats, divided into two big categories, each consisting of 24 rats, which were further divided into four groups, each group consisting of six rats. Administration of midazolam in doses of 0.5 and 1 mg/kg intraperitoneal to pyloric-ligated rats led to a significant decrease in gastric juice volume, acid concentration and the total acid output compared with the control group, which received normal saline. Midazolam administration in a dose of 2.5 mg/kg led to a significant increase in the gastric juice volume, and a significant decrease in the acid concentration and the total acid output compared with the control group. Our results concluded that midazolam administration in a dose of 0.5 mg/kg to children as a prophylactic dose during preanaesthetic medication leads to prevention of aspiration pneumonia, morbidity and mortality of children during endoscopies and elective surgical operations. Restraint-induced stress ulcers approach the ideal technique for ulcer production and testing of antiulcer agents. Our results showed that intraperitoneal administration of midazolam in doses of 0.5, 1 and 2.5 mg/kg to rats in a dose-dependent manner leads to a prophylactic effect against stress-induced gastric ulcers with a protection index of 9.4, 23.8 and 32.2%, respectively. The mechanism of prophylaxis is due to its sedative, anxiolytic and antisecretory effect.

Keywords: gastric secretion, gastric ulcer, immobilization stress, midazolam


How to cite this article:
El-Ficky MS, MohamedA, El-Gaby SS. Effect of midazolam on gastric secretion and stress-induced gastric ulceration in male albino rats. Res Opin Anesth Intensive Care 2016;3:191-8

How to cite this URL:
El-Ficky MS, MohamedA, El-Gaby SS. Effect of midazolam on gastric secretion and stress-induced gastric ulceration in male albino rats. Res Opin Anesth Intensive Care [serial online] 2016 [cited 2020 Feb 20];3:191-8. Available from: http://www.roaic.eg.net/text.asp?2016/3/4/191/195876


  Introduction Top


The term ‘benzodiazepine’ refers to a distinct chemical structure. Thousands of compounds have been made and tested, and about 20 are available for clinical use. They are basically similar in their pharmacological actions, although some degree of selectivity has been reported. From a clinical point of view, differences in pharmacokinetic behaviour among different benzodiazepines are more important than the differences in the profile of activity [1].

Benzodiazepines show anxiolytic effects in animal tests, and also exert a marked ‘taming’ effect, allowing animals to be handled more easily [2].

Benzodiazepines are now used for testing acute anxiety states, and are also used as premedication before surgery. Under these circumstances, their anxiolytic, sedative and amnestic properties may be beneficial. Benzodiazepines can be useful for patients who need acute treatment as they reduce anxiety within 30 min, and can be taken on ‘as needed’ basis [1]. Although diazepam is the prototype of benzodiazepine, lorazepam and midazolam are more potent − all three facilitate amnesia while causing sedation [3].

Peptic ulcers are now being diagnosed more often in school children. This diagnosis should be suspected if there is a family history of ulceration. Gastroscopy provides a higher yield of positive results than does barium meals [4].

Preanaesthetic management is difficult in children. The use of preoperative sedatives may help to diminish anxiety, minimize psychological trauma and improve the quality of anaesthesia [5],[6].

Among drugs used for premedication, benzodiazepines have been shown to be the most efficient and safe [7]. Within this group, midazolam has special characteristics that make it particularly useful for anaesthetic premedication in children: rapid onset, short duration of action and a good correlation between clinical effects and plasma levels [8].

Midazolam is often used as a preoperative sedative and during procedures such as endoscopy, where full anaesthesia is not required [1].

The integrity of the gastric mucosa depends on a delicate balance between aggressive (gastric acid, pepsin, free radicals, Helicobacter pylori) and defensive (mucus, bicarbonate, prostaglandins, mucosal blood flow) factors [9].

It has been shown that ulcer pathophysiology has two sides, a gastric acid attack and a mucosal defence that is affected by several elements, and that an impaired mucosal defence is more crucial to the formation and occurrence of an ulcer [10]. The balance of offensive and defensive factors plays an important role in gastric haemorrhage and ulcer formation in the stomach [11].

Restraint-induced ulcer approaches the ideal technique for ulcer production and testing of antiulcer agents in rats [12]. The lesion can be induced relatively rapidly with high incidence in the acid-secreting portion of the stomach [13].

Restraint brings the central nervous system (CNS) into play, and thus is similar to a stress ulcer and Curling’s ulcer in humans [14], and the CNS injury has been reported to predispose to acute gastric mucosal ulceration [15]. There is no available data about the effect of single injection of various doses of midazolam on gastric contents and on restraint-induced gastric ulcer formation. Therefore, the aim of the present work was to study the effect of intraperitoneal administration of various doses (0.5, 1 and 2.5 mg/kg) of midazolam on gastric contents as well as on restraint-induced gastric ulcers in rats.


  Materials and methods Top


Animals

A total of 48 adult albino male rats of local strain were included in the present study. Their body weights ranged from 160 to 200 g (average weight of 180 g). All animals were about the same age and were healthy. They were kept for 2 weeks in the laboratory at comfortable room temperature for adaptation before any experimental interference.

They were kept on a standard diet and fasted for 48 h before the experiment. Tap water was allowed ad libitum and the rats were housed in a cage with a wide-meshed wire flooring to prevent coprophagia. Each cage housed three rats and measured 25×25×30 cm. The rats were weighed at the beginning of the experiment and immediately before pyloric ligation. The rats were divided into two main categories:

(a) Those used to study the effect of various doses of midazolam on immobilization-induced changes in gastric secretion

Twenty-four rats were divided into four equal groups as follows:

Group I (the control group), in which the immobilized rats received physiological saline intraperitoneally (0.5 ml/rat) before immobilization stress.

Group II, in which the immobilized rats received midazolam in a dose of 0.5 mg/kg before immobilization stress.

Group III, in which the immobilized rats received midazolam in a dose of 1 mg/kg before immobilization stress.

Group IV, in which the immobilized rats received midazolam in a dose of 2.5 mg/kg before immobilization stress.

(b) Those used to study the effect of various doses of midazolam on immobilization-induced gastric ulceration

Twenty-four rats were divided into four equal groups as follows:

Group I (the control group), in which the immobilized rats received physiological saline intraperitoneally (0.5 ml/rat) before immobilization.

Group II, in which the immobilized rats received midazolam in a dose of 0.5 mg/kg before immobilization.

Group III, in which the immobilized rats received midazolam in a dose of 1 mg/kg before immobilization.

Group IV, in which the immobilized rats received midazolam in a dose of 2.5 mg/kg before immobilization.

Drugs

  1. Saline: physiological saline 0.9%.
  2. Midazolam: midazolam ampoules 5 mg/ml (manufactured by Sunny, Egypt, under the licence of Hameln Pharmaceuticals, Germany).


Method of induction of gastric ulcers in albino rats

The animals were housed under similar environmental conditions in cages with wide-meshed flooring to prevent coprophagia, and were fasted but allowed water for 24 h before experimental intervention. The animals were immobilized in the supine position for 24 h by fixing their four limbs at the four corners of a wooden board (35×45 cm).

The mechanism of induction of gastric lesions by using the immobilization technique described by Anchkov and Zovodskoya [16] is nervous as the mechanism of production of neurogenic form of ulcers in man.

After 24 h, the animals were killed by an ether overdose. Abdominal cavity was opened along the greater curvature. The mucosa was washed with normal saline and pinned out on a cork, and was inspected for the presence of ulceration and haemorrhage by the naked eye and with the help of a magnifying lens (×2). Lesions were defined as erosions of the gastric mucosa, which may be linear along the rugae folds or punched out, and their bases were red or black. The ulcers were evaluated by an independently trained observer who was unaware of the identity of the specimen. Only those ulcers visible to the naked eye were counted. Haemorrhage without actual erosion was considered negative [17].

Examination of the stomach for ulceration was expressed in terms of ‘ulcer index’ according to the method described by Robert et al. (1968) [18], which is the sum of the following:

  1. Percentage incidence (divided by 10) of animals with ulcers.
  2. Severity score per group in pluses (from a scale of 0 to 3+). In addition, the scale adapted by Guth and Kozbur [19] was used:
    1. 1+=small petechiae or erosions.
    2. 2+=linear erosions up to 5 mm.
    3. 3+=linear erosions greater than 5 mm.The severity of lesion for a given stomach was that of the most severe ulcer for that stomach [18].
  3. Average number of ulcer per stomach.


In the restraint method, the drug was administered to the animal before the ulcer production and the preventive effect on the ulcer producing processes was tested [20].

The preventive index of the drug was recorded according to the method proposed by Hano et al. [21].

Method of collection and analysis of gastric secretion in albino rats

The gastric juice was collected according to the technique described by Shay et al. [22]. Each animal was housed singly in a cage with a raised bottom of wire mesh to insure immediate passage of faeces from the cage. The animals were starved for 48 h to insure complete emptying of the stomach and water was permitted ad libitum. Fasting of the animals was started in early morning. The animals were weighted immediately before fasting and at the end of 48 h of starvation.

Operative procedure

Under light ether anaesthesia, the abdomen was shaved and a mid-line incision was made, extending from the xiphoid downward for about 2 cm. The duodenum was identified and the junction between the pylorus and duodenum was picked up gently with a curved probe. The stomach itself was not disturbed. Pyloric ligation was made by silk, care being taken to avoid damage to blood vessels or traction on the stomach. In satisfactorily prepared animals, the abdominal wall was then closed with interrupted sutures. The abdominal wound was cleaned thoroughly with physiological saline, dried and covered with a solution of collodion. The anaesthesia was discontinued and the animal usually recovered consciousness within a few minutes.

Three hours later, the animal was again anaesthetized with ether, abdomen was opened and the oesophagus, the duodenum and the appropriate peritoneal ligaments were clipped. The stomach was removed and washed in physiological saline and then dried. An opening was then made along the greater curvature and the gastric juice was drained into a graduated centrifuge tube through a funnel.

Determination of titratable acidity

After centrifuging the gastric contents, the volume of the supernatant was recorded and used for analysis. This was removed by pipetting. A liquid of 0.2 ml was then titrated with 0.01 N NaOH using an end point of pH 7.0 as determined colorimetrically with phenol red as an indicator [23]. Results were expressed as milliequivalents per litre. Titratable acid output was calculated as microequivalents/3 h by multiplying the volume in millilitres by the acid concentration in milliequivalents per litre divided by 1000 according to the method described by Okabe et al. [24].


  Results Top


Effect of midazolam on gastric secretion

In the present study, administration of midazolam in a dose of 0.5 and 1 mg/kg led to a significant decrease in gastric juice volume (ml) (3.81±0.91 and 3.33±0.08, respectively) and a significant increase in rats who received midazolam in a dose of 2.5 mg/kg (5.31±0.17) compared with the control group, which received normal saline (4.56±0.12). In addition, there was a significant decrease in acid concentration (mEq/l) (1.2±0.17, 1.33±0.08 and 1.11±0.07, respectively) compared with the control group (1.5±0.12). Our results showed that there were significant decreases in mean total acid output (microequivalents/3 h) (0.00457±0.00059, 0.00444±0.00024 and 0.000593±0.00042, respectively) compared with the control group (0.00696±0.00038).

The effect of midazolam on gastric ulceration

In group I (immobilized rats who received saline) ([Figure 1]a), the mucosa of the corpus showed ulcers spread all over the mucosa; in-between ulcers appeared normal or hyperaemic. The number of ulcers/rat ranged between 1 and 6, with a mean of 5.8 ulcers/rat. The severity score ranged between 2 and 3, with a mean score of 2.2; the ulcer index was 18. In group II (in which rats received midazolam 0.5 mg/kg before immobilization) ([Figure 1]b), the mucosa of the corpus showed fewer ulcers with moderate degree of hyperaemia. The number of ulcers/rat ranged between 1 and 7, with a mean of 4.3 ulcers/rat. The severity score ranged between 2–2, with a mean score of 2; the ulcer index was 16.3 and preventive index was 9.4%. In group III (in which rats received midazolam 1 mg/kg before immobilization) ([Figure 1]c), the mucosa of the corpus showed fewer ulcers than did group II, and the mucosa appeared more healthy. The number of ulcers/rat ranged between 0 and 7, with a mean of 3.7 ulcers/rat. The severity score ranged between 0 and 2, with a mean score of 1.7; the ulcer index was 13.7 and the preventive index was 23.8%. In group IV (in which rats received midazolam 2.5 mg/kg before immobilization) ([Figure 1]d), the mucosa of the corpus showed very few ulcers, fewer than group III, with more healthy mucosa. The number of ulcers/rat ranged between 0 and 2, with a mean of 4 ulcers/rat. The severity score ranged between 0 and 2, with a mean score of 1.5; the ulcer index was 12.2 and the preventive index was 32.2%.
Figure 1: Photographs of rat gastric mucosa; (a) controls who received saline before immobilization, (b) rats who received midazolam 0.5 mg/kg, (c) rats who received midazolam 1 mg/kg and (d) those who midazolam 2.5 mg/kg.

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Histopathological examination

All the sections were stained with haematoxylin and eosin (×100). Histopathological examination of the stomachs of rats that received saline and were subjected to immobilization stress showed shedding of the surface epithelium of the gastric mucosa with mild distortion of the gastric glands ([Figure 2]a). Moreover, there were mild oedema and mild mucosal blood vessel dilatation and mild cellular infiltration. Histopathological examination of the stomachs of rats that received 0.5 mg/kg midazolam before immobilization stress showed shedding of the surface epithelium of the gastric mucosa with mild distortion of the gastric glands, normal mucosal blood vessels and no oedema ([Figure 2]b). Histopathological examination of the stomachs of rats that received 1 mg/kg midazolam before immobilization stress showed normal gastric mucosal epithelium with normal mucosal blood vessels ([Figure 2]c). Histopathological examination of the stomachs of rats that received 2.5 mg/kg midazolam before immobilization stress showed normal gastric mucosal epithelium and no changes in gastric microcirculation with normal mucosal blood vessels ([Figure 2]d).
Figure 2: Histopathological examination of rat gastric mucosa; (a) controls received saline before immobilization, (b) rats who received midazolam 0.5 mg/kg, (c) midazolam 1 mg/kg and (d) midazolam 2.5 mg/kg.

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  Discussion Top


Effect of midazolam on gastric acid secretion

Stimulation of the autonomic function of the hypothalamus by higher regulatory structures in the CNS (the cerebral cortex and brain stem reticular formation) under the influence of stressful stimulation leads to stimulation of gastric juice volume and acidity [25]. Therefore, cholinergic stimuli to the oxyntic cells appear to have a central mechanism of formation. Aspiration of gastric contents is one of the main causes of anaesthesia morbidity and mortality [26].

In the present study, intraperitoneal administration of midazolam in a dose of 0.5 mg/kg led to a significant decrease in gastric juice volume compared with the control group. This is in contrast to the findings of Haavik et al. [27], who reported that benzodiazepines do not have any effect on the volume of gastric contents in patients undergoing elective surgery, and also to those of Riva et al. [28], who showed no difference in gastric juice volume in children who received midazolam as oral premedication in pediatric anaesthesia compared with the control group, and those of Laydon et al. [29], who reported that benzodiazepines were unlikely to affect the volume of gastric contents during anaesthesia induction. Our results were in agreement with those of Akhlagh et al. (2014) [30], who reported that midazolam premedication in a dose of 0.5 mg/kg leads to a decrease in gastric juice volume and has an effect on the reduction of aspiration pneumonia during anaesthesia in children.

In the present study, intraperitoneal administration of midazolam in a dose of 0.5 mg/kg to rats showed a significant decrease in gastric acid concentration and in the total acid output compared with the control group. This was in contrast to the findings of Haavik et al. [27], how reported that benzodiazepines did not have any effect on gastric pH in patients under elective surgery, and also to those of Akhlagh et al. (2014) [30], who reported that midazolam premedication in a dose of 0.5 mg/kg cannot increase gastric pH during anaesthesia in children.

Intraperitoneal administration of midazolam in a dose of 1 mg/kg led to a significant decrease in the gastric juice volume, acid concentration and total acid output compared with the control group.

Administration of midazolam in a dose of 2.5 mg/kg led to a significant increase in the gastric juice volume and significant decrease in gastric acid concentration and the total acid output compared with the control group.

It has been shown that, oral premedication with midazolam in children improves the quality of preparation for surgery without adverse effects [28]. A central reduction in gastric acid secretion due to a decrease in vagal activity may follow acute treatment with benzodiazepines [31].

Midazolam administration in doses of 0.5, 1 and 2.5 mg/kg works through this central mechanism, which has been shown to inhibit the effect of stereostatic stimulation of certain areas in the hypothalamus [the headmaster of the autonomic nervous system (ANS)] [32], decreasing the frequency of impulses from the cerebral cortex and brain stem reticular formation to the central vagal nucleus in the medulla oblongata, which may lead to a decrease in the vagal hyperactivity, with subsequent inhibition in gastric acid secretion by the oxyntic cells and a decrease in the total acid output.

Effect of midazolam on gastric ulcer

In the present study, gastric ulceration was induced in the stomachs of rats by immobilization stress. Immobilization of rats is a well-known model of emotional stress [33].

Various physical and psychological stressors cause gastric ulceration in humans and experimental animals [11]. Immobilization stress produces patterns of activation of various stress effector systems as endocrinal, physiological, and behavioural responses through activating hypothalamo- pituitary axis HPA and motor autonomic systems [34].

The major effects of stress on gut physiology include the following: (a) alteration in gastrointestinal motility, (b) increase in visceral perception, (c) changes in gastrointestinal secretion, (d) decrease in the prostaglandin E2 content in the gastric mucosa, (e) mast cell degranulation and (f) negative effects on regenerative capacity of the gastrointestinal mucosa and mucosal blood flow ([35–37], Yalken et al., 1999; Konturek et al., 2011).

Excitation of the CNS by stressful stimuli has a crucial role in the genesis of stress-induced gastric ulcers [38]. The reticular formation takes place in the central part of the brain stem [39], and terminates in various forebrain regions including the hypothalamus [32]. Thus, arousal of the reticular formation leads to a strong stimulation of the central vagal nuclei in the medulla oblongata. The finding of Dai and Ogle [13], coupled with the observations of Guth and Kozbur [19], support the theory that vagal overactivity plays an important role in the mechanism of stress ulceration in the rat stomach, and manifests itself by an increase in gastric motility. Excess parasympathetic stimuli may lead to local vasculoparalysis with subsequent ischaemia, necrosis and ulceration. This mechanism has been postulated in the experimental induction of ulcerative colitis in dogs [40]. Increased gastric motility is suspected to reduce gastric mucosal blood flow [35].

Congestion and sluggishness of the mucosal microcirculation lead to ischaemia of the gastric mucosa, and prevent nutrition of the mucosa, thus causing necrosis [41].

In a study by Watanabe et al. [42], it was shown that stress induces an increase in gastric motility, and that pretreatment with parasympatholytic agents or vagotomy prevents stress-induced ulceration in the rat stomach [13],[43].

There is a growing body of evidence supporting the claim that both psychological and physical stress reduction are positive for gastrointestinal health and normal function, as has been shown for other organ systems [44].

In the present study, our results showed that midazolam administration in doses of 0.5, 1 and 2.5 mg/kg immediately before immobilization stress (in a dose-dependent manner) leads to a protection index percentage of 9.4, 24 and 32.2%, respectively.

Sedative activity appears to be the most obvious limiting factor in the clinical usage of a tranquillosedative in the therapy of peptic ulcer [38]. The sedative, antianxiety, antisecretory and antiulcer effects of benzodiazepines stem from a common underlying mechanism in the brain [38]. Benzodiazepines act selectively on GABAA receptors, which mediate inhibitory transmission throughout the CNS [1].

Acute treatment with benzodiazepines is reported to reduce the formation of gastric stress ulcer in rats [45],[46].

Midazolam by its sedative effect on the CNS (i.e. cerebral cortex and reticular formation) mediates inhibition of the transmission of impulses in synapses of the CNS, which leads to a suppression of the frequency of excitatory impulses to the autonomic centres in the hypothalamus [47], with subsequent decrease in the frequency of excitatory impulses to the central vagal nuclei in the medulla oblongata, with subsequent decrease in the local vasculoparalysis and gastric motility, which leads to an improvement in the gastric mucosal ischaemia, necrosis and reduction in gastric ulceration.


  Conclusion Top


Midazolam has a prophylactic effect against immobilization-induced gastric ulcers, and it is better to use it as a preanaesthetic medication in patients subjected to endoscopy or elective surgery and in patients suffering from or with a liability to the occurrence of gastrointestinal erosions. Furthermore, midazolam also shows a prophylactic effect against the hazards of aspiration pneumonia, due to a significant decrease in the gastric juice volume, acid concentration and the total gastric acid output. The best tolerable dose of midazolam is 0.5 mg/kg.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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