Original Articles
Copyright ©The Author(s) 2000. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 15, 2000; 6(1): 84-88
Published online Feb 15, 2000. doi: 10.3748/wjg.v6.i1.84
Reduced gastric acid production in burn shock period and its significance in the prevention and treatment of acute gastric mucosal lesions
Li Zhu, Zhong-Cheng Yang, Ao Li, De-Chang Cheng
Li Zhu, Zhong-Cheng Yang, Ao Li, Institute of Burn Research, Southwest Hospital, Third Military Me dical University, Chongqing 400038, China
De-Chang Cheng, Critical Care Department, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences (CAMS), Beijing 100730, China
Li Zhu, male, born on 1958-02-03 in Nanyang City, Henan Province, graduated from Third Military Medical University as a doctor in 1996 and now working in PUMCH as a postdoctoral research fellow, major in traumatic surgery and critical care medicine, having 17 papers published.
Author contributions: All authors contributed equally to the work.
Correspondence to: Dr. Li Zhu, Institute of Burn Research, South west Hospital, Third Military Medical University, Chongqing 400038, China. zhuli58@263.net
Telephone: +86-10-65233768, 65142049
Received: July 21, 1999
Revised: November 22, 1999
Accepted: October 9, 1999
Published online: February 15, 2000

Abstract

AIM: To investigate the changes of gastric acid production and its mechanism in shock period of severe burn in rats.

METHODS: A rat model with 30% TBSA full-thickness burn injury w as employed and the gastric acid production, together with gastric mucosal blood flow (GMBF) and energy charge (EC) were measured serially within 48 h postburn.

RESULTS: The gastric acid production in the acute shock period was markedly inhibited after severe burn injury. At the 3rd h postburn, the gas tricjuice volume, total acidity and acid output were already significantly decreased (P < 0.01), and reached the lowest point, 0.63 mL/L ± 0.20 mL/L, 10.81 mmol/L ± 2.58 mmol/L and 2.23 mmol/h ± 0.73 mmol/h respectively, at the 12th h postburn. Although restored to some degree 24 h after thermal injury, the variables above were still statistically lower, compared with those of control animals at the 48th h postburn. The GMBF and EC were also significantly reduced after severe burns, co nsistent with the trend of gastric acid production changes.

CONCLUSION: Gastric acid production, as well as GMBF and EC was predominantly decreased in the early postburn stage, suggesting that gastric mucosal ischemia and hypoxia with resultant disturbance in energy metabolism, but not gastric acid proper, might be the decisive factor in the pathogenesis of AGML after thermal injury, and that the preventive use of anti-acid drugs during burn shock period was unreasonable in some respects. Therefore, taking effective measures to improve gastric mucosal blood perfusion as early as possible postburn might be more preferable for the AGML prevention and treatment.

Key Words: gastric mucosal lesions, gastric acid, burn shock



INTRODUCTION

Acute gastric mucosal lesion (AGML) is one of the most common visceral complications early after severe burns. In patients with thermal injury that involves 30% or were of the total body surface area (TBSA), there was a 14% to 25% incidence of clinically evident gastrointestinal complications and 83.5% of the patients had endoscopic evidence of gastrointestinal disease[1]. Although it was reported recently that, burn-induced stress ulcer occurred less frequently wit h the advances of intensive care supports, AGML still caused a high mortality when complicated with severe bleeding[2], which was recognized as a potentially life- threatening event in such critically ill patients[3,4]. Therefore, such gastrointestinal complications after cutaneous thermal burn remain a problem of great interest and importance.

Several hypotheses have been proposed to explain the mechanism of burn-induced gastric mucosal injury, but no single factor appears to be invariably capable of producing lesions of the gastric mucosa[5]. Traditionally, increased gastric acid production has been long considered as one part of the stress response and the main contributor to the pathogenesis of AGML after severe burns[6]. Consequently, much attention has been paid to acid-neutralizing and/or in hibiting agents in the prevention and treatment of burn-induced gastrointestinal complications. In recent years, however, it is increasingly and widely assumed that tissue ischemia resulting from hypoperfusion is the initial and principal factor, which may trigger re-perfusion injury, for the AGML formation[7]. Meanwhile, the necessity and rationality of AGML prophylaxis by using acid-neu tralizing and/or inhibiting agents have also been challenged[8,9].

Gastric acid secretion is an active metabolic process with energy consumption, which requires sustained and adequate blood supply[8]. It has well been documented that the splanchnic circulation is the first to be reduced in critical illness and the gut is one of the first organs to have the adequacy of its tissue oxygenation compromised in shock[10,11]. We therefore presumed that the gastric acid production in burn shock period might be reduced, which is contrary to what we have thought of before but remains lack of direct evidence.

With this background, the present study is conducted to serially determine the gastric acid production, and the changes of blood flow and energy charge of the gastric mucosa during burn shock period, in order to elucidate the characteristics of gastric acid production in early postburn stage and their mechanisms, as well as to provide useful information for the AGML prophylaxis at clinical settings.

MATERIALS AND METHODS
Animals

Healthy adult Wistar rats of either sex, weighing 220 g ± 30 g, were employed in the study. They were housed in individual metabolic cages in a temperature conditioned room (22 °C-24 °C) with a 12 h light-dark cycle, allowed access to standard rat chow (provided by experimental animal center, Third Military Medical University) and water ad libium, and acc limatized to the surroundings for 7 days prior to the experiments.

Burn injury and resuscitation

Animals were fasted for 12 h before burn injury, and during 48 h postburn period they were allowed water ad libitum. After induction of anesthesia with 1% pentobarbital sodium ( 30 mg/kg, ip ), dorsal hair was shaved, and animals were placed in a wooden template designed to expose 30% of the total body surface area (TBSA), and then immersed in water at 92 °C for 20 seconds, which results in a clearly demarcated full-thickness burn. One hour after burn injury, the animals were resuscitated with 10 mL of warm 0.9% NaCl (normal saline solution, 37 °C) given by intraperitoneal injection. Control animals were similarly anesthetized, shaved and resuscitated but not burned.

The animals burned were randomly divided into five groups for the different measurements and assays that were performed 3, 6, 12, 24 and 48 h postburn ( PBH3, PBH6, PBH12, PBH24 and PBH48).

Measurement of gastric acid production

Three hours prior to each timepoint, animals were anaesthetized, laparotomized, and then the pylorus were ligated. After sacrificed by decapitation at each tim epoint, rats were re-laparotomized to obtain the gastric juice. The pH and volume of each collection were recorded and by using a microtitrator its hydrogen ion concentration was measured by titration with 0.02 mol/L sodium hydroxide to an endpoint indicated by phenolphthalein. The total acidity and total acid output of each gastric juice collection were calculated.

Determination of gastric mucosal blood flow

GMBF was determined as previously described[12]. Radioactive biomicrospheres were prepared with toad red blood cells labeled with 99mTc. At each timepoint, anesthetized animals underwent cannulation of right carotid artery for the injection of radioactive microspheres with PE-50 polyethylene tubing (inside diameter 0.58 mm and outside 0.97 mm). The catheter was care fully advanced into the left ventricle, as confirmed by the ventricular pressure curves monitored with a four-channel physiological recorder. Another catheter for drawing a reference blood sample was introduced into the aorta abdominalis via left femoral artery. The prepared suspension of radioactive microspheres was mixed vigorously for at least 2 min before each injection. Then 0.2 mL of the suspension in an injection syringe (approximately 1.5-2.0 × 105 microspheres) was counted for radioactivity by a γ-scintillation counter before being slowly and uniformly injected into the left ventricle during a 30sec period and the infusion tube was flushed with 0.2 mL heparinized saline solution. The injection syringe was rinsed five times with saline solution into a counting tube for measurement of residual radioactivity in the syringe. Thus net radioactivity injected into the animal was the original minus residual radioactivity. Withdrawal of the reference blood sample, having st arted 20sec before the microsphere injection, was performed by a syringe pump at a constant rate of 0.4 mL/min for 90sec. After withdrawal of the reference blood, animals were killed with an overdose of sodium pentobarbital. The gastric mucosa was sampled, weighed and then counted in γ-scintillation counter. The GMBL was calculated by the following equation and expressed as “mL/min·g tissue”[13]:

Biochemical assays of gastric mucosal energy charge

At each timepoint, the glandular mucosa of stomach was sampled by scraping with razor and stored in liquid nitrogen. On determination, adenine nucleotides were assayed as previously reported with some modifications[14]. Briefly, the sample was powdered in a liquid nitrogen bath and then weighed and homogenized in 20 volume of 10% perchloric acid for deproteinization. The homogenate was centrifuged for 30 min at 12000 × g. The pH of the resulting supernatent was adjusted to 7.0-7.6 with 5 mol K2CO3/L. Then another centrifugation was performed and the supernatent was used to assay for adenine nucleotides by using high-per formance liquid chromatography with a reverse-phase column at a flow rate of 1 mL/min with a buffer of 0.1 mol PBS/L. The ATP, ADP and AMP con centrations in gastric mucosa were then obtained from the eluant fractions. The adenylate energy charge was calculated according to the following equation:

Energy charge = (ATP + 0.5 × ADP) / (ATP + ADP + AMP)

Statistical analysis

Data are expressed as mean ± SE. Experi mental results were analyzed by analysis of variance and t tests for multiple comparisons. P values less than 0.05 were considered to be statistically significant.

RESULTS

The gastric acid production in the acute shock period was markedly inhibited after severe burn injury. At the 3rd h postburn, the gastric juice volume, total acidity and acid output were already significantly decreased, on decreasing, to reach the lowest point at the 12th h postburn. Although restored to some degree and kept 24 h after thermal injury, the variables above were still statistically lower as compared with those of control animals 48 h postburn (Table 1). The GMBF and EC were also significantly reduced after severe burns, and were co nsistent with the trend of gastric acid production changes (Table 2 and 3).

Table 1 The postburn changes of gastric acid production in rats (-x ± s).
GroupsAnimalsVolume (mL/3h)Total acidity (mmol/L)Total acid output (μmol/h)
Control104.41 ± 0.8897.36 ± 14.40140.14 ± 16.84
PBH3101.65 ± 0.24b60.28 ± 10.46b32.84 ± 6.14b
PBH6101.07 ± 0.19b43.78 ± 4.59b15.47 ± 2.21b
PBH12100.63 ± 0.20b10.81 ± 2.58b2.23 ± 0.73b
PBH24102.58 ± 0.39b86.89 ± 12.21a75.45 ± 18.69b
PBH48102.52 ± 0.20b82.34 ± 12.82b69.28 ± 12.92b
Table 2 The postburn changes of gastric mucosal blood flow in rats (mL/min·g, -x ± s).
GroupsAnimalsGMBFGroupsAnimalsGMBF
Control60.89 ± 0.25PBH1260.24 ± 0.05b
PBH360.36 ± 0.12bPBH2460.54 ± 0.11b
PBH660.31 ± 0.05bPBH4860.71 ± 0.17a
Table 3 The postburn changes of ATP, ADP, AMP and EC in gastric muco sa in rats (-x ± s).
GroupsAnimalsATP(μmol/g)ADP(μmol/g)AMP(μmol/g)EC
Control64.76 ± 0.412.58 ± 0.181.06 ± 0.090.72 ± 0.02
PBH363.53 ± 0.24b2.37 ± 0.171.39 ± 0.15a0.65 ± 0.02b
PBH663.16 ± 0.40b2.03 ± 0.23b1.99 ± 0.24b0.58 ± 0.03b
PBH1262.38 ± 0.34b1.56 ± 0.17b2.64 ± 0.31b0.48 ± 0.03b
PBH2463.41 ± 0.38b2.26 ± 0.22a1.73 ± 0.26b0.62 ± 0.02b
PBH4863.96 ± 0.37b2.34 ± 0.261.69 ± 0.15b0.64 ± 0.01b
DISCUSSION

It has been long considered that certain amount of hydrogenion existing in gastric lumen is the prerequisite for the AGML formation[15,16]. However, the roles of gastric acid in the pathogenesis of AGML have not been fully elucidated so far. In a clinical study, Pruitt et al[6] noted that the mean outputs of total gastric acid in burn patients with normal mucosa, AGML, and AGML with complications (such as bleeding and perforation) were 1.42, 3.32, and 5.37 mmol/h respectively. Lucas et al[17] also found an increase in gastric acid production was positively related the severity of AGML in traumatic patients observed with endoscopy. Interventions designed to decrease gastric acid production, such as vagotomy or administration of aluminum hydroxide or anticholinergic drugs, have all been shown to decrease the incidence of ulcers. In the cace of a burn injury or other severe injury, the presence of acid even at subnormal levels may be sufficient to produce gastrointestinal complications. However, in humans and experimental animals there has not been a consistent association of acute gastric ulcerations after burn injury with hypersecretion of gastric acid[18].

The early phase after severe burn is the critical period for AGML formation. It was reported that the incidence of AMGL within 72 h reached as high as 76%[1,19]. Therefore, investigating the changes of gastric acid production in shock period is both theoretically and practically of importance for the further understanding of the pathogenesis of AGML and, on this basis, improving its treatment and prophylaxis. In present study, we showed that gastric juice volume, total acidity and acid output in burned rats during the early phase of severe burns were significantly decreased compared with unburned controls, with the lowest at 12th h and persisting at lower levels until 48 h postburn. In particular, the total acid outputs at the 6th, 12th, and 24th h in burn animals corresponded only to 1/9, 1/63, and 1/2 of those in control rats. These results indicate that in burn shock period the gastric acid secretion is markedly inhibited.

The production of gastric acid is an active metabolic process with energy consumption, requiring sustained and adequate blood supply[8]. It is well known that during the period of hypovolemic shock such as that induced by burn, blood is preferentially shunted to the “vital” organs, such as the brain and heart, at expense of the splanchnic circulation, causing a sharp reduce of blood flow to the gastrointestinal tract[20]. Therefore, ischemia may be a major factor in the development of AGML after shock and injury. In a report by Horton, blood flow to the small intestine and stomach decreased significantly 5 h postburn, but flow returned to the normal level 24 h after burn only in the small intestine, but not in the stomach[18]. In this murine burn model, we noted that there was a significantly decrease in GMBF and EC with a trend consistent with the serious inhibition of gastric acid production after severe burns. Thus, the decreased acid production might be resulted from ischemia and hypoxia of the gastric mucosa that are metabolically unable to produce normal quantities of acid. Furthermore, while being a causative factor for the AGML formation, gastric acid is also one of the most important barriers against invading pathogenic miero-organisms[21]. Gastric pH < 3.5 is usually bactericidal for most species[22]. In this sense, the inhibition of acid secretion in early postburn period is the manifestations of both local impairment of gastric mucosal function, as well as the dysfunction of host defense mechanism as a whole.

Prophylaxis for stress ulceration continues to be an important part of the management of critically burned patients. However, controversy remains regarding the necessity and rationality of the regimen used[23,24]. Available options at present include antacids, various H2-receptor antagonists, prostaglandins, proton pump inhibitors, and sucralfate, nearly all of which exert their pharmacological actions, to more or less extent, through the acid-neutralizing and/or inhibiting mechanism[25]. In fact, postburn acute mucosal lesions occurred not only in the gastric mucosa, but also in some organs that cannot produce acid such as small and large intestines, and even the gallbladder mucosa[26]. In patients without titratable gastric acid, diffuse erosive gastritis remains occurring within 72 h of burn injury[18]. It was documented in some reports that the incidence of pathological changes in gastric mucosa was not alleviated by using antacids in clinical settings[27], but could be prevented or reduced by satisfactory resuscitation and advanced intensive care support, even in a condition lack of anti acid prophylaxis[28,29]. In burned rats, Skolleborg et al[5] found with postburn fluid resuscitation sufficient to maintain aortic blood presure, gastric mucosal erosions were prevented even when gastric pH was at 1.0. All of these, combined with our results, show in different aspects that gastric acid is not a leading and crucial, but an aggravating factor that functions on the basis of ischemic impairments, for the AGML formation. Whereas, the present AGML prophylaxis mainly by the use of anti-and neutralizing acid drugs is not only making the mucosa more susceptible to acid injury[30], but also resulting in numerous side-effects including breaking the defensive barrier of gastric acid, which may lead to the colonization and translocation of gut organisms and thus increase the risk of nosocomical infections[25,27,28,31]; therefore, taking effective measures to improve splanchnic blood perfusion as early as possible postburn may be more preferable than the mere blockade of gastric acid production for the AGML prevention and treatment.

Footnotes

Project supported by the National Natural Science Foundation of China, No.39290700.

Edited by Lu HM

References
1.  Czaja AJ, McAlhany JC, Andes WA, Pruitt BA. Acute gastric disease after cutaneous thermal injury. Arch Surg. 1975;110:600-605.  [PubMed]  [DOI]
2.  Battal MN, Hata Y, Matsuka K, Ito O, Matsuda H, Yoshida Y, Kawazoe T, Nagao M. Effect of a prostaglandin I2 analogue, beraprost sodium, on burn-induced gastric mucosal injury in rats. Burns. 1997;23:232-237.  [PubMed]  [DOI]
3.  Lam NP, Lê PD, Crawford SY, Patel S. National survey of stress ulcer prophylaxis. Crit Care Med. 1999;27:98-103.  [PubMed]  [DOI]
4.  Afessa B. Systemic inflammatory response syndrome in patients hospitalized for gastrointestinal bleeding. Crit Care Med. 1999;27:554-557.  [PubMed]  [DOI]
5.  Skolleborg KC, Grønbech JE, Abyholm FE, Svanes K, Lekven J. Acute erosions of the gastric mucosa in burned rats: effect of gastric acidity and fluid replacement. Scand J Plast Reconstr Surg Hand Surg. 1990;24:185-192.  [PubMed]  [DOI]
6.  Pruitt BA, Goodwin CW. Stress ulcer disease in the burned patient. World J Surg. 1981;5:209-222.  [PubMed]  [DOI]
7.  Nada Y, Sasaki K, Nozaki M, Takeuchi M, Chen X, Nakazawa H. The effect of early burn wound excision on regional gastric blood flow in rats. Burns. 1998;24:519-524.  [PubMed]  [DOI]
8.  Higgins D, Mythen MG, Webb AR. Low intramucosal pH is associated with failure to acidify the gastric lumen in response to pentagastrin. Intensive Care Med. 1994;20:105-108.  [PubMed]  [DOI]
9.  Tryba M. Research on stress ulcer prophylaxis: wrong questions, wrong answers. Crit Care Med. 1999;27:16-17.  [PubMed]  [DOI]
10.  Antonsson JB, Fiddian-Green RG. The role of the gut in shock and multiple system organ failure. Eur J Surg. 1991;157:3-12.  [PubMed]  [DOI]
11.  Arnold J, Hendriks J, Ince C, Bruining H. Tonometry to assess the adequacy of splanchnic oxygenation in the critically ill patient. Intensive Care Med. 1994;20:452-456.  [PubMed]  [DOI]
12.  Malik AB, Kaplan JE, Saba TM. Reference sample method for cardiac output and regional blood flow determinations in the rat. J Appl Physiol. 1976;40:472-475.  [PubMed]  [DOI]
13.  Inoue S, Lukes S, Alexander JW, Trocki O, Silberstein EB. Increased gut blood flow with early enteral feeding in burned guinea pigs. J Burn Care Rehabil. 1989;10:300-308.  [PubMed]  [DOI]
14.  Kamiyama Y, Ozawa K, Honjo I. Changes in mitochondrial phosphorylative activity and adenylate energy charge of regenerating rabbit liver. J Biochem. 1976;80:875-881.  [PubMed]  [DOI]
15.  Geus WP, Lamers CB. Prevention of stress ulcer bleeding: a review. Scand J Gastroenterol Suppl. 1990;178:32-41.  [PubMed]  [DOI]
16.  Silen W, Merhav A, Simson JN. The pathophysiology of stress ulcer disease. World J Surg. 1981;5:165-174.  [PubMed]  [DOI]
17.  Lucas CE. Stress ulceration: the clinical problem. World J Surg. 1981;5:139-151.  [PubMed]  [DOI]
18.  Zapata-Sirvent RL, Greenleaf G, Hansbrough JF, Steinsapir E. Burn injury results in decreased gastric acid production in the acute shock period. J Burn Care Rehabil. 1995;16:622-626.  [PubMed]  [DOI]
19.  Zhu L, Yang ZC. Acute gastric mucosal lesion and its patogenesis. Zhongguo Shaoshang Chuangyang Zazhi. 1997;2:7-15.  [PubMed]  [DOI]
20.  Swank GM, Deitch EA. Role of the gut in multiple organ failure: bacterial translocation and permeability changes. World J Surg. 1996;20:411-417.  [PubMed]  [DOI]
21.  Heyland D, Bradley C, Mandell LA. Effect of acidified enteral feedings on gastric colonization in the critically ill patient. Crit Care Med. 1992;20:1388-1394.  [PubMed]  [DOI]
22.  Bengmark S, Gianotti L. Nutritional support to prevent and treat multiple organ failure. World J Surg. 1996;20:474-481.  [PubMed]  [DOI]
23.  O'Keefe GE, Gentilello LM, Maier RV. Incidence of infectious complications associated with the use of histamine2-receptor antagonists in critically ill trauma patients. Ann Surg. 1998;227:120-125.  [PubMed]  [DOI]
24.  Devlin JW, Ben-Menachem T, Ulep SK, Peters MJ, Fogel RP, Zarowitz BJ. Stress ulcer prophylaxis in medical ICU patients: annual utilization in relation to the incidence of endoscopically proven stress ulceration. Ann Pharmacother. 1998;32:869-874.  [PubMed]  [DOI]
25.  Souney P. Stress ulcer prophylaxis therapy: impact on gastric colonization. Am J Gastroenterol. 1999;94:850-851.  [PubMed]  [DOI]
26.  Cheng YS, Shi JQ, Liang YJ. The pathological changes of visceral organs after burn injury. In: Li A, Yang ZC, eds.Therapeutics of burns. Second edition, Beijing: People's Hygiene Publishing House. 1995;31-46.  [PubMed]  [DOI]
27.  Rubinstein E, Gjørup I, Schulze S, Jonsson T, Højgaard L. Development of stress ulcers assessed by gastric electrical potential difference, pH of gastric juice, and endoscopy in patients in the intensive care unit. Eur J Surg. 1992;158:361-364.  [PubMed]  [DOI]
28.  Zandstra DF, Stoutenbeek CP. The virtual absence of stress-ulceration related bleeding in ICU patients receiving prolonged mechanical ventilation without any prophylaxis. A prospective cohort study. Intensive Care Med. 1994;20:335-340.  [PubMed]  [DOI]
29.  Kiviluoto T, Grönbech JE, Kivilaakso E, Lund T, Pitkänen J, Svanes K. Acute gastric mucosal lesions, haemodynamic and microcirculatory changes in the thermally injured rat. Burns. 1989;15:365-370.  [PubMed]  [DOI]
30.  O'Brine P, Silen W. Influence of acid secretory state on the gastric mucosal tolerance to back diffusion of H+. Gastroenterology. 1976;71:760-765.  [PubMed]  [DOI]
31.  Matamis D. Prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Intensive Care Med. 1999;25:118-119.  [PubMed]  [DOI]