% vol = 14 number = 3 prevlink = 115 nextlink = 126 titolo = "ENDOGENOUS INTOXICATION AS THE LEADING CAUSE OF ACUTE GASTRODUODENAL HAEMORRHAGES IN BURN PATIENTS" volromano = "XIV" data_pubblicazione = "september 2001" header titolo %>
SUMMARY. Acute erosive-ulcerous gastroduodenal haemorrhages are among the severest complications of burn injury. The pathogenesis of acute ulceration is complicated and diverse. This study was conducted to assess endogenous intoxication level using data on middle molecular weight peptides, lipid peroxidation processes, biogenic amines, and circulating immune complexes in the blood of 32 burn patients admitted to the Burn Centre of the N.V. Sklifosovsky Institute for Emergency Medicine (Moscow). The study measurements were performed at 1, 3, 7, 14, and 21 days post-burn. At the same time points, all the patients were examined by oesophagogastroduodenoscopy, and in accordance with the results the patients were divided into two groups: group 1 was comprised of 18 patients with gastrointestinal mucosa lesions, without evidence of haemorrhage, while group 2 contained 14 patients with mucosa lesions accompanied by gastroduodenal haemorrhage (the differences between the groups by age and burn area were statistically insignificant). The comparative analysis of the data obtained revealed that patients in group 2 had significantly higher levels of endogenous intoxication than patients in group 1, which was the main cause of gastrointestinal mucosa lesions, resulting in the development of erosive-ulcerous haemorrhages.
Acute erosive-ulcerous gastroduodenal (GD) lesions may be found at any time in the burn injury course.1-3 In the vast majority of cases they progress asymptomatically, and they are observed in only 0.15-3% of burn patients when accompanied by haemorrhages or perforation.4 More frequently they are found at necropsy (27% or less), and only endoscopic studies are capable of revealing practically 100% of existing destructive changes (acute erosions and ulcers), both complicated and non-complicated by haemorrhage.5
It is believed that the risk group consists primarily of patients with extensive burns in whom ulcerations develop in the first hours post-burn – this may be one of the causes of death in conditions of shock.1,2 Dynamic endoscopic studies performed in 98 patients in the Burn Centre at the N.V. Sklifosovsky Institute for Emergency Medicine in 1995-99 demonstrated that erosive-ulcerous lesions of the gastrointestinal tract (GIT) were seen in more than 91% patients with a burned TBSA of more than 20%; in 45-55% of cases the lesions were accompanied by erosive-ulcerous GD haemorrhages. In our data, 28.8% of the haemorrhages occurred in the shock period. Destructive mucosa lesions were more often complicated by a haemorrhage in patients over the age of 45 yr. Also, a history of duodenal peptic ulcer disease always increases the risk of acute erosive-ulcerous haemorrhage. The presence of hyperacidic stomach content causes destructive mucosa changes in the oesophagus, stomach, and duodenum and requires drug correction by histamine receptor H2-blockers.4,6
The pathogenesis of acute ulcerations of GIT mucosa in burn patients has not been clearly described. Besides the above-mentioned risk factors, an important role in the pathogenesis is played by the endogenous intoxication that occurs in burn injury, characterized by the accumulation of pathogenic metabolites and substances in blood (middle molecular weight peptides [MMWP], lipid peroxidation [LP] products, and biogenic amines [BA]), with various structure and functions, which either directly or through the cascade of biochemical reactions make a negative impact on cells and tissues and affect their functions.7-9
The objective of the present study is to evaluate the endogenous intoxication level in burn patients presenting acute erosive-ulcerous lesions of the GIT.
With the aim of assessing the level of endogenous intoxication in patients with erosive-ulcerous lesions due to burn injury, we selected 32 patients representing a risk group for acute GD haemorrhage (age, 20-60 yr; burns in patients with 20-40% TBSA, in whom oesophagogastroduodenoscopy (OGDS) examinations performed on days 1, 3, 7, 14, and 21 post-burn injury showed the presence of acute erosions or ulcers in oesophageal, stomach, or duodenum mucosa at various time points. All the patients received complex treatment in relation to the indications of burn injury severity, including infusion therapy, antibiotic therapy, nutritional support, and early surgical procedures. In cases of gastric hyperacidity, both anacid therapy (zantac, cimetidine) and antacid drugs (almagel, maolox) were used.
On the basis of the OGDS findings, the patients were divided into two groups: the first group was made up of 18 patients in whom the erosive-ulcerous mucosa lesions were not accompanied by haemorrhagic signs during the study period, and the second group of 14 patients in whom OGDS examination at one or more time points revealed haemorrhages, assessed by Forrest’s classification as FIA, FIB, FIIB, and FIIC. In active haemorrhages we used the endoscopic methods of haemostasis (injections of 70% alcohol solution around the vessel, mucosa irrigation with 5% 8-aminocapronic acid solution), which made it possible to control the haemorrhage in all cases.
The average patient age was 42.6 ± 3.3 yr in group 1 and 43.7 ± 3.9 yr in group 2. The average burn area in groups 1 and 2 was respectively 35.3 ± 3.4% and 34.9 ± 2.8% TBSA; the area of deep burns was respectively 17.6 ± 1.4% and 17.9 ± 1.6% TBSA in the two groups. Seven patients (four in group 1 and three in group 2) had a history of duodenal peptic ulcer.
Mortality among patients in group 2 was 2.5 times higher than in group 1 (27.8% versus 11.1%); however, in no case was mortality caused by haemorrhage.
The level of endogenous intoxication was studied in patients of both groups on days l, 3, 7, 14, and 21, taking homeostasis parameters into account. The Gabrielian-Lipatova10 spectrophotometry screening method was used to study MMWP fractions: fraction I (D254, corresponding Ï = 254 nm) and fraction II (D280, Ï = 280 nm). Biogenic amines (BA) in whole blood were studied by fluorometry using the Aminko spectrofluorometer; specifically, serotonin was studied according to Kogan et al.,11 and histamine according to Shore et al.12 LP products in blood serum were studied using spectrophotometry according to Kagan et al.13 for diene conjugates (CDs) and using spectrofluorometry according to Gavrilov et al.14 for malonic dialdegide (MDA).
The lipid oxidation degree (LOD) was determined by calculating the ratio of lipid extract light absorption in Ï = 233 nm to its value in Ï = 218 nm according to Bilenko.15 The antioxidant system (AOS) was evaluated using the resulting measurements. The lipid-soluble antioxidant ·-tocopherol (TP) was studied by spectrofluorometry, calculating its concentration using Duggan’s TF Sigma calibration curve.16 The content of the extracellular antioxidant enzyme ceruloplasmin (CP) was studied by spectrophotometry using paraphenylendiamine dihydrochloride as a substrate, as proposed by Ravin.17
The balance in the LP/AOS system was evaluated by means of the K coefficient calculated using the following equation proposed by Golykov et al.:
K=(CDi/CDn * MDAi/MDAn * LODi/LODn) / (TPi/TPn * CPi/CPn)
where the parameters with the “i” index indicate patients’ values and those with the “n” index indicate normal values. If there is a balance in the LP/AOS system, K coefficient is equal to 1; the K coefficient increase from 1.1 is indicative of a system imbalance reflecting the intensification of the LP process. The use of the K coefficient makes it possible to assess simultaneously both LP processes and AOS status and to reveal the degree of imbalance in LP/AOS system.
Corresponding blood parameter values of obtained from samples of 20 healthy donors were used as controls.
The serum immunoglobulins (Ig) A, M, and G were studied using the radial immunodiffusion method of Manchini et al.19 The circulating immune complexes (CICs) (absolute counts and percentage) were studied by the polyethylene glycol precipitation method (PEG-4000) according to Nasonov,20 slightly modified by the use of different PEG concentrations for differential identification of large-, medium-, and small-sized CICs. The measurements were performed at the same time points and on day 28.
The obtained data were analysed using ANOVA for repeated measurement.21
1. Results of endoscopic studies
OGDS findings that were similar in the oesophageal, gastric, and duodenal mucosa in patients in both groups were as follows: hyperaemia alone or in combination with ischaemia sites (i.e. “parti-coloured” appearance of mucosa), oedema (significant and impeding evacuation in some cases), faded or completely absent vascular pattern, slightly increased vulnerability of mucosa to the contact of the endoscope and the gastric tube, and multiple submucosa haemorrhage.
Acute ulcerations of mucosa were observed in all the patients at one or several time points during the study period (from day 1 to day 21). Their sizes ranged from very small (0.1-0.2 cm) to significant (maximum 1.2-1.5 cm), the form being linear in an oesophageal localization and irregular if localized in the stomach and duodenum. Even the largest ulcers were no more than 0.1 cm in depth.
The endoscopic picture over time was characterized by the variability of destructive changes in the mucosa (even within a few hours) and their correlation with the clinical course of the burn disease. The disappearance of the vascular pattern, the irregular mucosa colour, the occurrence of new, acute erosions and ulcers, the signs of an active current (FIA) or capillary (FIB) haemorrhage, large (FIIB) or small (FIIC) thrombosed vessels, and freely lying haematin or a “coffee dregs” content were considered negative changes in the mucosa over time. The commonest sources of haemorrhage were stomach erosions; combinations of acute erosions with ulcers of the stomach antrum and duodenum were less frequent. In 14 patients, a total number of 25 episodes of erosive-ulcerous haemorrhage were documented during the study, occurring most frequently in the period day 1-day 14. The occurrence of haemorrhage coincided with the development of pneumonia in one patient, with sepsis in three patients, and with multi-organ failure syndrome in four patients.
The primary endoscopic evidence of the patient improvement was the disappearance of the signs of haemorrhage. The remaining ulcerous lesions were gradually covered by fibrin. These became reduced in size and were totally closed by margin epithelialization, with the creation of “bright hyperaemia” zones. Small erosions disappeared without trace.
2. Studies of endogenous intoxication
2.1 Middle molecular weight peptides
The levels of fraction I (D254) in patients in both groups considerably exceeded normal values (p < 0.05) at all points of the study. The levels of fraction II (D280) in patients in the first group were higher than normal values on days 1, 3, and 14. In patients in the second group the fraction-II (F-II) increase was more significant and F-II levels exceeded normal levels at all time points of the study (p < 0.05). Fig. 1 shows that F-I and F-II values reflecting the endogenous intoxication level in the second group were significantly higher than in the first group. A statistically significant difference was observed in F-I on day 7 and in F-II on days 3, 7, and 14 (p < 0.05), with the highest levels of both fractions in the second group on day 14.<% Immagine "Fig. 1","gr0000022.jpg","Middle molecular weight peptides in burn patients with erosive-ulcerous GI tract lesions",230 %>
2.2 Lipid peroxidation and antioxidant system
In both groups of patients, CD, MDA, and LOD increases above normal were observed, which is typical of burn injury. In the first 14 days, the CD content in patients in the first group increased 1.3-1.5-fold compared to normal, and their CD content approached normal values only 3 weeks post-burn. Measurements of MDA concentrations were increased at all time points of the study, being highest on day 1 post-burn (3.1-fold) and remaining elevated (1.8-fold) on day 21. LOD increased 1.4-fold on day 3 and remained at this level until day 21 (Table I).<% createTable "Table I","Changes in lipid peroxidian and antioxidant system (LP/AOS) in burn patients with erosive-ulcerous GI tract lesions","§2§#Parameters LP/AOS§2§#Normal§2§#Group of patients§1,5§#Days post-burn@;1;3;7;14;21@;CD, D233/mLmg;0.66±0.05;1
A more marked LP activation was observed in the second group of patients, and CD content exceeded normal values (1.8-2.4-fold) in all periods of the study. The MDA level increased, exceeding the normal level 2.6-fold on day 1, reaching its maximum increase (3.9-fold) on day 14, and remaining as much as 2.7 times the normal level on day 21. LOD remained high during the whole study, exceeding the normal level maximum 1.7-fold on day 1 and increasing 1.4-fold on day 21.
The response of AOS to burn-induced LP abnormalities was delayed (the response was less delayed in patients in the first group). Specifically, in patients in group 1, the TP increase in blood serum was identified from day 3; in patients in group 2, this was observed significantly later, starting from day 14 post-burn. The CP increase in blood was even more delayed, with statistical significance (compared to the normal CD level) from day 14 in group 1 and only from day 21 in patients in group 2, a finding that was undoubtedly indicative of pronounced AOS insufficiency and LP/AOS imbalance (Table I) and reflected a higher endogenous intoxication level in patents with erosive-ulcerous GD haemorrhages.
The LP/AOS imbalance is more distinctly illustrated by the K coefficient. Its values in both groups at all time points of the study were significantly higher than normal values, with a maximum of 3.9 in group 1 and of 7.6 in group 2, reflecting a more severe LP/AOS imbalance in the second group of patients (Fig. 2).<% Immagine "Fig. 2","gr0000023.jpg","Lipid peroxidation-antioxidant system imbalance (K coefficient) in burn patients without haemorrhage (group I) and with haemorrhage (group 2)",230 %>
We consider the K coefficient to be the most appropriate criterion for assessing disturbances in LP/AOS.
2.3 Biogenic amines
Hyperserotoninaemia in patients in both groups was observed from day 1 post-burn and persisted during the whole study period. Statistical differences between the groups were observed on days 3 and 7 of the study (p < 0.05), when serotonin levels in the second group of patients were 1.3-fold higher than in the first group (Fig. 3).<% Immagine "Fig. 3","gr0000024.jpg","Blood biogenic amine indices in burn patients with erosive-ulcerous GI tract lesions",230 %>
Histamine levels in the same periods were also significantly higher than normal in both groups of patients - the statistically significant difference between the groups was observed only on the first day of the study (p < 0.05).
2.4 Circulation immune complexes and immunoglobulins
In both groups of patients, medium- and small-sized CICs steadily increased from day 3 post-burn, exceeding normal values 2-5-fold and deviating from normal 100-600% and more until day 21 (Fig. 4), with a slight decrease only on day 28. The most marked increase was observed in small-sized CICs. During the entire study period the counts of small- and medium-sized CICs were statistically higher in patients in group 2 (p < 0.05).<% Immagine "Fig. 4","gr0000025.jpg","Changes in the count of CICs in burn patients with erosive-ulcerous GI tract lesions. Horizontal lines in the diagram show the normal percentage for medium-sized and small-sized CICs",230 %>
Serum IgM and IgG levels were similar in the two groups of patients, whereas in the first two weeks patients in group 2 had a significantly lower IgA level (Fig. 5) than patients in group 1 (p < 0.05).<% Immagine "Fig. 5","gr0000026.jpg","Immunoglobulin A levels in the blood serum of burns patients with erosive-ulcerous GI tract lesions",230 %>
The treatment of severely burned patients is a challenge to physicians and requires a complex approach, including treatment of burn shock, infection control, early skin surface recovery, and hypermetabolic reaction correction.22 Acute erosive-ulcerous GIT haemorrhage is one of the severest complications2,4 and makes burn injury prognosis unfavourable in both conservative and operative treatment.
A burn, like any other severe injury, is accompanied by the systemic inflammatory response syndrome (SIRS). This is characterized by the activation of numerous mediators and pro-inflammatory compounds; SIRS can reach a critical uncontrollable level, resulting in the development of the multiple organ dysfunction syndrome (MODS).23-25
Our comparative assessment of the results of our study is based on the fact that the groups of patients analysed did not present any significant differences of age, burn injury severity, or Frank’s prognostic index. Also, haemorrhages developed in only 43.7% of the 32 patients with erosive-ulcerous mucosa lesions. This suggests that the degree of GIT mucosa damage was also influenced by other factors.
Primary ischaemic injury of the GIT mucosa (known as Curling’s ulcers) occurs in the burn shock period, and the extent of the ischaemia depends not only on the severity of shock but also on timely and appropriate anti-shock therapy. The ischaemia of organs and tissues, including GIT mucosa, triggers at least two links of pathogenesis.
First, ischaemia is one of the trigger moments in the cascade of biochemical reactions resulting in the entrance and accumulation in the blood of excessive amounts of highly active metabolites and intermediate metabolism products causing endogenous intoxication. These substances have a direct or intermediary destructive impact on cells, initiate and maintain SIRS, and disturb the phagocytic activity of macrophages. MMWP, BA, and LP products are the most informative indicators of endogenous intoxication.26-28 For three weeks post-burn the blood BA levels are significantly higher than in healthy subjects, which may be related to the prolonged hypermetabolic response to the burn injury. The developing haemodynamic impairments include circulation disorders, spasm of peripheral vessels, increased blood viscosity, platelet aggregation, microcirculation impairments with increased capillary permeability, and entrance into the blood of non-specific low-molecular components: histamine, serotonin, toxic oligopeptides (middle weight molecules), LP products, and components of the kinin and prostaglandin systems.29
A comparison of the data regarding MMWPs, serotonin, histamine, LP, and AOS in patients of both groups indicated that patients with haemorrhage had a significantly higher level of endogenous intoxication, which probably accounts for the severer lesions of the GIT mucosa and the development of acute erosive-ulcerous haemorrhages.
Second, the ischaemic damage to the GIT mucosa always results in increased bacterial translocation.30,31 The intestine barrier function breaks down 5 min post-burn and intestinal permeability reaches its maximum 4 h later, remaining high for 21 days post-burn.32 The prolonged hyperhistaminaemia also results in increased cell membrane permeability in various organs, including the intestine. This promotes the absorption of bacteria and endotoxins from the intestine, causing a significant ejection of mediators and constituting a prerequisite for the occurrence of GD haemorrhage in burn patients.
Long-lasting increased intestinal permeability after burn injury leads to the persistent translocation of bacteria and toxins from the intestine into the blood stream. The intestinal flora becomes the primary source of transitory bacteriaemia, infecting the burn wound and the central venous catheters, leading to infectious complications. The massive entrance of antigens into the blood stream, including the translocation of bacteria from the intestine, creates the prerequisites for the development of sepsis and multiple organ dysfunction.33,34 Skin destruction products and visceral tissue antigens are alternative sources of hyperantigenaemia.35
The higher content of CICs in blood serum is indirect evidence of a higher endogenous intoxication level in the second group of patients. We explain this finding by the more pronounced destructive-inflammatory changes in GIT mucosa and by the increase of intestinal permeability, leading to the massive entrance of antigens into the blood and to the increase of CIC formation. The elimination of CICs necessitates the presence of active phagocytes and complement components capable of dissolving the immune complexes. However, as burn injury is characterized by phagocytosis dysfunction on the one hand and by a deficiency of opsonizing complement components on the other, these abnormalities prevent the degradation of CICs and result in their accumulation in the circulating blood.
It is useful to note that the dysfunction of CIC elimination led to a significantly higher accumulation of small- and medium-size immune complexes in the blood of patients with erosive-ulcerous haemorrhages. Normally, CICs play a physiologically protective role and possess a broad spectrum of interactions with many other protective body systems. However, CICs of small and medium size in excessive amounts are known to have pathogenic properties and to be able to circulate in the blood for a long time, adversely affecting such tissues as the basal membranes of renal glomeruli and the skin, lung alveoli, hepatocytes, and others. CICs are able to cause the SIRS by activating the complement system, interacting with Fc- and C-receptors on the platelets, neutrophils, basophils, and other blood cells; CICs initiate the cellular secretion of enzymes, kinin system mediators, and activate the prostaglandin and blood coagulation systems.36
We suggest that in burn injuries characterized by high endotoxaemia and bacteraemia, the CICs excessively accumulated in the blood acquire pathogenic properties and become a negative “perpetual engine” that supports the long-lasting and multiple disturbances of homeostasis in the body of burn patients.
We found that the serum IgA content was significantly lower in the second group than in the first group and the normal level. This may be due to the excessive IgA expenditure for the secretory component formation in the intestinal wall in terms of the local immunity deficit in patients in the second group.37 We suggest that the decrease of serum IgA in conditions of a simultaneous increase in the CIC level could serve as a predictor of GD haemorrhage in burn patients.
Our work thus demonstrates that endogenous intoxication, which is both the cause and the consequence of impairment of the intestine barrier function, appears to be the most important pathogenic mechanism in acute GIT erosive-ulcerous lesions. As SIRS and endogenous intoxication develop in haemorrhagic patients, they reach a critical level and lead to dysfunctions in CIC formation and elimination. In turn, the high content of small- and medium-sized CICs increases the body’s systemic inflammatory response and leads to increased intestinal wall permeability, bacterial translocation, and hyperantigenaemia.
In brief, the ischaemic and endotoxaemic changes in the GIT mucosa, in combination with local aggression factors (hyperacidic gastric content, dysfunction of the locking mechanism of sphincters, paresis of the gastric and intestinal walls), cause damage to oesophageal, stomach, and duodenal mucosa and to the development of haemorrhage. We believe that small- and medium-sized CICs accumulating in excessive amounts become part of the pathogenic mechanisms that maintain severe disturbances in haemorheology, blood coagulation, and microcirculation and may constitute the basis for the development of the multiple organ dysfunction syndrome.
RESUME. Les hémorragies érosives-ulcéreuses aiguës sont parmi les complications les plus sévères des brûlures. La pathogénèse de l’ulcération aiguë est compliquée et variée. Les Auteurs ont effectué cette étude au Centre des Brûlures de l’Institut N.V. Sklifosovsky pour la Médecine des Urgences (Moscou) pour évaluer le niveau d’intoxication endogène utilisant les données sur les peptides de poids moléculaire moyen, les processus de la peroxidation lipidique, les amines biogéniques et les complexes immuns circulants. Les mesurages de l’étude ont été effectués les jours 1, 3, 7, 14 et 21 après la brûlure. Dans le même moment tous les patients ont été examinés moyennant l’oesophagogastroduodénoscopie, et selon les résultats les patients ont été divisés en deux groupes: le premier groupe comprenait 18 patients atteints de lésions de la muqueuse gastrointestinale, sans évidence d’hémorragie, tandis que le deuxième groupe contenait 14 patients atteints de lésions de la muqueuse accompagnées par une hémorragie gastroduodénale (les différences entre les groupes par âge et superficie brûlée n’étaient pas statistiquement significatives). L’analyse comparative des données a indiqué que les patients du deuxième groupe présentaient des niveaux d’intoxication endogène significativement plus élevés que les patients du premier groupe, ce qui était la cause principale des lésions de la muqueuse gastrointestinale et provoquait le développement des hémorragies erosives-ulcéreuses.