Language


Download PDF (Spanish)

Comparative analysis of two cohorts of pediatric patients with acute diarrhea and response to the oral rehydration solution (ORS) vs. ORS + gelatin tannate

J. Esteban Carretero, F. Durbán Reguera1, S. López-Argüeta Álvarez2 and J. López Montes3

Gastroenterology and 1Emergency Services. Torrecárdenas Hospital. 2General Practice and Pediatric Diseases. Clinic Prescribes. 3General Practice and Pediatric Diseases. Roquetas de Mar. Almería.

ABSTRACT

Aim: the study aims to observe the response to the treatment with ORS or ORS + gelatin tannate in two cohorts of pediatric patients suffering from acute diarrhea, in which the number of stools after 12 hours from the initial treatment is the main criterion to assess efficacy.

Methods: children aged 3 months to 12 years were included in the study. Only children suffering from acute diarrhea, with more than 3 liquid stools and with a disease development period not exceeding 72 hours, were included. The main variable of the number of stools and of analyses was recorded as an absolute number, categorized as ≤ 3 and ≥ 4 stools within 12 hours, and as a stool decrease index (SDI). Other clinical variables were recorded, such as weight, fever, vomiting, stool characteristics, and signs of peritonitis/sepsis.

Results: the main characteristics for both populations included an average age amounting to 2.3 years in the ORS group and to 2.6 years in the ORS + gelatin tannate group. Children younger than 2 years represented 59.8% of the individuals included in the ORS group and 54.3% of the individuals included in the ORS + gelatin tannate group. Clinical variables were recorded, such as vomiting, dehydration, weight, fever, vomiting, stool characteristics and signs of peritonitis/sepsis. A stool decrease index (SDI = final [12 hours] - initial stools / initial stool) was created in order to compare both groups. We found a statistically significant difference between these two groups (p < 0.0001): the SDI for the ORS group was -0.1894, and -0.6023 for the ORS + gelatin tannate group.

Conclusions: we observed a significant decrease in the number of stools and an improvement in the consistency of stools in the ORS + gelatin tannate group. Other clinical variables such as vomiting, dehydration, weight, bloody stools, and signs of peritonitis/sepsis showed no statistical differences between the two groups, but a general trend toward improvement was observed. The Stool Decrease Index (SDI) showed a decrease by 18% in the number of stools for the ORS group and by 60% for the ORS + gelatin tannate group. The use of ORS + gelatin tannate was associated with a greater decrease in the SDI. Gelatin tannate reduced the number of stools after twelve hours in children.

Key words: Acute diarrhea. Gelatin tannate. Tannins. Intestinal infection.

The study was conducted according to the principles of the Declaration of Helsinki.

INTRODUCTION

In the 1980s, the annual global mortality rate as a result of acute diarrhea was estimated at 4.6 million people. Since the introduction of oral rehydration therapies, mortality has fallen to 2.5 million people a year, although this figure continues to be an estimate. In any case, mortality figures are still very high.

It is estimated that acute diarrhea is the third cause of death (15%) in children under the age of 5 who live in developing countries, only after perinatal death (23%) and acute respiratory infection (18%) (1).

Intestinal infection is by far the most common cause of acute diarrhea. There are two well-defined risk factors that stand out from the rest: to live in the world’s most depressed regions (Indian sub-continent, Africa, and Latin America) and the pediatric age, in particular newborn babies and toddlers. Other risk factors such as immune suppression, travels, and the intake of acid secretion inhibitors and antibiotics play a less significant role (2).

In acute infectious diarrhea, the stimulation process of intestinal secretion is induced in most cases by enterotoxins binding to receptors in the apical pole of the enterocyte and to other cells, such as enterochromaffin cells. A “second messenger” intracellular cascade is activated (especially, in the case of the V. Cholerae toxin), the substance P, VIP and 5 HT receptors, giving rise to changes in the intracellular concentration of cAMP, which allows the opening of Cl channels, leading to a net flow of chlorine into the intestinal lumen. Sodium attempts to maintain electroneutrality, and there is a secondary passive movement of water in order to maintain isotonicity. Multiple substances have been sought to antagonize the pro-secretory effects of these substances (3).

According to the WHO, the recommended treatment for acute diarrhea consists of oral rehydration, and the use of certain antibiotics, motility inhibitors (such as loperamide) or substances that decrease water and electrolyte secretion (such as racecadotril) can be useful only in certain and very specific situations. It is well known that the administration of motility-reducing drugs can favor bacterial overgrowth.

Some controlled studies have shown the efficacy of tannins in the treatment of acute diarrhea, with a greater effect than that of placebo (4), by shortening the duration of the disorder and with no undesirable effects. This is further supported by a high prescription volume exceeding 350,000 units of gelatin tannate.

Gelatin tannate powder is a mixture of tannic acid and gelatin. Tannic acid is a gallic acid and glucose polymer, which has the great capacity to form macromolecular complexes with proteins to which it binds by means of hydrogen bonds (astringent property), polysaccharides, nucleic acids, steroids, alkaloids, and saponins. It is also attributed antibacterial and antioxidant properties.

It has been shown that tannins are capable of inhibiting the Vibrio Cholerae toxin, which reduces intracellular cAMP formation by inhibiting ADP ribosylation, and therefore it reduces the intestinal secretion of chlorine and water. The cholerae toxin (CT) is an oligomeric protein formed by a single A unit and five B subunits. Its biological action starts when the B unit binds to the GM receptor of the apical membrane of the enterocyte, which gives rise to a number of changes in the CT molecule leading to the insertion of the A sub-unit in the cell resulting in the activation of adenylyl cyclase, which induces, among others, the activation of prostaglandins that gives rise to the accumulation of Na and water in the intestinal lumen. Tannins are capable of inhibiting ADP ribosyltransferase activity (5), probably by means of the formation of macromolecular aggregates with CT, which prevents it from binding to GM receptors at the apical portion of the enterocyte and, thus, it inhibits cAMP synthesis (6).

Tannic acids have several undesirable gastrointestinal effects: they induce digestive symptoms, such as nausea and vomiting, and inhibit the absorption of Fe and other metals. The use of tannic derivatives, such as albumin tannate and gelatin tannate, which is hydrolyzed to gelatin and tannic acids in the intestine, prevents thus the development of gastric lesions due to tannic acid affecting the gastric mucosa. There are very few studies on the effect of tannins on intestinal motility, but they appear to confirm the absence of the inhibiting effect on the same (7).

The objective of this study is to show the clinical effectiveness and safety of gelatin tannate in the pediatric population of Spain, under usual prescription conditions, and to evaluate its speed of action that, according to some studies, is lower than 12 hours.

MATERIALS AND METHODS

We performed an observational study of two cohorts of patients (ORS and ORS + gelatin tannate) with acute diarrhea in medical centers of Almería, Spain. The inclusion criteria were: children aged 3 months to 12 years, patients with a diagnosis of acute diarrhea, three or more liquid stools a day, and a disease development period not exceeding 72 hours. Exclusion criteria included: chronic or toxic diarrhea, the use of antidiarrheals (other than gelatin tannate), and the impossibility to monitor the patient for more than 12 hours. The use of antibiotics was allowed in both groups, according to the discretion of the physician in charge of the treatment. The primary variable of the study was the number of stools at two time points: at the beginning and 12 hours later. In addition to the number of stools, we recorded stool characteristics, presence of blood in the stool, vomiting, dehydration, signs of peritonitis or sepsis, and weight. Standard socio-demographic variables, such as sex and age, were collected.

Statistical analysis

An initial quality control check of the database was performed in order to ensure that data used for the statistical analysis were adequate. The effectiveness of the treatment was analyzed as the decrease in the symptoms of diarrhea after 12 hours following the beginning of the treatment. To that end, we analyzed the differences between the initial and final periods for the variables collected in the study from each group of patients, by means of the McNemar (2-x-2) test for categorical variables and the Wilcoxon’s test for quantitative variables (when normality conditions were not present). For comparisons between the treatments of both groups at the initial moment and after 12 hours, we used the Chi-square test or Fisher’s exact test for categorical variables and the t-test or Mann-Whitney U test (when normality conditions were not present) for quantitative variables.

RESULTS

A total of 239 children were included in the study. 28 patients did not meet the inclusion criteria and, thus, were not included in the analysis. A total of 211 patients were included in the final analysis and were distributed as follows: 114 patients in the ORS group and 97 patients in the ORS + gelatin tannate group.

Socio-demographic characteristics

The average age of the study population was 2.5 years (SD ± 2.42) with a median amounting to 1.7 years; 54.1% of patients were male and 42.7% female. The average age was 2.3 years (SD ± 2.46) for the ORS group, and 2.6 years (SD ± 2.39) for the ORS + gelatin tannate group. Children under the age of 2 represented 59.8% and 54.3% of individuals for the ORS and ORS + gelatin tannate groups, respectively. The distribution according to sex in the ORS group was 50% for each, while in the ORS + gelatin tannate 59% were males and 41% were females.

Clinical characteristics

At the beginning, the absolute number of stools for the ORS group was 114, and 93 for the ORS + gelatin tannate group. The initial average amounted to 7.26 (SD ± 2.95) stools for the ORS group and to 6.19 (SD ± 1.76) stools for the ORS + gelatin tannate group. The average number of stools after 12 hours was 5.86 (SD ± 2.45) for the ORS group and 2.06 (SD ± 1.04) for the ORS + gelatin tannate group. The differences as regards the number of stools at the initial moment were statistically significant (p = 0.01) between the groups, at the beginning and at the end (12 h) (p < 0.0001). A stool decrease index (SDI = Final (12 h) - initial stools / initial stool) was created in order to compare both groups. We found a statistically significant difference between these two groups (p < 0.0001): the SDI for the ORS group was 18.9% (SD ± 20.2), and 60.2% (SD ± 18.8) for the ORS + gelatin tannate group. Likewise, we grouped the number of stools as ≥ 4 and < 4, and also found statistically significant differences between the two groups at the beginning and at the end of the treatment (p = 0.037).

We also observed an improvement in the stool consistency from the beginning to the end (12 h) in both groups with liquid stools from 90.3% and 97.8% for the ORS and ORS + gelatin tannate groups, respectively, to 71.9% and 28.3% at the end of the treatment for the ORS and ORS + gelatin tannate groups, respectively.

The presence of vomiting at the beginning was 78.1% for the ORS group and 72.6% for the ORS + gelatin tannate group. At the end of the treatment (12 h), vomiting was present in 41.6% of the ORS group and 35% of the ORS + gelatin tannate group. No statistically significant differences were observed between both groups. As per dehydration, we observed a dehydration percentage amounting to 9.7% in the ORS group and to 12% in the ORS + gelatin tannate group at the beginning, and a dehydration percentage amounting to 0.9% in the ORS group and to 4.5% in the ORS + gelatin tannate group at the end of the treatment; again, no statistically significant differences were observed.

At the beginning, bloody diarrhea was only found in 2.7% of patients included in the ORS group and in 8.4% of patients in the ORS + gelatin tannate group. The ORS group maintained the same values, while the ORS + gelatin tannate group showed a decrease amounting to 3.3%. No statistically significant differences were found between the treatment groups. As regards weight and signs of peritonitis/sepsis, we did not find any statistically significant difference between both groups. The variable “Fever” showed a statistically significant difference (p < 000,1) between the two groups at the end of the treatment. However, we observed a decrease in temperature values for the two study groups from 37.81 ºC to 36.98 ºC in the ORS group and from 37.7 ºC to 36.6 ºC in the ORS + gelatin tannate group.

DISCUSSION

Death caused by diarrhea and dehydration is the second cause of death in the pediatric population after pneumonia. Oral rehydration salts (ORS) with low glucose and salt concentrations enable the effective management of pediatric diarrhea and the drastic reduction in the number of child deaths in developing countries.

The objective of this study was to determine the efficacy of the treatment with ORS + gelatin tannate versus the treatment with ORS alone, measured as the cessation of diarrheic stools after 12, 24 and 48 hours following the beginning of the treatment in the pediatric population. Reported data show the efficacy and safety of gelatin tannate in combination with ORS in the treatment of acute diarrhea for children aged 3 months to 12 years.

Two hundred and eleven children suffering from acute diarrhea for less than 72 hours and more than three diarrheic stools a day met the inclusion criteria and were included in the study.

Children were randomly assigned to one of the two study groups (ORS, n = 114, or ORS + gelatin tannate n = 97). The statistical analysis of initial socio-demographic characteristics shows that these two groups are comparable.

Unfortunately, there is an initial difference in the primary variable of the study, the number of stools of patients; the group treated with ORS + gelatin tannate was the group that started with a smaller number of stools before the beginning of the treatment (p < 0.05). However, in order to determine the efficacy of the ORS + gelatin tannate therapy, a decrease index was created for the number of stools (reduction in the number of stools = [final stools - initial stools] / initial stools), and a statistically significant difference in the average reduction of stools was found (p < 0.0001). Twelve hours after the beginning of the antidiarrheal treatment, the number of stools was reduced by 18% in the ORS group and by 60% in the ORS + gelatin tannate group.

In both groups, there was an improvement in stool consistency, from liquid stools at the beginning to soft/hard stools after 12 hours following the beginning of the treatment. Although the improvement was more remarkable in the ORS + gelatin tannate group, this difference was not statistically significant.

A reduction in the body temperature was observed in both groups of patients between the beginning and the end of the study, which was associated with the disappearance of the diarrheic symptoms.

No significant differences were found between the groups at the start and at the end of the treatment with regard to the rest of variables collected: presence of bloody diarrhea, weight of the patient, peritonitis, sepsis, presence of vomiting, or dehydration.

The initial treatment of acute diarrhea is based on several alternatives with a different degree of evidence: ORS, empirical antibiotic treatment, use of intestinal motility inhibitors such as loperamide, or use of substances that reduce water and electrolyte secretion, such as racecadotril (8).

Gelatin tannate is a mixture of tannic acid and gelatin with antidiarrheal effect. Gelatin tannate is also attributed antibacterial and antioxidant properties, which represents an advantageous property given that the use of conventional antibiotics in empirical therapy can contribute to the development of resistance and dysbacteriosis (9). Furthermore, unlike other antidiarrheal agents such as loperamide, it has no effects on the central nervous system, which allows its safe use in children under two years of age, and it has no undesirable effects, such as reactive constipation (10). No undesirable effects related to the use of gelatin tannate were registered during the treatment, and the product’s tolerance was excellent.

The efficacy and safety of a similar product in the treatment of acute diarrhea in pediatric patients were studied by Loeb and colleagues (11). The patients that were administered the product containing tannate reported a normalization in defecation, body temperature and weight, as well as a cessation of vomiting much faster than those that were administered placebo.

The results of this study are consistent with many other published clinical studies showing the efficacy and good safety profile of gelatin tannate.

Plein and colleagues studied the effect of tannate on diarrhea in patients suffering from Crohn’s disease (12). The results obtained showed that there was a significant reduction in stool frequency at the end of the treatment.

Another clinical experience was reported by Ziegenhagen and colleagues, who showed that the efficacy and safety profile of tannin salts was better than that of activated charcoal (13). Moreover, in the group that was administered tannin salts, the frequency of abdominal pain was lower than in the activated charcoal group (50% versus 82%).

Bellknap and colleagues conducted a study on the efficacy of gelatin in the prevention of diarrhea for hospitalized patients starting to receive enteral feeding by tube (14). Patients that were administered gelatin showed a significantly smaller number of liquid stools and a greater number of normal stools as compared to the group that was not administered the gelatin product.

The main limitation of this study is the lack of control in the distribution of variables among the two groups. The experience, however, is positive, shows that the addition of gelatin tannate to the treatment with ORS can reduce the duration of the antidiarrheal treatment, and provides sufficient data to consider the combination of ORS + gelatin tannate in the treatment of acute diarrhea in the pediatric population.

The treatment of acute diarrhea with ORS + gelatin tannate meets Edelman’s criteria (15) established for an ideal antidiarrheal treatment, given that it is effective, has a rapid onset of action, and has no undesirable effects. Furthermore, the addition of gelatin tannate to the conventional treatment with ORS represents an affordable incremental direct cost, which may be reduced given that this treatment enables a reduction in the quantity of ORS.

© Durban Laboratorios, 2011 | Legal notice