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The American Journal of Surgery 181 (2001) 512–515 Effects of diphenhydramine HCl and methylprednisolone in

The American Journal of Surgery 181 (2001) 512–515

The American Journal of Surgery 181 (2001) 512–515 Effects of diphenhydramine HCl and methylprednisolone in the

Effects of diphenhydramine HCl and methylprednisolone in the prevention of abdominal adhesions

Fatih Mehmet Avsar, M.D. a, *, Mustafa Sahin, M.D. b , Faruk Aksoy, M.D. b , A. Filiz Avsar, M.D. c, , Mehmet Ako¨z, M.D. d , Su¨leyman Hengirmen, M.D. a , Sami Bilici, M.D. b

a Ankara Numune Training Research and Hospital, Clinic of 1st Surgery, Ankara, Turkey b Department of General Surgery, Faculty of Medicine, Selcuk University, Konya, Turkey c Zekai Tahir Burak Maternity Hospital, Ankara, Turkey d Department of Biochemistry, Faculty of Medicine, Selcuk University, Konya, Turkey

Manuscript received August 11, 2000; revised manuscript January 2, 2001

Abstract

Objective: The purpose of this study was to determine the effects of diphenhydramine hydrochloride and methylprednisolone in peritoneal adhesions. Materials and methods: Forty-eight male rats were used in the study. The rats were anesthetized by 5 mg/kg ketamine hydrochloride. After opening the abdomen, 10 longitudinal incisions of 2 to 3 cm in length were made on the right parietal peritoneum, and a 2 cm 2 peritoneal layer was excised from the left abdominal wall. The abdomen was closed with 3/0 silk suture. Group I was the control group, group II was given 10 mg/kg diphenhydramine intravenously, group III was given 20 mg/kg methylprednisolone intravenously, and group IV was administered both of the drugs in the above doses. A blood sample of 2 mL was taken from the rats on the 14th day after the operation. The animals were then sacrificed. The abdomen was opened and abdominal adhesions were examined. A tissue sample of 1 g was taken from the abdominal incision line. Albumin, zinc, and hemoglobin levels and leucocyte counts in the blood were determined as well as hydroxyproline levels in the tissue. Results: Numbers of adhesions were as follows: 9 in group I, 3 in group II, and 2 in group III. No adhesion was observed in group IV. Albumin, zinc, and hemoglobin levels and leucocyte counts were found to be similar in all groups. Hydroxyproline levels in the tissue were significantly lower in groups III and IV than in groups I and II (P 0.05). Conclusions: Diphenhydramine and methylprednisolone reduced postoperative adhesions significantly in rats. Further investigations are needed in order to use these drugs as antiadhesive agents in humans. © 2001 Excerpta Medica, Inc. All rights reserved.

Keywords: Postoperative adhesion; Ileus; Infertility; Diphenhydramine hydrochloride; Methylprednisolone; Hydroxyprolone

Peritoneal adhesions develop in the majority of the patients who have undergone an abdominal operation for various reasons. Such adhesions are among important causes of mechanic intestinal obstruction in clinics of general surgery, and of infertility in clinics of gynecology and obstetrics

[1–3].

It was reported that 67% of the patients who had under- gone an abdominal operation later developed adhesions [4],

* Corresponding author. Dr. Fatih Mehmet Avsar, Mesrutiyet Cad. 28/6, 06640 Kocatepe, Ankara, Turkey. Tel.: 90.312.4182410; fax:

90.312.4182760. E-mail address: fatihmehmet@superonline.com, avsar59@hotmail. com.

and 3% to 8% of the cases resulting from these adhesions were operated on [5]. It is argued that among the causes of ileus in various clinical series, peritoneal adhesions hold the first rank, and that ileus occurs more frequently after pelvic operations [1,6]. Injuries on peritoneal surfaces and existence of ischemic lesions play an important role in abdominal adhesions. For- eign bodies such as talc powder and suture materials, infec- tions and intestinal leakage are also important [5,7–12]. Histamine, which is released by mast cells immediately after injuries in peritoneal surfaces, causes vasodilatation and an exudation enriched in protein [5,7,13]. This exudate constitutes the base of adhesions. It has been argued that blocking histamine release and preventing its effects by

0002-9610/01/$ – see front matter © 2001 Excerpta Medica, Inc. All rights reserved. PII: S0002-9610(01)00617-1

F.M. Avsar et al. / The American Journal of Surgery 181 (2001) 512–515

Table 1 Serological, hematological, and tissue parameters investigated in the study groups

513

Groups

I

II

III

IV

Albumin, g/dL 1 Zinc, g/dL 2 Hemoglobin, g/dL 3 Leucocyte/mm 4 Hydroxyproline, g/mg wet tissue 5

3.83 0.30 90.6 10.9 12.4 1.2 6.01 0.82 3.23 0.27

3.88 0.28 88.5 13.8 12.4 1.6 6.02 0.91 3.24 0.25

3.95 0.41 90.8 15.8 12.1 1.2 6.39 0.85 2.58 0.37

3.92 0.27 87.6 11.4 12.2 1.4 6.10 0.86 2.50 0.30

1 P 0.799; 2 P 0.916; 3 P 0.949; 4 P 0.648; 5 P 0.000.

using steroids reduces or eliminates peritoneal adhesions, which still constitute serious surgical problems [11,13,14]. This study was carried out to investigate separate and combined effects of diphenhydramine hydrochloride and methylprednisolone on the prevention of peritoneal adhe- sions.

Materials and methods

This study was performed in the Experimental Surgical

Research Center, Selcuk University, Konya, Turkey, with

the permission of the Ethics Committee of Selcuk Univer-

sity. Animal rights oversight rules provided by Turkish laws were followed in the study. Forty-eight male rats of the Wistar-Albino type were used in the study. Their average weight was 215 20 g. The animals were divided into 4 groups, each with 12 rats.

All the rats were fed standard rat diet, and were kept hungry

on the eve of the experiment. The animals were anesthetized by administration of 5 mg/kg ketamine hydrochloride subcutaneously. The abdo-

men was opened by a midline incision of approximately 4

cm in length. Ten longitudinal incisions of 2 to 3 cm in

length were made on the peritoneal surface of the right abdominal wall, and a peritoneal section of 2 cm 2 was excised from the inside of the left abdominal wall. The abdomen was closed with 3/0 atraumatic continuous silk sutures. The groups were as follows: group I was the control group; group II was given 10 mg/kg diphenhydramine hy- drochloride; group III was given 20 mg/kg methylpred- nisolone; and group IV was administered 10 mg/kg diphen- hydramine plus 20 mg/kg methylprednisolone. The drugs were administered just before the operation from the tail vein.

After the operation, all rats were placed into their cages

and allowed tap water and rat pellets ad libitum for 14 days.

They were kept under controlled temperature (in 22°C), humidity and lighting (12-hour light-dark cycle) during this

period (following the Guide for the Care and Use of Lab- oratory Animals, 1988). The subjects were reanesthetized with 5 mg/kg ketamine after 14 days of the operation. A blood sample of 2 mL was taken by cardiac puncture from the rats for biologic and

hemathologic analysis. The abdomen was opened from the previous incision line. Right and left abdominal walls and the incision line were investigated with regard to formation of adhesions. The number of subjects having adhesions and the grade of adhesions were assessed. The scoring method developed by Granat et al [15] was used in the grading. In order to determine tissue hydroxyproline levels, 1-g tissue samples were taken from the incision line on the abdominal wall. The samples were preserved in the deep freeze until examination. We used the method described by Bergman and Loxley [16,17] in the measurements of tissue hy- droxyproline levels. Statistical analysis of biochemical and hematologic pa- rameters was made according to the Mann-Whitney U test. The chi-square test was used in the comparison of grades of adhesion. Values of P 0.05 were taken as significant in statistical evaluations.

Results

Zinc and albumin levels studied in the sera, hemoglobin levels and leukocyte counts found in blood, and hy- droxyproline levels measured in tissue are given in Table 1. No significant differences among the groups were found with regard to zinc, albumin, and hemoglobin levels and leucocyte counts. In the comparison of hydroxyproline lev- els measured in the tissue among the groups, it was found that the levels of group III and group IV, which were administered methylprednisolone, were lower than that of the control group and group II, which was administered diphenhydramine HCl alone (P 0.05). Number of formations and grades of abdominal adhe- sions are presented in Table 2. Although adhesions were observed in 9 rats in the control group, in 3 rats in group II, and in 2 rats in group III, no adhesions were observed in group IV. It was found that frequencies and grades of adhesions in the groups that had been administered the drugs decreased significantly in comparison with the control group (P 0.05).

Comments

Abdominal adhesions occurring during the postoperative period still constitute a serious problem in general surgery

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F.M. Avsar et al. / The American Journal of Surgery 181 (2001) 512–515

Table 2 Grading of the adhesions and the number of rats that had adhesion

Grade

Group I n 12

Group II n 12

Group III n 12

Group IV n 12

0

3

9

10

12

I2

2

1

0

II

4

1

1

0

III

2

0

0

0

IV

1

0

0

0

Total

9

3

2

0

Grade 0 no adhesion; I thin, filamentous, easily separated adhe- sions; II thick adhesions in a limited area; III widespread thick adhesions; IV III plus adherence of visceral organs to the abdominal wall [15].

and obstetrics and gynecology due to high morbidity and mortality rates associated with them. Approximately 3% to 8% of patients who have undergone an abdominal operation for various reasons are reoperated on for adhesive intestinal obstruction at some point in their lives [5]. Repeating lap- arotomies, pelvic operations, and inflammatory diseases such as acute appendicitis, salpingitis, and intestinal perfo- rations increase the risk of adhesion formation, and adhe- sion ratio is reported to be very high among patients having relaparotomy [6]. Peritoneal adhesions are classified into three catego- ries—congenital, inflammatory, and postoperative adhe- sions—according to their mechanisms of formation. Con- genital adhesions have not been covered by our study. Several mechanisms have been proposed for the develop- ment of inflammatory and postoperative adhesions, and many factors have been described. Of these factors, the most important ones are peritoneal injuries, infections, and foreign bodies left within the abdominal cavity [5,7,10,18]. Also, ischemic lesions formed on peritoneal surfaces are accepted as one of the most important factors in adhesion formation [5,8,12]. In this study, induced peritoneal injury was taken as a model, and treatment of pathophysiologic events developing upon peritoneal injury was planned. Clinical and experimental studies show that the fre- quency of adhesion development after abdominal operations is very high. A most definitive work made on postoperative adhesion frequency is the postmortem study carried out by Weibel et al [4] on a large cadaver series. Frequency of adhesion in the cadavers, which had undergone previous abdominal operation for various reasons, was determined to be 67% in their work. In our study, this figure was found to be similar, at 75%, in the control group. Most of the studies associated with adhesion have been performed with animal models. Nevertheless, the literature contains a few clinical studies. Jansen’s work [2] could be taken as an outstanding example in this respect. In that study, mechanical barriers were used in order to prevent adhesion formation in young women undergoing gyneco- logic surgery, and their effects were examined at regular

intervals laparoscopically. The type of the study rather than its results seems most interesting. Several treatment modalities and agents have been pro- posed along with protective measures to prevent postoper- ative abdominal adhesions [5,9,11]. However, it is not pos- sible to prevent formation of adhesions completely. Agents used for this purpose may be divided mainly into two groups as having local and systemic effects [9]. Locally applied agents prevent formation of adhesion by blocking the contact between peritoneal surfaces or by their fibrino- lytic effects. Systemic agents have more complex effects in the prevention of adhesions. Because locally applied agents have limited effects and cause complications, their use is restricted [9]. That the size of peritoneal surface is too large and that such agents are removed from the peritoneum quickly constitute their most serious disadvantages. Injuries occurring in on peritoneum surface play an im- portant role in the development of postoperative adhesions. Histamine released from mast cells after the injury causes vasodilatation and increases vascular permeability. As a result of such changes, a liquid rich in protein passes to the peritoneal cavity. The coagulum formed in this liquid causes adhesion of peritoneal surfaces to each other [7]. Fibroblasts, starting from the first day, by synthesizing col- lagen cause the adhesions to mature [18]. Antihistamines applied by the systemic route have been reported to prevent development of adhesion by reducing vasodilatation and vascular permeability, and corticoste- roids have also been reported to have the same effect by decreasing vascular permeability by their antiinflammatory effects and by stopping cell proliferation and collagen syn- thesis [13,18,19]. It was also found in our study that di- phenhydramine, an antihistaminic agent, and methylpred- nisolone prevented peritoneal adhesions significantly. When the two agents were used together, their effects increased even more. Kappas et al [19] have investigated the effects of sys- temic and local corticosteroids on the development of ad- hesions and have found that steroids administered system- ically decreased formation of adhesion significantly. While there are other works indicating corticosteroids may be applied as antiadhesive agents, side effects of these drugs have also been emphasized [9,11,15]. Although it has been proposed that antihistaminics may be used as antiadhesives [9,13,15], the literature does not contain a sufficient number of studies on the subject. When the chain of pathologic events occurring after peritoneal injury is taken into account, it is understood that histamine plays an important role in the formation of adhe- sion [7]. Blocking this substance with antihistamines and thus preventing formation of adhesion seems to be very reasonable. Very similar results were obtained in the anti- histaminic group and in the corticosteroid group in our study. In addition, antihistamines have the advantage in that they have no side effects, they do not have the immune suppressive effects that steroids have, and they do not im-

F.M. Avsar et al. / The American Journal of Surgery 181 (2001) 512–515

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pair injury healing. The decreased hydroxyproline levels in the groups given steroids show that healing is adversely affected by steroids. Hydroxyproline is a product formed from destruction of collagen, and it is a sign of injury healing [14,18]. In our study, the levels of hydroxyproline in the antihistamine-treated group were found to be unaf- fected. Gazzaniga et al [13] have shown in their experimen- tal work carried out on rats that antihistaminics have pre- vented formation of adhesions more efficiently than steroids have done. In addition, they have obtained better results in the groups with combined antihistamines and steroids, which is similar to our results. We conclude that the use of antihistamines and steroids separately or in combination in abdominal, abdominopelvic, and gynecologic operations will reduce the rate of postop- erative adhesions and related complications. We believe that these drugs will have an important role in the preven- tion of peritoneal adhesions, especially among patients at high risk for peritoneal adhesion.

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