THE EFFECT OF THE SOMATOSTATIN ANALOGUE OCTREOTIDE ON EXPERIMENTAL INTESTINAL OBSTRUCTION IN RATS

Abstracts

Objetivo: A somatostatina tem efeito inibidor nas secreτ⌡es end≤crina e ex≤crina do intestino. Poderß ter efeito benΘfico no tratamento conservador da obstruτπo intestinal. O objetivo do presente estudo Θ investigar o efeito do octreotide na obstruτπo mecΓnica do intestino delgado de ratos. MΘtodo: A obstruτπo intestinal foi induzida em ratos pela ligadura do segmento distal do ileum. Os animais foram tratados com somatostatina anßloga octreotide (n=16) ou com soluτπo salina (n=16). Oito ratos foram operados mas o intestino delgado nπo foi ligado (n=8) servindo como o grupo sham. Quarenta oito horas ap≤s a operaτπo os animais foram re-operados e submetidos a colheita de sangue da veia femoral a fim de verificar os eletr≤litos, urΘia, glicose, ßcido lßtico, amilase, pH e bicarbonato. Obteve-se tambΘm amostra de sangue da veia porta para verificar os nφveis de ßcido lßtico e amilase. Resultados: Ap≤s 48 horas de obstruτπo houve intensa dilataτπo das alτas intestinais. Observou-se aumento significante dos nφveis plasmßticos de urΘia, amilase e ßcido lßtico. Diminuiu o pH plasmßtico. Observou-se aumento do ßcido lßtico no sangue portal, indicando acidose metab≤lica, provavelmente secundßria a isquemia intestinal. O tratamento com octreotide resultou em menos acidose, com nφveis baixos de urΘia e ßcido lßtico no plasma, e especialmente na veia porta. Conclusπo: O emprego de octreotide pode ter efeito benΘfico no tratamento conservador de casos selecionados de obstruτπo intestinal.

Somatostatina; Octreotide; Obstruo intestinal

THE EFFECT OF THE SOMATOSTATIN ANALOGUE OCTREOTIDE ON EXPERIMENTAL INTESTINAL OBSTRUCTION IN RATS ¹ Haim Paran ²

Tzahi Wider ²

Ami Mayo ²

David Neufeld ²

Sergio Susmalian ²

Ivan Shwartz ²

Uri Freund ³

PARAN, H.; WIDER, T.; MAYO, A.; NEUFELD, D.; SUSMALIAN, S.; SHWARTZ, I.; FREUND, U. - The effect of the somatostatin analogue octreotide on experimental intestinal obstruction in rats. Acta Cir.Bras., 13(4):207-11, 1998.

SUMMARY: Background: Somatostatin has an inhibitory effect on theendocrine and exocrine secretions of the gut. It may have a beneficial effect in the conservative treatment ofintestinal obstruction. The aim of the present study is to investigate the effect of octreotide in mechanicalintestinal obstruction in rats.Method: Intestinal obstruction was induced in rats by ligation of a segment of the distal ileum. Animals were treated with the somatostatin analogue octreotide (n=16), or saline (n=16). Eight rats were operated but their intestine was not ligated (n=8) serving as sham controls. Forty eight hours after the operation, the animals were operated upon again and blood samples from the femoral vein were tested for electrolytes, urea, glucose, lactic acid, amylase, ph and bicarbonate. Portal vein blood samples were also obtained and tested for lactic acid and amylase.Results: Intestinal obstruction resulted, after 48 hours, in severe dilatation of bowel loops. A significant increase in plasma levels of urea, amylase and lactic acid was observed. Plasma pH decreased. In blood samples from the portal vein, a significant increase in lactic acid was observed, indicating metabolic acidosis, probably secondary to bowel ischemia. Octreotide treatment, resulted in less acidosis, with concomitant lower urea and lactic acid levels in the plasma and especially in the portal vein.Conclusion: Octreotide treatment may have a beneficialeffect in the conservative treatment of selected cases ofintestinal obstruction.

SUBJECT HEADINGS: Somatostatin. Octreotide. Intestinal obstruction.

Somatostatin has a wide spectrum of gastrointestinal and endocrine actions, mainly inhibitory in nature¹. The somatostatin analogue octreotide has a half life of 3 hours, and less influence on insulin secretion than the native somatostatin. Both animal and human studies indicate that somatostatin decreases peristalsis by direct action on the myenteric plexus, and inhibition of V.I.P^2,3. Other studies have postulated that somatostatin promotes an abnormal peristaltic wave, which proved to be effective in the treatment of severe constipation secondary to scleroderma⁴ Somatostatin and its analogue octreotide also increases water and electrolyte absorption from the gut, and increases the intestinal wall compliance. A decreased intestinal fluid sequestration has also been described in experimental studies with these drugs⁵. The hormone also reduces the splanchnic blood flow without changing the cardiac output⁶.

The effect of octreotide in the treatment of intestinal obstruction, is currently being evaluated. The rationale for this treatment modality is based on the assumption that it has a beneficial effect by increasing intestinal compliance, and by promoting water and electrolyte absorption on the other. Its possible therapeutic effects include: a) less fluid sequestration in the gut with concomitant improved fluid and electrolyte balance; b) decreased intestinal damage secondary to edema and ischemia.

The present study was designed to further investigate theeffect of octreotide as treatment of experimental mechanical intestinal obstruction in rats.

METHOD

Male Wistar rats (250-350 grams) were studied. Animals were kept as outlined in the" Guide for the Care and use of Laboratory Animals" ( NIH Publication #85-23, 1985). General anesthesia was induced by intraperitoneal injection of 70 mg/kg of ketamine hydrochloride. Additional anesthesia was induced, when needed, by repeated intramuscular injections into the thigh of small doses of ketamine hydrochloride. The left femoral vein was cannulated through a small incision in the left thigh with a 20G PFTE catheter (Venflon, Helsingborg, Sweden). The abdominal wall was shaved and a midline laparotomy was performed. The intestine was brought out through the incision. The terminal ileum was tied with a silk ligature, and the abdomen was closed. After the operation, the animals were kept in unrestraining cages (four animals each) and allowed only water ad libitum.

The animals were divided into 3 main groups:

Group 1: (n= 8) Were sham controls, they were operated upon, but the intestine was not tied.

Group 2: (n= 16) Were operated upon and the terminal ileumÓ tied. They were treated only by saline administered subcutaneously in the same fashion as octreotide (v/v) serving as a control group.

Group 3: (n= 16) After the terminal ileum was tied, the3: animals were treated with octreotide given subcutaneously every 8 hours (10 ugr/kg, t.i.d).

Blood samples were obtained from the catheter in the femoral vein immediately before, and 48 hours after the operation and tested for glucose, electrolytes, urea, amylase, lactic acid, pH, base excess and bicarbonate.

Forty eight hours after the first operation, the animals were operated upon again. A portal vein blood sample was then obtained and tested for electrolytes, glucose and lactic acid.

STATISTICAL ANALYSIS:

Results are expressed as mean + standard deviation.QQ

Non-paired T test and non-parametric test (SPSS,SPSS inc.software, USA) were used.

RESULTS

No mortality occurred after 48 hours,in any of the animals® of all 4 groups, but for a single animal in group 3, which died 12 hours after the operation. This animal was found to have a volvulus of the distal small intestine as well of the proximal colon. The volvulus was related to the way the intestine was placed back in to the abdominal cavity.

Forty eight hours after the operation, severe dilatation® of the small intestine was found in all the animals with the obstruction (groups 2 and 3), while it had a normal appearance in the sham operated rats (group 1).

Glucose levels increased in all three groups, with no difference between them. No significant changes were detected in the sodium, chloride or calcium plasma levels of all three groups.

Intestinal obstruction (group 2) resulted in a moderate increase in the plasma amylase levels after 48 hours (fig.1), as expressed by a significant difference between sham controls (group 1) and animals with intestinal obstruction (group 2): 885+350U/l versus 1485+550U/l (p=0.006). TT Significant differences between groups 1 and 2 were also observed in plasma urea levels 34.9+7.7mg% versus 60.6+28.5mg%, p=0.003 (fig.2) and plasma lactic acid levels (11.9+4.9mg% versus 33.1+27.1mg%, p=0.01)(fig.3). Metabolic acidosis was also observed 48 hours after intestinal obstruction, as demonstrated by a lower pH, 7.291+0.216 versus 7.359+0.034, and lower base excess and bicarbonate levels, although these did not reach statistical significance. Higher amylase and lactate levels (group 2 compared to group 1) were also observed in the portal venous blood. Portal venous amylase levels (fig.4) were 1637+793U/l and 835+282U/l, respectively p=0.012, and lactate levels (fig.5) were 29.9+12.6mg% and 20.3+5.4mg%, respectively p=0.07.

Fig. 1: Intestinal obstruction resulted after 48 hours in an increase in plasma amylase levels (p=0.006). Treatment with octreotide had no effect in plasma amylase levels.

Fig. 2: Plasma urea increased 48 hours after the induction of intestinal obstruction (p=0.003). Treatment with octreotide attenuated the increase in plasma urea levels. Plasma urea levels were lower then in untreated rats (p=0.03), but still higher than in sham controls (p=0.05).

Fig. 3: Plasma lactic acid levels increased 48 hours after intestinal obstruction induction (p=0.01). A small decrease in plasma lactic acid was observed (N.S.).

Fig. 4: Portal vein amylase levels increased 48 hours after intestinal obstruction induction (p=0.012). Octreotide treatment resulted in small decrease in the portal vein amylase levels (N.S.).

Fig. 5: Portal vein lactic acid increase 48 hours after intestinal obstruction induction (p=0.07). Octreotide treatment prevented the increase in the portal vein lactate levels. Portal vein lactate levels in the treated rats were lower than in the untreated animals (p=0.05), and unchanged from the sham controls (p=0.9).

Treatment with octreotide (group 3) attenuated the increase in urea (fig.2) and lactate (fig 3), but did not affect the amylase levels in the systemic plasma (fig.1). The plasma urea level was significantly lower when compared to the level in untreated rats (43.5+9.2mg% versus 60.6+28.5mg%, gg p=0.03) but higher than in the sham controls (43.5+9.2mg%ee versus 34.9+7.7mg%, p=0.05). The plasma lactate level in theÓ treated animals was lower than in the untreated rats (20.5+8.9mg% versus 33.1+27.1mg%, N.S.), but also higher than in sham controls (20.5+8.9mg% versus 11.9+4.9mg%, p=0.03).

Octreotide also attenuated the metabolic acidosis, but againwith no statistical significance. The plasma pH of the treated rats (group 3) was 7.373+0.05, while in the untreated animals (group 2) it was 7.291+0.21, p=0.2. The base excess and bicarbonate where also slightly higher in the treated animals (N.S.).

The effect of octreotide on the portal venous lactate levels was more pronounced (fig.5). The lactate level (20.6+8.5mg%) was lower than in the untreated rats, (29.9+12.6mg%) p=0.09 and unchanged from the sham controls (20.3+5.4mg%), p=0.9.Ë

fig.4

DISCUSSION

Small bowel obstruction in the adult patient is usually due to mechanical reasons such as post-operative adhesions, herniations or cancerous conditions in the peritoneal cavity⁷. In cases of herniations or cancer, immediate surgery is indicated. Up to 80% of adhesions induced, simple small bowel obstruction will resolve spontaneously, with aggressive conservative treatment, without the need of another operation⁸. The treatment consists of naso-gastric or naso-intestinal tube decompression and aggressive fluid and electrolyte replacement. Watchful follow up, for signs of strangulation, closed loop obstruction, or perforation is essential, in which case, prompt surgery is mandatory⁹.

Somatostatin has a strong inhibitory effect on the exocrine secretions of the stomach, pancreas and small intestine. It promotes the absorption of water and electrolytes, thus reducing fluid sequestration. It also inhibits the normal peristalsis, and increases the bowel compliance^10,11.

In view of these properties, it is reasonable to expect a beneficial effect from the somatostatin analogue octreotide in the treatment of simple small bowel obstruction, when the conservative treatment is chosen. Indeed, in the present experimental study, octreotide treatment reduced urea levels in the peripheral blood, and also prevented metabolic acidosis, as reflected by an increase in pH, and decreased lactate levels. Since lactic acid produced by the intestine is mainly drained into the venous portal system, we also measured lactic acid levels in the portal venous blood, where it is a direct indicator of the metabolism of the bowel. In the portal venous blood, treatment with octreotide prevented the increase in lactic acid levels observed in untreated animals, indicating an improved metabolism.

Some previous studies have demonstrated a possible beneficial effect of somatostatin in the treatment of intestinal obstruction^12,13,14,15 and its use in terminally ill patients as a palliative agent has also been advocated^16,17.

The results of the present study suggest that the somatostatin analogue octreotide may have a beneficial effect in the conservative treatment of selected cases of intestinal obstruction.

REFERENCES

N. Engl. J. Med,309:

2. O'DONNELL, L.J.D.; FARTHING, M.J.G. - Therapeutic potential of a long acting somatostatin analogue in gastrointestinal diseases. Gut, 30:1165-72, 1989.

3. NELLGARD, P.; BOJO, L.; CASSUTO, J. - Importance of vasoactive intestinal peptide and somatostatin for fluid losses in small bowel obstruction. Scand. J. Gastroenterol,, 30(5):464-9, 1995.

4. EMMERICH, J.; ROUX, M.E.; CAPRON, L.; FIESSINGER, J.N. - Treatment with octreotide for functional obstructions in scleroderma. Presse Med.,21 (7):316-7, 1992.

5. YAMANER, S.; BUGRA, D.; MUSLUMANOGLU, M.P.; BULUT, T.; CUBUKCU, O.; ADEMOGLU, E. - Effect of octreotide on healing of intestinal anastomosis following smallbowel obstruction in rats. Dis.Colon Rectum, 38 (3):308-12, 1995.

6. HURST, R.D.; MODLIN, I.M. - The therapeutic role of octreotide in the management of surgical disorders. Am. J. Surg., 162:499-507, 1991.

7. BROLIN, R.E. - Partial small bowel obstruction. Surgery, 95:145-8, 1984.

8. RICHARDS, W.O.; WILLIAMS, L.F. - Obstruction of the large and small intestine. Surg. Clin. North Am., 68:355-62, 1988.

9. WANGENSTEEN, O.H. - Understanding the bowel obstruction problem. Am. J. Surg., 135:131-9, 1978.

10. LAYER, P.; HOLTMANN, G. - Octreotide in intestinal pseudo-obstruction? Z. Gastroenterol.,30 (5):346-7, 1992.

11. ROSSOWSKY, W.J.; ERTAN, A.; RICE, J.; OZDEN, A.; COVINGTON, S.; MCCORD, R.- Alterations in cholinergic muscarinic and somatostatin binding sites in a patient with idiopathic intestinal pseudo-obstruction. Am. J. Med. Sci.,296 (6):399-405, 1988.

12. BASTOUNIS, E.; HADJINIKOLAOU, L.; IONNOU, N.; Papastamatiou M, Toumbis E, Makri G. - Somatostatin as adjuvant therapy in the management of obstructive ileus. Hepatogastroenterology, 36(6):538-9, 1989.

13. JIMENEZ, G.A.; AHMAD, A.O.; BALONGO, G.R.; NOGALES, M.A.; SALGUEIRO, V.M.; CANTILLANA, M.J. - Action de la somatostatine 14 dans l'oclusion mecanique simple de l'intestine grele. J. Chir., 131:104-10, 1994.

14. GITTES, G.K.; NELSON, M.T.; DEBAS, H.T.; MULVIHILL, S.J.- Improvement in survival of mice with proximal small bowel obstruction treated with octreotide. Am. J. Surg., 163 (2):231-3, 1992.

15. MULVIHILL, S.J.; PAPPAS, T.N.; FONKALSCRUD, E.W.; DEBAS, H.T. - The effect of somatostatin on experimental intestinal obstruction. Ann. Surg., 207 (20):169-73, 1988.

16. KHOO, D.; RILEY, J.; WAXMAN, J. - Control of emesis in bowel obstruction in terminally ill patients. Lancet, 339(8789):375-6, 1992.

17. KHOO, D.; HALL, E.; MOTSON, R.; RILEY, J.; DENMAN, K.; WAXMAN, J.- Palliation of malignant intestinal obstruction using octreotide. Eur. J. Cancer, 30A:28-30, 1994.

Supported in part by the Nickols and Elizabeth Slezac grant from the Tel-Aviv University

PARAN, H.; WIDER, T.; MAYO, A.; NEUFELD, D.; SUSMALIAN, S.; SHWARTZ, I.; FREUND, U.- O efeito da somatostatina análoga octreotide na obstrução intestinal experimental em ratos. Acta Cir.Bras., 13(4):207-11, 1998.

RESUMO: Objetivo: A somatostatina tem efeito inibidor nas secretções endócrina e exócrina do intestino. Poderá ter efeito benéfico no tratamento conservador da obstrutpo intestinal. O objetivo do presente estudo é investigar o efeito do octreotide na obstrução mecânica do intestino delgado de ratos. Método: A obstrução intestinal foi induzida em ratos pela ligadura do segmento distal do ileum. Os animais foram tratados com somatostatina análoga octreotide (n=16) ou com solução salina (n=16). Oito ratos foram operados mas o intestino delgado não foi ligado (n=8) servindo como o grupo sham. Quarenta oito horas após a operação os animais foram re-operados e submetidos a colheita de sangue da veia femoral a fim de verificar os eletrólitos, uréia, glicose, ácido lático, amilase, pH e bicarbonato. Obteve-se também amostra de sangue da veia porta para verificar os níveis de ácido lático e amilase. Resultados: Após 48 horas de obstrução houve intensa dilatação das alças intestinais. Observou-se aumento significante dos níveis plasmóticos de uréia, amilase e ácido lático. Diminuiu o pH plasmático. Observou-se aumento do ácido lático no sangue portal, indicando acidose metabólica, provavelmente secundária a isquemia intestinal. O tratamento com octreotide resultou em menos acidose, com níveis baixos de uréia e ácido lático no plasma, e especialmente na veia porta. Conclusão: O emprego de octreotide pode ter efeito benéfico no tratamento conservador de casos selecionados de obstrução intestinal.

DESCRITORES: Somatostatina. Octreotide. Obstrutpo intestinal.

Address for correspondence:

Haim Paran MD

Dept. of Surgery 'A' Meir Hospital,

Kfar-Sava, Israel

TEL: [phone]

FAX: [phone]

e-mail: [e-mail]

Accepted for publication June 25, 1998.

• 1. REICHLIN, S. - Somatostatin. N. Engl. J. Med,309:1556-63, 1983;
• 2. O'DONNELL, L.J.D.; FARTHING, M.J.G. - Therapeutic potential of a long acting somatostatin analogue in gastrointestinal diseases. Gut, 30:1165-72, 1989.
• 3. NELLGARD, P.; BOJO, L.; CASSUTO, J. - Importance of vasoactive intestinal peptide and somatostatin for fluid losses in small bowel obstruction. Scand. J. Gastroenterol,, 30(5):464-9, 1995.
• 6. HURST, R.D.; MODLIN, I.M. - The therapeutic role of octreotide in the management of surgical disorders. Am. J. Surg., 162:499-507, 1991.
• 7. BROLIN, R.E. - Partial small bowel obstruction. Surgery, 95:145-8, 1984.
• 8. RICHARDS, W.O.; WILLIAMS, L.F. - Obstruction of the large and small intestine. Surg. Clin. North Am., 68:355-62, 1988.
• 9. WANGENSTEEN, O.H. - Understanding the bowel obstruction problem. Am. J. Surg., 135:131-9, 1978.
• 10. LAYER, P.; HOLTMANN, G. - Octreotide in intestinal pseudo-obstruction? Z. Gastroenterol.,30 (5):346-7, 1992.
• 11. ROSSOWSKY, W.J.; ERTAN, A.; RICE, J.; OZDEN, A.; COVINGTON, S.; MCCORD, R.- Alterations in cholinergic muscarinic and somatostatin binding sites in a patient with idiopathic intestinal pseudo-obstruction. Am. J. Med. Sci.,296 (6):399-405, 1988.
• 12. BASTOUNIS, E.; HADJINIKOLAOU, L.; IONNOU, N.; Papastamatiou M, Toumbis E, Makri G. - Somatostatin as adjuvant therapy in the management of obstructive ileus. Hepatogastroenterology, 36(6):538-9, 1989.
• 13. JIMENEZ, G.A.; AHMAD, A.O.; BALONGO, G.R.; NOGALES, M.A.; SALGUEIRO, V.M.; CANTILLANA, M.J. - Action de la somatostatine 14 dans l'oclusion mecanique simple de l'intestine grele. J. Chir., 131:104-10, 1994.
• 14. GITTES, G.K.; NELSON, M.T.; DEBAS, H.T.; MULVIHILL, S.J.- Improvement in survival of mice with proximal small bowel obstruction treated with octreotide. Am. J. Surg., 163 (2):231-3, 1992.
• 15. MULVIHILL, S.J.; PAPPAS, T.N.; FONKALSCRUD, E.W.; DEBAS, H.T. - The effect of somatostatin on experimental intestinal obstruction. Ann. Surg., 207 (20):169-73, 1988.
• 16. KHOO, D.; RILEY, J.; WAXMAN, J. - Control of emesis in bowel obstruction in terminally ill patients. Lancet, 339(8789):375-6, 1992.
• 17. KHOO, D.; HALL, E.; MOTSON, R.; RILEY, J.; DENMAN, K.; WAXMAN, J.- Palliation of malignant intestinal obstruction using octreotide. Eur. J. Cancer, 30A:28-30, 1994.

¹ - Article from the Department of Surgery A, Meir Hospital, Kfar-Sava, Israel. Affiliated to the Sackler School of Medicine, Tel-Aviv University

- Article from the Department of Surgery A, Meir Hospital, Kfar-Sava, Israel. Affiliated to the Sackler School of Medicine, Tel-Aviv University

² - MD

³ - MD/FACS

Publication Dates

• Publication in this collection
  14 Jan 1999
• Date of issue
  Oct 1998