Allopurinol as prophylaxis against pouchitis following ileal pouch-anal anastomosis for ulcerative colitis. A randomized placebo-controlled double-blind study.

BACKGROUND: Pouchitis is the major long-term complication of restorative proctocolectomy for ulcerative colitis (UC). Allopurinol is a scavenger of oxygen-derived free radicals, which it is suggested play a role in the development of UC and pouchitis. The first aim was to test the hypothesis that the incidence of pouchitis can be reduced by prophylactic Allopurinol, and secondly to evaluate if Allopurinol influences the overall pouch function. METHODS: 273 patients with UC who were planned for proctocolectomy and ileal pouch-anal anastomosis at 12 centres in Sweden between October 1994 and June 1997 were offered the opportunity to participate. 184 patients (67%) were randomized to receive postoperative prophylactic Allopurinol 100 mg twice daily or placebo. All 273 patients had clinical and endoscopic follow-up at 1, 3, 6, 12, 18, 24 months after surgery. RESULTS: Of the 184 randomized patients, 94 were randomized to Allopurinol and 90 to placebo; 116 patients (63%) completed follow-up and the crude incidence of pouchitis among those patients fullfilling the protocol was 31% in the Allopurinol group and 28% in the placebo group (ns). The cumulative risk for a first attack of pouchitis was 30% and 26% after 24 months (ns). The overall pouch function improved over time and did not differ significantly between the two groups. CONCLUSIONS: Prophylactic Allopurinol did not reduce the risk of a first attack of pouchitis.

Neuropeptides in idiopathic chronic constipation (slow transit constipation).

Tissue specimens from the large bowel of 18 patients with long-standing slow transit constipation were investigated to determine the distribution and density of several neuropeptides and amines in the enteric nerve system, and also of endocrine cells in comparison to normal individuals. CGRP (calcitonin gene-related peptide), galanin, glucagon, GRP (gastrin-releasing peptide), metenkephalin, motilin, neuropeptide Y (NPY), PACAP, peptide YY (PYY), serotonin, somatostatin, substance P and VIP were studied by immunohistochemistry. Tissue concentrations of VIP, substance P and galanin were also measured by radioimmunoassay. Significantly increased VIP, SP and galanin contents were found in specimens from the ascending colon. Levels of VIP and galanin were also increased in the transverse colon. Immunohistochemistry revealed only marginal changes with an increased density of PACAP nerve fibres in the smooth muscle and of VIP and PACAP nerves in the myenteric plexus of the transverse colon. In the descending colon substance P and NPY immunoreactivity were also increased in the myenteric plexus while the density of VIP nerve fibres was reduced in the mucosa/submucosa. The frequency of PYY-containing cells and the 5-HT-containing cells in the ascending colon was significantly increased in the constipated patients.

Experimental colonic healing in relation to timing of 5-fluorouracil therapy.

In an experimental study resembling clinical use of adjuvant 5-fluorouracil (5-FU) treatment of colorectal carcinoma, 97 male Wistar rats were operated on with a standardized left colonic resection. Treatment was given as a daily intraperitoneal injection. The animals were randomized to one of four groups: early treatment with 5-FU 20 mg/kg or saline 0.1 mol/l from the day of operation to day 7 after operation, and delayed treatment with 5-FU 20 mg/kg or saline 0.1 mol/l from the third day after operation to the day before killing. The animals were killed in groups on day 7 or 10 after operation. In the group receiving early 5-FU treatment there was an increased rate of anastomotic complications (seven of 26) compared with none in the control or delayed 5-FU groups. The anastomotic breaking strength in animals having early 5-FU treatment (day 7, median 1.45 (range 0.20-2.95) N; day 10, median 1.80 (range 0.95-3.20) N) was significantly lower than that in controls on both day 7 (median 3.20 (range 2.50-3.80)N) and day 10 (median 3.20 (range 2.20-3.60)N). In the delayed 5-FU treatment group anastomotic breaking strength did not differ from that in controls. Colonic healing was not impaired when intraperitoneal 5-FU treatment was started on day 3 after operation, whereas immediate postoperative administration of 5-FU had a detrimental effect on wound healing.

The roles of nutritional depletion and drug concentration in 5-fluorouracil-induced inhibition of colonic healing.

This study was performed to investigate whether poor nutrition is responsible for 5-fluorouracil (5-FU)-induced inhibition of large bowel healing and if the concentration of intraperitoneal (ip) 5-FU affects anastomotic healing. Male Wistar rats underwent a left colonic resection and were randomly assigned to a control group (n = 9, ip NaCl, normal diet), a nutritional depletion group (n = 12, ip NaCl, restricted diet), or a 5-FU group (n = 12, ip 5-FU, normal diet). Treatment was started immediately after surgery and continued until sacrifice after 7 days. Although the weight loss in the nutritional depletion group exceeded that in the 5-FU group, the anastomotic and skin breaking strength was lower in the latter group compared with that in the former group (P < 0.01 and P < 0.05, respectively). There were no significant differences in breaking strength between the nutritional depletion group and controls. A second series of male Wistar rats were similarly operated on and randomly assigned to a control group (n = 6, ip NaCl), a 5-FU high-concentration group (n = 10, (5 mg/ml ip 5-FU) or a 5-FU low-concentration group (n = 10, (1 mg/ml ip 5-FU). The 5-FU dose was the same in the two latter groups. The anastomotic breaking strength on Day 7 was reduced to a similar extent in the 5-FU groups (P < 0.01). These results indicate that the impaired anastomotic healing after ip 5-FU is not mainly due to nutritional factors or drug concentration.

The effect of 5-fluorouracil on wound healing and collagen synthesis in left colon anastomoses. An experimental study in the rat.

In an experimental study resembling clinical use of adjuvant 5-fluorouracil (5-FU) treatment of colorectal carcinoma 86 male Wistar rats were operated with a standardized left colon resection and anastomosis with interrupted sutures. Treatment was given as daily intraperitoneal (i.p.) injections. The animals were randomized to one of two groups: (A) 5-FU (20 mg/kg) i.p., and (B) NaCl i.p. from the day of operation to sacrifice. Anastomotic complications were registered. In experiment 1 animals were randomized within treatment groups to be tested for anastomotic breaking strength with or without sutures in place when sacrificed 7 days postoperatively. In experiment 2 collagen synthesis was studied by an in vivo incorporation and hydroxylation of 3H-proline in the anastomotic segment during 24 h prior to sacrifice. The animals were sacrificed in groups on the third or seventh postoperative day. A higher number of anastomotic complications was registered when 5-FU was given. The anastomotic breaking strength was only 40% of controls both when tested with and without sutures. A reduced radioactivity of 3H-hydroxyproline in the anastomotic segment after 7 days of 5-FU treatment was found implying a reduction in collagen synthesis. In our model colonic healing was impaired after i.p. 5-FU treatment and this could be attributed to a reduced collagen synthesis in the wound gap as well as in the adjacent tissue responsible for the suture-holding capacity.

Preoperative irradiation and colonic healing.

OBJECTIVE: To find out if preoperative irradiation of 10 + 10 Gy influences anastomotic healing in the lower left colon of the rat. DESIGN: Randomised study. MATERIAL: 120 male Wistar rats. INTERVENTIONS: Rats were randomised to be given localised preoperative irradiation or sham treatment 8 and 4 days before a standardised left colon resection. The post-operative course was studied for up to two months. MAIN OUTCOME MEASURES: Changes in body weight, white cell count, haemoglobin and albumin concentrations, anastomotic complications, anastomotic breaking strength, hydroxyproline content and myeloperoxidase activity in the anastomotic segment. RESULTS: General effects of irradiation were seen as delayed increase in body weight and low white cell count. Anastomotic complications were not increased. Anastomotic breaking strength was similar in the early postoperative phase but reduced after 2 months. Hydroxyproline content and myeloperoxidase activity of the anastomotic segments were similar in irradiation and control animals. CONCLUSION: Anastomotic healing was not compromised by preoperative irradiation. Late effects may be present in the bowel wall but further investigation is required.

Radiation effects in the colon. An experimental study in the rat.

In an experimental study, resembling a clinical trial of preoperative irradiation, 10 + 10 Gy was given to the pelvic and lower abdominal region of rats with a 4-day interval. The early effect on the colonic wall was evaluated by myeloperoxidase activity and hydroxyproline content of the bowel wall and correlated to histological findings. Groups of animals were followed up to eight months after irradiation for evaluation of later effects. General effects of irradiation were seen as low WBC during the first week and delayed body weight development up to two months after irradiation. Local effect in the colonic wall was noted as an increase in myeloperoxidase activity (indicating a leucocyte accumulation) in irradiated parts of colon during the first 11 days and again significantly elevated after two months in parts of colon, irradiated as well as protected. This correlated well with histological findings of inflammatory reaction, atypia and dysplasia during the first 10 days after irradiation but not at two months after irradiation. Hydroxyproline content was not affected. There were no major complications due to irradiation seen in the late course of the study period.

Influence of 5-fluorouracil and folinic acid on colonic healing: an experimental study in the rat.

Male Wistar rats were subjected to colonic resection and randomized to one of four groups: control group (intraperitoneal NaCl, intravenous NaCl); 5-fluorouracil (5-FU) group (intraperitoneal 5-FU, intravenous NaCl); folinic acid group (intraperitoneal NaCl, intravenous folinic acid); and 5-FU-folinic acid group (intraperitoneal 5-FU, intravenous folinic acid). Treatment was started immediately after surgery and continued until the animals were killed at 3 or 7 days. Anastomotic complications (abscesses or dehiscence) occurred in four of 33 animals in the control group, 12 of 36 in the 5-FU group, one of 32 in the folinic acid group and nine of 36 in the 5-FU-folinic acid group. Anastomotic and skin breaking strength did not differ between groups on day 3 but by day 7 were significantly reduced in the 5-FU group. In rats given 5-FU-folinic acid, breaking strength was also reduced, but less so than in the 5-FU group. Breaking strength in animals receiving folinic acid was similar to that in the control group. In this model colonic healing was impaired after intraperitoneal 5-FU administration, but when folinic acid was added no further deterioration occurred.

Bacterial load and inflammatory reaction in the bowel wall after colonic obstruction. An experimental study in rats.

To quantify the inflammatory reaction to obstruction, alkaline phosphatase and myeloperoxidase activities were measured in specimens of colonic wall from 60 rats. Twenty rats had undergone laparotomy and band obstruction, 20 laparotomy without obstruction and 20 had no operation. The mean activities of both enzymes were increased proximal but not distal to the obstruction, that of alkaline phosphatase significantly so. Despite increase in the number of bacteria, both proximal and distal to the obstruction, no signs of bacterial invasion of the bowel wall were seen either on histological examination or culture. These findings indicate that mechanical factors may be more important than bacteria in causing the increased inflammatory reaction in bowel wall proximal to an obstruction.

Peroperative contamination and anastomotic leakage after resection for left colon stenosis. An experimental study in the rat.

In this experimental study the effect of peroperative faecal soiling on immediate postoperative anastomotic leakage after resection and primary anastomosis of a left colon obstruction was evaluated. Faecal soiling was quantified by a standardized irrigation of the abdominal cavity and then culturing of the fluid. An increased peroperative soiling was found after resection of a stenosis compared to resection of a non-stenotic bowel. Anastomotic complications were correlated to the degree of bacterial contamination and a breakpoint of 10(4) CFU/ml was found. Immediate postoperative leakage, tested with the bacteria Serratia marcescens, was not increased in the stenosis group. Thus, peroperative bacterial contamination seems to be one important factor in developing anastomotic complications after resection of colonic obstruction while an immediate leakage of bacteria through the anastomosis seems to be less important.

The effect of diverting colostomy on anastomotic healing after resection of left colon obstruction. An experimental study in the rat.

A standardized stenosis of the left colon was created in the rat model. After four days the stenosis was resected and a primary anastomosis made. Half of the animals (n = 21) were randomized to a proximal diverting colostomy and the other half to a non-colostomy control group. On postoperative days two and seven anastomotic complications were recorded and anastomotic strength was determined. Collagen content in the anastomotic area was measured. In the colostomy group no anastomotic complications occurred, while 6/21 (29%) animals in the non-colostomy group had complications. On day two there was no difference between the groups as regards anastomotic strength and collagen content. After a week, however, the control group showed a significant increase in both anastomotic strength and collagen content which was not observed in the colostomy group. The absence of increase in anastomotic strength in the colostomy group had no adverse effect on anastomotic healing, as judged by complications. Thus, a diverting colostomy may be of value in reducing anastomotic complications after resection of a left colon obstruction.

Impact of bacteria on metabolism of collagen in colonic obstruction in rats.

The influence of bacteria on metabolism of collagen in the colonic wall under normal conditions and after obstruction was evaluated by using germ-free and conventionally bred rats. Under normal conditions, no differences in synthesis and content of collagen or tissue dry weight in the colonic wall were found between germ-free and conventionally bred rats. After obstruction, both groups reacted similarly with an equally increased collagen synthesis. The findings imply that bacteria do not play any major role in the regulation of collagen metabolism in the colonic wall, neither under normal conditions nor in the strained situation with colonic obstruction and fecal impaction.

Anastomotic healing after resection of left-colon stenosis: effect on collagen metabolism and anastomotic strength. An experimental study in the rat.

Anastomotic breaking strength and collagen metabolism in the colonic wall were studied after resection of a standardized left-colon stenosis in the rat. An increased complication rate was found in the stenosis group compared with the control group (27 percent vs. 2 percent) and the complications arise soon after surgery. The collagen turnover in the anastomotic area, as well as the changes of breaking strength, were equal between the groups in the early healing course, implying that the stenosis group, as an entity, did not show impairment in the studied parameters predisposing for complications. Other factors such as mechanical strain by the increased fecal bulk and increased bacterial load may contribute to occurrence of the anastomotic complications.

Compartment syndrome after prolonged surgery with leg supports.

Compartment syndrome has been reported in a few cases after prolonged surgery with patients in leg supports. A recent case in our hospital (57-year-old man undergoing cystourethrectomy because of cancer) made us interested in the problem. This case together with six from the literature are analysed. Moreover, the first 11 cases operated on with a pelvic pouch and ileoanal anastomosis at our department were reviewed. They had been in the leg support position for a median duration of 6.4 (5.8-8) h. In four of them leg pain and swelling developed within 12 h. Three showed regression within a few days, one after a week. In one patient with swelling compartment pressure was measured with a transducer tipped catheter. Intermittently the pressure was up to 50 mm Hg. There was an obvious decrease in pressure on knee bending. Also, in a patient without swelling large pressure variations were seen but not to critical levels.

Influence of long-term relative bowel rest on the healing of a left colon anastomosis.

The influence of long-term relative bowel rest, using a low residue diet, on healing of a left colon anastomosis was experimentally studied. Retarded and diminished gain of postoperative anastomotic collagen and strength was found. The healing of the anastomosis was uncomplicated, however, and it is concluded that anastomotic integrity after surgery in this condition is safe.

Impact of long-term relative bowel rest on conditions for colonic surgery.

Collagen content, bursting wall tension, and suture-holding capacity in the proximal and distal colon of the rat were studied after long-term treatment with a low-residue or a standard laboratory chow diet. Collagen content decreased uniformly in both the proximal and distal colon of the low-residue diet group. In addition, the bursting wall tension of the nonoperated proximal colon was reduced, whereas the breaking strength of a newly constructed anastomosis at three different colonic sites was unaffected.

Healing of anastomoses after obstruction of small intestine.

Anastomotic healing after obstruction of the small intestine was investigated by measurements of development of strength, content of collagen and synthesis of collagen in standardized specimens taken at biopsy of the intestinal wall on both sides of the anastomosis. One hundred and sixteen male Wistar rats were used. Forty-eight rats were used for studies of synthesis of collagen by in vivo labeling with 100 microcuries of tritiated L-proline. Anastomoses performed after two days of obstruction in the ileum had a higher rate of complications than operations performed upon control rats (p less than 0.05). Obstruction of the small intestine resulted in increased content of collagen of the ileal wall as a consequence of increased synthesis of collagen, but this resulted in neither increased capacity to hold suture nor in any differences in development of strength between rats operated upon for obstruction of the small intestine and control rats. Increased turnover of collagen was noted in the vicinity of the anastomoses after obstruction, which might be related to the increased rate of complications found. Rats with complications accumulated more collagen in the intestinal wall after one week compared with rats with obstruction and uncomplicated healing. These rats had persistent obstruction or formation of granuloma, or both.

Volvulus of the cecum. Report of 26 cases and review of the literature.

The management of cecal volvulus is controversial. From 1971 to 1986, 26 patients with cecal volvulus were treated at Malmö General Hospital. Treatment and patient follow-up are presented, together with a review of 350 patients reported in the literature during the past 15 years. Anatomic background and types of volvulus are described. Simple detorsion is an alternative in high-risk patients without gangrene, but resection is the method of choice also when there is no gangrene present.