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International Journal of Surgery 7 (2009) 126–129

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International Journal of Surgery

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Effect of eradication on ulcer recurrence after simple closure of perforated duodenal ulcerq

Ayman El-Nakeeb a,*, Amir Fikry a, Tito M. Abd El-Hamed a, El Yamani Fouda a, Saleh El Awady a, Tamer Youssef a, Doaa Sherief b, Mohamed Farid a

a Mansoura University Hospital, General Surgery Department, Dep. 8, Egypt b Department of Microbiology, Dep., Mansoura University Hospital, Egypt

article info abstract

Article history: Background: This study was conducted to elucidate the prevalence of Helicobacter pylori in patients with Received 8 October 2008 a perforated duodenal ulcer and to determine whether eradication of H. pylori prevent ulcer recurrence Received in revised form following simple repair of the perforation. 10 November 2008 Accepted 1 December 2008 Patients and method: Eighty-three patients with perforated duodenal ulcer (68 males); mean age was Available online 6 December 2008 47.8 years 7.2. Antral mucosal (to determine the status of HP by rapid test, culture and histological examination/) were obtained during by passing a forceps through Keywords: the perforation site. H. pylori positive patients who had undergone patch repair were randomized into Peptic the eradication group who received amoxicillin, metranidazole plus omperazole and the control group Omperazole was given omeprazole alone. Follow-up and antral biopsies were performed at 8 weeks, 16 Triple therapy weeks and 1 year to show ulcer healing and determine H. pylori state. Omental patch Results: Of 77 patients in the study, 65 patients (84.8%) had H. pylori. These patients were randomly Antral biopsies divided into the triple therapy group (34 patients) and the control group (31 patients). Eradication of H. pylori was significantly higher in the triple therapy group than the control group and initial ulcer healing was significantly better in the eradication group. After 1 year, ulcer recurrence was (6.1%) in the eradication group vs. (29.6%) in the control group (P ¼ 0.001). Conclusion: H. pylori was present in a high proportion of patients with duodenal ulcer perforation. Eradication of H. pylori after simple closure of a perforated duodenal ulcer reduced the incidence of recurrent ulcer. Ó 2008 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

1. Introduction results.5–7 Immediate definite surgery although is effective with low recurrence rate, is associated with long-term side effects.5 Perforation is a serious and potentially fatal complication of Helicobacter pylori (H. pylori) has been described as an oppor- duodenal ulcer. The incidence of perforated duodenal ulcer has not tunistic pathogen attracted by changes in the gastric mucosa decreased despite advances in medical treatment.1 Simple closure caused by inflammation and ulcer.11 However, its role in duodenal was initially and remains one of the treatments of perforated perforation has been investigated extensively and the results are duodenal ulcer. However, the long-term results of omental patch conflicting.6–10 Eradication of H. pylori heals most uncomplicated repair for perforated duodenal ulcer are unsatisfactory; a high duodenal ulcers and prevent relapse.8–12 incidence of ulcer recurrence has been reported, reaching 40–50% The aim of this study was to elucidate the prevalence of H. pylori in some series.2–4 Use of acid suppressing agents to reduce ulcer in patients with a perforated duodenal ulcer and to determine recurrence after simple patch closure produced debatable whether eradication of H. pylori prevent ulcer recurrence following simple repair of the perforation.

q Ayman M. El-Nakeeb, Saleh El Awady, Amir Fekry and Tamer Yousef wrote the 2. Patients and methods paper. Ayman El-Nakeeb, F. El Yamani Fouda, Saleh EL Awady, and Doaa Sherief designed research. Ayman El-Nakeeb, Amir A. Fikry, Saleh El Awady, Doaa Sherief, Of the 83 patients admitted with perforated duodenal ulcer Tito M. Abd El-Hamed, and Mohamed Farid performed research. Ayman El-Nakeeb, between March 2005 and January 2007 at the Emergency Man- Saleh El Awady, Amir Fikry, Elyamani Fouda, and Mohamed M. Farid analyzed data. * Corresponding author. Tel.: þ20 106752021/502353430/502251543. soura University Hospital, 77 patients were treated by simple E-mail address: [email protected] (A. El-Nakeeb). closure and they were included in our study. Exclusion criteria were

1743-9191/$ – see front matter Ó 2008 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijsu.2008.12.001 A. El-Nakeeb et al. / International Journal of Surgery 7 (2009) 126–129 127 age younger than 16 or older than 75 years, history of recent intake samples was used to detect differences in the means of continuous of antibiotics, H2 antagonists or proton pump inhibitors within 4 variables and Chi-square test was used in cases with low expected weeks before admission, sealed off perforation, previous gastrec- frequencies (P-value < 0.05 was considered to be significant). tomy or or patients with perforated gastric ulcers. Demographic data, history of dyspepsia for more than 3 months, 3. Results smoking and the use of non-steroidal anti-inflammatory drug (NSAIDs) were recorded at time of admission. From March 2005 to January 2007 at the Emergency Mansoura All patients were resuscitated before surgery. Informed consent University Hospital, 83 patients (68 male and 15 female) with was obtained from every patient for surgical exploration and a mean age of 47.8 years 7.2 were found to have perforated inclusion in the study. Intravenous cefuroxime (1.5 gm) was duodenal ulcer at laparotomy. Six patients were excluded: two administered during induction of anesthesia; no other antibiotics were older than 75 years and four required definitive operation. Of or acid suppressing treatment was prescribed before the operation. the remaining 77 patients, 65 (84.8%) were infected with H. pylori When duodenal ulcer perforation was confirmed at laparotomy, (Table 1). Patients with positive H. pylori were randomly assigned to multiple antral mucosal biopsies were obtained by passing a biopsy one of the two treatment options by opening sealed envelops:- 34 forceps through the perforation site. Antral biopsies were exam- patients were assigned to triple therapy (the eradication group) and ined as follows:- one piece for a rapid urease test (Campylobacter- 31 patients to omeprazole alone (the control group). The two like organism CLO, Delta West, West Australia); three pieces groups were comparable in age, sex, smoking habit, use of NSAID, transported in brain–heart solution at room temperature for size of perforation, severity of peritonitis and postoperative subsequent culture (Columbia agar supplemented with 5% horse complications (Table 2). blood at 37 C for 5 days under microaerophilic conditions) and the H. pylori eradication was significantly higher in the triple presence of H. pylori was confirmed by and biochemical therapy group than the omeprazole alone group (at 8 weeks 91.2% tests (for oxidase, and urease); and three pieces were fixed vs. 22.6% and at 16 weeks 97.6% vs. 51.6%). Initial healing of ulcers at with 10% buffered formalin for histological examination after 8 weeks follow-up endoscopy was significantly better in the Haematoxylin and Eosin (H & E) staining. Patients were considered eradication group. There were 85.3% healed ulcers in the triple to be H. pylori positive when two of three tests showed presence of therapy group and 48.4% in the omeprazole alone group (P < 0.05). the bacteria.14 At 16 weeks endoscopy the healed ulcer rates increased to 97.6% in Omental patch repair was then commenced unless there were the triple therapy group and 87.1% in the omeprazole group indications for definitive acid reduction surgery (large perfo- (P ¼ 0.48) (Table 3). Patients with documented ulcer healing were ration > 1 cm in diameter not amenable to simple closure or scheduled for follow up visits following the study protocol. perforation concomitant with obstruction). Patients who under- After 1 year, three patients in the triple therapy group and went immediate definitive surgery were excluded from the study. another four patients in the omeprazole group were lost to follow Peritoneal lavage was performed before closure of the abdominal up. They reported no significant dyspeptic symptoms and refused incision. Intravenous cefuroxime was continued every 8 h for 3 to undergo further endoscopic examination. Of the remaining 58 days after surgery. patients who followed the study protocol, 10 patients had ulcer H. pylori positive patients who had undergone patch repair were recurrence (Table 4). Two patients in the triple therapy group had eligible for randomization. After resuming an oral diet, patients ulcer relapse: one patient was asymptomatic and had recurrent were randomly assigned to one of the two treatment options by ulcer diagnosed at the scheduled 1-year endoscopy, the other had opening a sealed envelop. Patients in group I: eradication group melena 7 months after the repair operation and was found to have (triple therapy) received 1 week of oral amoxicillin 750 three times recurrent H. pylori infection. Of the eight patients with ulcer daily, metranidazole 500 mg twice daily for 10 days and omepra- recurrence in the omeprazole alone group, five were symptomatic zole 40 mg for 4 weeks. Patients in group II (control group) were given omeprazole alone 40 mg daily for 4 weeks. Table 1 All patients were called back for personal interview and follow- Demographic data of the all patients (83 patients) with perforated duodenal ulcer. up endoscopy at 8 weeks and after 1 year. At each endoscopy, Variables No (%) mucosal ulceration of 5 mm or more in the duodenum was Age 47.8 7.2 considered as persistent or recurrent ulcer.13 Ulcer healing was defined as either complete re-epithelialization of the duodenal Sex mucosa or presence of a scar.14 Endoscopic antral biopsies were Male 68 (81.9%) Female 15 (18.1%) obtained to reevaluate the H. pylori status. Additional biopsies were taken from the body of the to avoid false negative results Smoking Yes 56 (67.5%) secondary to proximal gastric migration of the bacterium after No 27 (32.5%) therapy. All patients with complete ulcer healing on the scheduled NSAID intake Yes 21 (25.3%) endoscopy were then interviewed every 6 months. Maintenance No 62 (74.7%) acid suppression agents were not prescribed during follow up period. Repeated endoscopic examination was performed when- Exclusion 6 Age above 75 years 2 ever the patients were symptomatic. Definite surgery 4 For patients who had ulcers which was not healed at 8 weeks, Patients in the study 77 another 4 weeks course of omeprazole 20 mg twice daily was Age (mean SD) 46.7 10.2 prescribed and a second endoscopy was scheduled at 16 weeks. Sex Primary treatment failure was considered to be present if the Male 64 (83.1%) patients had persistent non-healing ulcer at 16 weeks. Female 13 (17.9%) Statistical analysis of data was performed using SPSS version 10. H. pylori status For continuous variables, descriptive statistics were calculated and Positive 65 (84.4%) were reported as mean SD. Categorical variables were described Negative 12 (15.6%) using frequency distributions. The Student’s t-test for paired NSAID: non-steroidal anti-inflammatory drug, and H. pylori: Helicobacter pylori. 128 A. El-Nakeeb et al. / International Journal of Surgery 7 (2009) 126–129

Table 2 Table 4 Patients in triple therapy group and omeprazole alone group. One year follow up (triple therapy vs. omeprazole alone group).

Variables Triple therapy (34) Omeprazole alone (31) P-value Triple therapy Omeprazole alone P-value Age (mean SD) 46 12.9 46.6 10.5 0.6 Patients with complete ulcer healing 33 27 at the end of 16 weeks follow up Sex H. pylori eradicated 28 (84.8%) 14 (51.9%) 0.05 Male 32 (94.1%) 27 (87.1%) 0.413 Ulcer recurrence 2 (6.1%) 8 (29.6%) 0.001 Female 2 (5.9%) 4 (12.9%) Symptomatic ulcer recurrence 1 (3.03%) 5 (18.5%) 0.05 Smoking Pain 0 3 Yes 29 (85.3%) 24 (77.4%) 0.7 Bleeding 1 2 No 5 (14.7%) 7 (22.6%) Obstruction 0 0 Reperforation 0 0 NSAID H. pylori positive in recurrent ulcer 1 (3.03%) 7 (25.9%) 0.01 Yes 10 (29.4%) 9 (29.1%) 0.06 No 24 (70.6%) 22 (70.9%) H. pylori: Helicobacter pylori.

Dyspepsia > 3 months Yes 27 (79.4%) 22 (70.9%) 0.09 a high incidence of postoperative complications like dumping No 7 (20.6%) 9 (29.1%) syndrome, loss of weight, or diarrhea.13,20–22 Size of perforation (mm) 4.5 1.3 mm 4.6 1.5 mm 0.432 Although the relationship between H. pylori infection and peptic ulcer has been well defined, the relationship with perforated ulcer Stage of peritonitis 26 Chemical 24 (70.6%) 22 (70.9%) 0.83 is controversial. In our study, the frequency of H. pylori infection Purulent 10 (29.4%) 9 (29.1%) in patients with perforated duodenal ulcer is 84.4%. This figure is much higher than those reported by Reinbach et al (47%)10 and Chu Postoperative complication 20 Wound infection 2 (5.9%) 3 (9.7%) 0.64 et al (47%) but is consistent with those reported by Juan et al 21 13 9 Chest infection 7(20.6%) 5 (16.2%) 0.75 (73.9%), Enders et al (80.6%), Sebastian et al (83%), Matsukura Urine retention 1(2.95%) 0 – et al (95%),22 Jurg Metzger et al (73.3%)24 and Ng et al (70%),25 Ileus 5(14.7%) 4 (12.9%) 0.54 suggesting an association between H. pylori infection and duodenal Leakage 2 (5.9%) 1 (3.2%) 0.65 ulcer perforation. NSAID: non-steroidal anti-inflammatory drug. Standard triple therapy was used in this study as it is a gold standard for H. pylori eradication.23 Omeprazole was given to both groups as it was considered unethical to leave patients with (three with severe ulcer pain, two with melena) and three patients a proven ulcer without antisecretory therapy. Eradication rate were were asymptomatic and had recurrent ulcer diagnosed at the significantly higher after triple therapy than omeprazole alone, at 8 scheduled 1-year endoscopy. The difference in ulcer recurrence weeks follow up it was (91.2% vs. 22.6% P ¼ 0.001) and at 16 weeks between the two groups was statistically significant [two (6.1%) in it became (97.6% vs. 51.6% P ¼ 0.05). Kate et al23 reported eradica- the eradication group vs. eight (29.6%) in the omeprazole alone tion rate was higher in the eradication group than the ranitidine group P ¼ 0.001]. Eight of these 10 ulcer recurrences were associ- alone group at 8 weeks (80% in the eradication group vs. 57% in the ated with H. pylori, with seven in the omeprazole group and one in ranitidine group). Enders Ng et al.13 showed that H. pylori eradi- the triple therapy group. cation in the triple therapy group was significantly higher than the omeprazole alone group (84.3% vs. 16.7%, P < 0.001). Jurg Metzger 4. Discussion et al.24 reported the eradication rate was 96% with triple therapy. In the present study, initial healing of ulcers shown at 8-week Perforated duodenal ulcer is a common surgical emergency. follow up endoscopy was significantly better in the eradication Simple omental patch repair is a quick procedure but results in group (85.3% healed ulcers in the triple therapy group and 48.4% in recurrent ulceration in up to 42% of patients.15–18 Because of the the omeprazole alone group). After 1 year, two patients in the triple unsatisfactory result of simple repair, immediate acid-reducing therapy group had ulcer relapse, one patient had melena 7 months procedures have been strongly advocated. Several prospective after the perforation and was found to have recurrent H. pylori randomized studies reported significantly fewer ulcer recurrences infection. Of the eight patients with ulcer recurrence in the ome- by adding immediate vagotomy to patch repair of ulcer perfora- prazole alone group, five were symptomatic (three with severe tion.13,19 Immediate definitive surgery requires a longer operative ulcer pain, two with melena). The difference in ulcer recurrence time. It is not a procedure that can be carried out by most surgical between the two groups was statistically significant [two (6.1%) in residents who are the front line medical personnel managing the eradication group vs. eight (29.6%) in the omeprazole alone patients with duodenal ulcer perforation. It is also associated with group P ¼ 0.001]. Eight of these 10 ulcer recurrences were associ- ated with H. pylori, seven in the omeprazole group and one in the triple therapy group. Table 3 Kate et al23 from India reported a study on 202 patients with Early follow up (8 weeks and 16 weeks) in (triple therapy vs. omeprazole alone perforated duodenal ulcer treated by simple closure. These patients group). were then randomly divided into two groups: one group received Triple therapy Omeprazole alone P-value eradication therapy and another group received ranitidine alone. Patients who underwent initial 34 31 After a routine endoscopy at various follow up intervals, a clear follow up endoscopy relationship was established between the persistence of H. pylori 13 H. pylori eradication infection and ulcer persistence or relapse. Enders Ng et al from At 8 weeks 31 (91.2%) 7 (22.6%) 0.001 Hong Kong reported 51 out of 129 patients with perforated At 16 weeks 33 (97.6%) 16 (51.6%) 0.05 duodenal ulcer treated by simple closure and eradication therapy. Complete ulcer healing After follow up for 1 year, two patients (4.8%) had endoscopic At 8 weeks 29 (85.3%) 15 (48.4%) 0.05 recurrence, which was significantly lower than those patients At 16 weeks 33 (97.6%) 27 (87.1%) 0.48 without eradication therapy. In another study, Bose et al27 reported H. pylori: Helicobacter pylori. that 60 out of 93 patients who had H. pylori infection received A. El-Nakeeb et al. / International Journal of Surgery 7 (2009) 126–129 129 eradication therapy. At the end of the study only 53 of 60 patients 5. Sevvel S, Ananthakrishnan N, Kate V. Role of histamine-2 receptor antagonist d were available for follow up. H. pylori eradication was achieved in after simple closure of perforated duodenal ulcer a double blind randomized, controlled study. Trop Gastroenterol 1996;17:277–9. 43 (81.1%) patients. It was found that 8 of 43 (18.6%) patients in the 6. Kumar S, Mittal GS, Guoto S, Kaour I, Aggawal S. Prevalence of Helicobacter eradicated group had persistence or recurrence of ulcer as opposed pylori in patients with perforated duodenal ulcer. Trop Gastroenterol 2004; to 7 of 10 (70%) patients in the non-eradicated group. Tran et al28 24(3):121–4. 7. Gillen P, Ryan W, Peel ALG, Devlin HB. Duodenal ulcer perforation: the effect of from Vietnam reported that 111 patients were treated by simple H2 antagonist? Ann R Coll Surg Engl 1986;68:240–2. closure; 107 had H. pylori infection and received eradication 8. Jesen DW, You S, Pelayo E, Jensen ME. The prevalence of Helicobacter therapy. After 12 months 95 patients were available for followed pylori and NSAID use in patients with severe UGI hemorrhage and their potential role in recurrence of ulcer bleeding. Gastroenterology 1992;102:A90. up. H. pylori eradication was achieved in 79 patients. Three of 79 9. Sebastian M, Prem Chandran VP, Elashaal YIM, Sim AJW. Helicobacter pylori (3.8%) patients in the eradicated group had persistence or recur- infection in perforated . Br J Surg 1995;82:360–2. rence of ulcer as opposed to 4 of 16 (25%) patients in the H. pylori 10. Reinbach DH, Cruickshank G, McColl KEL. Acute perforated duodenal ulcer is not associated with Helicobacter pylori. Gut 1993;34:1344–7. infected group. After 60 months only 62 patients were available for 11. Mihmanli M, Isgar A, Kabukcuoglu F, Turkay B, Cikla B, Baykan A. Effect of follow up. Three of 40 (7.5%) patients in the eradicated group had Helicobacter pylori in perforation of duodenal ulcer. Hepatogastroenterology persistence ulcer as opposed to 3 of 22 (13.6%) patients in the 1998 Sep–Oct;45(23):1610–2. H. pylori infected group. 12. Noguiera C, Silva AS, Santos JN, Silva AG, Ferreira J, Matos E. Perforated peptic ulcer, main factors of morbidity and mortality. World J Surg 2003;27:782–7. In light of the high prevalence of H. pylori infection and the few 13. Enders Ng KW, Lam YY, Sung JJ, Yung MY, To KF, Chan AC, et al. Eradication recurrence after eradication, the bacterium is likely to be causally of Helicobacter pylori prevents recurrence of ulcer after simple closure related to the strong ulcer diathesis in patients with duodenal ulcer of duodenal ulcer perforation: a randomized controlled trial. Ann Surg 2000;231:153–8. perforation. H. pylori plays an important role in duodenal ulcer 14. Pajares Garcia JM. Diagnosis of Helicobacter pylori: invasive methods. Ital recurrence following simple closure of perforated duodenal ulcer. J Gastroenterol Hepatol 1998;30:S320–33. We concluded from these results that H. pylori was present in 15. Blakestone MO. Endoscopic interpretations. Normal and pathologic appearances of . New York: Raven Press; 1984. a high proportion of patients with duodenal ulcer perforation. 16. Whitehead R. Mucosal biopsy of the gastrointestinal tract. 3rd ed. Philadelphia, Eradication of H. pylori after simple closure of a perforated Pennsylvania: Saunders; 1985. duodenal ulcer reduced the incidence of recurrent ulcer. H. pylori 17. Raimes SA, Devlin HB. Perforated duodenal ulcer. Br J Surg 1987;74:81–2. 18. Bornman PC, Theodorou NA, Jeffery PC. Simple closure of perforated duodenal infection should be assessed at operation and initial endoscopy. If ulcer. A prospective evaluation of a conservative management policy. Br J Surg H. pylori infection is confirmed, an appropriate eradication therapy 1990;77:73–5. should be given. 19. Hay JM, Lacaine F, Kohlmann G, Fingerhut A. Immediate definitive surgery for perforated duodenal ulcer doesn’t increase operative mortality. A prospective control trial. World J Surg 1988;12:705–9. 20. Chu KM, Kwok KF, Law SY, Tuen HH, Tung PH, Branicki FJ. Helicobacter pylori Conflict of interest statement status and endoscopy follow up of patients having a history of perforated ulcer. None to declare. Gastrointest Endosc 1999;50:58–62. 21. Rodriguez-Sanjuan JC, Fernandez-Santiago R, Gracia RA, Trugeda S, Isabel M. Perforated peptic ulcer treated by simple closure and eradication of Heli- Funding cobacter pylori. World J Surg 2005;29:849–52. None to declare. 22. Matsukura N, Onda M, Tokunago A. Role of Helicobacter pylori infection in perforation of peptic ulcer: an age and genderdmatched case–control study. J Clin Gastroenterol 1997;25:5235–9. Ethical approval 23. Kate V, Ananthakrishnan N, Badrinath S. Effect of Helicobacter pylori eradication Ethical approval by local ethical committee. on ulcer recurrence rate after simple closure of perforated duodenal ulcer. Retrospective and prospective randomized controlled study. Br J Surg 2001; 88:1054. 24. Metzger J, Stygar S, Sieber C, Von Flue M, Vogelbach P, Harder F. Prevalence of Helicobacter pylori infection in peptic ulcer perforation. Swiss Med Wkly 2001; References 131:99–103. 25. Ng EKW, Chung SCS, Sung JJY, Lam YH, Lee WH. High prevalence of Helicobacter 1. Christansen A, Bousfield R, Christiansen J. Incidence of perforated and bleeding pylori infection in duodenal ulcer perforation not caused by NSAID. Br J Surg peptic ulcer before and after the introduction of H2 blocker. Ann Surg 1996;83:1779–81. 1988;207:4–6. 26. Gisbert JP, Legido J, Garcia S, Pajares JM. Helicobacter pylori and perforated 2. Sawyer JL, Herrington JL, Mulherin JO, Whitehead WA, Moby B, Marsh J. Acute peptic ulcer prevalence of the infection and role of NSAID. Dig Dis perforated ulcer an evaluation of surgical management. Arch Surg 2004;36(2):116–20. 1975;110:527–30. 27. Bose AC, Kate V, Ananthakrishnan N, Parija SC. Helicobacter pylori eradication 3. Griffin GE, Organ CH. The natural history of perforated duodenal ulcer treated prevents recurrence after simple closure of perforated duodenal ulcer. J Gas- by suture closure. Ann Surg 1976;183:382–5. troenterol Hepatol 2007;22:345–8. 4. Ananthakrishnan N, Angami K. Is Visick grading alone reliable for selecting 28. Tran TT, Quandalle P. Long term results of treatment by simple surgical closure patients requiring endoscopic workup for recurrence after simple closure of of perforated gastroduodenal ulcer followed by eradication of Helicobacter duodenal ulcer? Indian J Surg 1993;55:357–60. pylori. Ann Chir 2006;131:502–4.