Management of perforated diverticulitis with generalized peritonitis. A multidisciplinary review and position paper.

Perforated diverticulitis is an emergent clinical condition and its management is challenging and still debated. The aim of this position paper was to critically review the available evidence on the management of perforated diverticulitis and generalized peritonitis in order to provide evidence-based suggestions for a management strategy. Four Italian scientific societies (SICCR, SICUT, SIRM, AIGO), selected experts who identified 5 clinically relevant topics in the management of perforated diverticulitis with generalized peritonitis that would benefit from a multidisciplinary review. The following 5 issues were tackled: 1) Criteria to decide between conservative and surgical treatment in case of perforated diverticulitis with peritonitis; 2) Criteria or scoring system to choose the most appropriate surgical option when diffuse peritonitis is confirmed 3); The appropriate surgical procedure in hemodynamically stable or stabilized patients with diffuse peritonitis; 4) The appropriate surgical procedure for patients with generalized peritonitis and septic shock and 5) Optimal medical therapy in patients with generalized peritonitis from diverticular perforation before and after surgery. In perforated diverticulitis surgery is indicated in case of diffuse peritonitis or failure of conservative management and the decision to operate is not based on the presence of extraluminal air. If diffuse peritonitis is confirmed the choice of surgical technique is based on intraoperative findings and the presence or risk of severe septic shock. Further prognostic factors to consider are physiological derangement, age, comorbidities, and immune status. In hemodynamically stable patients, emergency laparoscopy has benefits over open surgery. Options include resection and anastomosis, Hartmann's procedure or laparoscopic lavage. In generalized peritonitis with septic shock, an open surgical approach is preferred. Non-restorative resection and/or damage control surgery appear to be the only viable options, depending on the severity of hemodynamic instability. Multidisciplinary medical management should be applied with the main aims of controlling infection, relieving postoperative pain and preventing and/or treating postoperative ileus. In conclusion, the complexity and diversity of patients with diverticular perforation and diffuse peritonitis requires a personalized strategy, involving a thorough classification of physiological derangement, staging of intra-abdominal infection and choice of the most appropriate surgical procedure.

Impact of primary antibiotic resistance on the effectiveness of sequential therapy for Helicobacter pylori infection: lessons from a 5-year study on a large number of strains.

BACKGROUND: The increasing prevalence of strains resistant to antimicrobial agents is a critical issue in the management of Helicobacter pylori (H. pylori) infection. AIMS: (1) To evaluate the prevalence of primary resistance to clarithromycin, metronidazole and levofloxacin (2) to assess the effectiveness of sequential therapy on resistant strains (3) to identify the minimum number of subjects to enrol for evaluating the effectiveness of an eradication regimen in patients harbouring resistant strains. METHODS: Consecutive 1682 treatment naïve H. pylori-positive patients referred for upper GI endoscopy between 2010 and 2015 were studied and resistances assessed by E-test. Sequential therapy was offered, effectiveness evaluated and analysed. RESULTS: H. pylori-primary resistance to antimicrobials tested was high, and increased between 2010 and 2015. Eradication rates were (estimates and 95% CIs): 97.3% (95.6-98.4) in strains susceptible to clarithromycin and metronidazole; 96.1% (91.7-98.2) in strains resistant to metronidazole but susceptible to clarithromycin; 93.4% (88.2-96.4) in strains resistant to clarithromycin but susceptible to metronidazole; 83.1% (77.7-87.3) in strains resistant to clarithromycin and metronidazole. For any treatment with a 75%-85% eradication rate, some 98-144 patients with resistant strains need to be studied to get reliable information on effectiveness in these patients. CONCLUSIONS: H. pylori-primary resistance is increasing and represents the most critical factor affecting effectiveness. Sequential therapy eradicated 83% of strains resistant to clarithromycin and metronidazole. Reliable estimates of the effectiveness of a given regimen in patients harbouring resistant strains can be obtained only by assessing a large number of strains.

Randomised clinical trial: mucosal protection combined with acid suppression in the treatment of non-erosive reflux disease - efficacy of Esoxx, a hyaluronic acid-chondroitin sulphate based bioadhesive formulation.

BACKGROUND: Several studies have shown that patients with non-erosive reflux disease (NERD) are less responsive to proton pump inhibitors (PPIs) than those with erosive disease as they belong to different subgroups, in whom factors other than acid can trigger symptoms. AIM: To evaluate whether combined therapy (mucosal protection plus acid suppression) would improve symptom relief compared to PPI treatment alone. METHODS: In a multicenter, randomised, double-blind trial, 154 patients with NERD were randomised to receive Esoxx (Alfa Wassermann, Bologna, Italy), a hyaluronic acid-chondroitin sulphate based bioadhesive formulation, or placebo, in addition to acid suppression with standard dose PPIs for 2 weeks. Symptoms (heartburn, acid regurgitation, retrosternal pain and acid taste in the mouth) and health-related quality of life (HRQL) were evaluated before and after treatment. The primary endpoint was the proportion of patients with at least a 3-point reduction in the total symptom score. RESULTS: At the end of treatment, the primary endpoint was reached by 52.6% of patients taking Esoxx compared to 32.1% of those given placebo (P < 0.01). The same was true also for HRQL, evaluated by means of the Short Form-36 questionnaire, which improved with both treatments, but some items were significantly better after Esoxx plus PPI therapy. CONCLUSION: The synergistic effect of Essox with PPI treatment suggests that mucosal protection added to acid suppression could improve symptoms and HRQL in NERD patients.

Systematic review with meta-analysis: rifaximin is effective and safe for the treatment of small intestine bacterial overgrowth.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is a heterogeneous syndrome, characterised by an increased number and/or abnormal type of bacteria in the small bowel. Over the past decades, rifaximin has gained popularity for this indication despite its use is not evidence based. AIM: To perform a systematic review and meta-analysis to summarise evidence about the efficacy and safety of rifaximin to eradicate SIBO in adult patients. METHODS: MEDLINE, EMBASE, CCRCT, Scopus and Web of Science were searched from inception to March 16, 2015 for RCTs and observational studies. Furthermore, abstract books of major European, American and Asian gastroenterological meetings were also examined. RESULTS: Thirty-two studies involving 1331 patients were included. The overall eradication rate according to intention-to-treat analysis was 70.8% (95% CI: 61.4-78.2; I2 = 89.4%) and to per protocol analysis 72.9% (95% CI: 65.5-79.8; I2 = 87.5%). Meta-regression identified three covariates (drug dose, study design and co-therapy) independently associated with an increased eradication rate. The overall rate of adverse events was 4.6% (95% CI: 2.3-7.5; I2 = 63.6%). In the subset of studies (n= 10) allowing the analysis, improvement or resolution of symptoms in patients with eradicated SIBO was found to be 67.7% (95% CI: 44.7-86.9; I2 = 91.3%). CONCLUSIONS: Rifaximin treatment seems to be effective and safe for the treatment of SIBO. However, the quality of the available studies is generally poor. Well-designed RCTs are needed to substantiate these findings and to establish the optimal regimen.

An expert consensus definition of failure of a treatment to provide adequate relief (F-PAR) for chronic constipation - an international Delphi survey.

BACKGROUND: As treatments for constipation become increasingly available, it is important to know when to progress along the treatment algorithm if the patient is not better. AIM: To establish the definition of failure of a treatment to provide adequate relief (F-PAR) to support this management and referral process in patients with chronic constipation. METHODS: We conducted an international Delphi Survey among gastroenterologists and general practitioners with a special interest in chronic constipation. An initial questionnaire based on recognised rating scales was developed following a focus group. Data were collected from two subsequent rounds of questionnaires completed by all authors. Likert scales were used to establish a consensus on a shorter list of more severe symptoms. RESULTS: The initial focus group yielded a first round questionnaire with 84 statements. There was good consensus on symptom severity and a clear severity response curve, allowing 67 of the symptom-severity pairings to be eliminated. Subsequently, a clear consensus was established on further reduction to eight symptom statements in the final definition, condensed by the steering committee into five diagnostic statements (after replicate statements had been removed). CONCLUSIONS: We present an international consensus on chronic constipation, of five symptoms and their severities, any of which would be sufficient to provide clinical evidence of treatment failure. We also provide data representing an expert calibration of commonly used rating scales, thus allowing results of clinical trials expressed in terms of those scales to be converted into estimates of rates of provision of adequate relief.

Role of the A(2B) receptor-adenosine deaminase complex in colonic dysmotility associated with bowel inflammation in rats.

BACKGROUND AND PURPOSE: Adenosine A(2B) receptors regulate several physiological enteric functions. However, their role in the pathophysiology of intestinal dysmotility associated with inflammation has not been elucidated. Hence, we investigated the expression of A2B receptors in rat colon and their role in the control of cholinergic motility in the presence of bowel inflammation. EXPERIMENTAL APPROACH: Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS). Colonic A(2B) receptor expression and localization were examined by RT-PCR and immunofluorescence. The interaction between A(2B) receptors and adenosine deaminase was assayed by immunoprecipitation. The role of A(2B) receptors in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). KEY RESULTS: A(2B) receptor mRNA was present in colon from both normal and DNBS-treated rats but levels were increased in the latter. A(2B) receptors were predominantly located in the neuromuscular layer, but, in the presence of colitis, were increased mainly in longitudinal muscle. Functionally, the A(2B) receptor antagonist MRS 1754 enhanced both electrically-evoked and carbachol-induced cholinergic contractions in normal LMPs, but was less effective in inflamed tissues. The A(2B) receptor agonist NECA decreased colonic cholinergic motility, with increased efficacy in inflamed LMP. Immunoprecipitation and functional tests revealed a link between A(2B) receptors and adenosine deaminase, which colocalize in the neuromuscular compartment. CONCLUSIONS AND IMPLICATIONS: Under normal conditions, endogenous adenosine modulates colonic motility via A2B receptors located in the neuromuscular compartment. In the presence of colitis, this inhibitory control is impaired due to a link between A2B receptors and adenosine deaminase, which catabolizes adenosine, thus preventing A(2B) receptor activation.

Relaxant effect of proton pump inhibitors on in vitro myometrium from pregnant women.

AIM: In this study we investigate in in vitro myometrial tissue samples of pregnant women: (a) the effects of proton pomp inhibitors (PPIs) (omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole) on spontaneous contractions; (b) the muscle-relaxant efficacy of the most active PPI considered (pantoprazole) in comparison with that of other known tocolytics (nifedipine, atosiban, MgSO4, isoxsuprine); (c) the effect of pantoprazole on contractions induced by calcium (Ca(++)), KCl, oxytocin and prostaglandin (PGE2); (d) the possible mediators of pantoprazole relaxant effect. METHODS: Organ bath studies were performed on myometrial tissue samples (40×10×10 mm) from pregnant women (38-42 weeks of gestational age) undergoing elective caesarian section. RESULTS: All the PPIs studied reduce the spontaneous contraction of the myometrial smooth muscle. Pantoprazole is the most effective and most potent inhibitor among those analyzed. Pantoprazole also reduces the contractions induced by Ca(++), KCl, oxytocin and PGE2. Neither NO, nor PGs, or the activation of Ca(++)-dependent K(+) currents mediate the muscle-relaxant effect of this PPI. CONCLUSION: These data, together with the fact that PPIs almost do not present side effects, suggest that these drugs can offer new therapeutic strategies for preterm delivery. Undoubtedly, further investigations and clinical studies are necessary before adding PPIs to the list of drugs available for the treatment of preterm delivery.

Intermittent versus every-day mesalazine therapy in preventing complications of diverticular disease: a long-term follow-up study.

BACKGROUND: Mesalazine seems to be effective in preventing recurrence of acute uncomplicated diverticulitis (AUD), but the optimal mesalazine scheme to achieve these results is still debated. AIM: To assess the effectiveness of two different mesalazine-based treatments in preventing recurrence of AUD and the occurrence of other complications of diverticular disease (DD) during a long-term follow-up. PATIENTS AND METHODS: We reviewed 311 patients suffer from recent episode of AUD and undergoing to mesalazine treatment: 207 (group A, 105 males, median age 63 years, range 47-74 years) were treated with mesalazine 1.6 g for 10 days each month, whilst 104 (group B, 55 males, median age 65 years, range 50-72 years) were treated with mesalazine 1.6 g every day. Patients were followed-up every 6 months (median 7.5 months, range 5-13 months). RESULTS: Patients were followed-up for a mean time of 3 years (range 12-72 months). Overall, occurrence of complication recurred more frequently in group A than in group B (p = 0.030, log-rank test). Acute diverticulitis recurred in 17 (8.2%) patients in group A and in 3 (2.9%) in group B; diverticular bleeding occurred in 4 (1.9%) patients in group A and in 1 (0.96%) patient in group B; surgery was required in 3 (1.4%) patients in group A and in no (0%) patient in group B. CONCLUSIONS: This is the first study showing that long-term mesalazine treatment is significantly better that intermittent mesalazine treatment in preventing occurrence of DD complications after an attack of acute diverticulitis.

Piroxicam-ß-cyclodextrin: a GI safer piroxicam.

Although NSAIDs are very effective drugs, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular (CV) system, skin and gut. Gastrointestinal (GI) side effects are the most common and constitute a wide clinical spectrum ranging from dyspepsia, heartburn and abdominal discomfort to more serious events such as peptic ulcer with life-threatening complications of bleeding and perforation. The appreciation that CV risk is also increased further complicates the choices of physicians prescribing anti-inflammatory therapy. Despite prevention strategies should be implemented in patients at risk, gastroprotection is often underused and adherence to treatment is generally poor. A more appealing approach would be therefore to develop drugs that are devoid of or have reduced GI toxicity. Gastro- duodenal mucosa possesses many defensive mechanisms and NSAIDs have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. NSAIDs cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and systemic inhibition of gastric mucosal protection, through inhibition of cyclooxygenase (COX, PG endoperoxide G/H synthase) activity of the GI mucosa. However, against a background of COX inhibition by anti-inflammatory doses of NSAIDs, their physicochemical properties, in particular their acidity, underlie the topical effect leading to short-term damage. It has been shown that esterification of acidic NSAIDs suppresses their gastrotoxicity without adversely affecting anti-inflammatory activity. Another way to develop NSAIDs with better GI tolerability is to complex these molecules with cyclodextrins (CDs), giving rise to so-called "inclusion complexes" that can have physical, chemical and biological properties very different from either those of the drug or the cyclodextrin. Complexation of NSAIDs with ß-cyclodextrin potentially leads to a more rapid onset of action after oral administration and improved GI tolerability because of minimization of the drug gastric effects. One such drug, piroxicam-ß-cyclodextrin (PBC), has been used in Europe for 25 years. Preclinical and clinical pharmacology of PBC do show that the ß-cyclodextrin inclusion complex of piroxicam is better tolerated from the upper GI tract than free piroxicam, while retaining all the analgesic and anti-inflammatory properties of the parent compound. In addition, the drug is endowed with a quick absorption rate, which translates into a faster onset of analgesic activity, an effect confirmed in several clinical studies. An analysis of the available trials show that PBC has a GI safety profile, which is better than that displayed by uncomplexed piroxicam. Being an inclusion complex of piroxicam, whose CV safety has been pointed out by several observational studies, PBC should be viewed as a CV safe anti-inflmmatory compound and a GI safer alternative to piroxicam. As a consequence, it should be considered as a useful addition to our therapeutic armamentarium.

Pharmaceutical principles of acid inhibitors: unmet needs.

Despite the well-established benefits of currently approved delayed-release proton pump inhibitors (PPIs) in the treatment of acid-related diseases, the unmet needs are still present and although often frustrating, they challenge clinicians. The unmet needs relate to the lack of complete control of acid secretion with oral PPI administration in the management of patients with gastroesophageal symptoms. These substantial groups of patients, who do not respond completely to standard doses of PPIs, are nonresponders, and their lack of response should be considered as PPI failure. Several mechanisms could explain PPI failure: differences in pharmacokinetics, PPI formulation, dosing time and diet, noncompliance, transient lower esophageal sphincter relaxations, esophageal hypersensitivity, and nocturnal acid breakthrough. To increase the quality of life of these patients and avoid multiple medical consultations and unnecessary investigations, we have to go one step forward and use combined therapy or look towards new treatments beyond acid suppression.

[Functional endoscopy : the physiological and pathophysiological basis of reflux disease, diagnosis and therapy]. / Funktionelle Endoskopie : Physiologische und pathophysiologische Grundlagen der Refluxerkrankung, ihre Diagnostik und Therapie.

ENT specialists and gastroenterologists are increasingly confronted with the question of how to recognize and evaluate extra-esophageal complications of reflux. Both specialities need to collaborate, since they are connected via the esophagus, and both need to know more about the speciality of their neighbor than was hitherto usual. This publication presents the observations and measurements of little-known physiological functions. This is followed by an attempt to define the border between healthy and diseased. Finally, the possible consequences of functional disorders are described. The leap from observation of function to the microcosm of biochemical links is discussed and supported using experimental work. This overview highlights the limitations of our current knowledge. The success of functional endoscopy in terms of therapeutic approaches is immense. The required therapy is finally based on a clear diagnostic concept; probatory therapy is a waste of money.

Corrosive oesophageal strictures in children: outcomes after timely or delayed dilatation.

BACKGROUND AND STUDY AIMS: Among benign oesophageal lesions, caustic strictures are the most difficult to dilate. In low-income countries, children suffering caustic oesophageal injury are frequently referred to the hospitals late, sometimes weeks after ingestion. Therefore, dilatation may be performed late and in highly fibrotic strictures. Reports about endoscopic and clinical outcome of such delayed dilatations are scanty. The aim of this study was to evaluate the safety and efficacy of late caustic stricture dilatations in children, comparing it with the results of timely dilatations, both performed at the Hospital of the Italian Non-Governmental Organization "Emergency" at Goderich, Sierra Leone. PATIENTS AND METHODS: From December 2005 to May 2007, 78 children (<15 years) complaining alkaline caustic ingestion were submitted to oesophageal dilatation, mainly (97%) using Savary dilators. Two groups were identified: children (group 1) with a late treatment (>6 weeks, 37+/-12 weeks), having arrived to the hospital late after ingestion, and children (group 2) dilated timely, i.e. at <6 weeks (4+/-1.4 weeks) after injury. RESULTS: Strictures were severe in all patients. Twenty-five children were dilated late after injury (6.4 dilatations/patient) with a follow-up of 11+/-2.5 months. A successful clinical outcome was observed in 91.6%. Four perforations (2.6% procedure-related) and one death (4.0%) were observed. Strictures recurred once in 72% of patients, twice in 31.8%. Thirty-one children were dilated timely (4.5 dilatations/patient) with a follow-up of 10+/-2.1 months and a clinical success rate of 96.7%. Procedure-related perforation rate was 0.7% with one death (3.2%). Stricture recurred once in 30% and twice in 3.3%. CONCLUSIONS: Delayed dilatation of caustic oesophageal strictures in children carries a higher risk of perforation and a higher recurrence rate.