EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy.

Food allergy can result in considerable morbidity, impact negatively on quality of life, and prove costly in terms of medical care. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group, building on previous EAACI position papers on adverse reaction to foods and three recent systematic reviews on the epidemiology, diagnosis, and management of food allergy, and provide evidence-based recommendations for the diagnosis and management of food allergy. While the primary audience is allergists, this document is relevant for all other healthcare professionals, including primary care physicians, and pediatric and adult specialists, dieticians, pharmacists and paramedics. Our current understanding of the manifestations of food allergy, the role of diagnostic tests, and the effective management of patients of all ages with food allergy is presented. The acute management of non-life-threatening reactions is covered in these guidelines, but for guidance on the emergency management of anaphylaxis, readers are referred to the related EAACI Anaphylaxis Guidelines.

The diagnosis of food allergy: a systematic review and meta-analysis.

BACKGROUND: We investigated the accuracy of tests used to diagnose food allergy. METHODS: Skin prick tests (SPT), specific-IgE (sIgE), component-resolved diagnosis and the atopy patch test (APT) were compared with the reference standard of double-blind placebo-controlled food challenge. Seven databases were searched and international experts were contacted. Two reviewers independently identified studies, extracted data, and used QUADAS-2 to assess risk of bias. Where possible, meta-analysis was undertaken. RESULTS: Twenty-four (2831 participants) studies were included. For cows' milk allergy, the pooled sensitivities were 53% (95% CI 33-72), 88% (95 % CI 76-94), and 87% (95% CI 75-94), and specificities were 88% (95% CI 76-95), 68% (95% CI 56-77), and 48% (95% CI 36-59) for APT, SPT, and sIgE, respectively. For egg, pooled sensitivities were 92% (95% CI 80-97) and 93% (95% CI 82-98), and specificities were 58% (95% CI 49-67) and 49% (40-58%) for skin prick tests and specific-IgE. For wheat, pooled sensitivities were 73% (95% CI 56-85) and 83% (95% CI 69-92), and specificities were 73% (95% CI 48-89) and 43% (95% CI 20-69%) for SPT and sIgE. For soy, pooled sensitivities were 55% (95% CI 33-75) and 83% (95% CI 64-93), and specificities were 68% (95% CI 52-80) and 38% (95% CI 24-54) for SPT and sIgE. For peanut, pooled sensitivities were 95% (95% CI 88-98) and 96% (95% CI 92-98), and specificities were 61% (95% CI 47-74), and 59% (95% CI 45-72) for SPT and sIgE. CONCLUSIONS: The evidence base is limited and weak and is therefore difficult to interpret. Overall, SPT and sIgE appear sensitive although not specific for diagnosing IgE-mediated food allergy.

Can morphine still be considered to be the standard for treating chronic pain? A systematic review including pair-wise and network meta-analyses.

OBJECTIVE: For chronic pain treatment many health care authorities consider morphine to be the reference standard for strategic decisions in pain therapy. Although morphine's effectiveness is clear and its cost is low, it's unclear whether morphine should remain the first choice or reference treatment. RESEARCH DESIGN AND METHODS: We performed a systematic review to evaluate the evidence available to support the position of morphine as the reference standard for step III opioids based on efficacy and tolerability outcomes. RESULTS: The search yielded 5,675 titles and 56 studies were included. Considerable heterogeneity precluded pair-wise meta-analysis on change of pain intensity and no difference between morphine and other opioids were found for tolerability outcomes. The network meta-analysis showed no statistically significant difference in change of pain intensity between morphine and oxycodone, methadone and oxymorphone. Compared to morphine, patients using buprenorphine are more likely to discontinue treatment due to lack of effect (OR 2.32, 95% CI 1.37 to 3.95). Patients using methadone are more likely to discontinue due to adverse events (OR 3.09, 95% CI 1.14 to 8.36), whereas this risk is decreased for patients using fentanyl (OR 0.29, 95% CI 0.17 to 0.50) or buprenorphine (OR 0.30, 95% CI 0.16 to 0.53). The most important limitation of this review is that the included studies are heterogeneous with regard to study population and intervention, which may affect the pooled effect estimates. The main strength is that we only included parallel RCTs, the strongest design for intervention studies. CONCLUSIONS: The current evidence is moderate, both in respect to the number of directly comparative studies and in the quality of reporting of these studies. No clear superiority in efficacy and tolerability of morphine over other opioids was found in pair-wise and network analyses. Based on these results, a justification for the placement of morphine as the reference standard for the treatment of severe chronic pain cannot be supported.

Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding - an updated Cochrane review.

BACKGROUND: Antibiotic prophylaxis seems to decrease the incidence of bacterial infections in patients with cirrhosis and upper gastrointestinal bleeding and is considered standard of care. However, there is no updated information regarding the effects of this intervention. AIM: To assess the benefits and harms of antibiotic prophylaxis in cirrhotic patients with gastrointestinal bleeding by performing a systematic review of randomised trials. METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE and Science Citation Index EXPANDED until June 2010. We statistically combined data calculating relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes. RESULTS: Twelve trials (1241 patients) evaluating antibiotic prophylaxis against placebo or no antibiotic prophylaxis were included. Antibiotic prophylaxis was associated with reduced mortality (RR 0.79, 95% CI 0.63-0.98), mortality from bacterial infections (RR 0.43, 95% CI 0.19-0.97), bacterial infections (RR 0.35, 95% CI 0.26-0.47), rebleeding (RR 0.53, 95% CI 0.38-0.74) and days of hospitalisation (MD -1.91, 95% CI -3.80-0.02). Trials analysing rebleeding rate and hospitalisation length are still scarce, thus, caution should be exerted when interpreting the results. CONCLUSIONS: Antibiotic prophylaxis in patients with cirrhosis and upper gastrointestinal bleeding significantly reduced bacterial infections, and reduce all-cause mortality, bacterial infection mortality, rebleeding events and hospitalisation length. Novel clinically significant outcomes were included in this meta-analysis. Some benefits are biased and the risks are not yet properly assessed, this encourages future research in this field.

Pharmacological interventions for the prevention of relapse in bipolar disorder: a systematic review of controlled trials.

We conducted a systematic review and meta-analysis of randomised and quasi-randomised controlled trials evaluating all clinically relevant pharmacological interventions for the prevention of relapse in people with bipolar disorder. Thirty-four trials were included in the review. Direct comparisons with placebo and with lithium were available for most drugs. In addition, there were direct comparisons of valproate vs. olanzapine, imipramine vs. lithium plus imipramine, olanzapine plus mood stabilisers vs. mood stabilisers and perphenazine plus mood stabilisers vs. mood stabilisers. Methodological quality varied across studies and the strength of evidence was not equal for all treatments or for all comparisons. There is evidence from placebo-controlled trials for the efficacy of lithium, valproate and lamotrigine as maintenance therapy for the prevention of relapse in bipolar disorder. Three drugs have a significant effect in the prevention of manic relapses (lithium, olanzapine and aripiprazole) and three in the prevention of depressive symptoms (valproate, lamotrigine and imipramine). Imipramine is little used in practice, because of concern about adverse effects. The significant effects of olanzapine and aripiprazole were demonstrated in selected responsive bipolar I patients only. Despite widespread use in clinical practice, there is little evidence to support the efficacy of combination therapy.

Diagnostic accuracy of faecal occult blood tests used in screening for colorectal cancer: a systematic review.

OBJECTIVE: To determine the accuracy of guaiac and immunochemical faecal occult blood tests (FOBTs) for the detection of colorectal cancer in an average-risk screening population. METHODS: Fifteen electronic databases, the internet, key journals and reference lists of included studies were searched. We included diagnostic accuracy studies that compared guaiac or immunochemical FOBTs with any reference standard, for the detection of colorectal cancer in an average-risk adult population, with sufficient data to construct a 2 x 2 table. RESULTS: Fifty-nine studies were included. Thirty-three evaluated guaiac FOBTs, 35 immunochemical FOBTs and one evaluated sequential FOBTs. Sensitivities for the detection of all neoplasms ranged from 6.2% (specificity 98.0%) to 83.3% (specificity 98.4%) for guaiac FOBTs, and 5.4% (specificity 98.5%) to 62.6% (specificity 94.3%) for immunochemical FOBTs. Specificity ranged from 65.0% (sensitivity 44.1%) to 99.0% (sensitivity 19.3%) for guaiac FOBTs, and 89.4% (sensitivity 30.3%) to 98.5% (sensitivity 5.4%) for immunochemical FOBTs. Diagnostic case-control studies generally reported higher sensitivities. Sensitivities were higher for the detection of CRC, and lower for adenomas, in both the diagnostic cohort and diagnostic case-control studies for both guaiac and immunochemical FOBTs. CONCLUSIONS: Immudia HemSp appeared to be the most accurate immunochemical FOBT, however, there was no clear evidence to suggest whether guaiac or immunochemical FOBTs performed better, either from direct or indirect comparisons. Poor reporting of data limited the scope of this review, and the use the Standards for Reporting of Diagnostic Accuracy guidelines is recommended for reporting future diagnostic accuracy studies.

A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.

OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of pharmacological and/or psychosocial interventions for the prevention of relapse in people with bipolar disorder. DATA SOURCES: Major electronic databases were searched up to September 2005. REVIEW METHODS: Systematic reviews were undertaken on the clinical and economic effectiveness of treatments. An analysis was performed using the methods of mixed treatment comparison (MTC) to enable indirect comparisons to be made between the treatments. An economic model of treatments for the prevention of relapse in bipolar disorder was developed. RESULTS: Forty-five trials were included in the clinical effectiveness review; all but one studied adults. This review found that for the prevention of all relapses, lithium, valproate, lamotrigine and olanzapine performed better than placebo, with lithium and lamotrigine having the strongest evidence. For depressive relapse prevention, valproate, lamotrigine and imipramine performed better than placebo, with evidence strongest for lamotrigine and weakest for imipramine. For manic relapses, lithium and olanzapine performed significantly better than placebo. The MTC found that the best treatment for bipolar I patients with mainly depressive symptoms was valproate, followed by lithium plus imipramine. For bipolar I patients with mainly manic symptoms, olanzapine was the best treatment. From the studies investigating psychosocial interventions, there were few data for each comparison and outcome. The evidence suggests that cognitive behaviour therapy (CBT), in combination with usual treatment, is effective for the prevention of relapse. Group psychoeducation and possibly family therapy may also have roles as adjunctive therapy for preventing relapse. The results from the decision analytic model developed on the cost-effectiveness of long-term maintenance treatments of bipolar I patients suggest that the choice of treatment is dependent upon a number of factors: the previous episode history of a patient and the mortality benefit assumed for lithium strategies. The results from the base-case analysis for patients with a recent history of depression suggest that valproate, lithium and the combination of lithium and imipramine are potentially cost-effective depending upon the amount that a decision-maker is willing to pay for additional health gain. Using conventional amounts that the NHS is prepared to pay for health gain, then the lithium-based strategies appear to be potentially cost-effective for this group. For patients with a recent history of mania, the choice of pharmacological intervention appears to be between olanzapine and lithium monotherapy. Again using conventional threshold as a reference point, the results suggest that lithium is the most cost-effective therapy. Excluding the additional mortality benefit associated with lithium-based strategies resulted in all treatments for patients with a recent history of a depressive episode being dominated by valproate and, in the case of patients with a recent history of a manic episode, by olanzapine. CONCLUSIONS: Lithium, valproate, lamotrigine and olanzapine are effective as maintenance therapy for the prevention of relapse in bipolar disorder. Olanzapine and lithium are efficacious for the prevention of manic relapses and valproate, lamotrigine and imipramine for the prevention of depressive relapse. There is some evidence that CBT, group psychoeducation and family therapy might be beneficial as adjuncts to pharmacological maintenance treatments. Insufficient information is available regarding the relative tolerability of the treatments or their relative effects on suicide rate and mortality. For patients with a recent depressive episode, valproate, lithium monotherapy and the combination of lithium and imipramine are potentially cost-effective. For patients with a recent manic episode, olanzapine and lithium monotherapy are potentially cost-effective. The cost-effectiveness estimates in both groups of patients were shown to be sensitive to the assumption of a reduced suicidal risk associated with lithium-based strategies. Further research is needed into the adverse effects of all treatments and the differential effects of agents. Good-quality trials of valproate, of combination therapy, e.g. lithium plus a selective serotonin reuptake inhibitor antidepressant, of psychosocial interventions and of the disorder in children are also required.

Anticholinergics for neuroleptic-induced acute akathisia.

BACKGROUND: Neuroleptic-induced akathisia is one of the most common and distressing early-onset adverse effects of first generation 'typical' antipsychotic drugs. It is associated with poor compliance with treatment, and thus, ultimately, with an increased risk of relapse. We assessed the role of anticholinergic drugs as an adjunct therapy to standard antipsychotic medication in the pharmacological treatment of this adverse effect. OBJECTIVES: To review anticholinergic drugs for neuroleptic-induced acute akathisia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (October 1999), Biological Abstracts (1982-1999), CINAHL (1982-1999), Cochrane Library (Issue 4 1999), EMBASE (1980-1999), LILACS (1982-1999), MEDLINE (1966-1999) and PsycLIT (1974-1999). References of all identified studies were inspected for more trials and we contacted first authors. Each included study was sought as a citation on the Science Citation Index database. For this 2005-6 update, we searched the Cochrane Schizophrenia Group's Register (July 2005). SELECTION CRITERIA: We included all randomised clinical trials of adjunctive anticholinergic drugs in addition to antipsychotic medication compared with placebo, for people with neuroleptic-induced acute akathisia. DATA COLLECTION AND ANALYSIS: We quality assessed and extracted data independently. We calculated the fixed effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) for homogeneous dichotomous data on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). MAIN RESULTS: We identified no relevant randomised controlled trials. AUTHORS' CONCLUSIONS: At present, there is no reliable evidence to support or refute the use of anticholinergics for people suffering from neuroleptic-induced acute akathisia. Akathisia is a distressing movement disorder that remains highly prevalent in people with schizophrenia, both in the developed and developing world. This review highlights the need for well designed, conducted and reported clinical trials to address the claims of open studies as regards the effects of the anticholinergic group of drugs for akathisia.

Benzodiazepines for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is a disfiguring movement disorder, often of the orofacial region, frequently caused by the use of neuroleptic drugs. A wide range of strategies have been used to help manage tardive dyskinesia, and for those who are unable to have their antipsychotic medication stopped or substantially changed, the benzodiazepine group of drugs have been suggested as a useful adjunctive treatment. OBJECTIVES: To determine the effects of benzodiazepines for neuroleptic-induced tardive dyskinesia in people with schizophrenia or other chronic mental illnesses. SEARCH STRATEGY: 1. Electronic searches. For the update of 2006, we searched The Cochrane Schizophrenia Group Trials Register (November 2005). For the previous two updates (1996, 2002) the review authors searched Biological Abstracts (1982-2002), the Cochrane Schizophrenia Group's Register of trials (February 2002), EMBASE (1980-2002), LILACS (1982-2002), MEDLINE (1966-2002), PsycLIT (1974-2002), SCISEARCH (2002), hand searched references of all included/excluded studies and contacted the first author of each included trial. SELECTION CRITERIA: We included all randomised clinical studies focusing on people with schizophrenia (or other chronic mental illnesses) and neuroleptic-induced tardive dyskinesia that compared benzodiazepines with placebo or no intervention. DATA COLLECTION AND ANALYSIS: We independently extracted data from the studies and ensured that they were reliably selected, and quality assessed. For homogenous dichotomous data we calculated random effects, relative risk (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat (NNT) on an intention-to-treat basis. We synthesised continuous data from valid scales by using a weighted mean difference (WMD). For continuous outcomes we preferred endpoint data to change data. MAIN RESULTS: We identified three trials (total N=56, one additional trial since 2002, n=24). Using benzodiazepines as an adjunctive treatment did not result in any clear changes for a series of tardive dyskinesia medium-term outcomes (n=30, 2 RCTs, RR not improved to clinically important extent 1.08 CI 0.57 to 2.05). One trial (n=24) found end point abnormal movement scores to be better for those receiving adjunct benzodiazepines(WMD AIMS -3.22 CI -4.63 to -1.81 ). Less than 10% in both groups left these studies before completion and none of the studies reported clear adverse effects. AUTHORS' CONCLUSIONS: One small study reports some preliminary evidence that benzodiazepines may have some effect in neuroleptic induced tardive dyskinesia. Inconclusive results from other studies means routine clinical use is not indicated and these treatments remain experimental.

Neuroleptic reduction and/or cessation and neuroleptics as specific treatments for tardive dyskinesia.

BACKGROUND: Since the 1950s neuroleptic medication has been extensively used to treat people with chronic mental illnesses such as schizophrenia. These drugs, however, have been also associated with a wide range of adverse effects, including movement disorders such as tardive dyskinesia (TD). Various strategies have been examined to reduce a person's cumulative exposure to neuroleptics. These studies include dose reduction, intermittent dosing strategies such as drug holidays, and neuroleptic cessation. OBJECTIVES: To determine whether a reduction or cessation of neuroleptic drugs is associated with a reduction in TD, for people with schizophrenia (or other chronic mental illnesses) who have existing TD. Our secondary objective was to determine whether the use of specific neuroleptics for similar groups of people could be a treatment for TD that was already established. SEARCH STRATEGY: We updated previous searches of the Cochrane Schizophrenia Groups Register (1997), Biological Abstracts (1982-1997), EMBASE (1980-1997), LILACS (1982-1996), MEDLINE (1966-1997), PsycLIT (1974-1997), and SCISEARCH (1997) by searching the Cochrane Schizophrenia Groups Register (July 2003). We searched references of all identified studies for further trial citations. We also contacted the principal authors of trials for further unpublished trials. SELECTION CRITERIA: We included reports if they assessed people with schizophrenia or other chronic mental illnesses who had established neuroleptic-induced TD, and had been randomly allocated to (a) neuroleptic maintenance versus neuroleptic cessation (placebo or no intervention), (b) neuroleptic maintenance versus neuroleptic reduction (including intermittent strategies), and (c) specific neuroleptics for the treatment of TD versus, placebo or intervention. A post hoc decision was made to broaden comparison (c) to include specific neuroleptics versus other neuroleptics for the treatment of TD. DATA COLLECTION AND ANALYSIS: We (KSW, JR) independently inspected citations and, where possible, abstracts, ordered papers, and re-inspected and quality assessed these and extracted data. We analysed dichotomous data using random effects relative risk (RR) and estimated the 95% confidence interval (CI). Where possible we calculated the number needed to treat (NNT) or number needed to harm statistic (NNH). We excluded continuous data if more than 50% of people were lost to follow up, but, where possible, we calculated the weighted mean difference (WMD). It was assumed that those leaving the study early showed no improvement. MAIN RESULTS: We included five trials and excluded 102. One small two week study (n=18), reported on the 'masking' effects of molindone and haloperidol on TD, which favoured haloperidol (RR 3.44 CI 1.1 to 5.8). Two (total n=17) studies found no reduction in TD associated with neuroleptic reduction (RR 0.38 CI 0.1 to 1.0). One study (n=20) found no significant differences in oral dyskinesia (RR 2.45 CI 0.3 to 19.7) when neuroleptics were compared as a specific treatment for TD. Dyskinesia was found to be not significantly different (n=32, RR 0.62 CI 0.3 to 1.26) between quetiapine and haloperidol when these neuroleptics were used as specific treatments for TD, although the need for additional neuroleptics was significantly lower in the quetiapine group (n=47, RR 0.49 CI 0.2 to 1.0) than in those given haloperidol. AUTHORS' CONCLUSIONS: Limited data from small studies using neuroleptic reduction or specific neuroleptic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration in order to fully investigate this area.

Non-neuroleptic catecholaminergic drugs for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of neuroleptic medication. Several strategies have been examined in the treatment of TD. Currently, however, there is no clear evidence of the effectiveness of these drugs in TD and they have been associated with many side effects. One particular strategy would be to use pharmaceutical agents which are known to influence the catecholaminergic system at various junctures. OBJECTIVES: To determine whether catecholaminergic drugs for people with schizophrenia or other chronic mental illnesses are associated with a reduction in neuroleptic-induced tardive dyskinesia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (January 1996), Biological Abstracts (1982-1995), EMBASE (1980-1995), LILACS (1982-1996), MEDLINE (1966-1995) and PsycLIT (1974-1995). We searched the Cochrane Schizophrenia Group's Register again in December 2002 and September 2005. We also searched references of all relevant studies for further trial citations and contacted principal authors of trials. SELECTION CRITERIA: We selected studies if they were randomised controlled trials focusing on people with schizophrenia or other chronic mental illnesses who also suffered from neuroleptic-induced tardive dyskinesia. We compared the use of catecholaminergic interventions versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: We independently extracted data. For homogenous dichotomous data, we calculated the random effects, relative risk (RR), and 95% confidence interval (CI) and, where appropriate, the numbers needed to treat (NNT) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). MAIN RESULTS: We excluded 20 studies, mainly due to an inability to extract data from the first arm of the study crossover. One included study has shown that patients on placebo were no more likely to leave the study early than those on tiapride (n=24). The other included study (n=35) also reported equivocal data (RR 5.28 CI 0.3 to 102.6) for leaving the study early when participants were randomised to either celiprolol or placebo. However, in both studies, sample size was limited. AUTHORS' CONCLUSIONS: Although there has been a large amount of research in this area, most studies were excluded due to inherent problems in the nature of their crossover designs. Usually data are not reported before the crossover and the nature of TD and its likely response to treatments makes it imprudent to use this data. The review provides little usable information for service users or providers and more well designed and reported studies are indicated.

Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis.

BACKGROUND: Optimal antibiotic treatment for sepsis is imperative. Combining a beta-lactam antibiotic with an aminoglycoside antibiotic may have certain advantages over beta-lactam monotherapy. OBJECTIVES: We compared clinical outcomes for beta lactam-aminoglycoside combination therapy versus beta lactam monotherapy for sepsis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2004); MEDLINE (1966 to July 2004); EMBASE (1980 to March 2003); LILACS (1982 to July 2004); and conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (1995 to 2003). We scanned citations of all identified studies and contacted all corresponding authors. SELECTION CRITERIA: We included randomized and quasi-randomized trials comparing any beta-lactam monotherapy to any combination of one beta-lactam and one aminoglycoside for sepsis. DATA COLLECTION AND ANALYSIS: The primary outcome was all-cause fatality. Secondary outcomes included treatment failure, superinfections, colonization, and adverse events. Two authors independently collected data. We pooled relative risks (RR) with their 95% confidence intervals (CI) using the fixed effect model. We extracted outcomes by intention-to-treat analysis whenever possible. MAIN RESULTS: We included 64 trials, randomizing 7586 patients. Twenty trials compared the same beta-lactam in both study arms, while the remaining compared different beta-lactams using a broader spectrum beta-lactam in the monotherapy arm. In studies comparing the same beta-lactam, we observed no difference between study groups with regard to all-cause fatality, RR 1.01 (95% CI 0.75-1.35) and clinical failure, RR 1.11 (95% CI 0.95-1.29). In studies comparing different beta-lactams, we observed an advantage to monotherapy: all cause fatality RR 0.85 (95% CI 0.71-1.01), clinical failure RR 0.77 (95% CI 0.69-0.86). No significant disparities emerged from subgroup and sensitivity analyses, including the assessment of patients with Gram-negative and Pseudomonas aeruginosa infections. We detected no differences in the rate of resistance development. Adverse events rates did not differ significantly between the study groups overall, although nephrotoxicity was significantly more frequent with combination therapy, RR 0.30 (95% CI 0.23-0.39). We found no heterogeneity for all comparisons. We included a small subset of studies addressing patients with Gram-positive infections, mainly endocarditis. We identified no difference between monotherapy and combination therapy in these studies. AUTHORS' CONCLUSIONS: The addition of an aminoglycoside to beta-lactams for sepsis should be discouraged. All-cause fatality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity.

Cyclosporine A for induction of remission in severe ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is characterized by a life-long chronic course with remissions and exacerbations. Approximately 15% of patients have a severe attack requiring hospitalization at some time during their illness. These patients are traditionally treated with intravenous corticosteroids, with a response rate of approximately 60%. The patients who do not respond to steroid treatment usually require surgical removal of the large bowel (proctocolectomy or colectomy with an anal pouch). This surgical procedure essentially cures the patient from the disease but is associated with complications such as pouchitis. Few alternative treatments exist for severe ulcerative colitis: immunosuppressive medications (such as azathioprine) have a slow onset of action and are therefore usually ineffective. Antibiotics are not proven to be effective and biological treatments such as infliximab are still under investigation. The introduction of cyclosporine-A (CsA) for use in patients with severe ulcerative colitis (UC) has provided an alternative to patients previously facing only surgical options. Cyclosporine acts mainly by inhibiting T lymphocyte function, which is essential for the propagation of inflammation. Unlike most other immunosuppressive agents, CsA does not suppress the activity of other hematopoietic cells, does not cause bone marrow suppression and has a rapid onset of action. This reviews aims to systematically assess the effectiveness and safety of CsA for severe UC. OBJECTIVES: This review aimed to evaluate the effectiveness of cyclosporine A for patients with severe ulcerative colitis. SEARCH STRATEGY: Electronic searches of The Cochrane Library (Issue 1, 2004), EMBASE (1980-2004), and MEDLINE (1966-2004); hand searching the references of all identified studies; contacting the first author of each included trial. SELECTION CRITERIA: Randomised clinical trials comparing cyclosporine A with placebo or no intervention to obtain and maintain remission of idiopathic ulcerative colitis. DATA COLLECTION AND ANALYSIS: Two reviewers independently appraised the quality of each trial and extracted the data from the included trials. Relative risks (RR) with 95% confidence intervals (CI) were estimated. The reviewers assumed an intention to treat analysis for the outcome measures. MAIN RESULTS: Only two randomized controlled trials were identified that satisfied the inclusion criteria. These two trials could not be pooled for analysis because of major differences in design and patient populations. In the first trial, 11 patients received intravenous cyclosporine (4 mg/kg) and 9 received placebo. Two of 11 in the treatment group failed to respond to therapy compared with nine of nine in the placebo group (RR 0.18, 95% CI 0.05 - 0.64). However, 3/11 and 4/9 eventually underwent colectomy in the treatment and placebo groups respectively and follow-up was less than a month. In the second trial 15 patients were treated with intravenous cyclosporine and 15 with intravenous methylprednisolone. Five of 15 patients in the cyclosporine group failed to respond to therapy as compared to 7/15 in the methylprednisolone group (RR 0.71, 95% CI 0.29 - 1.75). After 1 year 7/9 responders in the cyclosporine group were still in remission compared with 4/8 in the steroid group (p > 0.05) and the colectomy rate was similar in both groups. The mean time to response in the cyclosporine group in the 2 trials was short (7 days and 5.2 days). These results should be interpreted with caution given the small numbers of trials and patients evaluated for comparison, and limited follow-up (few weeks in one trial to a year in the other). The precise assessment of the occurrence of adverse events was difficult because the trials described different adverse reactions, which reversed after discontinuation of cyclosporine. There was no evidence in the trials reviewed that cyclosporine was more effective than standard treatment for preventing colectomy but this effect cannot be excluded due to the small sample size and rarity of this outcome. Additional limitations of current research include lack of data on quality of life, costs and long-term results of cyclosporine therapy. AUTHORS' CONCLUSIONS: There is limited evidence that cyclosporine is more effective than standard treatment alone for severe ulcerative colitis. The relatively quick response makes the short-term use of cyclosporine potentially attractive, but the long-term benefit is unclear, when adverse events such as cyclosporine-induced nephrotoxicity may become more obvious. There is a need for additional research on quality of life, costs and long-term results from cyclosporine therapy in severe ulcerative colitis.

Central action beta-blockers versus placebo for neuroleptic-induced acute akathisia.

BACKGROUND: Neuroleptic-induced akathisia is a common, distressing early-onset adverse effect of neuroleptic drugs. It has been associated with poor treatment compliance and an increased risk of relapse. OBJECTIVES: To determine the effects of central action beta-blockers compared with placebo for people with neuroleptic-induced acute akathisia. SEARCH STRATEGY: We updated previous searches of the Cochrane Schizophrenia Group Register (May 1999), Biological Abstracts (January 1982-March 1999), The Cochrane Library (issue 3 1999), EMBASE (January 1980-March 1999), LILACS (January 1982-March 1999), MEDLINE (January 1964-March 1999), PsycLIT (January 1974-March 1999), and SCISEARCH by searching the Cochrane Schizophrenia Group Register (November 2003). We sought further references from published trials and their authors. SELECTION CRITERIA: We included all randomised controlled clinical trials of central action beta-blockers versus placebo for people with neuroleptic-induced acute akathisia. DATA COLLECTION AND ANALYSIS: Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to treat (NNT). For continuous data we calculated Weighted Mean Differences (WMD). MAIN RESULTS: We identified three randomised controlled trials (total n=51, maximum duration 72 hours). We were not able to draw any firm conclusions from such a small data set. In the two 48 hour studies no-one experienced full remission of akathisia, and only one person in each group experienced a 50% remission (n=11, 1 RCT, RR 1.04 CI 0.59 -1.83). One trial stated that no adverse effects occurred in the two groups (n=20, 1 RCT, RR not estimable). The 72 hour study did not show any statistical difference between the central acting beta-blocker (ICI 118,551) and placebo for the outcome 'no change/worse' (n=10, RR 0.22 CI 0.0 to 1.5). REVIEWERS' CONCLUSIONS: There are insufficient data to recommend beta-blocking drugs for akathisia. These drugs are experimental for this problem, and this review highlights the need for more evaluative studies.

Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients.

BACKGROUND: Fever occurring in a neutropenic patient remains a common life-threatening complication of cancer chemotherapy. The common practice is to admit the patient to hospital and treat empirically with intravenous broad-spectrum antibiotics. Oral therapy could be an alternative approach for selected patients. OBJECTIVES: To compare the efficacy of oral antibiotics versus intravenous (IV) antibiotic therapy in febrile neutropenic cancer patients. SEARCH STRATEGY: We searched the Cochrane Cancer Network Register of trials (November 2002), the Cochrane Library (issue 2, 2002), MEDLINE (1966 to 2002), EMBASE (January 1980 to 2002) and LILACS (1982 to 2002). We searched several databases for ongoing trials. We checked the conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) 1995 to 2002 and all references of included studies and major reviews were scanned. SELECTION CRITERIA: Randomised controlled trials comparing oral antibiotic/s to intravenous antibiotic/s for the treatment of neutropenic cancer patients with fever. The comparison between the two could be started initially (initial oral), or following an initial course of intravenous antibiotic treatment (sequential). DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility, methodological quality and extracted data. Data concerning mortality, treatment failures and adverse events were extracted from included studies assuming an "intention-to-treat" basis for the outcome measures whenever possible. Relative risks (RR) with 95% confidence intervals (CI) for dichotomous data were estimated. MAIN RESULTS: Fifteen trials (median mortality 0, range 0 to 8.8%) were included in the analyses. The mortality rate was similar comparing oral to intravenous antibiotic treatment (RR 0.91, 95% CI 0.51 to 1.62, 7 trials, 1223 patients). Treatment failure rates were also similar (RR 0.94, 95% CI 0.84 to 1.05, all trials). No significant heterogeneity was shown for all comparisons but adverse events. This effect was stable in a wide range of patients. Quinolones alone or combined with another antibiotics were used with comparable results. Adverse reactions, mostly gastrointestinal were more common with oral antibiotics. REVIEWERS' CONCLUSIONS: Based on the present data, oral treatment is an acceptable alternative to intravenous antibiotic treatment in febrile neutropenic cancer patients (excluding patients with acute leukaemia) who are haemodynamically stable, without organ failure, not having pneumonia, infection of a central line or a severe soft-tissue infection. The wide confidence interval for mortality allows the present use of oral treatment in groups of patients with an expected low risk for mortality, and further research should be aimed at clarifying the definition of low risk patients.

Calcium channel blockers for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia is a disfiguring movement disorder of the orofacial region often caused by antipsychotic drugs. A wide range of strategies has been used to help manage tardive dyskinesia and, for people who are unable to have their antipsychotic medication stopped or substantially changed, the calcium-channel blocking group of drugs (diltiazem, nifedipine, nimodipine, verapamil) has been suggested as a useful adjunctive treatment. OBJECTIVES: To determine the effects of calcium-channel blocker drugs (diltiazem, nifedipine, nimodipine, verapamil) for treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses. SEARCH STRATEGY: We updated previous searches of the Cochrane Schizophrenia Group Register (1982-2000), Cochrane Library (Issue 4, 2000), Cochrane Schizophrenia Group's register of trials (November 2000), EMBASE (1980-2000), LILACS (1982-2000), MEDLINE (1966-2000), PsycLIT (1974-2000), and SCISEARCH by searching the Cochrane Schizophrenia Group Register (September 2003). We searched references of all identified studies for further trial citations and contacted authors of trials. SELECTION CRITERIA: Randomised clinical trials comparing calcium-channel blockers to placebo or no intervention for people with both tardive dyskinesia and schizophrenia or serious mental illness. DATA COLLECTION AND ANALYSIS: Data were to have been independently extracted and analysed on an intention-to-treat basis. The relative risk (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data were to have been calculated using a random effects model, and, where possible, the number needed to treat calculated. Weighted mean differences (WMD) were to have been calculated for continuous data. MAIN RESULTS: No trials were included. We excluded fourteen studies; eight were not randomised, one did not use calcium channel blockers and five small, randomised, studies reported no usable data. REVIEWER'S CONCLUSIONS: The effects of calcium-channel blockers for antipsychotic induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well designed randomised studies.

Rotavirus vaccine for preventing diarrhoea.

BACKGROUND: Rotaviruses cause viral gastroenteritis and result in more deaths from diarrhoea in children under 5 years of age than any other single agent, particularly in low- and middle-income countries. OBJECTIVES: To assess rotavirus vaccines in relation to preventing rotavirus diarrhoea, death, and adverse events. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group's trial register (October 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to October 2003), EMBASE (January 1980 to October 2003), LILACS (1982 to October 2003), Biological Abstracts (January 1982 to October 2003), reference lists of articles, and contacted researchers and rotavirus vaccine manufacturers. SELECTION CRITERIA: Randomized controlled trials comparing rotavirus vaccines to placebo, no intervention, or other rotavirus vaccines in children and adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial methodological quality, and contacted trial authors for additional information. MAIN RESULTS: Sixty-four trials provided information on efficacy and safety of three main types of rotavirus vaccine (bovine, human, and rhesus) for 21,070 children. Different levels of efficacy were demonstrated with different vaccines varying from 22 to 89% to prevent one episode of rotavirus diarrhoea, 11 to 44% to prevent one episode of all-cause diarrhoea, and 43 to 90% to prevent one episode of severe rotavirus diarrhoea. Rhesus vaccine demonstrated a similar efficacy against one episode of rotavirus diarrhoea (37 and 44% respectively), and one episode of all-cause diarrhoea (around 15%) for trials performed in high and middle-income countries. Results on mortality and safety of the vaccines were scarce and incomplete. We noticed important heterogeneity among the pooled studies and were unable to discard a biased estimation of effect. REVIEWER'S CONCLUSIONS: Current evidence shows that rhesus rotavirus vaccines (particularly RRV-TV) and the human rotavirus vaccine 89-12 are efficacious in preventing diarrhoea caused by rotavirus and all-cause diarrhoea. Evidence about safety, and about mortality or prevention of severe outcomes, is scarce and inconclusive. Bovine rotavirus vaccines were also efficacious, but safety data are not available. Trials of new rotavirus vaccines will hopefully improve the evidence base. Randomized controlled trials should be performed simultaneously in high-, middle-, and low-income countries.

Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropaenia.

BACKGROUND: Chemotherapy treated cancer patients are prone to neutropaenia and life-threatening infections. Early, empirical antibiotic treatment is therefore administered routinely to febrile neutropaenic patients. Currently, either beta-lactam-aminoglycoside combination treatment or beta-lactam monotherapy are recommended. OBJECTIVES: We compared beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for cancer patients with fever and neutroepaenia. SEARCH STRATEGY: We searched the Cochrane Cancer Network Register (searched July, 2000), the Cochrane Controlled Trials Register (Cochrane Library Issue 4, 2001), EMBASE (January 1980 to December 2000), LILACS (January 1982 to August 2001), MEDLINE (January 1966 to August 2001), and ICAAC conference proceedings (1995 to 2000). We scanned references of all included studies, pertinent reviews, and contacted the first author of each included trial and the pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing any beta-lactam antibiotic monotherapy to any combination of a beta-lactam and an aminoglycoside antibiotic, for the initial, empirical treatment of febrile neutropaenic cancer patients. DATA COLLECTION AND ANALYSIS: Data concerning mortality, treatment failure (including treatment modifications), superinfections, adverse effects and study quality measures were extracted independently by two reviewers. Relative risks with their 95% confidence intervals (CI) were estimated. Outcomes were extracted by intention-to-treat analysis whenever possible. MAIN RESULTS: Forty-six trials and 7642 patients were included. All cause mortality was the primary outcome assessed. For all mortality comparisons, no significant difference between monotherapy and combination therapy was seen, relative risk 0.85 (95% CI 0.72-1.02) for all studies combined. Treatment failure was the outcome reported in all included trials. No significant difference between study groups was shown for studies comparing the same beta-lactam, relative risk 1.12 (95% CI 0.96-1.29). A significant advantage to monotherapy was observed for studies comparing different beta-lactams, relative risk 0.86 (95% CI 0.80-0.93). Bacterial and fungal superinfections developed with similar frequencies in the monotherapy and combination treatment groups. Adverse events were significantly more common in the combination treatment group, relative risk 0.83, (95% CI 0.72-0.97). These included events associated with significant morbidity, primarily renal toxicity. Results were consistent for subgroup and sensitivity analyses. REVIEWER'S CONCLUSIONS: We have shown an advantage to broad-spectrum beta-lactam monotherapy over beta-lactam-aminoglycoside combination therapy for febrile neutropaenia. This advantage comprises of 1) a similar, if not better, survival, 2) a significantly lower treatment failure rate, 3) comparable probability for secondary infections and, 4) most importantly, a lower rate of adverse events associated with significant morbidity. Monotherapy can be regarded, therefore, as the standard of care for febrile neutropaenic patients.

Miscellaneous treatments for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia is a disabling movement disorder associated with the prolonged use of neuroleptic medication. This review, one in a series examining the treatment of tardive dyskinesia, will cover miscellaneous treatments not covered elsewhere. OBJECTIVES: To determine whether the following interventions were associated with a reduction of neuroleptic induced tardive dyskinesia: botulin toxin, endorphin, essential fatty acid, EX11582A, ganglioside, insulin, lithium, naloxone, oestrogen, periactin, phenylalanine, piracetam, stepholidine, tryptophan, neurosurgery, or ECT. SEARCH STRATEGY: The initial search of Biological Abstracts (1982-1995), The Cochrane Schizophrenia Group's Register (January 1996), EMBASE (1980-1995), LILACS (1982-1996), MEDLINE (1966-1995) and PsycLIT (1974-1995) was updated by searching Cochrane Schizophrenia Group's Register in July 2002. References of all relevant studies were searched for further trial citations. Principal authors of trials were contacted. SELECTION CRITERIA: Studies were selected if they focused on people with schizophrenia or other chronic mental illnesses, with neuroleptic-induced tardive dyskinesia and compared the use of the interventions listed above versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: Studies were reliably selected, quality assessed and data extracted. Data were excluded where more than 50% of participants in any group were lost to follow up. For binary outcomes a random effects risk ratio (RR) and its 95% confidence interval (CI) was calculated. Where possible, the weighted number needed to treat/harm statistic (NNT/H), and its 95% confidence interval (CI), was also calculated. For continuous outcomes, endpoint data were preferred to change data. Non-skewed data from valid scales were to have been synthesised using a weighted mean difference (WMD). MAIN RESULTS: Fifty-seven references describing 37 different trials were identified by the search strategy. Seven of these were included, 27 excluded, and three await assessment. Ceruletide was not clearly more effective than placebo (n=132, 2 RCTs, RR not any improvement in tardive dyskinesia 0.82 CI 0.6 to 1.1). This also applied to gamma-linolenic acid, although data were sparse (n=16, 1 RCT, RR no clinical improvement 1.00 CI 0.7 to 1.5), oestrogen (n=12, 1 RCT, RR no clinically important improvement 1.2 CI 0.8 to 1.7), and lithium (n=11, 1 RCT, RR no clinically important improvement 1.39 CI 0.6 to 3.1). Phenylalanine may even be detrimental (n=18, 1 RCT, MD AIMS score 4.40 CI 1.16 to 7.64). One small study (n=20) found that insulin was more likely to produce a clinical improvement in tardive dyskinesia than placebo (RR no clinical improvement 0.5 CI 0.3 to 0.9, NNT 2 CI 1 to 5). REVIEWER'S CONCLUSIONS: There is no strong evidence to support the everyday use of any of the agents included in this review. All results must be considered inconclusive and these compounds probably should only be used within the context of a well-designed evaluative study.