Evolução na abordagem Fármaco-terapêutica da úlcera péptica

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer

BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of metastatic breast cancer. We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease, aged < or = 70 years, received one of the following regimens: a) sequential A-->T-->CMF: doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x 3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T-->CMF: A and T were administered at the same doses q 2 weeks; c) combination therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF x 4. When indicated, radiotherapy was administered during or after CMF, and tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been treated. Median age was 48 years. A 30% rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy (23% during A-->T), due principally to severe skin toxicity. Median relative dose-intensity was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c: 48%. After a median follow-up of 18 months, no late toxicity has been reported. CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity. The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy.

A strategy to advance the evidence base in palliative medicine: formation of a palliative care research cooperative group.

BACKGROUND: Palliative medicine has made rapid progress in establishing its scientific and clinical legitimacy, yet the evidence base to support clinical practice remains deficient in both the quantity and quality of published studies. Historically, the conduct of research in palliative care populations has been impeded by multiple barriers including health care system fragmentation, small number and size of potential sites for recruitment, vulnerability of the population, perceptions of inappropriateness, ethical concerns, and gate-keeping. METHODS: A group of experienced investigators with backgrounds in palliative care research convened to consider developing a research cooperative group as a mechanism for generating high-quality evidence on prioritized, clinically relevant topics in palliative care. RESULTS: The resulting Palliative Care Research Cooperative (PCRC) agreed on a set of core principles: active, interdisciplinary membership; commitment to shared research purposes; heterogeneity of participating sites; development of research capacity in participating sites; standardization of methodologies, such as consenting and data collection/management; agile response to research requests from government, industry, and investigators; focus on translation; education and training of future palliative care researchers; actionable results that can inform clinical practice and policy. Consensus was achieved on a first collaborative study, a randomized clinical trial of statin discontinuation versus continuation in patients with a prognosis of less than 6 months who are taking statins for primary or secondary prevention. This article describes the formation of the PCRC, highlighting processes and decisions taken to optimize the cooperative group's success.

Population-Growth And Vertical-Distribution Of Calanus-Helgolandicus In The Celtic Sea

Calanus helgolandicus over-winters in the shallow waters (100 m) of the Celtic Sea as copepodite stages V and VI; the minimum temperature in winter is approximately 8.0°C. This over-wintering is not a true hibernation or dormacy, accompanied by a reduced metabolic state with a discontinuation of feeding and development, but more of a lowered activity, involving reduced feeding and development, with predation on available microzooplankton and detritus. Analysis of specimens from the winter population showed that copepodite stages V and VI were actively feeding and still producing and possibly liberating eggs. The absence of late nauplii and young copepodites in the water column until late March indicated that there must be a high mortality of these winter cohorts. The copepodites of the first generation appeared in April–May, the younger stages, copepodites I to III, being distributed deeper in the water column below the euphotic zone and thermocline. This distribution would contribute to amuch slower rate of development. By August the ontogenetic vertical distributions observed in the copepodites were reversed, the younger stages occuring in the warmer surface layers within the euphotic zone. Diurnal migrations were observed in the later copepodites only, the younger stages I to III either remaining deep in spring or shallow in summer. The causal mechanisms which alter the behaviour of the young copepodites remain unexplained. The development of the population of Calanus helgolandicus in 1978, reaching its peak of abundance in August, was typical for the shelf seas around U.K. as observed from Continuous Plankton Recorder data, 1958 to 1977.

The effects of blood pressure lowering on development of cognitive impairment and dementia in patients without apparent prior cerebrovascular disease

BACKGROUND: Hypertension and cognitive impairment are prevalent in older people. It is known that hypertension is a direct risk factor for vascular dementia and recent studies have suggested hypertension also impacts upon prevalence of Alzheimer's disease. The question is therefore whether treatment of hypertension lowers the rate of cognitive decline. OBJECTIVES: To assess the effects of blood pressure lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease. SEARCH STRATEGY: The trials were identified through a search of CDCIG's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO and CINAHL on 27 April 2005. SELECTION CRITERIA: Randomized, double-blind, placebo controlled trials in which pharmacological or non-pharmacological interventions to lower blood pressure were given for at least six months. DATA COLLECTION AND ANALYSIS: Two independent reviewers assessed trial quality and extracted data. The following outcomes were assessed: incidence of dementia, cognitive change from baseline, blood pressure level, incidence and severity of side effects and quality of life. MAIN RESULTS: Three trials including 12,091 hypertensive subjects were identified. Average age was 72.8 years. Participants were recruited from industrialised countries. Mean blood pressure at entry across the studies was 170/84 mmHg. All trials instituted a stepped care approach to hypertension treatment, starting with a calcium-channel blocker, a diuretic or an angiotensin receptor blocker. The combined result of the three trials reporting incidence of dementia indicated no significant difference between treatment and placebo (Odds Ratio (OR) = 0.89, 95% CI 0.69, 1.16). Blood pressure reduction resulted in a 11% relative risk reduction of dementia in patients with no prior cerebrovascular disease but this effect was not statistically significant (p = 0.38) and there was considerable heterogeneity between the trials. The combined results from the two trials reporting change in Mini Mental State Examination (MMSE) did not indicate a benefit from treatment (Weighted Mean Difference (WMD) = 0.10, 95% CI -0.03, 0.23). Both systolic and diastolic blood pressure levels were reduced significantly in the two trials assessing this outcome (WMD = -7.53, 95% CI -8.28, -6.77 for systolic blood pressure, WMD = -3.87, 95% CI -4.25, -3.50 for diastolic blood pressure).Two trials reported adverse effects requiring discontinuation of treatment and the combined results indicated a significant benefit from placebo (OR = 1.18, 95% CI 1.06, 1.30). When analysed separately, however, more patients on placebo in SCOPE were likely to discontinue treatment due to side effects; the converse was true in SHEP 1991. Quality of life data could not be analysed in the three studies. There was difficulty with the control group in this review as many of the control subjects received antihypertensive treatment because their blood pressures exceeded pre-set values. In most cases the study became a comparison between the study drug against a usual antihypertensive regimen. AUTHORS' CONCLUSIONS: There was no convincing evidence from the trials identified that blood pressure lowering prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease. There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients given active treatment. This introduced bias. More robust results may be obtained by analysing one year data to reduce differential drop-out or by conducting a meta-analysis using individual patient data.

Claw removal and feeding ability in the edible crab, Cancer pagurus: Implications for fishery practice

Feeding ability and motivation were assessed in the edible crab, Cancer pagurus, to investigate how the fishery practice of de-clawing may affect live crabs returned to the sea. Crabs were either induced to autotomise one claw, or were only handled, before they were offered food. Initially, autotomised and handled crabs were offered mussels, Mytilis edulis, a large part of their natural diet. After 3 days, both autotomised and handled crabs were then offered fish, a more readily handled food source. Autotomy induced crabs consumed significantly fewer mussels and less mussel mass, but ate significantly more mass of fish. This indicates that the effect of autotomy was a reduction of ability to feed on mussels rather than a general reduction of feeding motivation. The discontinuation of claw removal needs to be considered, both for the sustainability of the fishery and animal welfare concerns. (C) 2008 Elsevier B.V. All rights reserved.

Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia

Background: This is an update of a previous review (McGuinness 2006). Hypertension and cognitive impairment are prevalent in older people. Hypertension is a direct risk factor for vascular dementia (VaD) and recent studies have suggested hypertension impacts upon prevalence of Alzheimer's disease (AD). Therefore does treatment of hypertension prevent cognitive decline?
Objectives: To assess the effects of blood pressure lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease.
Search strategy: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources were searched on 13 February 2008 using the terms: hypertens$ OR anti-hypertens$. Selection criteria: Randomized, double-blind, placebo controlled trials in which pharmacological or non-pharmacological interventions to lower blood pressure were given for at least six months.
Data collection and analysis: Two independent reviewers assessed trial quality and extracted data. The following outcomes were assessed: incidence of dementia, cognitive change from baseline, blood pressure level, incidence and severity of side effects and quality of life.
Main results: Four trials including 15,936 hypertensive subjects were identified. Average age was 75.4 years. Mean blood pressure at entry across the studies was 171/86 mmHg. The combined result of the four trials reporting incidence of dementia indicated no significant difference between treatment and placebo (236/7767 versus 259/7660, Odds Ratio (OR) = 0.89, 95% CI 0.74, 1.07) and there was considerable heterogeneity between the trials. The combined results from the three trials reporting change in Mini Mental State Examination (MMSE) did not indicate a benefit from treatment (Weighted Mean Difference (WMD) = 0.42, 95%CI 0.30, 0.53). Both systolic and diastolic blood pressure levels were reduced significantly in the three trials assessing this outcome (WMD = -10.22, 95% CI -10.78, -9.66 for systolic blood pressure, WMD = -4.28, 95% CI -4.58, -3.98 for diastolic blood pressure). Three trials reported adverse effects requiring discontinuation of treatment and the combined results indicated no significant difference (OR = 1.01, 95% CI 0.92, 1.11). When analysed separately, however, more patients on placebo in Syst Eur 1997 were likely to discontinue treatment due to side effects; the converse was true in SHEP 1991. Quality of life data could not be analysed in the four studies. Analysis of the included studies in this review was problematic as many of the control subjects received antihypertensive treatment because their blood pressures exceeded pre-set values. In most cases the study became a comparison between the study drug against a usual antihypertensive regimen.
Authors' conclusions: There is no convincing evidence fromthe trials identified that blood pressure lowering in late-life prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease. There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients who received active treatment. This introduced bias. More robust results may be obtained by conducting a meta-analysis using individual patient data.

Automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children (Review)

Abstract
Background: Automated closed loop systems may improve adaptation of the mechanical support to a patient's ventilatory needs and
facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of
ventilation.

Objectives: To compare the duration of weaning from mechanical ventilation for critically ill ventilated adults and children when managed
with automated closed loop systems versus non-automated strategies. Secondary objectives were to determine differences
in duration of ventilation, intensive care unit (ICU) and hospital length of stay (LOS), mortality, and adverse events.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2); MEDLINE (OvidSP) (1948 to August 2011); EMBASE (OvidSP) (1980 to August 2011); CINAHL (EBSCOhost) (1982 to August 2011); and the Latin American and Caribbean Health Sciences Literature (LILACS). In addition we received and reviewed auto-alerts for our search strategy in MEDLINE, EMBASE, and CINAHL up to August 2012. Relevant published reviews were sought using the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA Database). We also searched the Web of Science Proceedings; conference proceedings; trial registration websites; and reference lists of relevant articles.

Selection criteria: We included randomized controlled trials comparing automated closed loop ventilator applications to non-automated weaning
strategies including non-protocolized usual care and protocolized weaning in patients over four weeks of age receiving invasive mechanical ventilation in an intensive care unit (ICU).

Data collection and analysis: Two authors independently extracted study data and assessed risk of bias. We combined data into forest plots using random-effects modelling. Subgroup and sensitivity analyses were conducted according to a priori criteria.

Main results: Pooled data from 15 eligible trials (14 adult, one paediatric) totalling 1173 participants (1143 adults, 30 children) indicated that automated closed loop systems reduced the geometric mean duration of weaning by 32% (95% CI 19% to 46%, P =0.002), however heterogeneity was substantial (I2 = 89%, P < 0.00001). Reduced weaning duration was found with mixed or
medical ICU populations (43%, 95% CI 8% to 65%, P = 0.02) and Smartcare/PS™ (31%, 95% CI 7% to 49%, P = 0.02) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (17%, 95% CI 8% to 26%) and ICU length of stay (LOS) (11%, 95% CI 0% to 21%). There was no difference in mortality rates or hospital LOS. Overall the quality of evidence was high with the majority of trials rated as low risk.

Authors' conclusions: Automated closed loop systems may result in reduced duration of weaning, ventilation, and ICU stay. Reductions are more
likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PS™ and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized
controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population.

Patient selection for oncology phase I trials: a multi-institutional study of prognostic factors.

PURPOSE The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials. PATIENTS AND METHODS Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis. Results The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical tumor growth rate, lymphocytes, and WBC. Two different models of prognostic scores for 90-day mortality were generated by using these factors, including or excluding PS; both achieved specificities of more than 85% and sensitivities of approximately 50% when using a score cutoff of 5 or higher. These models were not superior to the previously published Royal Marsden Hospital score in their ability to predict 90-day mortality. CONCLUSION Patient selection using any of these prognostic scores will reduce non-drug-related 90-day mortality among patients enrolled in phase I trials by 50%. However, this can be achieved only by an overall reduction in recruitment to phase I studies of 20%, more than half of whom would in fact have survived beyond 90 days.

Withholding, discontinuing and withdrawing medications in dementia patients at the end of life:a neglected problem in the disadvantaged dying?

Recent years have seen a growing recognition that dementia is a terminal illness and that patients with advanced dementia nearing the end of life do not currently receive adequate palliative care. However, research into palliative care for these patients has thus far been limited. Furthermore, there has been little discussion in the literature regarding medication use in patients with advanced dementia who are nearing the end of life, and discontinuation of medication has not been well studied despite its potential to reduce the burden on the patient and to improve quality of life. There is limited, and sometimes contradictory, evidence available in the literature to guide evidence-based discontinuation of drugs such as acetylcholinesterase inhibitors, antipsychotic agents, HMG-CoA reductase inhibitors (statins), antibacterials, antihypertensives, antihyperglycaemic drugs and anticoagulants. Furthermore, end-of-life care of patients with advanced dementia may be complicated by difficulties in accurately estimating life expectancy, ethical considerations regarding withholding or withdrawing treatment, and the wishes of the patient and/or their family. Significant research must be undertaken in the area of medication discontinuation in patients with advanced dementia nearing the end of life to determine how physicians currently decide whether medications should be discontinued, and also to develop the evidence base and provide guidance on systematic medication discontinuation.

Addressing potentially inappropriate prescribing in older patients: development and pilot study of an intervention in primary care (the OPTI-SCRIPT study)

Background: Potentially inappropriate prescribing (PIP) in older people is common in primary care and can result in increased morbidity, adverse drug events, hospitalizations and mortality. The prevalence of PIP in Ireland is estimated at 36% with an associated expenditure of over [euro sign]45 million in 2007. The aim of this paper is to describe the application of the Medical Research Council (MRC) framework to the development of an intervention to decrease PIP in Irish primary care.

Methods: The MRC framework for the design and evaluation of complex interventions guided the development of the study intervention. In the development stage, literature was reviewed and combined with information obtained from experts in the field using a consensus based methodology and patient cases to define the main components of the intervention. In the pilot stage, five GPs tested the proposed intervention. Qualitative interviews were conducted with the GPs to inform the development and implementation of the intervention for the main randomised controlled trial.

Results: The literature review identified PIP criteria for inclusion in the study and two initial intervention components - academic detailing and medicines review supported by therapeutic treatment algorithms. Through patient case studies and a focus group with a group of 8 GPs, these components were refined and a third component of the intervention identified - patient information leaflets. The intervention was tested in a pilot study. In total, eight medicine reviews were conducted across five GP practices. These reviews addressed ten instances of PIP, nine of which were addressed in the form of either a dose reduction or a discontinuation of a targeted medication. Qualitative interviews highlighted that GPs were receptive to the intervention but patient preference and time needed both to prepare for and conduct the medicines review, emerged as potential barriers. Findings from the pilot study allowed further refinement to produce the finalised intervention of academic detailing with a pharmacist, medicines review with web-based therapeutic treatment algorithms and tailored patient information leaflets.

Conclusions: The MRC framework was used in the development of the OPTI-SCRIPT intervention to decrease the level of PIP in primary care in Ireland. Its application ensured that the intervention was developed using the best available evidence, was acceptable to GPs and feasible to deliver in the clinical setting. The effectiveness of this intervention is currently being tested in a pragmatic cluster randomised controlled trial.

Trial registration: Current controlled trials ISRCTN41694007.© 2013 Clyne et al.; licensee BioMed Central Ltd.

Evaluation of an algorithm to guide patients with type 1 diabetes treated with continuous subcutaneous insulin infusion on how to respond to real-time continuous glucose levels:A randomized controlled trial

OBJECTIVE - To evaluate an algorithm guiding responses of continuous subcutaneous insulin infusion (CSII)-treated type 1 diabetic patients using real-time continuous glucose monitoring (RT-CGM). RESEARCH DESIGN AND METHODS - Sixty CSII-treated type 1 diabetic participants (aged 13-70 years, including adult and adolescent subgroups, with A1C =9.5%) were randomized in age-, sex-, and A1C-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial. Group A was treated with CSII/RT-CGM with the algorithm, and group B was treated with CSII/RT-CGM without the algorithm. The primary outcome was the difference in time in target (4-10 mmol/l) glucose range on 6-day masked CGM. Secondary outcomes were differences in A1C, low (=3.9 mmol/l) glucose CGM time, and glycemic variability. Phase 2 was the week 16-32 follow-up. Group A was returned to usual care, and group B was provided with the algorithm. Glycemia parameters were as above. Comparisons were made between baseline and 16 weeks and 32 weeks. RESULTS - In phase 1, after withdrawals 29 of 30 subjects were left in group A and 28 of 30 subjects were left in group B. The change in target glucose time did not differ between groups. A1C fell (mean 7.9% [95% CI 7.7-8.2to 7.6% [7.2-8.0]; P <0.03) in group A but not in group B (7.8% [7.5-8.1] to 7.7 [7.3-8.0]; NS) with no difference between groups. More subjects in group A achieved A1C =7% than those in group B (2 of 29 to 14 of 29 vs. 4 of 28 to 7 of 28; P = 0.015). In phase 2, one participant was lost from each group. In group A, A1C returned to baseline with RT-CGM discontinuation but did not change in group B, who continued RT-CGM with addition of the algorithm. CONCLUSIONS - Early but not late algorithm provision to type 1 diabetic patients using CSII/RT-CGM did not increase the target glucose time but increased achievement of A1C =7%. Upon RT-CGM cessation, A1C returned to baseline. © 2010 by the American Diabetes Association.

A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia

Inhibition of histone deacetylases may be an important target in patients with myeloproliferative neoplasms. This investigator-initiated, non-randomized, open-label phase II multi-centre study included 63 patients (19 essential thrombocythaemia, 44 polycythaemia vera) from 15 centres. The primary objective was to evaluate if vorinostat was followed by a decline in clonal myeloproliferation as defined by European Leukaemia Net. Thirty patients (48%) completed the intervention period (24 weeks of therapy). An intention-to-treat response rate of 35% was identified. Pruritus was resolved [19% to 0% (P = 0·06)] and the prevalence of splenomegaly was lowered from 50% to 27% (P = 0·03). Sixty-five per cent of the patients experienced a decrease in JAK2 V617F allele burden (P = 0·006). Thirty-three patients (52% of patients) discontinued study drug before end of intervention due to adverse events (28 patients) or lack of response (5 patients). In conclusion, vorinostat showed effectiveness by normalizing elevated leucocyte and platelet counts, resolving pruritus and significantly reducing splenomegaly. However, vorinostat was associated with significant side effects resulting in a high discontinuation rate. A lower dose of vorinostat in combination with conventional and/or novel targeted therapies may be warranted in future studies.

Automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children: a cochrane systematic review and meta-analysis

IntroductionAutomated weaning systems may improve adaptation of mechanical support for a patient’s ventilatory needs and facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of ventilation. Our objective was to compare mechanical ventilator weaning duration for critically ill adults and children when managed with automated systems versus non-automated strategies. Secondary objectives were to determine differences in duration of ventilation, intensive care unit (ICU) and hospital length of stay (LOS), mortality, and adverse events.MethodsElectronic databases were searched to 30 September 2013 without language restrictions. We also searched conference proceedings; trial registration websites; and article reference lists. Two authors independently extracted data and assessed risk of bias. We combined data using random-effects modelling.ResultsWe identified 21 eligible trials totalling 1,676 participants. Pooled data from 16 trials indicated that automated systems reduced the geometric mean weaning duration by 30% (95% confidence interval (CI) 13% to 45%), with substantial heterogeneity (I2 = 87%, P <0.00001). Reduced weaning duration was found with mixed or medical ICU populations (42%, 95% CI 10% to 63%) and Smartcare/PS™ (28%, 95% CI 7% to 49%) but not with surgical populations or using other systems. Automated systems reduced ventilation duration with no heterogeneity (10%, 95% CI 3% to 16%) and ICU LOS (8%, 95% CI 0% to 15%). There was no strong evidence of effect on mortality, hospital LOS, reintubation, self-extubation and non-invasive ventilation following extubation. Automated systems reduced prolonged mechanical ventilation and tracheostomy. Overall quality of evidence was high.ConclusionsAutomated systems may reduce weaning and ventilation duration and ICU stay. Due to substantial trial heterogeneity an adequately powered, high quality, multi-centre randomized controlled trial is needed.

Automated versus non-automated weaning for reducing the duration of mechanical ventilation in critically ill adults & children (Review)

Background Automated closed loop systems may improve adaptation of mechanical support for a patient's ventilatory needs and facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of ventilation. This review was originally published in 2013 with an update published in 2014. Objectives The primary objective for this review was to compare the total duration of weaning from mechanical ventilation, defined as the time from study randomization to successful extubation (as defined by study authors), for critically ill ventilated patients managed with an automated weaning system versus no automated weaning system (usual care). Secondary objectives for this review were to determine differences in the duration of ventilation, intensive care unit (ICU) and hospital lengths of stay (LOS), mortality, and adverse events related to early or delayed extubation with the use of automated weaning systems compared to weaning in the absence of an automated weaning system. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8); MEDLINE (OvidSP) (1948 to September 2013); EMBASE (OvidSP) (1980 to September 2013); CINAHL (EBSCOhost) (1982 to September 2013); and the Latin American and Caribbean Health Sciences Literature (LILACS). Relevant published reviews were sought using the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA Database). We also searched the Web of Science Proceedings; conference proceedings; trial registration websites; and reference lists of relevant articles. The original search was run in August 2011, with database auto-alerts up to August 2012. Selection criteria We included randomized controlled trials comparing automated closed loop ventilator applications to non-automated weaning strategies including non-protocolized usual care and protocolized weaning in patients over four weeks of age receiving invasive mechanical ventilation in an ICU. Data collection and analysis Two authors independently extracted study data and assessed risk of bias. We combined data in forest plots using random-effects modelling. Subgroup and sensitivity analyses were conducted according to a priori criteria. Main results We included 21 trials (19 adult, two paediatric) totaling 1676 participants (1628 adults, 48 children) in this updated review. Pooled data from 16 eligible trials reporting weaning duration indicated that automated closed loop systems reduced the geometric mean duration of weaning by 30% (95% confidence interval (CI) 13% to 45%), however heterogeneity was substantial (I2 = 87%, P < 0.00001). Reduced weaning duration was found with mixed or medical ICU populations (42%, 95% CI 10% to 63%) and Smartcare/PS™ (28%, 95% CI 7% to 49%) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (10%, 95% CI 3% to 16%) and ICU LOS (8%, 95% CI 0% to 15%). There was no strong evidence of an effect on mortality rates, hospital LOS, reintubation rates, self-extubation and use of non-invasive ventilation following extubation. Prolonged mechanical ventilation > 21 days and tracheostomy were reduced in favour of automated systems (relative risk (RR) 0.51, 95% CI 0.27 to 0.95 and RR 0.67, 95% CI 0.50 to 0.90 respectively). Overall the quality of the evidence was high with the majority of trials rated as low risk. Authors' conclusions Automated closed loop systems may result in reduced duration of weaning, ventilation and ICU stay. Reductions are more likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PS™ and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population.