A prospective clinical trial of a real-time polymerase chain reaction assay for the diagnosis of candidemia in nonneutropenic, critically ill adults

Background. Invasive Candida infection among nonneutropenic, critically ill adults is a clinical problem that has received increasing attention in recent years. Poor performance of extant diagnostic modalities has promoted risk-based, preemptive prescribing in view of the poor outcomes associated with inadequate or delayed antifungal therapy; this risks unnecessary overtreatment. A rapid, reliable diagnostic test could have a substantial impact on therapeutic practice in this patient population.

Methods. Three TaqMan-based real-time polymerase chain reaction assays were developed that are capable of detecting the main medically important Candida species, categorized according to the likelihood of fluconazole susceptibility. Assay 1 detected Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida dubliniensis. Assays 2 and 3 detected Candida glabrata and Candida krusei, respectively. The clinical performance of these assays, applied to serum, was evaluated in a prospective trial of nonneutropenic adults in a single intensive care unit.

Results. In all, 527 specimens were obtained from 157 participants. All 3 assays were run in parallel for each specimen; they could be completed within 1 working day. Of these, 23 specimens were obtained from 23 participants categorized as having proven Candida infection at the time of sampling. If a single episode of Candida famata candidemia was excluded, the estimated clinical sensitivity, specificity, and positive and negative predictive values of the assays in this trial were 90.9%, 100%, 100% and 99.8%, respectively.

Conclusions. These data suggest that the described assays perform well in this population for enhancing the diagnosis of candidemia. The extent to which they may affect clinical outcomes, prescribing practice, and cost-effectiveness of care remains to be ascertained.

A randomized controlled trial of tea tree oil (5%) body wash versus standard body wash to prevent colonization with methicillin-resistant Staphylococcus aureus (MRSA) in critically ill adults: research protocol

Background
Over the past ten years MRSA has become endemic in hospitals and is associated with increased healthcare costs. Critically ill patients are most at risk, in part because of the number of invasive therapies that they require in the intensive care unit (ICU). Washing with 5% tea tree oil (TTO) has been shown to be effective in removing MRSA on the skin. However, to date, no trials have evaluated the potential of TTO body wash to prevent MRSA colonization or infection. In addition, detecting MRSA by usual culture methods is slow. A faster method using a PCR assay has been developed in the laboratory, but requires evaluation in a large number of patients.

Methods/Design
This study protocol describes the design of a multicentre, phase II/III prospective open-label randomized controlled clinical trial to evaluate whether a concentration of 5% TTO is effective in preventing MRSA colonization in comparison with a standard body wash (Johnsons Baby Softwash) in the ICU. In addition we will evaluate the cost-effectiveness of TTO body wash and assess the effectiveness of the PCR assay in detecting MRSA in critically ill patients. On admission to intensive care, swabs from the nose and groin will be taken to screen for MRSA as per current practice. Patients will be randomly assigned to be washed with the standard body wash or TTO body wash. On discharge from the unit, swabs will be taken again to identify whether there is a difference in MRSA colonization between the two groups.

Discussion
If TTO body wash is found to be effective, widespread implementation of such a simple colonization prevention tool has the potential to impact on patient outcomes, healthcare resource use and patient confidence both nationally and internationally.

Trial Registration
[ISRCTN65190967]

Outreach and Early Warning Systems (EWS) for the prevention of intensive care admission and death of critically ill adult patients on general hospital wards

BACKGROUND: Despite the fact that outreach and early warning systems (EWS) are an integral part of a hospital wide systems approach to improve the early identification and management of deteriorating patients on general hospital wards, the widespread implementation of these interventions in practice is not based on robust research evidence. OBJECTIVES: The primary objective was to determine the impact of critical care outreach services on hospital mortality rates. Secondary objectives included determining the effect of outreach services on intensive care unit (ICU) admission patterns, length of hospital stay and adverse events. SEARCH STRATEGY: The review authors searched the following electronic databases: EPOC Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL) and other Cochrane databases (all on The Cochrane Library 2006, Issue 3), MEDLINE (1996-June week 3 2006), EMBASE (1974-week 26 2006), CINAHL (1982-July week 5 2006), First Search (1992-2005) and CAB Health (1990-July 2006); also reference lists of relevant articles, conference abstracts, and made contact with experts and critical care organisations for further information. SELECTION CRITERIA: Randomised controlled trials (RCTs), controlled clinical trials (CCTs), controlled before and after studies (CBAs) and interrupted time series designs (ITS) which measured hospital mortality, unanticipated ICU admissions, ICU readmissions, length of hospital stay and adverse events following implementation of outreach and EWS in a general hospital ward to identify deteriorating adult patients versus general hospital ward setting without outreach and EWS were included in the review. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data and two review authors assessed the methodological quality of the included studies. Meta-analysis was not possible due to heterogeneity. Summary statistics and descriptive summaries of primary and secondary outcomes are presented for each study. MAIN RESULTS: Two cluster-randomised control trials were included: one randomised at hospital level (23 hospitals in Australia) and one at ward level (16 wards in the UK). The primary outcome in the Australian trial (a composite score comprising incidence of unexpected cardiac arrests, unexpected deaths and unplanned ICU admissions) showed no statistical significant difference between control and medical emergency team (MET) hospitals (adjusted P value 0.640; adjusted odds ratio (OR) 0.98; 95% confidence interval (CI) 0.83 to 1.16). The UK-based trial found that outreach reduced in-hospital mortality (adjusted OR 0.52; 95% CI 0.32 to 0.85) compared with the control group. AUTHORS' CONCLUSIONS: The evidence from this review highlights the diversity and poor methodological quality of most studies investigating outreach. The results of the two included studies showed either no evidence of the effectiveness of outreach or a reduction in overall mortality in patients receiving outreach. The lack of evidence on outreach requires further multi-site RCT's to determine potential effectiveness.

Prior colonisation with Candida species fails to guide empirical therapy for candidaemia in critically ill adults

Objectives Pre-emptive fluconazole (fcz) anti-fungal therapy is often based upon Candida colonisation of at least 2 non-contiguous non-sterile sites. The aim of this study was to evaluate the relationship between candidaemia and prior colonisation of non-sterile sites. Methods A retrospective observational study was performed in the intensive care unit/high dependency unit (ICU/HDU) of a University hospital on alternate years from 1999–2007, where a pre-emptive anti-fungal therapy policy was introduced in 2005. Results A higher proportion of blood isolates were Candida glabrata compared with non-sterile isolates (16/46 vs 106/1062; p

Use of weaning protocols for reducing duration of mechanical ventilation in critically ill adult patients: Cochrane systematic review and meta-analysis.

Objective To investigate the effects of weaning protocols on the total duration of mechanical ventilation, mortality, adverse events, quality of life, weaning duration, and length of stay in the intensive care unit and hospital.

Design Systematic review.

Data sources Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, LILACS, ISI Web of Science, ISI Conference Proceedings, Cambridge Scientific Abstracts, and reference lists of articles. We did not apply language restrictions.

Review methods We included randomised and quasi-randomised controlled trials of weaning from mechanical ventilation with and without protocols in critically ill adults.

Data selection Three authors independently assessed trial quality and extracted data. A priori subgroup and sensitivity analyses were performed. We contacted study authors for additional information.

Results Eleven trials that included 1971 patients met the inclusion criteria. Compared with usual care, the geometric mean duration of mechanical ventilation in the weaning protocol group was reduced by 25% (95% confidence interval 9% to 39%, P=0.006; 10 trials); the duration of weaning was reduced by 78% (31% to 93%, P=0.009; six trials); and stay in the intensive care unit length by 10% (2% to 19%, P=0.02; eight trials). There was significant heterogeneity among studies for total duration of mechanical ventilation (I(2)=76%, P

Conclusion There is evidence of a reduction in the duration of mechanical ventilation, weaning, and stay in the intensive care unit when standardised weaning protocols are used, but there is significant heterogeneity among studies and an insufficient number of studies to investigate the source of this heterogeneity. Some studies suggest that organisational context could influence outcomes, but this could not be evaluated as it was outside the scope of this review.

C5a-mediated neutrophil phagocytic dysfunction is RhoA-dependent and predicts nosocomial infection in critically ill patients.

Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kd. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection.

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.

A national clinical scenario-based survey of clinicians' attitudes towards fresh frozen plasma transfusion for critically ill patients

Background: It is known that 20-30% of fresh frozen plasma (FFP) is used in intensive care units (ICUs), but little is known about variations in decision making between clinicians in relation to coagulopathy management. Our aim was to describe ICU clinicians' beliefs and practice in relation to FFP treatment of non-bleeding coagulopathic critically ill patients.

Protocolized versus non-protocolized weaning for reducing the duration of invasive mechanical ventilation in critically ill paediatric patients (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of weaning by protocol for invasively ventilated critically ill children.

To compare the total duration of invasive mechanical ventilation of critically ill children who are weaned using protocols versus usual (non-protocolized) practice.
To ascertain any differences between protocolized weaning and usual care in terms of mortality, adverse events, ICU length of stay, and quality of life.