Talking to the people that really matter about their participation in pandemic clinical research: A qualitative study in four European countries.

BACKGROUND: Pandemics of new and emerging infectious diseases are unpredictable, recurrent events that rapidly threaten global health and security. We aimed to identify public views regarding provision of information and consent to participate in primary and critical care clinical research during a future influenza-like illness pandemic. METHODS: Descriptive-interpretive qualitative study, using focus groups (n = 10) and semi-structured interviews (n = 16), with 80 members of the public (>18 years) in Belgium, Spain, Poland and the UK. Local qualitative researchers followed a scenario-based topic guide to collect data. Data were transcribed verbatim, translated into English and subject to framework analysis. RESULTS: Public understandings of pandemics were shaped by personal factors (illness during the previous H1N1 pandemic, experience of life-threatening illness) and social factors (historical references, media, public health information). Informants appreciated safeguards provided by ethically robust research procedures, but current enrolment procedures were seen as a barrier. They proposed simplified enrolment processes for higher risk research and consent waiver for certain types of low-risk research. Decision making about research participation was influenced by contextual, research and personal factors. Informants generally either carefully weighed up various approaches to research participation or responded instinctively. They supported the principle of using routinely collected, anonymized clinical biological samples for research without explicit consent, but regarded this as less acceptable if researchers were motivated primarily by commercial gain. CONCLUSIONS: This bottom-up approach to ascertaining public views on pandemic clinical research has identified support for more proportionate research protection procedures for publically funded, low-risk studies.

The Efficacy of Earplugs as a Sleep Hygiene Strategy for Reducing Delirium in the ICU: A Systematic Review and Meta-Analysis.

OBJECTIVE: A systematic review and meta-analysis to assess the efficacy of earplugs as an ICU strategy for reducing delirium. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Central Register of controlled trials were searched using the terms "intensive care," "critical care," "earplugs," "sleep," "sleep disorders," and "delirium." STUDY SELECTION: Intervention studies (randomized or nonrandomized) assessing the efficacy of earplugs as a sleep hygiene strategy in patients admitted to a critical care environment were included. Studies were excluded if they included only healthy volunteers, did not report any outcomes of interest, did not contain an intervention group of interest, were crossover studies, or were only published in abstract form. DATA EXTRACTION: Nine studies published between 2009 and 2015, including 1,455 participants, fulfilled the eligibility criteria and were included in the systematic review. Studies included earplugs as an isolated intervention (n = 3), or as part of a bundle with eye shades (n = 2), or earplugs, eye shades, and additional sleep noise abatement strategies (n = 4). The risk of bias was high for all studies. DATA SYNTHESIS: Five studies comprising 832 participants reported incident delirium. Earplug placement was associated with a relative risk of delirium of 0.59 (95% CI, 0.44-0.78) and no significant heterogeneity between the studies (I, 39%; p = 0.16). Hospital mortality was reported in four studies (n = 481) and was associated with a relative risk of 0.77 (95% CI, 0.54-1.11; I, 0%; p < 0.001). Compliance with the placement of earplugs was reported in six studies (n = 681). The mean per-patient noncompliance was 13.1% (95% CI, 7.8-25.4) of those assigned to receive earplugs. CONCLUSIONS: Placement of earplugs in patients admitted to the ICU, either in isolation or as part of a bundle of sleep hygiene improvement, is associated with a significant reduction in risk of delirium. The potential effect of cointerventions and the optimal strategy for improving sleep hygiene and associated effect on patient-centered outcomes remains uncertain.

Preparing ICUs for pandemics.

PURPOSE OF REVIEW: Influenza pandemics occur intermittently and represent an existential global infectious diseases threat. The purpose of this review is to describe clinical and research preparedness for future pandemics. RECENT FINDINGS: Pandemic influenza typically results in large numbers of individuals with life-threatening pneumonia requiring treatment in ICUs. Clinical preparedness of ICUs relates to planning to provide increased 'surge' capacity to meet increased demand and requires consideration of staffing, equipment and consumables, bed-space availability and management systems. Research preparedness is also necessary, as timely clinical research has the potential to change the trajectory of a pandemic. The clinical research response during the 2009 H1N1 influenza pandemic was suboptimal. SUMMARY: Better planning is necessary to optimize both clinical and research responses to future pandemics.

Very old patients admitted to intensive care in Australia and New Zealand: a multi-centre cohort analysis.

INTRODUCTION: Older age is associated with higher prevalence of chronic illness and functional impairment, contributing to an increased rate of hospitalization and admission to intensive care. The primary objective was to evaluate the rate, characteristics and outcomes of very old (age >or= 80 years) patients admitted to intensive care units (ICUs). METHODS: Retrospective analysis of prospectively collected data from the Australian New Zealand Intensive Care Society Adult Patient Database. Data were obtained for 120,123 adult admissions for >or= 24 hours across 57 ICUs from 1 January 2000 to 31 December 2005. RESULTS: A total of 15,640 very old patients (13.0%) were admitted during the study. These patients were more likely to be from a chronic care facility, had greater co-morbid illness, greater illness severity, and were less likely to receive mechanical ventilation. Crude ICU and hospital mortalities were higher (ICU: 12% vs. 8.2%, P < 0.001; hospital: 24.0% vs. 13%, P < 0.001). By multivariable analysis, age >/= 80 years was associated with higher ICU and hospital death compared with younger age strata (ICU: odds ratio (OR) = 2.7, 95% confidence interval (CI) = 2.4 to 3.0; hospital: OR = 5.4, 95% CI = 4.9 to 5.9). Factors associated with lower survival included admission from a chronic care facility, co-morbid illness, nonsurgical admission, greater illness severity, mechanical ventilation, and longer stay in the ICU. Those aged >or= 80 years were more likely to be discharged to rehabilitation/long-term care (12.3% vs. 4.9%, OR = 2.7, 95% CI = 2.6 to 2.9). The admission rates of very old patients increased by 5.6% per year. This potentially translates to a 72.4% increase in demand for ICU bed-days by 2015. CONCLUSIONS: The proportion of patients aged >or= 80 years admitted to intensive care in Australia and New Zealand is rapidly increasing. Although these patients have more co-morbid illness, are less likely to be discharged home, and have a greater mortality than younger patients, approximately 80% survive to hospital discharge. These data also imply a potential major increase in demand for ICU bed-days for very old patients within a decade.

Randomised evaluation of active control of temperature versus ordinary temperature management (REACTOR) trial.

PURPOSE: It is unknown whether protocols targeting systematic prevention and treatment of fever achieve lower mean body temperature than usual care in intensive care unit (ICU) patients. The objective of the Randomised Evaluation of Active Control of temperature vs. ORdinary temperature management trial was to confirm the feasibility of such a protocol with a view to conducting a larger trial. METHODS: We randomly assigned 184 adults without acute brain pathologies who had a fever in the previous 12 h, and were expected to be ventilated beyond the calendar day after recruitment, to systematic prevention and treatment of fever or usual care. The primary outcome was mean body temperature in the ICU within 7 days of randomisation. Secondary outcomes included in-hospital mortality, ICU-free days and survival time censored at hospital discharge. RESULTS: Compared with usual temperature management, active management significantly reduced mean temperature. In both groups, fever generally abated within 72 h. The mean temperature difference between groups was greatest in the first 48 h, when it was generally in the order of 0.5 °C. Overall, 23 of 89 patients assigned to active management (25.8%) and 23 of 89 patients assigned to usual management (25.8%) died in hospital (odds ratio 1.0, 95% CI 0.51-1.96, P = 1.0). There were no statistically significant differences between groups in ICU-free days or survival to day 90. CONCLUSIONS: Active temperature management reduced body temperature compared with usual care; however, fever abated rapidly, even in patients assigned to usual care, and the magnitude of temperature separation was small. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry Number, ACTRN12616001285448.

Priority Needs for Conducting Pandemic-relevant Clinical Research With Children in Europe: A Consensus Study With Pediatric Clinician-researchers.

BACKGROUND: Infectious disease (ID) pandemics pose a considerable global threat and can disproportionately affect vulnerable populations including children. Pediatric clinical research in pandemics is essential to improve children's healthcare and minimize risks of harm by interventions that lack an adequate evidence base for this population. The unique features of ID pandemics require consideration of special processes to facilitate clinical research. We aimed to obtain consensus on pediatric clinician-researchers' perceptions of the priorities to feasibly conduct clinical pediatric pandemic research in Europe. METHODS: Mixed method study in 2 stages, recruiting pediatric clinician-researchers with experience of conducting pediatric ID research in clinical settings in Europe. Stage 1 was an expert stakeholder workshop and interviews. Discussions focused on participant's experience of conducting pediatric ID research and processes to facilitate pandemic research. Information informed stage 2, an online consensus survey to identify pediatric inician-researchers priorities to enable ID pandemic research. RESULTS: Twenty-three pediatric clinician-researchers attended the workshop and 39 completed the survey. Priorities were primarily focused on structural and operational requirements of research design and regulation: (1) clarity within the European Clinical Trials Directive for pediatric pandemic research; (2) simplified regulatory processes for research involving clinical samples and data; and (3) improved relationships between regulatory bodies and researchers. CONCLUSIONS: Results suggest that changes need to be made to the current regulatory environment to facilitate and improve pediatric research in the pandemic context. These findings can provide expert evidence to research policy decision-makers and regulators and to develop a strategy to lobby for change.

Bench-to-bedside review: the evaluation of complex interventions in critical care.

Complex interventions, such as the introduction of medical emergency teams or an early goal-directed therapy protocol, are developed from a number of components that may act both independently and inter-dependently. There is an emerging body of literature advocating the use of integrated complex interventions to optimise the treatment of critically ill patients. As with any other treatment, complex interventions should undergo careful evaluation prior to widespread introduction into clinical practice. During the development of an international collaboration of researchers investigating protocol-based approaches to the resuscitation of patients with severe sepsis, we examined the specific issues related to the evaluation of complex interventions. This review outlines some of these issues. The issues specific to trials of complex interventions that require particular attention include determining an appropriate study population and defining current treatments and outcomes in that population, defining the study intervention and the treatment to be used in the control group, and deploying the intervention in a standardised manner. The context in which the research takes place, including existing staffing levels and existing protocols and procedures, is crucial. We also discuss specific details of trial execution, in particular randomization, blinded outcome adjudication and analysis of the results, which are key to avoiding bias in the design and interpretation of such trials. These aspects of study design impact upon the evaluation of complex interventions in critical care. Clinicians should also consider these specific issues when implementing new complex interventions into their practice.

Protocol and statistical analysis plan for the Randomised Evaluation of Active Control of Temperature versus Ordinary Temperature Management (REACTOR) trial.

BACKGROUND: Body temperature can be reduced in febrile patients in the intensive care unit using medicines and physical cooling devices, but it is not known whether systematically preventing and treating fever reduces body temperature compared with standard care. OBJECTIVE: To describe the study protocol and statistical analysis plan for the Randomised Evaluation of Active Control of Temperature versus Ordinary Temperature Management (REACTOR) trial. DESIGN, SETTING AND PARTICIPANTS: Protocol for a phase II, multicentre trial to be conducted in Australian and New Zealand ICUs admitting adult patients. We will recruit 184 adults without acute brain injury who are expected to be ventilated in the ICU beyond the day after randomisation. We will use open, random, parallel assignment to systematic prevention and treatment of fever, or to standard temperature management. MAIN OUTCOME MEASURES: The primary end point will be mean body temperature, calculated from body temperatures measured 6-hourly for 7 days (168 hours) or until ICU discharge, whichever is sooner. Secondary end points are ICU-free days, in-hospital and cause-specific mortality (censored at Day 90) and survival time to Day 90 (censored at hospital discharge). RESULTS AND CONCLUSIONS: The trial will determine whether active temperature control reduces body temperature compared with standard care. It is primarily being conducted to establish whether a phase III trial with a patient-centred end point of Day 90 mortality is justified and feasible.

Long-term survival from intensive care: a review.

OBJECTIVE: To determine whether the long-term benefit of an ICU requires prolonged patient follow-up we reviewed long-term survival of patients from general ICUs. METHOD: We carried out a computerised search of online databases Medline (1966-2004), Embase (1966-2004) and Cochrane Library (1966-2004) for studies reporting patients' long-term survival for greater than 12 months from general ICUs. SELECTED STUDIES: We identified 19 studies that met the selection criteria. The casemix and severity of illness varied. Differences included the services provided, investigator inclusion/exclusion criteria and proportion of medical patients (range 13-79%). RESULTS: Mean reported ICU length of stay was 5.3 days. The study initiation time for follow-up varied (mostly from time of ICU admission), as did the duration of follow-up (16 months-13 years). ICU and hospital mortality rates ranged from 8% to 33% and 11% to 64%, respectively. The reported 5-year mortality ranged from 40% to 58%. CONCLUSIONS: Well designed studies on long-term outcomes are needed to demonstrate the value of intensive care. Deficiencies in design, methodology, and reporting make interpretation and comparison difficult. Recommendations are made for the reporting of outcome from the ICU. Optimum duration of follow-up has not been determined.

Oxygenation targets, monitoring in the critically ill: a point prevalence study of clinical practice in Australia and New Zealand.

BACKGROUND: Many critically ill patients require supplemental oxygen. However, the optimal oxygen saturation measured by pulse oximetry (SpO2) in intensive care unit patients is unknown. OBJECTIVE: To evaluate clinical practice in Australia and New Zealand ICUs in relation to SpO2monitoring, prescription of SpO2targets by doctors, and upper and lower limits of tolerance of high and low SpO2levels by ICU bedside nurses. METHOD: Cross-sectional, observational study conducted on 2 days in 2013 involving adult patients in Australia and New Zealand ICUs. RESULTS: Data from 350 adult ICU patients were included. SpO2alarms were less likely to be disabled in patients who were invasively ventilated than in patients not receiving supplemental oxygen (4.8% v 15.1%; P = 0.02). In mechanically ventilated patients and non-ventilated patients receiving supplemental oxygen, the lower prescribed SpO2limit and the ICU bedside nurses' stated limits for action for low SpO2levels were 92% (interquartile range, 90%-94%). Upper SpO2limits were less frequently prescribed than lower SpO2limits (4.9% [95% CI, 3.0%- 7.7%] v 36.6% [95% CI, 31.7%-41.7%]); P < 0.01) and the observed SpO2exceeded the prescribed upper limit on 10/17 occasions (59%) when an upper limit was prescribed. CONCLUSION: Our findings suggest a relatively low level of vigilance in relation to prevention of high SpO2compared with low SpO2for adult patients in Australian and New Zealand ICUs.

Key stakeholder perceptions about consent to participate in acute illness research: a rapid, systematic review to inform epi/pandemic research preparedness.

BACKGROUND: A rigorous research response is required to inform clinical and public health decision-making during an epi/pandemic. However, the ethical conduct of such research, which often involves critically ill patients, may be complicated by the diminished capacity to consent and an imperative to initiate trial therapies within short time frames. Alternative approaches to taking prospective informed consent may therefore be used. We aimed to rapidly review evidence on key stakeholder (patients, their proxy decision-makers, clinicians and regulators) views concerning the acceptability of various approaches for obtaining consent relevant to pandemic-related acute illness research. METHODS: We conducted a rapid evidence review, using the Internet, database and hand-searching for English language empirical publications from 1996 to 2014 on stakeholder opinions of consent models (prospective informed, third-party, deferred, or waived) used in acute illness research. We excluded research on consent to treatment, screening, or other such procedures, non-emergency research and secondary studies. Papers were categorised, and data summarised using narrative synthesis. RESULTS: We screened 689 citations, reviewed 104 full-text articles and included 52. Just one paper related specifically to pandemic research. In other emergency research contexts potential research participants, clinicians and research staff found third-party, deferred, and waived consent to be acceptable as a means to feasibly conduct such research. Acceptability to potential participants was motivated by altruism, trust in the medical community, and perceived value in medical research and decreased as the perceived risks associated with participation increased. Discrepancies were observed in the acceptability of the concept and application or experience of alternative consent models. Patients accepted clinicians acting as proxy-decision makers, with preference for two decision makers as invasiveness of interventions increased. Research regulators were more cautious when approving studies conducted with alternative consent models; however, their views were generally under-represented. CONCLUSIONS: Third-party, deferred, and waived consent models are broadly acceptable to potential participants, clinicians and/or researchers for emergency research. Further consultation with key stakeholders, particularly with regulators, and studies focused specifically on epi/pandemic research, are required. We highlight gaps and recommendations to inform set-up and protocol development for pandemic research and institutional review board processes. PROSPERO PROTOCOL REGISTRATION NUMBER: CRD42014014000.

Treatment goals: health care improvement through setting and measuring patient-centred outcomes.

OBJECTIVE: To determine how frequently stress ulcer prophylaxis (SUP) medications prescribed in the intensive care unit are inappropriately continued on the ward and on hospital discharge. DESIGN: Retrospective cohort study; chart review. SETTING: Two Australian ICUs: one tertiary centre and one metropolitan centre. PARTICIPANTS: We included 387 adult, non-pregnant patients who were admitted to the ICU between 1 February 2011 and 31 March 2011 and who survived to hospital discharge. MAIN OUTCOME MEASURES: Rate of unnecessary continuation of ICU-prescribed SUP medications on the ward and on discharge from hospital. RESULTS: While in the ICU, 329 of the 387 patients (85%) were prescribed SUP medications. Of the 233 patients who had not been taking acid-suppressive medications before admission to the ICU, 190 were prescribed SUP medications in the ICU. Of these 190 patients, most (63%) had their SUP continued in the ward without any obvious indication, and many (39%) had their SUP medications inappropriately continued on discharge from hospital. CONCLUSIONS: SUP medications commenced in ICU are frequently continued unnecessarily, both in the wards and on hospital discharge.

The impact of bacterial and viral co-infection in severe influenza.

BACKGROUND: Many questions remain concerning the burden, risk factors and impact of bacterial and viral co-infection in patients with pandemic influenza admitted to the intensive care unit (ICU). OBJECTIVES: To examine the burden, risk factors and impact of bacterial and viral co-infection in Australian patients with severe influenza. PATIENTS/METHODS: A cohort study conducted in 14 ICUs was performed. Patients with proven influenza A during the 2009 influenza season were eligible for inclusion. Demographics, risk factors, clinical data, microbiological data, complications and outcomes were collected. Polymerase chain reaction for additional bacterial and viral respiratory pathogens was performed on stored respiratory samples. RESULTS: Co-infection was identified in 23·3-26·9% of patients with severe influenza A infection: viral co-infection, 3·2-3·4% and bacterial co-infection, 20·5-24·7%. Staphylococcus aureus was the most frequent bacterial co-infection followed by Streptococcus pneumoniae and Haemophilus influenzae. Patients with co-infection were younger [mean difference in age = 8·46 years (95% CI: 0·18-16·74 years)], less likely to have significant co-morbidities (32·0% versus 66·2%, P = 0·004) and less frequently obese [mean difference in body mass index = 6·86 (95% CI: 1·77-11·96)] compared to those without co-infection. CONCLUSIONS: Bacterial or viral co-infection complicated one in four patients admitted to ICU with severe influenza A infection. Despite the co-infected patients being younger and with fewer co-morbidities, no significant difference in outcomes was observed. It is likely that co-infection contributed to a need for ICU admission in those without other risk factors for severe influenza disease. Empiric antibiotics with staphylococcal activity should be strongly considered in all patients with severe influenza A infection.

The ADRENAL study protocol: adjunctive corticosteroid treatment in critically ill patients with septic shock.

BACKGROUND: There is considerable global uncertainty on the role of low-dose corticosteroids in septic shock, which translates into variations in prescribing practices. OBJECTIVE: To describe the protocol for a large-scale multicentre randomised controlled trial in critically ill patients with septic shock, comparing the effects of hydrocortisone and placebo (in addition to standard treatment) on 90-day mortality and other outcomes such as shock reversal, duration of mechanical ventilation and quality of life. METHODS: We will recruit 3800 critically ill patients with septic shock treated in an intensive care unit, to concealed, randomised, parallel assignment of hydrocortisone or placebo. The primary outcome will be all-cause mortality at 90 days postrandomisation. Secondary outcomes will include ICU and hospital mortality, length of ICU stay and quality of life at 6 months. Subgroup analyses will be conducted in two predefined subgroups. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSIONS: The run-in phase has been completed and the main trial commenced in February 2013. The trial should generate results that will inform and influence prescribing of corticosteroids in septic shock.

Statistical analysis plan for the HEAT trial: a multicentre randomised placebo-controlled trial of intravenous paracetamol in intensive care unit patients with fever and infection.

BACKGROUND AND OBJECTIVE: We describe the statistical analysis plan (SAP) for the Permissive Hyperthermia through Avoidance of Paracetamol in Known or Suspected Infection in the Intensive Care Unit (HEAT) trial, a 700-patient, prospective, randomised, Phase 2b, multicentre, double-blind, parallel-groups, placebo-controlled trial of paracetamol administration for the treatment of fever in critically ill patients with known or suspected infection. METHODS: The data fields described are those outlined in the study protocol published previously. We describe the plan for the presentation and comparison of baseline characteristics, process measures and outcomes. We describe baseline characteristics, and define and categorise trial outcomes according to their assigned importance. RESULTS AND CONCLUSIONS: We developed an SAP for the HEAT trial, and produced a mock Consolidated Standards of Reporting Trials diagram and tables. Our prespecified SAP accords with high-quality standards of internal validity and should minimise future analysis bias.

The HEAT trial: a protocol for a multicentre randomised placebo-controlled trial of IV paracetamol in ICU patients with fever and infection.

BACKGROUND AND OBJECTIVE: Paracetamol is commonly administered to febrile critically ill patients with infection. However, there is limited information on the efficacy and safety of using paracetamol in this setting. We describe the study protocol for a Phase IIb multicentre randomised controlled trial (the Permissive Hyperthermia Through Avoidance of Paracetamol in Known or Suspected Infection in ICU [HEAT] trial) comparing intravenous paracetamol to placebo in the treatment of fever in critically ill adults with known or suspected infection. DESIGN AND SETTING: A pilot study followed by the main trial from November 2012. 700 patients will be recruited for concealed, random, parallel assignment of either 1 g of intravenous paracetamol or placebo (100mL of 5% dextrose) 6-hourly to treat fever while they remain on antimicrobial therapy in the intensive care unit. The primary end point will be ICU support-free survival at 28 days after randomisation. Secondary end points will include peak daily and mean daily body temperatures, prevalence of liver dysfunction requiring cessation of study treatment, degree of renal injury (based on delta creatinine), other organ failures, and Day 28 and Day 90 mortality. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSIONS: The HEAT trial should generate results that will inform and influence the prescribing of paracetamol. It will also determine if a large-scale Phase III trial of paracetamol is required in this patient group and whether such a trial is feasible. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12612000513819).

Urinary proteases degrade albumin: implications for measurement of albuminuria in stored samples.

BACKGROUND: Previous studies have shown that albumin in stored urine samples degrades over time, and that albumin losses are greatest in samples with low pH conditions (pH < 5). Furthermore, the high-performance liquid chromatography (HPLC) assay for urinary albumin has been shown to be particularly susceptible to the effects of prolonged storage. METHODS: Frozen urine samples, stored for 12 months at -70 and -20 degrees C, were analysed for albumin fragmentation. Urinary protease activity was investigated in vitro in urine adjusted to pH 2.3-2.5. Albumin was measured by nephelometry, HPLC and sodium dodecyl sulphate-polyacrylamide gel electrophoresis. RESULTS: In the unadjusted samples, albumin was degraded in 11 out of 40 samples stored at -20 degrees C. In the in vitro experiments, both endogenous albumin and exogenous albumin added to urine were rapidly degraded into large fragments within minutes after adjustment to low pH. The fragments produced were consistent with those produced during digestion with pepsin and urinary degradation was completely inhibited by pepstatin. Albumin concentration measured by HPLC was most dramatically affected, with near-complete loss of albumin-sized material within one hour of incubation at pH 2.3-2.5. Sample reactivity with antiserum in a nephelometry assay initially declined then increased, possibly due to exposure of internal epitopes during albumin digestion. CONCLUSIONS: This study demonstrated that proteases are present and active in stored human urine samples. Urinary albumin digestion occurred in a manner consistent with activity of endogenous urinary proteases. Adjustment to neutral pH or addition of protease inhibitors may be useful techniques for sample preservation.