The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data From the Multinational Sampling Antibiotics in Renal Replacement Therapy Study.

BACKGROUND: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. METHODS: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. RESULTS: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. CONCLUSIONS: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Melioidosis Causing Critical Illness: A Review of 24 Years of Experience From the Royal Darwin Hospital ICU.

OBJECTIVES: Melioidosis is increasing in incidence with newly recognized foci of melioidosis in the Americas, Africa, and elsewhere. This review describes the demographics, management, and outcomes of a large cohort of critically ill patients with melioidosis. DESIGN: Data were extracted from two prospective databases-the Menzies School of Health Research Melioidosis Database (1989-2013) and the Royal Darwin Hospital ICU Melioidosis Database (2001-2013). SETTING AND PATIENTS: The Royal Darwin Hospital ICU is the only ICU in the tropical Top End of Northern Territory of Australia, an endemic area for melioidosis. The study included all patients with melioidosis admitted to Royal Darwin Hospital ICU from 1989 to 2013. MEASUREMENTS AND MAIN RESULTS: From 1989 to 2013, 207 patients with melioidosis required admission to ICU. Mortality reduced from 92% (1989-1997) to 26% (1998-2013) (p < 0.001). The reduced mortality coincided with the introduction of an intensivist-led service, meropenem, and adjuvant granulocyte colony-stimulating factor for confirmed melioidosis sepsis in 1998. Pneumonia was the presenting illness in 155 of 207 (75%). ICU melioidosis patients (2001-2013) had an Acute Physiology and Chronic Health Evaluation II score of 23, median length of stay in the ICU of 7 days, and median ventilation hours of 130 and one third required renal replacement therapy. CONCLUSIONS: The mortality for critically ill patients with melioidosis in the Top End of the Northern Territory of Australia has substantially reduced over the past 24 years. The reduction in mortality coincided with the introduction of an intensivist-led model of care, the empiric use of meropenem, and adjunctive treatment with granulocyte colony-stimulating factor in 1998.

SaMpling Antibiotics in Renal Replacement Therapy (SMARRT): an observational pharmacokinetic study in critically ill patients.

BACKGROUND: Optimal antibiotic dosing is key to maximising patient survival, and minimising the emergence of bacterial resistance. Evidence-based antibiotic dosing guidelines for critically ill patients receiving RRT are currently not available, as RRT techniques and settings vary greatly between ICUs and even individual patients. We aim to develop a robust, evidence-based antibiotic dosing guideline for critically ill patients receiving various forms of RRT. We further aim to observe whether therapeutic antibiotic concentrations are associated with reduced 28-day mortality. METHODS/DESIGN: We designed a multi-national, observational pharmacokinetic study in critically ill patients requiring RRT. The study antibiotics will be vancomycin, linezolid, piperacillin/tazobactam and meropenem. Pharmacokinetic sampling of each patient's blood, RRT effluent and urine will take place during two separate dosing intervals. In addition, a comprehensive data set, which includes the patients' demographic and clinical parameters, as well as modality, technique and settings of RRT, will be collected. Pharmacokinetic data will be analysed using a population pharmacokinetic approach to identify covariates associated with changes in pharmacokinetic parameters in critically ill patients with AKI who are undergoing RRT for the five commonly prescribed antibiotics. DISCUSSION: Using the comprehensive data set collected, the pharmacokinetic profile of the five antibiotics will be constructed, including identification of RRT and other factors indicative of the need for altered antibiotic dosing requirements. This will enable us to develop a dosing guideline for each individual antibiotic that is likely to be relevant to any critically ill patient with acute kidney injury receiving any of the included forms of RRT. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ( ACTRN12613000241730 ) registered 28 February 2013.

Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial.

RATIONALE: The role of procalcitonin (PCT), a widely used sepsis biomarker, in critically ill patients with sepsis is undetermined. OBJECTIVES: To investigate the effect of a low PCT cut-off on antibiotic prescription and to describe the relationships between PCT plasma concentration and sepsis severity and mortality. METHODS: This was a multicenter (11 Australian intensive care units [ICUs]), prospective, single-blind, randomized controlled trial involving 400 patients with suspected bacterial infection/sepsis and expected to receive antibiotics and stay in ICU longer than 24 hours. The primary outcome was the cumulative number of antibiotics treatment days at Day 28. MEASUREMENTS AND MAIN RESULTS: PCT was measured daily while in the ICU. A PCT algorithm, including 0.1 ng/ml cut-off, determined antibiotic cessation. Published guidelines and antimicrobial stewardship were used in all patients. Primary analysis included 196 (PCT) versus 198 standard care patients. Ninety-three patients in each group had septic shock. The overall median (interquartile range) number of antibiotic treatment days were 9 (6-21) versus 11 (6-22), P = 0.58; in patients with positive pulmonary culture, 11 (7-27) versus 15 (8-27), P = 0.33; and in patients with septic shock, 9 (6-22) versus 11 (6-24), P = 0.64; with an overall 90-day all-cause mortality of 35 (18%) versus 31 (16%), P = 0.54 in the PCT versus standard care, respectively. Using logistic regression, adjusted for age, ventilation status, and positive culture, the decline rate in log(PCT) over the first 72 hours independently predicted hospital and 90-day mortality (odds ratio [95% confidence interval], 2.76 [1.10-6.96], P = 0.03; 3.20 [1.30-7.89], P = 0.01, respectively). CONCLUSIONS: In critically ill adults with undifferentiated infections, a PCT algorithm including 0.1 ng/ml cut-off did not achieve 25% reduction in duration of antibiotic treatment. Clinical trial registered with http://www.anzctr.org.au (ACTRN12610000809033).

The psychological well-being of people in a COVID-19 supervised quarantine facility: A mixed methods study.

WHAT IS KNOWN ON THE SUBJECT?: Supervised Quarantine has been shown to impact the psychological well-being of those in quarantine both during the COVID-19 pandemic and in previous pandemics. There are few studies regarding the psychological impact of supervised quarantine for the purpose of COVID-19 mitigation. There is little research regarding the psychological well-being of professionals maintaining quarantine, despite the fact they risk potential psychological distress. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: This paper addresses the paucity of knowledge regarding the psychological well-being of those undergoing quarantine in a purpose-built facility. The quarantined study population involved uniquely domestic arrivals and also professionals maintaining quarantine. Lack of control, isolation and miscommunication were perceived as challenging mental well-being. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Although psychological distress in Domestic arrivals appeared low, there are still identifiable stresses on mental well-being. Mental health workers need to be cognizant that point entry to COVID-19 quarantine (Domestic vs. International as well as specific regions) may influence risk of psychological distress. Mental Health nurses supporting those in quarantine should afford quarantined individuals a degree of choice, establish regular clear communication and consider how to establish peer support mechanisms within the quarantine environment. ABSTRACT: INTRODUCTION: Supervised quarantine may compromise psychological well-being. There is equivocal evidence regarding psychological distress in compulsory supervised quarantine facilities. AIMS: To evaluate the mental well-being of people undergoing and working in a supervised COVID-19 quarantine facility. METHOD: Mixed methodology was used, including a cross-sectional analysis of psychological distress (DASS-21) and individual semi-structured interviews (10 professionals maintaining quarantine and 10 quarantined persons). RESULTS: Overall levels of psychological distress were low. Those quarantining from Victoria had significantly lower depression scores compared to all other departure points. Qualitative analysis identified distress being linked to a lack of control, isolation and miscommunication. DISCUSSION: Quarantine was associated with low levels of psychological distress. This was lower in people travelling from Victoria, a state where there were higher rates of infections and restrictions. Interviews showed that psychological distress was conceptualized as being associated with supervised quarantine, but participants recognized the overall importance of quarantine. IMPLICATIONS FOR PRACTICE: Mental health professionals supporting quarantined people should consider original departure points may predict levels of psychological distress. Implementing ways of gaining control through affording choice, improving communication channels and establishing peer support networks within quarantine settings may help maintain mental well-being.

Critical care services and 2009 H1N1 influenza in Australia and New Zealand.

BACKGROUND: Planning for the treatment of infection with the 2009 pandemic influenza A (H1N1) virus through health care systems in developed countries during winter in the Northern Hemisphere is hampered by a lack of information from similar health care systems. METHODS: We conducted an inception-cohort study in all Australian and New Zealand intensive care units (ICUs) during the winter of 2009 in the Southern Hemisphere. We calculated, per million inhabitants, the numbers of ICU admissions, bed-days, and days of mechanical ventilation due to infection with the 2009 H1N1 virus. We collected data on demographic and clinical characteristics of the patients and on treatments and outcomes. RESULTS: From June 1 through August 31, 2009, a total of 722 patients with confirmed infection with the 2009 H1N1 virus (28.7 cases per million inhabitants; 95% confidence interval [CI], 26.5 to 30.8) were admitted to an ICU in Australia or New Zealand. Of the 722 patients, 669 (92.7%) were under 65 years of age and 66 (9.1%) were pregnant women; of the 601 adults for whom data were available, 172 (28.6%) had a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 35. Patients infected with the 2009 H1N1 virus were in the ICU for a total of 8815 bed-days (350 per million inhabitants). The median duration of treatment in the ICU was 7.0 days (interquartile range, 2.7 to 13.4); 456 of 706 patients (64.6%) with available data underwent mechanical ventilation for a median of 8 days (interquartile range, 4 to 16). The maximum daily occupancy of the ICU was 7.4 beds (95% CI, 6.3 to 8.5) per million inhabitants. As of September 7, 2009, a total of 103 of the 722 patients (14.3%; 95% CI, 11.7 to 16.9) had died, and 114 (15.8%) remained in the hospital. CONCLUSIONS: The 2009 H1N1 virus had a substantial effect on ICUs during the winter in Australia and New Zealand. Our data can assist planning for the treatment of patients during the winter in the Northern Hemisphere.

Heat Health Management in a Quarantine and Isolation Facility in the Tropics.

INTRODUCTION: The Howard Springs Quarantine Facility (HSQF) is located in tropical Northern Australia and has 875 blocks of four rooms (3,500 rooms in total) spread over 67 hectares. The HSQF requires a large outdoor workforce walking outdoor pathways to provide individual care in the ambient climate. The personal protective equipment (PPE) required for the safety of quarantine workers varies between workgroups and limits body heat dissipation that anecdotally contributes to excessive sweating, which combined with heat stress symptoms of fatigue, headache, and irritability, likely increases the risk of workplace injuries including infection control breaches. STUDY OBJECTIVE: The purpose of this study was the description of qualitative and quantitative assessment for HSQF workers exposed to tropical environmental conditions and provision of evidenced-based strategies to mitigate the risk of heat stress in an outdoor quarantine and isolation workforce. METHODS: The study comprised two components - a cross-sectional physiological monitoring study of 18 workers (eight males/ten females; means: 41.4 years; 1.69m; 80.6kg) during a single shift in November 2020 and a subjective heat health survey completed by participants on a minimum of four occasions across the wet season/summer period from November 2020 through February 2021. The physiological monitoring included continuous core temperature monitoring and assessment of fluid balance. RESULTS: The mean apparent temperature across first-half and second-half of the shift was 34.7°C (SD = 0.8) and 35.6°C (SD = 1.9), respectively. Across the work shift (mean duration 10.1 hours), the mean core temperature of participants was 37.3°C (SD = 0.2) with a range of 37.0°C - 37.7°C. The mean maximal core temperature of participants was 37.7°C (SD = 0.3). In the survey, for the workforce in full PPE, 57% reported feeling moderately, severely, or unbearably hot compared to 49% of those in non-contact PPE, and the level of fatigue was reported as moderate to severe in just over 25% of the workforce in both groups. CONCLUSION: Heat stress is a significant risk in outdoor workers in the tropics and is amplified in the coronavirus disease 2019 (COVID-19) frontline workforce required to wear PPE in outdoor settings. A heat health program aimed at mitigating risk, including workplace education, limiting exposure times, encouraging hydration, buddy system, active cooling, and monitoring, is recommended to limit PPE breaches and other workplace injuries in this workforce.

Understanding the Psychological Well-Being of International Arrivals in a Purpose-Designed Australian COVID-19 Quarantine Facility.

Equivocal evidence suggests that mandatory supervised quarantine can negatively affect psychological well-being in some settings. It was unclear if COVID-19 supervised quarantine was associated with psychological distress in Australia. The sociodemographic characteristics associated with distress and the lived experiences of quarantine are also poorly understood. Therefore, this study aimed to evaluate the mental well-being of international arrivals undergoing supervised COVID quarantine in a purpose designed facility in the Northern Territory, Australia. We conducted a concurrent triangulation mixed-methods study comprising of an observational cross-sectional survey (n = 117) and individual qualitative interviews (n = 26). The results revealed that several factors were associated with distress, including significantly higher levels of depression for those who smoked, drank alcohol, had pre-existing mental health conditions and had no social networks in quarantine. Levels of psychological distress were also related to waiting time for re-entry (the time between applying to repatriate and returning to Australia) and flight origin. Qualitative data showed that despite quarantine being viewed as necessary, unclear communication and a perception of lack of control were affecting emotional well-being. This information is useful to inform the further development of models to identify those at most risk and support psychological well-being in quarantine settings.

Sepsis in the tropical Top End of Australia's Northern Territory: disease burden and impact on Indigenous Australians.

OBJECTIVE: To describe the clinical and epidemiological features of sepsis and severe sepsis in the population of the tropical Top End of the Northern Territory of Australia and compare these with published estimates for temperate Australia, the United States and Europe. DESIGN, SETTING AND PARTICIPANTS: Prospective cohort study in the major hospital for tropical NT, a region where 27% of the population are Indigenous. We screened all adult (≥ 15 years) acute hospital admissions over a 12-month period (6 May 2007-5 May 2008) for sepsis by standard criteria, and collected standardised clinical data. MAIN OUTCOME MEASURES: Population-based incidence of community-onset sepsis and severe sepsis requiring intensive care unit (ICU) admission; 28-day mortality rate and microbial epidemiology. RESULTS: There were 1191 hospital admissions for sepsis in 1090 patients, of which 604 (50.7%) were Indigenous people; the average age was 46.7 years. The age-adjusted annual population-based incidence of sepsis was 11.8 admissions per 1000 (mortality rate, 5.4%), but for Indigenous people it was 40.8 per 1000 (mortality rate, 5.7%). For severe sepsis requiring ICU admission, the incidence was 1.3 per 1000 per year (mortality rate, 21.5%), with an Indigenous rate of 4.7 per 1000 (mortality rate, 19.3%). CONCLUSIONS: The incidence of sepsis in the tropical NT is substantially higher than that for temperate Australia, the United States and Europe, and these differences are mainly accounted for by the high rates of sepsis in Indigenous people. The findings support strategies to improve housing and access to health services, and reduce comorbidities, alcohol and tobacco use in Indigenous Australians. The burden of sepsis in indigenous populations worldwide requires further study to guide appropriate resourcing of health care and preventive strategies.

Development of a Mobile Laboratory for Sudden Onset Disasters.

OBJECTIVES: Clinical diagnostics in sudden onset disasters have historically been limited. We set out to design, implement, and evaluate a mobile diagnostic laboratory accompanying a type 2 emergency medical team (EMT) field hospital. METHODS: Available diagnostic platforms were reviewed and selected against in field need. Platforms included HemoCue301/WBC DIFF, i-STAT, BIOFIRE FILMARRAY multiplex rt-PCR, Olympus BX53 microscopy, ABO/Rh grouping, and specific rapid diagnostic tests. This equipment was trialed in Katherine, Australia, and Dili, Timor-Leste. RESULTS: During the initial deployment, an evaluation of FilmArray tests was successful using blood culture identification, gastrointestinal, and respiratory panels. HemoCue301 (n = 20) hemoglobin values were compared on Sysmex XN 550 (r = 0.94). HemoCue WBC DIFF had some variation, dependent on the cell, when compared with Sysmex XN 550 (r = 0.88-0.16). i-STAT showed nonsignificant differences against Vitros 250. Further evaluation of FilmArray in Dili, Timor-Leste, diagnosed 117 pathogens on 168 FilmArray pouches, including 25 separate organisms on blood culture and 4 separate cerebrospinal fluid pathogens. CONCLUSION: This mobile laboratory represents a major advance in sudden onset disaster. Setup of the service was quick (< 24 hr) and transport to site rapid. Future deployment in fragmented health systems after sudden onset disasters with EMT2 will now allow broader diagnostic capability.

SARS-CoV-2 infections among Australian passengers on the Diamond Princess cruise ship: A retrospective cohort study.

BACKGROUND: Prolonged periods of confined living on a cruise ship increase the risk for respiratory disease transmission. We describe the epidemiology and clinical characteristics of a SARS-CoV-2 outbreak in Australian passengers on the Diamond Princess cruise ship and provide recommendations to mitigate future cruise ship outbreaks. METHODS: We conducted a retrospective cohort study of Australian passengers who travelled on the Diamond Princess from 20 January until 4 February 2020 and were either hospitalised, remained in Japan or repatriated. The main outcome measures included an epidemic curve, demographics, symptoms, clinical and radiological signs, risk factors and length of time to clear infection. RESULTS: Among 223 Australian passengers, 56 were confirmed SARS-CoV-2 positive. Forty-nine cases had data available and of these over 70% had symptoms consistent with COVID-19. Of symptomatic cases, 17% showed signs and symptoms before the ship implemented quarantine and a further two-thirds had symptoms within one incubation period of quarantine commencing. Prior to ship-based quarantine, exposure to a close contact or cabin mate later confirmed SARS-CoV-2 positive was associated with a 3.78 fold (95% CI, 2.24-6.37) higher risk of COVID-19 acquisition compared to non-exposed passengers. Exposure to a positive cabin mate during the ship's quarantine carried a relative risk of 6.18 (95% CI, 1.96-19.46) of developing COVID-19. Persistently asymptomatic cases represented 29% of total cases. The median time to the first of two consecutive negative PCR-based SARS-CoV-2 assays was 13 days for asymptomatic cases and 19 days for symptomatic cases (p = 0.002). CONCLUSION: Ship based quarantine was effective at reducing transmission of SARS-CoV-2 amongst Australian passengers, but the risk of infection was higher if an individual shared a cabin or was a close contact of a confirmed case. Managing COVID-19 in cruise ship passengers is challenging and requires enhanced health measures and access to onshore quarantine and isolation facilities.

Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivity.

INTRODUCTION: Angiopoietin-2 (ang-2), an angiogenic peptide released by endothelial cell Weibel-Palade bodies (WPBs), increases endothelial activation and vascular permeability. Ang-2 is raised in severe sepsis but the mechanisms underlying this are not known. Nitric oxide (NO) inhibits WPB exocytosis, and bioavailability of endothelial NO is decreased in sepsis. We hypothesized that endothelial NO bioavailability would be inversely correlated with ang-2 concentrations in sepsis. METHODS: Plasma ang-2, vascular endothelial growth factor (VEGF) and endothelial-active cytokines were assessed in 83 patients with early sepsis and 41 hospital controls, and related to reactive hyperaemia-peripheral arterial tonometry, RH-PAT, a measure of endothelial NO bioavailability. RESULTS: Plasma Ang-2 was elevated in sepsis (median [interquartile range (IQR)], ng/ml: severe sepsis 12.4 [8.5-33.4], sepsis without organ failure 6.1 [5.0-10.4], controls 2.7 [2.2-3.6], P < 0.0001). It correlated inversely with RH-PAT (r = -0.38, P < 0.0001) and positively with IL-6 (r = 0.57, P < 0.0001) and degree of organ failure (sequential organ function assessment score) (r = 0.58, P < 0.0001). The correlation of ang-2 with RH-PAT persisted after controlling for sepsis severity. In a longitudinal mixed-effects model, recovery of RH-PAT over time was associated with decline in ang-2. CONCLUSIONS: Ang-2 is elevated in proportion to sepsis severity, and inversely correlated with NO-dependent microvascular reactivity. Impaired endothelial NO bioavailability may contribute to increased endothelial cell release of ang-2, endothelial activation and capillary leak. Agents that increase endothelial NO bioavailability or inhibit WPB exocytosis and/or Ang-2 activity may have therapeutic potential in sepsis.

Incident haemodialysis and outcomes in the Top End of Australia.

Objective The Northern Territory has the highest incidence of haemodialysis care for end-stage kidney disease in Australia. Although acute kidney injury (AKI) is a recognised risk for chronic kidney disease (CKD), the effect of AKI causing incident haemodialysis (iHD) is unknown. Audits identifying antecedents of iHD may inform health service planning. Thus, the aims of this study were to describe: (1) the development of an iHD recording system involving patients with AKI and CKD; and (2) the incidence, patient characteristics and mortality for patients with dialysis-requiring AKI. Methods A retrospective data linkage study was conducted using eight clinical and administrative datasets of adults receiving iHD during the period from July 2011 to December 2012 within a major northern Australian hospital for AKI without CKD (AKI), AKI in people with pre-existing CKD (AKI/CKD) and CKD (without AKI). The time to death was identified by the Northern Territory Register of deaths. Results In all, 121 iHD treatments were provided for the cohort, whose mean age was 51.5 years with 53.7% female, 68.6% Aboriginal ethnicity and 46.3% with diabetes. iHD was provided for AKI (23.1%), AKI/CKD (47.1%) and CKD (29.8%). The 90-day mortality rate was 25.6% (AKI 39.3%, AKI/CKD 22.8%, CKD 19.4%). The 3-year mortality rate was 45.5% (AKI 53.6%, AKI/CKD 22.8%, CKD 19.4%). The time between requesting data from custodians and receipt of data ranged from 15 to 1046 days. Conclusion AKI in people with pre-existing CKD was a common cause of iHD. Health service planning and community health may benefit from AKI prevention strategies and the implementation of sustainable and permanent linkages with the datasets used to monitor prospective incident haemodialysis. What is known about the topic? AKI is a risk factor for CKD. The Northern Territory has the highest national incidence rates of dialysis-dependent end-stage kidney disease, but has no audit tool describing outcomes of dialysis-requiring AKI. What does this paper add? We audited all iHD and showed 25.6% mortality within the first 90 days of iHD and 45.5% overall mortality at 3 years. AKI in people with pre-existing CKD caused 47.1% of iHD. What are the implications for practitioners? Health service planning and community health may benefit from AKI prevention strategies and the implementation of sustainable and permanent linkages with the datasets used to monitor prospective incident haemodialysis.

Sepsis-associated microvascular dysfunction measured by peripheral arterial tonometry: an observational study.

INTRODUCTION: Sepsis has a high mortality despite advances in management. Microcirculatory and endothelial dysfunction contribute to organ failure, and better tools are needed to assess microcirculatory responses to adjunctive therapies. We hypothesised that peripheral arterial tonometry (PAT), a novel user-independent measure of endothelium-dependent microvascular reactivity, would be impaired in proportion to sepsis severity and related to endothelial activation and plasma arginine concentrations. METHODS: Observational cohort study in a 350-bed teaching hospital in tropical Australia. Bedside microvascular reactivity was measured in 85 adults with sepsis and 45 controls at baseline and 2-4 days later by peripheral arterial tonometry. Microvascular reactivity was related to measures of disease severity, plasma concentrations of L-arginine (the substrate for nitric oxide synthase), and biomarkers of endothelial activation. RESULTS: Baseline reactive hyperaemia index (RH-PAT index), measuring endothelium-dependent microvascular reactivity; (mean [95% CI]) was lowest in severe sepsis (1.57 [1.43-1.70]), intermediate in sepsis without organ failure (1.85 [1.67-2.03]) and highest in controls (2.05 [1.91-2.19]); P < 0.00001. Independent predictors of baseline RH-PAT index in sepsis were APACHE II score and mean arterial pressure, but not plasma L-arginine or markers of endothelial activation. Low baseline RH-PAT index was significantly correlated with an increase in SOFA score over the first 2-4 days (r = -0.37, P = 0.02). CONCLUSIONS: Endothelium-dependent microvascular reactivity is impaired in proportion to sepsis severity and suggests decreased endothelial nitric oxide bioavailability in sepsis. Peripheral arterial tonometry may have a role as a user-independent method of monitoring responses to novel adjunctive therapies targeting endothelial dysfunction in sepsis.

Clinical management practices of life-threatening asthma: an audit of practices in intensive care.

OBJECTIVE: Lack of management guidelines for lifethreatening asthma (LTA) risks practice variation. This study aims to elucidate management practices of LTA in the intensive care unit (ICU). DESIGN: A retrospective cohort study. SETTING: Thirteen participating ICUs in Australia between July 2010 and June 2013. PARTICIPANTS: Patients with the principal diagnosis of LTA. MAIN OUTCOME MEASURES: Clinical history, ICU management, patient outcomes, ward education and discharge plans. RESULTS: Of the 270 (267 patients) ICU admissions, 69% were female, with a median age of 39 years (interquartile range [IQR], 26-53 years); 119 (44%) were current smokers; 89 patients (33%) previously required ICU admission, of whom 23 (25%) were intubated. The median ICU stay was 2 days (IQR, 2-4 days). Three patients (1%) died. Seventy-nine patients (29%) received non-invasive ventilation, with 11 (14%) needing subsequent invasive ventilation. Sixty-eight patients (25%) were intubated, with the majority of patients receiving volume cycled synchronised intermittent mechanical ventilation (n = 63; 93%). Drugs used included ß2-agonist by intravenous infusion (n = 69; 26%), inhaled adrenaline (n = 15; 6%) or an adrenaline intravenous infusion (n = 23; 9%), inhaled anticholinergics (n = 238; 90%), systemic corticosteroids (n = 232; 88%), antibiotics (n = 126; 48%) and antivirals (n = 22; 8%). When suitable, 105 patients (n = 200; 53%) had an asthma management plan and 122 (n = 202; 60%) had asthma education upon hospital discharge. Myopathy was associated with hyperglycaemia requiring treatment (odds ratio [OR], 31.6; 95% CI, 2.1-474). Asthma education was more common under specialist thoracic medicine care (OR, 3.0; 95% CI, 1.61-5.54). CONCLUSION: In LTA, practice variation is common, with opportunities to improve discharge management plans and asthma education.

Randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor in patients with septic shock.

OBJECTIVE: To investigate the effect of early administration of granulocyte colony-stimulating factor (G-CSF) on hospital mortality in nonneutropenic patients with septic shock, excluding patients with melioidosis. DESIGN: A randomized, placebo-controlled, double-blinded clinical trial. SETTING AND PATIENTS: Adult patients with septic shock admitted to the Royal Darwin Hospital Intensive Care Unit. INTERVENTIONS: Patients were randomized to receive G-CSF or placebo intravenously daily for 10 days, in addition to routine management of septic shock. MEASUREMENTS: Primary outcome was hospital mortality. Secondary outcomes included intensive care unit mortality, intensive care unit and hospital length of stay, ventilator hours, and time to resolution of shock. Patient comorbidities, baseline and daily physiology, and organ function were collected. RESULTS: Of 166 patients enrolled, 83 were allocated to receive G-CSF (81 included in analysis) and 83 were allocated to receive placebo. At baseline, 30% of patients had diabetes, 18% were known to have renal impairment or failure, and 38% had a history of hazardous alcohol use. The two groups had similar comorbidities at baseline and a similar severity of illness. The in-hospital mortality was 27% in the G-CSF group and 25% in the placebo group. Secondary end points were not different between groups. There was a higher rate of new organ failure in G-CSF-treated patients than placebo-treated patients (50% vs. 33%, p = .03), most of which was accounted for by new liver dysfunction (11% vs. 1%, p = .007). There was no significant difference in the proportion of patients with troponin I of >0.08 mg/L (78% vs. 66%, p = .09), and the prevalence of acute myocardial infarction (6% vs. 4%, p = .55) was not different during the study. The median peak troponin I level was higher in the G-CSF group (0.5 vs. 0.14 mg/L, p = .007), but baseline levels were not available. CONCLUSION: G-CSF does not improve outcomes in patients with septic shock, excluding melioidosis. Increased hepatic dysfunction and higher peak troponin levels in patients receiving G-CSF have not been reported in previous clinical trials and warrant further investigation.

A randomized controlled trial of granulocyte colony-stimulating factor for the treatment of severe sepsis due to melioidosis in Thailand.

BACKGROUND: Melioidosis is a tropical infectious disease associated with significant mortality. Most deaths occur early and are caused by fulminant sepsis. METHODS: In this randomized, placebo-controlled trial, we assessed the efficacy of lenograstim (granulocyte colony-stimulating factor [G-CSF], 263 mu g per day administered intravenously) in ceftazidime-treated patients with severe sepsis caused by suspected melioidosis in Thailand. RESULTS: Over a 27-month period, 60 patients were enrolled to receive either G-CSF (30 patients, 18 of whom had culture-confirmed melioidosis) or placebo (30 patients, 23 of whom had culture-confirmed melioidosis). Mortality rates were similar in both groups (G-CSF group, 70%; placebo group, 87%; risk ratio, 0.81; 95% confidence interval, 0.61-1.06; P=.2), including among patients with confirmed melioidosis (83% vs. 96%; P=.3). The duration of survival was longer for patients who received G-CSF than for patients who received placebo (33 h vs. 18.6 h; hazard ratio, 0.56; 95% confidence interval, 0.31-1.00; P=.05). CONCLUSIONS: Receipt of G-CSF is associated with a longer duration of survival but is not associated with a mortality benefit in patients with severe sepsis who are suspected of having melioidosis in Thailand. We hypothesize that G-CSF may "buy time" for severely septic patients, but survival is more likely to be improved by management of associated metabolic abnormalities and organ dysfunction associated with severe sepsis.

Murray Valley encephalitis in an adult traveller complicated by long-term flaccid paralysis: case report and review of the literature.

Murray Valley encephalitis (MVE) virus, a mosquito-borne flavivirus, is the most common cause of viral encephalitis in the tropical 'Top End' of northern Australia. Clinical encephalitis due to MVE virus has a mortality rate of approximately 30%, with a similar proportion of patients being left with significant neurological deficits. We report the case of a 25-year-old man from the UK who acquired MVE while travelling through northern Australia. He required prolonged admission to the Intensive Care Unit and several years later remains partly ventilator-dependent, with flaccid quadriparesis. To our knowledge, this is the first reported case of MVE virus-induced flaccid paralysis in an adult in northern Australia, although it is well described in children. Paralysis was thought to be due to anterior horn cell involvement in the spinal cord and extensive bilateral thalamic destruction, both of which are well recognised complications of infection with MVE virus. Cases of flaccid paralysis with similar pathology have been described following infection with the related flavivirus Japanese encephalitis virus as well as more recently with West Nile virus. Our case highlights the potential severity of flavivirus-induced encephalitis and the importance of avoiding mosquito bites while travelling through endemic areas.

Pulmonary artery catheter versus pulse contour analysis: a prospective epidemiological study.

INTRODUCTION: The choice of invasive systemic haemodynamic monitoring in critically ill patients remains controversial as no multicentre comparative clinical data exist. Accordingly, we sought to study and compare the features and outcomes of patients who receive haemodynamic monitoring with either the pulmonary artery catheter (PAC) or pulse contour cardiac output (PiCCO) technology. METHODS: We conducted a prospective multicentre, multinational epidemiological study in a cohort of 331 critically ill patients who received haemodynamic monitoring by PAC or PiCCO according to physician preference in intensive care units (ICUs) of eight hospitals in four countries. We collected data on haemodynamics, demographic features, daily fluid balance, mechanical ventilation days, ICU days, hospital days, and hospital mortality. We statistically compared the two techniques. RESULTS: Three hundred and forty-two catheters (PiCCO 192 and PAC 150) were inserted in 331 patients. On direct comparison, patients with PAC were older (68 versus 64 years of age; p = 0.0037), were given inotropic drugs more frequently (37.3% versus 13%; p < 0.0001), and had a lower cardiac index (2.6 versus 3.2 litres/minute per square meter; p < 0.0001). Mean daily fluid balance was significantly greater during PiCCO monitoring (+659 versus +350 ml/day; p = 0.017) and mechanical ventilation-free days were fewer (12 for PiCCO versus 21 for PAC; p = 0.045). However, after multiple regression analysis, we found no significant effect of monitoring technique on mean daily fluid balance, mechanical ventilation-free days, ICU-free days, or hospital mortality. A secondary multiple logistic regression analysis for hospital mortality which included mean daily fluid balance showed that positive fluid balance was a significant predictor of hospital mortality (odds ratio = 1.0002 for each ml/day; p = 0.0073). CONCLUSION: On direct comparison, the use of PiCCO was associated with a greater positive fluid balance and fewer ventilator-free days. After correction for confounding factors, the choice of monitoring did not influence major outcomes, whereas a positive fluid balance was a significant independent predictor of outcome. Future studies may best be targeted at understanding the effect of pursuing different fluid balance regimens rather than monitoring techniques per se.