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.

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.

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.

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.

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.

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.

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.

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.

Prevalence of bullying, discrimination and sexual harassment among trainees and Fellows of the College of Intensive Care Medicine of Australia and New Zealand.

BACKGROUND: Anecdotal reports about bullying behaviour in intensive care emerged during College of Intensive Care Medicine (CICM) hospital accreditation visits. Bullying, discrimination and sexual harassment (BDSH) in the medical profession, particularly in surgery, were widely reported in the media recently. This prompted the College to formally survey its Fellows and trainees to identify the prevalence of these behaviours in the intensive care workplace. METHODS: An online survey of all trainees (n = 951) and Fellows (n = 970) of the CICM. RESULTS: The survey response rate was 51% (Fellows, 60%; trainees, 41%). The overall prevalences of bullying, discrimination and sexual harassment were 32%, 12% and 3%, respectively. The proportions of Fellows and trainees who reported being bullied and discriminated against were similar across all age groups. Women reported a greater prevalence of sexual harassment (odds ratio [OR], 2.97 [95% CI, 1.35-6.51]; P = 0.006) and discrimination (OR, 2.10 [95% CI, 1.39-3.17]; P = 0.0004) than men. Respondents who obtained their primary medical qualification in Asia or Africa appeared to have been at increased risk of discrimination (OR, 1.88 [95% CI, 1.15-3.05]; P = 0.03). Respondents who obtained their degree in Australia, New Zealand or Hong Kong may have been at increased risk of being bullied. In all three domains of unprofessional behaviour, the perpetrators were predominantly consultants (70% overall), and the highest proportion of these was ICU consultants. CONCLUSIONS: The occurrence of BDSH appears to be common in the intensive care environment in Australia and New Zealand.

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).

An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.

Both endothelial and immune dysfunction contribute to the high mortality rate in human sepsis, but the underlying mechanisms are unclear. In response to infection, interferon-γ activates indoleamine 2,3-dioxygenase (IDO) which metabolizes the essential amino acid tryptophan to the toxic metabolite kynurenine. IDO can be expressed in endothelial cells, hepatocytes and mononuclear leukocytes, all of which contribute to sepsis pathophysiology. Increased IDO activity (measured by the kynurenine to tryptophan [KT] ratio in plasma) causes T-cell apoptosis, vasodilation and nitric oxide synthase inhibition. We hypothesized that IDO activity in sepsis would be related to plasma interferon-γ, interleukin-10, T cell lymphopenia and impairment of microvascular reactivity, a measure of endothelial nitric oxide bioavailability. In an observational cohort study of 80 sepsis patients (50 severe and 30 non-severe) and 40 hospital controls, we determined the relationship between IDO activity (plasma KT ratio) and selected plasma cytokines, sepsis severity, nitric oxide-dependent microvascular reactivity and lymphocyte subsets in sepsis. Plasma amino acids were measured by high performance liquid chromatography and microvascular reactivity by peripheral arterial tonometry. The plasma KT ratio was increased in sepsis (median 141 [IQR 64-235]) compared to controls (36 [28-52]); p<0.0001), and correlated with plasma interferon-γ and interleukin-10, and inversely with total lymphocyte count, CD8+ and CD4+ T-lymphocytes, systolic blood pressure and microvascular reactivity. In response to treatment of severe sepsis, the median KT ratio decreased from 162 [IQR 100-286] on day 0 to 89 [65-139] by day 7; p = 0.0006) and this decrease in KT ratio correlated with a decrease in the Sequential Organ Failure Assessment score (p<0.0001). IDO-mediated tryptophan catabolism is associated with dysregulated immune responses and impaired microvascular reactivity in sepsis and may link these two fundamental processes in sepsis pathophysiology.

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.

Asymmetric dimethylarginine, endothelial nitric oxide bioavailability and mortality in sepsis.

BACKGROUND: Plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are raised in patients with chronic vascular disease, causing increased cardiovascular risk and endothelial dysfunction, but the role of ADMA in acute inflammatory states is less well defined. METHODS AND RESULTS: In a prospective longitudinal study in 67 patients with acute sepsis and 31 controls, digital microvascular reactivity was measured by peripheral arterial tonometry and blood was collected at baseline and 2-4 days later. Plasma ADMA and L-arginine concentrations were determined by high performance liquid chromatography. Baseline plasma L-arginine: ADMA ratio was significantly lower in sepsis patients (median [IQR] 63 [45-103]) than in hospital controls (143 [123-166], p<0.0001) and correlated with microvascular reactivity (r = 0.34, R(2) = 0.12, p = 0.02). Baseline plasma ADMA was independently associated with 28-day mortality (Odds ratio [95% CI] for death in those in the highest quartile (≥ 0.66 µmol/L) = 20.8 [2.2-195.0], p = 0.008), and was independently correlated with severity of organ failure. Increase in ADMA over time correlated with increase in organ failure and decrease in microvascular reactivity. CONCLUSIONS: Impaired endothelial and microvascular function due to decreased endothelial NO bioavailability is a potential mechanism linking increased plasma ADMA with organ failure and death in sepsis.

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.