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.

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.

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.

Particulate face masks for protection against airborne pathogens - one size does not fit all: an observational study.

OBJECTIVE: To determine the proportion of hospital staff who pass fit tests with each of three commonly used particulate face masks, and factors influencing preference and fit test results. DESIGN: Observational study. SETTING AND PARTICIPANTS: 50 healthy hospital staff volunteers in an 18-bed general intensive care unit in an Australian teaching hospital. INTERVENTIONS: Participants were administered a questionnaire about mask use and their preferred mask and underwent qualitative fit-testing with each of three different particulate masks: Kimberly-Clark Tecnol FluidShield N95 particulate filter respirator (KC), 3M Flat Fold 9320 particulate respirator and 3M 8822 particulate respirator with exhalation valve. Participants who failed fittesting were trained in correct mask donning, and fittesting was repeated. MAIN OUTCOME MEASURES: Proportion of participants who passed the fit test for each mask and the effect of training. RESULTS: The proportion of participants who passed a fit test was low for all three masks tested (KC, 16%; flat fold, 28%; and valved, 34%). Rates improved after training: the first mask tested fitted in 18% of participants pre-training and 40% post-training (P = 0.02). None of the masks fitted for 28% of participants. There were no significant predictors of fit-test results. CONCLUSIONS: A large proportion of individuals failed a fit test with any given mask, and we were not able to identify any factors that predicted mask fit in individuals. Training on mask use improved the rates of adequate fit. Hospitals should carry a range of P2 masks, and should conduct systematic P2 mask training and fit-testing programs for all staff potentially exposed to airborne pathogens.

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.

Septic shock: the changing Zeitgeist of management.

Most interventions in critically unwell patients with septic shock are poorly supported by evidence, in part reflecting the difficulty of conducting trials in this heterogeneous group. Four important clinical trials in 2001-2 appeared to demonstrate mortality benefits associated with early goal-directed resuscitation, intensive glycaemic control, physiological-dose steroid replacement and activated protein C. However, recent evidence has not confirmed the beneficial effect of these interventions.

Infective endocarditis with Abiotrophia defectiva: the first Australian experience.

A 40-year old Indigenous woman with a history of mitral valve replacement was admitted to the Royal Darwin Hospital, Northern Territory, for an elective cone biopsy of the cervix. During the admission, she had recurrent fever and joint pain of the left knee. Blood was cultured, and she was treated with broad-spectrum antibiotics. Abiotrophia defectiva was identified from the culture, and a transoesophageal echocardiogram revealed endocarditis of the mitral valve prosthesis. A review of the English-language literature suggests that this is the first reported case of Abiotrophia endocarditis in Australia, and the third reported case of prosthetic-valve endocarditis caused by this species worldwide.

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.

A clinical audit of the efficacy of tegaserod as a prokinetic agent in the intensive care unit.

OBJECTIVE: To formally document the effectiveness of tegaserod as a prokinetic agent in intensive care patients. METHODS: The audit was designed in consultation with the Northern Territory Drug and Therapeutics Committee. Tegaserod was added to the feeding protocol and prokinetic algorithm in the ICU, and a prospective audit was performed of patients receiving the medication between May and September 2006. RESULTS: Over the 5-month period, 40 patients received tegaserod after failing to respond to two doses of metoclopramide. Median daily volume of gastric aspirate was reduced from 1220mL in the 24 hours before tegaserod to 887.5mL in the first 24 hours after its introduction, and to 280mL in the second 24 hours (P=0.01 and P<0.001, respectively). Tegaserod was an effective prokinetic agent in 85% (34) patients. Attributable diarrhoea occurred in 13% (5) patients, but did not require intervention. CONCLUSIONS: Tegaserod is an effective alternative prokinetic agent for ICU patients with a safer side-effect profile. We believe it warrants further investigation.

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.

Leptospirosis: an unusual presentation.

Leptospirosis is a common zoonosis that is endemic in the tropical Top End of the Northern Territory. Disease ranges from mild to very severe. We report a patient with anicteric leptospirosis who became critically ill, challenging the view that anicteric leptospirosis is less severe than the icteric form. Despite a typical but non-specific presentation and recreational high-risk activities, diagnosis of leptospirosis was delayed. The patient developed respiratory failure, resulting from pulmonary haemorrhage, and acute renal failure. This case highlights the multiple factors that should prompt health care workers to consider the diagnosis of leptospirosis in non-classical presentations.

Outcomes of patients with melioidosis treated with meropenem.

Melioidosis, an infection due to Burkholderia pseudomallei, is endemic in southeast Asia and northern Australia. We reviewed our experience with meropenem in the treatment of severe melioidosis in 63 patients over a 6-year period. Outcomes were similar to those of ceftazidime-treated patients (n = 153) despite a deliberate selection bias to more-unwell patients receiving meropenem. The mortality among meropenem-treated patients was 19%. One patient had a possible drug fever associated with the use of meropenem. We conclude that meropenem (1 g or 25 mg/kg every 8 h intravenously for >/=14 days) is an alternative to ceftazidime and imipenem in the treatment of melioidosis. The use of meropenem may be associated with improved outcomes in patients with severe sepsis associated with melioidosis.

Adjunctive granulocyte colony-stimulating factor for treatment of septic shock due to melioidosis.

Melioidosis, caused by the intracellular pathogen Burkholderia pseudomallei, is endemic in northern Australia and Southeast Asia. Risk factors for this infection have also been associated with functional neutrophil defects. Because of this, granulocyte colony-stimulating factor (G-CSF) was adopted for use in patients with septic shock due to melioidosis in December 1998. We compared the mortality rates from before and after the introduction of G-CSF therapy at the Royal Darwin Hospital (Darwin, Australia) during the period of 1989-2002. The mortality rate decreased from 95% to 10% after the introduction of G-CSF. Risk factors, the duration of illness before presentation, and the severity of illness were similar in both groups. A smaller decrease in mortality among patients in the intensive care unit who did not have melioidosis was observed, suggesting that other changes in management did not account for the magnitude of the benefit seen. We conclude that G-CSF may have contributed to the reduction in the mortality rate among patients with septic shock due to melioidosis.