The epidemiology of dying within 48 hours of presentation to emergency departments: a retrospective cohort study of older people across Australia and New Zealand.

BACKGROUND: Emergency department (ED) clinicians are more frequently providing care, including end-of-life care, to older people. OBJECTIVES: To estimate the need for ED end-of-life care for people aged ≥65 years, describe characteristics of those dying within 48 hours of ED presentation and compare those dying in ED with those dying elsewhere. METHODS: We conducted a retrospective cohort study analysing data from 177 hospitals in Australia and New Zealand. Data on older people presenting to ED from January to December 2018, and those who died within 48 hours of ED presentation, were analysed using simple descriptive statistics and univariate logistic regression. RESULTS: From participating hospitals in Australia or New Zealand, 10,921 deaths in older people occurred. The 48-hour mortality rate was 6.43 per 1,000 ED presentations (95% confidence interval: 6.31-6.56). Just over a quarter (n = 3,067, 28.1%) died in ED. About one-quarter of the cohort (n = 2,887, 26.4%) was triaged into less urgent triage categories. Factors with an increased risk of dying in ED included age 65-74 years, ambulance arrival, most urgent triage categories, principal diagnosis of circulatory system disorder, and not identifying as an Aboriginal or Torres Strait Islander person. Of the 7,677 older people admitted, half (n = 3,836, 50.0%) had an encounter for palliative care prior to, or during, this presentation. CONCLUSIONS: Our findings provide insight into the challenges of recognising the dying older patient and differentiating those appropriate for end-of-life care. We support recommendations for national advanced care planning registers and suggest a review of triage systems with an older person-focused lens.

End-of-life care: A retrospective cohort study of older people who died within 48 hours of presentation to the emergency department.

OBJECTIVES: To describe the characteristics of, and care provided to, older people who died within 48 h of ED presentation. METHODS: A descriptive retrospective cohort study of people 65 years and older presenting to two EDs in Queensland, Australia, between April 2018 and March 2019. Data from electronic medical records were collected and analysed. RESULTS: Two hundred and ninety-five older people who died within 48 h of ED presentation were included. Nearly all arrived by ambulance (92%, n = 272) and 36% (n = 106) were from aged care facilities. Three-quarters (75%, n = 222) were triaged into the most urgent triage categories (i.e. Australasian Triage Scale; ATS 1/2). Fewer than half were previously independent with mobility (38%, n = 111) and activities of daily living (43%, n = 128). Sixty-one per cent (n = 181) had a pre-existing healthcare directive. Twenty-two per cent (n = 66) died in ED, most commonly due to pneumonia, intracerebral haemorrhage, cardiac arrest and/or sepsis. Over half had one or more ED visits (52%, n = 154) and/or hospital admissions (52%, n = 152) 6 months prior. CONCLUSIONS: Identification of patients at end-of-life (EoL) is not always straightforward; consider recent reduction in independence and recent ED visits/hospital admissions. System-based strategies that span pre-hospital, ED and in-patient care are recommended to facilitate EoL pathway implementation and care continuity.

Differentiating infection, colonisation, and sterile inflammation in critical illness: the emerging role of host-response profiling.

Infection results when a pathogen produces host tissue damage and elicits an immune response. Critically ill patients experience immune activation secondary to both sterile and infectious insults, with overlapping clinical phenotypes and underlying immunological mechanisms. Patients also undergo a shift in microbiota with the emergence of pathogen-dominant microbiomes. Whilst the combination of inflammation and microbial shift has long challenged intensivists in the identification of true infection, the advent of highly sensitive molecular diagnostics has further confounded the diagnostic dilemma as the number of microbial detections increases. Given the key role of the host immune response in the development and definition of infection, profiling the host response offers the potential to help unravel the conundrum of distinguishing colonisation and sterile inflammation from true infection. This narrative review provides an overview of current approaches to distinguishing colonisation from infection using routinely available techniques and proposes matrices to support decision-making in this setting. In searching for new tools to better discriminate these states, the review turns to the understanding of the underlying pathobiology of the host response to infection. It then reviews the techniques available to assess this response in a clinically applicable context. It will cover techniques including profiling of transcriptome, protein expression, and immune functional assays, detailing the current state of knowledge in diagnostics along with the challenges and opportunities. The ultimate infection diagnostic tool will likely combine an assessment of both host immune response and sensitive pathogen detection to improve patient management and facilitate antimicrobial stewardship.

Diagnosing sepsis in the ICU: Comparison of a gene expression signature to pre-existing biomarkers.

PURPOSE: We aimed to identify a gene signature that discriminates between sepsis and aseptic inflammation in patients administered antibiotics in the intensive care unit and compare it to commonly utilised sepsis biomarkers. METHODS: 91 patients commenced on antibiotics were retrospectively diagnosed as having: (i) blood culture positive sepsis; (ii) blood culture negative sepsis; or (iii) aseptic inflammation. Bloods were collected after <24 h of antibiotic commencement for both gene expression sequencing analysis and measurement of previously identified biomarkers. RESULTS: 53 differentially expressed genes were identified that accurately discriminated between blood culture positive sepsis and aseptic inflammation in a cohort of patients given antibiotics [aROC 0.97 (95% CI, 0.95-0.99)]. This gene signature was validated in a publicly available database. The gene signature outperformed previously identified sepsis biomarkers including C-reactive protein [aROC 0.72 (95% CI, 0.57-0.87)], NT-Pro B-type Natriuretic Peptide [aROC 0.84 (95% CI, 0.73-0.96)], and Septicyte™ LAB [aROC 0.8 (95% CI, 0.68-0.93)], but was comparable to Procalcitonin [aROC 0.96 (95% CI, 0.9-1)]. CONCLUSIONS: A gene expression signature was identified that accurately discriminates between sepsis and aseptic inflammation in patients given antibiotics in the intensive care unit.

Antimicrobial Prescribing in the Emergency Department; Who Is Calling the Shots?

Objective: Inappropriate antimicrobial prescribing in the emergency department (ED) can lead to poor outcomes. It is unknown how often the prescribing clinician is guided by others, and whether prescriber factors affect appropriateness of prescribing. This study aims to describe decision making, confidence in, and appropriateness of antimicrobial prescribing in the ED. Methods: Descriptive study in two Australian EDs using both questionnaire and medical record review. Participants were clinicians who prescribed antimicrobials to patients in the ED. Outcomes of interest were level of decision-making (self or directed), confidence in indication for prescribing and appropriateness (5-point Likert scale, 5 most confident). Appropriateness assessment of the prescribing event was by blinded review using the National Antibiotic Prescribing Survey appropriateness assessment tool. All analyses were descriptive. Results: Data on 88 prescribers were included, with 61% making prescribing decisions themselves. The 39% directed by other clinicians were primarily guided by more senior ED and surgical subspecialty clinicians. Confidence that antibiotics were indicated (Likert score: 4.20, 4.35 and 4.35) and appropriate (Likert score: 4.07, 4.23 and 4.29) was similar for juniors, mid-level and senior prescribers, respectively. Eighty-five percent of prescriptions were assessed as appropriate, with no differences in appropriateness by seniority, decision-making or confidence. Conclusions: Over one-third of prescribing was guided by senior ED clinicians or based on specialty advice, primarily surgical specialties. Prescriber confidence was high regardless of seniority or decision-maker. Overall appropriateness of prescribing was good, but with room for improvement. Future qualitative research may provide further insight into the intricacies of prescribing decision-making.

Host Diagnostic Biomarkers of Infection in the ICU: Where Are We and Where Are We Going?

PURPOSE OF REVIEW: Early identification of infection in the critically ill patient and initiation of appropriate treatment is key to reducing morbidity and mortality. On the other hand, the indiscriminate use of antimicrobials leads to harms, many of which may be exaggerated in the critically ill population. The current method of diagnosing infection in the intensive care unit relies heavily on clinical gestalt; however, this approach is plagued by biases. Therefore, a reliable, independent biomarker holds promise in the accurate determination of infection. We discuss currently used host biomarkers used in the intensive care unit and review new and emerging approaches to biomarker discovery. RECENT FINDINGS: White cell count (including total white cell count, left shift, and the neutrophil-leucocyte ratio), C-reactive protein, and procalcitonin are the most common host diagnostic biomarkers for sepsis used in current clinical practice. However, their utility in the initial diagnosis of infection, and their role in the subsequent decision to commence treatment, remains limited. Novel approaches to biomarker discovery that are currently being investigated include combination biomarkers, host 'sepsis signatures' based on differential gene expression, site-specific biomarkers, biomechanical assays, and incorporation of new and pre-existing host biomarkers into machine learning algorithms. SUMMARY: To date, no single reliable independent biomarker of infection exists. Whilst new approaches to biomarker discovery hold promise, their clinical utility may be limited if previous mistakes that have afflicted sepsis biomarker research continue to be repeated.

Ceftriaxone dosing in patients admitted from the emergency department with sepsis.

PURPOSE: Unbound ceftriaxone pharmacokinetics in adult patients have been poorly characterised. The objective of this study is to determine the ceftriaxone dose that achieves an unbound trough concentration ≥ 0.5 mg/L in > 90% of adult patients receiving once-daily dosing presenting to the emergency department (ED) with sepsis. METHODS: We performed a prospective single-centre pharmacokinetic study. A single unbound plasma ceftriaxone concentration was obtained from each patient using blood collected as part of routine clinical practice within the first dosing interval. Samples were analysed using a validated ultra-high pressure liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. RESULTS: A ceftriaxone concentration obtained throughout the first dosing interval was available for fifty adult patients meeting sepsis criteria. Using this concentration time-curve data, a pharmacokinetic model was developed with acceptable predictive performance per the visual predictive check. Simulations show that a 1-g once-daily dose is unlikely to achieve the minimum therapeutic ceftriaxone exposure in > 90% patients with a creatinine clearance ≥ 60 mL/min. However, a 2-g once-daily dose will provide a therapeutic exposure for target pathogens infecting patients with a creatinine clearance ≤ 140 mL/min. CONCLUSIONS: Ceftriaxone administered as a 1-g once-daily dose is unlikely to achieve a therapeutic exposure in > 90% of patients presenting to the ED with sepsis. Increasing the ceftriaxone dose to 2 g once daily will likely achieve the desired exposure against target pathogens. Future clinical trials are required to determine any potential clinical benefit of optimised ceftriaxone dosing.

Antibiotic prescribing in patients who presented to the emergency department with dog bites: A descriptive review of current practice.

OBJECTIVE: To describe the current practice of prophylactic antibiotic prescribing for patients presenting to the ED with a dog bite, and compare management against existing guidelines. METHODS: We performed a descriptive retrospective study on all consecutive patients who presented to one tertiary teaching hospital and one regional district hospital in Southeast Queensland between 1 July 2017 and 30 June 2018 with a presentation of a dog bite. Data on demographics and management were collected from the electronic medical record using a standardised data collection tool. Risk factors supporting prophylaxis were taken from the electronic Therapeutic Guidelines. RESULTS: Of the 336 patients included for analysis, 299 received antibiotics, of which 23 were for established infection. A total of 276 (82% of overall cohort) received a prescription for prophylactic antibiotics, either in hospital (ED or admitting ward) and/or on discharge. Of the 178 patients who received prophylactic antibiotics in hospital, 91 (51.1%) received intravenous antibiotics. Of the patients who presented to ED without a previously established infection 271 (86.6%) received prophylactic antibiotics on discharge. Over one quarter (27.5%) of patients who were given prophylactic antibiotics did not meet any high-risk factors as outlined in guidelines. CONCLUSION: Prophylactic antibiotics are extensively used for patients with dog bites. There is scope to rationalise antibiotic use and route of antibiotic administration in patients with dog bites.

Extra-cardiac endovascular infections in the critically ill.

Vascular infections are associated with high complication rates and mortality. While there is an extensive body of literature surrounding cardiac infections including endocarditis, this is less so the case for other endovascular infections. The objective of this narrative review is to summarize the epidemiology, clinical features, and selected management of severe vascular infections exclusive of those involving the heart. Endovascular infections may involve either the arterial or venous vasculature and may arise in native vessels or secondary to implanted devices. Management is complex and requires multi-disciplinary involvement from the outset. Infective arteritis or device-related arterial infection involves removal of the infected tissue or device. In cases where complete excision is not possible, prolonged courses of antimicrobials are required. Serious infections associated with the venous system include septic thrombophlebitis of the internal jugular and other deep veins, and intracranial/venous sinuses. Source control is of paramount importance in these cases with adjunctive antimicrobial therapy. The role of anticoagulation is controversial although recommended in the absence of contraindications. An improved understanding of the management of these infections, and thus improved patient outcomes, requires multi-center, international collaboration.

Appropriateness of antibiotic prescribing in the Emergency Department.

Background: Antibiotics are some of the most commonly prescribed drugs in the Emergency Department (ED) and yet data describing the overall appropriateness of antibiotic prescribing in the ED is scarce. Objectives: To describe the appropriateness of antibiotic prescribing in the ED. Methods: A retrospective, observational study of current practice. All patients who presented to the ED during the study period and were prescribed at least one antibiotic were included. Specialists from Infectious Disease, Microbiology and Emergency Medicine and a Senior Pharmacist assessed antibiotic appropriateness against evidence-based guidelines. Results: A total of 1019 (13.6%) of patient presentations involved the prescription of at least one antibiotic. Of these, 640 (62.8%) antibiotic prescriptions were assessed as appropriate, 333 (32.7%) were assessed as inappropriate and 46 (4.5%) were deemed to be not assessable. Adults were more likely to receive an inappropriate antibiotic prescription than children (36.9% versus 22.9%; difference 14.1%, 95% CI 7.2%-21.0%). Patients who met quick Sepsis-related Organ Failure Assessment (qSOFA) criteria were more likely to be prescribed inappropriate antibiotics (56.7% versus 36.1%; difference 20.5%, 95% CI, 2.4%-38.7%). There was no difference in the incidence of appropriate antibiotic prescribing based on patient gender, disposition (admitted/discharged), reason for antibiotic administration (treatment/prophylaxis) or time of shift (day/night). Conclusions: Inappropriate administration of antibiotics can lead to unnecessary adverse events, treatment failure and antimicrobial resistance. With over one in three antibiotic prescriptions in the ED being assessed as inappropriate, there is a pressing need to develop initiatives to improve antibiotic prescribing to prevent antibiotic-associated patient and community harms.

Is it time for a culture change? Blood culture collection in the emergency department.

OBJECTIVE: To describe how frequently blood cultures (BCs) are obtained in the ED and to describe the incidence of true- and false-positive BC results. METHODS: Retrospective descriptive study of all patients presenting to a tertiary-level, mixed Australian ED over a 15 month period. RESULTS: A total of 3617 (3.67%) patients had BCs collected. Around one (12.1%) in eight of these BCs were positive; nearly half (45.2%) of which were identified as a false positive. CONCLUSIONS: BCs are a common investigation in the ED with a high false-positive rate. Strategies are required to reduce false positives, including reducing inappropriate collection and improving collection techniques.

The use and risks of antibiotics in critically ill patients.

INTRODUCTION: The altered pathophysiology in critically ill patients presents a unique challenge in both the diagnosis of infection and the appropriate prescription of antibiotics. In this context, the importance of effective and timely treatment needs to be weighed against the individual and community harms associated with antibiotic collateral damage and antibiotic resistance. AREAS COVERED: We evaluate the principles of antibiotic use in critically ill patients, including dose optimisation, use of combination antibiotic therapy, therapeutic drug monitoring, appropriate antibiotic therapy duration, de-escalation, and utilisation of sepsis biomarkers. We also describe the potential risks associated with antibiotic therapy including antibiotic resistance, delayed treatment, treatment failure, and collateral damage. EXPERT OPINION: Prescribing teams must be aware of the impact of critical illness on their patients and tailor antibiotic therapy appropriately to prevent the significant harms associated with suboptimal antibiotic administration.

Autoantibodies against homocysteinylated protein in a mouse model of folate deficiency-induced neural tube defects.

BACKGROUND: Periconceptional supplementation with folic acid results in a significant reduction in the incidence of neural tube defects (NTDs). Nonetheless, NTDs remain a leading cause of perinatal morbidity and mortality worldwide, and the mechanism(s) by which folate exerts its protective effects are unknown. Homocysteine is an amino acid that accumulates under conditions of folate-deficiency, and is suggested as a risk factor for NTDs. One proposed mechanism of homocysteine toxicity is its accumulation into proteins in a process termed homocysteinylation. METHODS & RESULTS: Herein, we used a folate-deficient diet in pregnant mice to demonstrate that there is: (i) a significant inverse correlation between maternal serum folate levels and serum homocysteine; (ii) a significant positive correlation between serum homocysteine levels and titers of autoantibodies against homocysteinylated protein; and (iii) a significant increase in congenital malformations and NTDs in mice deficient in serum folate. Furthermore, in mice administered the folate-deplete diet before conception, supplementation with folic acid during the gestational period completely rescued the embryos from congenital defects, and resulted in homocysteinylated protein titers at term that are comparable to that of mice administered a folate-replete diet throughout both the pre- and postconception period. These results demonstrate that a low-folate diet that induces NTDs also increases protein homocysteinylation and the subsequent generation of autoantibodies against homocysteinylated proteins. CONCLUSION: These data support the hypotheses that homocysteinylation results in neo-self antigen formation under conditions of maternal folate deficiency, and that this process is reversible with folic acid supplementation.

Placental lipase expression in pregnancies complicated by preeclampsia: a case-control study.

BACKGROUND: Preeclampsia (PE) is associated with maternal and neonatal morbidity and mortality. In PE, the physiological hyperlipidaemia of pregnancy is exaggerated. The purpose of this study was to examine the expression of adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), lipoprotein lipase (LPL) and endothelial lipase (EL) in pregnancies complicated by PE. METHODS: Placentae were collected from 16 women with PE and 20 women with uncomplicated pregnancies matched for maternal prepregnancy BMI and gestational age of delivery. Gene and protein expression of the placental lipases were measured by Q-PCR and Western blot. DNA methylation of the promoter of LPL was assessed by bisulfite sequencing. Lipase localisation and activity were analysed. RESULTS: Gene expression of all lipases was significantly reduced, as was HSL protein level in women with PE. All lipases were localised to trophoblasts and endothelial cells in PE and control placentae. There was no difference in methylation of the LPL promoter between PE and control placentae. Lipase activity was not altered in placentae from women with PE. CONCLUSION: These results suggest that the decreased placental lipase gene but not protein expression or lipase activity, which is associated with late-onset PE is not a major contributor to the abnormal lipids seen in PE.

The Role of C5a Receptor Signaling in Endotoxin-Induced Miscarriage and Preterm Birth.

PROBLEM: Complement factor 5a (C5a), a potent pro-inflammatory mediator of the complement system, has been implicated in fetal rejection throughout gestation, from miscarriage to preterm birth. This study aimed to investigate the role of the principal C5a receptor, C5aR1 (CD88), in both miscarriage and preterm birth, in a bacterial endotoxin (lipopolysaccharide; LPS) murine model. METHOD OF STUDY: Wild-type and C5ar1 knockout mice were administered LPS at 9.5 or 15.5 days post-conception to induce miscarriage or preterm birth, respectively. RESULTS: C5ar1 knockout mice were protected against miscarriage in response to administration of LPS in early gestation. However, the absence of C5aR1 had no effect on the rates of preterm birth when LPS was administered in late gestation. CONCLUSION: There may be a gestational window in which excessive activation of C5a can exert deleterious effects in pregnancy. Future strategies targeting the C5a-C5aR1 signaling axis should be considered to ameliorate miscarriages in patients with recurrent pregnancy loss.

Exercise in pregnancy does not alter gestational weight gain, MCP-1 or leptin in obese women.

BACKGROUND: Increasing physical activity in pregnancy may improve pregnancy outcomes for obese women. Exercise could reduce gestational weight gain, improve the maternal circulating lipid profile as well as alter leptin, Interleukin-8 (IL-8) and Monocyte Chemoattractant Protein-1 (MCP-1) levels. AIM: The aim of this study was to investigate the effects of exercise on gestational weight gain, maternal circulating lipids, IL-8, MCP-1 and leptin levels in obese pregnant women. MATERIALS AND METHODS: The analysis was performed in the 35 obese women enrolled in the pilot BAMBINO randomised controlled trial who provided blood samples at 12- and 28-weeks gestation. Women in the exercise intervention arm received an individualised exercise plan. Blood samples, exercise diary and pedometer data were obtained at 12-, 20-, 28- and 36-weeks' gestation. Cord blood was obtained at delivery. RESULTS: Women in the exercise arm exercised more than those in the control arm (P = 0.038). There was no difference in gestational weight gain, excess gestational weight gain, MCP-1 and leptin levels between women in the exercise intervention (n = 19) or the control arm (n = 16). IL-8 was not detectable. Exercise did not alter the maternal lipid profile. CONCLUSIONS: The low level of physical activity achieved in obese women in the exercise intervention arm was insufficient to alter gestational weight gain, MCP-1, leptin or circulating lipid levels.

Placental lipases in pregnancies complicated by gestational diabetes mellitus (GDM).

Infants of women with gestational diabetes mellitus (GDM) are more likely to be born large for gestational age with a higher percentage body fat. Elevated maternal lipids may contribute to this. Placental lipases such as lipoprotein lipase (LPL), endothelial lipase (EL) and hormone sensitive lipase (HSL) are involved in transferring lipids from mother to fetus. Previous studies of expression of these lipases in placentae in women with diabetes in pregnancy have reported divergent results. Intracellular lipases such as adipose triglyceride lipase (ATGL), and HSL are central to lipid droplet metabolism. The activities of these lipases are both influenced by Perilipin 1, and ATGL is also activated by a co-factor comparative gene identification-58 (CGI-58) and inhibited by G0/G1 switch gene 2 (GS02). None of these modifying factors or ATGL have been examined previously in placenta. The purpose of this study was therefore to examine the expression of ATGL, HSL, LPL, EL, as well as Perilipin 1, GS02 and CGI-58 in term pregnancies complicated by GDM. mRNA and protein expression of the lipases were measured in placentae from 17 women with GDM and 17 normoglycaemic pregnancies, matched for maternal BMI and gestational age of delivery. ATGL mRNA expression was increased and HSL mRNA expression reduced in placentae from GDM although there was no differences in protein expression of any of the lipases. All lipases were localised to trophoblasts and endothelial cells. The expression of Perilipin 1 and CGI-58 mRNA was increased and GS02 not altered in GDM. These results suggest that there is no difference in expression in these four lipases between GDM and normoglycaemic placentae, and therefore altered lipid transfer via these lipases does not contribute to large for gestational age in infants of women with GDM.

Increased placental expression of fibroblast growth factor 21 in gestational diabetes mellitus.

BACKGROUND: Fibroblast growth factor 21 (FGF21) can regulate glucose and lipid metabolism. The placenta actively synthesizes and secretes many hormones, but it is unknown whether this includes FGF21. This study aimed to analyze the placental expression of FGF21 in women with or without gestational diabetes mellitus (GDM). METHODS: FGF21 and peroxisome proliferator-activated receptor (PPAR)-α mRNA and protein expression were measured in the placentae of 20 women with and 18 without GDM. mRNA expression of PPARα, FGF receptors 1-4, the coreceptor ß-klotho, and glucose transporter (GLUT)-1, -3, and -4 was investigated. Maternal and fetal circulating FGF21 levels were assessed in 10 mother-baby dyads per condition. RESULTS: FGF21 was expressed in the placenta and its mRNA expression increased in women with GDM [10.75 (interquartile range 3.28-125.6 AU)] vs control [0.83 (0.22-4.78), P < .001], as is its protein expression [GDM 2.89 (1.44-5.10)] vs control [0.42 (0.05-1.98), P < .05]. PPARα mRNA but not protein expression was increased in GDM [2.94 (0.70-7.26)] vs control [0.99 (0.43-2.17), P < .05] and was positively correlated to FGF21 mRNA expression (ρ = 0.43, P < .01). Placental mRNA expression of FGF receptors and GLUT1 was unchanged, and ß-klotho, GLUT3, and GLUT4 showed increased expression in GDM. Maternal circulating FGF21 levels were similar [GDM 323 (75-921) vs control 269 (49-731) pg/mL, P = .81]. FGF21 was undetected in fetal cord blood. CONCLUSIONS: FGF21 is expressed in the placenta and its expression is increased in GDM. The absence of FGF21 in fetal cord blood suggests that neither placental FGF21 nor maternal circulating FGF21 is secreted into the fetal circulation. Placental FGF21 may be a regulator of placental metabolism.