Genes involved in platelet aggregation and activation are downregulated during acute anaphylaxis in humans.

Objective: Mechanisms underlying the anaphylactic reaction in humans are not fully understood. Here, we aimed at improving our understanding of anaphylaxis by investigating gene expression changes. Methods: Microarray data set GSE69063 was analysed, describing emergency department (ED) patients with severe anaphylaxis (n = 12), moderate anaphylaxis (n = 6), sepsis (n = 20) and trauma (n = 11). Samples were taken at ED presentation (T0) and 1 h later (T1). Healthy controls were age and sex matched to ED patient groups. Gene expression changes were determined using limma, and pathway analysis applied. Differentially expressed genes were validated in an independent cohort of anaphylaxis patients (n = 31) and matched healthy controls (n = 10), using quantitative reverse transcription-polymerase chain reaction. Results: Platelet aggregation was dysregulated in severe anaphylaxis at T0, but not in moderate anaphylaxis, sepsis or trauma. Dysregulation was not observed in patients who received adrenaline before T0. Seven genes (GATA1 (adjusted P-value = 5.57 × 10-4), TLN1 (adjusted P-value = 9.40 × 10-4), GP1BA (adjusted P-value = 2.15 × 10-2), SELP (adjusted P-value = 2.29 × 10-2), MPL (adjusted P-value = 1.20 × 10-2), F13A1 (adjusted P-value = 1.39 × 10-2) and SPARC (adjusted P-value = 4.06 × 10-2)) were significantly downregulated in severe anaphylaxis patients who did not receive adrenaline before ED arrival, compared with healthy controls. One gene (TLN1 (adjusted P-value = 1.29 × 10-2)) was significantly downregulated in moderate anaphylaxis patients who did not receive adrenaline before ED arrival, compared with healthy controls. Conclusion: Downregulation of genes involved in platelet aggregation and activation is a unique feature of the early anaphylactic reaction not previously reported and may be associated with reaction severity.

Safety of peripheral administration of vasopressor medications: A systematic review.

OBJECTIVE: Vasopressor medications have traditionally been administered via central venous catheters (CVCs), primarily due to concerns of peripheral extravasation of vasoconstrictive medications. Recent studies have suggested that vasopressor administration via peripheral intravenous catheters (PiVCs) may be a feasible and safe alternative. This systematic review evaluates the safety of delivering vasopressor medications via PiVCs. METHODS: We performed a systematic review to assess the frequency of complications associated with the delivery of vasopressors via PiVCs. A literature search for prospective and retrospective studies of vasopressor infusions in adults was performed. We included studies of continuous infusions of vasopressor medications (noradrenaline, adrenaline, metaraminol, phenylephrine, dopamine and vasopressin) delivered via a PiVCs that included at least 20 patients. Data on patient factors, cannulation approach, monitoring protocols, vasopressor dosing and dilutions and adverse events were collected and summarised. RESULTS: Seven studies were identified that fulfilled the inclusion criteria, including 1382 patients. No study fulfilled all of the validity criteria. Noradrenaline was the most commonly administered agent (n = 702 episodes of administration), followed by phenylephrine (n = 546), dopamine (n = 108), metaraminol (n = 74) and vasopressin and adrenaline (<5 patients). Mean duration of infusion was 22 h (95% confidence interval [CI] 8-36 h). Extravasation occurred in 3.4% (95% CI 2.5-4.7%) of patients. There were no reported episodes of tissue necrosis or limb ischaemia. All extravasation events were successfully managed conservatively or with vasodilatory medications. CONCLUSIONS: Reports of the administration of vasopressors via PiVCs, when given for a limited duration, under close observation, suggest that extravasation is uncommon and is unlikely to lead to major complications.

Consumer involvement in emergency medicine research: Lessons from engaging sepsis survivors.

Collaboration with consumers is an emerging focus for medical researchers worldwide. Public involvement is increasingly encouraged, and in some cases stipulated by funding bodies, in order to secure financial support. While consumer involvement could be viewed as another hurdle in the funding application process, it can add immense value to research outcomes. However, given the diverse and transient nature of our consumer group, how can we develop meaningful public engagement in emergency medicine research?

The Australasian Resuscitation In Sepsis Evaluation: Fluids or vasopressors in emergency department sepsis (ARISE FLUIDS), a multi-centre observational study describing current practice in Australia and New Zealand.

OBJECTIVES: To describe haemodynamic resuscitation practices in ED patients with suspected sepsis and hypotension. METHODS: This was a prospective, multicentre, observational study conducted in 70 hospitals in Australia and New Zealand between September 2018 and January 2019. Consecutive adults presenting to the ED during a 30-day period at each site, with suspected sepsis and hypotension (systolic blood pressure <100 mmHg) despite at least 1000 mL fluid resuscitation, were eligible. Data included baseline demographics, clinical and laboratory variables and intravenous fluid volume administered, vasopressor administration at baseline and 6- and 24-h post-enrolment, time to antimicrobial administration, intensive care admission, organ support and in-hospital mortality. RESULTS: A total of 4477 patients were screened and 591 were included with a mean (standard deviation) age of 62 (19) years, Acute Physiology and Chronic Health Evaluation II score 15.2 (6.6) and a median (interquartile range) systolic blood pressure of 94 mmHg (87-100). Median time to first intravenous antimicrobials was 77 min (42-148). A vasopressor infusion was commenced within 24 h in 177 (30.2%) patients, with noradrenaline the most frequently used (n = 138, 78%). A median of 2000 mL (1500-3000) of intravenous fluids was administered prior to commencing vasopressors. The total volume of fluid administered from pre-enrolment to 24 h was 4200 mL (3000-5661), with a range from 1000 to 12 200 mL. Two hundred and eighteen patients (37.1%) were admitted to an intensive care unit. Overall in-hospital mortality was 6.2% (95% confidence interval 4.4-8.5%). CONCLUSION: Current resuscitation practice in patients with sepsis and hypotension varies widely and occupies the spectrum between a restricted volume/earlier vasopressor and liberal fluid/later vasopressor strategy.

The Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In Emergency Department Sepsis, a multicentre observational study (ARISE FLUIDS observational study): Rationale, methods and analysis plan.

OBJECTIVE: There is uncertainty about the optimal i.v. fluid volume and timing of vasopressor commencement in the resuscitation of patients with sepsis and hypotension. We aim to study current resuscitation practices in EDs in Australia and New Zealand (the Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In Emergency Department Sepsis [ARISE FLUIDS] observational study). METHODS: ARISE FLUIDS is a prospective, multicentre observational study in 71 hospitals in Australia and New Zealand. It will include adult patients presenting to the ED during a 30 day period with suspected sepsis and hypotension (systolic blood pressure <100 mmHg) despite at least 1000 mL fluid resuscitation. We will obtain data on baseline demographics, clinical and laboratory variables, all i.v. fluid given in the first 24 h, vasopressor use, time to antimicrobial administration, admission to intensive care, organ failure and in-hospital mortality. We will specifically describe (i) the volume of fluid administered at the following time points: when meeting eligibility criteria, in the first 6 h, at 24 h and prior to vasopressor commencement and (ii) the frequency and timing of vasopressor use in the first 6 h and at 24 h. Screening logs will provide reliable estimates of the proportion of ED patients meeting eligibility criteria for a subsequent randomised controlled trial. DISCUSSION: This multicentre, observational study will provide insight into current haemodynamic resuscitation practices in patients with sepsis and hypotension as well as estimates of practice variation and patient outcomes. The results will inform the design and feasibility of a multicentre phase III trial of early haemodynamic resuscitation in patients presenting to ED with sepsis and hypotension.

Patient perspectives on priorities for emergency medicine research: The PERSPEX study.

OBJECTIVES: To determine the priorities for emergency medicine research of patients currently in an ED and to compare their priorities with those of ACEM researchers. METHODS: A survey of current patients in the EDs of Royal Perth Hospital and Armadale Health Service. Patients gave their reason for presentation, suggested three important research priorities for emergency medicine and ranked their top 5 choices from a pre-specified list published by the ACEM researchers. Results were analysed using qualitative and quantitative research methods. RESULTS: A total of 430 patients completed the survey, of which 218 were men (50.7%), with median age 44 years (interquartile range [IQR] 30-61 years, range 18-92 years). The top 5 priorities suggested by patients were cardiology, trauma, ED processes, mental health and haematology/oncology. The top 5 patient rankings of the ACEM researcher list were resuscitation, trauma, cardiology, infectious diseases and paediatrics. Older age groups tended to rank cardiology high, while trauma and resuscitation were ranked high among all age groups. There was moderate agreement between patients and ACEM researchers (ρ = 0.51, P = 0.03). CONCLUSIONS: The top 5 emergency medicine research priorities nominated by patients in ED were cardiology, trauma, ED processes, mental health and haematology/oncology, although many 'system priorities' were identified as well. These priorities were generally consistent with ACEM researchers, but patients also suggested alternative directions for future research.

Review article: Sepsis in the emergency department - Part 3: Treatment.

Although comprehensive guidelines for treatment of sepsis exist, current research continues to refine and revise several aspects of management. Imperatives for rapid administration of broad-spectrum antibiotics for all patients with sepsis may not be supported by contemporary data. Many patients may be better served by a more judicious approach allowing consideration of investigation results and evidence-based guidelines. Conventional fluid therapy has been challenged with early evidence supporting balanced, restricted fluid and early vasopressor use. Albumin, vasopressin and hydrocortisone have each been shown to support blood pressure and reduce catecholamine requirements but without effect on mortality, and as such should be considered for ED patients with septic shock on a case-by-case basis. Measurement of quality care in sepsis should incorporate quality of blood cultures and guideline-appropriateness of antibiotics, as well as timeliness of therapy. Local audit is an essential and effective means to improve practice. Multicentre consolidation of data through agreed minimum sepsis data sets would provide baseline quality data, required for the design and evaluation of interventions.

Review article: Sepsis in the emergency department - Part 2: Investigations and monitoring.

Sepsis is characterised by organ dysfunction resulting from infection, with no reliable single objective test and current diagnosis based on clinical features and results of investigations. In the ED, investigations may be conducted to diagnose infection as the cause of the presenting illness, identify the source, distinguish sepsis from uncomplicated infection (i.e. without organ dysfunction) and/ or risk stratification. Appropriate sample collection for microbiological testing remains key for subsequent confirmation of diagnosis and rationalisation of antimicrobials. Routine laboratory investigations such as creatinine, bilirubin, platelet count and lactate are now critical elements in the diagnosis of sepsis and septic shock. With no biomarker sufficiently validated to rule out bacterial infection in the ED, there remains substantial interest in biomarkers representing various pathogenic pathways. New technologies for screening multiple genes and proteins are identifying unique network 'signatures' of clinical interest. Other future directions include rapid detection of bacterial DNA in blood, genes for antibiotic resistance and EMR-based computational biomarkers that collate multiple information sources. Reliable, cost-effective tests, validated in the ED to promptly and accurately identify sepsis, and to guide initial antibiotic choices, are important goals of current research efforts.

Serum mast cell tryptase measurements: Sensitivity and specificity for a diagnosis of anaphylaxis in emergency department patients with shock or hypoxaemia.

OBJECTIVE: Clinical diagnosis of anaphylaxis is principally based on symptoms and signs. However, particularly for patients with atypical symptoms, laboratory confirmation of anaphylaxis would be useful. This study investigated the utility of mast cell tryptase, an available clinical biomarker, for differentiating anaphylaxis from other causes of critical illness, which can also involve mast cell activation. METHODS: Tryptase was measured (ImmunoCAP) in serum from patients with anaphylaxis and non-anaphylactic critical illness (controls) at ED arrival, and after 1-2, 3-4 and 12-24 h. Differences in both peak and delta (difference between highest and lowest) tryptase concentrations between groups were investigated using linear regression models, and diagnostic ability was analysed using Receiver Operating Characteristic curve analysis. RESULTS: Peak tryptase was fourfold (95% CI: 2.9, 5.5) higher in anaphylaxis patients (n = 67) than controls (n = 120) (P < 0.001). Delta-tryptase was 5.1-fold (95% CI: 2.9, 8.9) higher in anaphylaxis than controls (P < 0.001). Optimal test characteristics (sensitivity: 72% [95% CI: 59, 82] and specificity: 72% [95%CI: 63, 80]) were observed when peak tryptase concentrations were >11.4 ng/mL and/or delta-tryptase ≥2.0 ng/mL. For hypotensive patients, peak tryptase >11.4 ng/mL had improved test characteristics (sensitivity: 85% [95% CI: 65, 96] and specificity: 92% [95% CI: 85, 97]); the use of delta-tryptase reduced test specificity. CONCLUSION: While peak and delta tryptase concentrations were higher in anaphylaxis than other forms of critical illness, the test lacks sufficient sensitivity and specificity. Therefore, mast cell tryptase values alone cannot be used to establish the diagnosis of anaphylaxis in the ED. In particular, tryptase has limited utility for differentiating anaphylactic from non-anaphylactic shock.

Review article: Sepsis in the emergency department - Part 1: Definitions and outcomes.

Sepsis has recently been redefined as acute organ dysfunction due to infection. The ED plays a critical role in identifying patients with sepsis. This is challenging due to the heterogeneity of the syndrome, and the lack of an objective standard diagnostic test. While overall mortality rates from sepsis appear to be falling, there is an increasing burden of morbidity among survivors. This largely reflects the growing proportion of older patients with comorbid illnesses among those treated for sepsis.

Lactate ≥2 mmol/L plus qSOFA improves utility over qSOFA alone in emergency department patients presenting with suspected sepsis.

OBJECTIVE: The Sepsis-3 task force recommends the use of the quick Sequential Organ Failure Assessment (qSOFA) score to identify risk for adverse outcomes in patients presenting with suspected infection. Lactate has been shown to predict adverse outcomes in patients with suspected infection. The aim of the study is to investigate the utility of a post hoc lactate threshold (≥2 mmol/L) added qSOFA score (LqSOFA(2) score) to predict primary composite adverse outcomes (mortality and/or ICU stay ≥72 h) in patients presenting to ED with suspected sepsis. METHODS: Retrospective cohort study was conducted on a merged dataset of suspected or proven sepsis patients presenting to ED across multiple sites in Australia and The Netherlands. Patients are identified as candidates for quality improvement initiatives or research studies at respective sites based on local screening procedures. Data-sharing was performed across sites of demographics, qSOFA, SOFA, lactate thresholds and outcome data for included patients. LqSOFA(2) scores were calculated by adding an extra point to qSOFA score in patients who met lactate thresholds of ≥2 mmol/L. RESULTS: In a merged dataset of 12 555 patients where a full qSOFA score and outcome data were available, LqSOFA(2) ≥2 identified more patients with an adverse outcome (sensitivity 65.5%, 95% confidence interval 62.6-68.4) than qSOFA ≥2 (sensitivity 47.6%, 95% confidence interval 44.6- 50.6). The post hoc addition of lactate threshold identified higher proportion of patients at risk of adverse outcomes. CONCLUSIONS: The lactate ≥2 mmol/L threshold-based LqSOFA(2) score performs better than qSOFA alone in identifying risk of adverse outcomes in ED patients with suspected sepsis.

Sepsis Early Alert Tool: Early recognition and timely management in the emergency department.

INTRODUCTION: The Surviving Sepsis Campaign guidelines recommend administration of appropriate antibiotics within 1 h in patients with severe sepsis, with two sets of blood cultures taken prior to administration. OBJECTIVE: We evaluated the effect of introducing a Sepsis Early Alert Tool (SEAT) in the ED. Outcomes were antibiotic timing, antibiotic choice and obtaining adequate blood cultures. METHODS: A retrospective chart review compared consecutive severe sepsis presentations admitted to ICU via the ED during two equivalent 6 month periods before and after SEAT introduction. RESULTS: The analyses included 55 patients before and 45 following SEAT introduction. The groups were similar in age, sex, triage category, sepsis source, Acute Physiology and Chronic Health Evaluation III scores and hospital mortality. The percentage receiving antibiotics within 60 min of triage increased from 24% (95% CI 13-37%) to 44% (95% CI 30-60%), P = 0.03. Median time from triage to first antibiotic was 105 (IQR 65-170) min and 85 (IQR 50-140) min before and after SEAT introduction, respectively, P = 0.15. Percentages receiving antibiotics within 60 min of first recognition of severe sepsis were 67% (95% CI 53-79%) and 71% (95% CI 56-84%) before and after SEAT introduction, P = 0.83. The percentage having two sets of blood cultures drawn prior to antibiotic administration increased from 18% (95% CI 9-34%) to 44% (95% CI 27-60%), P = 0.008. Appropriateness of antibiotics was 58% (95% CI 44-71%) and 75% (95% CI 60-87%) before and after SEAT implementation, P = 0.09. CONCLUSION: The introduction of a SEAT in the ED is associated with earlier recognition of severe sepsis and improvements in quality of care.

The VHOT (Vindaloo Hastens Outpouring of Troponins) Study.

BACKGROUND: Multiple cardiac and non-cardiac processes may cause an elevated highly sensitive troponin (hsTn). We postulated that the consumption of a seriously hot vindaloo could cause an increase in hsTn levels in seemingly healthy volunteers. OBJECTIVE: To determine whether eating a very hot curry can cause elevated hsTn. METHODS: This was a prospective observational cohort study. Participants had blood drawn for hsTn pre-ingestion and at 2 and 4 h post-ingestion of, first, a rather mild butter chicken and, 2 weeks later, a seriously hot lamb vindaloo. We assessed pre-curry tolerance and perception of curry hotness for both curries using the VHOT scale. RESULTS: Although no participant had a troponin above the reference range at any point in time, we found dramatic relative increases in troponin in many of our participants. In the vindaloo phase, 8/22 (36%) had a relative change >20%, whereas 5/22 (23%) had a relative change >50% at 4 h. However, these changes were not significantly different to those in the butter chicken phase. Based on biological variability alone, 15/22 (68%) had a relative change of >20%, and 11/22 (50%) had a relative change of >50% between the two sessions (pre-ingestion). CONCLUSIONS: Eating a seriously hot vindaloo does not appear to be a risk factor for troponitis, and people may consume vindaloo safely with the knowledge that this is unlikely to result in significant damage to their myocardium. However, clinicians should be aware of the biological variability of hsTn and exercise caution when interpreting apparent changes within the normal range.

The TARGET pain study: Lessons from a painful marathon.

This perspective article summarises the experience of conducting a multicentre research project. We describe expected and unexpected hurdles we experienced as well as suggesting possible solutions for researchers embarking on multicentre studies.

Best-practice pain management in the emergency department: A cluster-randomised, controlled, intervention trial.

OBJECTIVES: We aimed to provide 'adequate analgesia' (which decreases the pain score by ≥2 and to <4 [0-10 scale]) and determine the effect on patient satisfaction. METHODS: We undertook a multicentre, cluster-randomised, controlled, intervention trial in nine EDs. Patients with moderate pain (pain score of ≥4) were eligible for inclusion. The intervention was a range of educational activities to encourage staff to provide 'adequate analgesia'. It was introduced into five early intervention EDs between the 0 and 6 months time points and at four late intervention EDs between 3 and 6 months. At 0, 3 and 6 months, data were collected on demographics, pain scores, analgesia provided and pain management satisfaction 48 h post-discharge (6 point scale). RESULTS: Overall, 1317 patients were enrolled. Logistic regression (controlling for site and other confounders) indicated that, between 0 and 3 months, satisfaction increased significantly at the early intervention EDs (OR 2.2, 95% CI 1.5 to 3.4 [P < 0.01]) but was stable at the control EDs (OR 0.8, 95% CI 0.5 to 1.3 [P = 0.35]). Pooling of data from all sites indicated that the proportion of patients very satisfied with their pain management increased from 42.9% immediately pre-intervention to 53.9% after 3 months of intervention (difference in proportions 11.0%, 95% CI 4.2 to 17.8 [P = 0.001]). Logistic regression of all data indicated that 'adequate analgesia' was significantly associated with patient satisfaction (OR 1.4, 95% CI 1.1 to 1.8 [P < 0.01]). CONCLUSIONS: The 'adequate analgesia' intervention significantly improved patient satisfaction. It provides a simple and efficient target in the pursuit of best-practice ED pain management.