Apnoeic oxygenation was associated with decreased desaturation rates during rapid sequence intubation in multiple Australian and New Zealand emergency departments.

Apnoeic oxygenation (ApOx) has been demonstrated to reduce the incidence of desaturation, although evidence of benefit has been conflicting depending on the technique used. The aim of this study was to compare the incidence of desaturation between patients who received ApOx via conventional nasal cannula (NC) and those who did not, using a large, multicentre airway registry. METHODS: This study is an analysis of 24 months of prospectively collected data in the Australia and New Zealand Emergency Department Airway Registry (June 2013-June 2015). The registry includes information on all intubated adults from 43 emergency departments. Patients intubated during cardiac arrest (n=393), those who received active ventilation prior to the first intubation attempt (n=486), and where the use of ApOx was not recorded either way (n=312) were excluded. The proportion of patients who desaturated (Sa02 <93) in the group that received ApOx and those that did not were compared. To evaluate the association of ApOx with patient desaturation, a logistic regression model based on factors expected to influence desaturation was performed. RESULTS: Of 2519 patients analysed, 1669 (66.3%) received ApOx via NC while 850 (33.7%) did not. Desaturation in the cohort receiving ApOx was 10.4% compared with standard care (no ApOx) 13.7%. ApOx had a protective effect for desaturation (OR 0.71 95% CI 0.53 to 0.95). Single intubation attempt was associated with reduced risk of desaturation of (OR 0.10, 95% CI 0.06 to 0.17); this was increased on second attempt (OR 0.37, 95% CI 0.21 to 0.68). Desaturation was also associated with the physician recording that they had anticipated a difficult airway (OR 1.83, 95% CI 1.34 to 2.48). CONCLUSION: This large multicentre registry study provides evidence that ApOx delivered through a conventional NC is associated with a lower incidence of desaturation in patients undergoing rapid sequence intubation. TRIAL REGISTRATION NUMBER: ACTRN12613001052729.

Who Benefits from Aggressive Rapid Response System Treatments Near the End of Life? A Retrospective Cohort Study.

BACKGROUND: Many patients near the end of life are subject to rapid response system (RRS) calls. A study was conducted in a large Sydney teaching hospital to identify a cutoff point that defines nonbeneficial treatment for older hospital patients receiving an RRS call, describe interventions administered, and measure the cost of hospitalization. METHODS: This was a retrospective cohort of 733 adult inpatients with data for the period three months before and after their last placed RRS call. Subgroup analysis of patients aged ≥ 80 years was conducted. Log-rank, chi-square, and t-tests were used to compare survival, and logistic regression was used to examine predictors of death. RESULTS: Overall, 65 (8.9%) patients had a preexisting not-for-resuscitation (NFR) or not-for-RRS order; none of those patients survived to three months. By contrast, patients without an NFR or not-for-RRS order had three-month survival probability of 71% (log-rank χ2 145.63; p < 0.001). Compared with survivors, RRS recipients who died were more likely to be older, to be admitted to a medical ward, and to have a larger mean number of admissions before the RRS. The average cost of hospitalization for the very old transferred to the ICU was higher than for those not requiring treatment in the ICU (US$33,990 vs. US$14,774; p = 0.045). CONCLUSION: Identifiable risk factors clearly associated with poor clinical outcomes and death can be used as a guide to administer less aggressive treatments, including reconsideration of ICU transfers, adherence to NFR orders, and transition to end-of-life management instead of calls to the RRS team.

A sequential case series of 23 intubations in a rural emergency department in New Zealand.

OBJECTIVE: To describe the practice and procedure of emergency intubation in Whanganui Emergency Department, New Zealand and determine whether intubation can be carried out effectively in the rural setting. METHOD: A prospective observational study using the Australia and New Zealand Airway Registry proforma to collect data on the indication, lead intubator, first-pass success rate and peri-procedural complications. Data were also collected on whether a formal airway assessment was carried out and whether a checklist was used. RESULTS: Twenty-three patients were intubated in the emergency department over a 12-month period. Sixty-two percent (14/23 cases) were medical encounters and the remaining 38% of indications due to a trauma. Head injury was the most common indication (23%). Ninety-two percent of primary intubators were emergency department-based Fellowship of the Australasian College for Emergency Medicine or resident medical officers, while anaesthetic-trained operators accounted for just 8%. Our first-pass intubation success rate was 87% and 16% of cases had procedural complications. Sixty-five percent (15/23) carried out a formal airway assessment and a checklist was only used in 23% of cases. CONCLUSION: This sequential case series is the first study looking at airway management in rural New Zealand emergency department airway practice. Overall intubation success rates were comparable to larger tertiary centres across Australasia. We have demonstrated that with adequate resources and adherence to interventions, a rural emergency department can provide effective airway management.

Corticosteroids inhibit sphingosine 1-phosphate-induced interleukin-6 secretion from human airway smooth muscle via mitogen-activated protein kinase phosphatase 1-mediated repression of mitogen and stress-activated protein kinase 1.

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that plays an important proinflammatory role in asthmatic airways. Corticosteroids are first-line antiinflammatories in asthma; however, their repressive effects on S1P-induced cytokine secretion have not been investigated. To address this, our in vitro study reveals the molecular mechanisms by which corticosteroids inhibit S1P-induced IL-6 expression in the pivotal immunomodulatory cell type, airway smooth muscle (ASM). We first uncover the cellular signaling pathways responsible: S1P activates a cyclic adenosine monophosphate/cAMP response-element-binding protein (CREB)/CRE-dependent pathway to induce IL-6 transcription, concomitant with stimulation of the mitogen-activated protein kinase (MAPK) superfamily and downstream mitogen and stress-activated protein kinase 1 (MSK1) and histone H3 phosphorylation. In this way, S1P stimulates parallel signaling pathways to induce IL-6 secretion via CRE-driven transcription of the IL-6 gene promoter in a relaxed chromatin environment achieved through histone H3 phosphorylation. Second, we investigated how corticosteroids mediate their repressive effects. The corticosteroid dexamethasone inhibits S1P-induced IL-6 protein secretion and mRNA expression, but CREB/CRE transrepression, inhibition of IL-6 mRNA stability, or subcellular relocation of MSK1 were not responsible for the repressive effects of dexamethasone. Rather, we show that dexamethasone rapidly induces up-regulation of the MAPK deactivator MAPK phosphatase 1 (MKP-1) and that MKP-1 blocks the MAPK-driven activation of MSK1 and phosphorylation of histone H3. This was confirmed by treatment with triptolide, an inhibitor of MKP-1 up-regulation, where repressive effects of corticosteroids were reversed. Our study reveals the molecular mechanism underlying the antiinflammatory capacity of corticosteroids to repress proinflammatory functions induced by the potent bioactive sphingolipid S1P in the lung.

Mast cells produce novel shorter forms of perlecan that contain functional endorepellin: a role in angiogenesis and wound healing.

Mast cells are derived from hematopoietic progenitors that are known to migrate to and reside within connective and mucosal tissues, where they differentiate and respond to various stimuli by releasing pro-inflammatory mediators, including histamine, growth factors, and proteases. This study demonstrated that primary human mast cells as well as the rat and human mast cell lines, RBL-2H3 and HMC-1, produce the heparan sulfate proteoglycan, perlecan, with a molecular mass of 640 kDa as well as smaller molecular mass species of 300 and 130 kDa. Utilizing domain-specific antibodies coupled with N-terminal sequencing, it was confirmed that both forms contained the C-terminal module of the protein core known as endorepellin, which were generated by mast cell-derived proteases. Domain-specific RT-PCR experiments demonstrated that transcripts corresponding to domains I and V, including endorepellin, were present; however, mRNA transcripts corresponding to regions of domain III were not present, suggesting that these cells were capable of producing spliced forms of the protein core. Fractions from mast cell cultures that were enriched for these fragments were shown to bind endothelial cells via the α(2)ß(1) integrin and stimulate the migration of cells in "scratch assays," both activities of which were inhibited by incubation with either anti-endorepellin or anti-perlecan antibodies. This study shows for the first time that mast cells secrete and process the extracellular proteoglycan perlecan into fragments containing the endorepellin C-terminal region that regulate angiogenesis and matrix turnover, which are both key events in wound healing.

Effects of cigarette smoke extract on human airway smooth muscle cells in COPD.

We hypothesised that the response to cigarette smoke in airway smooth muscle (ASM) cells from smokers with chronic obstructive pulmonary disease (COPD) would be intrinsically different from smokers without COPD, producing greater pro-inflammatory mediators and factors relating to airway remodelling. ASM cells were obtained from smokers with or without COPD, and then stimulated with cigarette smoke extract (CSE) or transforming growth factor-ß1. The production of chemokines and matrix metalloproteinases (MMPs) were measured by ELISA, and the deposition of collagens by extracellular matrix ELISA. The effects of CSE on cell attachment and wound healing were measured by toluidine blue attachment and cell tracker green wound healing assays. CSE increased the release of CXCL8 and CXCL1 from human ASM cells, and cells from smokers with COPD produced more CSE-induced CXCL1. The production of MMP-1, -3 and -10, and the deposition of collagen VIII alpha 1 (COL8A1) were increased by CSE, especially in the COPD group which had higher production of MMP-1 and deposition of COL8A1. CSE decreased ASM cell attachment and wound healing in the COPD group only. ASM cells from smokers with COPD were more sensitive to CSE stimulation, which may explain, in part, why some smokers develop COPD.

Regulation of pulmonary inflammation by mesenchymal cells.

Pulmonary inflammation and tissue remodelling are common elements of chronic respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension (PH). In disease, pulmonary mesenchymal cells not only contribute to tissue remodelling, but also have an important role in pulmonary inflammation. This review will describe the immunomodulatory functions of pulmonary mesenchymal cells, such as airway smooth muscle (ASM) cells and lung fibroblasts, in chronic respiratory disease. An important theme of the review is that pulmonary mesenchymal cells not only respond to inflammatory mediators, but also produce their own mediators, whether pro-inflammatory or pro-resolving, which influence the quantity and quality of the lung immune response. The notion that defective pro-inflammatory or pro-resolving signalling in these cells potentially contributes to disease progression is also discussed. Finally, the concept of specifically targeting pulmonary mesenchymal cell immunomodulatory function to improve therapeutic control of chronic respiratory disease is considered.

The nucleotide-binding domain and leucine-rich repeat protein-3 inflammasome is not activated in airway smooth muscle upon toll-like receptor-2 ligation.

Inflammasomes have emerged as playing key roles in inflammation and innate immunity. A growing body of evidence has suggested that the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome is important in chronic airway diseases such as asthma and chronic obstructive pulmonary disease. Inflammasome activation results, in part, in pro-IL-1ß processing and the secretion of the proinflammatory cytokine IL-1ß. Because asthma exacerbations are associated with elevated concentrations of secreted IL-1ß, we addressed whether the NLRP3 inflammasome is activated under in vitro conditions that mimic infectious exacerbations in asthma. Primary cultures of airway smooth muscle (ASM) cells were treated with infectious stimuli (mimicked using the Toll-like receptor-2 agonist Pam3CSK4, a synthetic bacterial lipopeptide). Whereas Pam3CSK4 robustly up-regulated ASM cytokine expression in response to TNF-α and significantly enhanced IL-1ß mRNA expression, we were unable to detect IL-1ß in the cell supernatants. Thus, IL-1ß was not secreted and therefore was unable to act in an autocrine manner to promote the amplification of ASM inflammatory responses. Moreover, Toll-like receptor-2 ligation did not enhance NLRP3 or caspase-1 expression in ASM cells, and NLRP3 and caspase-1 protein were not present in the ASM layer of tracheal sections from human donors. In conclusion, these data demonstrate that the enhanced synthetic function of ASM cells, induced by infectious exacerbations of airway inflammation, is NLRP3 inflammasome-independent and IL-1ß-independent. Activation of the NLRP3 inflammasome by invading pathogens may prove cell type-specific in exacerbations of airway inflammation in asthma.

Bed tilt and ramp positions are associated with increased first-pass success of adult endotracheal intubation in the emergency department: A registry study.

OBJECTIVE: Successful endotracheal intubation in the ED requires optimum body positioning. In patients with obesity, the ramp position was suggested to achieve better intubating conditions. However, limited data are available on the airway management practices for patients with obesity in Australasian EDs. The aim of this study was to identify current patient positioning practices during endotracheal intubation and its association with first-pass success (FPS) at intubation and adverse event (AE) rates in obese and non-obese populations. METHODS: Prospectively collected data from the Australia and New Zealand ED Airway Registry (ANZEDAR) between 2012 and 2019 were analysed. Patients were categorised into two groups according to their weight: <100 kg (non-obese) or ≥100 kg (obese). Four position categories were investigated; supine, pillow or occipital pad, bed tilt and ramp or head-up with relation to FPS and complication rate using logistic regression modelling. RESULTS: A total of 3708 intubations from 43 EDs were included. Overall, the non-obese cohort had a greater FPS rate (85.9%) compared to the obese group (77.0%). The bed tilt position had the highest FPS rate (87.2%), whereas the supine position had the lowest (83.0%). AE rates were highest in the ramp position (31.2%) compared to all other positions (23.8%). Regression analysis showed ramp, or bed tilt positions and a consultant-level intubator were associated with higher FPS. Obesity, in addition to other factors, was independently associated with lower FPS. CONCLUSION: Obesity was associated with lower FPS, which could be improved through performing a bed tilt or ramp positioning.

24 hours - Life in the E.R.: A state-wide data linkage analysis of in-patients with prolonged emergency department length of stay in New South Wales, Australia.

OBJECTIVE: Describe the characteristics and predictors of mortality for patients who spend more than 24 h in the ED waiting for an in-patient bed and compare baseline clinical and demographic characteristics between tertiary and non-tertiary hospitals. METHODS: This was a state-wide analysis data linkage analysis of adult (age >16 years) ED presentations across New South Wales from 2019 to 2020. Cases were included if their mode of separation from ED indicated admission to an in-patient unit including critical care ward and their ED length of stay was greater than or equal to 24 h. Cases were categorised by service-related groups based on principle diagnosis. RESULTS: A total of 26 854 eligible cases were identified. The most common diagnosis groups were psychiatry, cardiology and respiratory. The odds ratio (OR) for 30-day all-cause mortality in admitted patients with an ED length of stay greater than 24 h were highest in those aged >75 years (OR 15.18, 95% confidence interval [CI] 9.99-23.07, P < 0.001), oncology (OR 10.45, 95% CI 7.93-13.77, P < 0.001) and haematology patients (OR 2.95, 95% CI 2.01-4.33, P < 0.001). CONCLUSION: Interventions and models of care to address ED access block need to focus on mental health patients, older patients particularly those with cardiorespiratory illness and oncology and haematology patients for whom risk of mortality is disproportionately higher.

Implementation evaluation of an evidence-based emergency nursing framework (HIRAID): study protocol for a step-wedge randomised control trial.

INTRODUCTION: Poor patient assessment results in undetected clinical deterioration. Yet, there is no standardised assessment framework for >29 000 Australian emergency nurses. To reduce clinical variation and increase safety and quality of initial emergency nursing care, the evidence-based emergency nursing framework HIRAID (History, Identify Red flags, Assessment, Interventions, Diagnostics, communication and reassessment) was developed and piloted. This paper presents the rationale and protocol for a multicentre clinical trial of HIRAID. METHODS AND ANALYSIS: Using an effectiveness-implementation hybrid design, the study incorporates a stepped-wedge cluster randomised controlled trial of HIRAID at 31 emergency departments (EDs) in New South Wales, Victoria and Queensland. The primary outcomes are incidence of inpatient deterioration related to ED care, time to analgesia, patient satisfaction and medical satisfaction with nursing clinical handover (effectiveness). Strategies that optimise HIRAID uptake (implementation) and implementation fidelity will be determined to assess if HIRAID was implemented as intended at all sites. ETHICS AND DISSEMINATION: Ethics has been approved for NSW sites through Greater Western Human Research Ethics Committee (2020/ETH02164), and for Victoria and Queensland sites through Royal Brisbane & Woman's Hospital Human Research Ethics Committee (2021/QRBW/80026). The final phase of the study will integrate the findings in a toolkit for national rollout. A dissemination, communications (variety of platforms) and upscaling strategy will be designed and actioned with the organisations that influence state and national level health policy and emergency nurse education, including the Australian Commission for Quality and Safety in Health Care. Scaling up of findings could be achieved by embedding HIRAID into national transition to nursing programmes, 'business as usual' ED training schedules and university curricula. TRIAL REGISTRATION NUMBER: ACTRN12621001456842.

Incidence of multiple organ failure in adult polytrauma patients: A systematic review and meta-analysis.

BACKGROUND: Postinjury multiple organ failure (MOF) is the leading cause of late death in trauma patients. Although MOF was first described 50 years ago, its definition, epidemiology, and change in incidence over time are poorly understood. We aimed to describe the incidence of MOF in the context of different MOF definitions, study inclusion criteria, and its change over time. METHODS: Cochrane Library, EMBASE, MEDLINE, PubMed, and Web of Science databases were searched for articles published between 1977 and 2022 in English and German. Random-effects meta-analysis was performed when applicable. RESULTS: The search returned 11,440 results, of which 842 full-text articles were screened. Multiple organ failure incidence was reported in 284 studies that used 11 unique inclusion criteria and 40 MOF definitions. One hundred six studies published from 1992 to 2022 were included. Weighted MOF incidence by publication year fluctuated from 11% to 56% without significant decrease over time. Multiple organ failure was defined using four scoring systems (Denver, Goris, Marshall, Sequential Organ Failure Assessment [SOFA]) and 10 different cutoff values. Overall, 351,942 trauma patients were included, of whom 82,971 (24%) developed MOF. The weighted incidences of MOF from meta-analysis of 30 eligible studies were as follows: 14.7% (95% confidence interval [CI], 12.1-17.2%) in Denver score >3, 12.7% (95% CI, 9.3-16.1%) in Denver score >3 with blunt injuries only, 28.6% (95% CI, 12-45.1%) in Denver score >8, 25.6% (95% CI, 10.4-40.7%) in Goris score >4, 29.9% (95% CI, 14.9-45%) in Marshall score >5, 20.3% (95% CI, 9.4-31.2%) in Marshall score >5 with blunt injuries only, 38.6% (95% CI, 33-44.3%) in SOFA score >3, 55.1% (95% CI, 49.7-60.5%) in SOFA score >3 with blunt injuries only, and 34.8% (95% CI, 28.7-40.8%) in SOFA score >5. CONCLUSION: The incidence of postinjury MOF varies largely because of lack of a consensus definition and study population. Until an international consensus is reached, further research will be hindered. LEVEL OF EVIDENCE: Systematic Review and Meta-analysis; Level III.

Development and preliminary usability testing of an electronic conversation guide incorporating patient values and prognostic information in preparation for older people's decision-making near the end of life.

Initiating end-of-life conversations can be daunting for clinicians and overwhelming for patients and families. This leads to delays in communicating prognosis and preparing for the inevitable in old age, often generating potentially harmful overtreatment and poor-quality deaths. We aimed to develop an electronic resource, called Communicating Health Alternatives Tool (CHAT) that was compatible with hospital medical records software to facilitate preparation for shared decision-making across health settings with older adults deemed to be in the last year of life. The project used mixed methods including: literature review, user-directed specifications, web-based interface development with authentication and authorization; clinician and consumer co-design, iterative consultation for user testing; and ongoing developer integration of user feedback. An internet-based conversation guide to facilitate clinician-led advance care planning was co-developed covering screening for short-term risk of death, patient values and preferences, and treatment choices for chronic kidney disease and dementia. Printed summary of such discussion could be used to begin the process in hospital or community health services. Clinicians, patients, and caregivers agreed with its ease of use and were generally accepting of its contents and format. CHAT is available to health services for implementation in effectiveness trials to determine whether the interaction and documentation leads to formal decision-making, goal-concordant care, and subsequent reduction of unwanted treatments at the end of life.

The Emergency nurse Protocols Initiating Care-Sydney Triage to Admission Risk Tool (EPIC-START) trial: protocol for a stepped wedge implementation trial.

INTRODUCTION: Emergency department (ED) overcrowding is a global problem and a threat to the quality and safety of emergency care. Providing timely and safe emergency care therein is challenging. To address this in New South Wales (NSW), Australia, the Emergency nurse Protocol Initiating Care-Sydney Triage to Admission Risk Tool (EPIC-START) was developed. EPIC-START is a model of care incorporating EPIC protocols, the START patient admission prediction tool, and a clinical deterioration tool to support ED flow, timely care, and patient safety. The aim of this study is to evaluate the impact of EPIC-START implementation across 30 EDs on patient, implementation, and health service outcomes. METHODS AND ANALYSIS: This study protocol adopts an effectiveness-implementation hybrid design (Med Care 50: 217-226, 2012) and uses a stepped-wedge cluster randomised control trial of EPIC-START, including uptake and sustainability, within 30 EDs across four NSW local health districts spanning rural, regional, and metropolitan settings. Each cluster will be randomised independently of the research team to 1 of 4 dates until all EDs have been exposed to the intervention. Quantitative and qualitative evaluations will be conducted on data from medical records and routinely collected data, and patient, nursing, and medical staff pre- and post-surveys. ETHICS AND DISSEMINATION: Ethical approval for the research was received from the Sydney Local Health District Research Ethics Committee (Reference Number 2022/ETH01940) on 14 December 2022. TRIAL REGISTRATION: Australian and New Zealand Clinical trial, ACTRN12622001480774p. Registered on 27 October 2022.

Th1 cytokine-induced syndecan-4 shedding by airway smooth muscle cells is dependent on mitogen-activated protein kinases.

In asthma, airway smooth muscle (ASM) chemokine secretion can induce mast cell recruitment into the airways. The functions of the mast cell chemoattractant CXCL10, and other chemokines, are regulated by binding to heparan sulphates such as syndecan-4. This study is the first demonstration that airway smooth muscle cells (ASMC) from people with and without asthma express and shed syndecan-4 under basal conditions. Syndecan-4 shedding was enhanced by stimulation for 24 h with the Th1 cytokines interleukin-1ß (IL-1ß) or tumor necrosis factor-α (TNF-α), but not interferon-γ (IFNγ), nor the Th2 cytokines IL-4 and IL-13. ASMC stimulation with IL-1ß, TNF-α, and IFNγ (cytomix) induced the highest level of syndecan-4 shedding. Nonasthmatic and asthmatic ASM cell-associated syndecan-4 protein expression was also increased by TNF-α or cytomix at 4-8 h, with the highest levels detected in cytomix-stimulated asthmatic cells. Cell-associated syndecan-4 levels were decreased by 24 h, whereas shedding remained elevated at 24 h, consistent with newly synthesized syndecan-4 being shed. Inhibition of ASMC matrix metalloproteinase-2 did not prevent syndecan-4 shedding, whereas inhibition of ERK MAPK activation reduced shedding from cytomix-stimulated ASMC. Although ERK inhibition had no effect on syndecan-4 mRNA levels stimulated by cytomix, it did cause an increase in cell-associated syndecan-4 levels, consistent with the shedding being inhibited. In conclusion, ASMC produce and shed syndecan-4 and although this is increased by the Th1 cytokines, the MAPK ERK only regulates shedding. ASMC syndecan-4 production during Th1 inflammatory conditions may regulate chemokine activity and mast cell recruitment to the ASM in asthma.

Asthmatic airway smooth muscle CXCL10 production: mitogen-activated protein kinase JNK involvement.

CXCL10 (IP10) is involved in mast cell migration to airway smooth muscle (ASM) bundles in asthma. We aimed to investigate the role of cytokine-induced MAPK activation in CXCL10 production by ASM cells from people with and without asthma. Confluent growth-arrested ASM cells were treated with inhibitors of the MAPKs ERK, p38, and JNK and transcription factor NF-κB, or vehicle, and stimulated with IL-1ß, TNF-α, or IFN-γ, alone or combined (cytomix). CXCL10 mRNA and protein, JNK, NF-κB p65 phosphorylation, and Iκ-Bα protein degradation were assessed using real-time PCR, ELISA, and immunoblotting, respectively. Cytomix, IL-1ß, and TNF-α induced CXCL10 mRNA expression more rapidly in asthmatic than nonasthmatic ASM cells. IL-1ß and/or TNF-α combined with IFN-γ synergistically increased asthmatic ASM cell CXCL10 release. Inhibitor effects were similar in asthmatic and nonasthmatic cells, but cytomix-induced release was least affected, with only JNK and NF-κB inhibitors halving it. Notably, JNK phosphorylation was markedly less in asthmatic compared with nonasthmatic cells. However, in both, the JNK inhibitor SP600125 reduced JNK phosphorylation and CXCL10 mRNA levels but did not affect CXCL10 mRNA stability or Iκ-Bα degradation. Together, the JNK and NF-κB inhibitors completely inhibited their CXCL10 release. We concluded that, in asthmatic compared with nonasthmatic ASM cells, JNK activation was reduced and CXCL10 gene expression was more rapid following cytomix stimulation. However, in both, JNK activation did not regulate early events leading to NF-κB activation. Thus JNK and NF-κB provide independent therapeutic targets for limiting CXCL10 production and mast cell migration to the ASM in asthma.

Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies.

BACKGROUND: Activated mast cells are present within airway smooth muscle (ASM) bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide), long-acting ß2-agonists (salmeterol, formoterol) and thiazolidinediones (ciglitazone, rosiglitazone) on CXCL10 production by ASM cells (ASMC) from people with and without asthma were investigated in vitro. METHODS: Confluent serum-deprived cells were treated with the agents before and during cytokine stimulation for 0-24 h. CXCL10 protein/mRNA, IκB-α levels and p65 activity were measured using ELISA, RT PCR, immunoblotting and p65 activity assays respectively. Data were analysed using ANOVA followed by Fisher's post-hoc test. RESULTS: Fluticasone and/or salmeterol at 1 and 100 nM inhibited CXCL10 release induced by IL-1ß and TNF-α, but not IFNγ or all three cytokines (cytomix). The latter was also not affected by budesonide and formoterol. In asthmatic ASMC low salmeterol, but not formoterol, concentrations increased cytomix-induced CXCL10 release and at 0.01 nM enhanced NF-κB activity. Salmeterol 0.1 nM together with fluticasone 0.1 and 10 nM still increased CXCL10 release. The thiazolidinediones ciglitazone and rosiglitazone (at 25 and 100 µM) inhibited cytomix-induced CXCL10 release but these inhibitory effects were not prevented by the PPAR-g antagonist GW9662. Ciglitazone did not affect early NF-κB activity and CXCL10 mRNA production. CONCLUSIONS: Thus the thiazolidinediones inhibited asthmatic ASMC CXCL10 release under conditions when common asthma therapies were ineffective or enhanced it. They may provide an alternative strategy to reduce mast cell-ASM interactions and restore normal airway physiology in asthma.

Mapping haemodynamic changes with rapid sequence induction agents in the emergency department.

OBJECTIVE: Patients intubated in the ED are at an increased risk of post-intubation hypotension. However, evidence regarding the most appropriate induction agent is lacking. The present study aims to describe and compare the haemodynamic effect of propofol, ketamine and thiopentone during rapid sequence induction. METHODS: This is an observational study using data prospectively collected from the Australian and New Zealand Emergency Department Airway Registry between June 2012 and March 2019. The distribution of induction agents across medical and trauma patients were obtained with descriptive statistics. The relationship between induction agent, dose and change in pre- and post-intubation systolic blood pressure (SBP) was described using multivariable logistic regression. The SBP pre- and post-intubation was the primary measure of haemodynamic stability. RESULTS: From the 5063 intubation episodes, 2229 met the inclusion criteria. Of those, 785 (35.2%) patients were induced with thiopentone, 773 (34.7%) with propofol and 671 (30.1%) with ketamine. Of the included population, 396 (17.8%) patients experienced a reduction in pre-intubation SBP exceeding 20%. Both propofol (P = 0.01) and ketamine (P = 0.01) had an independent and dose-dependent association with hypotension, noting that a higher proportion of patients induced with ketamine had a shock index exceeding 0.9. CONCLUSION: Propofol was associated with post-intubation hypotension and it is recommended clinicians consider using the lowest effective dose to reduce this risk. Reflecting its perceived haemodynamic stability, patients who received ketamine were more likely to have a higher shock index; however, there was also an association with post-intubation hypotension.

Review article: Effectiveness and risks of cricoid pressure during rapid sequence induction for endotracheal intubation in the emergency department: A systematic review.

The use of cricoid pressure (CP) to prevent aspiration during rapid sequence induction (RSI) has become controversial, although CP is considered central to the practice of RSI. There is insufficient research to support its efficacy in reducing aspiration, and emerging concerns it reduces the first-pass success (FPS) of intubation. This systematic review aims to assess the safety and efficacy of CP during RSI in EDs by investigating its effect on FPS and the incidence of complications, including gastric regurgitation and aspiration. A systematic review of four databases was performed for all primary research investigating CP during RSI in EDs. The primary outcome was FPS; secondary outcomes included complications such as gastric regurgitation, aspiration, hypoxia, hypotension and oesophageal intubation. After screening 4208 citations, three studies were included: one randomised controlled trial (n = 54) investigating the incidence of aspiration during the application of CP and two registry studies (n = 3710) comparing the rate of FPS of RSI with and without CP. The results of these individual studies are not sufficient to draw concrete conclusions but do suggest that aspiration occurs regardless of the application of CP, and that FPS is not reduced by the application of CP. There is insufficient evidence to conclude whether applying CP during RSI in EDs affects the rate of FPS or the incidence of complications such as aspiration. Further research in the ED, including introducing CP usage into other existing airway registries, is needed.

Identifying the activities of physiotherapy practitioners through primary and secondary models of care provided in New South Wales emergency departments.

BACKGROUND: Following the introduction of the emergency department (ED) primary contact physiotherapy role, emergency physiotherapy models of care have evolved and are increasingly being adopted in the Australian ED. This has occurred due to growing ED patient demand and a need for greater workforce flexibility. Since introduction, there here has been limited evaluation of the scope of work physiotherapists are providing in Australian ED. OBJECTIVES: To identify the activities of ED physiotherapists provided through different models of care in NSW. METHODS: Prospective observation study in 19 participating EDs conducted over 6 months between September 2014 and April 2015. RESULTS: The study identified different models of care across participating hospitals where physiotherapists worked independently or in conjunction with a team through a referral service. The individual's scope of work was determined by organisational policy, culture, individual competence, knowledge and skills, and varied significantly between sites. CONCLUSIONS: These findings could guide both ED work flow and the development of multidisciplinary workforce structures to improve the utilisation of the physiotherapy service in EDs. This will allow for better service levels in hospitals, better access for patients and better use of resources.