Publications by authors named "Stephen MacDonald"

80 Publications

Single high-sensitivity troponin levels to assess patients with potential acute coronary syndromes.

Authors:
Cara Barnes Daniel M Fatovich Stephen P J Macdonald Richard F Alcock Jon R Spiro Tom G Briffa Carl J Schultz Graham S Hillis

Heart 2021 May 12;107(9):721-727. Epub 2021 Jan 12.

Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia

Objective: We tested the hypothesis that patients with a potential acute coronary syndrome (ACS) and very low levels of high-sensitivity cardiac troponin I can be efficiently and safely discharged from the emergency department after a single troponin measurement.

Methods: This prospective cohort study recruited 2255 consecutive patients aged ≥18 years presenting to the Emergency Department, Royal Perth Hospital, Western Australia, with chest pain without high-risk features but requiring the exclusion of ACS. Patients were managed using a guideline-recommended pathway or our novel Single Troponin Accelerated Triage (STAT) pathway. The primary outcome was the percentage of patients discharged in <3 hours. Secondary outcomes included the duration of observation and death or acute myocardial infarction in the next 30 days.

Results: The study enrolled 1131 patients to the standard cohort and 1124 to the STAT cohort. Thirty-eight per cent of the standard cohort were discharged directly from emergency department compared with 63% of the STAT cohort (p<0.001). The median duration of observation was 4.3 (IQR 3.3-7.1) hours in the standard cohort and 3.6 (2.6-5.4) hours in the STAT cohort (p<0.001), with 21% and 38% discharged in <3 hours, respectively (p<0.001). No patients discharged directly from the emergency department died or suffered an acute myocardial infarction within 30 days in either cohort.

Conclusions: Among low-risk patients with a potential ACS, a pathway which incorporates early discharge based on a single very low level of high-sensitivity cardiac troponin increases the proportion of patients discharged directly from the emergency department, reduces length of stay and is safe.

Trial Registration Number: ACTRN12618000797279.
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http://dx.doi.org/10.1136/heartjnl-2020-317997DOI Listing
May 2021

Prospective validation study of prognostic biomarkers to predict adverse outcomes in patients with COVID-19: a study protocol.

Authors:
Benjamin Tang Maryam Shojaei Ya Wang Marek Nalos Anthony Mclean Ali Afrasiabi Tim N Kwan Win Sen Kuan Yoann Zerbib Velma Herwanto Gunawan Gunawan Davide Bedognetti Gabriele Zoppoli Alberto Ballestrero Darawan Rinchai Paolo Cremonesi Michele Bedognetti Martin Matejovic Thomas Karvunidis Stephen P J Macdonald Amanda J Cox Nicholas P West Allan William Cripps Klaus Schughart Andrea de Maria Damien Chaussabel Jonathan Iredell Stephen Weng

BMJ Open 2021 01 6;11(1):e044497. Epub 2021 Jan 6.

Division of Primary Care, University of Nottingham, Nottingham, UK.

Introduction: Accurate triage is an important first step to effectively manage the clinical treatment of severe cases in a pandemic outbreak. In the current COVID-19 global pandemic, there is a lack of reliable clinical tools to assist clinicians to perform accurate triage. Host response biomarkers have recently shown promise in risk stratification of disease progression; however, the role of these biomarkers in predicting disease progression in patients with COVID-19 is unknown. Here, we present a protocol outlining a prospective validation study to evaluate the biomarkers' performance in predicting clinical outcomes of patients with COVID-19.

Methods And Analysis: This prospective validation study assesses patients infected with COVID-19, in whom blood samples are prospectively collected. Recruited patients include a range of infection severity from asymptomatic to critically ill patients, recruited from the community, outpatient clinics, emergency departments and hospitals. Study samples consist of peripheral blood samples collected into RNA-preserving (PAXgene/Tempus) tubes on patient presentation or immediately on study enrolment. Real-time PCR (RT-PCR) will be performed on total RNA extracted from collected blood samples using primers specific to host response gene expression biomarkers that have been previously identified in studies of respiratory viral infections. The RT-PCR data will be analysed to assess the diagnostic performance of individual biomarkers in predicting COVID-19-related outcomes, such as viral pneumonia, acute respiratory distress syndrome or bacterial pneumonia. Biomarker performance will be evaluated using sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operating characteristic curve.

Ethics And Dissemination: This research protocol aims to study the host response gene expression biomarkers in severe respiratory viral infections with a pandemic potential (COVID-19). It has been approved by the local ethics committee with approval number 2020/ETH00886. The results of this project will be disseminated in international peer-reviewed scientific journals.
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http://dx.doi.org/10.1136/bmjopen-2020-044497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789210PMC
January 2021

Effect of age and comorbidity on the ability of quick-Sequential Organ Failure Assessment score to predict outcome in emergency department patients with suspected infection.

Authors:
Alex Williams Thomas Griffies Sophie Damianopoulos Daniel Fatovich Stephen Macdonald

Emerg Med Australas 2020 Dec 21. Epub 2020 Dec 21.

Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.

Objective: To determine if a combination of the Charlson Comorbidity Index (CCI) and quick-Sequential Organ Failure Assessment (qSOFA) score is superior to qSOFA alone for predicting the outcome of ED patients with suspected infection.

Methods: A prospective, observational single-centre study recruited consecutive adult patients who underwent blood culture collection in the ED and were admitted to hospital. The primary outcome was 28-day in-hospital mortality, and the secondary outcome a composite of mortality and/or ICU admission ≥72 h duration. The qSOFA and CCI were combined using logistic regression models, and the resulting area under the receiver operating characteristic curve (AUROC) compared to that for qSOFA alone.

Results: Of 551 patients recruited, 18 (3%) died and 27 (5%) attained the composite outcome. The AUROC for qSOFA/CCI versus qSOFA for the primary outcome is 0.79 versus 0.72 (95% confidence interval 0.71-0.88 vs 0.62-0.82, P = 0.055) and 0.80 versus 0.76 (95% confidence interval 0.73-0.86 vs 0.68-0.84, P = 0.048). Deaths among patients not admitted to ICU (12/495) accounted for most of the overall differences in AUROC.

Conclusions: This generates the hypothesis that age and comorbid disease status augment the qSOFA score for predicting adverse outcome among patients with suspected infection in the ED. The results may reflect the predominance of these factors in determining suitability for admission to ICU. Reported limitations of qSOFA to detect the risk of adverse outcome may reflect the influence of unmeasured patient factors.
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http://dx.doi.org/10.1111/1742-6723.13703DOI Listing
December 2020

Updated hospital associated venous thromboembolism outcomes with 90-days follow-up after hospitalisation for severe COVID-19 in two UK critical care units.

Authors:
Andrew J Doyle Will Thomas Andrew Retter Martin Besser Stephen MacDonald Karen A Breen Michael J R Desborough Beverley J Hunt

Thromb Res 2020 12 8;196:454-456. Epub 2020 Oct 8.

Centre for Thrombosis and Haemostasis, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543947PMC
December 2020

Evaluation of COVID-19 coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays.

Authors:
Danielle White Stephen MacDonald Tara Edwards Chris Bridgeman Megan Hayman Megan Sharp Sally Cox-Morton Emily Duff Swati Mahajan Chloe Moore Melissa Kirk Richard Williams Martin Besser Will Thomas

Int J Lab Hematol 2021 Feb 5;43(1):123-130. Epub 2020 Sep 5.

Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.

Introduction: Patients with COVID-19 are known to have a coagulopathy with a thrombosis risk. It is unknown whether this is due to a generalized humoral prothrombotic state or endothelial factors such as inflammation and dysfunction. The aim was to further characterize thrombin generation using a novel analyser (ST Genesia, Diagnostica Stago, Asnières, France) and a panel of haematological analytes in patients with COVID-19.

Methods: Platelet poor plasma of 34 patients with noncritical COVID-19 was compared with 75 patients with critical COVID-19 (as defined by WHO criteria) in a retrospective study by calibrated automated thrombography and ELISA. Patients were matched for baseline characteristics of age and gender.

Results: Critical patients had significantly increased fibrinogen, CRP, interleukin-6 and D-dimer compared to noncritical patients. Thrombin generation, in critical patients, was right shifted without significant differences in peak, velocity index or endogenous thrombin potential. Tissue plasminogen activator (tPA), tissue factor pathway inhibitor (TFPI) and vascular endothelial growth factor (VEGF) were significantly increased in the critical versus noncritical patients. Critically ill patients were on haemodiafiltration (31%; heparin used in the circuit) or often received escalated prophylactic low-molecular weight heparin.

Conclusion: These results confirm increased fibrinogen and D-dimer in critical COVID-19-infected patients. Importantly, disease severity did not increase thrombin generation (including thrombin-antithrombin complexes and prothrombin fragment 1 + 2) when comparing both cohorts; counter-intuitively critical patients were hypocoaguable. tPA, TFPI and VEGF were increased in critical patients, which are hypothesized to reflect endothelial dysfunction and/or contribution of heparin (which may cause endothelial TFPI/tPA release).
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http://dx.doi.org/10.1111/ijlh.13329DOI Listing
February 2021

Direct Oral Anticoagulant Concentrations in Obese and High Body Weight Patients: A Cohort Study.

Authors:
Anne Céline Martin William Thomas Zahra Mahir Maeve P Crowley Terry Dowling Karen Breen Victoria Collings Gary W Moore Stephen MacDonald Beverley J Hunt Alexander T Cohen

Thromb Haemost 2021 Feb 30;121(2):224-233. Epub 2020 Aug 30.

Department of Haematology, Thrombosis & Haemophilia Centre, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom.

Background:  Direct oral anticoagulants (DOACs) are prescribed for atrial fibrillation (AF) and venous thromboembolism (VTE) and both occur more frequently in obese patients. Outcomes from DOAC trials included few individuals ≥ 120 kg leading to uncertainty whether high body weight (BW) reduces DOAC concentrations.

Objectives:  This article investigates the relationship between factor Xa (FXa) inhibitor concentrations, BW, and renal function, and compares them in high BW patients with unselected populations.

Methods:  Consecutive patients in two United Kingdom centers, weighing ≥ 120 kg receiving 5 mg twice daily apixaban or 20 mg once daily rivaroxaban for AF or VTE were prospectively included. Peak or trough concentrations were measured using specific chromogenic assays, expressed in mean or median (5th-95th percentiles). On-therapy range was the interval from the 5th percentile trough concentration to the 95th percentile peak concentration.

Results:  One hundred patients were included; age range: 23 to 78 years, 31% were women, 58% had AF, creatinine clearance range: 67 to 474 mL/min. Median BW was 139 kg, and 84% had body mass index (BMI) ≥ 40 kg/m. DOAC peak and trough concentrations varied from 44 to 727 and 14 to 299 ng/mL, respectively. There was no linear relationship between FXa inhibitor concentrations at peak or trough and BW or BMI, and creatinine clearance. Apixaban troughs in AF and rivaroxaban peaks in VTE were lower than in unselected populations. However, only two trough concentrations were below the expected range, and 109/116 were within the on-therapy range.

Conclusion:  These data indicated that obese or high BW patients generally achieve therapeutic FXa inhibitor concentrations. However, further investigations assessing clinical outcomes are required.
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http://dx.doi.org/10.1055/s-0040-1715834DOI Listing
February 2021

Does age-adjusted D-dimer have a role in assessment of VTE recurrence rates? Comment.

Authors:
Will Thomas Irina Mindlina Stephen MacDonald Martin Besser

Int J Lab Hematol 2020 10 23;42(5):e240-e242. Epub 2020 Jul 23.

Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.

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http://dx.doi.org/10.1111/ijlh.13294DOI Listing
October 2020

Evaluation of Point-of-Care ACT Coagulometers and Anti-Xa Activity During Cardiopulmonary Bypass.

Authors:
Florian Falter Stephen MacDonald Claire Matthews Evelien Kemna José Cañameres Martin Besser

J Cardiothorac Vasc Anesth 2020 Nov 12;34(11):2921-2927. Epub 2020 Jun 12.

Division of Clinical Haematology and Blood Transfusion, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Objective: The activated clotting time (ACT) is used worldwide to confirm safe heparin anticoagulation for cardiopulmonary bypass. For the present study, the performances of 2 commonly used ACT devices were compared with each other and with anti-Xa levels throughout the surgical procedure in order to understand whether they can be used interchangeably.

Design: Prospective study.

Setting: Tertiary care center.

Participants: The study comprised 33 elective adult cardiac surgical patients.

Interventions: Blood samples were taken at standard times throughout the surgery (after induction, after heparin bolus, 4 samples at 30-minute intervals during cardiopulmonary bypass, after protamine), and ACTs and anti-Xa levels were analyzed. Data were compared using receiver operating characteristics and LOESS regression.

Measurements And Main Results: The correlation between anti-Xa levels and the Hemochron ACT (Instrumentation Laboratory, Bedford, MA) was acceptable (r = 0.82, 95% confidence interval [CI] 0.757-0.868; p < 0.0001), as was the correlation between anti-Xa levels and the i-STAT (Abbott Point of Care, Abbott Park, IL) (r = 0.81, 95% CI 0.738-0.858; p < 0.0001). The correlation between the 2 ACT methods was poorer (r = 0.77, 95% CI 0.707-0.828; p < 0.0001) than their correlation to anti-Xa levels. When compared with anti-Xa levels, the sensitivity and specificity were mediocre for both devices, although the i-STAT performed better than the Hemochron ACT. The Hemochron ACT read higher values than the i-STAT ACT throughout the course of the surgery.

Conclusion: The correlation between the Hemochron ACT and i-STAT ACT is moderate, and they have different sensitivity and specificity when compared with anti-Xa levels. This suggests that ACT devices should not be used interchangeably, but cut-off values for safe anticoagulation during cardiopulmonary bypass should be determined for each type of device, particularly when switching supplier.
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http://dx.doi.org/10.1053/j.jvca.2020.06.027DOI Listing
November 2020

Diagnostic work up of patients with increased bleeding tendency: Comment.

Authors:
Will Thomas Danielle White Stephen MacDonald Kate Downes Samya Obaji Michael Desborough

Haemophilia 2020 Jul 20;26(4):e209-e210. Epub 2020 Apr 20.

Haemostasis and Thrombosis Centre, St Thomas' Hospital, London, UK.

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http://dx.doi.org/10.1111/hae.13989DOI Listing
July 2020

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

Authors:
Rachel L Sills Stephen Pj Macdonald Briony G Williams Jonathon D Burcham David McCutcheon Anne E Cordingley Daniel M Fatovich

Emerg Med Australas 2020 06 27;32(3):515-517. Epub 2020 Feb 27.

Department of Emergency Medicine, Royal Perth Hospital, Perth, Western Australia, Australia.

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?
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http://dx.doi.org/10.1111/1742-6723.13488DOI Listing
June 2020

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.

Authors:
Gerben Keijzers Stephen Pj Macdonald Andrew A Udy Glenn Arendts Michael Bailey Rinaldo Bellomo Gabriel E Blecher Jonathon Burcham Andrew R Coggins Anthony Delaney Daniel M Fatovich John F Fraser Amanda Harley Peter Jones Frances B Kinnear Katya May Sandra Peake David McD Taylor Patricia Williams

Emerg Med Australas 2020 08 10;32(4):586-598. Epub 2020 Feb 10.

Department of Intensive Care Medicine, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.

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.
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http://dx.doi.org/10.1111/1742-6723.13469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496107PMC
August 2020

Primary care interventions to address physical frailty among community-dwelling adults aged 60 years or older: A meta-analysis.

Authors:
Stephen H-F Macdonald John Travers Éidín Ní Shé Jade Bailey Roman Romero-Ortuno Michael Keyes Diarmuid O'Shea Marie Therese Cooney

PLoS One 2020 7;15(2):e0228821. Epub 2020 Feb 7.

St Vincent's University Hospital, Dublin, Ireland.

Introduction: The best interventions to address frailty among older adults have not yet been fully defined, and the diversity of interventions and outcome measures makes this process challenging. Consequently, there is a lack of guidance for clinicians and researchers regarding which interventions are most likely to help older persons remain robust and independent. This paper uses meta-analysis to assess effectiveness of primary care interventions for physical frailty among community-dwelling adults aged 60+ and provides an up-to-date synthesis of literature in this area.

Methods: PubMed, CINAHL, Cochrane Register of Controlled Trials, and PEDro databases were searched, and RCTs, controlled pilot studies, or trials with similar study designs addressing frailty in the primary care setting among persons aged 60+ were chosen. Study data was abstracted following PRISMA guidelines, then meta-analysis was performed using the random effects model.

Results: 31 studies with a total of 4794 participants were analysed. Interventions using predominantly resistance-based exercise and nutrition supplementation seemed to improve frailty status versus control (RR = 0.62 (CI 0.48-0.79), I2 = 0%). Exercise plus nutrition education also reduced frailty (RR = 0.69 (CI 0.58-0.82), I2 = 0%). Exercise alone seemed effective in reducing frailty (RR = 0.63 (CI 0.47-0.84), I2 = 0%) and improving physical performance (RR = 0.43 (CI 0.18-0.67), I2 = 0%). Exercise alone also appeared superior to control in improving gait speed (SMD = 0.36 (CI 0.10-0.61, I2 = 74%), leg strength (SMD = 0.61 (CI 0.09-1.13), I2 = 87%), and grip strength (Mean Difference = 1.08 (CI 0.02-2.15), I2 = 71%) though a high degree of heterogeneity was observed. Comprehensive geriatric assessment (RR = 0.77 (CI 0.64-0.93), I2 = 0%) also seemed superior to control in reducing frailty.

Conclusion: Exercise alone or with nutrition supplementation or education, and comprehensive geriatric assessment, may reduce physical frailty. Individual-level factors and health systems resource availability will likely determine configuration of future interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228821PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006935PMC
May 2020

Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity.

Authors:
Stephen MacDonald Danielle White Jon Langdown Kate Downes Will Thomas

Int J Lab Hematol 2020 Jun 31;42(3):246-255. Epub 2020 Jan 31.

Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Introduction: We have routinely used thrombin generation to investigate patients with unclassified bleeding disorder (UBD).

Aims: To investigate haemostatic abnormalities in patients with UBD that had abnormal thrombin generation on at least one occasion.

Methods: Investigation of 13 known UBD patients with thrombin generation and detailed haemostatic testing was undertaken including TFPI assays but also thrombomodulin and fibrinogen-γ.

Results: 12 females and 1 male were included. No patient had a platelet function disorder or coagulation factor deficiency that explained the bleeding phenotype, though 2 patients had factor deficiencies; a factor X of 0.41 IU/mL and a factor XI of 0.51 IU/mL. ThromboGenomics revealed variants for these factors but no other abnormalities. Patients were included who previously had either prolonged lag time or decreased endogenous thrombin potential (ETP) via high dose tissue factor (5 pmol/L) or low dose tissue factor (1.5 pmol/L) with corn trypsin inhibitor (CTI). Tissue factor pathway inhibitor (TFPI) activity was significantly increased (P < .001; increased in 8 patients) compared with controls and abnormalities in soluble thrombomodulin (2 patients), fibrinogen-γ (1 patient) and tPA (4 patients for each) were seen. Total and free TFPI levels were not increased. Mixing studies of patient plasma with 50:50 normal plasma for thrombin generation via low dose tissue factor failed to correct the ETP consistent with ongoing inhibition. Addition of an anti-TFPI antibody partially corrected thrombin generation to normal levels. TFPI sequencing was unremarkable.

Conclusion: TFPI activity may be increased in a subset of UBD patients. Further research studies are warranted in UBD patients for coagulation inhibitor abnormalities.
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http://dx.doi.org/10.1111/ijlh.13155DOI Listing
June 2020

Towards the Development of an Integrative, Evidence-Based Suite of Indicators for the Prediction of Outcome Following Mild Traumatic Brain Injury: Results from a Pilot Study.

Authors:
Aleksandra Gozt Melissa Licari Alison Halstrom Hannah Milbourn Stephen Lydiard Anna Black Glenn Arendts Stephen Macdonald Swithin Song Ellen MacDonald Philip Vlaskovsky Sally Burrows Michael Bynevelt Carmela Pestell Daniel Fatovich Melinda Fitzgerald

Brain Sci 2020 Jan 2;10(1). Epub 2020 Jan 2.

Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia.

Background: Persisting post-concussion symptoms (PPCS) is a complex, multifaceted condition in which individuals continue to experience the symptoms of mild traumatic brain injury (mTBI; concussion) beyond the timeframe that it typically takes to recover. Currently, there is no way of knowing which individuals may develop this condition.

Method: Patients presenting to a hospital emergency department (ED) within 48 h of sustaining a mTBI underwent neuropsychological assessment and demographic, injury-related information and blood samples were collected. Concentrations of blood-based biomarkers neuron specific enolase, neurofilament protein-light, and glial fibrillary acidic protein were assessed, and a subset of patients also underwent diffusion tensor-magnetic resonance imaging; both relative to healthy controls. Individuals were classified as having PPCS if they reported a score of 25 or higher on the Rivermead Postconcussion Symptoms Questionnaire at ~28 days post-injury. Univariate exact logistic regression was performed to identify measures that may be predictive of PPCS. Neuroimaging data were examined for differences in fractional anisotropy (FA) and mean diffusivity in regions of interest.

Results: Of = 36 individuals, three (8.33%) were classified as having PPCS. Increased performance on the Repeatable Battery for the Assessment of Neuropsychological Status Update Total Score (OR = 0.81, 95% CI: 0.61-0.95, = 0.004), Immediate Memory (OR = 0.79, 95% CI: 0.56-0.94, = 0.001), and Attention (OR = 0.86, 95% CI: 0.71-0.97, = 0.007) indices, as well as faster completion of the Trails Making Test B (OR = 1.06, 95% CI: 1.00-1.12, = 0.032) at ED presentation were associated with a statistically significant decreased odds of an individual being classified as having PPCS. There was no significant association between blood-based biomarkers and PPCS in this small sample, although glial fibrillary acidic protein (GFAP) was significantly increased in individuals with mTBI relative to healthy controls. Furthermore, relative to healthy age and sex-matched controls ( = 8), individuals with mTBI ( = 14) had higher levels of FA within the left inferior frontal occipital fasciculus ( (18.06) = -3.01, = 0.008).

Conclusion: Performance on neuropsychological measures may be useful for predicting PPCS, but further investigation is required to elucidate the utility of this and other potential predictors.
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http://dx.doi.org/10.3390/brainsci10010023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017246PMC
January 2020

Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment.

Authors:
Stephen MacDonald Alfie Wright Frederik Beuche Kate Downes Martin Besser Emily Symington Anne Kelly Will Thomas

Int J Lab Hematol 2020 Apr 20;42(2):116-125. Epub 2019 Nov 20.

Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Introduction: There is an unmet need to characterize the diagnosis and management of patients with an unclassified bleeding disorder (UBD).

Methods: Retrospective review of registered patients with UBD at our centre. Assessment including rotational thromboelastometry (ROTEM) and thrombin generation (TG) were used.

Results: A total of 124 patients were identified; 91% female. Mean age of presentation was 38.3 years. Mean bleeding score was 8.8 (standard deviation [SD] 3.8); 6.6 in men (SD 1.4) and 9.7 in women (SD 3.3), which was significantly different (P < .05). In women, after deduction of scores for menorrhagia and postpartum haemorrhage, the mean score was 6.4 which was not significantly different to the male score (P = .11). Twenty-three percent of patients have been transfused, 61% women had treatment for menorrhagia and 17% for epistaxis. TxA and desmopressin were effective at preventing bleeding in 69 procedures and 13 deliveries. TG revealed 26% patients with a long lag time and 19% with a decreased endogenous thrombin potential but no diagnostic pattern was seen. ROTEM (NATEM) was unable to characterize patients; 9% had a prolonged clot time or maximum lysis. ThromboGenomics was normal in 45 tested patients.

Conclusions: We provide data which shows the bleeding score is biased towards gynaecological bleeding but which remains elevated even when the bleeding score is deducted. Tranexamic acid and desmopressin are effective as haemostatic prophylaxis but there is an urgent need for clinical trials. In conclusion, we describe the use of the bleeding score in these patients and phenotype, diagnosis (including ThromboGenomic testing) and management with practice recommendations.
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http://dx.doi.org/10.1111/ijlh.13124DOI Listing
April 2020

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

Authors:
David H Tian Claire Smyth Gerben Keijzers Stephen Pj Macdonald Sandra Peake Andrew Udy Anthony Delaney

Emerg Med Australas 2020 04 7;32(2):220-227. Epub 2019 Nov 7.

Malcolm Fisher Department of Intensive Care Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1111/1742-6723.13406DOI Listing
April 2020

Initiation of vasopressor infusions via peripheral versus central access in patients with early septic shock: A retrospective cohort study.

Authors:
Anthony Delaney Mark Finnis Rinaldo Bellomo Andrew Udy Daryl Jones Gerben Keijzers Stephen MacDonald Sandra Peake

Emerg Med Australas 2020 04 9;32(2):210-219. Epub 2019 Oct 9.

Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Objective: To assess whether the initiation of vasopressor infusions via peripheral venous catheters (PVC) compared to central venous catheters (CVC) in ED patients with early septic shock was associated with differences in processes of care and outcomes.

Methods: We conducted a post-hoc analysis of the ARISE trial. We compared participants who had a vasopressor infusion first commenced via a PVC versus a CVC. The primary outcome was 90 day mortality.

Results: We studied 937 participants. Of these, 389 (42%) had early vasopressor infusion commenced via a PVC and 548 (58%) via a CVC. Trial participants who received a vasopressor infusion via a PVC were more severely ill, with higher median (interquartile range [IQR]) Acute Physiology And Chronic Health Evaluation (APACHE II) scores (17 [13-23] versus 16 [12-21], P = 0.003), and higher median (IQR) lactate (mmol/L) (3.6 [1.9-5.8] versus 2.5 [1.5-4.5], P < 0.001). After adjusting for baseline covariates, the estimated odds ratio for mortality for PVC-treated patients was 1.26 (95% confidence interval 0.95-1.67, P = 0.11). Trial participants who had vasopressors commenced via PVC had a shorter median (IQR) time to commencement of antimicrobials (55 [32-96] versus 71.5 [39-119] min, P < 0.001) and a shorter median (IQR) time to commencement of vasopressors (2.4 [1.3-3.9] versus 4.9 [3.5-6.6] h, P < 0.001).

Conclusion: The practice of commencing a vasopressor infusion via a PVC was common in the ARISE trial and more frequent in trial participants with higher severity of illness. Commencement of a vasopressor infusion via a PVC was associated with some improvements in processes of care and, after adjustment, was not associated with an increased risk of death.
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http://dx.doi.org/10.1111/1742-6723.13394DOI Listing
April 2020

A diagnostic solution for haemostasis laboratories for patients taking direct oral anticoagulants using DOAC-Remove.

Authors:
Sally Cox-Morton Stephen MacDonald Will Thomas

Br J Haematol 2019 11 10;187(3):377-385. Epub 2019 Jul 10.

Haemophilia and Thrombophilia Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

This study describes the use of a simple charcoal product (DOAC-Remove ) to allow haemostasis assays on patients taking direct oral anticoagulants (DOAC). In the proposed algorithm, patients taking DOAC are screened using the dilute thrombin time (dTT) and anti-Xa assay. If either are positive then DOAC-Remove is utilised. In a validation, DOAC-Remove did not interfere with coagulation testing in normal plasma or in patients on DOAC with a known lupus anticoagulant (LA). Of 1566 routine patient samples tested, 125 (8%) had evidence of anti-Xa activity (>0·1 iu/ml) or prolonged dTT suggestive of either a direct/indirect Xa inhibitor or direct thrombin inhibitor. All of these 125 patients had a prolonged dilute Russell viper venom time (dRVVT) screening test and 106 had a LA detected by dRVVT after phospholipid correction. After DOAC-Remove, 91 patients (73%) had a negative dRVVT screen. After further investigation only 9 (7%) had a positive LA. DOAC-Remove prevented 5% of patients having a LA inappropriately detected. DOAC did not significantly affect the LA activated partial thromboplastin time (aPTT) ratio, protein S antigen or protein C activity. DOAC cause low intrinsic factor assays, high prothrombin time/aPTT and high activated protein C sensitivity ratio, which DOAC-Remove reversed (P < 0·05). Despite recommendations, haemostasis testing for patients on DOAC continues; this algorithm aids diagnostic accuracy. Further validation and research are warranted.
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http://dx.doi.org/10.1111/bjh.16091DOI Listing
November 2019

Bolus therapy with 3% hypertonic saline or 0.9% saline in emergency department patients with suspected sepsis: A pilot randomised controlled trial.

Authors:
Lisa Smart Stephen P J Macdonald Erika Bosio Daniel Fatovich Claire Neil Glenn Arendts

J Crit Care 2019 08 28;52:33-39. Epub 2019 Mar 28.

Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Perth, Australia; Emergency Medicine, University of Western Australia, Perth, Australia; Emergency Department, Fiona Stanley Hospital, Perth, Australia.

Objective And Design: Hypertonic saline administered during fluid resuscitation may mitigate endothelial glycocalyx (EG) shedding and inflammation. The objective of this pilot randomised controlled trial was to measure the effect of hypertonic saline, compared to isotonic saline, on biomarkers of EG shedding and inflammation in emergency department patients with suspected sepsis.

Methods: Patients received either 5 mL/kg of 3% saline (hypertonic group, n = 34) or 10 mL/kg of 0.9% saline (isotonic group, n = 31). Change in serum biomarker concentrations of syndecan-1, hyaluronan, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, interleukin-6, -8, -10, interferon-γ, neutrophil gelatinase-associated lipocalin and resistin were compared from baseline (T0) to after fluid (T1), 3 h (T3) and 12-24 h (T24) later, as was serum osmolality, using linear mixed effects models.

Results: The hypertonic group had significantly increased mean serum osmolality compared to the isotonic group at T1 (P < .001) and T3 (P = .004). Minor differences were found in some biomarker outcomes, including a decreased fold-change in syndecan-1 at T1 (P = .012) and in interleukin-10 at T24 (P = .006) in the isotonic group, compared to the hypertonic group.

Conclusions: Although a single bolus of hypertonic saline increased serum osmolality, it did not reduce biomarkers of EG shedding or inflammation, compared to patients that received isotonic saline.

Trial Registration: ANZCTR.org.au, ACTRN12611001021965, Registered on 23rd September 2011.
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http://dx.doi.org/10.1016/j.jcrc.2019.03.009DOI Listing
August 2019

Living on the edge: Exploring the role of coastal refugia in the Alexander Archipelago of Alaska.

Authors:
Yadéeh E Sawyer Stephen O MacDonald Enrique P Lessa Joseph A Cook

Ecol Evol 2019 Feb 1;9(4):1777-1797. Epub 2019 Feb 1.

Department of Biology and Museum of Southwestern Biology University of New Mexico Albuquerque New Mexico.

Although islands are of long-standing interest to biologists, only a handful of studies have investigated the role of climatic history in shaping evolutionary diversification in high-latitude archipelagos. In this study of the Alexander Archipelago (AA) of Southeast Alaska, we address the impact of glacial cycles on geographic genetic structure for three mammals co-distributed along the North Pacific Coast. We examined variation in mitochondrial and nuclear loci for long-tailed voles (), northwestern deermice (), and dusky shrews (), and then tested hypotheses derived from Species Distribution Models, reconstructions of paleoshorelines, and island area and isolation. In all three species, we identified paleoendemic clades that likely originated in coastal refugia, a finding consistent with other paleoendemic lineages identified in the region such as ermine. Although there is spatial concordance at the regional level for endemism, finer scale spatial and temporal patterns are less clearly defined. Demographic expansion across the region for these distinctive clades is also evident and highlights the dynamic history of Late Quaternary contraction and expansion that characterizes high-latitude species.
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http://dx.doi.org/10.1002/ece3.4861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392352PMC
February 2019

Correction: 'We are the change'-An innovative community-based response to address self-stigma: A pilot study focusing on people living with HIV in Zimbabwe.

Authors:
Nadine Ferris France Stephen H-F Macdonald Ronan M Conroy Patrick Chiroro Deirdre Ni Cheallaigh Masimba Nyamucheta Bekezela Mapanda Godsway Shumba Dennis Mudede Elaine Byrne

PLoS One 2019 28;14(2):e0213465. Epub 2019 Feb 28.

[This corrects the article DOI: 10.1371/journal.pone.0210152.].
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213465PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394963PMC
February 2019

'We are the change' - An innovative community-based response to address self-stigma: A pilot study focusing on people living with HIV in Zimbabwe.

Authors:
Nadine Ferris France Stephen H-F Macdonald Ronan R Conroy Patrick Chiroro Deirdre Ni Cheallaigh Masimba Nyamucheta Bekezela Mapanda Godsway Shumba Dennis Mudede Elaine Byrne

PLoS One 2019 13;14(2):e0210152. Epub 2019 Feb 13.

RCSI Institute of Leadership, Royal College of Surgeons in Ireland, Dublin, Ireland.

Introduction: Self-stigma-negative self-judgements resulting in shame, worthlessness and self-blame-may play a crucial role in emotional reactions and cause emotional distress among many people living with HIV and other chronic illnesses. Furthermore, self-stigma negatively impacts on self-agency, quality of life, adherence to treatment, and access to services. High levels of self-stigma have been reported across many countries, however few programmes or interventions exist to specifically tackle this phenomenon. This paper reports the findings of a pilot study carried out in Zimbabwe using a programme incorporating "Inquiry-Based Stress Reduction (IBSR): The Work of Byron Katie"-a guided form of self-inquiry which helps users to overcome negative thoughts and beliefs.

Objectives: The primary objective of this uncontrolled pilot study was to examine the potential role of the IBSR intervention in helping people living with HIV to overcome self-stigma and associated states.

Methods: 23 people living with HIV (17 Female, 6 male, average age 41 years) were recruited from a local HIV support network, via open call for volunteers. All participants received the intervention, consisting of a 12-week facilitated programme using techniques derived from IBSR: The Work of Byron Katie. Qualitative and quantitative data were collected and analysed pre- and post-programme.

Results: After taking part in the intervention, participants reported significant improvements in factors including self-stigma (1-month follow-up vs baseline Z = 2.1, p = 0.039; 3-month follow-up vs baseline Z = 3.0, p = 0.003, n = 23, Wilcoxon Matched Pairs Signed Rank Test) and depression (1mo vs baseline Z = 3.7, p = <0.001; 3mo vs baseline Z = 3.3, p = 0.001). Qualitatively, participants reported improvements including lessened fears around disclosure of their HIV status, reduced feelings of life limitations due to HIV, and greater positive mentality. Improvements persisted at three-month follow-up.

Conclusion: With further development and larger comparative studies to confirm effects, the IBSR programme could become a novel tool to enable people living with HIV to support themselves in overcoming self-stigma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210152PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373928PMC
October 2019

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.

Authors:
Gerben Keijzers Stephen Pj Macdonald Andrew A Udy Glenn Arendts Michael Bailey Rinaldo Bellomo Gabriel E Blecher Jonathon Burcham Anthony Delaney Andrew R Coggins Daniel M Fatovich John F Fraser Amanda Harley Peter Jones Fran Kinnear Katya May Sandra Peake David McD Taylor Julian Williams Patricia Williams

Emerg Med Australas 2019 02 22;31(1):90-96. Epub 2019 Jan 22.

Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1111/1742-6723.13223DOI Listing
February 2019

Twice upon a time: Examining the effect socio-economic status has on the experience of dyslexia in the United Kingdom.

Authors:
Stephen J Macdonald Lesley Deacon

Dyslexia 2019 Feb 7;25(1):3-19. Epub 2019 Jan 7.

Senior Lecturer Applied Social Studies and Social Work, School of Social Sciences, Faculty of Education and Society, University of Sunderland, Sunderland, UK.

From the mid-1990s, there have been a number of campaigns aimed at raising awareness of dyslexia and social inclusion. In conjunction with these campaigns, educational and employment policies have been implemented that advocate inclusive and workplace adjustments for people with dyslexia. This study aims to explore the intersectional relationship between dyslexia and socio-economic status. The findings analyse adult perceptions of education and employment, which have been shaped by 23 years of social policies promoting anti-discriminatory practice. The study applies a quantitative approach, which collected data from a national survey conducted from 2015 to 2017. The sample consists of 442 adult participants who reported having dyslexia. The social model of disability has been applied in this study to interpret the data findings from a disability studies perspective. The article suggests that socio-economic status significantly affects issues of diagnosis, educational, and employment experiences. The findings illustrate an intersectional relationship between socio-economic status and disability inequalities, which have an effect on the experiences of people with dyslexia in adulthood.
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http://dx.doi.org/10.1002/dys.1606DOI Listing
February 2019

Utility of the DASH score after unprovoked venous thromboembolism; a single centre study.

Authors:
Stephen MacDonald Rajani Chengal Anida Hanxhiu Emily Symington Karen Sheares Martin Besser Will Thomas

Br J Haematol 2019 05 15;185(3):631-633. Epub 2018 Nov 15.

Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.

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http://dx.doi.org/10.1111/bjh.15597DOI Listing
May 2019

Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial.

Authors:
Stephen P J Macdonald Gerben Keijzers David McD Taylor Frances Kinnear Glenn Arendts Daniel M Fatovich Rinaldo Bellomo David McCutcheon John F Fraser Juan-Carlos Ascencio-Lane Sally Burrows Edward Litton Amanda Harley Matthew Anstey Ashes Mukherjee

Intensive Care Med 2018 Dec 31;44(12):2070-2078. Epub 2018 Oct 31.

Emergency Department, Armadale-Kelmscott Memorial Hospital, Perth, Australia.

Purpose: To determine if a regimen of restricted fluids and early vasopressor compared to usual care is feasible for initial resuscitation of hypotension due to suspected sepsis.

Methods: A prospective, randomised, open-label, clinical trial of a restricted fluid resuscitation regimen in the first 6 h among patients in the emergency department (ED) with suspected sepsis and a systolic blood pressure under 100 mmHg, after minimum 1000 ml of IV fluid. Primary outcome was total fluid administered within 6 h post randomisation.

Results: There were 99 participants (50 restricted volume and 49 usual care) in the intention-to-treat analysis. Median volume from presentation to 6 h in the restricted volume group was 2387 ml [first to third quartile (Q1-Q3) 1750-2750 ml]; 30 ml/kg (Q1-Q3 32-39 ml/kg) vs. 3000 ml (Q1-Q3 2250-3900 ml); 43 ml/kg (Q1-Q3 35-50 ml/kg) in the usual care group (p < 0.001). Median duration of vasopressor support was 21 h (Q1-Q3 9-42 h) vs. 33 h (Q1-Q3 15-50 h), (p = 0.13) in the restricted volume and usual care groups, respectively. At 90-days, 4 of 48 (8%) in the restricted volume group and 3 of 47 (6%) in the usual care group had died. Protocol deviations occurred in 6/50 (12%) in restricted group and 11/49 (22%) in the usual care group, and serious adverse events in four cases (8%) in each group.

Conclusions: A regimen of restricted fluids and early vasopressor in ED patients with suspected sepsis and hypotension appears feasible. Illness severity was moderate and mortality rates low. A future trial is necessary with recruitment of high-risk patients to determine effects on clinical outcomes in this setting.
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http://dx.doi.org/10.1007/s00134-018-5433-0DOI Listing
December 2018

Incidence, Patient Characteristics, Mode of Drug Delivery, and Outcomes of Septic Shock Patients Treated With Vasopressors in the Arise Trial.

Authors:
Andrew A Udy Mark Finnis Daryl Jones Anthony Delaney Stephen Macdonald Rinaldo Bellomo Sandra Peake

Shock 2019 10;52(4):400-407

Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Introduction: To describe the utilization of vasopressors (VP) in patients enrolled in the Australasian Resuscitation In Sepsis Evaluation (ARISE) trial, and to explore the association between time to VP and 90-day mortality.

Methods: The primary exposure variable was VP use after arrival in the emergency department (ED). Vasoactive agents considered as VP included: norepinephrine, epinephrine, metaraminol, or vasopressin. Time-to-event analysis, multivariable logistic regression, and propensity-matched treatment effects modeling were used to assess the association between time to VP and 90-day mortality.

Results: In total 1,102 of 1,588 patients (69%) in ARISE received VP at any point. The median [interquartile range (IQR)] time from ED presentation to commencing VP was 4.4 [2.7, 7.1] h, and 38% did so prior to central venous access. The median [IQR] volume of intravenous (i.v.) fluid administered prior to commencing VP was 3.1 [2.3, 4.3] L. Increasing age and volume of i.v. fluid therapy were associated with a lower likelihood of commencing VP early (within 4 h of ED presentation), while greater illness severity was associated with a higher likelihood, P < 0.001, respectively. In those who subsequently died within 90 days, the sub-hazard ratio (95% confidence interval) for commencing VP was 1.4 (1.20, 1.68), P < 0.001, adjusted for age, acute physiology and chronic health evaluation II score, study group, inclusion criteria, plasma lactate, i.v. fluid prior to VP, study institution, and site of infection.

Discussion: 50% of the ARISE cohort commenced VP within 4.4 h of ED presentation, and many did so prior to central venous access. Earlier initiation of VP was associated with greater crude and adjusted 90-day mortality.
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http://dx.doi.org/10.1097/SHK.0000000000001281DOI Listing
October 2019

Markers Involved in Innate Immunity and Neutrophil Activation are Elevated during Acute Human Anaphylaxis: Validation of a Microarray Study.

Authors:
Abbie Francis Erika Bosio Shelley F Stone Daniel M Fatovich Glenn Arendts Stephen P J MacDonald Sally Burrows Simon G A Brown

J Innate Immun 2019 6;11(1):63-73. Epub 2018 Sep 6.

Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Perth, Washington, Australia.

Background: We have previously identified the upregulation of the innate immune response, neutrophil activation, and apoptosis during anaphylaxis using a microarray approach. This study aimed to validate the differential gene expression and investigate protein concentrations of "hub genes" and upstream regulators during anaphylaxis.

Methods: Samples were collected from patients with anaphylaxis on their arrival at the emergency department, and after 1 and 3 h. mRNA levels of 11 genes (interleukin-6 [IL-6], IL-10, oncostatin M [OSM], S100A8, S100A9, matrix metalloproteinase 9 [MMP9], FASL, toll-like receptor 4 [TLR4], MYD88, triggering receptor expressed on myeloid cells 1 [TREM1], and cluster of differentiation 64 [CD64]) were measured in peripheral blood leucocytes using qPCR. Serum protein concentrations were measured by ELISA or cytometric bead array for 6 of these candidates.

Results: Of 69 anaphylaxis patients enrolled, 36 (52%) had severe reactions, and 38 (55%) were female. Increases in both mRNA and protein of IL-10, S100A9, MMP9, and TREM1 were observed. OSM, S100A8, TLR4, and CD64 were upregulated and IL-6 protein concentrations were increased during anaphylaxis. Both FASL and soluble Fas ligand decreased during anaphylaxis.

Conclusion: These results provide evidence for the involvement of innate immune pathways and myeloid cells during human anaphylaxis, validating previous microarray findings. Elevated S100A8, S100A9, TLR4, and TREM1 expression, and increased S100A9 and soluble TREM1 protein concentrations strongly suggest that neutrophils are activated during acute anaphylaxis.
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http://dx.doi.org/10.1159/000492301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738247PMC
February 2020

Liberal or restricted fluid resuscitation in critical illness: Shifting the needle back towards equipoise.

Authors:
Stephen Pj Macdonald Nathan I Shapiro

Emerg Med Australas 2018 08;30(4):446-447

Emergency Department, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1111/1742-6723.13130DOI Listing
August 2018

Glycocalyx biomarker syndecan-1 is a stronger predictor of respiratory failure in patients with sepsis due to pneumonia, compared to endocan.

Authors:
Lisa Smart Erika Bosio Stephen P J Macdonald Randal Dull Daniel M Fatovich Claire Neil Glenn Arendts

J Crit Care 2018 10 18;47:93-98. Epub 2018 Jun 18.

Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia; Division of Emergency Medicine, University of Western Australia, Perth, Western Australia, Australia; Emergency Department, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.

Purpose: Endocan, a component of the endothelial glycocalyx (EG), has been linked with respiratory failure in sepsis. This study explored the temporal patterns of three EG biomarkers, including endocan, and their relationships with inflammation and respiratory failure.

Materials And Methods: Plasma endocan, syndecan-1, and hyaluronan concentrations were measured in Emergency Department (ED) patients with sepsis due to pneumonia (n = 44) on ED arrival (T0), 1 h (T1), 3 h (T3) and 12-24 h (T24) later, with change over time tested using mixed regression models. Biomarker associations with inflammatory cytokine concentrations and with respiratory failure on days 1, 2 or 3, need for mechanical ventilation and 30-day mortality were also tested.

Results: Endocan concentration significantly decreased over time (T0-T24, P = 0.003) whereas both syndecan-1 (T0-T3, P = 0.010; T0-T24, P < 0.001) and hyaluronan (T0-T1, P = 0.010; T0-T3, P < 0.001; T0-T24, P = 0.003) significantly increased over time. Increased syndecan-1 was significantly correlated with neutrophil activation biomarkers and significantly increased the odds of respiratory failure (OR 1.18, 95% CI 1.05-1.33, P = 0.004), need for mechanical ventilation (OR 1.24, 95% CI 1.04-1.48, P = 0.014) and 30-day mortality (OR 1.29, 95% CI 1.07-1.55, P = 0.008).

Conclusion: Syndecan-1, but not endocan, was associated with neutrophil activation and was the best EG biomarker predictor of adverse clinical outcomes.
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http://dx.doi.org/10.1016/j.jcrc.2018.06.015DOI Listing
October 2018