Papers by Dorrilyn Rajbhandari
Yearbook of pediatric endocrinology, Sep 11, 2018
BACKGROUND Whether hydrocortisone reduces mortality among patients with septic shock is unclear. ... more BACKGROUND Whether hydrocortisone reduces mortality among patients with septic shock is unclear. METHODS We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. RESULTS From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P = 0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P = 0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. CONCLUSIONS Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.
PubMed, Mar 1, 2017
Background: Cross-sectional point prevalence studies collect observational data at a single time ... more Background: Cross-sectional point prevalence studies collect observational data at a single time point and may be used to facilitate subsequent research hypotheses and discovery. Methods: We report the process of implementation and substantive outputs of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG) point prevalence program, conducted in participating intensive care units from 2009 to 2016. Results: Seventy-seven of a maximum 197 adult ICUs across Australia and New Zealand participated in 9 specified study days over 18 days of data collection and collected data on 5043 participants, with an average of 44 ICUs per study day. All eight Australian and New Zealand paediatric ICUs have participated in dedicated simultaneous paediatric study days. Thirteen manuscripts were published in peer-reviewed journals and data have contributed to 14 individual programs of research, including 18 subsequent grant applications for further research. Conclusion: The ANZICS CTG point prevalence program has resulted in the collection of a substantial body of observational data that has facilitated the development and completion of subsequent research programs and provided opportunities for subsequent capacity development.
International Journal of Multiple Research Approaches, Dec 1, 2009
Contemporary clinical work involves the collaboration of different health care practitioners to p... more Contemporary clinical work involves the collaboration of different health care practitioners to provide safe, effective, and high quality services. Yet practitioner collaboration is often fraught with political, professional and ideological divergences. For these reasons opportunities for health care practitioners to come together and develop a shared meaning of practice is often constrained by organizational and professional agendas. The methodology reported on here has allowed health care practitioners to critically engage with their own practice, and the practice of their colleagues, in a way that enables them to negotiate and mitigate their differences and divergent opinions and practices. Through the use of video reflexive methods health care practitioners were able to articulate systematizing or 'meta discursive' solutions to address previously taken-as-given organizational and clinical (handover) practices.
The New England Journal of Medicine, Nov 15, 2012
Journal Club AINS, Dec 28, 2015
IntroductionIn vitroandin vivopharmacokinetic/pharmacodynamic data describe improved activity of ... more IntroductionIn vitroandin vivopharmacokinetic/pharmacodynamic data describe improved activity of beta-lactam antibiotics when administered by prolonged infusion compared with standard intermittent infusion. There remains insufficient robust clinical trial data to support a widespread practice change. Patients with sepsis and septic shock are a population in whom prolonged infusion of beta-lactam antibiotics may improve survival. Two large multicentre randomised controlled trials (RCTs) comparing prolonged versus intermittent infusion of beta-lactam antibiotics in critically ill patients with sepsis or septic shock are due for completion in 2023. With existing RCT evidence, this systematic review and meta-analysis will include these new data to measure the clinical benefits of prolonged beta-lactam infusion in critically ill patients with sepsis.Methods and analysisThis protocol has been prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Proto...
Annals of Emergency Medicine, 2017
The influence of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsi... more The influence of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) on the conduct of future sepsis research is unknown. We seek to examine the potential effect of the new definitions on the identification and outcomes of patients enrolled in a sepsis trial. Methods: This was a post hoc analysis of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial of early goal-directed therapy that recruited 1,591 adult patients presenting to the emergency department (ED) with early septic shock diagnosed by greater than or equal to 2 systemic inflammatory response syndrome criteria and either refractory hypotension or hyperlactatemia. The proportion of participants who would have met the Sepsis-3 criteria for quick Sequential Organ Failure Assessment (qSOFA) score, sepsis (an increased Sequential Organ Failure Assessment score !2 because of infection) and septic shock before randomization, their baseline characteristics, interventions delivered, and mortality were determined. Results: There were 1,139 participants who had a qSOFA score of greater than or equal to 2 at baseline (71.6% [95% confidence interval {CI} 69.4% to 73.8%]). In contrast, 1,347 participants (84.7% [95% CI 82.9% to 86.4%]) met the Sepsis-3 criteria for sepsis. Only 1,010 participants were both qSOFA positive and met the Sepsis-3 criteria for sepsis (63.5% [95% CI 61.1% to 65.8%]). The Sepsis-3 definition for septic shock was met at baseline by 203 participants (12.8% [95% CI 11.2% to 14.5%]), of whom 175 (86.2% [95% CI 81.5% to 91.0%]) were also qSOFA positive. Ninety-day mortality for participants fulfilling the Sepsis-3 criteria for sepsis and septic shock was 20.4% (95% CI 18.2% to 22.5%) (274/1,344) and 29.6% (95% CI 23.3% to 35.8% [60/203]) versus 9.4% (95% CI 5.8% to 13.1%) (23/244) and 17.1% (95% CI 15.1% to 19.1% [237/1,388]), respectively, for participants not meeting the criteria (risk differences 11.0% [95% CI 6.2% to 14.8%] and 12.5% [95% CI 6.3% to 19.4%], respectively). Conclusion: Most ARISE participants did not meet the Sepsis-3 definition for septic shock at baseline. However, the majority fulfilled the new sepsis definition and mortality was higher than for participants not fulfilling the criteria. A quarter of participants meeting the new sepsis definition did not fulfill the qSOFA screening criteria, potentially limiting its utility as a screening tool for sepsis trials with patients with suspected infection in the ED. The implications of the new definitions for patients not eligible for recruitment into the ARISE trial are unknown. [
FluDReSS is an open label randomised controlled clinical trial of three different dosing regimens... more FluDReSS is an open label randomised controlled clinical trial of three different dosing regimens of fludrocortisone in critically ill patients with septic shock compared to no fludrocortisone. The primary objective is to determine whether the combination of hydrocortisone plus fludrocortisone compared to hydrocortisone alone reduces time to shock reversal. This detailed statistical analysis plan (SAP) was written by the trial statistician and study investigators prior to unblinding.
Critical Care and Resuscitation
SSRN Electronic Journal, 2021
Background: Healthcare workers (HCWs),particularly from lower-middle income countries (LMIC), are... more Background: Healthcare workers (HCWs),particularly from lower-middle income countries (LMIC), are at high risk of acquiring COVID-19. Limited data exist on the effectiveness of hydroxychloroquine as prophylaxis. Our trial evaluated the effectiveness of a 12-week regimen of hydroxychloroquine among HCWs on the risk of laboratory-confirmed COVID-19 in the 6 months after randomization Methods: We conducted a multicentre parallel-group open-label randomized controlled trial in 9 centres across India. HCWs serving in an environment with exposure to COVID-19 were eligible and randomized in a 1:1 ratio to hydroxychloroquine plus standard practice or to standard practice alone (role-appropriate personal protective equipment). In the intervention arm, participants received 2 doses of 400mg hydroxychloroquine at randomization followed by a weekly dose for 12 weeks. The primary outcome was the proportion of laboratory-confirmed COVID-19 in the 6 months after randomization using an intention-to-treat analysis. The trial was registered on Clinical Trials Registry of India(CTRI/2020/05/025067). Findings: From 29th June 2020 to 4th February 2021, 886 participants were screened and 416 were randomized (203-standard practice and 213- hydroxychloroquine plus standard practice). In the 6 months after randomization (primary analysis population=413), 11 participants assigned to the hydroxychloroquine group and 12 participants assigned to the standard practice group met the primary end point[ 5.1% vs 5.9%; OR 0.85, [95% CI 0.35-2.06] p=0.71]. There was no heterogeneity of treatment effect on the primary outcome in any of the pre-specified subgroups. There were no significant differences in any of the secondary outcomes. The adverse event rates were 9.9% and 6.9% in the hydroxychloroquine and standard practice arms respectively. There were no serious adverse events in either group. Interpretation: Hydroxychloroquine along with standard practice was not superior to standard practice alone on the proportion of lab-confirmed COVID-19. However, conclusions are limited by the premature trial cessation. Trial Registration: Clinical Trials Registry of India (CTRI/2020/05/025067). Funding: Wesley Medical Research, Australia Declaration of Interest: OJ reports being a member of the WHO R&D Blueprint Safety Monitoring Team, ACT Acclerator-R&D Digital Health working group and COVID-19 Clinical Research Coalition data sharing working group. Remaining authors have nothing to declare. Ethical Approval: Written informed consent was obtained from all participants. The trial was approved by the Ethics Committee at all participating sites (coordinating centre EC approval number: The George Institute Ethics Committee:08-2020)
Intensive Care Medicine, 2021
To determine if adrenocortical gene expression is associated with clinical outcomes or response t... more To determine if adrenocortical gene expression is associated with clinical outcomes or response to corticosteroid treatment in septic shock. A pre-specified nested cohort study of a randomised controlled trial of hydrocortisone compared to placebo in septic shock. Blood was collected for RNAseq analysis prior to treatment with hydrocortisone or placebo. The expression of adrenocortical candidate genes related to pituitary releasing hormones, mineralocorticoid and glucocorticoid receptors, intracellular glucocorticoid metabolism and transport proteins was measured. From May 2014 to April 2017, 671 patients were enrolled in the nested cohort study, from which 494 samples were available for analysis. We found no evidence of an association between candidate gene expression levels and either 90-day mortality, 28-day mortality or time to shock reversal. We observed evidence of a significant interaction between expression and treatment group for time to shock reversal in two genes; GLCCI1 (HR 3.81, 95%CI 0.57–25.47 vs. HR 0.64, 95%CI 0.13–3.07 for hydrocortisone and placebo respectively, p for interaction 0.008) and BHSD1 (HR 0.55, 95%CI 0.28–1.09 vs. HR 1.32 95%CI 0.67–2.60, p for interaction 0.01). In patients with septic shock, there is no association between adrenocortical candidate gene expression and mortality. Patients with higher expression of GLCCI1 who received hydrocortisone achieved shock resolution faster than those receiving placebo; conversely, patients who had higher expression of BHSD1 who received hydrocortisone achieved shock resolution slower than those who received placebo. Variation in gene expression may be a mechanism for heterogeneity of treatment response to corticosteroids in septic shock.
The Lancet Global Health, 2021
Australian Critical Care, 2021
OBJECTIVE The aim of the study was to determine whether adjunctive hydrocortisone reduced healthc... more OBJECTIVE The aim of the study was to determine whether adjunctive hydrocortisone reduced healthcare expenditure and was cost-effective compared with placebo in New Zealand patients in the Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial. DESIGN This is a health economic analysis using data linkage to New Zealand Ministry of Health databases to determine resource use, costs, and cost-effectiveness for a 24-month period. SETTING The study was conducted in New Zealand. PARTICIPANTS AND INTERVENTION Patients with septic shock were randomised to receive a 7-day continuous infusion of 200 mg of hydrocortisone or placebo in the ADRENAL trial. MAIN OUTCOME MEASURES Healthcare expenditure was associated with all hospital admissions, emergency department presentations, outpatient visits, and pharmacy expenditure. Effectiveness outcomes included mortality at 6 months and 24 months and quality of life at 6 months. Cost-effectiveness outcomes were assessed with reference to quality-adjusted life years gained at 6 months and life years gained at 24 months. RESULTS Of 3800 patients in the ADRENAL trial, 419 (11.0%) were eligible, and 405 (96.7% of those eligible) were included. The mean total costs per patient over 24 months were $143,627 ± 100,890 and $143,772 ± 97,117 for the hydrocortisone and placebo groups, respectively (p = 0.99). Intensive care unit costs for the index admission were $50,492 and $62,288 per patient for the hydrocortisone and placebo groups, respectively (p = 0.09). The mean number of quality-adjusted life years gained at 6 months and mean number of life years gained at 24 months was not significantly different by treatment group, and the probability of hydrocortisone being cost-effective was 55% at 24 months. CONCLUSIONS In New Zealand, adjunctive hydrocortisone did not reduce total healthcare expenditure or improve outcomes compared with placebo in patients with septic shock.
Research and Practice in Thrombosis and Haemostasis, 2017
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Circulation, Oct 28, 2008
Kynurenine is produced when the enzyme indoleamine 2,3-dioxygenase (IDO) metabolises the essentia... more Kynurenine is produced when the enzyme indoleamine 2,3-dioxygenase (IDO) metabolises the essential amino acid tryptophan. IDO expression is induced in endothelial cells of resistance vessels when mice are infected with malaria (a model of systemic inflammation). These mice become hypotensive and treatment with 1-methyl-tryptophan, an IDO inhibitor, restores normal blood pressure. In vitro vessel function studies have shown that kynurenine acts as an endothelium-independent relaxant. Kynurenine contributes to the hypotension in human septic shock. Patients admitted to ICU with a diagnosis of septic shock (sepsis with hypotension not responsive to fluids) had serum levels of kynurenine and tryptophan measured throughout the course of their illness. Systemic IDO activity was inferred from the kynurenine/tryptophan ratio and was correlated with the degree of hypotension assessed as each patient’s inotrope requirements. The kynurenine/tryptophan ratio changed in parallel with the inotrope requirements in our c...
Intensive Care Medicine, 2011
Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine, 2019
BACKGROUND AND RATIONALE β-Lactam antibiotics display a time-dependent mechanism of action, with ... more BACKGROUND AND RATIONALE β-Lactam antibiotics display a time-dependent mechanism of action, with evidence suggesting improved outcomes when administering these drugs via continuous infusion compared with standard intermittent infusion. However, there is no phase 3 randomised controlled trial (RCT) evidence to support one method of administration over another in critically ill patients with sepsis. DESIGN AND SETTING The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 RCT to compare continuous infusion with standard intermittent infusion of β-lactam antibiotics in critically ill patients with sepsis. The study will be conducted in about 70 intensive care units (ICUs) in Australia, New Zealand, the United Kingdom, Belgium and selected other countries, from 2018 to 2021. PARTICIPANTS AND INTERVENTIONS BLING III will recruit 7000 critically ill patients with sepsis being treated with one of two β-lactam antibiotics (piperacillin-tazobactam or merop...
Australian Critical Care, 2005
Traditionally, intensive care unit (ICU) delirium was viewed as benign and was under-diagnosed in... more Traditionally, intensive care unit (ICU) delirium was viewed as benign and was under-diagnosed in the absence of ICU-appropriate screening tools. Research suggests that up to half of all ICU patients experiencing delirium will continue to do so after discharge to the ward, and half of those experiencing delirium in the ward will die within 1 year of delirium diagnosis. ICU-specific screening tools are now available. The purpose of this study was to identify the incidence of delirium in ICU and explore its associations to clinical factors and outcomes. A secondary aim was to evaluate the usefulness of the intensive care delirium screening checklist (ICDSC). A total of 185 patients in six ICUs in Australia and New Zealand were screened for delirium using the ICDSC over two 12-hour periods per day for the duration of their ICU admission. Some 84 patients (45%) developed delirium. Development of delirium was associated with increased severity of illness (acute physiology and chronic hea...
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Papers by Dorrilyn Rajbhandari