[Show abstract][Hide abstract] ABSTRACT: Objectives:
To determine the effect of two doses of intramuscular cholecalciferol on serial serum 25-hydroxy-vitamin-D levels and on pharmacodynamics endpoints: calcium, phosphate, parathyroid hormone, C-reactive protein, interleukin-6, and cathelicidin in critically ill adults.
Prospective randomized interventional study.
Tertiary, academic adult ICU.
Fifty critically ill adults with the systemic inflammatory response syndrome.
Patients were randomly allocated to receive a single intramuscular dose of either 150,000 IU (0.15 mU) or 300,000 IU (0.3 mU) cholecalciferol.
Measurements and main results:
Pharmacokinetic, pharmacodynamic parameters, and outcome measures were collected over a 14-day period or until ICU discharge, whichever was earlier. Prior to randomization, 28 of 50 patients (56%) were classified as vitamin D deficient. By day 7 after randomization, 15 of 23 (65%) and 14 of 21 patients (67%) normalized vitamin D levels with 0.15 and 0.3 mU, respectively (p = 0.01) and by day 14, 8 of 10 (80%) and 10 of 12 patients (83%) (p = 0.004), respectively. Secondary hyperparathyroidism was manifested in 28% of patients at baseline. Parathyroid hormone levels decreased over the study period with patients achieving vitamin D sufficiency at day 7 having significantly lower parathyroid hormone levels (p < 0.01). Inflammatory markers (C-reactive protein and interleukin-6) fell significantly over the study period. Greater increments in 25-hydroxy-vitamin-D were significantly associated with greater increments in cathelicidin at days 1 and 3 (p = 0.04 and 0.004, respectively). Although in-hospital mortality rate did not differ between the groups, patients who did not mount a parathyroid hormone response to vitamin D deficiency had a higher mortality (35% vs 12%; p = 0.05). No significant adverse effects were observed.
A single dose of either dose of intramuscular cholecalciferol corrected vitamin D deficiency in the majority of critically ill patients. Greater vitamin D increments were associated with early greater cathelicidin increases, suggesting a possible mechanism of vitamin D supplementation in inducing bactericidal pleiotropic effects.
Critical care medicine 07/2015; 43(11). DOI:10.1097/CCM.0000000000001201 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Measurements of total plasma cortisol (TPC) in the acute phase of aneurysmal subarachnoid haemorrhage (aSAH) have suggested a high incidence of adrenal insufficiency (AI).
To compare TPC and free plasma cortisol (FPC) measurements in acute aSAH and to assess whether rates of diagnosis of AI based on TPC and FPC criteria were discordant.
A prospective, observational study of 20 patients admitted within 7 days of aSAH to a tertiary intensive care unit. Cortisol binding globulin (CBG), TPC and FPC levels were measured at baseline, and cortisol profiles at 30 and 60 minutes after administration of 250_g corticotropin.
Compared with controls, the mean baseline FPC (46nmol/L [SD, 48 nmol/L] v 9nmol/L [SD, 6nmol/L], P <0.0001), and TPC (566 nmol/L [SD, 288 nmol/L] v 352 nmol/L [SD, 146nmol/L], P=0.01) were significantly elevated with a greater proportional increase of FPC over TPC (6 v 1.2 times, P <0.0001). The relative increment of FPC compared with TPC in the patient group was 505% v 114% (P <0.0001) and in the control group was 662% v 145% (P <0.0001). The prevalence of AI, measured using TPC compared with FPC, was 30% v 0% (P=0.04).
In the acute phase after aSAH, the FPC increase is fivefold greater than that of TPC. There is discordance between TPC and FPC responses to corticotropin. The prevalence of AI, as assessed by FPC measurements, is negligible. We advocate caution in the assessment of adrenal cortical function using measurements of TPC in this population.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 03/2015; 17(1):37-42. · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vitamin D is recognized to have important actions outside its well-recognized role in musculoskeletal health. These include antimicrobial action, anti-inflammatory, and cardio-protective properties. A high prevalence of vitamin D deficiency and its association with adverse clinical outcomes have now been widely documented in observational studies in the critically ill. These studies of association, however, do not necessarily imply causation, as vitamin D deficiency may be merely a marker of higher illness severity and consequently poorer outcomes. This issue can be clarified only by undertaking high-quality randomized controlled trials of vitamin D supplementation in this vulnerable population.
[Show abstract][Hide abstract] ABSTRACT: We studied the association between admission serum 25-hydroxy vitamin D3 level and in-hospital mortality in a prospective cohort of critically ill patients admitted to the medical intensive care unit of a tertiary care referral center. Of the 180 patients enrolled, 129 were included. Vitamin D3 deficiency was observed in 37 % (n = 48) and supra-physiological levels (≥250 nmol/L) in 15.5 % (n = 20). Patients with supraphysiological vitamin D3 levels were grouped as outliers. There was no difference in mortality (p = 0.41) between vitamin D3 deficient (21/48) and non-deficient (36/81) patients in analysis with and without outliers. Patients with vitamin D3
≥250 nmol/L had a significantly higher (p = 0.02) Simplified Acute Physiology Score (SAPS) II and mortality (p = 0.003) [mean (SD) 60.1 ± 17.1 and 75 % (15/20), respectively] when compared with the rest [45.6 ± 18 and 38.5 % (42/109), respectively]. The sensitivity, specificity and SAPS II independent odds ratio to predict mortality in patients with supraphysiological vitamin D3 levels were 26.3, 93.1 and 3.7 % (95 % confidence interval 1.2–11.4; p = 0.03), respectively. In conclusion, vitamin D3 deficiency in our cohort was not associated with mortality. A patient subset with supra-physiological vitamin D levels had higher illness severity scores and mortality. Extrinsic factors interfering with test results were ruled out. A biological hypothesis to explain this observation is proposed. Further clarification of mechanisms leading to this observation is warranted.
Journal of Bone and Mineral Metabolism 04/2014; 33(2). DOI:10.1007/s00774-014-0585-7 · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the use of high-fidelity simulation for summative high-stakes assessment of intensive care trainees, focusing on non-technical skills (NTS), testing feasibility and acceptability of simulation assessment, and the reliability of two NTS rating scales.
Prospective observational study of senior intensive care trainees in a simulated specialist examination.
Participants undertook a simulated patientmanagement scenario and were assessed using two rating scales: the Anaesthesia Non-technical Skills (ANTS) scale and the Ottawa Global Rating Scale (GRS). Assessors were trained, currently active, high-stakes examiners. Participants also completed a survey on simulation-based summative assessment.
The inter-rater reliability of two rating scales for NTS assessment. We evaluated the feasibility of simulation-based assessment, and used survey results to assess acceptability to participants.
Simulation assessment was feasible. Participants considered simulation-based high-stakes assessment to be acceptable and felt their scenario performance was reflective of real-world performance. Participants identified a need for debriefing following scenario-based assessment. Inter-rater reliability was fair for the ANTS and Ottawa GRS scores (intra-class correlation coefficient, 0.39 and 0.42, respectively). There was only fair agreement between raters for an NTS pass or fail (weighted kappa, 0.32) and for a technical skills pass or fail (weighted kappa, 0.36).
Summative high-stakes assessment using a single simulated scenario was feasible and acceptable to senior intensive care trainees. The low inter-rater reliability for the ANTS and Ottawa GRS rating scales and for pass or fail discrimination may limit its incorporation into an existing examination format.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 03/2014; 16(1):6-12. · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Statins have become the most widely used drugs for lowering cholesterol levels worldwide. At least 20 % of patients requiring admission to hospital are on established statin therapy, and this proportion is growing each year. Evidence from observational studies and basic science research suggests that statins might be associated with a reduced mortality in sepsis. Randomized trials are producing equivocal results but have not shown the marked improvement in outcome suggested by the observational studies. Continued use in current statin users appears a more fruitful area for future research than statin use de novo as an adjuvant therapy in sepsis. Statin use in patients with pneumonia, acute lung injury or early sepsis warrants further study. International practice of statin use in critically ill patients is variable, and potential toxicity mandates careful monitoring. Further studies are required to address fundamental issues such as efficacy, potential target patient populations, dose, class equivalence and safety.
Current Atherosclerosis Reports 01/2014; 16(1):378. DOI:10.1007/s11883-013-0378-9 · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patient safety can be improved by redesigning how medication and bedside equipment is stored in the intensive care unit (ICU). Grundgeiger (2011) noted that an ICU emergency bedside drawer often was not fully stocked. He used human factors principles to design an illustrated and divided drawer that significantly improved drawer restocking compliance and is still in use in the ICU. In two studies we set out to clarify exactly why Grundgeiger’s redesign succeeded. In Experiment 1 we tested the redesigned vs. old drawer design using stationery contents and psychology student participants. In Experiment 2 we used the tests developed in Experiment 1 to compare ICU nurses’ performance with the redesigned vs. old drawer design. Both experiments indicate that the divided and illustrated drawer leads to faster restocking times and overwhelmingly positive user acceptance.
[Show abstract][Hide abstract] ABSTRACT: Vitamin D deficiency, as measured by a random level of 25-hydroxyvitamin D is very prevalent in critically ill patients admitted to the ICU and is associated with adverse outcomes. Both 25(OH)vitamin D and 1α,25(OH)2D3 are difficult to analyse because of their lipophilic nature, affinity for VDBP and small concentrations. Also, the various tests used to estimate vitamin D levels show significant inter- and intra-assay variability, which significantly affect the veracity of the results obtained and confound their interpretation. The two main types of assays include those that directly estimate vitamin D levels (HPLC, LC-MS/MS) and competitive binding assays (RIA, EIA). The former methods require skilled operators, with prolonged assay times and increased cost, whereas the latter are cheaper and easy to perform, but with decreased accuracy. The direct assays are not affected by lipophilic substances in plasma and heterophile antibodies, but may overestimate vitamin D levels by measuring the 3-epimers. These problems can be eliminated by adequate standardization of the test using SRMs provided by NIST, as well as participating in proficiency schemes like DEQAS. It is therefore important to consider the test employed as well as laboratory quality control, while interpreting vitamin D results. A single random measurement may not be reflective of the vitamin D status in ICU patients because of changes with fluid administration, and intra-day variation in 25-hydroxyvitamin D levels. 1α,25(OH)2D3 may behave differently to 25-hydroxyvitamin D, both in plasma and at tissue level, in inflammatory states. Measurement of tissue 1α,25(OH)2D3 levels may provide the true estimate of vitamin D activity.
[Show abstract][Hide abstract] ABSTRACT: There is considerable global uncertainty on the role of low-dose corticosteroids in septic shock, which translates into variations in prescribing practices.
To describe the protocol for a large-scale multicentre randomised controlled trial in critically ill patients with septic shock, comparing the effects of hydrocortisone and placebo (in addition to standard treatment) on 90-day mortality and other outcomes such as shock reversal, duration of mechanical ventilation and quality of life.
We will recruit 3800 critically ill patients with septic shock treated in an intensive care unit, to concealed, randomised, parallel assignment of hydrocortisone or placebo. The primary outcome will be all-cause mortality at 90 days postrandomisation. Secondary outcomes will include ICU and hospital mortality, length of ICU stay and quality of life at 6 months. Subgroup analyses will be conducted in two predefined subgroups. All analyses will be conducted on an intention-to-treat basis.
The run-in phase has been completed and the main trial commenced in February 2013. The trial should generate results that will inform and influence prescribing of corticosteroids in septic shock.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 06/2013; 15(2):83-8. · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CONTEXT: The anti-inflammatory role of adiponectin has prompted interest in a potential role in acute inflammatory conditions associated with critical illness. It is unclear whether a random adiponectin measurement adequately reflects the 24 hr profile in critically ill patients. OBJECTIVE: To assess the temporal profile of total and high-molecular weight (HMW) adiponectin and Interleukin-6 (IL-6) in 15 critically ill patients. DESIGN: A prospective, observational study. SETTING: Level II intensive care unit in a metropolitan hospital. PATIENTS OR OTHER PARTICIPANTS: Fifteen critically ill patients expected to stay in the ICU for longer than 48h were eligible for enrolment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serial, hourly measurements of total and HMW adiponectin and IL-6. RESULTS: Over a 24h period, total and HMW adiponectin display considerable within-patient variability, (coefficient of variation 34% and 87% respectively) and show no trend over time. Averaging 2 or 3 continuous measures reduced within patient variability of both total and HMW adiponectin by up to 50% compared to 1 measure. There was a negative correlation between serum glucose and adiponectin (total p=0.016, HMW p=0.039). No relationship existed between adiponectin and IL-6 (total p=0.62, HMW p=0.35). CONCLUSIONS: Marked within patient hourly variability in total and HMW adiponectin is evident in critically ill patients. A random measurement may not be reflective of the 24-hour profile in these patients. A negative correlation exists between adiponectin and blood glucose levels and a positive correlation between adiponectin and oxygen saturation. No clear relationship exists between adiponectin and IL-6. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Despite the potential dangers of clinical tasks being forgotten, few researchers have investigated prospective memory (PM) - the ability to remember to execute future tasks - in health-care contexts. Visual cues help people remember to execute intentions at the appropriate moment. Using an intensive care unit simulator, we investigated whether nurses' memory for future tasks improves when visual cues are present, and how nurses manage PM demands. Twenty-four nurses participated in a 40-minute scenario simulating the start of a morning shift. The scenario included eight PM tasks. The presence or absence of a visually conspicuous cue for each task was manipulated. The presence of a visual cue improved recall compared to no cue (64% vs. 50%, p = 0.03 one-tailed, η(p)(2) = 0.15). Nurses used deliberate reminders to manage their PM demands. PM in critical care might be supported by increasing the visibility of cues related to tasks.
Nurses must remember to execute multiple future tasks to ensure patient safety. We investigated the effect of visual cues on nurses' ability to remember future tasks. Experimental manipulation of cues in a representative intensive care unit simulation indicated that visual cues increase the likelihood that future tasks are executed.
[Show abstract][Hide abstract] ABSTRACT: Bolus dose concentrations of hydrocortisone (50mg/mL) are reported to be incompatible with midazolam and ciprofloxacin in Y-site mixing studies. We evaluated the physical and chemical compatibility of low concentrations of hydrocortisone sodium succinate (1 mg/ mL) with midazolam (1 mg/mL and 2mg/mL) and ciprofloxacin (2 mg/mL) solutions during a simulated Y-site administration study.
The midazolam 1mg/mL, midazolam 2mg/mL and ciprofloxacin 2mg/mL solutions were individually combined with hydrocortisone sodium succinate 1mg/mL solution in a 1:1 ratio and tested in triplicate. Physical compatibility was evaluated using a previously described method immediately on mixing, after 60 minutes and after 120 minutes. Chemical compatibility was determined by measuring the hydrocortisone sodium succinate concentration of the test solutions 120 minutes after mixing compared with that of a reference sample of hydrocortisone sodium succinate solution.
At all time points, when hydrocortisone was mixed with midazolam (1 mg/mL and 2mg/mL) and ciprofloxacin (2 mg/mL), the solutions remained clear, with no haziness, colour change, gas or precipitate formation, thus showing total physical compatibility. There were pharmacologically significant reductions (>10%) in measured hydrocortisone concentration (18.6% with midazolam 2mg/mL, P = 0.06; and 21.3% with ciprofloxacin, P = 0.01) in all of the test samples, as compared with the reference sample.
According to currently recommended criteria, combining hydrocortisone sodium succinate at a concentration of 1mg/mL with a 1mg/mL solution of midazolam appears to be both chemically and physically compatible. However, mixing 1mg/mL hydrocortisone sodium succinate with 2mg/mL midazolam or with 2mg/ mL ciprofloxacin cannot be recommended.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 03/2013; 15(1):67. · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the agreement between two methods of measurement of plasma free cortisol in acutely ill patients; an indirect method using the Coolens equation, and direct measurement using high-performance liquid chromatography-tandem mass spectrometry, which is the gold standard.
Prospective observational study among patients with septic shock in a tertiary intensive care unit and patients with liver failure attending a hospital outpatient clinic while awaiting transplantation. Paired values of free cortisol levels obtained from direct measurement and from calculation were analysed to provide estimates of bias and precision for the two methods.
Free and total plasma cortisol and corticosteroid binding globulin concentrations.
102 samples were analysed. The overall bias was -17%± 50%, with 95% limits of agreement of - 115% to 80%. Bias was noted to be greater in specimens with higher albumin concentration, and was proportional to free cortisol concentration.
The observed bias between the two methods is of a magnitude that would be expected to produce clinically relevant discrepancies. Due to the proportional nature of the error, adding a correction factor is not feasible. Results obtained from using the Coolens method to calculate free cortisol concentration in acutely ill patients should be interpreted with caution.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 03/2013; 15(1):39-41. · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: RATIONALE: Observational studies link statin therapy with improved outcomes in patients with severe sepsis. OBJECTIVES: To test whether atorvastatin therapy affects biological and clinical outcomes in critically ill patients with severe sepsis. METHODS: Phase II, multicenter, prospective, randomized, double-blind, placebo controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo. MEASUREMENTS AND MAIN RESULTS: There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (p=0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (p= 0.26). Baseline plasma IL-6, was lower among previous statin users [129(87-191) vs. 244 (187-317) pg/ml, p=0.01]. There was no difference in length of stay, change in SOFA scores or mortality at ICU discharge, hospital discharge, 28 days or 90 days (15 vs. 19%) or adverse effects between the two groups. Cholesterol was lower in atorvastatin treated patients [2.4(0.07) vs. 2.6(0.06) mmol/L, p=0.006]. In the pre -defined group of 77 prior statin users, those randomised to placebo had a greater 28 day mortality (28% vs.5%, P=0.01) compared to those who received atorvastatin. The difference was not statistically significant at 90 days (28 vs. 11%, p=0.06) CONCLUSIONS: Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival. Clinical trial registration information available at http://www.anzctr.org.au, i.d. = ACTRN12607000028404.
American Journal of Respiratory and Critical Care Medicine 01/2013; 187(7). DOI:10.1164/rccm.201209-1718OC · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The recent recognition of the myriad roles of vitamin D beyond those of bone health and calcium homoeostasis has resulted in a large body of clinical studies demonstrating an association between vitamin D deficiency and a number of adverse health outcomes. While these studies in chronic disease states have shown a strong association between vitamin D deficiency and poor outcomes, they have been unable to demonstrate cause and effect. Several studies to date have demonstrated a high prevalence of vitamin D deficiency in critically ill patients, and some of these have shown an association with poor outcomes. It is possible that low vitamin D levels may contribute to the acute multiorgan dysfunction seen in critical illness by similar mechanisms to those seen in chronic conditions. In this commentary, we briefly review the physiology of vitamin D, examine the evidence for association of hypovitaminosis with poor outcome in both ambulatory and intensive care unit patients, and debate the role of routine vitamin D supplementation in the ICU.
Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 12/2012; 14(4):268-73. · 2.01 Impact Factor