A pilot feasibility randomised controlled trial of bone antiresorptive agents on bone turnover markers in critically ill women.

Critical illness is associated with increased bone turnover, loss of bone density, and increased risk of fragility fractures. The impact of bone antiresorptive agents in this population is not established. This trial examined the efficacy, feasibility, and safety of antiresorptive agents administered to critically ill women aged fifty years or greater. Women aged 50 years or greater admitted to an intensive care unit for at least 24 h were randomised to receive an antiresorptive agent (zoledronic acid or denosumab) or placebo, during critical illness and six months later (denosumab only). Bone turnover markers and bone mineral density (BMD) were monitored for 1 year. We studied 18 patients over 35 months before stopping the study due to the COVID-19 pandemic. Antiresorptive medications decreased the bone turnover marker type 1 cross-linked c-telopeptide (CTX) from day 0 to 28 by 43% (± 40%), compared to an increase of 26% (± 55%) observed with placebo (absolute difference - 69%, 95% CI - 127% to - 11%), p = 0.03). Mixed linear modelling revealed differences in the month after trial drug administration between the groups in serum CTX, alkaline phosphatase, parathyroid hormone, and phosphate. Change in BMD between antiresorptive and placebo groups was not statistically analysed due to small numbers. No serious adverse events were recorded. In critically ill women aged 50-years and over, antiresorptive agents suppressed bone resorption markers without serious adverse events. However, recruitment was slow. Further phase 2 trials examining the efficacy of these agents are warranted and should address barriers to enrolment.Trial registration: ACTRN12617000545369, registered 18th April 2017.

Study protocol for TARGET protein: The effect of augmented administration of enteral protein to critically ill adults on clinical outcomes: A cluster randomised, cross-sectional, double cross-over, clinical trial.

Background: It is unknown whether increasing dietary protein to 1.2-2.0 g/kg/day as recommended in international guidelines compared to current practice improves outcomes in intensive care unit (ICU) patients. The TARGET Protein trial will evaluate this. Objective: To describe the study protocol for the TARGET Protein trial. Design setting and participants: TARGET Protein is a cluster randomised, cross-sectional, double cross-over, pragmatic clinical trial undertaken in eight ICUs in Australia and New Zealand. Each ICU will be randomised to use one of two trial enteral formulae for three months before crossing over to the other formula, which is then repeated, with enrolment continuing at each ICU for 12 months. All patients aged ≥16 years in their index ICU admission commencing enteral nutrition will be eligible for inclusion. Eligible patients will receive the trial enteral formula to which their ICU is allocated. The two trial enteral formulae are isocaloric with a difference in protein dose: intervention 100g/1000 ml and comparator 63g/1000 ml. Staggered recruitment commenced in May 2022. Main outcomes measures: The primary outcome is days free of the index hospital and alive at day 90. Secondary outcomes include days free of the index hospital at day 90 in survivors, alive at day 90, duration of invasive ventilation, ICU and hospital length of stay, incidence of tracheostomy insertion, renal replacement therapy, and discharge destination. Conclusion: TARGET Protein aims to determine whether augmented enteral protein delivery reduces days free of the index hospital and alive at day 90. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12621001484831).

"Likely overassistance" during invasive pressure support ventilation in patients in the intensive care unit: a multicentre prospective observational study.

OBJECTIVE: To evaluate the prevalence of "likely overassistance" (categorised by respiratory rate [RR] ≤ 17 breaths/min or rapid shallow breathing index [RSBI] ≤ 37 breaths/min/L) during invasive pressure support ventilation (PSV), and the additional prevalence of fixed ventilator settings. DESIGN: Multicentre prospective observational study of invasive PSV practice in six general Victorian intensive care units with blinding of staff members to data collection. PATIENTS: At each hospital, investigators collected data between 11 am and 2 pm on all invasive PSV-treated patients on 60 sequential days, excluding weekends and public holidays, between 22 February and 30 August 2017. Each patient was included for maximum of 3 days. MAIN RESULTS: We studied 231 patients, with a total of 379 observations episodes over the study period. There were 131 patients (56.7%) with at least one episode of RR ≤ 17 breaths/min; 146 patients (63.2%) with at least one episode of RSBI ≤ 37 breaths/min/L, and 85 patients (36.8%) with at least one episode of combined RR ≤ 17 breaths/min and RSBI ≤ 37 breaths/min/L. Moreover, the total number of observations with "likely overassistance" (RR ≤ 17 or RSBI ≤ 37 breaths/min/L) was 178 (47%) and 204 (53.8%), respectively; while for both combined criteria, it was 154 (40.6%). We also found that 10 cmH2O pressure support was delivered on 210 of the observations (55.4%) and adjusted in less than 25% of observations. Finally, less than half (179 observations) of all PSV-delivered tidal volumes (VT) were at the recommended value of 6-8 mL/kg predicted body weight (PBW) and more than 20% (79 observations) were at ≥ 10 mL/kg PBW. CONCLUSION: In a cohort of Victorian hospitals in Australia, during invasive PSV, "likely overassistance" was common, and the pressure support level was delivered in a standardised and unadjusted manner at 10 cmH2O, resulting in the frequent delivery of potentially injurious VT.

Intensity of early correction of hyperglycaemia and outcome of critically ill patients with diabetic ketoacidosis.

OBJECTIVES: To determine the impact of the intensity of early correction of hyperglycaemia on outcomes in patients with diabetic ketoacidosis (DKA) admitted to the intensive care unit. METHODS: We studied adult patients with DKA admitted to 171 ICUs in Australia and New Zealand from 2000 to 2013. We used their blood glucose levels (BGLs) in the first 24 hours after ICU admission to determine whether intensive early correction of hyperglycemia to ≤ 180 mg/dL was independently associated with hypoglycaemia, hypokalaemia, hypo-osmolarity or mortality, compared with partial early correction to > 180 mg/dL as recommended by DKA-specific guidelines. RESULTS: Among 8553 patients, intensive early correction of BGL was applied to 605 patients (7.1%). A greater proportion of these patients experienced hypoglycaemia (20.2% v 9.1%; P < 0.001) and/or hypo-osmolarity (29.4% v 22.0%; P < 0.001), but not hypokalaemia (16.7% v 15.6%; P = 0.47). Overall, 11 patients (1.8%) in the intensive correction group and 112 patients (1.4%) in the partial correction group died (P = 0.42). However, after adjustment for illness severity, partial early correction of BGL was independently associated with a lower risk of hypoglycaemia (odds ratio [OR], 0.38; 95% CI, 0.30-0.48; P < 0.001), lower risk of hypo-osmolarity (OR, 0.80; 95% CI, 0.65-0.98; P < 0.03) and lower risk of death (OR, 0.44; 95% CI, 0.22-0.86; P = 0.02). CONCLUSIONS: In a large cohort of patients with DKA, partial early correction of BGL according to DKA-specific guidelines, when compared with intensive early correction of BGL, was independently associated with a lower risk of hypoglycaemia, hypo-osmolarity and death.