A Randomized Noninferiority Trial to Compare Enteral to Parenteral Phosphate Replacement on Biochemistry, Waste, and Environmental Impact and Healthcare Cost in Critically Ill Patients With Mild to Moderate Hypophosphatemia.

OBJECTIVES: Hypophosphatemia occurs frequently. Enteral, rather than IV, phosphate replacement may reduce fluid replacement, cost, and waste. DESIGN: Prospective, randomized, parallel group, noninferiority clinical trial. SETTING: Single center, 42-bed state trauma, medical and surgical ICUs, from April 20, 2022, to July 1, 2022. PATIENTS: Patients with serum phosphate concentration between 0.3 and 0.75 mmol/L. INTERVENTIONS: We randomized patients to either enteral or IV phosphate replacement using electronic medical record-embedded program. MEASUREMENT AND MAIN RESULTS: Our primary outcome was serum phosphate at 24 hours with a noninferiority margin of 0.2 mmol/L. Secondary outcomes included cost savings and environmental waste reduction and additional IV fluid administered. The modified intention-to-treat cohort comprised 131 patients. Baseline phosphate concentrations were similar between the two groups. At 24 hours, mean ( sd ) serum phosphate concentration were enteral 0.89 mmol/L (0.24 mmol/L) and IV 0.82 mmol/L (0.28 mmol/L). This difference was noninferior at the margin of 0.2 mmol/L (difference, 0.07 mmol/L; 95% CI, -0.02 to 0.17 mmol/L). When assigned IV replacement, patients received 408 mL (372 mL) of solvent IV fluid. Compared with IV replacement, the mean cost per patient was ten-fold less with enteral replacement ($3.7 [$4.0] vs. IV: $37.7 [$31.4]; difference = $34.0 [95% CI, $26.3-$41.7]) and weight of waste was less (7.7 g [8.3 g] vs. 217 g [169 g]; difference = 209 g [95% CI, 168-250 g]). C O2 emissions were 60-fold less for comparable phosphate replacement (enteral: 2 g producing 14.2 g and 20 mmol of potassium dihydrogen phosphate producing 843 g of C O2 equivalents). CONCLUSIONS: Enteral phosphate replacement in ICU is noninferior to IV replacement at a margin of 0.2 mmol/L but leads to a substantial reduction in cost and waste.

Feasibility of Embedding a Randomised Clinical Trial (RCT) into an Electronic Medical Record (EMR) for Patients Admitted to an Intensive Care Unit (ICU).

To establish the feasibility of embedding an RCT into EMR in the ICU, we evaluated the route of phosphate replacement. The EMR screened 207 patients who met the inclusion criteria from 20 April 2022 to 30 June 2022. 162 patients were randomised and 145 patients allocated to treatment. Our study showed that it was feasible to embed screening, randomisation, and treatment allocation for an RCT within an EMR in the ICU.

Aggression, violence and threatening behaviour during critical illness.

Objective: This article aims to quantify prevalence of patient aggression or threatened/actual violence during critical illness. Design: This is a retrospective cohort study. Setting: This study was conducted in single adult trauma intensive care unit (ICU). Participants: Patients aged 18 years or over, admitted between January 2015 and December 2020, who triggered a "Code Grey" response due to aggression or threatened/actual violence. Main outcome measure: The primary outcome was prevalence of Code Grey events. Secondary outcomes included unadjusted and adjusted (logistic mixed model) effects of patient demographics, diagnoses and severity of illness on Code Grey events. Results: There were 16175 ICU admissions relating to 14085 patients and 807 Code Grey events involving 379 (2.7%) patients. The observed count of events increased progressively from 2015 (n = 77) to 2020 (n = 204). For patients with a Code Grey, the median count of events was 3 (range 1-33). Independent predictors of at least one ICU Code Grey event included male sex (OR 2.5; 95% CI 1.8 to 3.4), young age (most elevated odds ratio in patients 20-30 years), admission from the emergency department (OR 2.8, 95% CI 2.1 to 3.6) and a trauma diagnosis (OR 1.4, 95% CI 1.1 to 1.9). Code Grey patients had longer admissions with a reduced risk of death. Conclusions: The prevalence of Code Grey events in ICU appears to be increasing. Patients may have repeated events. Younger male patients admitted to ICU via the emergency department with a trauma or medical diagnosis are at greatest risk of a Code Grey event.

Precision-based approaches to delirium in critical illness: A narrative review.

Delirium occurs in critical illness and is associated with poor clinical outcomes, having a longstanding impact on survivors. Understanding the complexity of delirium in critical illness and its deleterious outcome has expanded since early reports. Delirium is a culmination of predisposing and precipitating risk factors that result in a transition to delirium. Known risks range from advanced age, frailty, medication exposure or withdrawal, sedation depth, and sepsis. Because of its multifactorial nature, different clinical phenotypes, and potential neurobiological causes, a precise approach to reducing delirium in critical illness requires a broad understanding of its complexity. Refinement in the categorization of delirium subtypes or phenotypes (i.e., psychomotor classifications) requires attention. Recent advances in the association of clinical phenotypes with clinical outcomes expand our understanding and highlight potentially modifiable targets. Several delirium biomarkers in critical care have been examined, with disrupted functional connectivity being precise in detecting delirium. Recent advances reinforce delirium as an acute, and partially modifiable, brain dysfunction, and place emphasis on the importance of mechanistic pathways including cholinergic activity and glucose metabolism. Pharmacologic agents have been assessed in randomized controlled prevention and treatment trials, with a disappointing lack of efficacy. Antipsychotics remain widely used after "negative" trials, yet may have a role in specific subtypes. However, antipsychotics do not appear to improve clinical outcomes. Alpha-2 agonists perhaps hold greater potential for current use and future investigation. The role of thiamine appears promising, yet requires evidence. Looking forward, clinical pharmacists should prioritize the mitigation of predisposing and precipitating risk factors as able. Future research is needed within individual delirium psychomotor subtypes and clinical phenotypes to identify modifiable targets that hold the potential to improve not only delirium duration and severity, but long-term outcomes including cognitive impairment.

Relationship of blood thiamine pyrophosphate to plasma phosphate and the response to enteral nutrition plus co-administration of intravenous thiamine during critical illness.

BACKGROUND: Hypovitamin B1 occurs frequently during critical illness but is challenging to predict or rapidly diagnose. The aim of this study was to evaluate whether plasma phosphate concentrations predict hypovitamin B1, enteral nutrition prevents hypovitamin B1 and intravenous thiamine supplementation achieves supraphysiological concentrations in critically ill patients. METHODS: Thirty-two enterally fed critically ill patients, with a plasma phosphate concentration ≤0.65 mmol/L, formed a nested cohort within a larger randomised clinical trial. Patients were assigned to receive intravenous thiamine (200 mg) twice daily, and controls were not administered intravenous thiamine. Thiamine pyrophosphate concentrations were measured at four time points (pre- and post-infusion and 4- and 6-h post-infusion) on days 1 and 3 in those allocated to thiamine and once in the control group. RESULTS: Baseline thiamine pyrophosphate concentrations were similar (intervention 88 [67, 93] vs. control 89 [62, 110] nmol/L, p = 0.49). Eight (25%) patients had hypovitamin B1 (intervention 3 vs. control 5), with two patients in the control group remaining insufficient at day 3. There was no association between baseline phosphate and thiamine pyrophosphate concentrations. Intravenous thiamine achieved supraphysiological concentrations 6 h post first infusion, with concentrations increasing to day 3. In the control group, thiamine pyrophosphate concentrations were not statistically different between baseline and day 3 (mean change: 8.6 [-6.0, 23.1] nmol/L, p = 0.25). CONCLUSIONS: Phosphate concentrations did not predict hypovitamin B1, which was observed in 25% of the participants. Enteral nutrition alone prevented the development of new hypovitamin B1. Administration of a single 200-mg dose of intravenous thiamine achieved supraphysiological concentrations of thiamine pyrophosphate, with repeated dosing sustaining this effect.

Clearance of Piperacillin-Tazobactam and Vancomycin During Continuous Renal Replacement With Regional Citrate Anticoagulation.

BACKGROUND: The use of regional citrate anticoagulation during continuous venovenous hemodiafiltration (CVVHDF) has increased worldwide. However, data on its effect on the pharmacokinetics of antibiotics are limited. In this study, the authors aimed to measure the clearance of piperacillin-tazobactam and vancomycin in patients receiving CVVHDF with regional citrate anticoagulation. METHODS: This study measured piperacillin-tazobactam and vancomycin concentrations in patients receiving CVVHDF with regional citrate anticoagulation. Dosing regimens were independently selected by intensivists. Arterial blood and effluent fluid samples were obtained over a single dosing interval and analyzed using ultra-high-performance liquid chromatography with tandem mass spectrometry. RESULTS: Seventeen sampling intervals in 15 patients (9 receiving piperacillin-tazobactam only, 4 receiving vancomycin only, and 2 receiving both) were used. The median overall clearance for piperacillin was 35.2 mL/min [interquartile range (IQR): 32.2-38.6], 70 mL/min (IQR: 62.7-76.2) for tazobactam, and 29.5 mL/min (IQR: 26.2-32) for vancomycin. CONCLUSIONS: This is the first study to quantify the pharmacokinetics of vancomycin and piperacillin-tazobactam in patients receiving CVVHDF with regional citrate anticoagulation. These results indicate high clearance and provide key information to guide optimal dosing.

Administration of pharmacological sleep aids prior to, during and following critical illness.

BACKGROUND: Sleep in the intensive care unit (ICU) is frequently disturbed and this may have a detrimental effect on recovery. AIM: To determine the use of pharmacological sleep aids in critically ill patients prior to, during and after ICU admission. METHODS: We conducted a single-centre period prevalence study of all adult patients admitted to a university-associated adult medical-surgical ICU for more than two nights in a 3-month period ending September 2019. The major outcome of interest was the proportion of ICU patients who had a pharmacological sleep aid administered prior to, during and after ICU admission. Associations of selected patient variables with sleep aid prescription in the ICU were summarised both as unadjusted univariable comparisons and as adjusted effect estimates returned by a multivariable logistic regression model. RESULTS: During the study period, 370 patients met all eligibility criteria. A pharmacological sleep aid was identified prior to hospital admission in 34 (9%) patients and in 62 (17%) patients during ICU admission. Of the 340 ICU survivors, 292 remained in the same hospital. Of these, 96 (33%) received a pharmacological sleep aid at least once during their post-ICU general hospital ward stay. Pre-hospital sleep aid use, male sex, longer ICU admission and higher APACHE (Acute Physiology and Chronic Health Evaluation) III scores were associated with sleep aid prescription in the ICU. CONCLUSIONS: Pharmacological sleep aids are administered frequently in the ICU with administration increasing substantially after ICU discharge.

A microcosting analysis of ICU expenditure in the interval between brain death and organ donation.

Objective: The cost of providing care in an intensive care unit (ICU) after brain death to facilitate organ donation is unknown. The objective of this study was to estimate expenditure for the care delivered in the ICU between the diagnosis of brain death and subsequent organ donation. Design: Cohort study of direct and indirect costs using bottom-up and top-down microcosting techniques. Setting: Single adult ICU in Australia. Participants: All patients who met criteria for brain death and proceeded to organ donation during a 13-month period between 1 January 2018 and 31 January 2019. Main outcome measures: A comprehensive cost estimate for care provided in the ICU from determination of brain death to transfer to theatre for organ donation. Results: Forty-five patients with brain death became organ donors during the study period. The mean duration of postdeath care in the ICU was 37.9 hours (standard deviation [SD], 16.5) at a mean total cost of $7520 (SD, $3136) per donor. ICU staff salaries were the greatest contributor to total costs, accounting for a median proportion of 0.72 of total expenditure (interquartile range, 0.68-0.75). Conclusions: Substantial costs are incurred in ICU for the provision of patient care in the interval between brain death and organ donation.

A fixed dose approach to thrombosis chemoprophylaxis may be inadequate in heavier critically ill patients.

Objectives: Overweight patients are at greater risk of venous thromboembolism. We aimed to describe prescribing patterns of thrombosis chemoprophylaxis in critically ill patients weighing ≥ 100 kg and quantify the effectiveness of these regimens using the surrogate biomarker of plasma anti-Xa level. Design, setting and patients: A prospective single-centre cohort study was conducted over a 6-month period. Patients weighing ≥ 100 kg who were prescribed enoxaparin for chemoprophylaxis and expected to remain in the intensive care unit for > 48 hours were eligible. Anti-Xa levels were measured once a patient had received at least three consecutive doses of enoxaparin. Peak levels were measured 4-6 hours after the third dose and trough levels were measured before the fourth dose. Anti-Xa levels were compared with established target ranges for peak and trough anti-Xa levels (0.2-0.5 IU/mL and > 0.1 IU/mL, respectively). Results: Eighty-eight patients met the eligibility criteria, and anti-Xa levels for 42 patients were obtained. Fixed dose chemoprophylaxis approaches varied considerably, with 40 mg once daily (54/88 [61%]) and 40 mg twice daily (20/88 [23%]) being the most frequently prescribed regimens. No patient had a peak anti-Xa level > 0.5 IU/mL. When comparing 40 mg once daily versus twice daily, the once daily regimen had lower median trough levels (0.01 IU/mL [interquartile range (IQR), 0.00-0.04] v 0.09 IU/mL [IQR, 0.05-0.13]; P < 0.001) and greater proportions of patients with levels below the established range (< 0.1 IU/mL) (15/16 [95%] v 7/14 [50%]; P = 0.002) and levels that were undetectable (0.00 IU/mL) (8/16 [50%] v 1/14 [7%]; P = 0.01). Conclusions: At a single centre, thrombosis chemoprophylaxis prescribing patterns for heavier critically ill patients varied considerably. Current fixed dose approaches may be inadequate in this cohort.

A multicentre point prevalence study of delirium assessment and management in patients admitted to Australian and New Zealand intensive care units.

Objective: To characterise the assessment and management of delirium in patients admitted to intensive care units (ICUs) in Australia and New Zealand. Methods: We conducted a multicentre observational point prevalence study across 44 adult Australian and New Zealand ICUs. Data were extracted for all patients in the ICU in terms of assessment and treatment of delirium. ICU-level data were collected regarding the use of explicit protocols related to delirium. Results: We studied 627 patients, with 54% (336/627) having at least one delirium screening assessment performed. The Confusion Assessment Method for the ICU (CAM-ICU) was the most frequently used tool (88%, 296/336). Of patients assessed, 20% (68) were identified to have delirium. Eighteen per cent (111) of patients were administered a drug to manage delirium, with 41% (46) of those receiving a drug having no recorded assessment for delirium on that day. Of the drugs used to treat delirium, quetiapine was the most frequently administered. Physical restraints were applied to 8% (48/626) of patients, but only 17% (8/48) of such patients had been diagnosed with delirium. Most physically restrained patients either did not have delirium diagnosed (31%, 15/48) or had no formal assessment recorded (52%, 25/48) on that day. Conclusions: On the study day, more than 50% of patients had a delirium screening assessment performed, with 20% of screened patients deemed to have delirium. Drugs that are prescribed to treat delirium and physical restraints were frequently used in the absence of delirium or the formal assessment for its presence.

The hospital-based evaluation of laxative prophylaxis in ICU (HELP-ICU): A pilot cluster-crossover randomized clinical trial.

PURPOSE: Prophylactic laxative regimens may prevent constipation but may increase diarrhea and subsequent rectal tube insertion. Our aim was to compare three prophylactic laxative regimens on the rate of rectal tube insertion (primary outcome) and major constipation- or diarrhea-associated complications. MATERIAL AND METHODS: We conducted a cluster-crossover trial. Three pods in a single ICU were each randomized to one of three regimens for four months with rolling cross-over. All mechanically-ventilated and enterally-fed adult patients received either regimen: A) one coloxyl with senna BD from day one; B) two coloxyl with senna +20 ml lactulose BD commencing on day 3; or C) two coloxyl with senna tablets +20 ml lactulose BD commencing on day 6. RESULTS: We enrolled 570 patients (A = 170, B = 205, C = 195) with similar baseline features. Overall, 53 (9.3%) patients received a rectal tube, and insertion rate was not statistically different between the three regimens (A = 12.9%, B = 7.8%, C = 7.7%; p = 0.15). The proportions of patients with other major constipation- or diarrhea-associated complications were similar, as were major patient-centred outcomes. CONCLUSION: Earlier commencement of a prophylactic coloxyl-based laxative regimen (day 1 or 3) did not affect the rates of complications associated with constipation or diarrhea when compared to delayed introduction (day 6).