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.

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.

20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients After Cardiac Surgery (the HAS FLAIR Study).

OBJECTIVE: To compare the effects of fluid bolus therapy using 20% albumin versus crystalloid on fluid balance, hemodynamic parameters, and intensive care unit (ICU) treatment effects in post-cardiac surgery patients. DESIGN: Sequential period open-label pilot study. SETTING: University teaching hospital. PARTICIPANTS: One hundred adult cardiac surgery patients who were prescribed fluid bolus therapy to correct hypotension or perceived hypovolemia or to optimize cardiac index during the first 24 hours in the ICU. INTERVENTIONS: The first 50 patients were treated with crystalloid fluid bolus therapy in the first period (control), and 50 patients with up to 2 treatments of 100 mL of 20% albumin fluid bolus therapy in the second period (intervention), followed by crystalloid therapy if needed. MEASUREMENTS AND MAIN RESULTS: Demographic characteristics were similar at baseline. The intervention was associated with a less positive median fluid balance in the first 24 hours (albumin: 1,100 [650-1,960] v crystalloid: 1,970 [1,430-2,550] p = 0.001), fewer episodes of fluid bolus therapy (3 [2-5] v 5 [4-7]; p < 0.0001) and a lesser volume of fluid bolus therapy (700 [200-1,450] v 1,500 mL/24 h [1,100-2,250]; p < 0.0001). The intervention also was associated with a decreased median overall dose of norepinephrine in the first 24 hours of ICU stay (19 [0-52] v 47 µg/kg/24 hours [0-134]; p = 0.025) and shorter median time to cessation of norepinephrine (17 [5-28] v 28 hours [20-48]; p = 0.002). CONCLUSION: Post-cardiac surgery fluid bolus therapy with 20% albumin when compared with crystalloid fluid resulted in less positive fluid balance as well as several hemodynamic and potential ICU treatment advantages.

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.

Communication with bereaved family members after death in the ICU: the CATHARTIC randomised clinical trial.

Objective: It is uncertain whether psychological distress in the family members of patients who die during an intensive care unit (ICU) admission may be improved by bereavement interventions. In this trial, relatives' symptoms of anxiety and depression after 6 months were measured when allocated to three commonly used bereavement follow-up strategies. Design: Single-centre, randomised, three parallel-group trial. Setting: A tertiary ICU in Australia. Participants: Relatives of patients who died in the ICU. Interventions: Relatives received bereavement follow-up 4 weeks after the death using a condolence letter, short telephone call or no contact. Main outcome measures: The primary outcome was the total Hospital Anxiety and Depression Scale (HADS-T) score. Secondary outcomes estimated anxiety, depression, complicated grief, post-traumatic stress, and satisfaction with ICU care. Results: Seventy-one relatives participated (24 had no contact, 19 were contacted by letter and 28 by telephone 4 weeks after the death). The mean HADS-T score for no contact was 16.1 (95% CI, 12.4-19.8). Receipt of a letter was associated with a mean HADS-T increase of 1.4 (4.0 decrease to 6.8 increase), and a condolence call was accompanied by a mean decrease of 1.6 (6.6 decrease to 3.4 increase; P > 0.5). Non-significant differences were observed for all secondary outcomes. Conclusions: Anxiety and depression at 6 months in the relatives of patients who died in the ICU was not meaningfully alleviated by receipt of either a condolence letter or telephone call. Trial registration: Australia New Zealand Clinical Trials Registry (ACTRN12619000917134).

Quantifying Response to Nutrition Therapy During Critical Illness: Implications for Clinical Practice and Research? A Narrative Review.

Critical illness causes substantial muscle loss that adversely impacts recovery and health-related quality of life. Treatments are therefore needed that reduce mortality and/or improve the quality of survivorship. The purpose of this Review is to describe both patient-centered and surrogate outcomes that quantify responses to nutrition therapy in critically ill patients. The use of these outcomes in randomized clinical trials will be described and the strengths and limitations of these outcomes detailed. Outcomes used to quantify the response of nutrition therapy must have a plausible mechanistic relationship to nutrition therapy and either be an accepted measure for the quality of survivorship or highly likely to lead to improvements in survivorship. This Review identified that previous trials have utilized diverse outcomes. The variety of outcomes observed is probably due to a lack of consensus as to the most appropriate surrogate outcomes to quantify response to nutrition therapy during research or clinical practice. Recent studies have used, with some success, measures of muscle mass to evaluate and monitor nutrition interventions administered to critically ill patients.

Urinary and renal oxygenation during dexmedetomidine infusion in critically ill adults with mechanistic insights from an ovine model.

PURPOSE: Examine effects of dexmedetomidine on bladder urinary oxygen tension (PuO2) in critically ill patients and delineate mechanisms in an ovine model. MATERIALS AND METHODS: In 12 critically ill patients: oxygen-sensing probe inserted in the bladder catheter and dexmedetomidine infusion at a mean (SD) rate of 0.9 ± 0.3 µg/kg/h for 24-h. In 9 sheep: implantation of flow probes around the renal and pulmonary arteries, and oxygen-sensing probes in the renal cortex, renal medulla and bladder catheter; dexmedetomidine infusion at 0.5 µg/kg/h for 4-h and 1.0 µg/kg/h for 4-h then 16 h observation. RESULTS: In patients, dexmedetomidine decreased bladder PuO2at 2 (-Δ11 (95% CI 7-16)mmHg), 8 (-Δ 7 (0.1-13)mmHg) and 24 h (-Δ 11 (0.4-21)mmHg). In sheep, dexmedetomidine at 1 µg/kg/h reduced renal medullary oxygenation (-Δ 19 (14-24)mmHg) and bladder PuO2 (-Δ 12 (7-17)mmHg). There was moderate correlation between renal medullary oxygenation and bladder PuO2; intraclass correlation co-efficient 0.59 (0.34-0.80). Reductions in renal medullary oxygenation were associated with reductions in blood pressure, cardiac output and renal blood flow (P < 0.01). CONCLUSIONS: Dexmedetomidine decreases PuO2in critically ill patients and in sheep. In sheep this reflects a decrease in renal medullary oxygenation, associated with reductions in cardiac output, blood pressure and renal blood flow.

Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. METHODS: The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . FINDINGS: Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). INTERPRETATION: In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. FUNDING: Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.

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).

Audit of safety and quality of the use of enoxaparin for anticoagulation in continuous renal replacement therapy.

OBJECTIVE: To evaluate the safety and efficacy of enoxaparin for anticoagulation during continuous renal replacement therapy (CRRT). DESIGN: Six-month prospective audit on filter life, anti-Xa activity and bleeding complications among patients undergoing continuous venovenous haemodiafiltration with 1.5mg/kg enoxaparin per 24 hours. The audit was conducted between June and December 2009. RESULTS: Thirteen patients were included. The median overall filter survival time was 22 hours (range, 2-176 hours). Two patients experienced minor bleeding events, but there were no major bleeding events. Systemic activity of enoxaparin was demonstrated, with a significant rise in median anti-Xa activity between assays before and during filtration (0.00 [range, 0.00-0.13] v 0.31 [range, 0.07-1.26] anti-Xa U/mL; P = 0.03). CONCLUSIONS: Enoxaparin at 1.5mg/kg/24 h appears to be effective for circuit anticoagulation in CRRT and provides significant systemic anticoagulation. Further research is required to evaluate its safety, particularly in the absence of routine anti-Xa monitoring.

Venous thromboembolism prophylaxis in the critically ill: a point prevalence survey of current practice in Australian and New Zealand intensive care units.

BACKGROUND: Critically ill patients are at high risk of morbidity and mortality caused by venous thromboembolism (VTE). In addition to premorbid predisposing conditions, critically ill patients may be exposed to prolonged immobility, invasive intravascular catheters and frequent operative procedures, and further may have contraindications to pharmaceutical prophylactic measures designed to attenuate VTE risk. There are limited data describing current VTE prophylaxis regimens in Australia and New Zealand. OBJECTIVE: To document current Australian and New Zealand management of VTE prophylaxis in a large mixed cohort of critically ill patients. DESIGN: Prospective, multicentre point prevalence survey endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG). SETTING: 30 public hospital ICUs in Australia and New Zealand surveyed on Wednesday 9 May 2007. METHODS: For all patients in each ICU on the study day, demographic data, admission diagnosis and information on VTE prophylaxis were prospectively collected. RESULTS: 502 patients were included in the survey, and 431 of these (86%) received VTE prophylaxis. Of these, 64% (276/431) received pharmacological prophylaxis and 80% (345/431) received mechanical prophylaxis, with 44% (190/431) receiving both. Of those receiving pharmacological prophylaxis, unfractionated heparin was used in 74%, and enoxaparin (low molecular weight heparin) in 23%. Contraindications to pharmacological prophylaxis were reported in 122 patients. Overall, pharmacological prophylaxis was administered to 87% of potentially suitable patients. CONCLUSIONS: We observed a high prevalence of VTE prophylaxis, with many critically ill patients receiving two or more modalities of prophylaxis. These results show that the potential risk of VTE in critically ill patients is recognised in Australia and New Zealand, and strategies to mitigate this serious complication are widely implemented.

Epidemiology of sepsis in Victoria, Australia.

OBJECTIVE: To determine the clinical and epidemiologic characteristics of patients with sepsis admitted to hospitals in Victoria, Australia, including the incidence of sepsis and severe sepsis, utilization of intensive care unit (ICU) resources, and hospital mortality. DESIGN: A population-based hospital morbidity database generated from hospital discharge coding. SETTING: State of Victoria, Australia (population, 4.5 million), the 4-yr period from July 1, 1999, to June 30, 2003. PATIENTS: A total of 3,122,515 overnight hospitalizations. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The overall hospital incidence of sepsis was 1.1%, with a mortality of 18.4%. Of septic patients, 23.8% received some care in an ICU. For these patients, hospital mortality was 28.9%. Severe sepsis, defined by sepsis and at least one organ dysfunction, occurred in 39% of sepsis patients and was accompanied by a hospital mortality of 31.1%. Fifty percent of patients with severe sepsis received at least some care in an ICU. CONCLUSIONS: Australian state hospital administrative data reveal epidemiologic features of sepsis and severe sepsis that are strikingly similar to those recently reported from comparable populations in North American and Europe. This suggests that lessons learned in this area may be directly applicable internationally.