Population pharmacokinetics of posaconazole in allogeneic haematopoietic stem cell transplant patients.

BACKGROUND: Invasive fungal disease (IFD) in the early post-allogeneic HSCT (alloHCT) period is associated with increased likelihood of catastrophic outcomes. The utility of oral modified release (MR) posaconazole tablets is limited by reduced drug absorption from gastrointestinal toxicity induced by cytotoxic chemotherapy, necessitating a switch to the IV posaconazole formulation. OBJECTIVES: To describe the population pharmacokinetics of posaconazole for oral MR and IV formulations in alloHCT patients and determine dosing regimens likely to achieve therapeutic exposures. METHODS: We performed a prospective observational pharmacokinetic study in adult patients in the early post-alloHCT period requiring a change in posaconazole formulation (oral to IV). Samples were analysed using a validated LC-MS/MS method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. RESULTS: Twenty patients aged between 21 and 70 years were included in the study. A two-compartment model, incorporating mucositis/diarrhoea to modify the bioavailability for oral administration best described the data. To achieve ≥90% PTA, simulations showed that higher than currently recommended doses of oral MR posaconazole were required for prophylaxis Cmin targets (≥0.5 and ≥0.7 mg/L), while increased doses of both formulations were required for IFD treatment PK/PD targets, with patients experiencing oral mucositis/diarrhoea unlikely to achieve these. CONCLUSIONS: Increased doses of posaconazole should be considered for both prophylaxis and treatment of IFD to increase the proportion of alloHCT patients achieving therapeutic exposures, particularly the oral formulation in patients with mucositis and/or diarrhoea. Posaconazole therapeutic drug monitoring should be considered for all formulations in this setting.

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).

Early sepsis in Australia and New Zealand: A point-prevalence study of haemodynamic resuscitation practices.

OBJECTIVE: Optimal resuscitation of sepsis-induced hypotension is uncertain, particularly the role of restrictive fluid strategies, leading to variability in usual practice. The objective of this study is to understand resuscitation practices in patients presenting to ED with early sepsis. METHODS: Design, participants and setting: Prospective, observational, multicentre, single-day, point-prevalence study enrolling adult patients present in 51 Australian and New Zealand ICUs at 10.00 hours, 8 June 2021. MAIN OUTCOME MEASURES: Site-level data on sepsis policies and patient-level demographic data, presence of sepsis and fluid and vasopressor administration in the first 24 h post-ED presentation. RESULTS: A total of 722 patients were enrolled. ED was the ICU admission source for 222 of 722 patients (31.2%) and 78 of 222 patients (35%) met the criteria for sepsis within 24 h of ED presentation. Median age of the sepsis cohort was 61 (48-72) years, 58% were male and respiratory infection was the commonest cause (53.8%). The sepsis cohort had a higher severity of illness than the non-sepsis cohort (144/222 patients) and chronic immunocompromise was more common. Of 78 sepsis patients, 55 (71%) received ≥1 fluid boluses with 500 and 1000 mL boluses equally common (both 49%). In the first 24 h, 2335 (1409-3125) mL (25.3 [13.2-42.9] mL/kg) was administered. Vasopressors were administered in 53 of 78 patients (68%) and for 25 patients (47%) administration was peripheral. CONCLUSIONS: ICU patients presenting to the ED with sepsis receive less fluids than current international recommendations and peripheral vasopressor administration is common. This finding supports the conduct of clinical trials evaluating optimal fluid dose and vasopressor timing for early sepsis-induced hypotension.

Population Pharmacokinetics of Ganciclovir in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Treatment of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (alloHCT) patients with ganciclovir is complicated by toxicity and resistance. This study aimed to develop an intravenous ganciclovir population pharmacokinetic model for post-alloHCT patients and to determine dosing regimens likely to achieve suggested therapeutic exposure targets. We performed a prospective observational single-center pharmacokinetic study in adult alloHCT patients requiring treatment with intravenous ganciclovir for CMV viremia or disease. Samples were analyzed using a validated ultraperformance liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. Twenty patients aged 18 to 69 years were included in the study. A 2-compartment model with linear elimination from the central compartment and between occasion variability best described the data. Incorporating creatinine clearance (CLCR) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and presence of continuous renal replacement therapy as covariates for ganciclovir clearance improved the model. Compared to current dosing recommendations, simulations demonstrated loading doses were required to achieve a target AUC24 of 80 to 120 mg.h/L on day 1 of induction therapy. Increased individualization of post-loading induction and maintenance doses based on CLCR is required to achieve the suggested exposures for efficacy (AUC24 >80/>40 mg.h/L for induction/maintenance) while remaining below the exposure thresholds for toxicity (AUC24 <120/<60 mg.h/L for induction/maintenance). Intravenous ganciclovir dosing in alloHCT patients can be guided by CLCR estimated by CKD-EPI. Incorporation of loading doses into induction dosing regimens should be considered for timely achievement of currently suggested exposures.

Fluids or vasopressors for the initial resuscitation of septic shock.

Intravenous fluid resuscitation is recommended first-line treatment for sepsis-associated hypotension and/or hypoperfusion. The rationale is to restore circulating volume and optimize cardiac output in the setting of shock. Nonetheless, there is limited high-level evidence to support this practice. Over the past decade emerging evidence of harm associated with large volume fluid resuscitation among patients with septic shock has led to calls for a more conservative approach. Specifically, clinical trials undertaken in Africa have found harm associated with initial fluid resuscitation in the setting of infection and hypoperfusion. While translating these findings to practice in other settings is problematic, there has been a re-appraisal of current practice with some recommending earlier use of vasopressors rather than repeated fluid boluses as an alternative to restore perfusion in septic shock. There is consequently uncertainty and variation in practice. The question of fluids or vasopressors for initial resuscitation in septic shock is the subject of international multicentre clinical trials.

Optimizing antifungal prophylaxis in allogeneic stem cell transplantation: A cohort study of two different approaches.

BACKGROUND: Limited consensus exists on the optimal use of antifungal agents to prevent invasive fungal infection in the early post allogeneic hematopoietic stem cell transplant (alloHCT) period, particularly when patients cannot tolerate oral medication administration. METHODS: We undertook a retrospective observational cohort study to assess the tolerability, efficacy, and cost of a new antifungal prophylaxis pathway at a major tertiary alloHCT centre. Patients aged ≥16 years who underwent alloHCT between February 2018 and October 2019 (cohort 1) or between April 2020 and November 2021 (cohort 2) were included. In both cohorts, first line prophylactic therapy was oral posaconazole. The second line drugs where oral therapy was unable to be administered were intravenous voriconazole (cohort 1) versus intravenous posaconazole (cohort 2). RESULTS: There were 142 patients enrolled in the study, 71 in each cohort. The proportion of patients remaining on first-line prophylaxis or progressing to second-, third-, and fourth-line options was 22.5%, 39.4%, 29.6%, and 8.5% in cohort 1 and 39.4%, 59.2%, 1.4%, and 0% in cohort 2, respectively. The frequency of neuropsychiatric adverse events was significantly higher in cohort 1 compared to cohort 2 (49.3% vs. 19.8%, p = .0004). Occurrence of proven and probable fungal infections was not significantly different between cohorts. Antifungal drug expenditure was $359 935 (AUD) more in cohort 1 ($830 486 AUD) compared to cohort 2 ($477 149 AUD). CONCLUSION: The antifungal prophylaxis pathway used in cohort 2 resulted in reduced antifungal-associated adverse effects, less patients requiring progression to 3rd and 4th line prophylaxis and reduced antifungal drug costs.

Temporal changes in the epidemiology of sepsis-related intensive care admissions from the emergency department in Australia and New Zealand.

OBJECTIVES: The Australasian Resuscitation in Sepsis Evaluation (ARISE) study researched septic shock treatment within EDs. This study aims to evaluate whether: (i) conduct of the ARISE study was associated with changes in epidemiology and care for adults (≥18 years) admitted from EDs to ICUs with sepsis in Australia and New Zealand; and (ii) such changes differed among 45 ARISE trial hospitals compared with 120 non-trial hospitals. METHODS: Retrospective study using interrupted time series analysis in three time periods; 'Pre-ARISE' (January 1997 to December 2007), 'During ARISE' (January 2008 to May 2014) and 'Post-ARISE' (June 2014 to December 2017) using data from the Australian and New Zealand Intensive Care Society Adult Patient Database. RESULTS: Over 21 years there were 54 121 ICU admissions from the ED with sepsis; which increased from 8.1% to 16.4%; 54.6% male, median (interquartile range) age 66 (53-76) years. In the pre-ARISE period, pre-ICU ED length of stay (LOS) decreased in trial hospitals but increased in non-trial hospitals (P = 0.174). During the ARISE study, pre-ICU ED LOS declined more in trial hospitals (P = 0.039) as did the frequency of mechanical ventilation in the first 24 h (P = 0.003). However, ICU and hospital LOS, in-hospital mortality and risk of death declined similarly in both trial and non-trial hospitals. CONCLUSIONS: Sepsis-related admissions increased from 8.1% to 16.4%. During the ARISE study, there was more rapid ICU admission and decreased early ventilation. However, these changes were not sustained nor associated with decreased risk of death or duration of hospitalisation.

Gastrointestinal dysfunction during enteral nutrition delivery in intensive care unit (ICU) patients: Risk factors, natural history, and clinical implications. A post-hoc analysis of The Augmented versus Routine approach to Giving Energy Trial (TARGET).

BACKGROUND: Slow gastric emptying occurs frequently during critical illness and is roughly quantified at bedside by large gastric residual volumes (GRVs). A previously published trial (The Augmented versus Routine approach to Giving Energy Trial; TARGET) reported larger GRVs with energy-dense (1.5 kcal/mL) compared with standard (1.0 kcal/mL) enteral nutrition (EN), warranting further exploration. OBJECTIVE: To assess the incidence, risk factors, duration, and timing of large GRVs (≥250 mL) and its relation to clinical outcomes in mechanically ventilated adults. METHODS: A post-hoc analysis of TARGET data in patients with ≥1 GRV recorded. Data are n (%) or median [IQR]. RESULTS: Of 3876 included patients, 1777 (46%) had ≥1 GRV ≥250 mL, which was more common in males (50 compared with 39%; P < 0.001) and in patients receiving energy-dense compared with standard EN (52 compared with 40%; RR = 1.27 (95% CI: 1.19, 1.36); P < 0.001) in whom it also lasted longer (1 [0-2] compared with 0 [0-1] d; P < 0.001), with no difference in time of onset after EN initiation (day 1 [0-2] compared with 1 [0-2]; P = 0.970). Patients with GRV ≥250 mL were more likely to have the following: vasopressor administration (88 compared with 76%; RR = 1.15 [1.12, 1.19]; P < 0.001), positive blood cultures (16 compared with 8%; RR = 1.92 [1.60, 2.31]; P < 0.001), intravenous antimicrobials (88 compared with 81%; RR = 1.09 [1.06, 1.12]; P < 0.001), and prolonged intensive care unit (ICU) stay (ICU-free days to day 28; 12.9 [0.0-21.0] compared with 20.0 [3.9-24.0]; P < 0.001), hospital stay (hospital-free days to day 28: 0.0 [0.0-12.0] compared with 7.0 [0.0-17.6] d; P < 0.001), ventilatory support (ventilator-free days to day 28: 16.0 [0.0-23.0] compared with 22.0 [8.0-25.0]; P < 0.001), and a higher 90-d mortality (29 compared with 23%; adjusted: RR = 1.17 [1.05, 1.30]; P = 0.003). CONCLUSION: Large GRVs were more common in males and those receiving energy-dense formulae, occurred early and were short-lived, and were associated with a number of negative clinical sequelae, including increased mortality, even when adjusted for illness severity. This trial was registered at clinicaltrials.gov as NCT02306746.

A Systematic Review of the Clinical Pharmacokinetics, Pharmacodynamics and Toxicodynamics of Ganciclovir/Valganciclovir in Allogeneic Haematopoietic Stem Cell Transplant Patients.

BACKGROUND: Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line agents used to prevent and treat cytomegalovirus (CMV) infection in allogeneic haematopoietic stem cell transplant (alloHCT) patients. OBJECTIVE: The aim of this work was to describe available data for the clinical pharmacokinetics, pharmacodynamics and toxicodynamics of GCV and VGCV and the potential of a therapeutic drug monitoring strategy to improve outcomes in the alloHCT population. METHODS: We systematically reviewed the pharmacokinetics (dose-exposure), pharmacodynamics (exposure-efficacy) and toxicodynamics (exposure-toxicity) of GCV and VGCV in alloHCT patients with CMV infection. Studies including alloHCT patients treated for CMV infection reporting the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV or VGCV were searched for using the PUBMED and EMBASE databases from 1946 to 2019. Only studies involving participants > 12 years of age and available in the English language were included. RESULTS: A total of 179 patients were included in the 14 studies that met the inclusion criteria, of which 6 examined GCV pharmacokinetics only, while 8 also examined GCV pharmacodynamics and toxicodynamics. Reported pharmacokinetic parameters showed considerable interpatient variability and were different from other populations, such as solid organ transplant and human immunodeficiency virus-infected patients. Only one study found a correlation between neutropenia and elevated peak and trough GCV concentrations, with no other significant pharmacodynamic and toxicodynamic relationships identified. While therapeutic drug monitoring of GCV is performed in some institutions, no association between GCV therapeutic drug monitoring and clinical outcomes was identified. CONCLUSION: Further studies of the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV/VGCV in alloHCT patients are required to identify a more robust therapeutic range and to subsequently quantify the potential value of therapeutic drug monitoring of GCV/VGCV in the alloHCT population.

Use of a High-Protein Enteral Nutrition Formula to Increase Protein Delivery to Critically Ill Patients: A Randomized, Blinded, Parallel-Group, Feasibility Trial.

BACKGROUND: International guidelines recommend critically ill adults receive more protein than most receive. We aimed to establish the feasibility of a trial to evaluate whether feeding protein to international recommendations would improve outcomes, in which 1 group received protein doses representative of international guideline recommendations (high protein) and the other received doses similar to usual practice. METHODS: We conducted a prospective, randomized, blinded, parallel-group, feasibility trial across 6 intensive care units. Critically ill, mechanically ventilated adults expected to receive enteral nutrition (EN) for ≥2 days were randomized to receive EN containing 63 or 100 g/L protein for ≤28 days. Data are mean (SD) or median (interquartile range). RESULTS: The recruitment rate was 0.35 (0.13) patients per day, with 120 patients randomized and data available for 116 (n = 58 per group). Protein delivery was greater in the high-protein group (1.52 [0.52] vs 0.99 [0.27] grams of protein per kilogram of ideal body weight per day; difference, 0.53 [95% CI, 0.38-0.69] g/kg/d protein), with no difference in energy delivery (difference, -26 [95% CI, -190 to 137] kcal/kg/d). There were no between-group differences in the duration of feeding (8.7 [7.3] vs 8.1 [6.3] days), and blinding of the intervention was confirmed. There were no differences in clinical outcomes, including 90-day mortality (14/55 [26%] vs 15/56 [27%]; risk difference, -1.3% [95% CI, -17.7% to 15.0%]). CONCLUSION: Conducting a multicenter blinded trial is feasible to compare protein delivery at international guideline-recommended levels with doses similar to usual care during critical illness.

The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data From the Multinational Sampling Antibiotics in Renal Replacement Therapy Study.

BACKGROUND: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. METHODS: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. RESULTS: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. CONCLUSIONS: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Time to antimicrobial therapy in septic shock patients treated with an early goal-directed resuscitation protocol: A post-hoc analysis of the ARISE trial.

OBJECTIVE: Intravenous antimicrobial therapy within 1 h of the diagnosis of septic shock is recommended in international sepsis guidelines. We aimed to evaluate the association between antimicrobial timing and mortality in patients presenting to the ED with septic shock. METHODS: Post-hoc analysis of 1587 adult participants enrolled in the Australasian Resuscitation in Sepsis Evaluation (ARISE) multicentre trial of early goal-directed therapy for whom the time of initial antimicrobial therapy was recorded. We compared participants who had initiation of antimicrobials within the first hour (early) or later (delayed) of ED presentation. A propensity score model using inverse probability of treatment weighting was constructed to account for confounding baseline covariates. The primary outcome was 90-day mortality. RESULTS: The median (interquartile range) time to initiating antimicrobials was 69 (39-112) min with 712 (44.9%) participants receiving the first dose within the first hour of ED presentation. Compared with delayed therapy, early administration was associated with increased baseline illness severity score and greater intensity of resuscitation pre-randomisation (fluid volumes, vasopressors, invasive ventilation). All-cause 90-day mortality was also higher; 22.6% versus 15.5%; unadjusted odds ratio (OR) 1.58 (95% confidence interval [CI] 1.16-2.15), P = 0.004. After inverse probability of treatment weighting, the mortality difference was non-significant; OR 1.30 (95% CI 0.95-1.76), P = 0.1. Live discharge rates from ICU (OR 0.81, 95% CI 0.72-0.91; P = 0.80) and hospital (OR 0.93, 95% CI 0.82-1.06; P = 0.29) were also not different between groups. CONCLUSION: In this post-hoc analysis of the ARISE trial, early antimicrobial therapy was associated with increased illness severity, but 90-day adjusted mortality was not reduced.

The cost-effectiveness of early goal-directed therapy: an economic evaluation alongside the ARISE trial.

Objective: To determine the cost-effectiveness of early goal-directed therapy (EGDT) for patients with early septic shock. Design: Within-trial cost-effectiveness evaluation. Setting: Nineteen hospitals in Australia and New Zealand. Participants and interventions: Patients with early septic shock enrolled in the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial were randomly assigned to EGDT versus usual care. A subgroup of patients participated in a nested economic evaluation study in which detailed resource use data were collected until 12 months after randomisation. Outcome measures: Clinical outcomes included lives saved, life-years gained and quality-adjusted life-years (QALYs), with mortality collected until 12 months and health-related quality of life assessed at baseline, 6 and 12 months using the 3-level EuroQol five dimensions questionnaire (EQ-5D-3L). Economic outcomes included health care resource use, costs and cost-effectiveness from the Australian health care payer perspective. Results: A total of 205 patients (100 EGDT, 105 usual care) participated in the nested economic evaluation study, of which 203 had complete resource use data. Unadjusted mean health care costs to 12 months were $67 223 (standard deviation [SD], $72 397) in the EGDT group and $54 179 (SD, $61 980) in the usual care group, with a mean difference of $13 044 (95% CI, -$5791 to $31 878). There was no difference between groups with regards to lives saved (EGDT, 69.4% v usual care, 68.6%; P = 1.0), life-years gained (mean EGDT, 0.746 [SD, 0.406] v usual care, 0.725 [SD, 0.417]; P = 0.72) or QALYs (mean EGDT, 0.318 [SD, 0.291] v usual care, 0.367 [SD, 0.295]; P = 0.24). EGDT was dominated (higher costs, lower effectiveness) by usual care in 80.4% of bootstrap replications. For a willingness-to-pay threshold of $50 000 per QALY, the probability of EGDT being cost-effective was only 6.4%. Conclusions: In patients presenting to the emergency department with early septic shock, EGDT compared with usual care was not cost-effective. Clinical trial registration:ClinicalTrials.gov number NCT00975793.

Protein delivery in mechanically ventilated adults in Australia and New Zealand: current practice.

Objective: To quantify current protein prescription and delivery in critically ill adults in Australia and New Zealand and compare it with international guidelines. Design: Prospective, multicentre, observational study. Setting: Five intensive care units (ICUs) across Australia and New Zealand. Participants: Mechanically ventilated adults who were anticipated to receive enteral nutrition for ≥ 24 hours. Main outcome measures: Baseline demographic and nutrition data in ICU, including assessment of requirements, prescription and delivery of enteral nutrition, parenteral nutrition and protein supplementation, were collected. The primary outcome was enteral nutrition protein delivery (g/kg ideal body weight [IBW] per day). Data are reported as mean ± standard deviation or n (%). Results: 120 patients were studied (sex, 60% male; mean age, 59 ± 16 years; mean admission APACHE II score, 20 ± 8). Enteral nutrition was delivered on 88%, parenteral nutrition on 6.8%, and protein supplements on 0.3% of 1156 study days. For the 73% (88/120) of patients who had a nutritional assessment, the mean estimated protein requirements were 99 ± 22 g/day (1.46 ± 0.55 g/kg IBW per day). The mean daily protein delivery was 54 ± 23 g (0.85 ± 0.35 g/kg IBW per day) from enteral nutrition and 56 ± 23 g (0.88 ± 0.35 g/kg IBW per day) from all sources (enteral nutrition, parenteral nutrition, protein supplements). Protein delivery was ≥ 1.2 g/kg IBW per day on 29% of the total study days per patient. Conclusions: Protein delivery as a part of current usual care to critically ill adults in Australia and New Zealand remains below that recommended in international guidelines.

Energy-dense vs routine enteral nutrition in New Zealand Europeans, Maori, and Pacific Peoples who are critically ill.

AIMS: To evaluate the effect of energy-dense vs routine enteral nutrition on day-90 mortality by ethnic group in critically ill adults. METHODS: Pre-planned subgroup analysis of the 1,257 New Zealanders in a 4,000-participant randomised trial comparing energy-dense enteral nutrition (1.5kcal/mL) with routine enteral nutrition (1kcal/mL) in mechanically ventilated intensive care unit (ICU) patients. The primary purpose of this analysis was to evaluate responses to study treatment by ethnic group (European, Maori, and Pacific Peoples) using ethnicity data recorded in the clinical records. The secondary purpose was to compare the characteristics and outcomes of patients by ethnic group. The primary outcome was day-90 mortality. RESULTS: Among 1,138 patients included in the primary outcome analysis, 165 of 569 (29.0%) assigned to energy-dense nutrition and 156 of 569 patients (27.4%) assigned to routine nutrition died by day 90 (odds ratio; 1.06; 95% CI, 0.92-1.22). There was no statistically significant interaction between treatment allocation and ethnicity with respect to day-90 mortality. Day-90 mortality rates did not vary statistically significantly by ethnic group. CONCLUSIONS: Among mechanically ventilated adults in New Zealand ICUs, the effect on day-90 mortality of energy-dense vs routine enteral nutrition did not vary by ethnicity.

Outcomes Six Months after Delivering 100% or 70% of Enteral Calorie Requirements during Critical Illness (TARGET). A Randomized Controlled Trial.

Rationale: The long-term effects of delivering approximately 100% of recommended calorie intake via the enteral route during critical illness compared with a lesser amount of calories are unknown.Objectives: Our hypotheses were that achieving approximately 100% of recommended calorie intake during critical illness would increase quality-of-life scores, return to work, and key life activities and reduce death and disability 6 months later.Methods: We conducted a multicenter, blinded, parallel group, randomized clinical trial, with 3,957 mechanically ventilated critically ill adults allocated to energy-dense (1.5 kcal/ml) or routine (1.0 kcal/ml) enteral nutrition.Measurements and Main Results: Participants assigned energy-dense nutrition received more calories (percent recommended energy intake, mean [SD]; energy-dense: 103% [28] vs. usual: 69% [18]). Mortality at Day 180 was similar (560/1,895 [29.6%] vs. 539/1,920 [28.1%]; relative risk 1.05 [95% confidence interval, 0.95-1.16]). At a median (interquartile range) of 185 (182-193) days after randomization, 2,492 survivors were surveyed and reported similar quality of life (EuroQol five dimensions five-level quality-of-life questionnaire visual analog scale, median [interquartile range]: 75 [60-85]; group difference: 0 [95% confidence interval, 0-0]). Similar numbers of participants returned to work with no difference in hours worked or effectiveness at work (n = 818). There was no observed difference in disability (n = 1,208) or participation in key life activities (n = 705).Conclusions: The delivery of approximately 100% compared with 70% of recommended calorie intake during critical illness does not improve quality of life or functional outcomes or increase the number of survivors 6 months later.

Clinical Sequelae From Overfeeding in Enterally Fed Critically Ill Adults: Where Is the Evidence?

Enteral energy delivery above requirements (overfeeding) is believed to cause adverse effects during critical illness, but the literature supporting this is limited. We aimed to quantify the reported frequency and clinical sequelae of energy overfeeding with enterally delivered nutrition in critically ill adult patients. A systematic search of MEDLINE, EMBASE, and CINAHL from conception to November 28, 2018, identified clinical studies of nutrition interventions in enterally fed critically ill adults that reported overfeeding in 1 or more study arms. Overfeeding was defined as energy delivery > 2000 kcal/d, > 25 kcal/kg/d, or ≥ 110% of energy prescription. Data were extracted on methodology, demographics, prescribed and delivered nutrition, clinical variables, and predefined outcomes. Cochrane "Risk of Bias" tool was used to assess the quality of randomized controlled trials (RCTs). Eighteen studies were included, of which 10 were randomized (n = 4386 patients) and 8 were nonrandomized (n = 223). Only 4 studies reported a separation in energy delivery between treatment groups whereby 1 arm met the definition of overfeeding, which reported no between-group differences in mortality, infectious complications, or ventilatory support. Overfeeding was associated with increased insulin administration (median 3 [interquartile range: 0-41.8] vs 0 [0-30.6] units/d) and upper-gastrointestinal intolerance in 1 large RCT and with duration of antimicrobial therapy in a small RCT. There are limited high-quality data to determine the impact of energy overfeeding of critically ill patients by the enteral route; however, based on available evidence, overfeeding does not appear to affect mortality or other important clinical outcomes.

Quality of Life and 1-Year Survival in Patients With Early Septic Shock: Long-Term Follow-Up of the Australasian Resuscitation in Sepsis Evaluation Trial.

OBJECTIVES: To examine long-term survival and quality of life of patients with early septic shock. DESIGN: Prospective, randomized, parallel-group trial. SETTING: Fifty-one hospitals in Australia, New Zealand, Finland, Hong Kong, and the Republic of Ireland. PATIENTS: One-thousand five-hundred ninety-one patients who presented to the emergency department with early septic shock between October 2008 and April 2014, and were enrolled in the Australasian Resuscitation in Sepsis Evaluation trial. INTERVENTIONS: Early goal-directed therapy versus usual care. MEASUREMENTS AND MAIN RESULTS: Long-term survival was measured up to 12 months postrandomization. Health-related quality of life was measured using the EuroQoL-5D-3L, Short Form 36 and Assessment of Quality of Life 4D at baseline, and at 6 and 12 months following randomization. Mortality data were available for 1,548 patients (97.3%) and 1,515 patients (95.2%) at 6 and 12 months, respectively. Health-related quality of life data were available for 85.1% of survivors at 12 months. There were no significant differences in mortality between groups at either 6 months (early goal-directed therapy 21.8% vs usual care 22.6%; p = 0.70) or 12 months (early goal-directed therapy 26.4% vs usual care 27.9%; p = 0.50). There were no group differences in health-related quality of life at either 6 or 12 months (EuroQoL-5D-3L utility scores at 12 mo early goal-directed therapy 0.65 ± 0.33 vs usual care 0.64 ± 0.34; p = 0.50), with the health-related quality of life of both groups being significantly lower than population norms. CONCLUSIONS: In patients presenting to the emergency department with early septic shock, early goal-directed therapy compared with usual care did not reduce mortality nor improve health-related quality of life at either 6 or 12 months.