Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department ...with septic shock. However, its effectiveness is uncertain.
In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization.
Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (±SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964±1415 ml vs. 1713±1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P<0.001 for all comparisons). At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, -0.3 percentage points; 95% confidence interval, -4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay.
In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. (Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ARISE ClinicalTrials.gov number, NCT00975793.).
The effect of delivering nutrition at different calorie levels during critical illness is uncertain, and patients typically receive less than the recommended amount.
We conducted a multicenter, ...double-blind, randomized trial, involving adults undergoing mechanical ventilation in 46 Australian and New Zealand intensive care units (ICUs), to evaluate energy-dense (1.5 kcal per milliliter) as compared with routine (1.0 kcal per milliliter) enteral nutrition at a dose of 1 ml per kilogram of ideal body weight per hour, commencing at or within 12 hours of the initiation of nutrition support and continuing for up to 28 days while the patient was in the ICU. The primary outcome was all-cause mortality within 90 days.
There were 3957 patients included in the modified intention-to-treat analysis (1971 in the 1.5-kcal group and 1986 in the 1.0-kcal group). The volume of enteral nutrition delivered during the trial was similar in the two groups; however, patients in the 1.5-kcal group received a mean (±SD) of 1863±478 kcal per day as compared with 1262±313 kcal per day in the 1.0-kcal group (mean difference, 601 kcal per day; 95% confidence interval CI, 576 to 626). By day 90, a total of 523 of 1948 patients (26.8%) in the 1.5-kcal group and 505 of 1966 patients (25.7%) in the 1.0-kcal group had died (relative risk, 1.05; 95% CI, 0.94 to 1.16; P=0.41). The results were similar in seven predefined subgroups. Higher calorie delivery did not affect survival time, receipt of organ support, number of days alive and out of the ICU and hospital or free of organ support, or the incidence of infective complications or adverse events.
In patients undergoing mechanical ventilation, the rate of survival at 90 days associated with the use of an energy-dense formulation for enteral delivery of nutrition was not higher than that with routine enteral nutrition. (Funded by National Health and Medical Research Institute of Australia and the Health Research Council of New Zealand; TARGET ClinicalTrials.gov number, NCT02306746 .).
After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) ...showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT.
We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics.
We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients 24.9%) and usual care (475 of 1871 patients 25.4%); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation.
In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158 .).
In septic patients, it is uncertain whether isolated hyperlactatemia (lactate ≥4 mmol/L without refractory hypotension) can be used to diagnose septic shock and whether mortality rate differs from ...that of isolated refractory hypotension (refractory to 1000 mL or greater fluid bolus).
To compare baseline characteristics, treatments, and outcomes of participants enrolled into the Australian Resuscitation in Sepsis Evaluation (ARISE) trial according to the presence of isolated hyperlactatemia or isolated refractory hypotension.
Cohort of 1,332 ARISE participants with sepsis and either isolated hyperlactatemia or isolated refractory hypotension.
We performed a secondary analysis of the ARISE data, constructing a propensity score model to discriminate between hyperlactatemia and isolated refractory hypotension. We analyzed 90-day all-cause mortality using a generalized linear model and inverse propensity score weighting. We modeled length of intensive care unit (ICU) and hospital stay using time to event analyses incorporating mortality as a competing risk.
There were 478 participants (35.9%) with isolated hyperlactatemia and 854 (64.1%) with isolated refractory hypotension. They had similar median (interquartile range) ages (66.2 54.2, 76.3 years vs. 65.2 50.9, 75.5 years) and similar sources of infection. However, isolated hyperlactatemia participants had higher mean (standard deviation) baseline APACHE II scores (isolated hyperlactatemia 16.2 6.4) vs. 14.5 6.4 for isolated refractory hypotension; P < 0.001). Isolated hyperlactatemia participants had a 1.7 times higher risk of 90-day mortality (propensity-weighted risk ratio; 95% confidence intervals CI 1.2, 2.5, P = 0.003). They were less likely to be discharged alive from ICU and hospital (propensity weighted sub-hazard ratio 0.77 (95% CI 0.64, 0.92; P < 0.005) and 0.79 (95% CI 0.66, 0.95; P = 0.01), respectively).
ARISE trial participants with isolated hyperlactatemia had worse adjusted 90-day mortality than those with isolated refractory hypotension. In septic patients, isolated hyperlactatemia may define greater illness severity and worse outcomes than isolated refractory hypotension.
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 (
=
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 (CL
) 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 AUC
of 80 to 120 mg.h/L on day 1 of induction therapy. Increased individualization of post-loading induction and maintenance doses based on CL
is required to achieve the suggested exposures for efficacy (AUC
>80/>40 mg.h/L for induction/maintenance) while remaining below the exposure thresholds for toxicity (AUC
<120/<60 mg.h/L for induction/maintenance). Intravenous ganciclovir dosing in alloHCT patients can be guided by CL
estimated by CKD-EPI. Incorporation of loading doses into induction dosing regimens should be considered for timely achievement of currently suggested exposures.
The preferential use of the oral/enteral route in critically ill patients over gut rest is uniformly recommended and applied. This article provides practical guidance on enteral nutrition in ...compliance with recent American and European guidelines. Low-dose enteral nutrition can be safely started within 48 h after admission, even during treatment with small or moderate doses of vasopressor agents. A percutaneous access should be used when enteral nutrition is anticipated for ≥ 4 weeks. Energy delivery should not be calculated to match energy expenditure before day 4-7, and the use of energy-dense formulas can be restricted to cases of inability to tolerate full-volume isocaloric enteral nutrition or to patients who require fluid restriction. Low-dose protein (max 0.8 g/kg/day) can be provided during the early phase of critical illness, while a protein target of > 1.2 g/kg/day could be considered during the rehabilitation phase. The occurrence of refeeding syndrome should be assessed by daily measurement of plasma phosphate, and a phosphate drop of 30% should be managed by reduction of enteral feeding rate and high-dose thiamine. Vomiting and increased gastric residual volume may indicate gastric intolerance, while sudden abdominal pain, distension, gastrointestinal paralysis, or rising abdominal pressure may indicate lower gastrointestinal intolerance.
The pharmacokinetics of beta-lactam antibiotics in intensive care patients may be profoundly altered due to the dynamic, unpredictable pathophysiological changes that occur in critical illness. For ...many drugs, significant increases in the volume of distribution and/or variability in drug clearance are common. When “standard” beta-lactam doses are used, such pharmacokinetic changes can result in subtherapeutic plasma concentrations, treatment failure, and the development of antibiotic resistance. Emerging data support the use of beta-lactam therapeutic drug monitoring (TDM) and individualized dosing to ensure the achievement of pharmacodynamic targets associated with rapid bacterial killing and optimal clinical outcomes. The purpose of this work was to describe the pharmacokinetic variability of beta-lactams in the critically ill and to discuss the potential utility of TDM to optimize antibiotic therapy through a structured literature review of all relevant publications between 1946 and October 2011. Only a few studies have reported the utility of TDM as a tool to improve beta-lactam dosing in critically ill patients. Moreover, there is little agreement between studies on the pharmacodynamic targets required to optimize antibiotic therapy. The impact of TDM on important clinical outcomes also remains to be established. Whereas TDM may be theoretically rational, clinical studies to assess utility in the clinical setting are urgently required.
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.
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.
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.
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.
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.
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