To determine the existence of concentration–toxicity relationships for common β-lactam antibiotic adverse effects and define thresholds above which toxicity is more likely. Retrospective review of consecutive patients treated with piperacillin, meropenem or flucloxacillin who underwent therapeutic drug monitoring (TDM) at St Vincent’s Hospital (Sydney, Australia) between January 2013 and December 2015. Adverse events investigated included neurotoxicity, nephrotoxicity, hepatotoxicity and opportunistic Clostridium difficile infection. Toxicity was measured using observational grading criteria, clinical assessment and relevant serum biomarkers. These findings were correlated with trough TDM measurements at the time of toxicity presentation. TDM results from 378 patients (piperacillin = 223, meropenem = 94 and flucloxacillin = 61) were investigated. There was no difference in baseline patient characteristics across antibiotic groups. A statistically significant elevation in mean serum trough concentrations (C_min) was found in patients diagnosed with neurotoxicity (piperacillin, P < 0.01; meropenem, P = 0.04; flucloxacillin, P = 0.01) and those who developed nephrotoxicity whilst being treated with piperacillin (P < 0.01) or meropenem (P < 0.01). Incidence of hepatotoxicity and C. difficile was not related to C_min. Threshold concentrations for which there is 50% risk of developing a neurotoxicity event (piperacillin, C_min >361.4 mg/L; meropenem, C_min >64.2 mg/L; flucloxacillin, C_min >125.1 mg/L) or nephrotoxicity (piperacillin, C_min >452.65 mg/L; meropenem, C_min >44.45 mg/L) varied across antibiotics. Our data reveal an association between toxic concentrations for a number of β-lactam agents and neurotoxic/nephrotoxic effects. We have defined threshold concentrations above which these toxicities become more likely. Clinicians should balance concerns for therapeutic efficacy with potential toxicity when considering aggressive therapy.

Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is an effective rescue therapy for severe cardiorespiratory failure, but morbidity and mortality are high. We hypothesised that survival decreases with longer VA ECMO treatment. We examined the Extracorporeal Life Support Organization (ELSO) registry for a relationship between VA ECMO duration and in-hospital mortality, and covariates including indication for support. All VA runs from the ELSO database from 2002 to 2012 were extracted. Multiple runs and non-VA runs were excluded. Runs were categorized into diagnostic groups. Logistic regression for analysis of the effect of duration on outcome, and multivariate regression for diagnosis and other baseline factors were performed. Non-linear models including piecewise logistic models were fitted. There were 2699 runs analysed over 14,747 days. Logistic regression analysis of the effect of duration on outcome, and multivariate regression analysis of diagnosis and other baseline factors were performed. In-hospital survival was 41.4% (95% CI 39.6–43.3). 75% of patients were supported for less than 1 week and 96% for less than 3 weeks. Median duration (4 days IQR 2.0–6.8) was greater in survivors (4.1 (IQR 2.5–6.7) vs 3.8 (IQR 1.7–7.0) p = 0.002). The final multivariate model demonstrated increasing survival to day 4 (OR 1.53 (95% CI 1.37–1.71) p < 0.001), decreasing from day 4 to 12 (OR 0.86 (95% CI 0.81–0.91), p < 0.001) with no significant change thereafter (OR 0.98 (95% CI 0.94–1.02), p = 0.400). ECMO for 4 days or less is associated with higher mortality, likely reflecting early treatment failure. Survival is highest when patients are weaned on the fourth day of ECMO but likely decreases into the second week. While this does not suggest weaning at this point will produce better outcomes, it does reflect the likely time course of ECMO as a bridge in severe shock. Patients with some underlying conditions (like myocarditis and heart transplantation) achieve better outcomes despite longer support duration. These findings merit prospective study for the development of prognostic models and weaning strategies.

Whether adjunctive intermittent pneumatic compression in critically ill patients receiving pharmacologic thromboprophylaxis would result in a lower incidence of deep-vein thrombosis than pharmacologic thromboprophylaxis alone is uncertain. We randomly assigned patients who were considered adults according to the local standards at the participating sites (≥14, ≥16, or ≥18 years of age) within 48 hours after admission to an intensive care unit (ICU) to receive either intermittent pneumatic compression for at least 18 hours each day in addition to pharmacologic thromboprophylaxis with unfractionated or low-molecular-weight heparin (pneumatic compression group) or pharmacologic thromboprophylaxis alone (control group). The primary outcome was incident (i.e., new) proximal lower-limb deep-vein thrombosis, as detected on twice-weekly lower-limb ultrasonography after the third calendar day since randomization until ICU discharge, death, attainment of full mobility, or trial day 28, whichever occurred first. A total of 2003 patients underwent randomization — 991 were assigned to the pneumatic compression group and 1012 to the control group. Intermittent pneumatic compression was applied for a median of 22 hours (interquartile range, 21 to 23) daily for a median of 7 days (interquartile range, 4 to 13). The primary outcome occurred in 37 of 957 patients (3.9%) in the pneumatic compression group and in 41 of 985 patients (4.2%) in the control group (relative risk, 0.93; 95% confidence interval [CI], 0.60 to 1.44; P=0.74). Venous thromboembolism (pulmonary embolism or any lower-limb deep-vein thrombosis) occurred in 103 of 991 patients (10.4%) in the pneumatic compression group and in 95 of 1012 patients (9.4%) in the control group (relative risk, 1.11; 95% CI, 0.85 to 1.44), and death from any cause at 90 days occurred in 258 of 990 patients (26.1%) and 270 of 1011 patients (26.7%), respectively (relative risk, 0.98; 95% CI, 0.84 to 1.13). Among critically ill patients who were receiving pharmacologic thromboprophylaxis, adjunctive intermittent pneumatic compression did not result in a significantly lower incidence of proximal lower-limb deep-vein thrombosis than pharmacologic thromboprophylaxis alone. (Funded by King Abdulaziz City for Science and Technology and King Abdullah International Medical Research Center; PREVENT ClinicalTrials.gov number, NCT02040103; Current Controlled Trials number, ISRCTN44653506.)

Given the expanding scope of extracorporeal membrane oxygenation (ECMO) and its variable impact on drug pharmacokinetics as observed in neonatal studies, it is imperative that the effects of the device on the drugs commonly prescribed in the intensive care unit (ICU) are further investigated. Currently, there are no data to confirm the appropriateness of standard drug dosing in adult patients on ECMO. Ineffective drug regimens in these critically ill patients can seriously worsen patient outcomes. This study was designed to describe the pharmacokinetics of the commonly used antibiotic, analgesic and sedative drugs in adult patients receiving ECMO.