Eileen Gilder

ASAP ECMO: Antibiotic, Sedative and Analgesic Pharmacokinetics during Extracorporeal Membrane Oxygenation: a multi-centre study to optimise drug therapy during ECMO

BackgroundGiven 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.Methods/DesignThis is a multi-centre, open-label, descriptive pharmacokinetic (PK) study. Eligible patients will be adults treated with ECMO for severe cardiac and/or respiratory failure at five Intensive Care Units in Australia and New Zealand. Patients will receive the study drugs as part of their routine management. Blood samples will be taken from indwelling catheters to investigate plasma concentrations of several antibiotics (ceftriaxone, meropenem, vancomycin, ciprofloxacin, gentamicin, piperacillin-tazobactum, ticarcillin-clavulunate, linezolid, fluconazole, voriconazole, caspofungin, oseltamivir), sedatives and analgesics (midazolam, morphine, fentanyl, propofol, dexmedetomidine, thiopentone). The PK of each drug will be characterised to determine the variability of PK in these patients and to develop dosing guidelines for prescription during ECMO.DiscussionThe evidence-based dosing algorithms generated from this analysis can be evaluated in later clinical studies. This knowledge is vitally important for optimising pharmacotherapy in these most severely ill patients to maximise the opportunity for therapeutic success and minimise the risk of therapeutic failure.Trial registrationACTRN12612000559819

Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial)☆

BACKGROUND In intensive care observational studies, hypercapnia after cardiac arrest (CA) is independently associated with improved neurological outcome. However, the safety and feasibility of delivering targeted therapeutic mild hypercapnia (TTMH) for such patients is untested. METHODS In a phase II safety and feasibility multi-centre, randomised controlled trial, we allocated ICU patients after CA to 24h of targeted normocapnia (TN) (PaCO2 35-45mmHg) or TTMH (PaCO2 50-55mmHg). The primary outcome was serum neuron specific enolase (NSE) and S100b protein concentrations over the first 72h assessed in the first 50 patients surviving to day three. Secondary end-points included global measure of function assessment at six months and mortality for all patients. RESULTS We enrolled 86 patients. Their median age was 61 years (58, 64 years) and 66 (79%) were male. Of these, 50 patients (58%) survived to day three for full biomarker assessment. NSE concentrations increased in the TTMH group (p=0.02) and TN group (p=0.005) over time, with the increase being significantly more pronounced in the TN group (p(interaction)=0.04). S100b concentrations decreased over time in the TTMH group (p<0.001) but not in the TN group (p=0.68). However, the S100b change over time did not differ between the groups (p(interaction)=0.23). At six months, 23 (59%) TTMH patients had good functional recovery compared with 18 (46%) TN patients. Hospital mortality occurred in 11 (26%) TTMH patients and 15 (37%) TN patients (p=0.31). CONCLUSIONS In CA patients admitted to the ICU, TTMH was feasible, appeared safe and attenuated the release of NSE compared with TN. These findings justify further investigation of this novel treatment.

A Randomised feasibility study to assess a novel strategy to rationalise fluid in patients after cardiac surgery

BACKGROUND After cardiac surgery, patients receive large amounts of fluid in the Intensive Care Unit (ICU). We plan to conduct a multi-centre randomised controlled trial, of a conservative fluid regime, in patients after cardiac surgery, and have reported results of a feasibility study that evaluated efficacy and safety of the proposed regime. METHODS After ethical approval, a single-centre, prospectively randomised interventional study was undertaken. Participants were randomised to either usual care, or to a protocolised algorithm, utilising stroke volume variation, to guide fluid administration to patients who were deemed to have inadequate cardiac output and were likely to be volume responsive. The study protocol lasted from ICU admission to de-sedation or 24 h, whichever occurred first. RESULTS We randomised 144 subjects over 9 months. Less bolus fluid and less total overall fluid volume was administered in the intervention group (median (IQR) 1620 ml (500-3410) and 2525 ml (1440-5250; P<0.001), compared with the usual care group (2050 ml (910-4280) and 2980 ml (2070-6580; P=0.001), from ICU admission to extubation. There was no significant difference in incidence of acute kidney injury or the average amount of fluid administered to the usual care group at the beginning compared with the end of the study. CONCLUSION It is both possible and safe to achieve a significant reduction in the amount of fluid administered to patients, allocated to a conservative fluid protocol. These results suggest that a planned multi-centre study is both justified and feasible. CLINICAL TRIAL REGISTRATION Australia New Zealand Clinical Trials Registry www.anzctr.org.au (ACTRN12612000754842).