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Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is associated with high mortality. The creatinine-based stage of AKI is considered when deciding to start or delay RRT. However, creatinine is not only determined by renal function (excretion), but also by dilution (fluid balance) and creatinine generation (muscle mass). The aim of this study was to explore whether fluid balance-adjusted creatinine at initiation of RRT is related to 28-day mortality independent of other markers of AKI, surrogates of muscle mass and severity of disease. We performed a post-hoc analysis on data from the multicentre CASH trial comparing citrate to heparin anticoagulation during continuous venovenous hemofiltration (CVVH). To determine whether fluid balance-adjusted creatinine was associated with 28-day mortality, we performed a logistic regression analysis adjusting for confounders of creatinine generation (age, gender, body weight), other markers of AKI (creatinine, urine output) and severity of disease. Of the 139 patients, 32 patients were excluded. Of the 107 included patients, 36 died at 28 days (34%). Non-survivors were older, had higher APACHE II and inclusion SOFA scores, lower pH and bicarbonate, lower creatinine and fluid balance-adjusted creatinine at CVVH initiation. In multivariate analysis lower fluid balance-adjusted creatinine (OR 0.996, 95% CI 0.993-0.999, p = 0.019), but not unadjusted creatinine, remained associated with 28-day mortality together with bicarbonate (OR 0.869, 95% CI 0.769-0.982, P = 0.024), while the APACHE II score non-significantly contributed to the model. In this post-hoc analysis of a multicentre trial, low fluid balance-adjusted creatinine at CVVH initiation was associated with 28-day mortality, independent of other markers of AKI, organ failure, and surrogates of muscle mass, while unadjusted creatinine was not. More tools are needed for better understanding of the complex determinants of \"AKI classification\", \"CVVH initiation\" and their relation with mortality, fluid balance is only one.

PurposeIndividualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.MethodsThis multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.ResultsIn total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55–71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96–1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.ConclusionsWe could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

Drug–drug interactions (DDIs) can harm patients admitted to the intensive care unit (ICU). Yet, clinical decision support systems (CDSSs) aimed at helping physicians prevent DDIs are plagued by low-yield alerts, causing alert fatigue and compromising patient safety. The aim of this multicentre study was to evaluate the effect of tailoring potential DDI alerts to the ICU setting on the frequency of administered high-risk drug combinations. We implemented a cluster randomised stepped-wedge trial in nine ICUs in the Netherlands. Five ICUs already used potential DDI alerts. Patients aged 18 years or older admitted to the ICU with at least two drugs administered were included. Our intervention was an adapted CDSS, only providing alerts for potential DDIs considered as high risk. The intervention was delivered at the ICU level and targeted physicians. We hypothesised that showing only relevant alerts would improve CDSS effectiveness and lead to a decreased number of administered high-risk drug combinations. The order in which the intervention was implemented in the ICUs was randomised by an independent researcher. The primary outcome was the number of administered high-risk drug combinations per 1000 drug administrations per patient and was assessed in all included patients. This trial was registered in the Netherlands Trial Register (identifier NL6762) on Nov 26, 2018, and is now closed. In total, 10 423 patients admitted to the ICU between Sept 1, 2018, and Sept 1, 2019, were assessed and 9887 patients were included. The mean number of administered high-risk drug combinations per 1000 drug administrations per patient was 26·2 (SD 53·4) in the intervention group (n=5534), compared with 35·6 (65·0) in the control group (n=4353). Tailoring potential DDI alerts to the ICU led to a 12% decrease (95% CI 5–18%; p=0·0008) in the number of administered high-risk drug combinations per 1000 drug administrations per patient, after adjusting for clustering and prognostic factors. This cluster randomised stepped-wedge trial showed that tailoring potential DDI alerts to the ICU setting significantly reduced the number of administered high-risk drug combinations. Our list of high-risk drug combinations can be used in other ICUs, and our strategy of tailoring alerts based on clinical relevance could be applied to other clinical settings. ZonMw.

This study aims to assess pharmacodynamic target attainment in critically ill patients and identify factors influencing target attainment and mortality outcomes. We analysed data from the DOLPHIN trial. Beta-lactam and ciprofloxacin peak and trough concentration were measured within the first 36 h (T1) after initiation of treatment. The study outcome included the rate of pharmacodynamic target attainment of 100 % ƒT>1xEpidemiological cut-off value (ECOFF) for beta-lactams, and of fAUC0-24h/ECOFF>125 for ciprofloxacin at T1. The target attainment rates were 78.1 % (n = 228/292) for beta-lactams, and 41.5 % (n = 39/94) for ciprofloxacin, respectively. Lower estimated glomerular filtration rate and higher SOFA score were associated with target attainment. In patients receiving beta-lactams, 28-day mortality was significantly higher in patients who attained 100 % ƒT>1xECOFF (28.9 % vs. 12.5 %; p = 0.01). In the multivariate analysis, attainment of 100 % ƒT>4xECOFF, but not 100 % ƒT>1xECOFF, was associated with a higher 28-day mortality (OR 2.70, 95 % CI 1.36–5.48 vs. OR 1.28, 95 % CI 0.53–3.34). A high rate of target attainment (100 % ƒT>1xECOFF) for beta-lactams and a lower rate for ciprofloxacin was observed. Achieving exposures of 100 % ƒT>4xECOFF was associated with 28-day mortality. The impact of antibiotic target attainment on clinical outcome needs to be a focus of future research. •Pharmacodynamic target attainment of beta-lactam antibiotics was high.•Pharmacodynamic target attainment of ciprofloxacin was low.•Higher exposure of beta-lactams was an independent risk factor of 28-day mortality.•The impact of antibiotic target attainment on clinical outcome merits further investigations.

Background Brain computer tomography (brain CT) is an important imaging tool in patients with intracranial disorders. In ICU patients, a brain CT implies an intrahospital transport which has inherent risks. The proceeds and consequences of a brain CT in a critically ill patient should outweigh these risks. The aim of this study was to critically evaluate the diagnostic and therapeutic yield of brain CT in ICU patients. Methods In a prospective observational study data were collected during one year on the reasons to request a brain CT, expected abnormalities, abnormalities found by the radiologist and consequences for treatment. An “expected abnormality” was any finding that had been predicted by the physician requesting the brain CT. A brain CT was “diagnostically positive”, if the abnormality found was new or if an already known abnormality was increased. It was “diagnostically negative” if an already known abnormality was unchanged or if an expected abnormality was not found. The treatment consequences of the brain CT, were registered as “treatment as planned”, “treatment changed, not as planned”, “treatment unchanged”. Results Data of 225 brain CT in 175 patients were analyzed. In 115 (51%) brain CT the abnormalities found were new or increased known abnormalities. 115 (51%) brain CT were found to be diagnostically positive. In the medical group 29 (39%) of brain CT were positive, in the surgical group 86 (57%), p 0.01. After a positive brain CT, in which the expected abnormalities were found, treatment was changed as planned in 33%, and in 19% treatment was changed otherwise than planned. Conclusions The results of this study show that the diagnostic and therapeutic yield of brain CT in critically ill patients is moderate. The development of guidelines regarding the decision rules for performing a brain CT in ICU patients is needed.

Background Evidence for benefit of high positive end-expiratory pressure (PEEP) is largely lacking for invasively ventilated, critically ill patients with uninjured lungs. We hypothesize that ventilation with low PEEP is noninferior to ventilation with high PEEP with regard to the number of ventilator-free days and being alive at day 28 in this population.  Methods/Design The “REstricted versus Liberal positive end-expiratory pressure in patients without ARDS” trial (RELAx) is a national, multicenter, randomized controlled, noninferiority trial in adult intensive care unit (ICU) patients with uninjured lungs who are expected not to be extubated within 24 h. RELAx will run in 13 ICUs in the Netherlands to enroll 980 patients under invasive ventilation. In all patients, low tidal volumes are used. Patients assigned to ventilation with low PEEP will receive the lowest possible PEEP between 0 and 5 cm H 2 O, while patients assigned to ventilation with high PEEP will receive PEEP of 8 cm H 2 O. The primary endpoint is the number of ventilator-free days and being alive at day 28, a composite endpoint for liberation from the ventilator and mortality until day 28, with a noninferiority margin for a difference between groups of 0.5 days. Secondary endpoints are length of stay (LOS), mortality, and occurrence of pulmonary complications, including severe hypoxemia, major atelectasis, need for rescue therapies, pneumonia, pneumothorax, and development of acute respiratory distress syndrome (ARDS). Hemodynamic support and sedation needs will be collected and compared. Discussion RELAx will be the first sufficiently sized randomized controlled trial in invasively ventilated, critically ill patients with uninjured lungs using a clinically relevant and objective endpoint to determine whether invasive, low-tidal-volume ventilation with low PEEP is noninferior to ventilation with high PEEP. Trial registration ClinicalTrials.gov , ID: NCT03167580 . Registered on 23 May 2017.