Predicting Beta-Lactam Target Non-Attainment in ICU Patients at Treatment Initiation: Development and External Validation of Three Novel (Machine Learning) Models.

In the intensive care unit (ICU), infection-related mortality is high. Although adequate antibiotic treatment is essential in infections, beta-lactam target non-attainment occurs in up to 45% of ICU patients, which is associated with a lower likelihood of clinical success. To optimize antibiotic treatment, we aimed to develop beta-lactam target non-attainment prediction models in ICU patients. Patients from two multicenter studies were included, with intravenous intermittent beta-lactam antibiotics administered and blood samples drawn within 12-36 h after antibiotic initiation. Beta-lactam target non-attainment models were developed and validated using random forest (RF), logistic regression (LR), and naïve Bayes (NB) models from 376 patients. External validation was performed on 150 ICU patients. We assessed performance by measuring discrimination, calibration, and net benefit at the default threshold probability of 0.20. Age, sex, serum creatinine, and type of beta-lactam antibiotic were found to be predictive of beta-lactam target non-attainment. In the external validation, the RF, LR, and NB models confirmed good discrimination with an area under the curve of 0.79 [95% CI 0.72-0.86], 0.80 [95% CI 0.73-0.87], and 0.75 [95% CI 0.67-0.82], respectively, and net benefit in the RF and LR models. We developed prediction models for beta-lactam target non-attainment within 12-36 h after antibiotic initiation in ICU patients. These online-accessible models use readily available patient variables and help optimize antibiotic treatment. The RF and LR models showed the best performance among the three models tested.

Pharmacokinetics of zanamivir in critically ill patients undergoing continuous venovenous hemofiltration.

BACKGROUND: Limited data exist for dosing of zanamivir in the setting of CVVH in the intensive care unit (ICU). Our objective is to report the pharmacokinetics and sieving coefficient (Sv) of zanamivir in patients receiving continuous venovenous hemofiltration (CVVH). METHODS: In this prospective observational study, patients of ≥18 years admitted to the ICU with a life-threatening Influenza A or B infection, treated with zanamivir i.v. undergoing CVVH were included. Patients received a zanamivir loading dose of 600 mg i.v., 12 h later followed by maintenance dosages two times daily according to the treating physician. Per patient, nine CFT plasma and nine ultrafiltrate samples were drawn on day 2 of treatment and analysed with a validated HPLC-MS/MS method. RESULTS: Four patients were included in the study. The zanamivir elimination half-life was prolonged with 5.6-9.9 h, compared to patients with normal renal function. A Sv of approximately 1.0 was identified, with unrestricted transport of zanamivir to the ultrafiltrate. CONCLUSIONS: Zanamivir is well cleared by CVVH. In absence of the possibility for therapeutic drug monitoring, the ultrafiltration rate seems as a good surrogate parameter to estimate the CLCVVH and may help guide the dosing of zanamivir.

Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial.

PURPOSE: Individualising 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. METHODS: This 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. RESULTS: In 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. CONCLUSIONS: We 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.

Target attainment and pharmacokinetics of cefotaxime in critically ill patients undergoing continuous kidney replacement therapy.

OBJECTIVES: Limited data exist about the antimicrobial target attainment and pharmacokinetics of cefotaxime in critically ill patients in the ICU undergoing continuous kidney replacement therapy (CKRT). We conducted a prospective observational study in two large teaching hospitals [Isala Hospital (IH) and Zwolle and Maasstad Hospital (MH)] to investigate target attainment and pharmacokinetics of cefotaxime in patients undergoing CKRT. PATIENTS AND METHODS: Patients aged ≥18 years admitted to the ICU treated with IV cefotaxime 1000 mg three times daily (IH) or 4 times daily (MH) were included. Fifteen patients were enrolled in total. Per patient eight cefotaxime plasma and eight ultrafiltrate samples were drawn in IH and four plasma samples in MH on Day 2 of treatment. In ICU patients the recommended antimicrobial target of cefotaxime is a plasma concentration 100% of the time above the MIC. RESULTS: In IH 10/11 patients had higher plasma trough concentrations than the MIC breakpoint of Enterobacterales of 1 mg/L (clinical breakpoint for susceptible strains) and 9/11 patients had concentrations above 2 mg/L (clinical breakpoint for resistant strains). All patients (4/4) in MH had higher plasma trough concentrations than 2 mg/L. A sieving coefficient of 0.74 was identified, with a median amount of 40% of cefotaxime eliminated by CKRT. CONCLUSIONS: We conclude that cefotaxime 1000 mg 3-4 times daily gives adequate plasma concentrations in patients with anuria or oliguria undergoing CKRT. The 1000 mg four times daily dosage is recommended in patients undergoing CKRT with partially preserved renal function to achieve the target.

Workload scoring systems in the Intensive Care and their ability to quantify the need for nursing time: A systematic literature review.

INTRODUCTION: The Intensive Care Unit is a resource intense service with a high nursing workload per patient resulting in a low ratio of patients per nurse. This review aims to identify existing scoring systems for measuring nursing workload on the Intensive Care and assess their validity and reliability to quantify the needed nursing time. METHODS: We conducted a systematic review of the literature indexed before 01/Mar/2018 in the bibliographic databases MEDLINE, Embase, and Cinahl. Full-text articles were selected and data on systems measuring nursing workload on the Intensive Care and translation of this workload into the amount of nursing time needed was extracted. RESULTS: We included 71 articles identifying 34 different scoring systems of which 27 were included for further analysis as these described a translation of workload into nursing time needed. Almost all systems were developed with nurses. The validity of most scoring systems was evaluated by comparing them with another system (59%) or by using time measurements (26%). The most common way to translate workload-scores into nursing time needed was by categorizing the Nurse:Patient-ratios. Validation of the Nurse:Patient-ratios was mostly evaluated by comparing the results with other systems or with the actual planning and not with objective time measurements. CONCLUSION: Despite the large attention given to nursing workload systems for Intensive Care, only a few systems objectively evaluated the validity and reliability of measuring nursing workload with moderate results. The Nursing Activity Score system performed best. Poor methodology for the translation of workload scores into Nurse:Patient-ratio weakens the value of nursing workload scoring systems in daily Intensive Care practice.

RELAx - REstricted versus Liberal positive end-expiratory pressure in patients without ARDS: protocol for a randomized controlled trial.

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 H2O, while patients assigned to ventilation with high PEEP will receive PEEP of 8 cm H2O. 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.

Effect of On-Demand vs Routine Nebulization of Acetylcysteine With Salbutamol on Ventilator-Free Days in Intensive Care Unit Patients Receiving Invasive Ventilation: A Randomized Clinical Trial.

Importance: It remains uncertain whether nebulization of mucolytics with bronchodilators should be applied for clinical indication or preventively in intensive care unit (ICU) patients receiving invasive ventilation. Objective: To determine if a strategy that uses nebulization for clinical indication (on-demand) is noninferior to one that uses preventive (routine) nebulization. Design, Setting, and Participants: Randomized clinical trial enrolling adult patients expected to need invasive ventilation for more than 24 hours at 7 ICUs in the Netherlands. Interventions: On-demand nebulization of acetylcysteine or salbutamol (based on strict clinical indications, n = 471) or routine nebulization of acetylcysteine with salbutamol (every 6 hours until end of invasive ventilation, n = 473). Main Outcomes and Measures: The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for a difference between groups of -0.5 days. Secondary outcomes included length of stay, mortality rates, occurrence of pulmonary complications, and adverse events. Results: Nine hundred twenty-two patients (34% women; median age, 66 (interquartile range [IQR], 54-75 years) were enrolled and completed follow-up. At 28 days, patients in the on-demand group had a median 21 (IQR, 0-26) ventilator-free days, and patients in the routine group had a median 20 (IQR, 0-26) ventilator-free days (1-sided 95% CI, -0.00003 to ∞). There was no significant difference in length of stay or mortality, or in the proportion of patients developing pulmonary complications, between the 2 groups. Adverse events (13.8% vs 29.3%; difference, -15.5% [95% CI, -20.7% to -10.3%]; P < .001) were more frequent with routine nebulization and mainly related to tachyarrhythmia (12.5% vs 25.9%; difference, -13.4% [95% CI, -18.4% to -8.4%]; P < .001) and agitation (0.2% vs 4.3%; difference, -4.1% [95% CI, -5.9% to -2.2%]; P < .001). Conclusions and Relevance: Among ICU patients receiving invasive ventilation who were expected to not be extubated within 24 hours, on-demand compared with routine nebulization of acetylcysteine with salbutamol did not result in an inferior number of ventilator-free days. On-demand nebulization may be a reasonable alternative to routine nebulization. Trial Registration: clinicaltrials.gov Identifier: NCT02159196.

[Resuscitation for myocardial infarction and head injury: first the heart or first the head?]. / Reanimatie bij myocardinfarct en trauma capitis: eerst het hart of eerst het hoofd?

Loss of circulation in a patient results in collapse and therefore possible head injury. After percutaneous coronary intervention (PCI) including anticoagulation, comatose patients are sedated for mild therapeutic hypothermia. Recognised or unrecognised head trauma may have dramatic clinical consequences. A 42-year-old male with unrecognised head trauma died due to a massive intracranial haemorrhage (ICH) during the hypothermia phase after being treated with PCI. A 76-year-old female, on anticoagulation for atrial fibrillation, with recognised ICH which resulted in an adjusted PCI, died after five days due to a lethal re-bleed. In a 55-year-old male with neurological abnormalities after mild head trauma, the PCI was postponed for a (negative) head CT which might have increased cardiac muscle damage. Nowadays more patients reach hospital after being resuscitated for cardiac arrest and possible head trauma should be considered in all these patients. This could lead to adjustments being made in the treatment protocol.

Endoscopic clip-assisted feeding tube placement reduces repeat endoscopy rate: results from a randomized controlled trial.

OBJECTIVES: To determine whether endoscopic clip-assisted nasoenteral feeding tube placement is more effective than standard feeding tube placement with transnasal endoscopy. METHODS: Between August 2009 and February 2011, 143 patients referred for endoscopic nasoenteral feeding tube placement were randomized between clip-assisted and standard nasoenteral tube placement. Endoscopies were performed in the endoscopy unit and intensive care unit in a tertiary referral center in the Netherlands. For the clip-assisted procedure, the feeding tube was introduced with a suture fixed to the tip, picked up in the stomach with an endoclip and attached (as distal as possible) to the duodenal wall. In the standard group, a guide wire was placed in the duodenum using a transnasal endoscope, followed by blind insertion of a feeding tube over the guide wire. Primary end point was a repeat endoscopy for incorrect tube placement or spontaneous retrograde tube migration. Secondary end points were incorrect tube placement, spontaneous migration of feeding tube, directs medical costs, and procedure-related (serious) adverse event (SAE). RESULTS: Of the 143 patients included, 71 were randomly assigned to clip-assisted tube placement, and 72 to standard tube placement. Four (5.6%) repeat endoscopies were performed in the clip-assisted group vs. 19 (26.4%) in the standard group (relative risk reduction (RRR) 0.79; 95% confidence interval (CI) 0.40-0.92). The number needed to clip to avoid one repeat endoscopy was 4.8 (95% CI 3.1-11.3). Repeat endoscopies were mostly performed for incorrectly placed tubes, 3 (4.2%) in the clip-assisted group vs. 16 (22.2%, RRR 0.81; 95% CI 0.38-0.94) in the standard group. Spontaneous retrograde tube migration occurred in one (1.4%) clip-assisted placement and three (4.2%) standard tubes. Median costs were higher for clip-assisted tube placement (€519 vs. €423, P<0.01). Four (5.6%) SAEs occurred after clip-assisted feeding tube placement vs. one (1.4%) after standard feeding tube placement (P=0.21). CONCLUSIONS: Clip-assisted endoscopic nasoenteral feeding tube placement results in fewer repeat endoscopies than standard endoscopic nasoenteral tube placement, due to a higher success rate of initial placement. When tubes are adequately placed, retrograde tube migration rarely occurs.

A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis.

OBJECTIVE: Chemokines such as CCL2/monocyte chemotactic protein 1 (MCP-1) play a key role in leukocyte migration and are potential targets in the treatment of chronic inflammatory disorders. The objective of this study was to evaluate the effects of human anti-CCL2/MCP-1 monoclonal antibody (ABN912) treatment in patients with rheumatoid arthritis (RA). METHODS: Patients with active RA were enrolled in a randomized, placebo-controlled, dose-escalation study of ABN912. Infusions were administered on day 1 and day 15. In the dose-escalation phase, 4 cohorts of 8 patients each underwent serial arthroscopic biopsy of synovial tissue. Immunohistochemistry and digital image analysis were used to characterize biomarkers in synovial tissue. Laboratory evaluation included pharmacokinetic analysis and immunotypic studies of peripheral blood mononuclear cells. To assess the clinical effects of treatment with ABN912, an additional 21 patients were treated with the highest dose tolerated. RESULTS: The total study population comprised 45 patients: 33 patients received ABN912, and 12 patients received placebo. ABN912 treatment was well tolerated. Unexpectedly, there was a dose-related increase in ABN912-complexed total CCL2/MCP-1 levels in peripheral blood, up to 2,000-fold. There was no detectable clinical benefit of ABN912 compared with placebo, nor did treatment with the study drug result in a significant change in the levels of biomarkers in synovial tissue and peripheral blood. CONCLUSION: ABN912 treatment did not result in clinical or immunohistologic improvement and may have been associated with worsening of RA in patients treated with the highest dose. The results might be related to the greatly increased level of total CCL2/MCP-1 in serum that was observed following treatment with ABN912. This observation may be relevant for a variety of antibody-based therapies.

Synovial tissue analysis in clinical trials.

Synovial tissue analysis has considerable potential for future randomized controlled trials (RCT). The synovial membrane is the target tissue in treatment strategies of rheumatoid arthritis and other arthropathies. Effective modulation of synovitis is critical when attempting to control symptoms and signs, to prevent joint damage, and to maintain function. In RCT, the systematic evaluation of changes in synovial tissue after commencing treatment enables identification of an early therapeutic effect, using relatively small numbers of patients. This special interest group is working on establishing the evidence to have this endpoint meet the OMERACT filter criteria.

Reliability of computerized image analysis for the evaluation of serial synovial biopsies in randomized controlled trials in rheumatoid arthritis.

Analysis of biomarkers in synovial tissue is increasingly used in the evaluation of new targeted therapies for patients with rheumatoid arthritis (RA). This study determined the intrarater and inter-rater reliability of digital image analysis (DIA) of synovial biopsies from RA patients participating in clinical trials. Arthroscopic synovial biopsies were obtained before and after treatment from 19 RA patients participating in a randomized controlled trial with prednisolone. Immunohistochemistry was used to detect CD3+ T cells, CD38+ plasma cells and CD68+ macrophages. The mean change in positive cells per square millimetre for each marker was determined by different operators and at different times using DIA. Nonparametric tests were used to determine differences between observers and assessments, and to determine changes after treatment. The intraclass correlations (ICCs) were calculated to determine the intrarater and inter-rater reliability. Intrarater ICCs showed good reliability for measuring changes in T lymphocytes (R = 0.87), plasma cells (R = 0.62) and macrophages (R = 0.73). Analysis by Bland-Altman plots showed no systemic differences between measurements. The smallest detectable changes were calculated and their discriminatory power revealed good response in the prednisolone group compared with the placebo group. Similarly, inter-rater ICCs also revealed good reliability for measuring T lymphocytes (R = 0.68), plasma cells (R = 0.69) and macrophages (R = 0.72). All measurements identified the same cell types as changing significantly in the treated patients compared with the placebo group. The measurement of change in total positive cell numbers in synovial tissue can be determined reproducibly for various cell types by DIA in RA clinical trials.

Targeting cellular adhesion molecules, chemokines and chemokine receptors in rheumatoid arthritis.

The development of specific targeted therapies, such as anti-TNF-alpha treatment, for chronic inflammatory disorders such as rheumatoid arthritis, has significantly improved treatment, although not all patients respond. Targeting cellular adhesion molecules and chemokines/chemokine receptors as regulators of the extravasation and migration of leukocytes may provide a novel approach for the treatment of these diseases. Moreover, the possibility of developing small-molecule antagonists offers an excellent method for the oral delivery of compounds with a short half-life.

Effects of oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid arthritis.

OBJECTIVE: To create greater understanding of the changes in synovial tissue parameters that occur in conjunction with clinical response by using an effective therapy, in order to facilitate the planning of future studies with therapeutic agents for rheumatoid arthritis (RA). METHODS: Twenty-one patients with active RA were randomized to receive either oral prednisolone (n = 10) or placebo (n = 11) for 2 weeks. In all patients, synovial tissue biopsy specimens were obtained by arthroscopy directly before treatment and after 14 days of treatment. Immunohistochemical analysis was performed to characterize the cell infiltrate and vascularity. Stained tissue sections were analyzed by digital imaging. Statistical analysis was performed using an analysis of covariance model. RESULTS: After treatment, the mean Disease Activity Score in 28 joints (DAS28) was 2.0 units lower (95% confidence interval [95% CI] 1.0-3.0) in patients who received prednisolone than in those who received placebo. In the prednisolone group, the mean (+/-SD) DAS28 decreased from 6.27 +/- 0.95 to 4.11 +/- 1.43 after therapy; minimal change was observed in the placebo group. For macrophages, the estimated effect of prednisolone was large. Patients receiving active treatment had fewer (mean 628 cells/mm(2) [95% CI 328-927]) macrophages after therapy compared with those receiving placebo. A reduction in the total number of CD68+ macrophages, from 1,038 +/- 283 cells/mm(2) before treatment to 533 +/- 248 cells/mm(2) after treatment, was observed in the prednisolone group. There were clear trends toward decreased infiltration by T cells, plasma cells, and fibroblast-like synoviocytes after active treatment. We observed a trend toward a reduction in alphavbeta3+ newly formed blood vessels and expression of vascular growth factors after prednisolone therapy. CONCLUSION: Prednisolone therapy in RA is associated with a marked reduction in macrophage infiltration in synovial tissue, suggesting that synovial macrophage numbers could be used as a biomarker for clinical efficacy.

Chemokine blockade: a new era in the treatment of rheumatoid arthritis?

Blockade of chemokines or chemokine receptors is emerging as a new potential treatment for various immune-mediated conditions. This review focuses on the therapeutic potential in rheumatoid arthritis, based on studies in animal models and patients. Several knockout models as well as in vivo use of chemokine antagonists are discussed. Review of these data suggests that this approach might lead to novel therapeutic strategies in rheumatoid arthritis and other chronic inflammatory disorders.