Nephrotoxicity of continuous amphotericin B in critically ill patients with abdominal sepsis: a retrospective analysis with propensity score matching.

BACKGROUND: Continuous infusion of conventional amphotericin B (CCAB) is used in ICUs for pre-emptive treatment of invasive fungal infections. Amphotericin B has previously been associated with nephrotoxicity. OBJECTIVES: To investigate if CCAB with therapeutic drug monitoring (TDM) results in renal impairment over time in critically ill patients with abdominal sepsis. PATIENTS AND METHODS: The study was conducted at mixed medical-surgical ICUs of two large teaching hospitals in the Netherlands. Consecutive patients who were treated on the ICUs between 2006 and 2019 for abdominal sepsis, with or without CCAB, were included. CCAB dosing was guided by TDM. Serum creatinine concentrations and renal failure scores of patients with CCAB treatment were compared with those without CCAB treatment. Excluded were: (i) patients treated with CCAB for less than 72 h; and (ii) patients with renal replacement therapy. RESULTS: A total of 319 patients were included (185 treated with CCAB and 134 controls). A multiple linear regression model showed that the serum creatinine concentration was independent of CCAB treatment (ß = -0.023; 95% CI = -12.2 to 7.2; P = 0.615). Propensity score matching resulted in 134 pairs of CCAB-treated and non-treated patients. Again, the analysis of these pairs showed that the cumulative CCAB dose was not associated with serum creatinine concentration during intensive care treatment (ß = 0.299; 95% CI = -0.38 to 0.98; P = 0.388). CONCLUSIONS: CCAB with TDM did not result in renal impairment over time in critically ill patients with abdominal sepsis.

Accuracy and reliability of a subcutaneous continuous glucose monitoring device in critically ill patients.

Subcutaneous continuous glucose monitoring (CGM) may have benefits in achieving glycemic control in critically ill patients. The aim of this study was to assess the accuracy and reliability of the FreeStyle Navigator I in critically ill patients and to assess patient related factors influencing the accuracy and reliability. This study is a retrospective analysis of data from a randomized controlled trial conducted in a 20-bed mixed intensive care unit. Analytical accuracy, clinical accuracy and reliability were assessed against arterial blood glucose samples as reference. Assessment was according to recent consensus recommendations with median absolute relative difference (median ARD), Bland-Altman plots, the ISO system accuracy standards (ISO 15197:2013) and Clarke error grid analysis (CEG). We analyzed 2840 paired measurements from 155 critically ill patients. The median ARD of all paired values was 13.3 [6.9-22.1]%. The median ARD was significantly higher in both the hypoglycemic and the hyperglycemic range (32.4 [12.1-53.4]% and 18.7 [10.7-28.3]% respectively, p < 0.001). The Bland-Altman analysis showed a mean bias of - 0.82 mmol/L with a lower limit of agreement (LOA) of - 3.88 mmol/L and an upper LOA of 2.24 mmol/L. A total of 1626 (57.3%) values met the ISO-2013, standards and 1,334 (47%) CGM values were within 12.5% from the reference value. CEG: 71.0% zone A, 25.8% zone B, 0.5% zone C, 2.5% zone D, 0.3% zone E. The median overall real-time data display time was 94.0 ± 14.9% and in 23% of the patients, the sensor measured < 95% of the time. Additionally, data gaps longer than 30 min were found in 48% of the patients. The analytical accuracy of the FreeStyle Navigator I in critically ill patients was suboptimal. Furthermore, the clinical accuracy, did not meet the required standards. The reliability was satisfactory, however, in almost a quarter of the patients the realtime data display was < 95%. The accuracy was considerably and significantly lower in hyper- and hypoglycemic ranges.

Selective decontamination of the oropharynx and the digestive tract, and antimicrobial resistance: a 4 year ecological study in 38 intensive care units in the Netherlands.

OBJECTIVES: Selective oropharyngeal decontamination (SOD) and selective decontamination of the digestive tract (SDD) are associated with improved outcomes among patients in intensive care units (ICUs), but uncertainty remains about their long-term effects on resistance levels. We determined trends in antibiotic resistance among Gram-negative bacteria in 38 Dutch ICUs using and not using SOD/SDD. METHODS: The Infectious Disease Surveillance Information System-Antibiotic Resistance (ISIS-AR) was used to identify all Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. isolates from blood and respiratory tract specimens from ICUs between January 2008 and April 2012. Per patient, the last isolate per species per specimen per month was selected to determine cumulative resistance rates (per 100 beds/month) for colistin, tobramycin, ciprofloxacin, ceftazidime and cefotaxime/ceftriaxone in ICUs that continuously used or did not use SOD/SDD, and ICUs that introduced SOD/SDD. Time trends were analysed by multilevel Poisson regression. RESULTS: Seventeen ICUs continuously used SOD/SDD (859 months), 13 did not use SOD/SDD (663 months) and 8 introduced SOD/SDD (223 and 117 months before and after introduction). There were no discernible trends in antibiotic resistance among 637 blood isolates. For the 8353 respiratory isolates, resistance to cefotaxime/ceftriaxone increased in ICUs that did not use SOD/SDD (P < 0.001) and decreased in those that continuously used SOD/SDD (P = 0.04), as did resistance to ciprofloxacin (P < 0.001). The introduction of SOD/SDD was followed by statistically significant reductions in resistance rates for all antimicrobial agents. CONCLUSIONS: Continuous use of SOD/SDD was associated with decreasing trends for resistance to cefotaxime/ceftriaxone and ciprofloxacin. The introduction of SOD/SDD was associated with reductions in resistance rates for all antimicrobial agents included.

The use of indicators to improve the quality of intensive care: theoretical aspects and experiences from the Dutch intensive care registry.

In the concept of total quality management that was originally developed in industry, the use of quality indicators is essential. The implementation of quality indicators in the intensive care unit to improve the quality of care is a complex process. This process can be described in seven subsequent steps of an indicator-based quality improvement (IBQI) cycle. With this IBQI cycle, a continuous quality improvement can be achieved with the use of indicator data in a benchmark setting. After the development of evidence-based indicators, a sense of urgency has to be created, registration should start, raw data must be analysed, feedback must be given, and interpretation and conclusions must be made, followed by a quality improvement plan. The last step is the implementation of changes that needs a sense of urgency, and this completes the IBQI cycle. Barriers and facilitators are found in each step. They should be identified and addressed in a multifaceted quality improvement strategy.

The development of a glucose prediction model in critically ill patients.

PURPOSE: The aim of the current study is to develop a prediction model for glucose levels applicable for all patients admitted to the ICU with an expected ICU stay of at least 24 h. This model will be incorporated in a closed-loop glucose system to continuously and automatically control glucose values. METHODS: Data from a previous single-center randomized controlled study was used. All patients received a FreeStyle Navigator II subcutaneous CGM system from Abbott during their ICU stay. The total dataset was randomly divided into a training set and a validation set. A glucose prediction model was developed based on historical glucose data. Accuracy of the prediction model was determined using the Mean Squared Difference (MSD), the Mean Absolute Difference (MAD) and a Clarke Error Grid (CEG). RESULTS: The dataset included 94 ICU patients with a total of 134,673 glucose measurements points that were used for modelling. MSD was 0.410 ± 0.495 for the model, the MAD was 5.19 ± 2.63 and in the CEG 99.8% of the data points were in the clinically acceptable regions. CONCLUSION: In this study a glucose prediction model for ICU patients is developed. This study shows that it is possible to accurately predict a patient's glucose 30 min ahead based on historical glucose data. This is the first step in the development of a closed-loop glucose system.

Anti-infectious decontamination strategies in Dutch intensive care units: A survey study on contemporary practice and heterogeneity.

PURPOSE: Despite increasing evidence and updated national guidelines, practice of anti-infectious strategies appears to vary in the Netherlands. This study aimed to determine the variation of current practices of anti-infectious strategies in Dutch ICUs. MATERIALS AND METHODS: In 2018 and 2019 an online survey of all Dutch ICUs was conducted with detailed questions on their anti-infectious strategies. RESULTS: 89% (63 of 71) of the Dutch ICUs responded to the online survey. The remaining ICUs were contacted by telephone. 47 (66%) of the Dutch ICUs used SDD, 14 (20%) used SOD and 10 (14%) used neither SDD nor SOD. Within these strategies considerable heterogeneity was observed in the start criteria of SDD/SOD, the regimen adjustments based on microbiological surveillance and the monitoring of the interventions. CONCLUSIONS: The proportion of Dutch ICUs applying SDD or SOD increased over time. Considerable heterogeneity in the regimens was reported. The impact of the observed differences within SDD and SOD practices on clinical outcome remains to be explored.

The epidemiology of intra-abdominal flora in critically ill patients with secondary and tertiary abdominal sepsis.

BACKGROUND: Background: Different micro-organisms can be cultured from abdominal fluid obtained from patients with intra-abdominal infection resulting from a perforated digestive tract. We evaluated a cohort of patients with abdominal sepsis admitted to the intensive care with the aim of obtaining more insight into the type of microorganisms involved and the efficacy of treatment. MATERIALS AND METHODS: A 5-year prospective observational cohort study was performed in patients admitted to the intensive care unit with abdominal sepsis syndrome, defined as a perforation of the digestive tract and inflammatory response with organ failure. Abdominal fluid was obtained for microbial culture during the surgical procedures and from abdominal drains. The initial treatment protocol was cefotaxim, ciprofloxacin, metronidazole, and amphotericin B, tailored according to microbiological results. Selective decontamination of the digestive tract was administered to prevent secondary endogenous infections. RESULTS: Abdominal fluid was taken for microbial culture from 221 of the 239 patients admitted with abdominal sepsis. Aerobic Gram-negative bacteria (AGNB) were found in 52.9% of the cultures of abdominal fluid taken at the time of operation, of which 45% were Escherichia coli; in 36% of patients more than one AGNB was found. The incidence of AGNB was highest in colorectal perforations (68.6%) and perforated appendicitis (77.8%) and lowest in gastroduodenal perforations (20.5%). Gram-positive bacteria were found in 42.5% of the abdominal fluid cultures and most frequently in colorectal perforations (50.0%). Candida was found in 19.9% of patients, with 59.1% of these cultures being Candida albicans. The incidence of Candida was 41.0% in gastroduodenal perforations and 11.8% in colorectal perforation. Anaerobic bacteria were cultured in 77.8% of patients with perforated appendicitis. Over time, the prevalence of AGNB in abdominal fluid decreased from 117 patients (52.9%) in the first culture to one patient (6.7%) in week 4 (efficacy 87%). The prevalence of Gram-positive bacteria increased from 42.5% to 86.7% in a 4-week period. CONCLUSION: The composition of the intra-abdominal flora found in critically ill patients with abdominal sepsis varies depending on the location of the perforation. The efficacy of combined surgical and antibiotic treatment was 87% in 4 weeks for AGNB.

A serious complication in the puerperium: peripartum cardiomyopathy.

Two women, aged 27, presented with different symptoms shortly after giving birth to their first child. Peripartum cardiomyopathy (PPCM) was diagnosed. PPCM is a rare form of cardiac failure occurring late in pregnancy or in the postpartum period. Many women experience dyspnoea, fatigue, and pedal oedema in the last month of pregnancy or postpartum, symptoms which are identical to early congestive heart failure. Therefore, the diagnosis of PPCM requires vigilance. A high mortality rate and overall poor clinical outcome has been reported in a high percentage of these patients. Subsequent pregnancies remain controversial. (Neth Heart J 2008;16:415-8.).

An alternative ICU staffing model: implementation of the non-physician provider.

INTRODUCTION: Literature in Europe regarding implementation of nurse practitioners or physician assistants in the intensive care unit (ICU) is lacking, while some available studies indicate that this concept can improve the quality of care and overcome physician shortages on ICUs. The aim of this study is to provide insight on how a Dutch ICU implemented non-physician providers (NPP), besides residents, and what this staffing model adds to the care on the ICU. METHODS: This paper defines the training course and job description of NPPs on a Dutch ICU. It describes the number and quality of invasive interventions performed by NPPs, residents, and intensivists during the years 2015 and 2016. Salary scales of NPPs and residents are provided to describe potential cost-effectiveness. RESULTS: The tasks of NPPs on the ICU are equal to those of the residents. Analysis of the invasive interventions performed by NPPs showed an incidence of central venous catheter insertion for NPPs of 20 per fulltime equivalent (FTE) and for residents 4.3 per FTE in one year. For arterial catheters the NPP inserted 61.7 per FTE and the residents inserted 11.8 per FTE. The complication rate of both groups was in line with recent literature. Regarding their salary: after five years in service an NPP earns more than a starting resident. CONCLUSION: This is the first European study which describes the role of NPPs on the ICU and shows that practical interventions normally performed by physicians can be performed with equal safety and quality by NPPs.

External validation of prognostic models for critically ill patients required substantial sample sizes.

OBJECTIVE: To investigate the behavior of predictive performance measures that are commonly used in external validation of prognostic models for outcome at intensive care units (ICUs). STUDY DESIGN AND SETTING: Four prognostic models (Simplified Acute Physiology Score II, the Acute Physiology and Chronic Health Evaluation II, and the Mortality Probability Models II) were evaluated in the Dutch National Intensive Care Evaluation registry database. For each model discrimination (AUC), accuracy (Brier score), and two calibration measures were assessed on data from 41,239 ICU admissions. This validation procedure was repeated with smaller subsamples randomly drawn from the database, and the results were compared with those obtained on the entire data set. RESULTS: Differences in performance between the models were small. The AUC and Brier score showed large variation with small samples. Standard errors of AUC values were accurate but the power to detect differences in performance was low. Calibration tests were extremely sensitive to sample size. Direct comparison of performance, without statistical analysis, was unreliable with either measure. CONCLUSION: Substantial sample sizes are required for performance assessment and model comparison in external validation. Calibration statistics and significance tests should not be used in these settings. Instead, a simple customization method to repair lack-of-fit problems is recommended.

Safety of citrate based hemofiltration in critically ill patients at high risk for bleeding: a comparison with nadroparin.

PURPOSE: To study the incidence and severity of bleeding in high risk critically ill patients during high volume, citrate based continuous veno-venous hemofiltration (CVVH). DESIGN: A prospective 1-year observational cohort study comparing citrate based CVVH with nadroparin based CVVH. PROCEDURES: Critically ill patients with multiple organ dysfunction and in need of CVVH were observed for bleeding complications during their CVVH sessions. Pre-defined criteria determined that patients were treated with citrate based CVVH in case of active bleeding or increased risk for bleeding. Otherwise nadroparin was used as anticoagulant. Statistical and outcome methods: The incidence of bleeding complications, the number of transfused blood cell concentrates and the filter-run-time were recorded. Analyses were made by non-parametric tests. MAIN FINDINGS: Fifty-five patients received 272 CVVH sessions. In the citrate group 14.8% experienced a bleeding complication compared to 25% in the nadroparin group (p=0.04). The number of transfused red blood cell concentrates was not different between groups. The nadroparin group had a longer filter run time (median 31.5 hours versus 22.5 hours, p=0.0001). CONCLUSIONS: In high risk critically ill patients citrate based anticoagulation for CVVH is safe in terms of bleeding complications and transfusion requirements.

Trends in practice of blood glucose control in critically ill patients in the Netherlands.

BACKGROUND: Publication of the Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial in 2009 and several observational studies caused a change in the recommendations for blood glucose control in intensive care patients. We evaluated local trends in blood glucose control in intensive care units in the Netherlands before and after the publication of the NICE-SUGAR trial and the revised Surviving Sepsis Campaign (SSC) guidelines in 2012. METHODS: Survey focusing on the timing of changes in thresholds in local guidelines for blood glucose control and interrupted time-series analysis of patients admitted to seven intensive care units in the Netherlands from September 2008 through July 2014. Statistical process control was used to visualise and analyse trends in metrics for blood glucose control in association with the moment changes became effective. RESULTS: Overall, the mean blood glucose level increased and the median percentage of blood glucose levels within the normoglycaemic range and in the hypoglycaemic range decreased, while the relative proportion of hyperglycaemic measurements increased. Changes in metrics were notable after publication of the NICE-SUGAR trial and the SSC guidelines but more frequent after changes in local guidelines; some changes seemed to appear independent of changes in local guidelines. CONCLUSION: Local guidelines for blood glucose practice have changed in intensive care units in the Netherlands since the publication of the NICE-SUGAR trial and the revised SSC guidelines. Trends in the metrics for blood glucose control suggest new, higher target ranges for blood glucose control.

Valproic acid intoxication: sense and non-sense of haemodialysis.

INTRODUCTION: Valproic acid is increasingly used in the treatment of epilepsy, and also prescribed for bipolar affective disorders, schizoaffective disorders, schizophrenia and migraine prophylaxis. We describe two case reports involving valproic acid intoxication with ingestion of ethanol. METHODS: One patient was treated by supportive care, one patient received haemodialysis. RESULTS: From analysis of plasma concentrations before and during haemodialysis (pre- and post-filter) it is shown that valproic acid can be effectively eliminated by haemodialysis when plasma levels are way above 100 microg/ml. In the literature, plasma protein binding is reported to be around 90% for levels within the therapeutic range. In our patient plasma protein binding was around 50% after treatment with haemodialysis. CONCLUSION: These findings make haemodialysis in valproic acid intoxication a sensible therapeutic option with increasing efficiency when plasma concentration is high. Furthermore our findings suggest that lowering valproic acid concentrations to a therapeutic level by haemodialysis does not necessarily result in an immediate, simultaneous increase in plasma protein binding of valproic acid.

Ventilator setting in ICUs: comparing a Dutch with a European cohort.

BACKGROUND: From data collected during the third International Study on Mechanical Ventilation (ISMV), we compared data from a Dutch cohort with a European cohort. We hypothesised that tidal volumes were smaller and applied positive end-expiratory pressure (PEEP) was higher in the Netherlands, compared with the European cohort. We also compared use of non-invasive ventilation (NIV) and outcomes in both cohorts. METHODS: A post-hoc analysis of a prospective observational study of patients receiving mechanical ventilation. RESULTS: Tidal volumes were smaller (7.6 vs. 8.1 ml÷kg predicted bodyweight) in the Dutch cohort and applied PEEP was higher (8 vs. 6 cm H2O). Fewer patients admitted in the Netherlands received NIV as first mode of mechanical ventilation (7.1 vs. 16.7%). Fewer patients in the Dutch cohort developed an ICU-acquired pneumonia (4.5 vs. 12.3%, p < 0.01) and sepsis (5.7 vs. 10.9%, p = 0.03), but more patients were diagnosed as having delirium (15.8 vs. 4.6%, p < 0.01). ICU and in-hospital mortality rates were 19% and 25%, respectively, in Dutch ICUs vs. 26% and 33% in Europe (p = 0.06 and 0.03). CONCLUSION: Tidal volumes were smaller and applied PEEP was higher in the Dutch cohort compared with international data, but both Dutch and international patients received larger tidal volumes than recommended for prevention or treatment of acute respiratory distress syndrome. NIV as first mode of mechanical ventilation is less commonly used in the Netherlands. The incidence of ICU-acquired pneumonia is lower and of delirium higher in the Netherlands compared with international data.

Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study.

OBJECTIVES: To develop and validate a delirium prediction model for adult intensive care patients and determine its additional value compared with prediction by caregivers. DESIGN: Observational multicentre study. SETTING: Five intensive care units in the Netherlands (two university hospitals and three university affiliated teaching hospitals). PARTICIPANTS: 3056 intensive care patients aged 18 years or over. MAIN OUTCOME MEASURE: Development of delirium (defined as at least one positive delirium screening) during patients' stay in intensive care. RESULTS: The model was developed using 1613 consecutive intensive care patients in one hospital and temporally validated using 549 patients from the same hospital. For external validation, data were collected from 894 patients in four other hospitals. The prediction (PRE-DELIRIC) model contains 10 risk factors-age, APACHE-II score, admission group, coma, infection, metabolic acidosis, use of sedatives and morphine, urea concentration, and urgent admission. The model had an area under the receiver operating characteristics curve of 0.87 (95% confidence interval 0.85 to 0.89) and 0.86 after bootstrapping. Temporal validation and external validation resulted in areas under the curve of 0.89 (0.86 to 0.92) and 0.84 (0.82 to 0.87). The pooled area under the receiver operating characteristics curve (n=3056) was 0.85 (0.84 to 0.87). The area under the curve for nurses' and physicians' predictions (n=124) was significantly lower at 0.59 (0.49 to 0.70) for both. CONCLUSION: The PRE-DELIRIC model for intensive care patients consists of 10 risk factors that are readily available within 24 hours after intensive care admission and has a high predictive value. Clinical prediction by nurses and physicians performed significantly worse. The model allows for early prediction of delirium and initiation of preventive measures. Trial registration Clinical trials NCT00604773 (development study) and NCT00961389 (validation study).