Glucose measurement in intensive care medicine is performed intermittently with the risk of undetected hypoglycemia. The workload for the ICU nursing staff is substantial. Subcutaneous continuous ...glucose monitoring (CGM) systems are available and may be able to solve some of these issues in critically ill patients.
In a randomized controlled design in a mixed ICU in a teaching hospital we compared the use of subcutaneous CGM with frequent point of care (POC) to guide insulin treatment. Adult critically ill patients with an expected stay of more than 24 hours and in need of insulin therapy were included. All patients received subcutaneous CGM. CGM data were blinded in the control group, whereas in the intervention group these data were used to feed a computerized glucose regulation algorithm. The same algorithm was used in the control group fed by intermittent POC glucose measurements. Safety was assessed with the incidence of severe hypoglycemia (<2.2 mmol/L), efficacy with the percentage time in target range (5.0 to 9.0 mmol/L). In addition, we assessed nursing workload and costs.
In this study, 87 patients were randomized to the intervention and 90 to the control group. CGM device failure resulted in 78 and 78 patients for analysis. The incidence of severe glycemia and percentage of time within target range was similar in both groups. A significant reduction in daily nursing workload for glucose control was found in the intervention group (17 versus 36 minutes; P <0.001). Mean daily costs per patient were significantly reduced with EUR 12 (95% CI -32 to -18, P = 0.02) in the intervention group.
Subcutaneous CGM to guide insulin treatment in critically ill patients is as safe and effective as intermittent point-of-care measurements and reduces nursing workload and daily costs. A new algorithm designed for frequent measurements may lead to improved performance and should precede clinical implementation.
Clinicaltrials.gov, NCT01526044. Registered 1 February 2012.
Abstract
Background
Adequate antibiotic dosing may improve outcomes in critically ill patients but is challenging due to altered and variable pharmacokinetics. To address this challenge, AutoKinetics ...was developed, a decision support system for bedside, real-time, data-driven and personalised antibiotic dosing. This study evaluates the feasibility, safety and efficacy of its clinical implementation.
Methods
In this two-centre randomised clinical trial, critically ill patients with sepsis or septic shock were randomised to AutoKinetics dosing or standard dosing for four antibiotics: vancomycin, ciprofloxacin, meropenem, and ceftriaxone. Adult patients with a confirmed or suspected infection and either lactate > 2 mmol/L or vasopressor requirement were eligible for inclusion. The primary outcome was pharmacokinetic target attainment in the first 24 h after randomisation. Clinical endpoints included mortality, ICU length of stay and incidence of acute kidney injury.
Results
After inclusion of 252 patients, the study was stopped early due to the COVID-19 pandemic. In the ciprofloxacin intervention group, the primary outcome was obtained in 69% compared to 3% in the control group (OR 62.5, CI 11.4–1173.78,
p
< 0.001). Furthermore, target attainment was faster (26 h, CI 18–42 h,
p
< 0.001) and better (65% increase, CI 49–84%,
p
< 0.001). For the other antibiotics, AutoKinetics dosing did not improve target attainment. Clinical endpoints were not significantly different. Importantly, higher dosing did not lead to increased mortality or renal failure.
Conclusions
In critically ill patients, personalised dosing was feasible, safe and significantly improved target attainment for ciprofloxacin.
Trial registration
: The trial was prospectively registered at Netherlands Trial Register (NTR), NL6501/NTR6689 on 25 August 2017 and at the European Clinical Trials Database (EudraCT), 2017-002478-37 on 6 November 2017.
During resuscitation in severe sepsis and septic shock, several goals are set. However, usually not all goals are equally met. The aim of this study is to determine the relative importance of the ...different goals, such as mean arterial pressure (MAP), lactate, central venous oxygen saturation (ScvO2) and central to forefoot temperature (delta-T), and how they relate to intensive care unit (ICU) and hospital mortality.
In a retrospective cohort study in a 20-bed mixed medical and surgical ICU of a teaching hospital we studied consecutive critically ill patients who were admitted for confirmed infection and severe sepsis or septic shock between 2008 and 2014. All validated MAP, lactate levels, ScvO2 and delta-T for the first 24 hours of ICU treatment were extracted from a clinical database. Logistic regression analyses were performed on validated measurements in the first hour after admission and on mean values over 24 hours. Patients were categorized by MAP (24-hour mean below or above 65 mmHg) and lactate (24-hour mean below or above 2 mmol/l) for Cox regression analysis.
From 837 patients, 821 were eligible for analysis. All had MAP and lactate measurements. The delta-T was available in 812 (99%) and ScvO2 was available for 193 out of these patients (23.5%). Admission lactate (p < 0.001) and admission MAP (p < 0.001) were independent predictors of ICU and hospital mortality. The 24-hour mean values for lactate, MAP and delta-T were all independent predictors of ICU mortality. Hospital mortality was independently predicted by the 24-hour mean lactate (odds ratio (OR) 1.34, 95% confidence interval (CI) 1.30-1.40, p = 0.001) mean MAP (OR 0.96, 95% CI 0.95-0.97, p = 0.001) and mean delta-T (OR 1.09, 95% CI 1.06-1.12, p = 0.001). Patients with a 24-hour mean lactate below 2 mmol/l and a 24-hour mean MAP above 65 mmHg had the best survival, followed by patients with a low lactate and a low MAP.
Admission MAP and lactate independently predicted ICU and hospital mortality. The 24-hour mean lactate, mean MAP and mean delta-T independently predicted hospital mortality. A Cox regression analysis showed that 24-hour mean lactate above 2 mmol/l is the strongest predictor for ICU mortality.
OBJECTIVE:Continuous venovenous hemofiltration (CVVH) is applied in critically ill patients with acute renal failure for renal replacement. Heparins used to prevent circuit clotting may cause ...bleeding. Regional anticoagulation with citrate reduces bleeding, but has metabolic risks. The aim was to compare the safety and efficacy of the two.
DESIGN:Randomized, nonblinded, controlled single-center trial.
SETTING:General intensive care unit of a teaching hospital.
PATIENTS:Adult critically ill patients needing CVVH for acute renal failure and without an increased bleeding risk.
INTERVENTIONS:Regional anticoagulation with citrate or systemic anticoagulation with the low-molecular weight heparin nadroparin.
MEASUREMENTS AND MAIN RESULTS:End points were adverse events necessitating discontinuation of study anticoagulant, transfusion, metabolic and clinical outcomes, and circuit survival. Of the 215 randomized patients, 200 received CVVH per protocol (97 citrate and 103 nadroparin). Adverse events required discontinuation of citrate in two patients (accumulation and clotting) of nadroparin in 20 (bleeding and thrombocytopenia) (p < 0.001). Bleeding occurred in 6 vs. 16 patients (p = 0.08). The median number of red blood cell units transfused per CVVH day was 0.27 (interquartile range, 0.0–0.63) for citrate, 0.36 (interquartile range, 0–0.83) for nadroparin (p = 0.31). Citrate conferred less metabolic alkalosis (p = 0.001) and lower plasma calcium (p < 0.001). Circuit survival was similar. Three-month mortality on intention-to-treat was 48% (citrate) and 63% (nadroparin) (p = 0.03), per protocol 45% and 62% (p = 0.02). Citrate reduced mortality in surgical patients (p = 0.007), sepsis (p = 0.01), higher Sepsis-Related Organ Failure Assessment score (p = 0.006), and lower age (p = 0.009).
CONCLUSIONS:The efficacy of citrate and nadroparin anticoagulation for CVVH was similar, however, citrate was safer. Unexpectedly, citrate reduced mortality. Less bleeding could only partly explain this benefit, less clotting could not. Post hoc citrate appeared particularly beneficial after surgery, in sepsis and severe multiple organ failure, suggesting interference with inflammation.
Antibiotic exposure in intensive care patients with sepsis is frequently inadequate and is associated with poorer outcomes. Antibiotic dosing is challenging in the intensive care, as critically ill ...patients have altered and fluctuating antibiotic pharmacokinetics that make current one-size-fits-all regimens unsatisfactory. Real-time bedside dosing software is not available yet, and therapeutic drug monitoring is typically used for few antibiotic classes and only allows for delayed dosing adaptation. Thus, adequate and timely antibiotic dosing continues to rely largely on the level of pharmacokinetic expertise in the ICU. Therefore, we set out to assess the level of knowledge on antibiotic pharmacokinetics among these intensive care professionals.
In May 2018, we carried out a cross-sectional study by sending out an online survey on antibiotic dosing to more than 20,000 intensive care professionals. Questions were designed to cover relevant topics in pharmacokinetics related to intensive care antibiotic dosing. The preliminary pass mark was set by members of the examination committee for the European Diploma of Intensive Care using a modified Angoff approach. The final pass mark was corrected for clinical relevance as assessed for each question by international experts on pharmacokinetics.
A total of 1448 respondents completed the survey. Most of the respondents were intensivists (927 respondents, 64%) from 97 countries. Nearly all questions were considered clinically relevant by pharmacokinetic experts. The pass mark corrected for clinical relevance was 52.8 out of 93.7 points. Pass rates were 42.5% for intensivists, 36.1% for fellows, 24.8% for residents, and 5.8% for nurses. Scores without correction for clinical relevance were worse, indicating that respondents perform better on more relevant topics. Correct answers and concise clinical background are provided.
Clinically relevant pharmacokinetic knowledge on antibiotic dosing among intensive care professionals is insufficient. This should be addressed given the importance of adequate antibiotic exposure in critically ill patients with sepsis. Solutions include improved education, intensified pharmacy support, therapeutic drug monitoring, or the use of real-time bedside dosing software. Questions may provide useful for teaching purposes.
The long-term ecological effects on the emergence of antimicrobial resistance at the ICU level during selective decontamination of the digestive tract (SDD) are unknown. We determined the incidence ...of newly acquired antimicrobial resistance of aerobic gram-negative potentially pathogenic bacteria (AGNB) during SDD.
In a single-centre observational cohort study over a 21-year period, all consecutive patients, treated with or without SDD, admitted to the ICU were included. The antibiotic regime was unchanged over the study period. Incidence rates for ICU-acquired AGNB's resistance for third-generation cephalosporins, colistin/polymyxin B, tobramycin/gentamicin or ciprofloxacin were calculated per year. Changes over time were tested by negative binomial regression in a generalized linear model.
Eighty-six percent of 14,015 patients were treated with SDD. Most cultures were taken from the digestive tract (41.9%) and sputum (21.1%). A total of 20,593 isolates of AGNB were identified. The two most often found bacteria were Escherichia coli (N = 6409) and Pseudomonas (N = 5269). The incidence rate per 1000 patient-day for ICU-acquired resistance to cephalosporins was 2.03, for polymyxin B/colistin 0.51, for tobramycin 2.59 and for ciprofloxacin 2.2. The incidence rates for ICU-acquired resistant microbes per year ranged from 0 to 4.94 per 1000 patient-days, and no significant time-trend in incidence rates were found for any of the antimicrobials. The background prevalence rates of resistant strains measured on admission for cephalosporins, polymyxin B/colistin and ciprofloxacin rose over time with 7.9%, 3.5% and 8.0% respectively.
During more than 21-year SDD, the incidence rates of resistant microbes at the ICU level did not significantly increase over time but the background resistance rates increased. An overall ecological effect of prolonged application of SDD by counting resistant microorganisms in the ICU was not shown in a country with relatively low rates of resistant microorganisms.
Dosing of vancomycin is often guided by therapeutic drug monitoring and population pharmacokinetic models in the intensive care unit (ICU). The validity of these models is crucial, as ICU patients ...have marked pharmacokinetic variability. Therefore, we set out to evaluate the predictive performance of published population pharmacokinetic models of vancomycin in ICU patients. The PubMed database was used to search for population pharmacokinetic models of vancomycin in adult ICU patients. The identified models were evaluated in two independent data sets which were collected from two large hospitals in the Netherlands (Amsterdam UMC, Location VUmc, and OLVG Oost). We also tested a one-compartment model with fixed values for clearance and volume of distribution, in which a clinical standard dosage regimen (SDR) was mimicked to assess its predictive performance. Prediction error was calculated to assess the predictive performance of the models. Six models plus the SDR model were evaluated. The model of Roberts et al. (J. A. Roberts, F. S. Taccone, A. A. Udy, J.-L. Vincent, F. Jacobs, and J. Lipman, Antimicrob Agents Chemother 55:2704-2709, 2011, https://doi.org/10.1128/AAC.01708-10) performed satisfactorily, with mean and median values of prediction error of 5.1% and -7.5%, respectively, for Amsterdam UMC, Location VUmc, patients, and -12.6% and -17.2% respectively, for OLVG Oost patients. The other models, including the SDR model, yielded high mean values (-49.7% to 87.7%) and median values (-56.1% to 66.1%) for both populations. In conclusion, only the model of Roberts et al. was able to validly predict the concentrations of vancomycin for our data, whereas other models and standard dosing were largely inadequate. Extensive evaluation should precede the adoption of any model in clinical practice for ICU patients.
Selective Decontamination of the Digestive tract (SDD) aims to prevent nosocomial infections, by eradication of potentially pathogenic micro-organisms from the digestive tract.
To estimate the rate ...of and the time to eradication of resistant vs. susceptible facultative aerobic gram-negative bacteria (AGNB) in patients treated with SDD.
This observational and retrospective study included patients admitted to the ICU between January 2001 and August 2017. Patients were included when treated with SDD (tobramycin, polymyxin B, and amphotericin B) and colonized in the upper or lower gastro-intestinal (GI) tract with at least one AGNB present on admission. Decontamination was determined after the first negative set of cultures (rectal and throat). An additional analysis was performed of two consecutive negative cultures.
Of the 281 susceptible AGNB in the throat and 1,087 in the rectum on admission, 97.9 and 93.7%, respectively, of these microorganisms were successfully eradicated. In the upper GI-tract no differences in eradication rates were found between susceptible and resistant microorganisms. However, the median duration until eradication was significantly longer for aminoglycosides resistant vs. susceptible microorganisms (5 vs. 4 days,
< 0.01). In the lower GI-tract, differences in eradication rates between susceptible and resistant microorganisms were found for cephalosporins (90.0 vs. 95.6%), aminoglycosides (84.4 vs. 95.5%) and ciprofloxacin (90.0 vs. 95.2%). Differences in median duration until eradication between susceptible and resistant microorganisms were found for aminoglycosides and ciprofloxacin (both 5 days vs. 6 days,
= 0.001). Decontamination defined as two negative cultures was achieved in a lower rate (77-98% for the upper GI tract and 64-77% for the lower GI tract) and a median of 1 day later.
The vast majority of both susceptible and resistant microorganisms are effectively eradicated from the upper and lower GI tract. In the lower GI tract decontamination rates of susceptible microorganisms are significantly higher and achieved in a shorter time period compared to resistant strains.
Antibiotic dosing in critically ill patients is challenging because their pharmacokinetics (PK) are altered and may change rapidly with disease progression. Standard dosing frequently leads to ...inadequate PK exposure. Therapeutic drug monitoring (TDM) offers a potential solution but requires sampling and PK knowledge, which delays decision support. It is our philosophy that antibiotic dosing support should be directly available at the bedside through deep integration into the electronic health record (EHR) system. Therefore we developed AutoKinetics, a clinical decision support system (CDSS) for real time, model informed precision antibiotic dosing.
To provide a detailed description of the design, development, validation, testing, and implementation of AutoKinetics.
We created a development framework and used workflow analysis to facilitate integration into popular EHR systems. We used a development cycle to iteratively adjust and expand AutoKinetics functionalities. Furthermore, we performed a literature review to select and integrate pharmacokinetic models for five frequently prescribed antibiotics for sepsis. Finally, we tackled regulatory challenges, in particular those related to the Medical Device Regulation under the European regulatory framework.
We developed a SQL-based relational database as the backend of AutoKinetics. We developed a data loader to retrieve data in real time. We designed a clinical dosing algorithm to find a dose regimen to maintain antibiotic pharmacokinetic exposure within clinically relevant safety constraints. If needed, a loading dose is calculated to minimize the time until steady state is achieved. Finally, adaptive dosing using Bayesian estimation is applied if plasma levels are available. We implemented support for five extensively used antibiotics following model development, calibration, and validation. We integrated AutoKinetics into two popular EHRs (Metavision, Epic) and developed a user interface that provides textual and visual feedback to the physician.
We successfully developed a CDSS for real time model informed precision antibiotic dosing at the bedside of the critically ill. This holds great promise for improving sepsis outcome. Therefore, we recently started the Right Dose Right Now multi-center randomized control trial to validate this concept in 420 patients with severe sepsis and septic shock.
The Coronavirus disease 2019 (COVID-19) pandemic has underlined the urgent need for reliable, multicenter, and full-admission intensive care data to advance our understanding of the course of the ...disease and investigate potential treatment strategies. In this study, we present the Dutch Data Warehouse (DDW), the first multicenter electronic health record (EHR) database with full-admission data from critically ill COVID-19 patients.
A nation-wide data sharing collaboration was launched at the beginning of the pandemic in March 2020. All hospitals in the Netherlands were asked to participate and share pseudonymized EHR data from adult critically ill COVID-19 patients. Data included patient demographics, clinical observations, administered medication, laboratory determinations, and data from vital sign monitors and life support devices. Data sharing agreements were signed with participating hospitals before any data transfers took place. Data were extracted from the local EHRs with prespecified queries and combined into a staging dataset through an extract-transform-load (ETL) pipeline. In the consecutive processing pipeline, data were mapped to a common concept vocabulary and enriched with derived concepts. Data validation was a continuous process throughout the project. All participating hospitals have access to the DDW. Within legal and ethical boundaries, data are available to clinicians and researchers.
Out of the 81 intensive care units in the Netherlands, 66 participated in the collaboration, 47 have signed the data sharing agreement, and 35 have shared their data. Data from 25 hospitals have passed through the ETL and processing pipeline. Currently, 3464 patients are included in the DDW, both from wave 1 and wave 2 in the Netherlands. More than 200 million clinical data points are available. Overall ICU mortality was 24.4%. Respiratory and hemodynamic parameters were most frequently measured throughout a patient's stay. For each patient, all administered medication and their daily fluid balance were available. Missing data are reported for each descriptive.
In this study, we show that EHR data from critically ill COVID-19 patients may be lawfully collected and can be combined into a data warehouse. These initiatives are indispensable to advance medical data science in the field of intensive care medicine.
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