Creatinine clearance/eGFR ratio: a simple index for muscle mass related to mortality in ICU patients.

INTRODUCTION: In patients admitted to the intensive care unit (ICU), muscle mass is inversely associated with mortality. Although muscle mass can be estimated with 24-h urinary creatinine excretion (UCE), its use for risk prediction in individual patients is limited because age-, sex-, weight- and length-specific reference values for UCE are lacking. The ratio between measured creatinine clearance (mCC) and estimated glomerular filtration rate (eGFR) might circumvent this constraint. The main goal was to assess the association of the mCC/eGFR ratio in ICU patients with all-cause hospital and long-term mortality. METHODS: The mCC/eGFR ratio was determined in patients admitted to our ICU between 2005 and 2021 with KDIGO acute kidney injury (AKI) stage 0-2 and an ICU stay ≥ 24 h. mCC was calculated from UCE and plasma creatinine and indexed to 1.73 m2. mCC/eGFR was analyzed by categorizing patients in mCC/eGFR quartiles and as continuous variable. RESULTS: Seven thousand five hundred nine patients (mean age 61 ± 15 years; 38% female) were included. In-hospital mortality was 27% in the lowest mCC/eGFR quartile compared to 11% in the highest quartile (P < 0.001). Five-year post-hospital discharge actuarial mortality was 37% in the lowest mCC/eGFR quartile compared to 19% in the highest quartile (P < 0.001). mCC/eGFR ratio as continuous variable was independently associated with in-hospital mortality in multivariable logistic regression (odds ratio: 0.578 (95% CI: 0.465-0.719); P < 0.001). mCC/eGFR ratio as continuous variable was also significantly associated with 5-year post-hospital discharge mortality in Cox regression (hazard ratio: 0.27 (95% CI: 0.22-0.32); P < 0.001). CONCLUSIONS: The mCC/eGFR ratio is associated with both in-hospital and long-term mortality and may be an easily available index of muscle mass in ICU patients.

Production of physiological amounts of hemostatic proteins by human donor livers during ex situ long-term normothermic machine perfusion for up to 7 days.

BACKGROUND: Normothermic machine perfusion (NMP) is used for preservation and assessment of human donor livers prior to transplantation. During NMP, the liver is metabolically active, which allows detailed studies on the physiology of human livers. OBJECTIVES: To study the production of hemostatic proteins in human donor livers during NMP for up to 7 days. METHODS: In this observational study, 9 livers underwent NMP for up to 7 days with a heparinized perfusate based on red blood cells and colloids using a modified Liver Assist device (XVIVO). Perfusate samples were collected before NMP and daily thereafter for measurement of antigen and activity levels of a comprehensive panel of hemostatic proteins after heparin neutralization. RESULTS: Within 1 day, perfusate samples displayed the potential for coagulation activation as evidenced by international normalized ratio and activated partial thromboplastin assays. This was accompanied by detection of substantial quantities of functionally active coagulation proteins and inhibitors, although the specific activity of many proteins was decreased, compared with that in normal plasma. Perfusate levels of hemostatic proteins increased in the first days, reaching a stable level after 3 to 4 days of perfusion. CONCLUSION: During long-term NMP of human livers, functionally active hemostatic proteins are released into the perfusate in substantial quantities, but some proteins appear to have decreased functional properties compared with proteins in normal human plasma. We propose that NMP may be used as a platform to test efficacy of drugs that stimulate or inhibit the production of coagulation factors or to test liver-mediated clearance of prohemostatic protein therapeutics.

Comprehensive GC-MS Measurement of Amino Acids, Metabolites, and Malondialdehyde in Metformin-Associated Lactic Acidosis at Admission and during Renal Replacement Treatment.

Metformin is the most widely used drug in type 2 diabetes. Regular metformin use has been associated with changes in concentrations of amino acids. In the present study, we used valid stable-isotope labeled GC-MS methods to measure amino acids and metabolites, including creatinine as well as malondialdehyde (MDA), as an oxidative stress biomarker in plasma, urine, and dialysate samples in a patient at admission to the intensive care unit and during renal replacement treatment because of metformin-associated lactic acidosis (MALA, 21 mM lactate, 175 µM metformin). GC-MS revealed lower concentrations of amino acids in plasma, normal concentrations of the nitric oxide (NO) metabolites nitrite and nitrate, and normal concentrations of MDA. Renal tubular reabsorption rates were altered on admission. The patient received renal replacement therapy over 50 to 70 h of normalized plasma amino acid concentrations and their tubular reabsorption, as well as the tubular reabsorption of nitrite and nitrate. This study indicates that GC-MS is a versatile analytical tool to measure different classes of physiological inorganic and organic substances in complex biological samples in clinical settings such as MALA.

GC-MS analysis of 4-hydroxyproline: elevated proline hydroxylation in metformin-associated lactic acidosis and metformin-treated Becker muscular dystrophy patients.

Metformin (N,N-dimethylbiguanide), an inhibitor of gluconeogenesis and insulin sensitizer, is widely used for the treatment of type 2 diabetes. In some patients with renal insufficiency, metformin can accumulate and cause lactic acidosis, known as metformin-associated lactic acidosis (MALA, defined as lactate ≥ 5 mM, pH < 7.35, and metformin concentration > 38.7 µM). Here, we report on the post-translational modification (PTM) of proline (Pro) to 4-hydroxyproline (OH-Pro) in metformin-associated lactic acidosis and in metformin-treated patients with Becker muscular dystrophy (BMD). Pro and OH-Pro were measured simultaneously by gas chromatography-mass spectrometry before, during, and after renal replacement therapy in a patient admitted to the intensive care unit (ICU) because of MALA. At admission to the ICU, plasma metformin concentration was 175 µM, with a corresponding lactate concentration of 20 mM and a blood pH of 7.1. Throughout ICU admission, the Pro concentration was lower compared to healthy controls. Renal excretion of OH-Pro was initially high and decreased over time. Moreover, during the first 12 h of ICU admission, OH-Pro seems to be renally secreted while thereafter, it was reabsorbed. Our results suggest that MALA is associated with hyper-hydroxyprolinuria due to elevated PTM of Pro to OH-Pro by prolyl-hydroxylase and/or inhibition of OH-Pro metabolism in the kidneys. In BMD patients, metformin, at the therapeutic dose of 3 × 500 mg per day for 6 weeks, increased the urinary excretion of OH-Pro suggesting elevation of Pro hydroxylation to OH-Pro. Our study suggests that metformin induces specifically the expression/activity of prolyl-hydroxylase in metformin intoxication and BMD.

Continuous Renal Replacement Therapy During Long-term Normothermic Machine Perfusion of Human Donor Livers for up to 7 D.

Background: Normothermic machine perfusion (NMP) is used to preserve and test donor livers before transplantation. During NMP, the liver is metabolically active and produces waste products, which are released into the perfusate. In this study, we describe our simplified and inexpensive setup that integrates continuous renal replacement therapy (CRRT) with NMP for up to 7 d. We also investigated if the ultrafiltrate could be used for monitoring perfusate concentrations of small molecules such as glucose and lactate. Methods: Perfusate composition (urea, osmolarity, sodium, potassium, chloride, calcium, magnesium, phosphate, glucose, and lactate) was analyzed from 56 human NMP procedures without CRRT. Next, in 6 discarded human donor livers, CRRT was performed during NMP by integrating a small dialysis filter (0.2 m2) into the circuit to achieve continuous ultrafiltration combined with continuous fluid substitution for up to 7 d. Results: Within a few hours of NMP without CRRT, a linear increase in osmolarity and concentrations of urea and phosphate to supraphysiological levels was observed. After integration of CRRT into the NMP circuit, the composition of the perfusate was corrected to physiological values within 12 h, and this homeostasis was maintained during NMP for up to 7 d. Glucose and lactate levels, as measured in the CRRT ultrafiltrate, were strongly correlated with perfusate levels (r = 0.997, P < 0.001 and r = 0.999, P < 0.001, respectively). Conclusions: The integration of CRRT into the NMP system corrected the composition of the perfusate to near-physiological values, which could be maintained for up to 7 d. The ultrafiltrate can serve as an alternative to the perfusate to monitor concentrations of small molecules without potentially compromising sterility.

Identifying the need for infection-related consultations in intensive care patients using machine learning models.

Infection-related consultations on intensive care units (ICU) have a positive impact on quality of care and clinical outcome. However, timing of these consultations is essential and to date they are typically event-triggered and reactive. Here, we investigate a proactive approach to identify patients in need for infection-related consultations by machine learning models using routine electronic health records. Data was retrieved from a mixed ICU at a large academic tertiary care hospital including 9684 admissions. Infection-related consultations were predicted using logistic regression, random forest, gradient boosting machines, and long short-term memory neural networks (LSTM). Overall, 7.8% of admitted patients received an infection-related consultation. Time-sensitive modelling approaches performed better than static approaches. Using LSTM resulted in the prediction of infection-related consultations in the next clinical shift (up to eight hours in advance) with an area under the receiver operating curve (AUROC) of 0.921 and an area under the precision recall curve (AUPRC) of 0.541. The successful prediction of infection-related consultations for ICU patients was done without the use of classical triggers, such as (interim) microbiology reports. Predicting this key event can potentially streamline ICU and consultant workflows and improve care as well as outcome for critically ill patients with (suspected) infections.

[18F]FDG-PET/CT in mechanically ventilated critically ill patients with COVID-19 ARDS and persistent inflammation.

Purpose: We report the findings of four critically ill patients who underwent an [18F]FDG-PET/CT because of persistent inflammation during the late phase of their COVID-19. Methods: Four mechanically ventilated patients with COVID-19 were retrospectively discussed in a research group to evaluate the added value of [18F]FDG-PET/CT. Results: Although pulmonary PET/CT findings differed, bilateral lung anomalies could explain the increased CRP and leukocytes in all patients. This underscores the limited ability of the routine laboratory to discriminate inflammation from secondary infections. Based on PET/CT findings, a secondary infection/inflammatory focus was suspected in two patients (pancreatitis and gastritis). Lymphadenopathy was present in patients with a detectable SARS-CoV-2 viral load. Muscle uptake around the hips or shoulders was observed in all patients, possibly due to the process of heterotopic ossification. Conclusion: This case series illustrates the diagnostic potential of [18F]FDG-PET/CT imaging in critically ill patients with persistent COVID-19 for the identification of other causes of inflammation and demonstrates that this technique can be performed safely in mechanically ventilated critically ill patients.

Practice of 18F-FDG-PET/CT in ICU Patients: A Systematic Review.

18F-FDG-PET/CT imaging has become a key tool to evaluate infectious and inflammatory diseases. However, application of 18F-FDG-PET/CT in patients in the intensive care unit (ICU) is limited, which is remarkable since the development of critical illness is closely linked to infection and inflammation. This limited use is caused by perceived complexity and risk of planning and executing 18F-FDG-PET/CT in such patients. The aim of this systematic review was to investigate the feasibility of 18F-FDG-PET/CT in ICU patients with special emphasis on patient preparation, transport logistics and safety. Therefore, a systematic search was performed in PubMed, Embase, and Web of Science using the search terms: intensive care, critically ill, positron emission tomography and 18F-FDG or derivates. A total of 1183 articles were found of which 10 were included. Three studies evaluated the pathophysiology of acute respiratory distress syndrome, acute lung injury and acute chest syndrome. Three other studies applied 18F-FDG-PET/CT to increase understanding of pathophysiology after traumatic brain injury. The remaining four studies evaluated infection of unknown origin. These four studies showed a sensitivity and specificity between 85%-100% and 57%-88%, respectively. A remarkable low adverse event rate of 2% was found during the entire 18F-FDG-PET/CT procedure, including desaturation and hypotension. In all studies, a team consisting of an intensive care physician and nurse was present during transport to ensure continuation of necessary critical care. Full monitoring during transport was used in patients requiring mechanical ventilation or vasopressor support. None of the studies used specific patient preparation for ICU patients. However, one article described specific recommendations in their discussion. In conclusion, 18F-FDG-PET/CT has been shown to be feasible and safe in ICU patients, even when ventilated or requiring vasopressors. Specific recommendations regarding patient preparation, logistics and scanning are needed. Including 18F-FDG-PET/CT in routine workup of infection of unknown origin in ICU patients showed potential to identify source of infection and might improve outcome.

Impact of reduced antibiotic treatment duration on antimicrobial resistance in critically ill patients in the randomized controlled SAPS-trial.

Background: In the previously reported SAPS trial (https://clinicaltrials.gov/ct2/show/NCT01139489), procalcitonin-guidance safely reduced the duration of antibiotic treatment in critically ill patients. We assessed the impact of shorter antibiotic treatment on antimicrobial resistance development in SAPS patients. Materials and methods: Cultures were assessed for the presence of multi-drug resistant (MDR) or highly resistant organisms (HRMO) and compared between PCT-guided and control patients. Baseline isolates from 30 days before to 5 days after randomization were compared with those from 5 to 30 days post-randomization. The primary endpoint was the incidence of new MDR/HRMO positive patients. Results: In total, 8,113 cultures with 96,515 antibiotic test results were evaluated for 439 and 482 patients randomized to the PCT and control groups, respectively. Disease severity at admission was similar for both groups. Median (IQR) durations of the first course of antibiotics were 6 days (4-10) and 7 days (5-11), respectively (p = 0.0001). Antibiotic-free days were 7 days (IQR 0-14) and 6 days (0-13; p = 0.05). Of all isolates assessed, 13% were MDR/HRMO positive and at baseline 186 (20%) patients were MDR/HMRO-positive. The incidence of new MDR/HRMO was 39 (8.9%) and 45 (9.3%) in PCT and control patients, respectively (p = 0.82). The time courses for MDR/HRMO development were also similar for both groups (p = 0.33). Conclusions: In the 921 randomized patients studied, the small but statistically significant reduction in antibiotic treatment in the PCT-group did not translate into a detectable change in antimicrobial resistance. Studies with larger differences in antibiotic treatment duration, larger study populations or populations with higher MDR/HRMO incidences might detect such differences.

Muscle strength trajectories and their association with postoperative health-related quality of life in patients undergoing coronary artery bypass grafting surgery: a prospective cohort study.

BACKGROUND: Patients with sarcopenia have a higher risk of poor recovery after coronary artery bypass grafting (CABG). Little is known about the impact of changes in muscle strength (the primary indicator for sarcopenia) on health-related quality of life (HR-QoL). This study aimed to (1) identify subgroups with different muscle strength trajectories, (2) identify differences in preoperative risk factors among trajectory group membership, and (3) explore their prognostic value on postoperative HR-QoL in patients undergoing CABG. METHODS: In this prospective observational study 131 patients undergoing elective CABG completed grip strength tests and HR-QoL questionnaires. Latent Class Growth Mixture Modelling (LCGMM) was used to identify clinically relevant trajectories (> 5% of study population) for weight-normalised grip strength, measured at admission, 3 days, and 6 months after surgery. Differences between trajectory group membership at baseline were evaluated. The impact of trajectory group membership on postoperative HR-QoL was evaluated with multiple linear regression models. RESULTS: Due to low numbers (n = 15), female patients were excluded from LCGMM and subsequent statistical analyses. In males (n = 116), we identified two main weight-normalised grip strength trajectories: a "stable average" trajectory with a slight decline immediately post-surgery and recovery to preoperative levels (n = 85) and a "high" trajectory with a considerable immediate decline after surgery but followed towards a higher level of recovery compared to preoperative level (n = 27). The "stable average" patients were older (68 vs. 57 years; P = 0.003), had more diabetes (27% vs. 4%; P = 0.01) and had a higher BMI (27.8 vs. 24.8; P = 0.005) compared to the "high" group. After correction for age, diabetes, and baseline HR-QoL, group trajectory membership was not associated with postoperative HR-QoL, yet an increase in individual change scores of weight-normalised grip strength was associated with a better postoperative HR-QoL. We also identified one small trajectory group (n = 4, ≤ 5%). CONCLUSIONS: This study showed two relevant weight-normalised grip strength trajectories in male patients undergoing CABG, varying in important preoperative risk factors. While change scores of grip strength per weight did predict postoperative HR-QoL, the trajectory subgroups could not predict postoperative HR-QoL. Future research should focus on female patients, reacting potentially different on CABG and/or rehabilitation treatment. Trial registration NCT03774342, 12-12-2018.

Comparison of Machine Learning Models Including Preoperative, Intraoperative, and Postoperative Data and Mortality After Cardiac Surgery.

Importance: A variety of perioperative risk factors are associated with postoperative mortality risk. However, the relative contribution of routinely collected intraoperative clinical parameters to short-term and long-term mortality remains understudied. Objective: To examine the performance of multiple machine learning models with data from different perioperative periods to predict 30-day, 1-year, and 5-year mortality and investigate factors that contribute to these predictions. Design, Setting, and Participants: In this prognostic study using prospectively collected data, risk prediction models were developed for short-term and long-term mortality after cardiac surgery. Included participants were adult patients undergoing a first-time valve operation, coronary artery bypass grafting, or a combination of both between 1997 and 2017 in a single center, the University Medical Centre Groningen in the Netherlands. Mortality data were obtained in November 2017. Data analysis took place between February 2020 and August 2021. Exposure: Cardiac surgery. Main Outcomes and Measures: Postoperative mortality rates at 30 days, 1 year, and 5 years were the primary outcomes. The area under the receiver operating characteristic curve (AUROC) was used to assess discrimination. The contribution of all preoperative, intraoperative hemodynamic and temperature, and postoperative factors to mortality was investigated using Shapley additive explanations (SHAP) values. Results: Data from 9415 patients who underwent cardiac surgery (median [IQR] age, 68 [60-74] years; 2554 [27.1%] women) were included. Overall mortality rates at 30 days, 1 year, and 5 years were 268 patients (2.8%), 420 patients (4.5%), and 612 patients (6.5%), respectively. Models including preoperative, intraoperative, and postoperative data achieved AUROC values of 0.82 (95% CI, 0.78-0.86), 0.81 (95% CI, 0.77-0.85), and 0.80 (95% CI, 0.75-0.84) for 30-day, 1-year, and 5-year mortality, respectively. Models including only postoperative data performed similarly (30 days: 0.78 [95% CI, 0.73-0.82]; 1 year: 0.79 [95% CI, 0.74-0.83]; 5 years: 0.77 [95% CI, 0.73-0.82]). However, models based on all perioperative data provided less clinically usable predictions, with lower detection rates; for example, postoperative models identified a high-risk group with a 2.8-fold increase in risk for 5-year mortality (4.1 [95% CI, 3.3-5.1]) vs an increase of 11.3 (95% CI, 6.8-18.7) for the high-risk group identified by the full perioperative model. Postoperative markers associated with metabolic dysfunction and decreased kidney function were the main factors contributing to mortality risk. Conclusions and Relevance: This study found that the addition of continuous intraoperative hemodynamic and temperature data to postoperative data was not associated with improved machine learning-based identification of patients at increased risk of short-term and long-term mortality after cardiac operations.

Low Cancer Incidence in Naked Mole-Rats May Be Related to Their Inability to Express the Warburg Effect.

Metabolic flexibility in mammals enables stressed tissues to generate additional ATP by converting large amounts of glucose into lactic acid; however, this process can cause transient local or systemic acidosis. Certain mammals are adapted to extreme environments and are capable of enhanced metabolic flexibility as a specialized adaptation to challenging habitat niches. For example, naked mole-rats (NMRs) are a fossorial and hypoxia-tolerant mammal whose metabolic responses to environmental stressors markedly differ from most other mammals. When exposed to hypoxia, NMRs exhibit robust hypometabolism but develop minimal acidosis. Furthermore, and despite a very long lifespan relative to other rodents, NMRs have a remarkably low cancer incidence. Most advanced cancers in mammals display increased production of lactic acid from glucose, irrespective of oxygen availability. This hallmark of cancer is known as the Warburg effect (WE). Most malignancies acquire this metabolic phenotype during their somatic evolution, as the WE benefits tumor growth in several ways. We propose that the peculiar metabolism of the NMR makes development of the WE inherently difficult, which might contribute to the extraordinarily low cancer rate in NMRs. Such an adaptation of NMRs to their subterranean environment may have been facilitated by modified biochemical responses with a stronger inhibition of the production of CO2 and lactic acid by a decreased extracellular pH. Since this pH-inhibition could be deeply hard-wired in their metabolic make-up, it may be difficult for malignant cells in NMRs to acquire the WE-phenotype that facilitates cancer growth in other mammals. In the present commentary, we discuss this idea and propose experimental tests of our hypothesis.

Sequential hypothermic and normothermic machine perfusion enables safe transplantation of high-risk donor livers.

Ex situ normothermic machine perfusion (NMP) is increasingly used for viability assessment of high-risk donor livers, whereas dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia-reperfusion injury. We aimed to resuscitate and test the viability of initially-discarded, high-risk donor livers using sequential DHOPE and NMP with two different oxygen carriers: an artificial hemoglobin-based oxygen carrier (HBOC) or red blood cells (RBC). In a prospective observational cohort study of 54 livers that underwent DHOPE-NMP, the first 18 procedures were performed with a HBOC-based perfusion solution and the subsequent 36 procedures were performed with an RBC-based perfusion solution for the NMP phase. All but one livers were derived from extended criteria donation after circulatory death donors, with a median donor risk index of 2.84 (IQR 2.52-3.11). After functional assessment during NMP, 34 livers (63% utilization), met the viability criteria and were transplanted. One-year graft and patient survival were 94% and 100%, respectively. Post-transplant cholangiopathy occurred in 1 patient (3%). There were no significant differences in utilization rate and post-transplant outcomes between the HBOC and RBC group. Ex situ machine perfusion using sequential DHOPE-NMP for resuscitation and viability assessment of high-risk donor livers results in excellent transplant outcomes, irrespective of the oxygen carrier used.

Early Thromboembolic Stroke Risk of Postoperative Atrial Fibrillation Following Cardiac Surgery.

OBJECTIVE: The authors aimed to study the association between postoperative atrial fibrillation (POAF) and thromboembolic stroke and to determine risk factors for thromboembolic stroke after cardiac surgery. DESIGN: The authors performed a secondary analysis from a randomized controlled trial (GRIP-COMPASS). The patients with thromboembolic stroke were compared with those without thromboembolic stroke, and the difference in the incidence of POAF between these groups was assessed. Odds ratios (OR) were calculated using logistic regression analyses. Brain imaging was studied for the occurrence of thromboembolic stroke during hospital admission, and POAF was monitored for seven days. To assess which characteristics were associated with occurrence of thromboembolic stroke, stepwise backward regression analysis was performed. PARTICIPANTS: All adult consecutive cardiac surgery patients admitted postoperatively to the intensive care unit. SETTING: Academic tertiary care medical center. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 910 patients included in this study, 26 patients (2.9%) had a thromboembolic stroke during hospital admission. The incidence of POAF during the first seven days after cardiac surgery in those with thromboembolic stroke was 65%, compared with 39% in those without thromboembolic stroke: adjusted OR 3.01 (95% confidence interval, 1.13-8.00). POAF, a history of peripheral vascular disease, a higher EuroSCORE, and a longer duration of surgery were associated with thromboembolic stroke. CONCLUSIONS: POAF within seven days after cardiac surgery was associated with a three-fold increased risk for a thromboembolic stroke during hospital admission. Expeditious treatment of POAF may, therefore, reduce early stroke risk after cardiac surgery.

Long-term normothermic machine preservation of human livers: what is needed to succeed?

Although short-term machine perfusion (≤24 h) allows for resuscitation and viability assessment of high-risk donor livers, the donor organ shortage might be further remedied by long-term perfusion machines. Extended preservation of injured donor livers may allow reconditioning, repairing, and regeneration. This review summarizes the necessary requirements and challenges for long-term liver machine preservation, which requires integrating multiple core physiological functions to mimic the physiological environment inside the body. A pump simulates the heart in the perfusion system, including automatically controlled adjustment of flow and pressure settings. Oxygenation and ventilation are required to account for the absence of the lungs combined with continuous blood gas analysis. To avoid pressure necrosis and achieve heterogenic tissue perfusion during preservation, diaphragm movement should be simulated. An artificial kidney is required to remove waste products and control the perfusion solution's composition. The perfusate requires an oxygen carrier, but will also be challenged by coagulation and activation of the immune system. The role of the pancreas can be mimicked through closed-loop control of glucose concentrations by automatic injection of insulin or glucagon. Nutrients and bile salts, generally transported from the intestine to the liver, have to be supplemented when preserving livers long term. Especially for long-term perfusion, the container should allow maintenance of sterility. In summary, the main challenge to develop a long-term perfusion machine is to maintain the liver's homeostasis in a sterile, carefully controlled environment. Long-term machine preservation of human livers may allow organ regeneration and repair, thereby ultimately solving the shortage of donor livers.

Multi-infusion with integrated multiple pressure sensing allows earlier detection of line occlusions.

BACKGROUND: Occlusions of intravenous (IV) tubing can prevent vital and time-critical medication or solutions from being delivered into the bloodstream of patients receiving IV therapy. At low flow rates (≤ 1 ml/h) the alarm delay (time to an alert to the user) can be up to 2 h using conventional pressure threshold algorithms. In order to reduce alarm delays we developed and evaluated the performance of two new real-time occlusion detection algorithms and one co-occlusion detector that determines the correlation in trends in pressure changes for multiple pumps. METHODS: Bench-tested experimental runs were recorded in triplicate at rates of 1, 2, 4, 8, 16, and 32 ml/h. Each run consisted of 10 min of non-occluded infusion followed by a period of occluded infusion of 10 min or until a conventional occlusion alarm at 400 mmHg occurred. The first algorithm based on binary logistic regression attempts to detect occlusions based on the pump's administration rate Q(t) and pressure sensor readings P(t). The second algorithm continuously monitored whether the actual variation in the pressure exceeded a threshold of 2 standard deviations (SD) above the baseline pressure. When a pump detected an occlusion using the SD algorithm, a third algorithm correlated the pressures of multiple pumps to detect the presence of a shared occlusion. The algorithms were evaluated using 6 bench-tested baseline single-pump occlusion scenarios, 9 single-pump validation scenarios and 7 multi-pump co-occlusion scenarios (i.e. with flow rates of 1 + 1, 1 + 2, 1 + 4, 1 + 8, 1 + 16, and 1 + 32 ml/h respectively). Alarm delay was the primary performance measure. RESULTS: In the baseline single-pump occlusion scenarios, the overall mean ± SD alarm delay of the regression and SD algorithms were 1.8 ± 0.8 min and 0.4 ± 0.2 min, respectively. Compared to the delay of the conventional alarm this corresponds to a mean time reduction of 76% (P = 0.003) and 95% (P = 0.001), respectively. In the validation scenarios the overall mean ± SD alarm delay of the regression and SD algorithms were respectively 1.8 ± 1.6 min and 0.3 ± 0.2 min, corresponding to a mean time reduction of 77% and 95%. In the multi-pump scenarios a correlation > 0.8 between multiple pump pressures after initial occlusion detection by the SD algorithm had a mean ± SD alarm delay of 0.4 ± 0.2 min. In 2 out of the 9 validation scenarios an occlusion was not detected by the regression algorithm before a conventional occlusion alarm occurred. Otherwise no occlusions were missed. CONCLUSIONS: In single pumps, both the regression and SD algorithm considerably reduced alarm delay compared to conventional pressure limit-based detection. The SD algorithm appeared to be more robust than the regression algorithm. For multiple pumps the correlation algorithm reliably detected co-occlusions. The latter may be used to localize the segment of tubing in which the occlusion occurs. Trial registration Not applicable.

Antimicrobial stewardship, therapeutic drug monitoring and infection management in the ICU: results from the international A- TEAMICU survey.

BACKGROUND: Severe infections and multidrug-resistant pathogens are common in critically ill patients. Antimicrobial stewardship (AMS) and therapeutic drug monitoring (TDM) are contemporary tools to optimize the use of antimicrobials. The A-TEAMICU survey was initiated to gain contemporary insights into dissemination and structure of AMS programs and TDM practices in intensive care units. METHODS: This study involved online survey of members of ESICM and six national professional intensive care societies. RESULTS: Data of 812 respondents from mostly European high- and middle-income countries were available for analysis. 63% had AMS rounds available in their ICU, where 78% performed rounds weekly or more often. While 82% had local guidelines for treatment of infections, only 70% had cumulative antimicrobial susceptibility reports and 56% monitored the quantity of antimicrobials administered. A restriction of antimicrobials was reported by 62%. TDM of antimicrobial agents was used in 61% of ICUs, mostly glycopeptides (89%), aminoglycosides (77%), carbapenems (32%), penicillins (30%), azole antifungals (27%), cephalosporins (17%), and linezolid (16%). 76% of respondents used prolonged/continuous infusion of antimicrobials. The availability of an AMS had a significant association with the use of TDM. CONCLUSIONS: Many respondents of the survey have AMS in their ICUs. TDM of antimicrobials and optimized administration of antibiotics are broadly used among respondents. The availability of antimicrobial susceptibility reports and a surveillance of antimicrobial use should be actively sought by intensivists where unavailable. Results of this survey may inform further research and educational activities.