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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, nine livers underwent NMP for up to 7 days with a heparinised perfusate based on red blood cells and colloids using a modified Liver Assist device. Perfusate samples were collected before NMP and daily thereafter for measurement of antigen and activity levels of comprehensive panel of hemostatic proteins after heparin neutralization., Results: Within one 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 to that in normal plasma. Perfusate levels of hemostatic proteins increased in the first days, reaching a stable level after 3-4 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 to 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., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

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 m 2 ) 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., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

18 F-FDG-PET/CT imaging has become a key tool to evaluate infectious and inflammatory diseases. However, application of 18 F-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 18 F-FDG-PET/CT in such patients. The aim of this systematic review was to investigate the feasibility of 18 F-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 18 F-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 18 F-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 18 F-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, 18 F-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 18 F-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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: We report the findings of four critically ill patients who underwent an [ 18 F]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 [ 18 F]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 [ 18 F]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., Competing Interests: Conflict of interestNone of the authors have any conflicts of interest to disclose., (© The Author(s) 2023.)

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.

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., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

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.

Objectives: In critically ill patients, dysnatremia is common, and in these patients, in-hospital mortality is higher. It remains unknown whether changes of serum sodium after ICU admission affect mortality, especially whether normalization of mild hyponatremia improves survival., Design: Retrospective cohort study., Setting: Ten Dutch ICUs between January 2011 and April 2017., Patients: Adult patients were included if at least one serum sodium measurement within 24 hours of ICU admission and at least one serum sodium measurement 24-48 hours after ICU admission were available., Interventions: None., Measurements and Main Results: A logistic regression model adjusted for age, sex, and Acute Physiology and Chronic Health Evaluation-IV-predicted mortality was used to assess the difference between mean of sodium measurements 24-48 hours after ICU admission and first serum sodium measurement at ICU admission (Δ48 hr-[Na]) and in-hospital mortality. In total, 36,660 patients were included for analysis. An increase in serum sodium was independently associated with a higher risk of in-hospital mortality in patients admitted with normonatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.61 [1.44-1.79], Δ48 hr-[Na] > 10 mmol/L odds ratio: 4.10 [3.20-5.24]) and hypernatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.47 [1.02-2.14], Δ48 hr-[Na] > 10 mmol/L odds ratio: 8.46 [3.31-21.64]). In patients admitted with mild hyponatremia and Δ48 hr-[Na] greater than 5 mmol/L, no significant difference in hospital mortality was found (odds ratio, 1.11 [0.99-1.25])., Conclusions: An increase in serum sodium in the first 48 hours of ICU admission was associated with higher in-hospital mortality in patients admitted with normonatremia and in patients admitted with hypernatremia., Competing Interests: Drs. Termorshuizen’s and de Keizer’s institutions received funding from the National Intensive Care Evaluation Foundation. Dr. Termorshuizen received funding from the Mental Health Care Institute, Rivierduinen, Leiden. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) is an advanced imaging technique that can be used to examine the whole body for an infection focus in a single examination in patients with bloodstream infection (BSI) of unknown origin. However, literature on the use of this technique in intensive care patients is scarce. The purpose of this study was to evaluate the diagnostic yield of FDG-PET/CT in intensive care patients with BSI., Methods: In this retrospective cohort study, all intensive care patients from our Dutch university medical center who had culture-proven BSI between 2010 and 2020 and underwent FDG-PET/CT to find the focus of infection were included. Diagnostic performance was calculated and logistic regression analysis was performed to evaluate the association between FDG-PET/CT outcome and C-reactive protein level (CRP), leukocyte count, duration of antibiotic treatment, duration of ICU stay, quality of FDG-PET/CT, and dependency on mechanical ventilation. In addition, the impact of FDG-PET/CT on clinical treatment was evaluated., Results: 30 intensive care patients with BSI were included. In 21 patients, an infection focus was found on FDG-PET/CT which led to changes in clinical management in 14 patients. FDG-PET/CT achieved a sensitivity of 90.9% and specificity of 87.5% for identifying the focus of infection. Poor quality of the FDG-PET images significantly decreased the likelihood of finding an infection focus as compared to reasonable or good image quality (OR 0.16, P = 0.034). No other variables were significantly associated with FDG-PET/CT outcome. No adverse events during the FDG-PET/CT procedure were reported., Conclusion: FDG-PET/CT has a high diagnostic yield for detecting the infection focus in patients with BSI admitted to intensive care. Poor PET image quality was significantly associated with a decreased likelihood of finding the infection focus in patients with BSI. This could be improved by adequate dietary preparation and cessation of intravenous glucose and glucose-regulating drugs. Recent advances in PET/CT technology enable higher image quality with shorter imaging time and may contribute to routinely performing FDG-PET/CT in intensive care patients with BSI of unknown origin.

Despite having a similar post-operative complication profile, cardiac valve operations are associated with a higher mortality rate compared to coronary artery bypass grafting (CABG) operations. For long-term mortality, few predictors are known. In this study, we applied an ensemble machine learning (ML) algorithm to 88 routinely collected peri-operative variables to predict 5-year mortality after different types of cardiac operations. The Super Learner algorithm was trained using prospectively collected peri-operative data from 8241 patients who underwent cardiac valve, CABG and combined operations. Model performance and calibration were determined for all models, and variable importance analysis was conducted for all peri-operative parameters. Results showed that the predictive accuracy was the highest for solitary mitral (0.846 [95% CI 0.812-0.880]) and solitary aortic (0.838 [0.813-0.864]) valve operations, confirming that ensemble ML using routine data collected perioperatively can predict 5-year mortality after cardiac operations with high accuracy. Additionally, post-operative urea was identified as a novel and strong predictor of mortality for several types of operation, having a seemingly additive effect to better known risk factors such as age and postoperative creatinine.

For the quantification of the sedative and anesthetic drug midazolam and its main (active) metabolites 1-hydroxymidazolam, 4-hydroxymidazolam and 1-hydroxymidazolam glucuronide in human serum, human EDTA plasma, human heparin plasma and human urine a single accurate method by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) has been developed. Protein precipitation as sample preparation, without the need of a time-consuming deglucuronidation step for the quantification of 1-hydroxymidazolam glucuronide, resulted in a simple and rapid assay suitable for clinical practice with a total runtime of only 1.1  min. The four components and the isotope-labeled internal standards were separated on a C 18 column and detection was performed with a triple-stage quadrupole mass spectrometer operating in positive ionization mode. The method was validated based on the "Guidance for Industry Bioanalytical Method Validation" (Food and Drug Administration, FDA) and the "Guideline on bioanalytical method validation" of the European Medicines Agency (EMA). Linearity was proven over the ranges of 5-1500 μg/L for midazolam, 1-hydroxymidazolam and 4-hydroxymidazolam and 25-5000 μg/L for 1-hydroxymidazolam glucuronide, using a sample volume of 100 μL. Matrix comparison indicated that the assay is also applicable to other human matrices like EDTA and heparin plasma and urine. Stability experiments showed good results for the stability of midazolam, 1-hydroxymidazolam and 1-hydroxymidazolam glucuronide in serum, EDTA and heparin plasma and urine stored for 7 days under different conditions. At room temperature, 4-hydroxymidazo-lam is stable for 7 days in EDTA plasma, but stable for only 3 days in serum and heparin plasma and less than 24 h in urine. All four compounds were found to be stable in serum, EDTA plasma, heparin plasma and urine for 7 days after sample preparation and for 3 freeze-thaw cycles. The assay has been applied in therapeutic drug monitoring of midazolam for (pediatric) intensive care patients., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Oxygenated ex situ machine perfusion of donor livers is an alternative for static cold preservation that can be performed at temperatures from 0 °C to 37 °C. Organ metabolism depends on oxygen to produce adenosine triphosphate and temperatures below 37 °C reduce the metabolic rate and oxygen requirements. The transport and delivery of oxygen in machine perfusion are key determinants in preserving organ viability and cellular function. Oxygen delivery is more challenging than carbon dioxide removal, and oxygenation of the perfusion fluid is temperature dependent. The maximal oxygen content of water-based solutions is inversely related to the temperature, while cellular oxygen demand correlates positively with temperature. Machine perfusion above 20 °C will therefore require an oxygen carrier to enable sufficient oxygen delivery to the liver. Human red blood cells are the most physiological oxygen carriers. Alternative artificial oxygen transporters are hemoglobin-based oxygen carriers, perfluorocarbons, and an extracellular oxygen carrier derived from a marine invertebrate. We describe the principles of oxygen transport, delivery, and consumption in machine perfusion for donor livers using different oxygen carrier-based perfusion solutions and we discuss the properties, advantages, and disadvantages of these carriers and their use.

Here, we provide an overview of the concept of a lactate-protected hypoglycemia ("LPH"), originally proposed as lowering glucose while simultaneously increasing lactate concentration as a method by which tumors might be targeted. Central to this hypothesis is that lactate can act as a critical salvage fuel for the central nervous system, allowing for wide perturbations in whole body and central nervous system glucose concentrations. Further, many tumors exhibit "the Warburg" effect, consuming glucose and producing and exporting lactate despite adequate oxygenation. While some recent data have provided evidence for a "reverse-Warburg," where some tumors may preferentially consume lactate, many of these experimental methods rely on a significant elevation in lactate in the tumor microenvironment. To date it remains unclear how various tumors behave in vivo , and how they might respond to perturbations in lactate and glucose concentrations or transport inhibition. By exploiting and targeting lactate transport and metabolism in tumors (with a combination of changes in lactate and glucose concentrations, transport inhibitors, etc.), we can begin developing novel methods for targeting otherwise difficult to treat pathologies in the brain and spinal cord. Here we discuss evidence both experimental and observational, and provide direction for next steps in developing therapies based on these concepts., (Copyright © 2020 Goodwin, Gladden and Nijsten.)

Background: Preconditioning of donor livers before organ retrieval may improve organ quality after transplantation. We investigated whether preconditioning with metformin reduces preservation injury and improves hepatobiliary function in rat donor livers during ex situ normothermic machine perfusion (NMP) and after orthotopic liver transplantation., Methods: Lewis rats were administered metformin via oral gavage, after which a donor hepatectomy was performed followed by a standardized cold storage period of 4 hours. Graft assessment was performed using NMP via double perfusion of the hepatic artery and portal vein. In an additional experiment, rat donor livers preconditioned with metformin were stored on ice for 4 hours and transplanted to confirm postoperative liver function and survival. Data were analyzed and compared with sham-fed controls., Results: Graft assessment using NMP confirmed that preconditioning significantly improved ATP production, markers for hepatobiliary function (total bile production, biliary bilirubin, and bicarbonate), and significantly lowered levels of lactate, glucose, and apoptosis. After orthotopic liver transplantation, metformin preconditioning significantly reduced transaminase levels., Conclusions: Preconditioning with metformin lowers hepatobiliary injury and improves hepatobiliary function in an in situ and ex situ model of rat donor liver transplantation.

Objective: The aim of this study was to evaluate sequential hypothermic and normothermic machine perfusion (NMP) as a tool to resuscitate and assess viability of initially declined donor livers to enable safe transplantation., Summary Background Data: Machine perfusion is increasingly used to resuscitate and test the function of donor livers. Although (dual) hypothermic oxygenated machine perfusion ([D]HOPE) resuscitates livers after cold storage, NMP enables assessment of hepatobiliary function., Methods: In a prospective clinical trial, nationwide declined livers were subjected to ex situ NMP (viability assessment phase), preceded by 1-hour DHOPE (resuscitation phase) and 1 hour of controlled oxygenated rewarming (COR), using a perfusion fluid containing an hemoglobin-based oxygen carrier. During the first 2.5 hours of NMP, hepatobiliary viability was assessed, using predefined criteria: perfusate lactate <1.7 mmol/L, pH 7.35 to 7.45, bile production >10 mL, and bile pH >7.45. Livers meeting all criteria were accepted for transplantation. Primary endpoint was 3-month graft survival., Results: Sixteen livers underwent DHOPE-COR-NMP. All livers were from donors after circulatory death, with median age of 63 (range 42-82) years and median Eurotransplant donor risk index of 2.82. During NMP, all livers cleared lactate and produced sufficient bile volume, but in 5 livers bile pH remained <7.45. The 11 (69%) livers that met all viability criteria were successfully transplanted, with 100% patient and graft survival at 3 and 6 months. Introduction of DHOPE-COR-NMP increased the number of deceased donor liver transplants by 20%., Conclusions: Sequential DHOPE-COR-NMP enabled resuscitation and safe selection of initially declined high-risk donor livers, thereby increasing the number of transplantable livers by 20%., Trial Registration: www.trialregister.nl; NTR5972.

Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin-based oxygen carrier (HBOC)-based perfusion fluid (DHOPE-COR-NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE-COR-NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was ≥10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3-month graft survival, was a 100%. In conclusion, sequential DHOPE-COR-NMP using an HBOC-based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation., (© 2018 The Authors American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Procalcitonin (PCT) testing can help in safely reducing antibiotic treatment duration in intensive care patients with sepsis. However, the cost-effectiveness of such PCT guidance is not yet known., Methods: A trial-based analysis was performed to estimate the cost-effectiveness of PCT guidance compared with standard of care (without PCT guidance). Patient-level data were used from the SAPS trial in which 1546 patients were randomised. This trial was performed in the Netherlands, which is a country with, on average, low antibiotic use and a short duration of hospital stay. As quality of life among sepsis survivors was not measured during the SAPS, this was derived from a Dutch follow-up study. Outcome measures were (1) incremental direct hospital cost and (2) incremental cost per quality-adjusted life year (QALY) gained from a healthcare perspective over a one-year time horizon. Uncertainty in outcomes was assessed with bootstrapping., Results: Mean in-hospital costs were €46,081/patient in the PCT group compared with €46,146/patient with standard of care (i.e. - €65 (95% CI - €6314 to €6107); - 0.1%). The duration of the first course of antibiotic treatment was lower in the PCT group with 6.9 vs. 8.2 days (i.e. - 1.2 days (95% CI - 1.9 to - 0.4), - 14.8%). This was accompanied by lower in-hospital mortality of 21.8% vs. 29.8% (absolute decrease 7.9% (95% CI - 13.9% to - 1.8%), relative decrease 26.6%), resulting in an increase in mean QALYs/patient from 0.47 to 0.52 (i.e. + 0.05 (95% CI 0.00 to 0.10); + 10.1%). However, owing to high costs among sepsis survivors, healthcare costs over a one-year time horizon were €73,665/patient in the PCT group compared with €70,961/patient with standard of care (i.e. + €2704 (95% CI - €4495 to €10,005), + 3.8%), resulting in an incremental cost-effectiveness ratio of €57,402/QALY gained. Within this time frame, the probability of PCT guidance being cost-effective was 64% at a willingness-to-pay threshold of €80,000/QALY., Conclusions: Although the impact of PCT guidance on total healthcare-related costs during the initial hospitalisation episode is likely negligible, the lower in-hospital mortality may lead to a non-significant increase in costs over a one-year time horizon. However, since uncertainty remains, it is recommended to investigate the long-term cost-effectiveness of PCT guidance, from a societal perspective, in different countries and settings.

BACKGROUND Donor hypernatremia has been associated with reduced graft and recipient survival after heart, liver, kidney, and pancreas transplantation. However, it is unknown what effect donor hypernatremia has on graft and recipient outcomes after lung transplantation. The aim of this study was to investigate the relation of donor hypernatremia with the duration of postoperative mechanical ventilation, the incidence of severe primary graft dysfunction, and survival following lung transplantation. MATERIAL AND METHODS We analyzed all consecutive lung transplantations performed in adult patients at our center between 1995 and 2016. During the study period, donor hypernatremia was not considered a reason to reject lungs for transplantation. Donors were classified into 3 groups: normonatremia (sodium <145 mmol/L), moderate hypernatremia (sodium 145-154 mmol/L), or severe hypernatremia (sodium ≥155 mmol/L). Short-term outcome was defined by the duration of mechanical ventilation and incidence of primary graft dysfunction; long-term outcome was defined by 10-year mortality. RESULTS Donor hypernatremia was recorded in 275 (58%) of the 474 donors. There were no differences in baseline characteristics between the 3 study groups. The duration of mechanical ventilation was similar for all groups (8±25, 7±17, and 9±15 days respectively, P=0.204). Severe primary graft dysfunction was not different between the 3 groups (29%, 26%, 28%, P=0.724). Donor hypernatremia was not associated with (graft) survival, or after correction for potential confounders. CONCLUSIONS Donor hypernatremia was not associated with a worse outcome in lung transplant recipients. Thus, in contrast to solid organ transplantation, donor hypernatremia is not a contraindication for lung transplantation.

Background: Perioperative acute kidney injury (AKI) is an important predictor of long-term all-cause mortality after coronary artery bypass (CABG). However, the effect of AKI on long-term mortality after cardiac valve operations is hitherto undocumented., Methods: Perioperative renal injury and long-term all-cause mortality after valve operations were studied in a prospective cohort of patients undergoing solitary valve operations (n = 2,806) or valve operations combined with CABG (n = 1,260) with up to 18 years of follow-up. Postoperative serum creatinine increase was classified according to AKI staging 0 to 3. Patients undergoing solitary CABG (n = 4,938) with cardiopulmonary bypass served as reference., Results: In both valve and valve+CABG operations, postoperative renal injury of AKI stage 1 or higher was progressively associated with an increase in long-term mortality (hazard ratio [HR], 2.27, p < 0.05 for valve; HR, 1.65, p < 0.05 for valve+CABG; HR, 1.56, p < 0.05 for CABG). Notably, the mortality risk increased already substantially at serum creatinine increases of 10% to 25%-that is, far below the threshold for AKI stage 1 after valve operations (HR, 1.39, p < 0.05), but not after valve operations combined with CABG or CABG only., Conclusions: An increase in serum creatinine by more than 10% during the first week after valve operation is associated with an increased risk for long-term mortality after cardiac valve operation. Thus, AKI classification clearly underestimates long-term mortality risk in patients undergoing valve operations., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to provide more insight in the course of cytokine concentrations related to pathologic response (pR) and complications after neoadjuvant chemoradiotherapy (NCRT) and esophagectomy in esophageal cancer patients., Methods: Patients treated with NCRT followed by transthoracic esophagectomy (n = 35) or transthoracic esophagectomy alone (n = 8) were included. Eight different cytokine concentrations were determined during NCRT, esophagectomy, and the first postoperative week., Results: Platelet-activating factor before NCRT was associated with pR (P = .011) and remained elevated in patients with a better response. Concentrations of intestinal fatty acid-binding protein and angiopoietin 1 (Ang-1) were different between patients with and without NCRT. Decreased concentrations of Ang-1 on the third postoperative day were associated with postoperative complications (P = .046)., Conclusions: In this observational study, elevated platelet-activating factor concentrations before NCRT were associated with pR. NCRT is associated with decreased Ang-1 concentrations, whereas reduced Ang-1 concentrations were associated with postoperative complications., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Blood lactate levels are increasingly used to monitor patients. Steroids are frequently administered to critically ill patients. However, the effect of steroids on lactate levels has not been adequately investigated. We studied the effect of a single intraoperative high dose of dexamethasone on lactate and glucose levels in patients undergoing cardiac surgery., Methods: The Dexamethasone for Cardiac Surgery (DECS) trial was a multicenter randomized trial on the effect of dexamethasone 1 mg/kg versus placebo on clinical outcomes after cardiac surgery in adults. Here we report a pre-planned secondary analysis of data from DECS trial participants included at the University Medical Center Groningen. The use of a computer-assisted glucose regulation protocol--Glucose Regulation for Intensive care Patients (GRIP)--was part of routine postoperative care. GRIP aimed at glucose levels of 4 to 8 mmol/L. Primary outcome parameters were area under the lactate and glucose curves over the first 15 hours of ICU stay (AUC₁₅). ICU length of stay and mortality were observed as well., Results: The primary outcome could be determined in 497 patients of the 500 included patients. During the first 15 hours of ICU stay, lactate and glucose levels were significantly higher in the dexamethasone group than in the placebo group: lactate AUC₁₅ 25.8 (13.1) versus 19.9 (11.2) mmol/L × hour, P <0.001 and glucose AUC₁₅ 126.5 (13.0) versus 114.4 (13.9) mmol/L × hour, P <0.001. In this period, patients in the dexamethasone group required twice as much insulin compared with patients who had received placebo. Multivariate and cross-correlation analyses suggest that the effect of dexamethasone on lactate levels is related to preceding increased glucose levels. Patients in the placebo group were more likely to stay in the ICU for more than 24 hours (39.2%) compared with patients in the dexamethasone group (25.0%, P = 0.001), and 30-day mortality rates were 1.6% and 2.4%, respectively (P = 0.759)., Conclusions: Intraoperative high-dose dexamethasone increased postoperative lactate and glucose levels in the first 15 hours of ICU stay. Still, patients in the dexamethasone group had a shorter ICU length of stay and similar mortality compared with controls., Trial Registration: ClinicalTrials.gov NCT00293592 . Registered 16 February 2006.

Purpose: The association between metformin use and renal function needs further to be elucidated since data are insufficient whether metformin affects renal function in higher risk populations such as after ST-elevation myocardial infarction (STEMI)., Methods: We studied 379 patients included in the GIPS-III trial in which patients without diabetes or renal dysfunction, who underwent primary percutaneous coronary interventions (PCI) for STEMI, were randomized to metformin 500 mg or placebo twice daily for four months. At baseline and at seven scheduled visits up to four months after PCI, estimated glomerular filtration rate (eGFR) was determined (2582 values). Contrast-induced acute kidney injury (CI-AKI) was defined as an increase in serum creatinine of ≥0.3 mg/dl or 25 % rise within 48 h after PCI., Results: At all visits, the mean eGFR was similar in patients randomized to metformin or placebo. Over the four month period, mixed-effect repeated-measures model analysis showed a least-squares mean ± standard error change in eGFR of -5.9±0.8 ml/min/1.73 m2 in the metformin group and −7.1 ±0.8 ml/min/1.73 m2 in the control group (P=0.27 for overall interaction). The incidence of CI-AKI was 14.8 %; 29 (15.2 %) patients in the metformin group versus 27 (14.4 %) controls (P=0.89). After adjustment for covariates, metformin treatment was not associated with CI-AKI (odds ratio: 0.96, 95%CI 0.52−1.75, P=0.88)., Conclusion: We conclude that initiation of metformin shortly after primary PCI has no adverse effect on renal function in patients without diabetes or prior renal impairment, further providing evidence of the safety of metformin use after myocardial infarction and subsequent contrast exposure.

Introduction: Lactate is a marker of hypoperfusion and may be used for risk assessment in critically ill patients. Although evidence suggests that repeated lactate measurements are of clinical interest, how and when lactate should be analyzed is controversial. Intravascular microdialysis provides a novel method for the continuous monitoring of lactate, which may be clinically beneficial in critically ill patients., Methods: Circulating lactate levels were continuously monitored in 80 patients undergoing cardiac surgery using either a separate single-lumen microdialysis catheter or a triple-lumen central venous catheter with an integrated microdialysis function. The catheter was placed with the tip positioned in the superior vena cava. Arterial blood gas samples were taken every hour to obtain reference values, and the lactate levels were analyzed in a blood gas analyzer., Results: A total of 1,601 paired microdialysis-arterial blood gas lactate samples were obtained. Bland-Altman analysis showed a bias (mean difference) ± limits of agreement (±1.96 SD) of 0.02 ± 0.42 mmol/L. The regression coefficient was 0.98 (P = 0.0001)., Conclusions: Central venous microdialysis is an accurate and reliable method for continuous blood lactate monitoring in patients undergoing cardiac surgery. The system may be useful for early lactate-guided therapy in critically ill patients.

Multiple biomarkers improve prognostication for long-term mortality in ST-segment elevation myocardial infarction (STEMI). However, one-third of mortality after STEMI occurs within initial discharge. Our objective was to determine whether multiple biomarkers (glucose, N-terminal pro-brain natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR)) predict both short-term as long-term mortality in STEMI. We used a patient-pooled dataset of consecutive STEMI patients, with complete biomarkers, who underwent primary percutaneous coronary intervention (PCI) in two single centers (Amsterdam and Groningen). With a previously developed multimarker risk score, based on three biomarkers, patients were indicated as low-, intermediate- or high risk. Cumulative 4-year mortality was estimated with the Kaplan-Meier method and compared with a log-rank test. We compared short-term and long-term mortality with a landmark set at 30 days because previous studies have shown that mortality largely occurs within 30 days. A total of 2,355 STEMI-patients were treated with primary PCI. The mortality rates in the low- (n = 1,531), intermediate- (n = 403) and high-risk (n = 421) groups were 4.8, 16.1, and 43.9 %, respectively. The differences were observed at a follow-up up to 30 days (log-rank p < 0.001) as well as after 30 days (log-rank p < 0.001). A multimarker risk score, based on admission levels of glucose, NT-proBNP, and eGFR identifies STEMI patients at low-, intermediate-, and high-risk for short-term and long-term mortality.

Objectives: Insulin administration lowers plasma potassium concentration by augmenting intracellular uptake of potassium. The effect of insulin administration on renal potassium excretion is unclear. Some studies suggest that insulin has an antikaliuretic effect although plasma potassium levels were poorly controlled. Since the introduction of glycemic control in the intensive care unit, insulin use has increased. We examined the relation between administered insulin and renal potassium excretion in critically ill patients under computer-assisted glucose and potassium regulation., Design: Prospective observational study., Setting: Twelve-bed surgical intensive care unit of a university teaching hospital., Patients: Consecutive intensive care unit patients., Interventions: Potassium and glucose levels were regulated by a computer-assisted decision support system. Both potassium and insulin were continuously administered by syringe pump., Measurements and Main Results: Renal potassium excretion was measured daily in the 24-hr urine collections. The 24-hr urinary samples of patients with kidney failure or on renal replacement therapy were excluded. Multivariate analysis with potassium excretion as the dependent variable was performed. In 178 consecutive patients, 1,456 24-hr urinary samples, were analyzed. Mean ± SD plasma potassium was 4.2 ± 0.3 mmol/L, with 79 ± 46 mmol/d of potassium administered and a mean insulin dose of 53 ± 38 U/day. Renal potassium excretion was 126 ± 51 mmol/day. After multivariate analysis correcting for relevant variables (including diuretics, pH, potassium levels and renal sodium excretion), insulin administration was independently and positively associated with renal potassium excretion. Other significant variables were potassium levels, potassium administration, renal sodium and chloride excretion, creatinine clearance, diuretic therapy, pH, known diabetes and intensive care unit admission day (R = .52; p <. 001)., Conclusion: Insulin administration is associated with an increase in the renal potassium excretion in critically ill patients.

Objective: To report the case of a 48-year female with chronic remitting anorexia nervosa who was found comatose at home and admitted to our hospital with a deep hypoglycemia (glucose level 0.6 mmol/L; 11 mg/dL) and septic shock secondary to a bilateral pneumonia., Method: Case report., Results: After admission to the critical care unit, she further displayed a number of pronounced complications known to be associated with anorexia, including hypophosphatemia, disturbed liver functions and depression of all three hematological cell lines. The neurological recovery of the patient was complicated by encephalopathy and transient tetraparesis. With initial deep hypoglycemia at presentation and persisting coma, magnetic resonance imaging performed 5 days later did not demonstrate characteristic post-hypoglycemic abnormalities. Neuroradiological examination did however reveal the presence of extensive calcifications in the basal ganglia known as Fahr's syndrome., Discussion: The potential relation between anorexia nervosa and Fahr syndrome has not been described before. The fact that this patient survived a glucose level that is usually associated with a very poor outcome is probably related to its special origin., (Copyright © 2010 Wiley Periodicals, Inc.)

Background: In nondiabetic patients with ST-segment-elevation myocardial infarction, acute hyperglycemia is associated with adverse outcome. Whether this association is due merely to hyperglycemia as an acute stress response or whether longer-term glycometabolic derangements are also involved is uncertain. It was our aim to determine the association between both acute and chronic hyperglycemia (hemoglobin A(₁c) [HbA(₁c)]) and outcome in nondiabetic patients with ST-segment-elevation myocardial infarction., Methods and Results: This observational study included consecutive patients (n=4176) without known diabetes mellitus admitted with ST-segment-elevation myocardial infarction. All patients were treated with primary percutaneous intervention. Both glucose and HbA(1c) were measured on admission. Main outcome measure was total long-term mortality; secondary outcome measures were 1-year mortality and enzymatic infarct size. One-year mortality was 4.7%, and mortality after total follow-up (3.3 ± 1.5 years) was 10%. Both elevated HbA(1c) levels (P<0.001) and elevated admission glucose (P<0.001) were associated with 1-year and long-term mortality. After exclusion of early mortality (within 30 days), HbA(₁c) remained associated with long-term mortality (P<0.001), whereas glucose lost significance (P=0.09). Elevated glucose, but not elevated HbA(₁c), was associated with larger infarct size. After multivariate analysis, HbA(₁c) (hazard ratio, 1.2 per interquartile range; P<0.01), but not glucose, was independently associated with long-term mortality., Conclusions: In nondiabetic patients with ST-segment-elevation myocardial infarction, both elevated admission glucose and HbA(₁c) levels were associated with adverse outcome. Both of these parameters reflect different patient populations, and their association with outcome is probably due to different mechanisms. Measurement of both parameters enables identification of these high-risk groups for aggressive secondary risk prevention.

Background: Early delivery of calories is important in critically ill patients, and the administration of parenteral nutrition (PN) is sometimes required to achieve this goal. However, PN can induce acute hyperglycemia, which is associated with adverse outcome. We hypothesized that initiation of PN using a rapid "step-up" approach, coupled with a computerized insulin-dosing protocol, would result in a desirable caloric intake within 24 hours without causing hyperglycemia., Methods: In our surgical intensive care unit (ICU), glucose is regulated by a nurse-centered computerized glucose regulation program. When adequate enteral feeding was not possible, PN was initiated according to a simple step-up rule at an infusion rate of 10 mL/h (approximately 10 kcal/h) and subsequently increased by steps of 10 mL/h every 4 hours, provided glucose was <10 mmol/L, until the target caloric intake (1 kcal/kg/h) was reached. All glucose levels and insulin doses were collected during the step-up period and for 24 hours after achieving target feeding., Results: In all 23 consecutive patients requiring PN, mean intake was 1 kcal/kg/h within 24 hours. Of the 280 glucose samples during the 48-hour study period, mean ± standard deviation glucose level was 7.4 ± 1.4 mmol/L. Only 4.5% of glucose measurements during the step-up period were transiently ≥10 mmol/L. After initiating PN, the insulin requirement rose from 1.1 ± 1.5 units/h to 2.9 ± 2.5 units/h (P < .001)., Conclusions: This proof of concept study shows that rapid initiation of PN using a step-up approach coupled with computerized glucose control resulted in adequate caloric intake within 24 hours while maintaining adequate glycemic control.

Background: Multiple trials have documented that myocardial blush grade (MBG) after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) has prognostic value for long-term clinical outcome. However, to the best of our knowledge, no study has determined the clinical use of MBG in routine clinical practice. We determined the prognostic value of MBG scored by the operator during primary PCI in consecutive patients with STEMI., Methods and Results: The prognostic value of MBG scored by the operator in relation to 1-year all cause mortality was evaluated in all patients with STEMI who underwent primary PCI between January 2004 and July 2008 in our hospital. The incidence of MBG 0, 1, 2, and 3 was 12%, 14%, 36%, and 38%, respectively, in 2118 consecutive patients with STEMI. Follow-up of all 2118 patients showed a 1-year all cause mortality rate of 8% (168 of 2118): 24%, 10%, 6%, and 4%, respectively, among patients with MBG 0, 1, 2, and 3 (P<0.001). In the 1763 patients with Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 after PCI, these mortality rates were 17%, 10%, 6%, and 4%, respectively (P<0.001). MBG scored by the operator was a strong independent predictor of 1-year all cause mortality corrected for other well-known predictive variables, including TIMI flow grade., Conclusions: MBG scored by the operator during primary PCI has prognostic value for 1-year all cause mortality in patients with STEMI in routine clinical practice. Therefore, the MBG should be documented, in addition to the TIMI flow grade, during primary PCI in patients with STEMI in standard PCI reports in routine clinical practice.

Background: Potassium disorders can cause major complications and must be avoided in critically ill patients. Regulation of potassium in the intensive care unit (ICU) requires potassium administration with frequent blood potassium measurements and subsequent adjustments of the amount of potassium administrated. The use of a potassium replacement protocol can improve potassium regulation. For safety and efficiency, computerized protocols appear to be superior over paper protocols. The aim of this study was to evaluate if a computerized potassium regulation protocol in the ICU improved potassium regulation., Methods: In our surgical ICU (12 beds) and cardiothoracic ICU (14 beds) at a tertiary academic center, we implemented a nurse-centered computerized potassium protocol integrated with the pre-existent glucose control program called GRIP (Glucose Regulation in Intensive Care patients). Before implementation of the computerized protocol, potassium replacement was physician-driven. Potassium was delivered continuously either by central venous catheter or by gastric, duodenal or jejunal tube. After every potassium measurement, nurses received a recommendation for the potassium administration rate and the time to the next measurement. In this before-after study we evaluated potassium regulation with GRIP. The attitude of the nursing staff towards potassium regulation with computer support was measured with questionnaires., Results: The patient cohort consisted of 775 patients before and 1435 after the implementation of computerized potassium control. The number of patients with hypokalemia (<3.5 mmol/L) and hyperkalemia (>5.0 mmol/L) were recorded, as well as the time course of potassium levels after ICU admission. The incidence of hypokalemia and hyperkalemia was calculated. Median potassium-levels were similar in both study periods, but the level of potassium control improved: the incidence of hypokalemia decreased from 2.4% to 1.7% (P < 0.001) and hyperkalemia from 7.4% to 4.8% (P < 0.001). Nurses indicated that they considered computerized potassium control an improvement over previous practice., Conclusions: Computerized potassium control, integrated with the nurse-centered GRIP program for glucose regulation, is effective and reduces the prevalence of hypo- and hyperkalemia in the ICU compared with physician-driven potassium regulation.

Background: The time distribution of injuries is not random. To assess the potential impact of weather and the phase of the moon on accidents, adjustment for known periodic and nonperiodic factors may be important. We compared the incidence of injuries with quantitative and qualitative weather variables as well as the lunar cycle, after correction for calendar and holiday-related factors., Methods: We extracted the daily number of trauma patients treated at the emergency department over 36 years (1970-2005) from the trauma database of our regional hospital. For each patient, age, sex, cause of injury, and severity of injury were recorded. This was combined with daily meteorological data including temperature, precipitation, sunshine, humidity, air pressure, and wind as well as the lunar phase. We also related the rate of change of these parameters with the incidence of injuries. A qualitative weather variable derived from temperature, sunshine duration, and precipitation was defined as bad, normal, or good. Periodicities were adjusted for with Poisson regression spline fitting analysis., Results: Several weather variables were related with the number of injuries. For most of these, better weather conditions were associated with an increase in trauma incidence. Good weather, which was present on 16.5% of the days, resulted in 10.1% (9.3-11.4 95% CI) more traumas compared with normal weather. Full moon was associated with a 2.1% (1.1-3.0 95% CI) lower trauma incidence than new moon., Conclusions: Better weather conditions contribute to an increased incidence of trauma. Full moon is associated with a slightly lower trauma incidence.

The avid consumption of glucose with concomitant lactate production by malignant cells, even under aerobic conditions, is called the Warburg effect, or aerobic glycolysis. This metabolic state is a final common pathway that apparently serves various invasive purposes. As most invasive tumours display the Warburg effect, this has proven of great clinical importance in detecting malignancies with 18-fluorine 2-deoxyglucose positron emission tomography (FDG-PET) scans. However, using the Warburg effect to target malignancies has proven more difficult. Since hypoglycaemia has been shown to be tumouricidal for cancers that display the Warburg effect, various schemes to block glucose utilization have been investigated. But in vivo it is difficult to selectively target glucose utilization in malignant cells without harming normal cells. Cancer cells produce large amounts of lactate under the Warburg effect, without fully oxidizing it to CO(2). In contrast normal cells can completely oxidize lactate under aerobic conditions. Recent studies have demonstrated that vital organs such as the brain, heart, liver, kidneys and muscle are capable of oxidizing lactate as a fuel alternative to glucose. It has also been shown that during hypoglycaemia intravenous lactate can serve as a salvage fuel in man. Other clinical studies showed that patients can effectively metabolize large amounts of exogenous lactate. All this appears to reflect the recently recognized major physiological role of lactate as a glucose alternative. Consequently, lactate is the most logical candidate to serve as a salvage fuel when local or systemic hypoglycemia is induced. Thus, we hypothesize that the combination of hypoglycaemia induced by insulin and concomitant lactate administration will selectively suppress cancers manifesting the Warburg effect, since such cancers will have great difficulty in metabolizing lactate. This metabolic therapy could be modulated in many ways both in amplitude, in duration and in timing with respect to other therapies. The validated isolated limb perfusion (ILP) model for sarcoma appears an attractive model to evaluate local therapy with insulin and lactate and test its (adjuvant) tumouricidal effects in animals and man. Such effects could be evaluated with modern metabolic detection techniques such as FDG-PET and magnetic resonance imaging in local models both in animals and humans. Subsequently the systemic effects of hypoglycaemia combined with sodium lactate administration could be evaluated.

Background: Increased production of red blood cells (RBCs) should be reflected by increased reticulocyte counts (RC). With the introduction of modern fully automated measurements of RC, the recovery of hemoglobin (Hb) after blood loss might be assessed earlier. We investigated the temporal relation of Hb and RC in trauma patients., Methods: Over a 10-month period, all patients with trauma admitted to our University Medical Center were analyzed. Both Hb (reference values: males, 14.0-17.1 g/dL; females, 12.1-15.9 g/dL) and RC (8-26 promille) were determined with a Sysmex XE-2100 analyzer. RBC transfusions were administered in otherwise healthy patients below an Hb threshold of 6.9 g/dL. Hb and RC were analyzed for a maximum of 30 days posttrauma and related in multivariate analysis to age, sex, and comorbidity., Results: Two hundred and forty-one patients (age 52 years +/- 21 years) were studied. In 28 patients (12%), one or more RBCs were administered with a mean of 2.2 RBCs (range, 1-4). Hb decreased to 10.9 g/dL +/- 2.1 g/dL on day 3. RC rose from 16 +/- 11 at admission to 38 promille +/- 21 promille on day 13 (p < 0.0001). Nadir Hb values and maximum RC values were inversely related according to univariate analysis (Pearson R = -0.62, p < 0.001). In multivariate analysis, Hb remained the only significant determinant of RC (R = 0.64, p < 0.001)., Conclusions: Hb and RC are clearly related in trauma patients. Measuring RC may be helpful in predicting the rise of Hb after acute blood loss.

Objectives: Early estimation of the mortality risk of severely injured patients is mandatory. To estimate the seriousness of the condition of patients with trauma, we developed the emergency trauma score (EMTRAS) for ease of use, with simple parameters that are available within 30 minutes., Design: Prospective analysis of the German Trauma Registry of multitrauma patients., Setting: EMTRAS was derived from data from 1993 through 2003. Potential parameters that were prognostic for mortality in univariate analysis were evaluated by multivariate binary logistic regression. Selected parameters were then assigned a subscore that varied from 0 to 3. The EMTRAS score was a simple addition of these subscores. EMTRAS was compared with other scores' receiver operating characteristic curves. After completion, EMTRAS was validated in patients from 2004 and 2005., Patients: A total of 11,533 patients were to be used for developing the score and 3314 patients for validating it., Main Results: The strongest predictors of mortality were age, prehospital Glasgow Coma Scale, base excess (mmol/L), and prothrombin time (% of reference). These parameters were categorized in subscores of 0 through 3. Age: <40, 40 through 60, 61 through 75, and >75 scored 0, 1, 2, and 3, respectively. Glasgow Coma Scale: 13 through 15, 10 through 12, 6 through 9, and 3 through 5 scored 0, 1, 2, and 3, respectively. Base excess: >-1, -5 through -1, -10 through -5.1, and <-10 scored 0, 1, 2, and 3, respectively. Prothrombin time: <80%, 80% through 50%, 49% through 20%, and >20% received a score of 0, 1, 2, and 3, respectively. In the validation dataset, the area under the receiver operating characteristic curve for EMTRAS was 0.828., Conclusions: EMTRAS combines four early parameters from the emergency room and accurately predicts mortality. Knowledge of the anatomical injuries is not necessary. The determination of the EMTRAS will inform caregivers of the seriousness of patients with trauma at an early stage.

Aims: Myocardial reperfusion after acute myocardial infarction can be angiographically assessed by the myocardial blush grade (MBG) or TIMI Perfusion Grade. These scores are based on subjective human judgement and lead to a score of four categories. A more operator-independent way of scoring myocardial perfusion may facilitate research in this area., Methods and Results: We designed the 'Quantitative Blush Evaluator' (QuBE), a computer program which calculates a score for myocardial perfusion. This program will be freely available as open source software. The inter-observer concordance was 97.7%. We calculated values on prospectively collected angiograms in patients with acute ST-elevation myocardial infarction from the TAPAS trial. Quantitative blush evaluator values could be assessed on 790 out of 980 collected angiograms (81%). The QuBE score correlated significantly with MBG as determined by a core lab. The QuBE score predicted complete ST-elevation resolution, low enzyme levels, and 1 year survival (all P < 0.001). Quantitative blush evaluator value was an independent predictor of mortality at 1 year [OR 0.40 (0.17-0.90), P = 0.02]., Conclusion: The QuBE program provides a practical, freely available computer-assisted assessment of myocardial perfusion. The QuBE score provides a useful surrogate endpoint in trials of therapies aimed at improving myocardial reperfusion.

Current care guidelines recommend glucose control (GC) in critically ill patients. To achieve GC, many ICUs have implemented a (nurse-based) protocol on paper. However, such protocols are often complex, time-consuming, and can cause iatrogenic hypoglycemia. Computerized glucose regulation protocols may improve patient safety, efficiency, and nurse compliance. Such computerized clinical decision support systems (Cuss) use more complex logic to provide an insulin infusion rate based on previous blood glucose levels and other parameters. A computerized CDSS for glucose control has the potential to reduce overall workload, reduce the chance of human cognitive failure, and improve glucose control. Several computer-assisted glucose regulation programs have been published recently. In order of increasing complexity, the three main types of algorithms used are computerized flowcharts, Proportional-Integral-Derivative (PID), and Model Predictive Control (MPC). PID is essentially a closed-loop feedback system, whereas MPC models the behavior of glucose and insulin in ICU patients. Although the best approach has not yet been determined, it should be noted that PID controllers are generally thought to be more robust than MPC systems. The computerized Cuss that are most likely to emerge are those that are fully a part of the routine workflow, use patient-specific characteristics and apply variable sampling intervals.

Objective: Boussignac continuous positive airway pressure (BCPAP) delivered by face mask is useful for patients with acute cardiogenic pulmonary edema (ACPE). Although BCPAP is medically effective, we observed that not all suitable patients received it. In this descriptive, prospective, cohort study, we explored the experiences and attitudes of both patients and staff with BCPAP., Methods: Patients were interviewed 12 to 48 hours after treatment with BCPAP. Nurses on the coronary care unit were interviewed on their knowledge, skills, experiences, and opinions concerning BCPAP., Results: Of 117 patients with ACPE, 87 patients (74%) received BCPAP treatment. It was decided not to administer BCPAP in 30 patients with ACPE (26%). Patients who received BCPAP found that the reduction of dyspnea outweighed any discomfort. Barriers for the use of BCPAP were not related to nurses' skills but to the following: the nurses' belief that BCPAP created major discomfort, the lack of guidelines, the ultimate improvement of oxygenation without BCPAP, and the more labor-intensive treatment., Conclusion: Overestimation of patient discomfort by nurses and system-related factors impeded the use of BCPAP for all patients with ACPE.

Objective: Intensive insulin therapy is associated with the risk of hypoglycemia and increased costs of material and personnel. We therefore evaluated the safety and efficiency of a computer-assisted glucose control protocol in a large population of critically ill patients., Design and Setting: Observational cohort study in three intensive care units (32 beds) in a 1,300-bed university teaching hospital., Patients: All 2,800 patients admitted to the surgical, neurosurgical, and cardiothoracic units; the study period started at each ICU after implementation of Glucose Regulation for Intensive Care Patients (GRIP), a freely available computer-assisted glucose control protocol., Measurements and Results: We analysed compliance in relation to recommended insulin pump rates and glucose measurement frequency. Patients were on GRIP-ordered pump rates 97% of time. Median measurement time was 5min late (IQR 20min early to 34 min late). Hypoglycemia was uncommon (7% of patients for mild hypoglycemia, < 3.5mmol/l; 0.86% for severe hypoglycemia, < 2.2 mmol/l). Our predefined target range (4.0-7.5 mmol/l) was reached after a median of 5.6 h (IQR 0.2-11.8) and maintained for 89% (70-100%) of the remaining stay at the ICU. The number of measurements needed was 5.9 (4.8-7.3) per patient per day. In-hospital mortality was 10.1%., Conclusions: Our computer-assisted glucose control protocol provides safe and efficient glucose regulation in routine intensive care practice. A low rate of hypoglycemic episodes was achieved with a considerably lower number of glucose measurements than used in most other schemes.

Background: In patients who are weaned with a tracheostomy tube (TT), continuous positive airway pressure (CPAP) is frequently used. Dedicated CPAP systems or ventilators with bulky tubing are usually applied. However, CPAP can also be effective without a ventilator by the disposable Boussignac CPAP (BCPAP) system that is normally used with face masks., Objective: It was the aim of this audit to evaluate the feasibility of low-level BCPAP in patients who were weaned with a TT., Methods: All patients at our surgical intensive care unit who received a TT for weaning were considered for application of BCPAP. Once patients had received minimal pressure support from the mechanical ventilator, the BCPAP device was connected to the TT three times a day for 30 min with pressure set to 3-5 cm H(2)O, FiO(2) at 0.4 and with humidification. BCPAP was then gradually extended to 24 h/day. Patient acceptance, complications and outcome were recorded., Results: 58 patients received a TT to facilitate weaning. They had a median stay of 52 days in the intensive care unit during which they had an endotracheal tube for 22 days and a TT for 28 days. 50 of these patients (86%) received BCPAP for a median of 16 days. The lightweight BCPAP system was well tolerated without tube obstructions or accidental decannulations and may have contributed to patient mobility. No patient remained on ventilatory support after hospital discharge. In-hospital and 1-year survival were 86 and 71%, respectively., Conclusions: BCPAP is a feasible and safe method for weaning tracheostomy patients., ((c) 2007 S. Karger AG, Basel.)

Purpose: Many laboratory values are abnormal after surgery for a ruptured abdominal aortic aneurysm (RAAA). However, these changes have not been comprehensively evaluated. We analyzed the changes in routine laboratory values and how these changes related to outcome in a consecutive series of RAAA patients., Methods: All patients who underwent surgery for an RAAA between January 1990 and June 2003 at our hospital were included in this study. We analyzed laboratory data acquired during the first week for all patients and at discharge for survivors. We categorized 29 different measurements into six categories based on the related pathological process, including hematology and coagulation, metabolism, systemic inflammation, renal function, liver function, and electrolytes., Results: A total of 290 patients underwent RAAA surgery, with a hospital mortality of 34%. Hemorrhage was the most common cause of early death, whereas multiple-organ failure (MOF) was the most common cause of death several days after surgery. Most laboratory values deviated from normal at multiple time points and they differed significantly between survivors and nonsurvivors., Conclusions: Both survivors and nonsurvivors of RAAA surgery displayed characteristic time-dependent laboratory abnormalities. Awareness of these responses may help us predict patients prone to complications.

Background: Continuous positive airway pressure (CPAP) treatment for acute cardiogenic pulmonary edema can have important benefits in acute cardiac care. However, coronary care units are usually not equipped and their personnel not adequately trained for applying CPAP with mechanical ventilators. Therefore we investigated in the coronary care unit setting the feasibility and outcome of the simple Boussignac mask-CPAP (BCPAP) system that does not need a mechanical ventilator., Methods: BCPAP was introduced in a coronary care unit where staff had no CPAP experience. All consecutive patients transported to our hospital with acute cardiogenic pulmonary edema, a respiratory rate > 25 breaths/min and a peripheral arterial oxygen saturation of < 95% while receiving oxygen, were included in a prospective BCPAP group that was compared with a historical control group that received conventional treatment with oxygen alone., Results: During the 2-year prospective BCPAP study period 108 patients were admitted with acute cardiogenic pulmonary edema. Eighty-four of these patients (78%) were treated at the coronary care unit of which 66 (61%) were treated with BCPAP. During the control period 66 patients were admitted over a 1-year period of whom 31 (47%) needed respiratory support in the intensive care unit. BCPAP treatment was associated with a reduced hospital length of stay and fewer transfers to the intensive care unit for intubation and mechanical ventilation. Overall estimated savings of approximately euro 3,800 per patient were achieved with the BCPAP strategy compared to conventional treatment., Conclusion: At the coronary care unit, BCPAP was feasible, medically effective, and cost-effective in the treatment of acute cardiogenic pulmonary edema. Endpoints included mortality, coronary care unit and hospital length of stay, need of ventilatory support, and cost (savings).