Search

BACKGROUND: Early initiation of continuous positive airway pressure (CPAP) applied by face mask benefits patients with acute cardiogenic pulmonary oedema (ACPE). The simple disposable Boussignac CPAP (BCPAP) has been used in ambulances by physicians. In the Netherlands, ambulances are manned by nurses and not physicians. It was hypothesised that ambulance nurses are able to identify patients with ACPE and can successfully apply BCPAP. A prospective case series of patients with presumed ACPE treated with BCPAP by ambulance nurses is described. METHODS: After training of ambulance nurses, all 33 ambulances in the region were equipped with BCPAP. ACPE was diagnosed on clinical signs and pulse oximetry saturation (Spo(2)) <95%. BCPAP (5 cm H(2)O, Fio(2)>80%) was generated with an oxygen flow of 15 l/min. The physiological responses, experiences and clinical outcomes of the patients were collected from ambulance and hospital records, and ambulance nurses and patients received a questionnaire. RESULTS: From March to December 2006, 32 patients (age range 61-94 years) received BCPAP during transport to six different regional hospitals. In 26 patients (81%) a diagnosis of ACPE was confirmed. With BCPAP, median (IQR) Spo(2) increased from 79% (69-94%) to 96% (89-98%) within 20 min. The median (IQR) duration of BCPAP treatment was 26 min (21-32). The patients had no negative recollections of the treatment. Ambulance personnel were satisfied with the BCPAP therapy. CONCLUSION: When applied by ambulance nurses, BCPAP was feasible and effective in improving oxygen saturation in patients with ACPE. Although survival benefit can only be demonstrated by further research, it is considered that BCPAP can be implemented in all ambulances in the Netherlands. [ABSTRACT FROM AUTHOR]

Whereas urinary creatinine excretion (UCE) is an established marker of muscle mass, both in critically ill and non-critically ill patients, analysis of urinary urea excretion (UUE) may allow estimation of proteolysis that is associated with critical illness. We evaluated the time courses of plasma urea and creatinine as well UUE and UCE in critically ill patients with a prolonged ICU stay. Our goal was to evaluate changes in plasma urea and creatinine in conjunction with their urinary excretion, to get a better understanding of urea handling in ICU patients. From 2002 to 2021, plasma urea and creatinine, UUE and UCE were determined in routinely obtained 24 h urine samples between ICU admission and day 30, in adult patients with an ICU-stay ≥ 28d. Urea-to-creatinine ratios in plasma and urine were calculated. Patients with stage 3 acute kidney injury (AKI) were excluded. Analyses were performed separately for females and males and for patients with and without acute renal failure to account for respectively differences in muscle mass and impaired renal function. Of 47,120 patients, who were admitted to the ICU between 2002 and 2021, 638 patients met the inclusion criteria. During the first 10 days mean ± SD plasma urea increased from 9.7 ± 6.0 mmol/L at ICU admission to 12.4 ± 7.9 mmol/L (P < 0.001) on day 11 and decreased afterwards with a rate of 0.1 mmol/l/d. UUE peaked at 590 ± 317 mmol/day on day 13 whereas UCE peaked already on day 4. Males had higher plasma urea, plasma creatinine, UUE and UCE than females. Plasma and urinary urea-to-creatinine ratio (UCR) stabilized after day 7, with a gradual increase in plasma UCR and urinary UCR between day 7 and day 30. Similar courses, although less pronounced, were seen in patients without AKI. The course of urea in critically ill patients is characterized by an initial rise of both plasma urea and urinary urea excretion, presumably due to increased catabolism of endogenous and exogenous protein in the first week of ICU admission. Subsequently, UUE and UCE declined steadily in a rate that was comparable to the known loss of muscle mass during ICU admission of approximately 1%/day., (© 2024. The Author(s).)

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 m 2 . 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., (© 2024. The Author(s).)

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.

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., (© 2024. The Author(s).)

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., Competing Interests: MB was employed by Certe Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from Thermo Fisher Scientific (Waltham, MA, USA). This funder had the following involvement with the study: During the SAPS-trial we received financial support for the database design and randomization and received PCT kits at reduced cost from Thermo Fisher., (Copyright © 2023 Shajiei, Berends, Luz, van Oers, Harmsen, Vos, Klont, Loef, Reidinga, Bormans-Russell, Linsen, Dormans, Otten, van der Bij, Beishuizen, de Lange, de Jong and Nijsten.)

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 CO 2 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Freire Jorge, Goodwin, Renes, Nijsten and Pamenter.)

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., (© 2021. The Author(s).)

Purpose: Baseline urinary creatinine excretion (UCE) is associated with ICU outcome, but its time course is not known., Materials and Methods: We determined changes in UCE, plasma creatinine, measured creatinine clearance (mCC) and estimated glomerular filtration (eGFR) in patients with an ICU-stay ≥30d without acute kidney injury stage 3. The Cockcroft-Gault, MDRD (modification of diet in renal disease) and CKD-EPI (chronic kidney disease epidemiology collaboration) equations were used., Results: In 248 patients with 5143 UCEs hospital mortality was 24%. Over 30d, UCE absolutely decreased in male survivors and non-survivors and female survivors and nonsurvivors by 0.19, 0.16, 0.10 and 0.05 mmol/d/d (all P < 0.001). Relative decreases in UCE were similar in all four groups: 1.3, 1.4, 1.2 and 0.9%/d respectively. Over 30d, mCC remained unchanged, but eGFR rose by 31% (CKD-EPI) and 73% (MDRD) and creatinine clearance estimated by Cockcroft-Gault by 59% (all P < 0.001)., Conclusions: Over 1 month of ICU stay, UCE declined by ≥1%/d which may correspond to an equivalent decline in muscle mass. These rates of UCE decrease were similar in survivors, non-survivors, males and females underscoring the intransigent nature of this process. In contrast to measured creatinine clearance, estimates of eGFR progressively rose during ICU stay., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier Inc.)

Objective: Lactate has been shown to be preferentially metabolized in comparison to glucose after physiological stress, such as strenuous exercise. Derangements of lactate and glucose are common after out-of-hospital cardiac arrest (OHCA). Therefore, we hypothesized that lactate decreases faster than glucose after return-to-spontaneous-circulation (ROSC) after OHCA., Results: We included 155 OHCA patients in our analysis. Within the first 8 h of presentation to the emergency department, 843 lactates and 1019 glucoses were available, respectively. Lactate decreased to 50% of its initial value within 1.5 h (95% CI [0.2-3.6 h]), while glucose halved within 5.6 h (95% CI [5.4-5.7 h]). Also, in the first 8 h after presentation lactate decreases more than glucose in relation to their initial values (lactate 72.6% vs glucose 52.1%). In patients with marked hyperlactatemia after OHCA, lactate decreased expediently while glucose recovered more slowly, whereas arterial pH recovered at a similar rapid rate as lactate. Hospital non-survivors (N = 82) had a slower recovery of lactate (P = 0.002) than survivors (N = 82). The preferential clearance of lactate underscores its role as a prime energy substrate, when available, during recovery from extreme stress.

Metformin may act renoprotective prior to kidney transplantation by reducing ischemia-reperfusion injury (IRI). This study examined whether metformin preconditioning and postconditioning during ex vivo normothermic machine perfusion (NMP) of rat and porcine kidneys affect IRI. In the rat study, saline or 300 mg/kg metformin was administered orally twice on the day before nephrectomy. After 15 minutes of warm ischemia, kidneys were preserved with static cold storage for 24 hours. Thereafter, 90 minutes of NMP was performed with the addition of saline or metformin (30 or 300 mg/L). In the porcine study, after 30 minutes of warm ischemia, kidneys were preserved for 3 hours with oxygenated hypothermic machine perfusion. Subsequently, increasing doses of metformin were added during 4 hours of NMP. Metformin preconditioning of rat kidneys led to decreased injury perfusate biomarkers and reduced proteinuria. Postconditioning of rat kidneys resulted, dose-dependently, in less tubular cell necrosis and vacuolation. Heat shock protein 70 expression was increased in metformin-treated porcine kidneys. In all studies, creatinine clearance was not affected. In conclusion, both metformin preconditioning and postconditioning can be done safely and improved rat and porcine kidney quality. Because the effects are minor, it is unknown which strategy might result in improved organ quality after transplantation., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Administering a separator fluid between incompatible solutions can optimize the use of intravenous lumens. Factors affecting the required separator fluid volume to safely separate incompatible solutions are unknown., Methods: An intravenous tube (2-m, 2-mL, 6-French) containing methylene blue dye was flushed with separator fluid until a methylene blue concentration ⩽2% from initial was reached. Independent variables were administration rate, dye solvent (glucose 5% and NaCl 0.9%), and separator fluid. In the second part of the study, methylene blue, separator fluid, and eosin yellow were administered in various administration profiles using 2- and 4-mL (2 × 2 m, 4-mL, 6-French) intravenous tubes., Results: Neither administration rate nor solvent affected the separator fluid volume ( p =  0.24 and p =  0.12, respectively). Glucose 5% as separator fluid required a marginally smaller mean ± SD separator fluid volume than NaCl 0.9% (3.64 ± 0.13 mL vs 3.82 ± 0.11 mL, p <  0.001). Using 2-mL tubing required less separator fluid volume than 4-mL tubing for methylene blue (3.89 ± 0.57 mL vs 4.91 ± 0.88 mL, p =  0.01) and eosin yellow (4.41 ± 0.56 mL vs 5.63 ± 0.15 mL, p <  0.001). Extended tubing required less separator fluid volume/mL of tubing than smaller tubing for both methylene blue (2 vs 4 mL, 1.54 ± 0.22 vs 1.10 ± 0.19, p <  0.001) and eosin yellow (2 vs 4 mL, 1.75 ± 0.22 vs 1.25 ± 0.03, p <  0.001)., Conclusion: The separator fluid volume was neither affected by the administration rate nor by solvent. Glucose 5% required a marginally smaller separator fluid volume than NaCl 0.9%, however its clinical impact is debatable. A larger intravenous tubing volume requires a larger separator fluid volume. However, the ratio of separator fluid volume to the tubing's volume decreases as the tubing volume increases.

Background: Bioelectrical impedance analysis (BIA) is a validated method to assess body composition in persons with fluid homeostasis and reliable body weight. This is not the case during critical illness. The raw BIA markers resistance, reactance, phase angle, and vector length are body weight independent. Phase angle reflects cellular health and has prognostic significance. We aimed to assess the course of phase angle and vector length during intensive care unit (ICU) admission, and determine the relation between their changes (Δ) and changes in body hydration., Methods: A prospective, dual-center observational study of adult ICU patients was conducted. Univariate and multivariable regression analyses were performed, including reactance as a marker of cellular mass and integrity and total body water according to the Biasioli equation (TBW Biasioli ) and fluid balance as body weight independent markers of hydration., Results: One hundred and fifty-six ICU patients (mean ± SD age 62.5 ± 14.5 years, 67% male) were included. Between days 1 and 3, there was a significant decrease in reactance/m (-2.6 ± 6.0 Ω), phase angle (-0.4 ± 1.1°), and vector length (-12.2 ± 44.3 Ω/m). Markers of hydration significantly increased. Δphase angle and Δvector length were both positively related to Δreactance/m (r 2  = 0.55, p < 0.01; r 2  = 0.38, p < 0.01). Adding ΔTBW Biasioli as explaining factor strongly improved the association between Δphase angle and Δreactance/m (r 2  = 0.73, p < 0.01), and Δvector length and Δreactance/m (r 2  = 0.77, p < 0.01)., Conclusions: Our results show that during critical illness, changes in phase angle and vector length partially reflect changes in hydration.

Background: Machine learning (ML) is increasingly being used in many areas of health care. Its use in infection management is catching up as identified in a recent review in this journal. We present here a complementary review to this work., Objectives: To support clinicians and researchers in navigating through the methodological aspects of ML approaches in the field of infection management., Sources: A Medline search was performed with the keywords artificial intelligence, machine learning, infection∗, and infectious disease∗ for the years 2014-2019. Studies using routinely available electronic hospital record data from an inpatient setting with a focus on bacterial and fungal infections were included., Content: Fifty-two studies were included and divided into six groups based on their focus. These studies covered detection/prediction of sepsis (n = 19), hospital-acquired infections (n = 11), surgical site infections and other postoperative infections (n = 11), microbiological test results (n = 4), infections in general (n = 2), musculoskeletal infections (n = 2), and other topics (urinary tract infections, deep fungal infections, antimicrobial prescriptions; n = 1 each). In total, 35 different ML techniques were used. Logistic regression was applied in 18 studies followed by random forest, support vector machines, and artificial neural networks in 18, 12, and seven studies, respectively. Overall, the studies were very heterogeneous in their approach and their reporting. Detailed information on data handling and software code was often missing. Validation on new datasets and/or in other institutions was rarely done. Clinical studies on the impact of ML in infection management were lacking., Implications: Promising approaches for ML use in infectious diseases were identified. But building trust in these new technologies will require improved reporting. Explainability and interpretability of the models used were rarely addressed and should be further explored. Independent model validation and clinical studies evaluating the added value of ML approaches are needed., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Multi-drug intravenous (IV) therapy is one of the most common medical procedures used in intensive care units (ICUs), operating rooms, oncology wards and many other hospital departments worldwide. As drugs or their solvents are frequently chemically incompatible, many solutions must be administered through separate lumens. When the number of available lumens is too low to facilitate the safe administration of these solutions, additional (peripheral) IV catheters are often required, causing physical discomfort and increasing the risk for catheter related complications. Our objective was to develop and evaluate an algorithm designed to reduce the number of intravenous lumens required in multi-infusion settings by multiplexing the administration of various parenteral drugs and solutions., Methods: A multiplex algorithm was developed that schedules the alternating IV administration of multiple incompatible IV solutions through a single lumen, taking compatibility-related, pharmacokinetic and pharmacodynamic constraints of the relevant drugs into account. The conventional scheduling procedure executed by ICU nurses was used for comparison. The number of lumens required by the conventional procedure (L CONV ) and multiplex algorithm (L MX ) were compared., Results: We used data from 175,993 ICU drug combinations, with 2251 unique combinations received by 2715 consecutive ICU patients. The mean ± SD number of simultaneous IV solutions was 2.8 ± 1.6. In 27% of all drug combinations, and 61% of the unique combinations the multiplex algorithm required fewer lumens (p < 0.001). With increasing L CONV , the reduction in number of lumens by the multiplex algorithm further increased (p < 0.001). In only 1% of cases multiplexing required > 3 lm, versus 12% using the conventional procedure., Conclusion: The multiplex algorithm addresses a major issue that occurs in ICUs, operating rooms, oncology wards, and many other hospital departments where several incompatible drugs are infused through a restricted number of lumens. The multiplex algorithm allows for more efficient use of IV lumens compared to the conventional multi-infusion strategy.

Introduction: Metformin can accumulate and cause lactic acidosis in patients with renal insufficiency. Metformin is known to inhibit mitochondria, while renal secretion of the drug by proximal tubules indirectly requires energy. We investigated whether addition of metformin before or during ex vivo isolated normothermic machine perfusion (NMP) of porcine and rat kidneys affects its elimination., Research Design and Methods: First, Lewis rats were pretreated with metformin or saline the day before nephrectomy. Subsequently, NMP of the kidney was performed for 90 min. Metformin was added to the perfusion fluid in one of three different concentrations (none, 30 mg/L or 300 mg/L). Second, metformin was added in increasing doses to the perfusion fluid during 4 hours of NMP of porcine kidneys. Metformin concentration was determined in the perfusion fluid and urine by liquid chromatography-tandem mass spectrometry., Results: Metformin clearance was approximately 4-5 times higher than creatinine clearance in both models, underscoring secretion of the drug. Metformin clearance at the end of NMP in rat kidneys perfused with 30 mg/L was lower than in metformin pretreated rats without the addition of metformin during perfusion (both p≤0.05), but kidneys perfused with 300 mg/L trended toward lower metformin clearance (p=0.06). Creatinine clearance was not different between treatment groups. During NMP of porcine kidneys, metformin clearance peaked at 90 min of NMP (18.2±13.7 mL/min/100 g). Thereafter, metformin clearance declined, while creatinine clearance remained stable. This observation can be explained by saturation of metformin transporters with a Michaelis-Menten constant (95% CI) of 23.0 (10.0 to 52.3) mg/L., Conclusions: Metformin was secreted during NMP of both rat and porcine kidneys. Excretion of metformin decreased under increasing concentrations of metformin, which might be explained by saturation of metformin transporters rather than a self-inhibitory effect. It remains unknown whether a self-inhibitory effect contributes to metformin accumulation in humans with longer exposure times., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Liver transplantation is the standard treatment for end-stage liver disease. However, due to the ongoing disparity between supply and demand for optimal donor organs, there is increasing usage of extended criteria donor organs, including steatotic liver grafts. To mitigate the increased risks associated with extended criteria donor livers, ex situ oxygenated machine perfusion (MP) has received increasing attention in recent years as an emerging platform for dynamic preservation, reconditioning, and viability assessment to increase organ utilization. MP can be applied at different temperatures. During hypothermic MP (4-12°C), liver metabolism is reduced, while oxygenation restores the intracellular levels of adenosine triphosphate. The liver is quickly "recharged" to support metabolism when at normothermia (35-37°C) and to ameliorate the detrimental effects of ischemia/reperfusion injury during transplantation. During normothermia, MP can be applied to assess hepatocellular and cholangiocellular viability. MP at hyperthermic (>38°C) temperatures (HyMP), however, remains relatively understudied. The liver is an important component in the regulation of core body temperature and, as such, displays significant physiological and metabolic changes in response to different temperatures. Hyperthermia may promote vasodilation, increase aerobic metabolism and induce production of protective molecules such as heat shock proteins. Therefore, HyMP could provide an attractive reconditioning strategy for steatotic livers. In this review, we describe current literature on the physiological and metabolic effects of the liver at hyperthermia for human, rodents, and pigs and provide a rationale for using therapeutic HyMP during isolated liver machine perfusion to recondition extended criteria donor livers, including steatotic livers, before transplantation.

Background: Lactate is a robust prognostic marker for the outcome of critically ill patients. Several small studies reported that metformin users have higher lactate levels at ICU admission without a concomitant increase in mortality. However, this has not been investigated in a larger cohort. We aimed to determine whether the association between lactate levels around ICU admission and mortality is different in metformin users compared to metformin nonusers., Methods: This cohort study included patients admitted to ICUs in northern Denmark between January 2010 and August 2017 with any circulating lactate measured around ICU admission, which was defined as 12 h before until 6 h after admission. The association between the mean of the lactate levels measured during this period and 30-day mortality was determined for metformin users and nonusers by modelling restricted cubic splines obtained from a Cox regression model., Results: Of 37,293 included patients, 3183 (9%) used metformin. The median (interquartile range) lactate level was 1.8 (1.2-3.2) in metformin users and 1.6 (1.0-2.7) mmol/L in metformin nonusers. Lactate levels were strongly associated with mortality for both metformin users and nonusers. However, the association of lactate with mortality was different for metformin users, with a lower mortality rate in metformin users than in nonusers when admitted with similar lactate levels. This was observed over the whole range of lactate levels, and consequently, the relation of lactate with mortality was shifted rightwards for metformin users., Conclusion: In this large observational cohort of critically ill patients, early lactate levels were strongly associated with mortality. Irrespective of the degree of hyperlactataemia, similar lactate levels were associated with a lower mortality rate in metformin users compared with metformin nonusers. Therefore, lactate levels around ICU admission should be interpreted according to metformin use.

A central venous catheter with a built-in microdialysis membrane is available for continuous lactate and glucose monitoring in the intensive care unit (ICU). As this catheter might also be suitable for repeated measurements of unbound drug levels, we studied in vitro the feasibility of monitoring unbound antibiotic concentrations. The catheter was placed in various media at 37°C spiked with gentamicin or vancomycin. Dialysate fractions were repeatedly collected over 3 hours with a NaCl 0.9% perfusate flow of 5 μL/min. Total and unbound drug concentrations in medium and perfusate were measured by immunoassay. After 60 minutes stable recovery for both drugs was observed, with mean ±SD relative recoveries of vancomycin and gentamicin in human serum of 64% ±0.4% and 73% ±3%. The recoveries of the unbound concentrations were 91% ±3% and 91% ±4%. This intravenous microdialysis system may be a very useful platform for therapeutic drug monitoring in the ICU.

Liver transplantation is frequently associated with hyperkalemia, especially after graft reperfusion. Dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia/reperfusion injury and improves graft function, compared to conventional static cold storage (SCS). We examined the effect of DHOPE on ex situ and in vivo shifts of potassium and sodium. Potassium and sodium shifts were derived from balance measurements in a preclinical study of livers that underwent DHOPE (n = 6) or SCS alone (n = 9), followed by ex situ normothermic reperfusion. Similar measurements were performed in a clinical study of DHOPE-preserved livers (n = 10) and control livers that were transplanted after SCS only (n = 9). During DHOPE, preclinical and clinical livers released a mean of 17 ± 2 and 34 ± 6 mmol potassium and took up 25 ± 9 and 24 ± 14 mmol sodium, respectively. After subsequent normothermic reperfusion, DHOPE-preserved livers took up a mean of 19 ± 3 mmol potassium, while controls released 8 ± 5 mmol potassium. During liver transplantation, blood potassium levels decreased upon reperfusion of DHOPE-preserved livers while levels increased after reperfusion of SCS-preserved liver, delta potassium levels were -0.77 ± 0.20 vs. +0.64 ± 0.37 mmol/L, respectively (P = .002). While hyperkalemia is generally anticipated during transplantation of SCS-preserved livers, reperfusion of hypothermic machine perfused livers can lead to decreased blood potassium or even hypokalemia in the recipient., (© 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.)

Common methods to detect phlebitis may not be sufficient for patients in the intensive care unit (ICU). The goal of this study was to investigate the feasibility of infrared (IR) thermography to objectively detect phlebitis in adult ICU patients. We included a total of 128 adult ICU-patients in a pilot and subsequent validation study. Median [interquartile range] age was 62 [54-71] years and 88 (69%) patients were male. Severity of phlebitis was scored using the visual infusion phlebitis (VIP)-score, ranging from 0 (no phlebitis) to 5 (thrombophlebitis). The temperature difference (ΔT) between the insertion site and a proximal reference point was measured with IR thermography. In 78 (34%) catheters early phlebitis and onset of moderate phlebitis was observed (VIP-score of 1-3). In both the pilot and the validation study groups ΔT was significantly higher when the VIP-score was ≥1 compared to a VIP-score of 0 (p<0.01 and p<0.001, respectively). Multivariate analysis identified ΔT (p<0.001) and peripheral venous catheter (PVC) dwell time (p = 0.001) as significantly associated with phlebitis. IR thermography may be a promising technique to identify phlebitis in the ICU. An increased ΔT as determined with thermography may be a risk factor for phlebitis., Competing Interests: Frank Doesburg received funding from Fresenius Kabi for de joint development of a software module for the computerized control of multiple infusion pumps. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The work performed in collaboration with Fresenius Kabi is unrelated to the data presented in the submitted article. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

In vivo metabolic studies typically concern complex open systems. However, a closed system allows better assessment of the metabolic limits. Ischemic priapism (IP) constitutes a special model of the compartment syndrome that allows direct sampling from a relatively large blood compartment formed by the corpora cavernosa (CC). The purpose of our study was to measure metabolic changes and the accumulation of end products within the CC during IP. Blood gas and biochemical analyses of aspirates of the CC were analyzed over an 8-year period. Mean ± SD pH, pCO 2 , pO 2 , O 2 -saturation, lactate, and glucose of the aspirated blood were determined with a point-of-care analyzer. Forty-seven initial samples from 21 patients had a pH of 6.91 ± 0.16, pCO 2 of 15.3 ± 4.4 kPa, pO 2 of 2.4 ± 2.0 kPa, and an O 2 -saturation of 19 ± 24% indicating severe hypoxia with severe combined respiratory and metabolic acidosis. Glucose and lactate levels were 1.1 ± 1.5 and 14.6 ± 4.8 mmol/L, respectively. pH and pCO 2 were inversely correlated (R 2  = 0.86; P < 0.001), glucose and O 2 -saturation were positively correlated (R 2  = 0.83; P < 0.001), and glucose and lactate were inversely correlated (R 2  = 0.72; P < 0.001). The positive correlation of CO 2 and lactate (R 2  = 0.69; P < 0.001) was similar to that observed in vitro, when blood was titrated with lactic acid. The observed combined acidosis underscores that IP behaves as a closed system where severe hypoxia and glycopenia coexist, indicating that virtually all energy reserves have been consumed., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background:: Over the past decade, prehospital and in-hospital treatment for out-of-hospital cardiac arrest (OHCA) has improved considerably. There are sparse data on the long-term outcome, especially in elderly patients. We studied whether elderly patients benefit to the same extent compared with younger patients and at long-term follow up as compared with the general population., Methods:: Between 2001 and 2010, data from all patients presented to our hospital after OHCA were recorded. Elderly patients (⩾75 years) were compared with younger patients. Neurological outcome was classified as cerebral performance category (CPC) at hospital discharge and long-term survival was compared with younger patients and predicted survival rates of the general population., Results:: Of the 810 patients admitted after OHCA, a total of 551 patients (68%) achieved return of spontaneous circulation, including 125 (23%) elderly patients with a mean age of 81 ± 5 years. In-hospital survival was lower in elderly patients compared with younger patients with rates of 33% versus 57% ( p < 0.001). A CPC of 1 was present in 73% of the elderly patients versus 86% of the younger patients ( p = 0.031). In 7.3% of the elderly patients, a CPC >2 was observed versus 2.5% of their younger counterparts ( p = 0.103). Elderly patients had a median survival of 6.5 [95% confidence interval (CI) 2.0-7.9] years compared with 7.7 (95% CI 7.5-7.9) years of the general population ( p = 0.019)., Conclusions:: The survival rate after OHCA in elderly patients is approximately half that of younger patients. Elderly patients who survive to discharge frequently have favorable neurological outcomes and a long-term survival that approximates that of the general population.

Background: Nonosmotic sodium storage has been reported in animals, healthy individuals and patients with hypertension, hyperaldosteronism and end-stage kidney disease. Sodium storage has not been studied in ICU patients, who frequently receive large amounts of sodium chloride-containing fluids. The objective of our study was to estimate sodium that cannot be accounted for by balance studies in critically ill patients. Chloride was also studied. We used multiple scenarios and assumptions for estimating sodium and chloride balances., Methods: We retrospectively analyzed patients admitted to the ICU after cardiothoracic surgery with complete fluid, sodium and chloride balance data for the first 4 days of ICU treatment. Balances were obtained from meticulously recorded data on intake and output. Missing extracellular osmotically active sodium (MES) was calculated by subtracting the expected change in plasma sodium from the observed change in plasma sodium derived from balance data. The same method was used to calculate missing chloride (MEC). To address considerable uncertainties on the estimated extracellular volume (ECV) and perspiration rate, various scenarios were used in which the size of the ECV and perspiration were varied., Results: A total of 38 patients with 152 consecutive ICU days were analyzed. In our default scenario, we could not account for 296 ± 35 mmol of MES in the first four ICU days. The range of observed MES in the five scenarios varied from 111 ± 27 to 566 ± 41 mmol (P < 0.001). A cumulative value of 243 ± 46 mmol was calculated for MEC in the default scenario. The range of cumulative MEC was between 62 ± 27 and 471 ± 56 mmol (P = 0.001 and P = 0.003). MES minus MEC varied from 1 ± 51 to 123 ± 33 mmol in the five scenarios., Conclusions: Our study suggests considerable disappearance of osmotically active sodium in critically ill patients and is the first to also suggest rather similar disappearance of chloride from the extracellular space. Various scenarios for insensible water loss and estimated size for the ECV resulted in considerable MES and MEC, although these estimates showed a large variation. The mechanisms and the tissue compartments responsible for this phenomenon require further investigation.

Purpose: Patients with reduced muscle mass have a worse outcome, but muscle mass is difficult to quantify in the ICU. Urinary creatinine excretion (UCE) reflects muscle mass, but has not been studied in critically ill patients. We evaluated the relation of baseline UCE with short-term and long-term mortality in patients admitted to our ICU., Methods: Patients who stayed ≥ 24 h in the ICU with UCE measured within 3 days of admission were included. We excluded patients who developed acute kidney injury stage 3 during the first week of ICU stay. As muscle mass is considerably higher in men than women, we used sex-stratified UCE quintiles. We assessed the relation of UCE with both in-hospital mortality and long-term mortality., Results: From 37,283 patients, 6151 patients with 11,198 UCE measurements were included. Mean UCE was 54% higher in males compared to females. In-hospital mortality was 17%, while at 5-year follow-up, 1299 (25%) patients had died. After adjustment for age, sex, estimated glomerular filtration rate, body mass index, reason for admission and disease severity, patients in the lowest UCE quintile had an increased in-hospital mortality compared to the patients in the highest UCE quintile (OR 2.56, 95% CI 1.96-3.34). For long-term mortality, the highest risk was also observed for patients in the lowest UCE quintile (HR 2.32, 95% CI 1.89-2.85), independent of confounders., Conclusions: In ICU patients without severe renal dysfunction, low urinary creatinine excretion is associated with short-term and long-term mortality, independent of age, sex, renal function and disease characteristics, underscoring the role of muscle mass as risk factor for mortality and UCE as relevant biomarker.

Background: Deranged glucose metabolism is frequently observed in trauma patients after moderate to severe traumatic injury, but little data is available about pre-hospital blood glucose and its association with various cardiac rhythms and cardiac arrest following trauma., Methods: We retrospectively investigated adult trauma patients treated by a nationwide helicopter emergency medical service (34 bases) between 2005 and 2013. All patients with recorded initial cardiac rhythms and blood glucose levels were enrolled. Blood glucose concentrations were categorised; descriptive and regression analyses were performed., Results: In total, 18,879 patients were included, of whom 185 (1.0%) patients died on scene. Patients with tachycardia (≥100/min, 7.0 ± 2.4 mmol/L p < 0.0001), pulseless ventricular tachycardia (9.8 ± 1.8, mmol/L, p = 0.008) and those with ventricular fibrillation (9.0 ± 3.2 mmol/L, p < 0.0001) had significantly higher blood glucose concentrations than did patients with normal sinus rhythm between 61 and 99/min (6.7 ± 2.1 mmol/L). In patients with low (≤2.8 mmol/L, 7/79; 8.9%, p < 0.0001) and high (> 10.0 mmol/L, 70/1271; 5.5%, p < 0.0001) blood glucose concentrations cardiac arrest was more common than in normoglycaemic patients (166/9433, 1.8%). ROSC was more frequently achieved in hyperglycaemic (> 10 mmol/L; 47/69; 68.1%) than in hypoglycaemic (≤4.2 mmol/L; 13/31; 41.9%) trauma patients (p = 0.01)., Conclusions: In adult trauma patients, pre-hospital higher blood glucose levels were related to tachycardic and shockable rhythms. Cardiac arrest was more frequently observed in hypoglycaemic and hyperglycaemic pre-hospital trauma patients. The rate of ROSC rose significantly with rising blood glucose concentration. Blood glucose measurements in addition to common vital parameters (GCS, heart rate, blood pressure, breathing frequency) may help identify patients at risk for cardiopulmonary arrest and dysrhythmias.

Background: In intensive care unit (ICU) patients, many laboratory measurements can be deranged when compared with the standard reference interval (RI). The assumption that larger derangements are associated with worse outcome may not always be correct. The ICU-Labome study systematically evaluated the univariate association of routine laboratory measurements with outcome., Methods: We studied the 35 most frequent blood-based measurements in adults admitted ≥6 h to our ICU between 1992 and 2013. Measurements were from the first 14 ICU days and before ICU admission. Various metrics, including variability, were related with hospital survival. ICU- based RIs were derived from measurements obtained at ICU discharge in patients who were not readmitted to the ICU and survived for >1 year., Results: In 49,464 patients (cardiothoracic surgery 43%), we assessed >20·106 measurements. ICU readmissions, in-hospital and 1-year mortality were 13%, 14% and 19%, respectively. On ICU admission, lactate had the strongest relation with hospital mortality. Variability was independently related with hospital mortality in 30 of 35 measurements, and 16 of 35 measurements displayed a U-shaped outcome-relation. Medians of 14 of 35 ICU-based ranges were outside the standard RI. Remarkably, γ-glutamyltransferase (GGT) had a paradoxical relation with hospital mortality in the second ICU week because more abnormal GGT-levels were observed in hospital survivors., Conclusions: ICU-based RIs for may be more useful than standard RIs in identifying ICU patients at risk. The association of variability with outcome for most of the measurements suggests this is a consequence and not a cause of a worse ICU outcome. Late elevation of GGT may confer protection to ICU patients.

Normothermic machine perfusion (NMP) enables viability assessment of donor livers prior to transplantation. NMP is frequently performed by using human blood products including red blood cells (RBCs) and fresh frozen plasma (FFP). Our aim was to examine the efficacy of a novel machine perfusion solution based on polymerized bovine hemoglobin-based oxygen carrier (HBOC)-201. Twenty-four livers declined for transplantation were transported by using static cold storage. Upon arrival, livers underwent NMP for 6 hours using pressure-controlled portal and arterial perfusion. A total of 12 livers were perfused using a solution based on RBCs and FFPs (historical cohort), 6 livers with HBOC-201 and FFPs, and another 6 livers with HBOC-201 and gelofusine, a gelatin-based colloid solution. Compared with RBC + FFP perfused livers, livers perfused with HBOC-201 had significantly higher hepatic adenosine triphosphate content, cumulative bile production, and portal and arterial flows. Biliary secretion of bicarbonate, bilirubin, bile salts, and phospholipids was similar in all 3 groups. The alanine aminotransferase concentration in perfusate was lower in the HBOC-201-perfused groups. In conclusion, NMP of human donor livers can be performed effectively using HBOC-201 and gelofusine, eliminating the need for human blood products. Perfusing livers with HBOC-201 is at least similar to perfusion with RBCs and FFP. Some of the biomarkers of liver function and injury even suggest a possible superiority of an HBOC-201-based perfusion solution and opens a perspective for further optimization of machine perfusion techniques. Liver Transplantation 24 528-538 2018 AASLD., (© 2017 The Authors. Liver Transplantation published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

Background: Deranged glucose metabolism after moderate to severe trauma with either high or low concentrations of blood glucose is associated with poorer outcome. Data on prehospital blood glucose concentrations and trauma are scarce., Objectives: The primary aim was to describe the relationship between traumatic shock and prehospital blood glucose concentrations. The secondary aim was to determine the additional predictive value of prehospital blood glucose concentration for traumatic shock when compared with vital parameters alone., Design: Retrospective analysis of the predefined, observational database of a nationwide Helicopter Emergency Medical Service (34 bases)., Setting: Emergency trauma patients treated by Helicopter Emergency Medical Service between 2005 and 2013 were investigated., Patients: All adult trauma patients (≥18 years) with recorded blood glucose concentrations were enrolled., Outcomes: Primary outcome: upper and lower thresholds of blood glucose concentration more commonly associated with traumatic shock. Secondary outcome: additional predictive value of prehospital blood glucose concentrations when compared with vital parameters alone., Results: Of 51 936 trauma patients, 20 177 were included. In total, 220 (1.1%) patients died on scene. Hypoglycaemia (blood glucose concentration 2.8 mmol l or less) was observed in 132 (0.7%) patients, hyperglycaemia (blood glucose concentration exceeding 15 mmol l) was observed in 265 patients (1.3%). Blood glucose concentrations more than 10 mmol l (n = 1308 (6.5%)) and 2.8 mmol l or less were more common in patients with traumatic shock (P < 0.0001). The Youden index for traumatic shock ((sensitivity + specificity) - 1) was highest when blood glucose concentration was 3.35 mmol l (P < 0.001) for patients with low blood glucose concentrations and 7.75 mmol l (P < 0.001) for those with high blood glucose concentrations. In logistic regression analysis of patients with spontaneous circulation on scene, prehospital blood glucose concentrations (together with common vital parameters: Glasgow Coma Scale, heart rate, blood pressure, breathing frequency) significantly improved the prediction of traumatic shock in comparison with prediction by common vital parameters alone (P < 0.0001)., Conclusion: In adult trauma patients, low and high blood glucose concentrations were more common in patients with traumatic shock. Prehospital blood glucose concentration measurements in addition to common vital parameters may help identify patients at risk of traumatic shock.

Background: The development of renal and liver dysfunction may be accompanied by initially subtle derangements in the gluconeogenetic function. Discrepantly low glucose levels combined with high lactate levels might indicate an impaired Cori cycle. Our objective was to examine the relation between early lactate and glucose levels with subsequent renal and liver dysfunction and hospital mortality in critically ill patients., Methods: Over a 4-year period (2011 to 2014), all adult patients admitted to our adult 48-bed teaching hospital intensive care unit (ICU) for at least 12 h were retrospectively analyzed. Lactate and glucose were regularly measured with point-of-care analyzers in all ICU patients. Lactate and glucose measurements were collected from 6 h before to 24 h after ICU admission. Patients with fewer than four lactate/glucose measurements were excluded. Patients received insulin according to a computer-guided control algorithm that aimed at a glucose level <8.0 mmol/L. Renal dysfunction was defined as the development of acute kidney injury (AKI) within 7 days, and liver function was based on the maximal bilirubin in the 7-day period following ICU admission. Mean lactate and mean glucose were classified into quintiles and univariate and multivariate analyses were related with renal and liver dysfunction and hospital mortality. Since glucose has a known U-shaped relation with outcome, we also accounted for this., Results: We analyzed 92,000 blood samples from 9074 patients (63% males) with a median age of 64 years and a hospital mortality of 11%. Both lactate quintiles (≤1.0; 1.0-1.3; 1.3-1.7; 1.7-2.3; >2.3 mmol/L) and glucose quintiles (≤7.0; 7.0-7.6; 7.6-8.2; 8.2-9.0; >9.0 mmol/L) were related with outcome in univariate analysis (p < 0.001). Acute Physiology and Chronic Health Evaluation (APACHE) IV, lactate, and glucose were associated with renal and liver dysfunction in multivariate analysis (p < 0.001), with a U-shaped relationship for glucose. The combination of the highest lactate quintile with the lowest glucose quintile was associated with the highest rates of renal dysfunction, liver dysfunction, and mortality (p < 0.001) with a significant interaction between lactate and glucose (p ≤ 0.001)., Conclusions: Abnormal combined lactate and glucose measurements may provide an early indication of organ dysfunction. In critically ill patients a 'normal' glucose with an elevated lactate should not be considered desirable, as this combination is related with increased mortality.