Critically ill patients often develop hyperglycemia, which is associated with increased morbidity and mortality. Randomized controlled trials have shown that the benefits of tight glucose control (TGC) are context-dependent. TGC reduced morbidity and mortality in patients receiving early parenteral nutrition, using a protocol that included accurate glucose measurements and avoided insulin boluses. Benefit was less pronounced in patients not receiving early parenteral nutrition, which is associated with less severe hyperglycemia. Conversely, TGC caused harm when the protocol induced severe hypoglycemia and glucose variability by inaccurate measurements and insulin boluses. Altogether, evidence suggests to, at least, prevent severe hyperglycemia and hypoglycemia.

Many intensive care unit patients develop hyperglycaemia, and this is associated with an increased risk of adverse outcomes. Landmark randomised controlled trials (RCTs) suggest the impact of lowering blood glucose to the healthy, age-adjusted fasting range, hereafter called tight glucose control, depends on the accuracy of the glucose control protocol and the nutritional strategy. In the context of early parenteral nutrition, a condition that induces severe, iatrogenic hyperglycaemia, tight glucose control significantly reduced morbidity and mortality compared to tolerating severe hyperglycaemia. In the absence of early parenteral nutrition, hyperglycaemia was less severe; tight glucose control, applied with a computerised protocol that avoided severe hypoglycaemia, did not impact mortality nor the duration of ICU dependency as primary endpoint in a large multicentre RCT, but was associated with a less pronounced benefit on selected morbidity outcomes. Conversely, tight glucose control, using a protocol that considerably increased the risk of severe hypoglycaemic events, concomitantly increased mortality; nevertheless, the cause of excess mortality in this trial remains unproven and other mechanisms may have contributed as well. Altogether, evidence suggests that severe and iatrogenic hyperglycaemia and hypoglycaemia should both be avoided. From a pathophysiologic point of view, tight glucose control may be superior in selected settings if it can be applied with a validated protocol that avoids severe hypoglycaemia. In the absence of such a protocol, the increased risk of severe hypoglycaemia may offset any benefit of preventing hyperglycaemia, and tolerating intermediate blood glucose targets is likely the default setting. In the paper, we suggest specific blood glucose targets that differ according to the clinical context. Future research should aim at strategies that further optimise the quality of blood glucose control and study whether these improve patient-centred outcomes, and investigate whether specific patient populations benefit from individualised targets.

INTRODUCTION:Hyperglycaemia is common in intensive care unit (ICU) patients and blood glucose management practices likely vary, but there are limited contemporary data on ICU doctors' and nurses' preferences. METHODS:We conducted an international online survey of ICU doctors and nurses. The 16-question survey covered respondent characteristics, glucose management practices, perceived challenges with intermittent point of care (iPOC) glucose monitoring and continuous glucose monitoring (CGM), and preferences for a future trial on CGM versus usual care. Data were reported descriptively for all respondents and stratified by profession. RESULTS:We received 1424 responses from 12 countries, of which 63% were from nurses. The overall response rate was 36% and the highest proportion of missing data for any question was 9%. Most respondents (92%) reported that their ICU had a glucose management protocol. The median reported insulin initiation threshold was blood glucose of 10 mmol/L. Long-acting insulin was reported to be used occasionally by 68% of respondents. As needed pro re nata insulin was reported as most often given subcutaneously (43%) or intravenously (25%). Overall, 61% of ICU nurses reported concerns related to iPOC use versus 53% among ICU doctors (concerns among nurses versus doctors included risk of hypoglycaemia in 41% vs. 28%; risk of hyperglycaemia in 28% vs. 16%; patient discomfort in 26% vs. 27%). Overall, 75% of respondents never used CGM and 18% of ICU nurses reported concerns related to CGM use versus 22% of ICU doctors (accuracy and reliability in 14% vs. 18%; calibration and maintenance in 9% versus 16%; patient discomfort in 5% vs. 6%, respectively). Most respondents (89%) supported a randomised trial on CGM versus usual care in ICU and 68% preferred an intervention arm with a specific CGM-treatment protocol. CONCLUSIONS:Glucose management preferences varied among ICU staff, particularly in the administration of as needed doses and long-acting insulin. ICU nurses appeared more concerned about iPOC use than ICU doctors. The concerns about use of CGM appeared less common than concerns about iPOC. Most nurses and doctors would support a randomised trial on CGM versus usual care for glucose management in ICU and reported a preference for CGM to be used with a specific treatment protocol. EDITORIAL COMMENT:This international survey highlights substantial professional differences and heterogeneity in ICU glucose management practices, particularly regarding as-needed and long-acting insulin use. Nurses expressed greater concern than doctors about intermittentpoint point-of-care glucose monitoring, especially the risks of hypoglycaemia and hyperglycaemia. Although continuous glucose monitoring was rarely used, it was viewed favourably overall, with broad support for a future protocolised randomised CGM trial.

Patients admitted to the intensive care unit (ICU) after major surgery frequently develop anorexia, feeding intolerance, and hyperglycaemia in response to the severe stress. Although observational studies have associated accumulation of a caloric deficit with poor outcome, randomised controlled trials (RCTs) have shown that early nutrition support induces dose-dependent harm in ICU patients, which has been attributed to aggravation of hyperglycaemia and associated metabolic damage, as well as suppressed cellular repair mechanisms. Hence, early full nutrition support, including early parenteral nutrition, should be avoided. The ideal blood glucose control target depends on the context. Tight blood glucose control (TGC) may be superior, but should only be performed when it can be achieved with a protocol that avoids hypoglycaemia. Safe TGC requires a protocol that includes regular, accurate blood glucose measurements and avoidance of insulin boluses. In the absence of such protocol, at least severe hyperglycaemia and hypoglycaemia should be avoided.

Abstract Background Many children admitted to a pediatric intensive-care-unit (PICU) show impaired physical function years later. Testing physical function clinically is time-consuming and expensive, hampering routine follow-up. We investigated whether subjective parent-reported physical health-related quality-of-life correlates with and may replace objectively measured physical function of former PICU-patients. Methodology This secondary analysis of the PEPaNIC-RCT included 517 former PICU-patients with physical function tests and parent-reported health-related quality-of-life 4 years later. Parents scored physical function, bodily pain, general health and physical role functioning with questionnaires. Physical function tests included handgrip-strength, timed up-and-go-test, 6-minute-walk-test, and accelerometry. Questionnaire-items and test-scores were correlated with Pearson/Spearman correlation. Results Parent-reported physical function correlated moderately with daily time in sedentary state (ρ=-0.300, p < 0.0001), daily sedentary bouts (R=-0.330, p < 0.0001) and daily steps/hour monitored (R = 0.303, p < 0.0001), and weakly with handgrip-strength, physical activity energy expenditure, time in certain activity-intensity and daily steps (ρ/R = 0.185–0.289, p ≤ 0.019). Parent-reported general health (ρ/R=-0.228 to 0.296, p ≤ 0.033) and physical role functioning (ρ/R=-0.269 to 0.240, p ≤ 0.038) correlated weakly with roughly the same measured physical functions. Parent-reported bodily pain correlated weakly with daily sedentary bouts (R=-0.143, p = 0.024) and daily steps/hour monitored (R = 0.145, p = 0.022). Correlations among physical function test scores were mostly weak. Conclusions Several aspects of subjective parent-reported physical health-related quality-of-life correlated with former PICU-patients’ performance on physical function tests. The mostly weak strength of the correlations suggest that interrogated physical function cannot simply replace clinical testing. Nevertheless, when resources for clinical testing are lacking, interrogating physical function could still be valuable to get an idea about long-term physical functioning.

Abstract Background Atrial fibrillation often occurs during critical illness. Tight glucose control with insulin (TGC) is known to reduce inflammation and oxidative stress and may alter atrial metabolism, which, together, could affect atrial fibrillation pathogenesis. Our group has previously shown that TGC reduced morbidity and mortality in a mixed medical/surgical critically ill patient population receiving early parenteral nutrition as part of the contemporary standard of care. We here hypothesized that TGC reduces atrial fibrillation in the intensive care unit (ICU). Methods In this individual patient data meta-analysis of 2 randomized controlled trials (performed 2000–2001 and 2002–2005), we investigated the impact of TGC with insulin (targeting blood glucose 80–110 mg/dL) in comparison with tolerating hyperglycemia to 215 mg/dL (liberal glucose control [LGC]) on atrial fibrillation in mixed surgical (n = 1548) and medical (n = 1200) ICU patients admitted to a quaternary-care university hospital. Atrial fibrillation was further classified as new-onset or recurrent/persistent pre-existing atrial fibrillation. The primary endpoint was the impact of TGC on atrial fibrillation in ICU, determined via multivariable logistic regression analysis after adjusting for relevant baseline patient characteristics. Prespecified subgroup analyses were performed for patients with a history of diabetes mellitus, pre-existing atrial fibrillation, overall surgical admission, admission after cardiac surgery and for patients with an ICU-stay longer than 5 days, after assessing treatment heterogeneity via determination of interaction p-values. Results Atrial fibrillation in ICU occurred in 845/2639 patients (32.0%), 65.9% of which was new-onset atrial fibrillation. TGC had no impact on atrial fibrillation in ICU (adjusted OR 0.92 [0.77–1.11])(P = 0.40). TGC also did not affect new-onset atrial fibrillation (adjusted OR 0.92 [0.75–1.12])(P = 0.39). There was no treatment heterogeneity present for the pre-defined subgroups except for the subgroup of patients with history of diabetes mellitus (n = 390), in which atrial fibrillation was documented for 66/199 patients in the TGC-group (33.2%) and 80/191 patients in the LGC-group (41.9%), interaction P = 0.045). Atrial fibrillation in ICU was strongly associated with worse outcome. Conclusions TGC in the context of early use of parenteral nutrition did not reduce atrial fibrillation during ICU-stay in this large mixed medical-surgical ICU cohort. A possible exception was noted for patients with a history of diabetes mellitus.

Administration of ketone bodies attenuated the severity of sepsis-induced muscle weakness in preclinical studies. Whether lipid-rich emulsions may likewise mitigate such muscle weakness by stimulating the endogenous ketogenic capacity remains uncertain, especially in relation to glucose, a critical suppressor of ketogenesis. This study investigated the ketogenic potential of parenteral nutrition rich in long- and/or medium-chain triglycerides with differing glucose content on sepsis-induced muscle weakness. We used a parenterally fed murine model of prolonged sepsis-induced muscle weakness to investigate specific lipid mixtures in two consecutive studies. Septic mice receiving standard total parenteral nutrition (TPN) and healthy control (HC) animals were included as references in both studies. In a first study, septic mice received pure long-chain triglycerides (LCT) or long-chain triglycerides supplemented with glucose (gLCT). The second study compared a gLCT mixture to a mixed medium- and long-chain triglyceride emulsion supplemented with glucose (gMCT). After 5 days of sepsis, markers of ketone body metabolism, muscle function, and muscle and liver metabolomics were measured. In study one, ketosis was undetectable with TPN-treatment, but substantially increased with pure LCT (median 1.39 mmol/L, p < 0.001). Supplemental glucose suppressed ketosis sixfold (median 0.24 mmol/L, p < 0.001). The sepsis-induced muscle weakness was exacerbated in LCT mice, while muscle force was comparable between TPN-treated and gLCT mice (TPN 60.9

The PEPaNIC RCT showed that early supplementation of insufficient enteral nutrition by parenteral nutrition (early-PN) worsened outcome of critically ill children as compared with withholding PN for 1 week (late-PN). The best timing to initiate nutritional support in the pediatric intensive care unit (PICU) remains unclear. In adults, declining phosphate levels may identify patients who are particularly harmed by early-PN. We therefore assessed whether early hypophosphatemia in critically ill children may indicate metabolic intolerance to nutrition. In this secondary analysis of the PEPaNIC RCT (n = 1440), we investigated whether development of hypophosphatemia statistically interacts with the randomized intervention for its impact on clinical outcome, adjusting for baseline risk factors. Outcomes of interest included the incidence of new infections and the duration of PICU dependency as primary endpoints, 90-day mortality as safety endpoint, and duration of mechanical ventilation and of hospital stay as secondary endpoints. Subsequently, the impact of early-PN vs. late-PN in patients with and without early hypophosphatemia was assessed. Analyses were performed for phosphate abnormalities on PICU day 1 and 2, with and without imputing 20.3

BACKGROUND:The glycemic ratio (GR), defined as the ratio of mean intensive care unit (ICU) blood glucose (BG) to estimated preadmission BG (EPBG), may provide superior prognostic insight compared with the single admission snapshot represented by the stress hyperglycemia ratio (SHR, the ratio of ICU admission BG to EPAG). METHODS:This retrospective study included 4148 patients treated in a university-affiliated medical-surgical ICU from 2019 to 2023 who had >4 ICU BG measurements and a glycated hemoglobin (HbA1c) measured at admission. We compared SHR and GR prognostic ability for mortality, analyzed across prespecified GR and SHR bands, and calculated observed:expected mortality ratios (OEMRs). RESULTS:We observed a more sharply defined J-shaped relationship between GR and mortality compared with that generated by SHR. Mortality in the reference band of 0.8 to <1.0 for GR and SHR mortality was 7.5% vs 10.9%, respectively (P = .0087), and for the strata ≥1.4, mortality was 25.6% vs 20.5% (P = .0376). Compared with the reference band, GR < 0.8 and GR > 1.0 had higher OEMR (P < .0001 for each), but the OEMR for SHR <0.8 and >1.0 compared with the reference band was not significantly different. CONCLUSIONS:Glycemic ratio was superior to SHR as a predictor of mortality. This study demonstrates that a mean ICU BG level representing 80% to 100% of the patient's EPBG was associated with the lowest mortality rate in a heterogeneous cohort of critically ill patients. These results may inform current BG management strategies and should be considered when designing future interventional trials in the critically ill.

Carnitine deficiency affects mitochondrial and muscle function, but its relevance during critical illness remains unknown. Our aim was to investigate the relationship between plasma free carnitine concentrations and outcome in prolonged critical illness. In this secondary analysis of the EPaNIC randomised controlled trial, abnormal plasma free carnitine concentrations, measured on ICU-day-6 (N = 1600), were defined by their association with a lower likelihood of an earlier alive ICU discharge (the primary endpoint) in a Cox proportional hazards model. Subsequently, they were binned based on their distribution and partial residuals in the Cox-model. Adjusted multivariable Cox-model and logistic regression analysed both association of abnormal carnitinemia with acute and long-term morbidity and mortality, and predictive risk factors. The median plasma free carnitine concentration on ICU-day-6 was 34.8 (IQR 24.4–49.8 µmol/L). Surprisingly, higher concentrations associated with a lower likelihood of an earlier alive ICU discharge (HR [95

BACKGROUND:As compared to withholding parenteral nutrition (PN) until one week after intensive care unit (ICU) admission, Early PN prolonged ICU dependency in the EPaNIC randomized controlled trial (RCT). The Refeeding RCT showed improved outcome by temporary macronutrient restriction in ICU patients developing refeeding hypophosphatemia, defined as a phosphate decrease of > 0.16 mmol/L to levels < 0.65 mmol/L. We hypothesized that early phosphate changes may identify critically ill patients who are harmed by Early PN, and that dynamic phosphate changes are more discriminative than an absolute threshold for hypophosphatemia. METHODS:In this secondary analysis of the EPaNIC RCT, we studied whether absolute hypophosphatemia (AHP; < 0.65 mmol/L on the second ICU-day), relative hypophosphatemia (RHP; > 0.16 mmol/L decrease over the first 2 ICU-days), or a combination of both (CHP) interacted with the randomized nutritional strategy for its impact on outcome, adjusted for risk factors. In case of significant interaction, we studied whether the respective change could be predicted by baseline characteristics. RESULTS:Of 3520 patients with available phosphate measurements, AHP developed in 9.1%, RHP in 23.7%, and CHP in 5.3% of patients. RHP, but not AHP or CHP, interacted with the randomized intervention for its impact on outcome (p = 0.01). In RHP patients, Early PN independently associated with a lower likelihood of an earlier discharge alive from ICU (adjusted HR 0.75 [0.65-0.87]). In patients without RHP, Early PN did not significantly associate with this outcome (adjusted HR 0.93 [0.86-1.00]). Development of RHP was only poorly predicted by admission characteristics (adjusted pseudo R-squared = 1.7%). CONCLUSION:Development of RHP may identify patients who are particularly harmed by early PN. Future studies should prospectively validate the potential of including RHP in a ready-to-feed indicator.

Critically ill children requiring treatment in a pediatric intensive care unit (PICU) suffer from anorexia and/or feeding intolerance. The resulting macronutrient deficit associates with poor outcome. Until recently, this association formed the basis for initiating enteral or parenteral feeding early to improve outcome. The multicenter “Early-versus-Late-Parenteral-Nutrition-in-the-Pediatric-Intensive-Care-Unit” randomized controlled trial (PEPaNIC-RCT) addressed whether this association is causal. It showed that early supplementation of insufficient/contraindicated enteral nutrition with parenteral nutrition, as compared with accepting a macronutrient deficit throughout the first week in the PICU, did not improve outcome. On the contrary, it caused more infections and prolonged organ support and PICU stay, and adversely affected neurodevelopmental outcomes 2 and 4 years later. Harm was present in all subgroups and appeared explained by the macronutrient dose, more specifically the amino-acid dose, not lipid or glucose doses. These findings corroborated results from large-scale adult RCTs. Mechanisms of harm from early enhanced nutrition comprised suppressed cellular repair pathways like autophagy and ketogenesis, suppressed illness-induced alterations in thyroid hormone metabolism, more iatrogenic hyperglycemia, increased urea cycle activity through anabolic resistance, and induction of epigenetic modifications that mediate longer-term developmental impairments.These results came unexpected to many pediatric intensivists. Hence, the paradigm has only slowly begun to shift toward more restrictive macronutrient administration in the acute phase of critical illness. Benefits of early fasting responses have become clear, provided micronutrients are given to prevent deficiencies and refeeding syndrome. These insights open perspectives for studies investigating novel nutritional strategies to activate fasting-induced cellular repair while avoiding prolonged starvation.

ABSTRACT Background Suppression of the peroxisome proliferator‐activated receptor alpha (PPARα) has been related to poor outcomes in sepsis and may compromise ketogenesis during critical illness. Infusion of 3‐hydroxybutyrate (3HB) was shown to attenuate muscle weakness in septic mice. We hypothesise that endogenous ketogenesis induced by pharmacological PPARα activation, either alone or combined with ketogenic nutrition, is safe and can also mitigate muscle weakness in septic mice. Methods In a fluid‐resuscitated, antibiotic‐treated mouse model of prolonged sepsis, we first (Study 1) assessed the safety and effectiveness (impact on ketosis and muscle weakness) of the PPARα agonist pemafibrate (1 mg/kg/d, n = 16), versus placebo (n = 15) combined with standard balanced parenteral nutrition (PN), composed of glucose, amino acids and long‐chain triglycerides (LCT) (balanced‐TPN). We subsequently (Study 2) evaluated the impact of pemafibrate combined with four types of PN on ketosis and muscle weakness: balanced‐TPN (n = 18), TPN with extra LCTs (TPN + LCT, n = 18), low‐dose pure LCT emulsion (Low‐LCT, n = 16) and high‐dose pure LCT emulsion (High‐LCT n = 18). Carbohydrates and amino acids were omitted in the pure LCT groups. Healthy control mice (HC, n = 19) served as controls. Ex vivo muscle force was measured as the primary outcome. Metabolic, inflammatory and microstructural parameters were assessed on plasma and in muscle and liver tissue by targeted metabolomics, gene expression analysis, biochemical and metabolite assays and histological assessment. Results Pemafibrate treatment with balanced‐TPN upregulated hepatic gene expression of PPARα (Ppara) and its downstream genes (Cd36, Cpt1a, Atgl, Acadl, Hadha, Acox1, and Hmgcs2) (p < 0.0001) and was well tolerated. However, pemafibrate treatment with the use of balanced‐TPN administration did not induce detectable ketosis or improve muscle weakness. In combination with pemafibrate, TPN + LCT also did not induce ketosis, nor did it affect muscle weakness. In contrast, 3‐hydroxybutyrate plasma concentrations increased with High‐LCT (95‐fold) and Low‐LCT (10‐fold) (p < 0.0001) in combination with pemafibrate, yet muscle force declined further (High‐LCT 25.0%, Low‐LCT 10.7% of HC, p < 0.0001). Blood glucose was lowered with pure High‐LCT and Low‐LCT (High‐LCT 86.9%, Low‐LCT 55.1% of TPN, p < 0.05), while plasma lipids and LC‐carnitines were increased (p < 0.0001). Markers of hepatic protein catabolism were upregulated with High‐LCT and Low‐LCT (p < 0.007), while muscle glycolytic intermediates (p < 0.0001) and ATP levels (p < 0.0001) were depleted. Conclusions In septic mice, pemafibrate combined with balanced‐TPN or lipid‐rich TPN induced PPARα activation but did not result in ketosis nor affect muscle weakness. Pemafibrate combined with pure LCTs induced ketosis in sepsis but worsened muscle weakness, possibly explained by muscular bioenergetic failure.

Isoflurane anesthesia is often used to facilitate murine echocardiography, but can suppress cardiac function. Awake imaging avoids pharmacological interference, but can induce sympathetic activation. In this Midazolam sedation. Parameters were compared using repeated-measures ANOVA. Midazolam enabled imaging without overt stress behavior. Compared to midazolam, heart rate was similar under isoflurane and higher while awake (p ≤ 0.01). End-systolic volume was larger under isoflurane and smaller while awake; stroke volumes remained similar across conditions. Global longitudinal and circumferential strain were less negative under isoflurane (p = 0.03) but similar during awake imaging, while radial strain was higher during awake imaging. Peak longitudinal strain rate was less negative under isoflurane (p ≤ 0.01) and more negative while awake (p = 0.05). Early diastolic strain rate was similar under isoflurane and lower while awake (p = 0.02). In conclusion, cardiac function was most depressed under isoflurane and most enhanced during awake imaging, likely stress-driven. Murine echocardiography under midazolam sedation was feasible, yielding better function than isoflurane anesthesia, closer to awake imaging but without overt handling stress. These findings require further validation across disease models, sexes, and strains.

Disclosure: C. Lauwers: None. J. Gunst: None. S. Derde: None. I. Derese: None. S. Vander Perre: None. L. Pauwels: None. S. El Dawy: None. G.H. Van Den Berghe: None. M.P. Casaer: None. L. Langouche: None. Introduction: Ketogenic diets may mitigate age-related declines in muscle function. It remains unclear whether such diets may also attenuate critical illness-induced muscle weakness, and whether medium-chain triglycerides (MCTs) are more effective than long-chain triglycerides (LCTs) at inducing ketogenesis. We studied the impact of MCT- and LCT-rich nutrition as compared to standard feeding preparations on ketosis and muscle weakness in septic mice. Methods: Sepsis was induced in C57Bl/6j mice by caecal ligation and puncture. After 24h fluid resuscitation, mice were randomized to receive 3 types of parenteral nutrition (PN) with different ketogenic potential. The first group received total PN (TPN, composing 49% glucose, 35% LCT and 16% amino acids, n=16), the second an LCT-rich emulsion (LCT, composing 90% LCT and 10% glucose, n=17) and the third group a mixed MCT/LCT emulsion (MCT/LCT, composing 45% MCT, 45% LCT and 10% glucose, n=16). Healthy control mice (HC) were included to provide healthy reference values (n=17). After 5 days of sepsis, ex-vivo muscle force (Aurora Scientific®) was assessed as the primary outcome, and plasma 3-hydroxybutyrate (3HB), plasma lipids (TG, LDL- and HDL-cholesterol) were measured. Hepatic gene expression of ketogenic markers including the peroxisome-proliferator receptor α (PPARα, the transcriptional regulator of ketogenesis) and 3-hydroxymethylglutaryl-CoA synthase-2 (Hmgcs2, the rate-limiting enzyme of ketogenesis) was assessed, and immunoblotting was conducted for Hmgcs2 on liver tissue. Results: After 5 days of sepsis, survival was similar in the three groups (TPN: 84.2%; MCT/LCT: 66.2%; LCT: 85.0%; p=0.6). Muscle force was equally reduced in septic mice as compared with HC (TPN: 68.1%; MCT/LCT: 60.5%; LCT: 74.0% of 144.5 mN/mm²; p>0.05). Plasma 3HB levels were below the detection limit (0.005 mmol/L) in the TPN group. In LCT mice, 3HB levels increased to median 0.11 mmol/L (p<0.001 compared with TPN), while they were lower in MCT/LCT mice (median 0.02 mmol/L; p<0.001 compared with TPN). Plasma TG, glycerol, and HDL- and LDL-cholesterol were suppressed in TPN mice (p<0.03) but equally increased in both lipid-rich groups. Despite differences in plasma 3HB, hepatic gene expression of ketogenic markers was similarly upregulated in the lipid-rich groups compared to the TPN group (p<0.001). Yet, Hmgcs2 protein expression was suppressed in the TPN group as compared to the HC (p=0.009), but increased stepwise in the MCT/LCT and LCT mice (p=0.04 and p<0.001, resp., compared to TPN). Further gene expression and metabolomics analyses in liver and muscle tissue are ongoing. Conclusion: The tested ketogenic diets did not attenuate sepsis-induced muscle weakness. An MCT-rich emulsion was less effective at inducing ketosis than a pure LCT emulsion. Presentation: Monday, July 14, 2025

BACKGROUND:Recent studies suggest that fast and deep inspirations against either low or high external loads may provide patients with weaning difficulties with a training stimulus during inspiratory muscle training (IMT). However, the relationship between external IMT load, reflected by changes in airway pressure swings (ΔPaw), and total inspiratory effort, measured by oesophageal pressure swings (ΔPes), remains unexplored. Additionally, the association between ΔPes, ΔPaw, and inspiratory muscle activations remains unclear. OBJECTIVES:The ai of this study was to compare ΔPes and ΔPaw and their relationship with inspiratory muscle activation in patients with weaning difficulties during different breathing conditions. METHODS:ΔPes and scalene, sternocleidomastoid, and parasternal intercostal muscles activation were recorded during the following conditions: 1) (proportional) pressure support ventilation; 2) unsupported spontaneous breathing; 3) low-load IMT (load: <10% maximal inspiratory pressure, PImax = 3 cmH2O) executed with slow and deep inspirations (low-load slow) and 4) low-load IMT (load: <10% maximal inspiratory pressure, PImax = 3 cmH2O) executed with fast deep inspirations (low-load fast); and 5) high-load IMT (load ∼ 30% PImax) executed with fast and deep inspirations. ΔPaw, end-inspiratory lung volume, and peak inspiratory flow were recorded during conditions 2-5. Variables were compared across conditions using mixed-model analysis. Spearman's rank correlations were calculated between inspiratory muscle activations and both ΔPes and ΔPaw. RESULTS:Five patients (age: 68 ± 1 y; 20% male; PImax: 37 ± 7 cmH2O [59 ± 23% predicted]; forced vital capacity: 0.66 ± 0.16 L [21 ± 6% predicted]) were included in the study. ΔPes values were 3-4 times larger than ΔPaw values during unsupported spontaneous breathing and IMT conditions. ΔPes, sternocleidomastoid activation, end-inspiratory lung volume, and peak inspiratory flow were larger during low-load fast IMT than during low-load slow IMT and unsupported spontaneous breathing but were similar between low-load fast and high-load IMTs. Inspiratory muscle activations correlated weakly to moderately with ΔPaw and moderately with ΔPes. CONCLUSIONS:In five patients with weaning difficulties, low-load fast IMT provided a training stimulus similar to high-load IMT. Both yielded significantly higher training stimulus than low-load slow IMT and unsupported spontaneous breathing. These results should be considered in future trials comparing IMT with sham conditions. CLINICAL TRIAL REGISTRATION NUMBERS:NCT03240263 and NCT04658498.

Abstract Background Sepsis-induced cardiomyopathy (SICM) often occurs in the acute phase of sepsis and is associated with increased mortality due to cardiac dysfunction. The pathogenesis remains poorly understood, and no specific treatments are available. Although SICM is considered reversible, emerging evidence suggests potential long-term sequelae. We hypothesized that metabolic and inflammatory cardiac changes, previously observed in acute sepsis as potential drivers of SICM, partially persist in prolonged sepsis. Methods In 24-week-old C57BL/6J mice, sepsis was induced by cecal ligation and puncture, followed by intravenous fluid resuscitation, subcutaneous analgesics and antibiotics, and, in the prolonged phase, by parenteral nutrition. Mice were killed after 5 days of sepsis (prolonged sepsis, n = 15). For comparison, we included acutely septic mice killed at 30 h (acute sepsis, n = 15) and healthy controls animals (HC, n = 15). Cardiac tissue was collected for assessment of inflammatory and metabolic markers through gene expression, metabolomic analysis and histological assessment. Results In prolonged sepsis, cardiac expression of IL-1β and IL-6 and macrophage infiltration remained upregulated (p ≤ 0.05). In contrast, tissue levels of Krebs cycle intermediates and adenosine phosphates were normal, whereas NADPH levels were low in prolonged sepsis (p ≤ 0.05). Gene expression of fatty acid transporters and of the glucose transporter Slc2a1 was upregulated in prolonged sepsis (p ≤ 0.01). Lipid staining and glycogen content were elevated in prolonged sepsis together with increased gene expression of enzymes responsible for lipogenesis and glycogen synthesis (p ≤ 0.05). Intermediate glycolytic metabolites (hexose-phosphates, GADP, DHAP) were elevated (p ≤ 0.05), but gene expression of several enzymes for glycolysis and mitochondrial oxidation of pyruvate, fatty-acyl-CoA and ketone bodies to acetyl-CoA were suppressed in prolonged sepsis (p ≤ 0.05). Key metabolic transcription factors PPARα and PGC-1α were downregulated in acute, but upregulated in prolonged, sepsis (p ≤ 0.05 for both). Ketone body concentrations were normal but ketolytic enzymes remained suppressed (p ≤ 0.05). Amino acid metabolism showed mild, mixed changes. Conclusions Our results suggest myocardial lipid and glycogen accumulation and suppressed mitochondrial oxidation, with a functionally intact Krebs cycle, in the prolonged phase of sepsis, together with ongoing myocardial inflammation. Whether these alterations have functional consequences and predispose to long-term sequelae of SICM needs further research.

PURPOSE OF REVIEW:To summarize the clinical evidence on nutritional support for critically ill patients, the (patho)physiological mechanisms involved, and areas of future research. RECENT FINDINGS:Large randomized controlled trials have shown that early nutrition induces dose-dependent harm in critically ill patients, regardless of the feeding route, and that early high-dose amino acids are harmful. Harm has been attributed to feeding-induced suppression of cellular repair pathways including autophagy and ketogenesis, to aggravation of hyperglycemia and insulin needs, and to increased urea cycle activity. Additionally, acute critical illness was shown to be a state of anabolic resistance. The absence of benefit of early enhanced nutritional support on short- and long-term outcomes was observed in all studied subgroups. SUMMARY:While early high-dose nutrition should be avoided in all critically ill patients, the optimal initiation time of nutrition support for the individual patient, as well as ideal composition and dosing of nutrition over time remain unclear. Future studies should elucidate how fasting-induced repair pathways can be activated while avoiding prolonged starvation, and how hyperglycemia and high insulin need could be prevented. Potential strategies include intermittent fasting, ketogenic diets, ketone supplements, and alternative glucose-lowering agents, whether or not in combination with exercise.