Metabolism In Critical Illness Research Articles

High-resolution plasma metabolomics and thiamine status in critically Ill adult patients

IntroductionThiamine (Vitamin B1) is an essential micronutrient and is classically considered a co-factor in energy metabolism. The association between thiamine status and whole-body metabolism in critical illness has not been studied.ObjectivesTo determine association between whole blood thiamine pyrophosphate (TPP) concentrations and plasma metabolites and connected metabolic pathways using high resolution metabolomics (HRM) in critically ill patients.MethodsCross-sectional study performed at Erciyes University Hospital, Kayseri, Turkey and Emory University, Atlanta, GA, USA. Participants were critically ill adults with an expected length of intensive care unit stay longer than 48 h and receiving chronic furosemide therapy. A total of 76 participants were included. Mean age was 69 years (range 33–92 years); 65% were female. Blood for TPP and metabolomics was obtained on the day of ICU admission. Whole blood TPP was measured by HPLC and plasma HRM was performed using liquid chromatography/mass spectrometry. Data was analyzed using regression analysis of TPP levels against all plasma metabolomic features in metabolome-wide association studies (MWAS). MWAS using the highest and lowest TPP concentration tertiles was performed as a secondary analysis.ResultsSpecific metabolic pathways associated with whole blood TPP levels in regression and tertile analysis included pentose phosphate, fructose and mannose, branched chain amino acid, arginine and proline, linoleate, and butanoate pathways.ConclusionsPlasma HRM revealed that thiamine status, determined by whole blood TPP concentrations, was significantly associated with metabolites and metabolic pathways related to metabolism of energy, carbohydrates, amino acids, lipids, and the gut microbiome in adult critically ill patients.

Protein metabolism in critical illness.

Critically ill patients experience skeletal muscle wasting that may contribute to the profound functional deficits in those that survive the initial injury. Augmented protein delivery has the potential to attenuate muscle loss, yet the ability for dietary protein to improve patient outcomes is reliant on effective protein metabolism. This review will discuss the recent literature on protein delivery and digestion, amino acid absorption, and muscle protein synthesis (MPS) in critically ill adults. Critically ill patients are prescribed protein doses similar to international recommendations, yet actual delivery remains inadequate. The majority of trials that have achieved higher protein doses have observed no effect on muscle mass, strength or function. Critically ill patients have been observed to have minimal deficits in protein digestion and amino acid absorption when delivery bypasses the stomach, yet postprandial MPS is impaired. However, the literature is limited due to the complexities in the direct measurement of protein handling. Postprandial MPS is impaired in critically ill patients and may exacerbate muscle wasting experienced by these patients. Studies in critically ill patients require assessment not only of protein delivery, but also utilization prior to implementation of augmented protein doses.

Should nutrition therapy be modified to account for mitochondrial dysfunction in critical illness?

Metabolic dysfunction, and its associated muscle atrophy, remains the most common complication of critical care. At the center of this is mitochondrial dysfunction, secondary to hypoxia and systemic inflammation. This leads to a bioenergetic crisis, with decreased intramuscular adenosine triphosphate content and a reduction in the highly energy-dependent process of protein synthesis. Numerous methods have been studied to try and reduce these effects, with only limited success. Trials investigating the use of increased energy and protein administration have instead found a decrease in relative lean body mass and a potential increase in morbidity and mortality. Ketone bodies have been proposed as alternative substrates for metabolism in critical illness, with promising results seen in animal models. They are currently being investigated in critical care patients in the Alternative Substrates in the Critically Ill Subjects trial (ASICS). The evidence to date suggests that individualized feeding regimens may be key in the nutrition approach to critical illness. Consideration of individual patient factors will need to be combined with personalized protein content, total energy load received, and the timing of such feeds. This review covers mitochondrial dysfunction in critical illness, how it contributes to muscle wasting and the resultant morbidity and mortality, and the scientific basis of why current nutrition approaches to date have not been successful in negating this effect. These two factors underpin the need for consideration of alternative nutrition strategies in the critically ill patient.

Could Exogenous Insulin Ameliorate the Metabolic Dysfunction Induced by Glucocorticoids and COVID-19?

The finding that high-dose dexamethasone improves survival in those requiring critical care due to COVID-19 will mean much greater usage of glucocorticoids in the subsequent waves of coronavirus infection. Furthermore, the consistent finding of adverse outcomes from COVID-19 in individuals with obesity, hypertension and diabetes has focussed attention on the metabolic dysfunction that may arise with critical illness. The SARS coronavirus itself may promote relative insulin deficiency, ketogenesis and hyperglycaemia in susceptible individuals. In conjunction with prolonged critical care, these components will promote a catabolic state. Insulin infusion is the mainstay of therapy for treatment of hyperglycaemia in acute illness but what is the effect of insulin on the admixture of glucocorticoids and COVID-19? This article reviews the evidence for the effect of insulin on clinical outcomes and intermediary metabolism in critical illness.

Vitamin D levels in patients admitted to the intensive care unit and the association with organ dysfunction and glutamine levels.

Vitamin D deficiency is common in intensive care unit (ICU) patients (50 - 82%) and is associated with multi-organ dysfunction. Vitamin D deficiency alters pathways of glutamine metabolism in critical illness, but the impact of vitamin D status on glutamine levels is poorly characterised. To assess the prevalence of vitamin D deficiency and its association with organ dysfunction and glutamine levels in a South African (SA) ICU. Records of 103 adult patients admitted to the Wits Donald Gordon Medical Centre ICU, Johannesburg, SA were retrospectively reviewed. 25-hydroxyvitamin D (25(OH)D) and glutamine levels were measured on admission. The association between admission vitamin D levels and glutamine levels, illness severity scores, organ support and outcomes was examined. On ICU admission, 66% (68/103) of patients were vitamin D deficient (<20 ng/mL) (95% confidence interval (CI) 56 - 75). Vitamin D deficiency was significantly associated with mechanical ventilation (40% v. 14%) (p=0.013) and a higher median sequential organ failure assessment (SOFA) score on admission (6 (interquartile range (IQR) 3 - 8) v. 4 (IQR 2 - 6)) (p=0.047) and on day 7 (5 (IQR 2 - 10) v. 2 (IQR 1 - 4)) (p=0.017). Median admission serum glutamine levels were 481 μmol/L, with 38% deficient (<420 μmol/L) (95% CI 28 - 48). Vitamin D deficiency status on admission was not significantly associated with median admission glutamine levels (p=0.66). Vitamin D deficiency is common in ICU patients in SA. Deficient patients were more severely ill and required more respiratory support. No significant relationship between deficiency and median glutamine levels was noted.

Metabolism of Microbiota in Critical Illness (Review and Postulates)

This article discusses the importance of eliciting the mechanisms of action and the metabolism of microbiota in the critically ill patients, as well as the role of nutrition specialist in the management of these patients.In critically ill patients the impaired regulation of endogenous metabolic processes and protein-energy deficiency are aggravated by abnormal microbiota metabolic processes. There is growing awareness of the importance of studying microbial metabolism in the general metabolic process. Its implications for the improved efficacy of treatment in critical care and rehabilitation are obvious.Current international intensive care guidelines are being constantly revised in response to the new research data available on the mechanisms of critical illness. The course of the latter may significantly associate with the metabolic activity of human microbiota. Active management of metabolic processes is being sought through the subordination of bacterial metabolism to the interests of the host. Both antimicrobial and bioformulations (prebiotics, metabiotics) will be used in the long term in a targeted manner with the control of key microbial metabolites through available laboratory monitoring tools.Based on the literature data and the original research, the author formulates postulates of the microbiota metabolism in critical illness, introduces the concepts of «invisible organ dysfunction» and «signaling bacterial molecules», offers answers to the eternal «what is to be done?» question and suggests using a number of microbial aromatic amino acids metabolites as an integral indicator of a course of critical illness.

Nutritional metabolomics in critical illness.

Disruption of metabolic homeostasis is universal in the critically ill. Macronutrients and micronutrients are major environmental regulators of metabolite production through their gene regulation effects. The study of large numbers of circulating metabolites is beginning to emerge through the comprehensive profiling of the critically ill. In the critically ill, metabolomic studies consistently show that changes in fatty acids, lipids and tryptophan metabolite pathways are common and are associated with disease state and outcomes. Metabolomics is now being applied in research studies to determine the critical illness response to nutrient deficiency and delivery. Nutritional metabolomics approaches in nutrient deficiency, malnutrition and nutrient delivery have included single time point studies and dynamic studies of critically ill patients over time. Integration of metabolomics and clinical outcome data may create a more complete understanding of the control of metabolism in critical illness. The integration of metabolomic profiling with transcription and genomic data may allow for a unique window into the mechanism of how nutrient deficiency and delivery alters cellular homeostasis during critical illness and modulates the regain of cellular homeostasis during recovery. The progress and the challenges of the study of nutritional metabolomics are reviewed here.

High-Dose Vitamin D3 Administration Is Associated With Increases in Hemoglobin Concentrations in Mechanically Ventilated Critically Ill Adults: A Pilot Double-Blind, Randomized, Placebo-Controlled Trial.

Anemia and vitamin D deficiency are highly prevalent in critical illness, and vitamin D status has been associated with hemoglobin concentrations in epidemiologic studies. We examined the effect of high-dose vitamin D therapy on hemoglobin and hepcidin concentrations in critically ill adults. Mechanically ventilated critically ill adults (N = 30) enrolled in a pilot double-blind, randomized, placebo-controlled trial of high-dose vitamin D3 (D3 ) were included in this analysis. Participants were randomized to receive placebo, 50,000 IU D3 , or 100,000 IU D3 daily for 5 days (totaling 250,000 IU D3 and 500,000 IU D3 , respectively). Blood was drawn weekly throughout hospitalization for up to 4 weeks. Linear mixed-effects models were used to assess change in hemoglobin and hepcidin concentrations by treatment group over time. At enrollment, >75% of participants in all groups had plasma 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL, and >85% of participants across groups were anemic. In the 500,000-IU D3 group, hemoglobin concentrations increased significantly over time (Pgroup × time = .01) compared with placebo but did not change in the 250,000-IU D3 group (Pgroup × time = 0.59). Hepcidin concentrations decreased acutely in the 500,000-IU D3 group relative to placebo after 1 week (P = .007). Hepcidin did not change significantly in the 250,000-IU D3 group. In these critically ill adults, treatment with 500,000 IU D3 was associated with increased hemoglobin concentrations over time and acutely reduced serum hepcidin concentrations. These findings suggest that high-dose vitamin D may improve iron metabolism in critical illness and should be confirmed in larger studies.

What factors influence protein synthesis and degradation in critical illness?

The optimal approach to improve protein metabolism in critical illness is not yet fully defined. Here, we have summarized recent literature dealing with the main catabolic and anabolic factors influencing protein kinetics in acute hypercatabolic patients. Protein/amino acid intake levels should be adapted to type and severity of illness, keeping in mind that energy overfeeding is associated with poor outcome. A number of anticatabolic nutraceuticals and drugs have been tested in acute patients. The encouraging results have been obtained with β-hydroxy-β-methylbutyrate, omega-3 fatty acids, oxandrolone, propranolol, and metformin. Their efficacy and lack of side-effects need to be confirmed. Physical therapy, including muscle electro-stimulation, appears a very promising intervention, both effective and safe. Protein catabolism can be minimized in acute patients by adequate nutritional support, early mobilization, and, possibly, pharmacological and nutraceutical interventions. A combination of these strategies should be tested in randomized controlled trials.

Lipid metabolism in critical illness.

This article describes recent findings regarding lipid metabolism in critical illness as well as in lipid therapy. In critical illness, in the presence of a decrease in lipid absorption, adipose tissue lipolysis raises triglyceride levels. High-density lipoprotein and low-density lipoprotein are decreased because of impairment of lecithin-cholesterol acyltransferase, mainly in sepsis. In septic patients, lipid profile may be a predictor of survival. Nonsurvivors have lower levels of high-density lipoprotein and low-density lipoprotein. In metabolomic studies, most of the changes from baseline in septic patients were related to lipid metabolism. Lysophosphatidylcholine was also significantly lower in nonsurviving septic patients. Lipid profile results are too often neglected by the clinician despite increasing knowledge in the modifications related to septic state as well as the importance of these values in the prognosis of the critically ill. Lipid administration (enterally or parenterally) should be guided by better knowledge of the lipid metabolism of the patient.

Cortisol metabolism in critical illness: implications for clinical care.

Critical illness is uniformly characterized by elevated plasma cortisol concentrations, traditionally attributed exclusively to increased cortisol production driven by an activated hypothalamic pituitary adrenal axis. However, as plasma adrenocorticotropic hormone (ACTH) concentrations are often not elevated or even low during critical illness, alternative mechanisms must contribute. Recent investigations revealed that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the main cortisol metabolizing enzymes in liver and kidney. Furthermore, unlike previously inferred, cortisol production rate in critically ill patients was only moderately increased to less than double that of matched healthy subjects. In the face of low-plasma ACTH concentrations, these data suggest that other factors drive hypercortisolism during critical illness, which may suppress ACTH by feedback inhibition. These new insights add to the limitations of the current diagnostic tools to identify patients at risk of failing adrenal function during critical illness. They also urge to investigate the impact of lower hydrocortisone doses than those hitherto used. Recent novel insights reshape the current understanding of the hormonal stress response to critical illness and further underline the need for more studies to unravel the pathophysiology of adrenal (dys)functioning during critical illness.

Stress hyperglycemia, insulin treatment, and innate immune cells.

Hyperglycemia (HG) and insulin resistance are the hallmarks of a profoundly altered metabolism in critical illness resulting from the release of cortisol, catecholamines, and cytokines, as well as glucagon and growth hormone. Recent studies have proposed a fundamental role of the immune system towards the development of insulin resistance in traumatic patients. A comprehensive review of published literatures on the effects of hyperglycemia and insulin on innate immunity in critical illness was conducted. This review explored the interaction between the innate immune system and trauma-induced hypermetabolism, while providing greater insight into unraveling the relationship between innate immune cells and hyperglycemia. Critical illness substantially disturbs glucose metabolism resulting in a state of hyperglycemia. Alterations in glucose and insulin regulation affect the immune function of cellular components comprising the innate immunity system. Innate immune system dysfunction via hyperglycemia is associated with a higher morbidity and mortality in critical illness. Along with others, we hypothesize that reduction in morbidity and mortality observed in patients receiving insulin treatment is partially due to its effect on the attenuation of the immune response. However, there still remains substantial controversy regarding moderate versus intensive insulin treatment. Future studies need to determine the integrated effects of HG and insulin on the regulation of innate immunity in order to provide more effective insulin treatment regimen for these patients.

Efficacy of High-Dose Vitamin D Supplementation in the Critically Ill Patients

Vitamin D deficiency and its adverse skeletal sequelae are well recognized in the general population. Recent observation of high prevalence of low vitamin D states and their associations with worse clinical outcomes in critically ill populations have sparked interest in the role of supplementation for these patients. High-dose vitamin D efficaciously increases serum levels, but its impact on clinical outcome has not been examined. This article will review results from observational studies on prevalence and outcomes of hypovitaminosis D in critically ill patients, as well as caveats of vitamin D interventional trials. Improved understanding of vitamin D metabolism in critical illness will clarify the therapeutic potential of this pleiotropic hormone and facilitate implementation of cost-effective clinical trials.

Mechanisms of aberrant bone metabolism in critical illness

Mechanisms of aberrant bone metabolism in critical illness

Aberrant bone metabolism in critical illness

Critically ill patients present with distinct alterations in bone metabolism. We have previously reported a decrease in bone formation markers and a dramatic increase in bone resorption markers. In a rabbit model of critical illness, we observed significantly lower bone mineral content in the trabeculae of critically ill rabbits compared to healthy controls. This suggested uncoupling between bone formation and degradation during critical illness, and could increase risk of fracture during rehabilitation or impaired healing of bone fractures. In this study, we investigated the effect of critical illness on bone metabolism at the tissue and cellular level.

Insulin, Glucagon, and Leptin in Critically Ill Foals

Endocrine dysregulation of hormones of energy metabolism is well documented in critically ill humans, but limited information exists in septic foals. The purpose of this study was to provide information on the hormonal response to energy metabolism in critically ill foals, focusing on insulin, glucagon, and leptin. Concentrations of insulin, glucagon, leptin, and triglycerides will be higher, whereas glucose concentration will be lower in septic foals than in healthy and sick nonseptic foals. The magnitude of these differences will be associated with severity of disease and nonsurvival. Forty-four septic, 62 sick nonseptic, and 19 healthy foals <7 days of age. In this prospective multicenter cross-sectional study, blood samples were collected at admission. Foals with positive blood culture or sepsis score ≥12 were considered septic. Septic foals had lower glucose and insulin and higher triglyceride and glucagon concentrations than did healthy foals. Glucagon concentrations were not different between septic foals that died (n = 14) or survived (n = 30). Higher insulin and lower leptin concentrations were associated with mortality. Quantitative insulin-sensitivity check index was higher in septic foals. Energy metabolism and the endocrine response of related hormones in septic foals are characterized by hypoglycemia, hypertriglyceridemia, low insulin concentration, and high glucagon concentration. Leptin and insulin may have prognostic value for nonsurvival in septic foals. The hormonal response related to energy metabolism in critical illness differs between foals and humans.

Cortisol metabolism in critical illness: effects of intensive insulin therapy

An appropriate activation of the hypothalamic–pituitary–adrenal axis and cortisol response to critical illness is essential for survival. Indeed, both high and low cortisol levels are associated with increased mortality. We investigated the effect of intensive insulin therapy (IIT), a treatment recently shown to reduce mortality and morbidity of surgical ICU patients [1], on the cortisol response versus conventional insulin therapy (CIT). All patients included in the large randomized trial [1] who were dependent on intensive care for more than 5 days (n = 451) were selected for this study. Serum levels of total cortisol and cortisol-binding globulin (CBG) were measured upon ICU admission, day 5, day 15 and the last day of intensive care. Free cortisol levels were calculated from these data. Baseline characteristics were similar for both patient groups. The two levels of blood glucose control were well maintained throughout the study. Total cortisol, CBG and free cortisol levels were comparable in both groups on admission to the ICU. On day 5, day 15 and the last day, IIT significantly lowered total cortisol levels. CBG levels were similar except for slightly lower levels in the IIT group on the last day. IIT thus significantly decreased free cortisol on day 5 and day 15. Multivariate logistic regression analysis revealed that reducing cortisol at least in part explained the survival benefit of IIT [1]. Total and free cortisol levels were several-fold higher in critically ill patients receiving exogenous hydrocortisone in so-called 'replacement dose' as compared with patients who did not require such a therapy. IIT appeared to largely exert similar effects in patients with or without hydrocortisone therapy. In conclusion, by reducing serum cortisol levels, intensive insulin therapy beneficially affected outcome of critically ill patients. Studies are ongoing to elucidate the mechanisms underlying this effect.

Alterations in fuel metabolism in critical illness: hyperglycaemia.

Hyperglycaemia is common during critical illness and may be viewed teleologically as a means of ensuring an adequate supply of glucose for the brain and phagocytic cells. Under normal conditions, euglycaemia is maintained by neural, hormonal and hepatic autoregulatory mechanisms. Critical illness promotes hyperglycaemia through an activation of the hypothalamic-pituitary-adrenal axis, which in turn increases hepatic glucose production and inhibits insulin-mediated glucose uptake to skeletal muscle. Sustained hyperglycaemia is associated with adverse consequences that demand its control. Appropriate management includes discontinuing causative drugs, correcting hypokalaemia, treating infection and administering insulin. Insulin therapy also appears to be useful for promoting an anabolic response in skeletal muscle.

EVALUATION OF WHOLE BODY PROTEIN METABOLISM IN CRITICALLY ILL CHILDREN WITH THE "[15N]-GLYCINE SINGLE ORAL DOSE METHOD"

39 Introduction: Protein metabolism in critical illness is characterized by degradation of muscle proteins and negative nitrogen balance. The "[15N]-glycine single oral dose method" is a well described method to evaluate whole body protein metabolism in a non invasive manner. Reported results with this method are in good agreement with those obtained with "precursor" methods. In children, however, only few studies making use of the [15N]-glycine method have been reported. Aims: Evaluation of whole body protein metabolism with the "[15N]glycine single oral dose method" in critically ill children and healthy children. Methods: [15N]glycine (100 mg) was given orally to 8 children in the post-acute phase of meningococcal septic shock (MSS), 4 children with severe pneumonia, 10 healthy children in the fed state and 7 healthy children in the post-absorptive state. Urine was collected during the next 9 hours and total amount of NH3, labelled NH3 and total nitrogen excretion measured. Nitrogen turnover, protein synthesis, protein breakdown and nitrogen balance (all expressed as gram nitrogen /kg/9 hours) were calculated making use of NH3 as end-product. Results:(Table)TableConclusion: Protein turnover, protein synthesis and breakdown were significantly increased in critically ill children when compared to results of either fed or post-absorptive healthy children. These results are in agreement with reported studies. The "[15N]glycine single oral dose method" can be used to evaluate whole body protein metabolism in a non invasive manner in critically ill as well as healthy children.

Protein metabolism in critical illness: methodologies and their problems underlying in kinetic studies using isotope tracers in vivo.

The response to critical illness involves alterations in all aspects of metabolic control, favoring catabolism of body protein. In particular, as the result of the alteration of protein metabolism, body protein loss occurs, which has been reported to be inversely correlated with the survival of critically ill patients. Despite the availability of various therapeutic modalities aiming to prevent loss of body protein pool such as total parenteral nutrition, and enteral nutrition that has made to provide excessive calories as a form of energy substrate and protein itself, the loss of body protein could not be prevented. Loss of body protein store occurs as a consequence of the alteration of intermediate metabolism that works for the production of energy substrate. This alteration of substrate metabolism may link to the alteration of protein metabolism. However, no specific factors regulating protein metabolism have been identified. Thus, further investigations evaluating amino acid and protein metabolism are required to obtain a better understanding of the metabolic regulation in the body, which may lead to the development of novel and more effective therapeutic modalities for nutrition in the future.