Publications by authors named "Lies Langouche"

78 Publications

Role of ketones, ketogenic diets and intermittent fasting in ICU.

Curr Opin Crit Care 2021 May 6. Epub 2021 May 6.

Clinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Purpose Of Review: To summarize the clinical evidence for beneficial effects of ketones, ketogenic diets and intermittent fasting in critical illness, and to review potential mechanisms behind such effects.

Recent Findings: Recent evidence demonstrates that activation of a metabolic fasting response may be beneficial to recover from critical insults. Potential protective mechanisms are, among others, activation of ketogenesis and of damage removal by autophagy. Novel feeding strategies, including ketone supplements, ketogenic diets and intermittent fasting regimens, can activate these pathways - at least partially - in critically ill patients. Randomized controlled trials (RCTs) studying these novel feeding strategies as compared with standard care, are scarce and have not shown consistent benefit. Yet, all RCTs were small and underpowered for clinical endpoints. Moreover, in intermittent fasting studies, the duration of the fasting interval may have been too short to develop a sustained metabolic fasting response.

Summary: These findings open perspectives for the further development of fasting-mimicking diets. Ultimately, clinical benefit should be confirmed by RCTs that are adequately powered for clinically relevant, patient-centered endpoints.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCC.0000000000000841DOI Listing
May 2021

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.

Sci Adv 2021 May 7;7(19). Epub 2021 May 7.

Laboratory of Tumor Inflammation and Angiogenesis, CCB, VIB, Leuven, Belgium.

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210-based therapeutic and diagnostic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abf0466DOI Listing
May 2021

Impact of withholding early parenteral nutrition in adult critically ill patients on ketogenesis in relation to outcome.

Crit Care 2021 03 11;25(1):102. Epub 2021 Mar 11.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-021-03519-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953645PMC
March 2021

The role of pro-opiomelanocortin in the ACTH-cortisol dissociation of sepsis.

Crit Care 2021 02 16;25(1):65. Epub 2021 Feb 16.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Background: Sepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as 'ACTH-cortisol dissociation.' We hypothesized that sepsis acutely activates the hypothalamus to generate, via corticotropin-releasing hormone (CRH) and vasopressin (AVP), ACTH-induced hypercortisolemia. Thereafter, via increased availability of free cortisol, of which breakdown is reduced, feedback inhibition at the pituitary level interferes with normal processing of pro-opiomelanocortin (POMC) into ACTH, explaining the ACTH-cortisol dissociation. We further hypothesized that, in this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis.

Methods: In two human studies of acute (ICU admission to day 7, N = 71) and prolonged (from ICU day 7 until recovery; N = 65) sepsis-induced critical illness, POMC plasma concentrations were quantified in relation to plasma ACTH and cortisol. In a mouse study of acute (1 day), subacute (3 and 5 days) and prolonged (7 days) fluid-resuscitated, antibiotic-treated sepsis (N = 123), we further documented alterations in hypothalamic CRH and AVP, plasma and pituitary POMC and its glucocorticoid-receptor-regulated processing into ACTH, as well as adrenal cortex integrity and steroidogenesis markers.

Results: The two human studies revealed several-fold elevated plasma concentrations of the ACTH precursor POMC from the acute to the prolonged phase of sepsis and upon recovery (all p < 0.0001), coinciding with the known ACTH-cortisol dissociation. Elevated plasma POMC and ACTH-corticosterone dissociation were confirmed in the mouse model. In mice, sepsis acutely increased hypothalamic mRNA of CRH (p = 0.04) and AVP (p = 0.03) which subsequently normalized. From 3 days onward, pituitary expression of CRH receptor and AVP receptor was increased. From acute throughout prolonged sepsis, pituitary POMC mRNA was always elevated (all p < 0.05). In contrast, markers of POMC processing into ACTH and of ACTH secretion, negatively regulated by glucocorticoid receptor ligand binding, were suppressed at all time points (all p ≤ 0.05). Distorted adrenocortical structure (p < 0.05) and lipid depletion (p < 0.05) were present, while most markers of adrenocortical steroidogenic activity were increased at all time points (all p < 0.05).

Conclusion: Together, these findings suggest that increased circulating POMC, through CRH/AVP-driven POMC expression and impaired processing into ACTH, could represent a new piece in the puzzling ACTH-cortisol dissociation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-021-03475-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885358PMC
February 2021

Impact of prolonged sepsis on neural and muscular components of muscle contractions in a mouse model.

J Cachexia Sarcopenia Muscle 2021 Apr 19;12(2):443-455. Epub 2021 Jan 19.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Background: Prolonged critically ill patients frequently develop debilitating muscle weakness that can affect both peripheral nerves and skeletal muscle. In-depth knowledge on the temporal contribution of neural and muscular components to muscle weakness is currently incomplete.

Methods: We used a fluid-resuscitated, antibiotic-treated, parenterally fed murine model of prolonged (5 days) sepsis-induced muscle weakness (caecal ligation and puncture; n = 148). Electromyography (EMG) measurements were performed in two nerve-muscle complexes, combined with histological analysis of neuromuscular junction denervation, axonal degeneration, and demyelination. In situ muscle force measurements distinguished neural from muscular contribution to reduced muscle force generation. In myofibres, imaging and biomechanics were combined to evaluate myofibrillar contractile calcium sensitivity, sarcomere organization, and fibre structural properties. Myosin and actin protein content and titin gene expression were measured on the whole muscle.

Results: Five days of sepsis resulted in increased EMG latency (P = 0.006) and decreased EMG amplitude (P < 0.0001) in the dorsal caudal tail nerve-tail complex, whereas only EMG amplitude was affected in the sciatic nerve-gastrocnemius muscle complex (P < 0.0001). Myelin sheath abnormalities (P = 0.2), axonal degeneration (number of axons; P = 0.4), and neuromuscular junction denervation (P = 0.09) were largely absent in response to sepsis, but signs of axonal swelling [higher axon area (P < 0.0001) and g-ratio (P = 0.03)] were observed. A reduction in maximal muscle force was present after indirect nerve stimulation (P = 0.007) and after direct muscle stimulation (P = 0.03). The degree of force reduction was similar with both stimulations (P = 0.2), identifying skeletal muscle, but not peripheral nerves, as the main contributor to muscle weakness. Myofibrillar calcium sensitivity of the contractile apparatus was unaffected by sepsis (P ≥ 0.6), whereas septic myofibres displayed disorganized sarcomeres (P < 0.0001) and altered myofibre axial elasticity (P < 0.0001). Septic myofibres suffered from increased rupturing in a passive stretching protocol (25% more than control myofibres; P = 0.04), which was associated with impaired myofibre active force generation (P = 0.04), linking altered myofibre integrity to function. Sepsis also caused a reduction in muscle titin gene expression (P = 0.04) and myosin and actin protein content (P = 0.05), but not the myosin-to-actin ratio (P = 0.7).

Conclusions: Prolonged sepsis-induced muscle weakness may predominantly be related to a disruption in myofibrillar cytoarchitectural structure, rather than to neural abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcsm.12668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061378PMC
April 2021

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit.

Crit Care 2020 08 31;24(1):536. Epub 2020 Aug 31.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.

Background: In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits.

Methods: In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators.

Results: In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1-5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04-0.04] mmol/L to 0.75 [0.04-2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN statistically explained its impact on weaning from mechanical ventilation (P = 0.0002) and on time to live PICU discharge (P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings.

Conclusion: Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-020-03256-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456767PMC
August 2020

Nonthyroidal Illness Syndrome Across the Ages.

J Endocr Soc 2019 Dec 16;3(12):2313-2325. Epub 2019 Oct 16.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University Hospital, Leuven, Belgium.

In conditions of acute illness, patients present with reduced plasma T3 concentrations without a concomitant rise in TSH. In contrast, plasma concentrations of the inactive hormone rT3 increase, whereas plasma concentrations of T4 remain low-normal. This constellation of changes, referred to as nonthyroidal illness syndrome (NTIS), is present across all ages, from preterm neonates and over-term critically ill infants and children to critically ill adults. Although the severity of illness strongly correlates with the severity of the NTIS phenotype, the causality of this association remains debated, and pathophysiological mechanisms remain incompletely understood. In the acute phase of illness, NTIS appears to be caused predominantly by an increased peripheral inactivation of thyroid hormones, in which reduced nutritional intake plays a role. Current evidence suggests that these acute peripheral changes are part of a beneficial adaptation of the body to reduce expenditure of energy and to activate the innate immune response, which is important for survival. In contrast, in more severely ill and prolonged critically ill patients, an additional central suppression of the thyroid hormone axis alters and further aggravates the NTIS phenotype. Recent studies suggest that this central suppression may not be adaptive. Whether treatment of this central component of NTIS in prolonged critically ill patients, with the use of hypothalamic releasing factors, improves outcome remains to be investigated in large randomized control trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/js.2019-00325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853682PMC
December 2019

Anterior pituitary function in critical illness.

Endocr Connect 2019 Aug;8(8):R131-R143

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Critical illness is hallmarked by major changes in all hypothalamic-pituitary-peripheral hormonal axes. Extensive animal and human studies have identified a biphasic pattern in circulating pituitary and peripheral hormone levels throughout critical illness by analogy with the fasting state. In the acute phase of critical illness, following a deleterious event, rapid neuroendocrine changes try to direct the human body toward a catabolic state to ensure provision of elementary energy sources, whereas costly anabolic processes are postponed. Thanks to new technologies and improvements in critical care, the majority of patients survive the acute insult and recover within a week. However, an important part of patients admitted to the ICU fail to recover sufficiently, and a prolonged phase of critical illness sets in. This prolonged phase of critical illness is characterized by a uniform suppression of the hypothalamic-pituitary-peripheral hormonal axes. Whereas the alterations in hormonal levels during the first hours and days after the onset of critical illness are evolutionary selected and are likely beneficial for survival, endocrine changes in prolonged critically ill patients could be harmful and may hamper recovery. Most studies investigating the substitution of peripheral hormones or strategies to overcome resistance to anabolic stimuli failed to show benefit for morbidity and mortality. Research on treatment with selected and combined hypothalamic hormones has shown promising results. Well-controlled RCTs to corroborate these findings are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EC-19-0318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709544PMC
August 2019

Adipose tissue protects against sepsis-induced muscle weakness in mice: from lipolysis to ketones.

Crit Care 2019 Jul 1;23(1):236. Epub 2019 Jul 1.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.

Background: ICU-acquired weakness is a debilitating consequence of prolonged critical illness that is associated with poor outcome. Recently, premorbid obesity has been shown to protect against such illness-induced muscle wasting and weakness. Here, we hypothesized that this protection was due to increased lipid and ketone availability.

Methods: In a centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we compared markers of lipolysis and fatty acid oxidation in lean and obese septic mice (n = 117). Next, we compared markers of muscle wasting and weakness in septic obese wild-type and adipose tissue-specific ATGL knockout (AAKO) mice (n = 73), in lean septic mice receiving either intravenous infusion of lipids or standard parenteral nutrition (PN) (n = 70), and in lean septic mice receiving standard PN supplemented with either the ketone body 3-hydroxybutyrate or isocaloric glucose (n = 49).

Results: Obese septic mice had more pronounced lipolysis (p ≤ 0.05), peripheral fatty acid oxidation (p ≤ 0.05), and ketogenesis (p ≤ 0.05) than lean mice. Blocking lipolysis in obese septic mice caused severely reduced muscle mass (32% loss vs. 15% in wild-type, p < 0.001) and specific maximal muscle force (59% loss vs. 0% in wild-type; p < 0.001). In contrast, intravenous infusion of lipids in lean septic mice maintained specific maximal muscle force up to healthy control levels (p = 0.6), whereas this was reduced with 28% in septic mice receiving standard PN (p = 0.006). Muscle mass was evenly reduced with 29% in both lean septic groups (p < 0.001). Lipid administration enhanced fatty acid oxidation (p ≤ 0.05) and ketogenesis (p < 0.001), but caused unfavorable liver steatosis (p = 0.01) and a deranged lipid profile (p ≤ 0.01). Supplementation of standard PN with 3-hydroxybutyrate also attenuated specific maximal muscle force up to healthy control levels (p = 0.1), but loss of muscle mass could not be prevented (25% loss in both septic groups; p < 0.001). Importantly, this intervention improved muscle regeneration markers (p ≤ 0.05) without the unfavorable side effects seen with lipid infusion.

Conclusions: Obesity-induced muscle protection during sepsis is partly mediated by elevated mobilization and metabolism of endogenous fatty acids. Furthermore, increased availability of ketone bodies, either through ketogenesis or through parenteral infusion, appears to protect against sepsis-induced muscle weakness also in the lean.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-019-2506-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600878PMC
July 2019

Evolution of circulating thyroid hormone levels in preterm infants during the first week of life: perinatal influences and impact on neurodevelopment.

J Pediatr Endocrinol Metab 2019 Jun;32(6):597-606

Department of Neonatology, Neonatal Intensive Care Unit, University Hospitals Leuven, KU Leuven, Leuven, Belgium.

Background For several decades, transient hypothyroxinemia of prematurity (THOP) has been a topic of debate. The pathophysiology is incompletely understood and consensus on the therapeutic approach is lacking. This study aimed at gaining a better insight into the pathogenesis by studying the trends in thyroid hormone (TH) levels during the first week of life. Methods This single-center prospective observational study analyzed the plasma levels of total thyroxine (T4) and free thyroxine (fT4), total triiodothyronine (T3), thyroid-stimulating hormone (TSH) and T4-binding globulin (TBG) in cord blood and at the end of the first week of life in 120 preterm infants (gestational age [GA] <37 weeks). The change over time was calculated (delta, ∆). The impact of perinatal and subsequently postnatal variables on ∆ was studied by hierarchical multiple regression. The impact of ∆ on the neurodevelopmental outcome at the corrected ages of 9 and 24 months, measured by the Bayley Scales of Infant Development (BSID)-II, was assessed by logistic regression. Results ∆fT4 levels were negatively affected by GA and use of dopamine, whereas only GA was associated with low ∆T3 levels. Negative ∆fT4 levels were present in 75% of the extremely low-for-gestational-age infants, whereas 23.5% had a negative ∆T3 level. There was an increased risk for an abnormal mental developmental score (<85) with decreasing ∆T3 at 9 months, corrected age, but not at 24 months. Conclusions A negative evolution in circulating TH levels is principally an immaturity phenomenon, whereas dopamine can further suppress the hypothalamic-pituitary-thyroid axis. There is at least a temporary negative effect of this evolution on the infants' neurodevelopment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jpem-2018-0537DOI Listing
June 2019

Adrenal function and dysfunction in critically ill patients.

Nat Rev Endocrinol 2019 07;15(7):417-427

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, Leuven, Belgium.

Critical illnesses are characterized by increased systemic cortisol availability, which is a vital part of the stress response. Relative adrenal failure (later termed critical-illness-related corticosteroid insufficiency (CIRCI)) is a condition in which the systemic availability of cortisol is assumed to be insufficiently high to face the stress of the illness and is most typically thought to occur in the acute phase of septic shock. Researchers suggested that CIRCI could be diagnosed by a suppressed incremental cortisol response to an injection of adrenocorticotropic hormone, irrespective of the baseline plasma cortisol. This concept triggered several randomized clinical trials on the impact of large stress doses of hydrocortisone to treat CIRCI, which gave conflicting results. Recent novel insights into the response of the hypothalamic-pituitary-adrenal axis to acute and prolonged critical illnesses challenge the concept of CIRCI, as currently defined, as well as the current practice guidelines for diagnosis and treatment. In this Review, these novel insights are integrated within a novel conceptual framework that can be used to re-appreciate adrenocortical function and dysfunction in the context of critical illness. This framework opens new avenues for further research and for preventive and/or therapeutic innovations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41574-019-0185-7DOI Listing
July 2019

The placenta in fetal thyroid hormone delivery: from normal physiology to adaptive mechanisms in complicated pregnancies.

J Matern Fetal Neonatal Med 2020 Nov 19;33(22):3857-3866. Epub 2019 Mar 19.

Department of Neonatology, University Hospitals Leuven, Leuven, Belgium.

Thyroid hormones are indispensable for normal fetal development. Since the fetus depends to a large extent on maternal thyroid hormone supply through the placenta, this challenges maternal thyroid economy. Several molecular mechanisms are involved in placental thyroid hormone transport and metabolism. Chronic pregnancy complications, associated with utero-placental hypoxia, trigger the development of accelerated placental maturation in order to improve fetal-placental exchange to strengthen the offspring's chance of survival. This review provides an overview of normal maternal-fetal thyroid hormone supply and explores the presence of placental adaptive mechanisms in complicated pregnancies with chronical utero-placental hypoxia to improve the thyroid hormone supply to the fetus under pressure, to end with reflections about the long term health consequences. This work is based on a comprehensive literature review of the PubMed and Embase database, including relevant articles from 1969 to June 2018. The placenta is actively involved in fetal thyroid hormone delivery through a combination of stimulatory and inhibitory mechanisms. Parallel with histological adaptations to improve transplacental fetal-maternal exchange, there are indications of placental adaptive mechanisms in thyroid hormone transport and metabolism in case of complicated pregnancies, from animal models and experiments. Evidence from human studies is limited due to heterogeneity in study populations, small study samples, and technical limitations. Further research is necessary to reveal the role of the placenta in pathological circumstances. The placenta might thus be considered as the infants' black box of pregnancy. Results will contribute to more insights in the concept of fetal programming, which lays the foundations of optimum health, growth, and neurodevelopment across the lifespan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14767058.2019.1586875DOI Listing
November 2020

Non-Thyroidal Illness Syndrome in Critically Ill Children: Prognostic Value and Impact of Nutritional Management.

Thyroid 2019 04 11;29(4):480-492. Epub 2019 Mar 11.

1 Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University Hospital, Leuven, Belgium.

Introduction: Non-thyroidal illness (NTI), which occurs with fasting and in response to illness, is characterized by thyroid hormone inactivation with low triiodothyronine (T3) and high reverse T3 (rT3), followed by suppressed thyrotropin (TSH). Withholding supplemental parenteral nutrition early in pediatric critical illness (late-PN), thus accepting low/no macronutrient intake up to day 8 in the pediatric intensive care unit (PICU), accelerated recovery compared to initiating supplemental parenteral nutrition early (early-PN). Whether NTI is harmful or beneficial in pediatric critical illness and how it is affected by a macronutrient deficit remains unclear. This study investigated the prognostic value of NTI, the impact of late-PN on NTI, and whether such impact explains or counteracts the outcome benefit of late-PN in critically ill children.

Methods: This preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial quantified serum TSH, total thyroxine (T4), T3, and rT3 concentrations in 982 patients upon PICU admission versus 64 matched healthy children and in 772 propensity score-matched early-PN and late-PN patients upon admission and at day 3 or last PICU day for shorter PICU stay. Associations between thyroid hormone concentrations upon admission and outcome, as well as impact of late-PN on NTI in relation with outcome, were assessed with univariable analyses and multivariable logistic regression, linear regression, or Cox proportional hazard analysis, adjusted for baseline risk factors.

Results: Upon PICU admission, critically ill children revealed lower TSH, T4, T3, and T3/rT3 and higher rT3 than healthy children (p < 0.0001). A more pronounced NTI upon admission, with low T4, T3, and T3/rT3 and high rT3 was associated with higher mortality and morbidity. Late-PN further reduced T4, T3, and T3/rT3 and increased rT3 (p ≤ 0.001). Statistically, the further lowering of T4 by late-PN reduced the outcome benefit (p < 0.0001), whereas the further lowering of T3/rT3 explained part of the outcome benefit of late-PN (p ≤ 0.004). This effect was greater for infants than for older children.

Conclusion: In critically ill children, the peripheral inactivation of thyroid hormone, characterized by a decrease in T3/rT3, which is further accentuated by low/no macronutrient intake, appears beneficial. In contrast, the central component of NTI attributable to suppressed TSH, evidenced by the decrease in T4, seems to be a harmful response to critical illness. Whether treating the central component with TSH releasing hormone infusion in the PICU is beneficial requires further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2018.0420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457888PMC
April 2019

Reply to: "Outcome of critically ill cirrhotic patients admitted to the ICU: The role of ACLF".

J Hepatol 2019 04 23;70(4):804-805. Epub 2019 Jan 23.

Department of Internal Medicine, University Hospitals Leuven [KU Leuven], Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2019.01.001DOI Listing
April 2019

Hepatic PPARα is critical in the metabolic adaptation to sepsis.

J Hepatol 2019 05 21;70(5):963-973. Epub 2019 Jan 21.

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France. Electronic address:

Background & Aims: Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)α, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPARα in the response to sepsis.

Methods: Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Ppara-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPARα expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters.

Results: Both whole body and non-hematopoietic Ppara-deficiency in mice decreased survival upon bacterial infection. Livers of septic Ppara-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPARα impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers.

Conclusion: During sepsis, Ppara-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPARα in hepatocytes plays a key role in the host defense against infection.

Lay Summary: As the main cause of death in critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have mostly been overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPARα in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2018.12.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774768PMC
May 2019

Review shows that thyroid hormone substitution could benefit transient hypothyroxinaemia of prematurity but treatment strategies need to be clarified.

Acta Paediatr 2019 05 4;108(5):792-805. Epub 2019 Jan 4.

Department of Neonatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.

Aim: Thyroid hormones are crucial for foetal and neonatal brain development. This paper provides an overview of the normal role of thyroid hormones in foetal brain development and the pathophysiology of transient hypothyroxinaemia of prematurity (THOP). It also discusses the diagnostic and therapeutic controversies around THOP and looks at directions for future research.

Methods: We used the PubMed and Embase databases to identify papers published in English from 1969 to June 2018. This identified 20 papers about the impact of THOP on neurodevelopment and seven randomised controlled trials about therapeutic approaches from 1981-2016.

Results: THOP has been researched for more than three decades. The impact of temporarily low thyroxine levels, without any increase in pituitary-secreted thyroid-stimulating hormone at a critical timeframe in an infant's brain development, is still debated. Heterogeneity in THOP definitions, difficulties with thyroid hormone assessment, identifying patients at risk and a clear lack of sufficiently powered studies add to the current controversy. There are indications that thyroid hormone substitution might be useful in extremely low gestational age neonates with THOP.

Conclusion: Some preterm infants could benefit from THOP treatment, but more studies are needed to clarify further treatment strategies, including the optimal timing of initiation and duration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apa.14685DOI Listing
May 2019

ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study.

Intensive Care Med 2018 Dec 29;44(12):2048-2058. Epub 2018 Oct 29.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Purpose: Low plasma ACTH in critically ill patients may be explained by shock/inflammation-induced hypothalamus-pituitary damage or by feedback inhibition exerted by elevated plasma free cortisol. One can expect augmented/prolonged ACTH-responses to CRH injection with hypothalamic damage, immediately suppressed responses with pituitary damage, and delayed decreased responses in prolonged critical illness with feedback inhibition.

Methods: This randomized, double-blind, placebo-controlled crossover cohort study, compared ACTH responses to 100 µg IV CRH and placebo in 3 cohorts of 40 matched patients in the acute (ICU-day 3-6), subacute (ICU-day 7-16) or prolonged phase (ICU-day 17-28) of critical illness, with 20 demographically matched healthy subjects. CRH or placebo was injected in random order on two consecutive days. Blood was sampled repeatedly over 135 min and AUC responses to placebo were subtracted from those to CRH.

Results: Patients had normal mean ± SEM plasma ACTH concentrations (25.5 ± 1.6 versus 24.8 ± 3.6 pg/ml in healthy subjects, P = 0.54) but elevated free cortisol concentrations (3.11 ± 0.27 versus 0.58 ± 0.05 µg/dl in healthy subjects, P < 0.0001). The order of the CRH/placebo injections did not affect the ACTH responses, hence results were pooled. Patients in the acute phase of illness had normal mean ± SEM ACTH responses (5149 ± 848 pg/mL min versus 4120 ± 688 pg/mL min in healthy subjects; P = 0.77), whereas those in the subacute (2333 ± 387 pg/mL min, P = 0.01) and prolonged phases (2441 ± 685 pg/mL min, P = 0.001) were low, irrespective of sepsis/septic shock or risk of death.

Conclusions: Suppressed ACTH responses to CRH in the more prolonged phases, but not acute phase, of critical illness are compatible with feedback inhibition exerted by elevated free cortisol, rather than by cellular damage to hypothalamus and/or pituitary.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-018-5427-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280831PMC
December 2018

Prevalence and Prognostic Value of Abnormal Liver Test Results in Critically Ill Children and the Impact of Delaying Parenteral Nutrition.

Pediatr Crit Care Med 2018 Dec;19(12):1120-1129

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.

Objectives: In the Early versus Late Parenteral Nutrition in the Pediatric ICU randomized controlled trial, delaying parenteral nutrition to beyond day 7 (late parenteral nutrition) was clinically superior to supplemental parenteral nutrition initiated within 24 hours (early parenteral nutrition), but resulted in a higher rise in bilirubin. We aimed to document prevalence and prognostic value of abnormal liver tests in the PICU and the impact hereon of withholding early parenteral nutrition.

Design: Preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric ICU randomized controlled trial. Total bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase plasma concentrations were measured systematically in PICU. Liver test analyses were adjusted for baseline characteristics including severity of illness.

Setting: Three PICUs in Belgium, the Netherlands, and Canada.

Patients: As neonatal jaundice was considered a confounder, only the 1,231 of the 1,440 Early versus Late Parenteral Nutrition in the Pediatric ICU-patients 28 days to 17 years old were included.

Interventions: Late parenteral nutrition as compared with early parenteral nutrition.

Measurements And Main Results: During the first seven PICU days, the prevalence of cholestasis (> 2 mg/dL [34.2 μmol/L] bilirubin) ranged between 3.8% and 4.9% and of hypoxic hepatitis (≥ 20-fold upper limit of normality for alanine aminotransferase and aspartate aminotransferase) between 0.8% and 2.2%, both unaffected by the use of parenteral nutrition. Throughout the first week in PICU plasma bilirubin concentrations were higher in late parenteral nutrition patients (p < 0.05), but became comparable to early parenteral nutrition patients as soon as parenteral nutrition was started on day 8. Plasma concentrations of gamma-glutamyl transpeptidase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase were unaffected by parenteral nutrition. High day 1 plasma concentrations of gamma-glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase (p ≤ 0.01), but not alkaline phosphatase, were independent risk factors for PICU mortality. Day 1 plasma bilirubin concentrations displayed a U-shaped association with PICU mortality, with higher mortality associated with bilirubin less than 0.20 mg/dL and greater than 0.76 mg/dL (< 3.42 μmol/L and > 13 μmol/L) (p ≤ 0.01).

Conclusions: Overt cholestasis and hypoxic hepatitis were rare and unrelated to the nutritional strategy. However, withholding parenteral nutrition up to 1 week in PICU increased plasma bilirubin. A mild elevation of bilirubin on the first PICU day was associated with lower risk of death and may reflect a stress response, rather than true cholestasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PCC.0000000000001734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282934PMC
December 2018

Adrenocortical function during prolonged critical illness and beyond: a prospective observational study.

Intensive Care Med 2018 Oct 13;44(10):1720-1729. Epub 2018 Sep 13.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Purpose: For patients suffering from prolonged critical illness, it is unknown whether and when the hypothalamus-pituitary-adrenal axis alterations recover, and to what extent adrenocortical function parameters relate to sepsis/septic shock, to clinical need for glucocorticoid treatment, and to survival.

Methods: Patients still in ICU on day 7 (N = 392) and 20 matched healthy subjects were included. Morning blood and 24-h urine were collected daily and cosyntropin tests (250 µg) performed weekly, repeated 1 week after ICU discharge on the regular ward.

Results: In all patients free of glucocorticoid treatment up until ICU day 28 (N = 347), plasma ACTH always remained low/normal, whereas free cortisol remained high (P ≤ 0.002) explained by reduced binding proteins (P ≤ 0.02) and suppressed cortisol breakdown (P ≤ 0.001). Beyond ICU day 28 (N = 64 long-stayers), plasma (free)cortisol was no longer elevated. One week after ICU discharge, plasma ACTH and (free)cortisol always rose to supra-normal levels (P ≤ 0.006), most pronounced in long-stayers. Long-stayers always showed low incremental total (P ≤ 0.001), but normal incremental free cortisol responses to weekly cosyntropin tests, explained by low cortisol plasma binding proteins. Sepsis/septic shock patients were not different from others, patients subsequently receiving glucocorticoids (N = 45) were not different from those who did not, and non-survivors were distinguishable from survivors only by higher (free)cortisol.

Conclusions: Irrespective of sepsis/septic shock, need for glucocorticoids and survival, low cortisol plasma binding proteins and suppressed cortisol breakdown determine systemic (free)cortisol availability in prolonged critical illness, the latter no longer elevated beyond ICU day 28. The uniform rise in ACTH and cortisol to supra-normal levels 1 week after ICU discharge indicates recovery of a central adrenocortical suppression while in ICU. Low cortisol plasma binding invalidates the cosyntropin test.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-018-5366-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182356PMC
October 2018

The Hepatic Glucocorticoid Receptor Is Crucial for Cortisol Homeostasis and Sepsis Survival in Humans and Male Mice.

Endocrinology 2018 07;159(7):2790-2802

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Sepsis is hallmarked by hypercortisolemia, a stress response essential for survival. This elevation in plasma cortisol is partially brought about by suppressed hepatic cortisol breakdown. We demonstrate that a controlled downregulation of the hepatic glucocorticoid receptor (hepatic GR) is crucial. In a mouse model of fluid-resuscitated, antibiotic-treated abdominal sepsis and in human intensive care unit patients, sepsis reduced hepatic GR expression and signaling but increased (free) plasma cortisol/corticosterone, explained by suppressed cortisol/corticosterone-binding proteins and A-ring reductases. However, further experimental inhibition of hepatic GR with short hairpin RNA (shRNA) in septic mice increased mortality fivefold. Acutely, this further hepatic GR suppression prevented the rise in total corticosterone but further reduced binding proteins, resulting in elevated free corticosterone. After 3 days of shRNA-GR inhibition in sepsis, both total and free corticosterone levels were elevated, now explained by an additional reduction in A-ring reductase expression. Hepatic GR inhibition blunted the hyperglycemic stress response without causing hypoglycemia but also markedly increased circulating and hepatic inflammation markers and caused liver destruction, the severity of which explained increased mortality. In human sepsis, glucocorticoid treatment further suppressed hepatic GR expression, which could directly predispose to worse outcomes. In conclusion, sepsis partially suppressed hepatic GR expression, which appeared crucial to upregulate free cortisol/corticosterone availability. However, further sustained hepatic GR suppression evoked lethal excessive liver and systemic inflammation, independent of systemic cortisol/corticosterone availability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/en.2018-00344DOI Listing
July 2018

The intensive care unit course and outcome in acute-on-chronic liver failure are comparable to other populations.

J Hepatol 2018 Oct 4;69(4):803-809. Epub 2018 May 4.

Laboratory of Hepatology, University of Leuven [KU Leuven], Belgium; Department of Gastroenterology and Hepatology, University Hospitals Leuven [KU Leuven], Belgium. Electronic address:

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis, development of organ failure and high short-term mortality. Whether the outcome in patients admitted to the intensive care unit (ICU) with ACLF differs from other ICU populations is unknown. We compared the clinical course and host response in ICU patients with or without ACLF, matched for baseline severity of illness scores and characteristics.

Methods: From the large prospective EPaNIC randomized control trial database (n = 4,640), 133 patients were identified with cirrhosis of whom 71 fulfilled the Chronic Liver Failure Consortium criteria for ACLF. These patients were matched for type and severity of illness and demographics to 71 septic and 71 medical ICU patients from the same database without chronic liver disease. Clinical, biochemical and outcome parameters were compared in this cohort study of 213 patients. In a subset of 100 patients, day 1 serum cytokines were quantified.

Results: The outcome of ACLF, when compared to septic or medical ICU patients, matched for baseline parameters of illness severity, was similar regarding length of ICU stay, development of new infections, organ failure and septic shock. ICU, hospital and 90-day mortality were similar between the groups. C-reactive protein and platelet levels were lower in patients with ACLF throughout the first week. Cytokines, including IL-10, IL-1β, IL-6, and IL-8, were similarly elevated in ACLF and septic ICU patients on day 1. However, TNF-α levels were higher in patients with ACLF.

Conclusion: Patients with ACLF admitted to the ICU showed comparable clinical and ICU outcomes as ICU patients without chronic liver disease, but with similar baseline severity of illness characteristics. This suggests that ICU admission criteria should not be different in ACLF populations.

Lay Summary: Liver function may abruptly deteriorate in patients with chronic liver disease with cirrhosis, often resulting in these patients being admitted to an intensive care unit (ICU) with organ failure. Previous studies have indicated that this sudden deterioration, called acute-on-chronic liver failure is associated with very high mortality rates, which often resulted in deferred ICU care because of a perception of futility. Our study now shows that the ICU course and outcome are not different when patients with acute-on-chronic liver failure are compared to other ICU patients matched for severity of illness. This demonstrates that patients with acute-on-chronic liver failure deserve the same ICU care given to other ICU populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2018.04.025DOI Listing
October 2018

Maternal and placental responses before preterm birth: adaptations to increase fetal thyroid hormone availability?

J Matern Fetal Neonatal Med 2019 Aug 20;32(16):2746-2757. Epub 2018 Mar 20.

b Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine , KU Leuven , Belgium.

Background: During pregnancy, maternal thyroid hormone supply is crucial for fetal development. Preterm infants often present with hypothyroxinemia. Preterm birth, either spontaneous or medically indicated, is always the result of a complicated pregnancy. We hypothesized that in preterm birth, the maternal transplacental thyroid hormone supply is influenced by the pregnancy complication and we questioned whether maternal and placental compensatory mechanisms are activated to increase thyroid hormone transfer.

Methods: Observational case-control study in mother-infant-dyads with complicated pregnancies ending in spontaneous preterm birth (n = 31) or indicated preterm birth due to vascular complications (n = 45) and normal pregnancies (healthy term controls; n = 41). At delivery, maternal and cord blood and placenta samples were collected. Cord and maternal plasma concentrations of thyroid stimulating hormone (TSH), total T4, fT4/FTI, total T3, and T4 binding globulin (TBG), and maternal serum concentrations of thyroid peroxidase (TPO)-antibodies were measured. Placental maturity was evaluated histologically and mRNA and/or protein levels of thyroid hormone deiodinases (DiO) 1, 2 and 3, and transporters (MCT8, MCT10, and OATP1c1) were quantified.

Results: In indicated and spontaneous preterm births, cord plasma T4 concentrations were lower than in healthy term controls (p ≤ .001), whereas T3 was only decreased in spontaneous preterm birth (p ≤ .001). Compared with spontaneous preterm births and healthy term controls, indicated preterm birth was characterized by higher maternal plasma TSH (p ≤ .05), earlier placental maturation, higher placental DiO2 gene and MCT10 protein levels and lower DiO3 gene levels (all p ≤ .01).

Conclusions: Low T4 was observed in preterm infants irrespective of the cause of preterm birth, while maternal (TSH) and placental (DiO2, DiO3, and MCT10) compensatory responses were only activated in indicated preterm birth due to vascular complications. This may have mediated the normal fetal T3 availability in preterm infants born after indicated preterm birth but not after spontaneous preterm birth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14767058.2018.1449199DOI Listing
August 2019

Adrenocortical Stress Response during the Course of Critical Illness.

Compr Physiol 2017 12 12;8(1):283-298. Epub 2017 Dec 12.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.

Critically ill patients have elevated plasma cortisol concentrations, in proportion to illness severity. This was traditionally attributed exclusively to a central activation of the hypothalamus-pituitary axis. However, low rather than high plasma ACTH concentrations have been reported in critically ill patients, with loss of diurnal ACTH and cortisol rhythm. Low ACTH together with high cortisol is referred to as "ACTH-cortisol dissociation." Although cortisol production is somewhat increased with inflammation, a reduced cortisol breakdown explains to a larger extent the hypercortisolism during critical illness. Inflammation-driven decrease in cortisol binding proteins further increase the active free cortisol fraction. Several drugs administered to ICU patients suppress plasma cortisol in a dose-dependent manner. Sustained low circulating ACTH might contribute to adrenal atrophy and dysfunction in the prolonged phase of critical illness. In the acute phase of sepsis or septic shock, a condition referred to as "relative adrenal insufficiency" has been suggested to ensue from glucocorticoid resistance and insufficiently elevated circulating cortisol to overcome such resistance, with pathological changes possibly occurring at every level of the HPA axis. However, it remains highly controversial whether tissue-specific glucocorticoid resistance is adaptive or maladaptive, how to diagnose "relative" adrenal insufficiency, and how it should be treated. Large RCTs, investigating the effect of 200 mg/d hydrocortisone treatment for sepsis or septic shock have shown conflicting, mainly negative, results. Not taking into account the reduced cortisol breakdown, which increases the risk of overdosing hydrocortisone, might have played a role. Further research on diagnostic, therapeutic and dosing aspects is urgently warranted. Compr Physiol 8:283-298, 2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cphy.c170022DOI Listing
December 2017

On the Role of Illness Duration and Nutrient Restriction in Cholestatic Alterations that Occur During Critical Illness.

Shock 2018 08;50(2):187-198

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Background And Aims: Elevated markers of cholestasis are common in response to critical illness, and associated with adverse outcome. The role of illness duration and of nutrient restriction on underlying molecular pathways of such cholestatic responses have not been thoroughly investigated.

Methods: In a mouse model of surgery- and sepsis-induced critical illness, molecular pathways of cholestasis were investigated up to 7 days. To assess which changes are explained by illness-induced lack of feeding, nutrient-restricted healthy mice were studied and compared with ad libitum fed healthy mice. Furthermore, serum bile acid (BA) concentrations were quantified in 1,114 human patients with either short or long intensive care unit (ICU) stay, matched for type and severity of illness, up to ICU-day-7.

Results: In critically ill mice, either evoked by surgery or sepsis, circulating and hepatic BA-levels progressively increased with time from day-3 onward, preceded by unsuppressed or upregulated CYP7A1 and CYP27A1 protein expression. From 30 h onward, nuclear farnesoid-X-receptor-retinoid-X-receptor staining was significantly suppressed in both critically ill groups, followed from day-3 onward by decreased gene expression of the apical exporter BA-specific export pump and increased expression of basolateral exporters multidrug resistance-associated protein 3 (MRP3) and MRP4. Nutrient restriction in healthy mice only partly mirrored illness-induced alterations in circulating BA and BA-transporters, without changing nuclear receptors or synthesis markers expression. Also in human critically ill patients, serum BA increased with time in long-stay patients only, similarly for patients with or without sepsis.

Conclusions: Circulating BA concentrations rose days after onset of sepsis- and surgery-induced, critical illness, only partially explained by lack of feeding, preceded by suppressed nuclear feedback-sensors and ongoing BA synthesis. Expression of transporters suggested ongoing reversed BA-flow toward the blood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SHK.0000000000001001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039378PMC
August 2018

Cholestatic Alterations in the Critically Ill: Some New Light on an Old Problem.

Chest 2018 03 26;153(3):733-743. Epub 2017 Aug 26.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. Electronic address:

Liver dysfunction and jaundice are traditionally viewed as late features of sepsis and other critical illnesses and are associated with a complicated ICU stay. However, study results suggest that cholestatic alterations occur early in the course of critical illnesses, perceived only as minor abnormalities in routinely used biochemical liver tests. Inflammation-induced alterations in the transport of bile acids (BAs) appear to drive BAs and bilirubin toward the systemic circulation. Ongoing BA synthesis with an, at least partial, loss of feedback inhibition further contributes to elevated circulating BAs and bilirubin. To what extent these changes reflect a biochemical epiphenomenon, true illness-induced liver dysfunction, or a beneficial and adaptive response to illness should be investigated further. Because of the lack of specificity of standard laboratory tests, especially in the context of a complex systemic condition such as critical illness, identifying true cholestatic liver dysfunction remains a great challenge. However, high levels of cholestatic markers that are sustained in patients with prolonged critical illness almost always indicate a complicated illness course and should be monitored closely. Preventing cholestatic liver dysfunction comprises minimizing inflammation and hypoxia in the liver and preventing hyperglycemia, avoiding early use of parenteral nutrition, and reducing the administration of avoidable drugs. Future research on the effects of BAs and on modulating underlying drivers of cholestasis induced by critical illness is warranted as this could open perspectives for a targeted diagnostic approach and ultimately for novel therapies to improve outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2017.08.018DOI Listing
March 2018

Use of a Central Venous Line for Fluids, Drugs and Nutrient Administration in a Mouse Model of Critical Illness.

J Vis Exp 2017 05 2(123). Epub 2017 May 2.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven;

This protocol describes a centrally catheterized mouse model of prolonged critical illness. We combine the cecal ligation and puncture method to induce sepsis with the use of a central venous line for fluids, drugs and nutrient administration to mimic the human clinical setting. Critically ill patients require intensive medical support in order to survive. While the majority of patients will recover within a few days, about a quarter of the patients need prolonged intensive care and are at high risk of dying from non-resolving multiple organ failure. Furthermore, the prolonged phase of critical illness is hallmarked by profound muscle weakness, and endocrine and metabolic changes, of which the pathogenesis is currently incompletely understood. The most widely used animal model in critical care research is the cecal ligation and puncture model to induce sepsis. This is a very reproducible model, with acute inflammatory and hemodynamic changes similar to human sepsis, which is designed to study the acute phase of critical illness. However, this model is hallmarked by a high lethality, which is different from the clinical human situation, and is not developed to study the prolonged phase of critical illness. Therefore, we adapted the technique by placing a central venous catheter in the jugular vein allowing us to administer clinically relevant supportive care, to better mimic the human clinical situation of critical illness. This mouse model requires an extensive surgical procedure and daily intensive care of the animals, but it results in a relevant model of the acute and prolonged phase of critical illness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/55553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565154PMC
May 2017

Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition.

Am J Respir Crit Care Med 2017 11;196(9):1131-1143

1 Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, and.

Rationale: Critical illness is hallmarked by muscle wasting and disturbances in glucose, lipid, and amino acid homeostasis. Circulating concentrations of glucagon, a catabolic hormone that affects these metabolic pathways, are elevated during critical illness. Insight in the nutritional regulation of glucagon and its metabolic role during critical illness is lacking.

Objectives: To evaluate whether macronutrient infusion can suppress plasma glucagon during critical illness and study the role of illness-induced glucagon abundance in the disturbed glucose, lipid, and amino acid homeostasis and in muscle wasting during critical illness.

Methods: In human and mouse studies, we infused macronutrients and manipulated glucagon availability up and down to investigate its acute and chronic metabolic role during critical illness.

Measurements And Main Results: In critically ill patients, infusing glucose with insulin did not lower glucagon, whereas parenteral nutrition containing amino acids increased glucagon. In critically ill mice, infusion of amino acids increased glucagon and up-regulated markers of hepatic amino acid catabolism without affecting muscle wasting. Immunoneutralizing glucagon in critically ill mice only transiently affected glucose and lipid metabolism, did not affect muscle wasting, but drastically suppressed markers of hepatic amino acid catabolism and reversed the illness-induced hypoaminoacidemia.

Conclusions: These data suggest that elevated glucagon availability during critical illness increases hepatic amino acid catabolism, explaining the illness-induced hypoaminoacidemia, without affecting muscle wasting and without a sustained impact on blood glucose. Furthermore, amino acid infusion likely results in a further breakdown of amino acids in the liver, mediated by increased glucagon, without preventing muscle wasting. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201702-0354OCDOI Listing
November 2017

Circulating bile acids predict outcome in critically ill patients.

Ann Intensive Care 2017 Dec 2;7(1):48. Epub 2017 May 2.

Division of Gastroenterology and Hepatology, Department Internal Medicine 3, Medical University of Vienna, Vienna, Austria.

Background: Jaundice and cholestatic hepatic dysfunction are frequent findings in critically ill patients associated with increased mortality. Cholestasis in critically ill patients is closely associated with stimulation of pro-inflammatory cytokines resulting in impaired bile secretion and subsequent accumulation of bile acids. Aim of this study was to evaluate the clinical role of circulating bile acids in critically ill patients.

Methods: Total and individual serum bile acids were assessed via high-performance liquid chromatography in 320 critically ill patients and 19 controls.

Results: Total serum bile acids were threefold higher in septic than cardiogenic shock patients and sixfold higher than in post-surgical patients or controls (p < 0.001). Elevated bile acid levels correlated with severity of illness, renal dysfunction and inflammation (p < 0.05). Total bile acids predicted 28-day mortality independently of sex, age, serum bilirubin and severity of illness (HR 1.041, 95% CI 1.013-1.071, p < 0.005). Best prediction of mortality of total bile acids was seen in patients suffering from septic shock.

Conclusions: Individual and total BAs are elevated by various degrees in different shock conditions. BAs represent an early predictor of short-term survival in a mixed cohort of ICU patients and may serve as marker for early risk stratification in critically ill patients. Future studies should elucidate whether modulation of BA metabolism and signalling influences the clinical course and outcome in critically ill patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13613-017-0272-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413465PMC
December 2017

Proliferation and differentiation of adipose tissue in prolonged lean and obese critically ill patients.

Intensive Care Med Exp 2017 Dec 16;5(1):16. Epub 2017 Mar 16.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.

Background: In prolonged non-obese critically ill patients, preservation of adipose tissue is prioritized over that of the skeletal muscle and coincides with increased adipogenesis. However, we recently demonstrated that in obese critically ill mice, this priority was switched. In the obese, the use of abundantly available adipose tissue-derived energy substrates was preferred and counteracted muscle wasting. These observations suggest that different processes are ongoing in adipose tissue of lean vs. overweight/obese critically ill patients.

Methods: We hypothesize that to preserve adipose tissue mass during critical illness, adipogenesis is increased in prolonged lean critically ill patients, but not in overweight/obese critically ill patients, who enter the ICU with excess adipose tissue. To test this, we studied markers of adipogenesis in subcutaneous and visceral biopsies of matched lean (n = 24) and overweight/obese (n = 24) prolonged critically ill patients. Secondly, to further unravel the underlying mechanism of critical illness-induced adipogenesis, local production of eicosanoid PPARγ agonists was explored, as well as the adipogenic potential of serum from matched lean (n = 20) and overweight/obese (n = 20) critically ill patients.

Results: The number of small adipocytes, PPARγ protein, and CEBPB expression were equally upregulated (p ≤ 0.05) in subcutaneous and visceral adipose tissue biopsies of lean and overweight/obese prolonged critically ill patients. Gene expression of key enzymes involved in eicosanoid production was reduced (COX1, HPGDS, LPGDS, ALOX15, all p ≤ 0.05) or unaltered (COX2, ALOX5) during critical illness, irrespective of obesity. Gene expression of PLA2G2A and ALOX15B was upregulated in lean and overweight/obese patients (p ≤ 0.05), whereas their end products, the PPARγ-activating metabolites 15s-HETE and 9-HODE, were not increased in the adipose tissue. In vitro, serum of lean and overweight/obese prolonged critically ill patients equally stimulated adipocyte proliferation (p ≤ 0.05) and differentiation (lipid accumulation, DLK1, and CEBPB expression, p ≤ 0.05).

Conclusions: Contrary to what was hypothesized, adipogenesis increased independently of initial BMI in prolonged critically ill patients. Not the production of local eicosanoid PPARγ agonists but circulating adipogenic factors seem to be involved in critical illness-induced adipogenesis. Importantly, our findings suggest that abundantly available energy substrates from the adipose tissue, rather than excess adipocytes, can play a beneficial role during critical illness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40635-017-0128-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355396PMC
December 2017

Premorbid obesity, but not nutrition, prevents critical illness-induced muscle wasting and weakness.

J Cachexia Sarcopenia Muscle 2017 Feb 20;8(1):89-101. Epub 2016 Jul 20.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.

Background: The 'obesity paradox' of critical illness refers to better survival with a higher body mass index. We hypothesized that fat mobilized from excess adipose tissue during critical illness provides energy more efficiently than exogenous macronutrients and could prevent lean tissue wasting.

Methods: In lean and premorbidly obese mice, the effect of 5 days of sepsis-induced critical illness on body weight and composition, muscle wasting, and weakness was assessed, each with fasting and parenteral feeding. Also, in lean and overweight/obese prolonged critically ill patients, markers of muscle wasting and weakness were compared.

Results: In mice, sepsis reduced body weight similarly in the lean and obese, but in the obese with more fat loss and less loss of muscle mass, better preservation of myofibre size and muscle force, and less loss of ectopic lipids, irrespective of administered feeding. These differences between lean and obese septic mice coincided with signs of more effective hepatic fatty acid and glycerol metabolism, and ketogenesis in the obese. Also in humans, better preservation of myofibre size and muscle strength was observed in overweight/obese compared with lean prolonged critically ill patients.

Conclusions: During critical illness premorbid obesity, but not nutrition, optimized utilization of stored lipids and attenuated muscle wasting and weakness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcsm.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326828PMC
February 2017