Fabian Güiza

Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial

BACKGROUND Patients who are critically ill can develop so-called intensive-care unit acquired weakness, which delays rehabilitation. Reduced muscle mass, quality, or both might have a role. The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) trial (registered with ClinicalTrials.gov, number NCT00512122) showed that tolerating macronutrient deficit for 1 week in intensive-care units (late parenteral nutrition [PN]) accelerated recovery compared with early PN. The role of weakness was unclear. Our aim was to assess whether late PN and early PN differentially affect muscle weakness and autophagic quality control of myofibres. METHODS In this prospectively planned subanalysis of the EPaNIC trial, weakness (MRC sum score) was assessed in 600 awake, cooperative patients. Skeletal muscle biopsies, harvested from 122 patients 8 days after randomisation and from 20 matched healthy controls, were studied for autophagy and atrophy. We determined the significance of differences with Mann-Whitney U, Median, Kruskal-Wallis, or χ(2) (exact) tests, as appropriate. FINDINGS With late PN, 105 (34%) of 305 patients had weakness on first assessment (median day 9 post-randomisation) compared with 127 (43%) of 295 patients given early PN (absolute difference -9%, 95% CI -16 to -1; p=0·030). Weakness recovered faster with late PN than with early PN (p=0·021). Myofibre cross-sectional area was less and density was lower in critically ill patients than in healthy controls, similarly with early PN and late PN. The LC3 (microtubule-associated protein light chain 3) II to LC3I ratio, related to autophagosome formation, was higher in patients given late PN than early PN (p=0·026), reaching values almost double those in the healthy control group (p=0·0016), and coinciding with less ubiquitin staining (p=0·019). A higher LC3II to LC3I ratio was independently associated with less weakness (p=0·047). Expression of mRNA encoding contractile myofibrillary proteins was lower and E3-ligase expression higher in muscle biopsies from patients than in control participants (p≤0·0006), but was unaffected by nutrition. INTERPRETATION Tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness. FUNDING UZ Leuven, Research Foundation-Flanders, the Flemish Government, and the European Research Council.

Insufficient Activation of Autophagy Allows Cellular Damage to Accumulate in Critically Ill Patients

CONTEXT Responses to critical illness, such as excessive inflammation and hyperglycemia, may trigger detrimental chain reactions that damage cellular proteins and organelles. Such responses to illness contribute to the risk of (nonresolving) multiple organ dysfunction and adverse outcome. OBJECTIVE We studied autophagy as a bulk degradation pathway able to remove toxic protein aggregates and damaged organelles and how these are affected by preventing hyperglycemia with insulin during critical illness. DESIGN AND SETTING Patients participated in a randomized study, conducted at a university hospital surgical/medical intensive care unit. PATIENTS We studied adult prolonged critically ill patients vs. controls. INTERVENTIONS Tolerating excessive hyperglycemia was compared with intensive insulin therapy targeting normoglycemia. MAIN OUTCOME MEASURES We quantified (ultra)structural abnormalities and hepatic and skeletal muscle protein levels of key players in autophagy. RESULTS Morphologically, both liver and muscle revealed an autophagy-deficiency phenotype. Proteins involved in initiation and elongation steps of autophagy were induced 1.3- to 6.5-fold by critical illness (P ≤ 0.01), but mature autophagic vacuole formation was 62% impaired (P = 0.05) and proteins normally degraded by autophagy accumulated up to 97-fold (P ≤ 0.03). Mitophagy markers were unaltered or down-regulated (P = 0.05). Although insulin preserved hepatocytic mitochondrial integrity (P = 0.05), it further reduced the number of autophagic vacuoles by 80% (P = 0.05). CONCLUSIONS Insufficient autophagy in prolonged critical illness may cause inadequate removal of damaged proteins and mitochondria. Such incomplete clearance of cellular damage, inflicted by illness and aggravated by hyperglycemia, could explain lack of recovery from organ failure in prolonged critically ill patients. These data open perspectives for therapies that activate autophagy during critical illness.

Early parenteral nutrition evokes a phenotype of autophagy deficiency in liver and skeletal muscle of critically ill rabbits.

Muscular and hepatic abnormalities observed in artificially fed critically ill patients strikingly resemble the phenotype of autophagy-deficient mice. Autophagy is the only pathway to clear damaged organelles and large ubiquitinated proteins and aggregates. Fasting is its strongest physiological trigger. Severity of autophagy deficiency in critically ill patients correlated with the amount of infused amino acids. We hypothesized that impaired autophagy in critically ill patients could partly be evoked by early provision of parenteral nutrition enriched with amino acids in clinically used amounts. In a randomized laboratory investigation, we compared the effect of isocaloric moderate-dose iv feeding with fasting during illness on the previously studied markers of autophagy deficiency in skeletal muscle and liver. Critically ill rabbits were allocated to fasting or to iv nutrition (220 kcal/d, 921 kJ/d) supplemented with 50 kcal/d (209 kJ/d) of either glucose, amino acids, or lipids, while maintaining normoglycemia, and were compared with healthy controls. Fasted critically ill rabbits revealed weight loss and activation of autophagy. Feeding abolished these responses, with most impact of amino acid-enriched nutrition. Accumulation of p62 and ubiquitinated proteins in muscle and liver, indicative of insufficient autophagy, occurred with parenteral feeding enriched with amino acids and lipids. In liver, this was accompanied by fewer autophagosomes, fewer intact mitochondria, suppressed respiratory chain activity, and an increase in markers of liver damage. In muscle, early parenteral nutrition enriched with amino acids or lipids aggravated vacuolization of myofibers. In conclusion, early parenteral nutrition during critical illness evoked a phenotype of autophagy deficiency in liver and skeletal muscle.

Muscle atrophy and preferential loss of myosin in prolonged critically ill patients

Objective:Muscle weakness contributes to prolonged rehabilitation and adverse outcome of critically ill patients. Distinction between a neurogenic and/or myogenic underlying problem is difficult using routine diagnostic tools. Preferential loss of myosin has been suggested to point to a myogenic component. We evaluated markers of muscle atrophy and denervation, and the myosin/actin ratio in limb and abdominal wall skeletal muscle of prolonged critically ill patients and matched controls in relation to insulin therapy and known risk factors for intensive care unit-acquired weakness. Design:Secondary analysis of two large, prospective, single-center randomized clinical studies. Setting:University hospital surgical and medical intensive care unit. Patients:Critically ill patients and matched controls. Interventions:Intensive care unit patients had been randomized to blood glucose control to 80–110 mg/dL with insulin infusion or conventional glucose management, where insulin was only administered when glucose levels rose above 215 mg/dL. Measurements and Main Results:As compared with controls, rectus abdominis and vastus lateralis muscle of critically ill patients showed smaller myofiber size, decreased mRNA levels for myofibrillar proteins, increased proteolytic enzyme activities, and a lower myosin/actin ratio, virtually irrespective of insulin therapy. Increased forkhead box O1 action may have played a role. Most alterations were more severe in patients treated with corticosteroids. Duration of corticosteroid treatment, independent of duration of intensive care unit stay or other risk factors, was a dominant risk factor for a low myosin/actin ratio. The immature acetylcholine receptor subunit &ggr; messenger RNA expression was elevated in vastus lateralis, independent of the myosin/actin ratio. Conclusions:Both limb and abdominal wall skeletal muscles of prolonged critically ill patients showed downregulation of protein synthesis at the gene expression level as well as increased proteolysis. This affected myosin to a greater extent than actin, resulting in a decreased myosin/actin ratio. Muscle atrophy was not ameliorated by intensive insulin therapy, but possibly aggravated by corticosteroids.

Mining data from intensive care patients

In this paper we describe the application of data mining methods for predicting the evolution of patients in an intensive care unit. We discuss the importance of such methods for health care and other application domains of engineering. We argue that this problem is an important but challenging one for the current state of the art data mining methods and explain what improvements on current methods would be useful. We present a promising study on a preliminary data set that demonstrates some of the possibilities in this area.

Impact of early parenteral nutrition on muscle and adipose tissue compartments during critical illness.

Objective:The goal of enhanced nutrition in critically ill patients is to improve outcome by reducing lean tissue wasting. However, such effect has not been proven. This study aimed to assess the effect of early administration of parenteral nutrition on muscle volume and composition by repeated quantitative CT. Design:A preplanned substudy of a randomized controlled trial (Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients [EPaNIC]), which compared early initiation of parenteral nutrition when enteral nutrition was insufficient (early parenteral nutrition) with tolerating a pronounced nutritional deficit for 1 week in ICU (late parenteral nutrition). Late parenteral nutrition prevented infections and accelerated recovery. Setting:University hospital. Patients:Fifteen EPaNIC study neurosurgical patients requiring prescheduled repeated follow-up CT scans and six healthy volunteers matched for age, gender, and body mass index. Intervention:Repeated abdominal and femoral quantitative CT images were obtained in a standardized manner on median ICU day 2 (interquartile range, 2–3) and day 9 (interquartile range, 8–10). Intramuscular, subcutaneous, and visceral fat compartments were delineated manually. Muscle and adipose tissue volume and composition were quantified using standard Hounsfield Unit ranges. Measurements and Main Results:Critical illness evoked substantial loss of femoral muscle volume in 1 week’s time, irrespective of the nutritional regimen. Early parenteral nutrition reduced the quality of the muscle tissue, as reflected by the attenuation, revealing increased intramuscular water/lipid content. Early parenteral nutrition also increased the volume of adipose tissue islets within the femoral muscle compartment. These changes in skeletal muscle quality correlated with caloric intake. In the abdominal muscle compartments, changes were similar, albeit smaller. Femoral and abdominal subcutaneous adipose tissue compartments were unaffected by disease and nutritional strategy. Conclusions:Early parenteral nutrition did not prevent the pronounced wasting of skeletal muscle observed over the first week of critical illness. Furthermore, early parenteral nutrition increased the amount of adipose tissue within the muscle compartments.

Novel methods to predict increased intracranial pressure during intensive care and long-term neurologic outcome after traumatic brain injury: development and validation in a multicenter dataset.

Objective:Intracranial pressure monitoring is standard of care after severe traumatic brain injury. Episodes of increased intracranial pressure are secondary injuries associated with poor outcome. We developed a model to predict increased intracranial pressure episodes 30 mins in advance, by using the dynamic characteristics of continuous intracranial pressure and mean arterial pressure monitoring. In addition, we hypothesized that performance of current models to predict long-term neurologic outcome could be substantially improved by adding dynamic characteristics of continuous intracranial pressure and mean arterial pressure monitoring during the first 24 hrs in the ICU. Design:Prognostic modeling. Noninterventional, observational, retrospective study. Setting and Patients:The Brain Monitoring with Information Technology dataset consisted of 264 traumatic brain injury patients admitted to 22 neuro-ICUs from 11 European countries. Interventions:None. Measurements:Predictive models were built with multivariate logistic regression and Gaussian processes, a machine learning technique. Predictive attributes were Corticosteroid Randomisation After Significant Head Injury-basic and International Mission for Prognosis and Clinical Trial design in TBI-core predictors, together with time-series summary statistics of minute-by-minute mean arterial pressure and intracranial pressure. Main Results:Increased intracranial pressure episodes could be predicted 30 mins ahead with good calibration (Hosmer-Lemeshow p value 0.12, calibration slope 1.02, calibration-in-the-large −0.02) and discrimination (area under the receiver operating curve = 0.87) on an external validation dataset. Models for prediction of poor neurologic outcome at six months (Glasgow Outcome Score 1–2) based only on static admission data had 0.72 area under the receiver operating curve; adding dynamic information of intracranial pressure and mean arterial pressure during the first 24 hrs increased performance to 0.90. Similarly, prediction of Glasgow Outcome Score 1–3 was improved from 0.68 to 0.87 when including dynamic information. Conclusion:The dynamic information in continuous mean arterial pressure and intracranial pressure monitoring allows to accurately predict increased intracranial pressure in the neuro-ICU. Adding information of the first 24 hrs of intracranial pressure and mean arterial pressure monitoring to known baseline risk factors allows very accurate prediction of long-term neurologic outcome at 6 months.

Reduced nocturnal ACTH-driven cortisol secretion during critical illness

Recently, during critical illness, cortisol metabolism was found to be reduced. We hypothesize that such reduced cortisol breakdown may suppress pulsatile ACTH and cortisol secretion via feedback inhibition. To test this hypothesis, nocturnal ACTH and cortisol secretory profiles were constructed by deconvolution analysis from plasma concentration time series in 40 matched critically ill patients and eight healthy controls, excluding diseases or drugs that affect the hypothalamic-pituitary-adrenal axis. Blood was sampled every 10 min between 2100 and 0600 to quantify plasma concentrations of ACTH and (free) cortisol. Approximate entropy, an estimation of process irregularity, cross-approximate entropy, a measure of ACTH-cortisol asynchrony, and ACTH-cortisol dose-response relationships were calculated. Total and free plasma cortisol concentrations were higher at all times in patients than in controls (all P < 0.04). Pulsatile cortisol secretion was 54% lower in patients than in controls (P = 0.005), explained by reduced cortisol burst mass (P = 0.03), whereas cortisol pulse frequency (P = 0.35) and nonpulsatile cortisol secretion (P = 0.80) were unaltered. Pulsatile ACTH secretion was 31% lower in patients than in controls (P = 0.03), again explained by a lower ACTH burst mass (P = 0.02), whereas ACTH pulse frequency (P = 0.50) and nonpulsatile ACTH secretion (P = 0.80) were unchanged. ACTH-cortisol dose response estimates were similar in patients and controls. ACTH and cortisol approximate entropy were higher in patients (P ≤ 0.03), as was ACTH-cortisol cross-approximate entropy (P ≤ 0.001). We conclude that hypercortisolism during critical illness coincided with suppressed pulsatile ACTH and cortisol secretion and a normal ACTH-cortisol dose response. Increased irregularity and asynchrony of the ACTH and cortisol time series supported non-ACTH-dependent mechanisms driving hypercortisolism during critical illness.

Impact of hyperglycemia on neuropathological alterations during critical illness

CONTEXT Although preventing excessive hyperglycemia during critical illness may provide clinical neuroprotection, it remains debated whether normoglycemia is without risk for the brain. OBJECTIVE To address this question, we compared the neuropathological alterations in microglia, astrocytes, and neurons, with uncontrolled hyperglycemia, moderately controlled hyperglycemia, and normoglycemia during human critical illness. We further investigated the time course in an animal model. DESIGN AND SETTING We analyzed brain specimens from patients who died in the intensive care unit and from critically ill rabbits randomized to hyper- or normoglycemia. PATIENTS/OTHER PARTICIPANTS: We compared 10 critically ill patients randomized to normoglycemia (104 ±9 mg/dl) or moderate hyperglycemia (173 ±32 mg/dl), and five patients with uncontrolled hyperglycemia (254 ±83 mg/dl) with 16 controls (out of hospital sudden deaths). Critically ill rabbits were randomized to hyperglycemia (315 ±32 mg/dl) or normoglycemia (85 ±13 mg/dl) and studied after 3 and 7 d. INTERVENTIONS Insulin was infused to control blood glucose. MAIN OUTCOME MEASURES AND RESULTS Patients with uncontrolled hyperglycemia showed 3.7-6-fold increased microglial activation, 54-95% reduced number and activation of astrocytes, more than 9-fold increased neuronal and glial apoptosis, and a 1.5-2-fold increase in damaged neurons in hippocampus and frontal cortex (all P ≤ 0.05). Most of these abnormalities were attenuated with moderate hyperglycemia and virtually absent with normoglycemia. Frontal cortex of hyperglycemic rabbits that had been critically ill for 3 d only revealed microglial activation, followed after 7 d by astrocyte and neuronal abnormalities similar to those observed in patients, all prevented by normoglycemia. CONCLUSIONS Preventing hyperglycemia with insulin during critical illness reduced neuropathological abnormalities, with microglial activation being the earliest preventable event. Whether these pathological findings associate with neurological outcome remains unknown.

Contribution of Nutritional Deficit to the Pathogenesis of the Nonthyroidal Illness Syndrome in Critical Illness: A Rabbit Model Study

Both starvation and critical illness are hallmarked by changes in circulating thyroid hormone parameters with typically low T(3) concentrations in the absence of elevated TSH. This constellation is labeled nonthyroidal illness (NTI). Because critical illness is often accompanied by anorexia and a failing gastrointestinal tract, the NTI of critical illness may be confounded by nutrient deficiency. In an experimental study performed in a rabbit model, we investigated the impact of nutritional deficit on the NTI of sustained critical illness. Critically ill rabbits were randomly allocated to parenteral nutrition (moderate dose 270 kcal/d) initiated on the day after injury and continued until d 7 of illness or to infusing a similar volume of dextrose 1.4% (14 kcal/d). With early parenteral nutrition during illness, the decrease in serum T(3) observed with fasting was reversed, whereas the fall in T(4) was not significantly affected. The rise in T(3) with parenteral nutrition paralleled an increase of liver and kidney type-1 and a decrease of liver and kidney type-3 deiodinase activity and an increase in circulating and central leptin. Nuclear staining of constitutive androstane receptor and its downstream expression of sulfotransferases were reduced in fasting ill animals. TRH expression in the hypothalamus was not different in fasted and fed ill rabbits, although circulating TSH levels were higher with feeding. In conclusion, in this rabbit model of sustained critical illness, reduced circulating T(3), but not T(4), levels could be prevented by parenteral nutrition, which may be mediated by leptin and its actions on tissue deiodinase activity.