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Exploration of muscle loss and metabolic state during prolonged critical illness: Implications for intervention?

ABSTRACT: BACKGROUND:Muscle wasting in the critically ill is up to 2% per day and delays patient recovery and rehabilitation. It is linked to inflammation, organ failure and severity of illness. The aims of this study were to understand the relationship between muscle depth loss, and nutritional and inflammatory markers during prolonged critical illness. Secondly, to identify when during critical illness catabolism might decrease, such that targeted nutritional strategies may logically be initiated. METHODS:This study was conducted in adult intensive care units in two large teaching hospitals. Patients anticipated to be ventilated for >48 hours were included. Serum C-reactive protein (mg/L), urinary urea (mmol/24h), 3-methylhistidine (?mol/24h) and nitrogen balance (g/24h) were measured on days 1, 3, 7 and 14 of the study. Muscle depth (cm) on ultrasound were measured on the same days over the bicep (bicep and brachialis muscle), forearm (flexor compartment of muscle) and thigh (rectus femoris and vastus intermedius). RESULTS:Seventy-eight critically ill patients were included with mean age of 59 years (SD: 16) and median Intensive care unit (ICU) length of stay of 10 days (IQR: 6-16). Starting muscle depth, 8.5cm (SD: 3.2) to end muscle depth, 6.8cm (SD: 2.2) were on average significantly different over 14 days, with mean difference -1.67cm (95%CI: -2.3 to -1cm), p<0.0001. Protein breakdown and inflammation continued over 14 days of the study. CONCLUSION:Our patients demonstrated a continuous muscle depth loss and negative nitrogen balance over the 14 days of the study. Catabolism remained dominant throughout the study period. No obvious 'nutritional tipping point" to identify anabolism or recovery could be identified in our cohort. Our ICU patient cohort is one with a moderately prolonged stay. This group showed little consistency in data, reflecting the individuality of both disease and response. The data are consistent with a conclusion that a time based assumption of a tipping point does not exist. TRIAL REGISTRATION:International Standard Randomised Controlled Trial Number: ISRCTN79066838. Registration 25 July 2012.

SUBMITTER: Wandrag L

PROVIDER: S-EPMC6855435 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Exploration of muscle loss and metabolic state during prolonged critical illness: Implications for intervention?

Wandrag Liesl L Brett Stephen J SJ Frost Gary S GS Bountziouka Vasiliki V Hickson Mary M

PloS one 20191114 11

<h4>Background</h4>Muscle wasting in the critically ill is up to 2% per day and delays patient recovery and rehabilitation. It is linked to inflammation, organ failure and severity of illness. The aims of this study were to understand the relationship between muscle depth loss, and nutritional and inflammatory markers during prolonged critical illness. Secondly, to identify when during critical illness catabolism might decrease, such that targeted nutritional strategies may logically be initiate ...[more]

PMID: 31725748

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Project description:IntroductionCritical illness polyneuromyopathy (CIPNM) is a common complication of critical illness presenting with muscle weakness and is associated with increased duration of mechanical ventilation and weaning period. No preventive tool and no specific treatment have been proposed so far for CIPNM. Electrical muscle stimulation (EMS) has been shown to be beneficial in patients with severe chronic heart failure and chronic obstructive pulmonary disease. Aim of our study was to assess the efficacy of EMS in preventing CIPNM in critically ill patients.MethodsOne hundred and forty consecutive critically ill patients with an APACHE II score >or= 13 were randomly assigned after stratification to the EMS group (n = 68) (age:61 +/- 19 years) (APACHE II:18 +/- 4, SOFA:9 +/- 3) or to the control group (n = 72) (age:58 +/- 18 years) (APACHE II:18 +/- 5, SOFA:9 +/- 3). Patients of the EMS group received daily EMS sessions. CIPNM was diagnosed clinically with the medical research council (MRC) scale for muscle strength (maximum score 60, <48/60 cut off for diagnosis) by two unblinded independent investigators. Duration of weaning from mechanical ventilation and intensive care unit (ICU) stay were recorded.ResultsFifty two patients could be finally evaluated with MRC; 24 in the EMS group and 28 in the control group. CIPNM was diagnosed in 3 patients in the EMS group as compared to 11 patients in the control group (OR = 0.22; CI: 0.05 to 0.92, P = 0.04). The MRC score was significantly higher in patients of the EMS group as compared to the control group [58 (33 to 60) vs. 52 (2 to 60) respectively, median (range), P = 0.04). The weaning period was statistically significantly shorter in patients of the EMS group vs. the control group [1 (0 to 10) days vs. 3 (0 to 44) days, respectively, median (range), P = 0.003].ConclusionsThis study suggests that daily EMS sessions prevent the development of CIPNM in critically ill patients and also result in shorter duration of weaning. Further studies should evaluate which patients benefit more from EMS and explore the EMS characteristics most appropriate for preventing CIPNM.Trial registration numberClinicalTrials.gov NCT00882830.

Project description:ObjectivesProlonged critical illness after congenital heart surgery disproportionately harms patients and the healthcare system, yet much remains unknown. We aimed to define prolonged critical illness, delineate between nonmodifiable and potentially preventable predictors of prolonged critical illness and prolonged critical illness mortality, and understand the interhospital variation in prolonged critical illness.DesignObservational analysis.SettingPediatric Cardiac Critical Care Consortium clinical registry.PatientsAll patients, stratified into neonates (≤28 d) and nonneonates (29 d to 18 yr), admitted to the pediatric cardiac ICU after congenital heart surgery at Pediatric Cardiac Critical Care Consortium hospitals.InterventionsNone.Measurements and main resultsThere were 2,419 neonates and 10,687 nonneonates from 22 hospitals. The prolonged critical illness cutoff (90th percentile length of stay) was greater than or equal to 35 and greater than or equal to 10 days for neonates and nonneonates, respectively. Cardiac ICU prolonged critical illness mortality was 24% in neonates and 8% in nonneonates (vs 5% and 0.4%, respectively, in nonprolonged critical illness patients). Multivariable logistic regression identified 10 neonatal and 19 nonneonatal prolonged critical illness predictors within strata and eight predictors of mortality. Only mechanical ventilation days and acute renal failure requiring renal replacement therapy predicted prolonged critical illness and prolonged critical illness mortality in both strata. Approximately 40% of the prolonged critical illness predictors were nonmodifiable (preoperative/patient and operative factors), whereas only one of eight prolonged critical illness mortality predictors was nonmodifiable. The remainders were potentially preventable (postoperative critical care delivery variables and complications). Case-mix-adjusted prolonged critical illness rates were compared across hospitals; six hospitals each had lower- and higher-than-expected prolonged critical illness frequency.ConclusionsAlthough many prolonged critical illness predictors are nonmodifiable, we identified several predictors to target for improvement. Furthermore, we observed that complications and prolonged critical care therapy drive prolonged critical illness mortality. Wide variation of prolonged critical illness frequency suggests that identifying practices at hospitals with lower-than-expected prolonged critical illness could lead to broader quality improvement initiatives.

Project description:PurposeFor 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.MethodsPatients 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.ResultsIn 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.ConclusionsIrrespective 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.

Project description:BackgroundThe number of patients with prolonged critical illness (PCI) has been increasing in many countries, and the adrenal gland plays an important role in maintaining homeostasis during PCI. Chronic disease burden is reportedly associated with shorter telomere lengths in human tissues. Telomere shortening in human somatic cells is largely dependent on cell divisions, and critically short telomeres lead to cellular dysfunction and aging. However, the association between PCI and telomere lengths in human adrenal cells is poorly understood. In this study, we investigated this association to assess whether the burden of PCI could accelerate the aging process in adrenal cells.MethodsAdrenocortical tissues from patients who died after PCI usually show a diffuse pattern of intracellular cholesterol ester depletion (i.e., lipid depletion). This study examined near-normal adrenal glands obtained from autopsied patients who died suddenly (control group) and lipid-depleted adrenal glands obtained from autopsied patients who died after PCI (PCI group). The control group included 7 men aged 80 to 94 years (mean age: 85.3 years) and 7 women aged 84 to 94 years (mean age: 87.7 years). The PCI group included 10 men aged 71 to 88 years (mean age: 78.8 years) and 8 women aged 77 to 95 years (mean age: 85.6 years). By using quantitative fluorescence in situ hybridization, relative telomere lengths (RTLs) were determined in the parenchymal cells of the three adrenocortical zones (zona glomerulosa, zona fasciculata, and zona reticularis [ZR]) and in the chromaffin cells of the medulla. The number of adrenal parenchymal cells was determined by immunohistochemistry and digital image analysis.ResultsRTLs in ZR cells were significantly shorter in the PCI group than in the control group for both men and women (P = 0.0001 for men and P = 0.0012 for women). However, RTLs in the remaining three types of adrenal cells did not differ between the control and PCI groups for both men and women. The number of ZR cells was higher in the PCI group than in the control group for both men and women (P < 0.0001 for both men and women). The proportion of the number of ZR cells to the total number of adrenocortical parenchymal cells was also higher in the PCI group than in the control group (P < 0.0001 for both men and women). The Ki-67 proliferation index in ZR cells was higher in the PCI group than in the control group (P = 0.0039 for men and P = 0.0063 for women).ConclusionsThis study demonstrated ZR cell-specific telomere shortening in patients with adrenal lipid depletion who died after PCI. Our results suggest that the reactive proliferation of ZR cells accelerates the telomere shortening and aging process in ZR cells in these patients. The results of our study may contribute to the understanding of adrenal aging during PCI.

Project description:BackgroundCritical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a by-product of critical care, attributed to impaired recovery, long-term complications, and mortality. CIM pathophysiology is complex, heterogeneous and remains incompletely understood; however, loss of mechanical stimuli contributes to critical illness-associated muscle atrophy and weakness. Passive mechanical loading and electrical stimulation (ES) therapies augment muscle mass and function. While having beneficial outcomes, the mechanistic underpinning of these therapies is less known. Therefore, here we aimed to assess the mechanism by which chronic supramaximal ES ameliorates CIM in a unique experimental rat model of critical care.MethodsRats were subjected to 8 days of critical care conditions entailing deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES. Muscle size and function were assessed at the single cell level. RNAseq and western blotting were employed to understand the mechanisms driving ES muscle outcomes in CIM.ResultsFollowing 8 days of controlled mechanical ventilation and immobilization, soleus muscle mass, myosin : actin ratio, and single muscle fibre maximum force normalized to cross-sectional area (CSA; specific force) were reduced by 40-50% (P < 0.0001). ES significantly reduced the loss of soleus muscle fibre CSA and myosin : actin ratio by approximately 30% (P < 0.05) yet failed to effect specific force. RNAseq pathway analysis revealed downregulation of insulin signalling in the soleus muscle following critical care, and GLUT4 trafficking was reduced by 55% leading to an 85% reduction of muscle glycogen content (P < 0.01). ES promoted phosphofructokinase and insulin signalling pathways to control levels (P < 0.05), consistent with the maintenance of GLUT4 translocation and glycogen levels. AMPK, but not AKT, signalling pathway was stimulated following ES, where the downstream target TBC1D4 increased 3 logFC (P = 0.029) and AMPK-specific P-TBC1D4 levels were increased approximately two-fold (P = 0.06). Reduction of muscle protein degradation rather than increased synthesis promoted soleus CSA, as ES reduced E3 ubiquitin proteins, Atrogin-1 (P = 0.006) and MuRF1 (P = 0.08) by approximately 50%, downstream of AMPK-FoxO3.ConclusionsES maintained GLUT4 translocation through increased AMPK-TBC1D4 signalling leading to improved muscle glucose homeostasis. Soleus CSA and myosin content was promoted through reduced protein degradation via AMPK-FoxO3 E3 ligases, Atrogin-1 and MuRF1. These results demonstrate chronic supramaximal ES reduces critical care associated muscle wasting, preserved glucose signalling, and reduced muscle protein degradation in CIM.

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Exploration of muscle loss and metabolic state during prolonged critical illness: Implications for intervention?

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Exploration of muscle loss and metabolic state during prolonged critical illness: Implications for intervention?

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