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Purpose: To assess the association between respiratory muscle weakness (RMW) at intensive care unit (ICU) discharge and 5-year mortality and morbidity, independent from confounders including peripheral muscle strength., Methods: Secondary analysis of the prospective 5-year follow-up of the EPaNIC cohort (ClinicalTrials.gov: NCT00512122), limited to 366 patients screened for respiratory and peripheral muscle strength in the ICU with maximal inspiratory pressure (MIP) after removal of the artificial airway, and the Medical Research Council sum score. RMW was defined as an absolute value of MIP <30 cmH 2 O. Associations between RMW at (or closest to) ICU discharge and all-cause 5-year mortality, and key measures of 5-year physical function, comprising respiratory muscle strength (MIP), hand-grip strength (HGF), 6 min walk distance (6MWD) and physical function of the SF-36 quality-of-life questionnaire (PF-SF-36), were assessed with Cox proportional hazards and linear regression models, adjusted for confounders including peripheral muscle strength., Results: RMW was present in 136/366 (37.2%) patients at ICU discharge. RMW was not independently associated with 5-year mortality (HR with 95% CI 1.273 (0.751 to 1.943), p=0.352). Among 156five-year survivors, those with, as compared with those without RMW demonstrated worse physical function (MIP (absolute value, cmH 2 O): 62(42-77) vs 94(78-109), p<0.001; HGF (%pred): 67(44-87) vs 96(68-110), p<0.001; 6MWD (%pred): 87(74-102) vs 99 (80-111), p=0.009; PF-SF-36 (score): 55 (30-80) vs 80 (55-95), p<0.001). Associations between RMW and morbidity endpoints remained significant after adjustment for confounders (effect size with 95% CI: MIP: -23.858 (-32.097 to -15.027), p=0.001; HGF: -18.591 (-30.941 to -5.744), p=0.001; 6MWD (transformed): -1587.007 (-3073.763 to -179.253), p=0.034; PF-SF-36 (transformed): 1.176 (0.144-2.270), p=0.036)., Conclusions: RMW at ICU discharge is independently associated with 5-year morbidity but not 5-year mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

We present areas of uncertainty concerning intensive care unit-acquired weakness (ICUAW) and identify areas for future research. Age, pre-ICU functional and cognitive state, concurrent illness, frailty, and health trajectories impact outcomes and should be assessed to stratify patients. In the ICU, early assessment of limb and diaphragm muscle strength and function using nonvolitional tests may be useful, but comparison with established methods of global and specific muscle strength and physical function and determination of their reliability and normal values would be important to advance these techniques. Serial measurements of limb and respiratory muscle strength, and systematic screening for dysphagia, would be helpful to clarify if and how weakness of these muscle groups is independently associated with outcome. ICUAW, delirium, and sedatives and analgesics may interact with each other, amplifying the effects of each individual factor. Reduced mobility in patients with hypoactive delirium needs investigations into dysfunction of central and peripheral nervous system motor pathways. Interventional nutritional studies should include muscle mass, strength, and physical function as outcomes, and prioritize elucidation of mechanisms. At follow-up, ICU survivors may suffer from prolonged muscle weakness and wasting and other physical impairments, as well as fatigue without demonstrable weakness on examination. Further studies should evaluate the prevalence and severity of fatigue in ICU survivors and define its association with psychiatric disorders, pain, cognitive impairment, and axonal loss. Finally, methodological issues, including accounting for baseline status, handling of missing data, and inclusion of patient-centered outcome measures should be addressed in future studies.

Rationale: Intensive care unit (ICU)-acquired weakness is a frequent complication of critical illness. It is unclear whether it is a marker or mediator of poor outcomes., Objectives: To determine acute outcomes, 1-year mortality, and costs of ICU-acquired weakness among long-stay (≥8 d) ICU patients and to assess the impact of recovery of weakness at ICU discharge., Methods: Data were prospectively collected during a randomized controlled trial. Impact of weakness on outcomes and costs was analyzed with a one-to-one propensity-score-matching for baseline characteristics, illness severity, and risk factor exposure before assessment. Among weak patients, impact of persistent weakness at ICU discharge on risk of death after 1 year was examined with multivariable Cox proportional hazards analysis., Measurements and Main Results: A total of 78.6% were admitted to the surgical ICU; 227 of 415 (55%) long-stay assessable ICU patients were weak; 122 weak patients were matched to 122 not-weak patients. As compared with matched not-weak patients, weak patients had a lower likelihood for live weaning from mechanical ventilation (hazard ratio [HR], 0.709 [0.549-0.888]; P = 0.009), live ICU (HR, 0.698 [0.553-0.861]; P = 0.008) and hospital discharge (HR, 0.680 [0.514-0.871]; P = 0.007). In-hospital costs per patient (+30.5%, +5,443 Euro per patient; P = 0.04) and 1-year mortality (30.6% vs. 17.2%; P = 0.015) were also higher. The 105 of 227 (46%) weak patients not matchable to not-weak patients had even worse prognosis and higher costs. The 1-year risk of death was further increased if weakness persisted and was more severe as compared with recovery of weakness at ICU discharge (P < 0.001)., Conclusions: After careful matching the data suggest that ICU-acquired weakness worsens acute morbidity and increases healthcare-related costs and 1-year mortality. Persistence and severity of weakness at ICU discharge further increased 1-year mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A poor nutritional state and a caloric deficit associate with increased morbidity and mortality, but a recent multicenter, randomized controlled trial found that early parenteral nutrition to supplement insufficient enteral nutrition increases morbidity in the intensive care unit, including prolonging the duration of renal replacement therapy, compared with withholding parenteral nutrition for 1 week. Whether early versus late parenteral nutrition impacts the incidence and recovery of AKI is unknown. Here, we report a prespecified analysis from this trial, the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study. The timing of parenteral nutrition did not affect the incidence of AKI, but early initiation seemed to slow renal recovery in patients with stage 2 AKI. Early parenteral nutrition did not affect the time course of creatinine and creatinine clearance but did increase plasma urea, urea/creatinine ratio, and nitrogen excretion beginning on the first day of amino acid infusion. In the group that received late parenteral nutrition, infusing amino acids after the first week also increased ureagenesis. During the first 2 weeks, ureagenesis resulted in net waste of 63% of the extra nitrogen intake from early parenteral nutrition. In conclusion, early parenteral nutrition does not seem to impact AKI incidence, although it may delay recovery in patients with stage 2 AKI. Substantial catabolism of the extra amino acids, which leads to higher levels of plasma urea, might explain the prolonged duration of renal replacement therapy observed with early parenteral nutrition.

Rationale: Early parenteral nutrition to supplement insufficient enteral feeding during intensive care (early PN) delays recovery as compared with withholding parenteral nutrition for 1 week (late PN)., Objectives: To assess whether deleterious effects of early PN relate to severity of illness or to the dose or type of macronutrients., Methods: Secondary analyses of a randomized controlled trial (EPaNIC; n = 4,640) performed in seven intensive care units from three departments in two Belgian hospitals. In part 1, all patients were included to assess the effect of the randomized allocation to early PN or late PN in subgroups of patients with increasing-on-admission severity of illness. In part 2, observationally, the association of the amount and type of macronutrients with recovery was documented in those patient cohorts still present in intensive care on Days 3, 5, 7, 10, and 14., Measurements and Main Results: The primary end point was time to live discharge from the intensive care unit. For part 1, a secondary end point, acquisition of new infections, was also analyzed. All statistical analyses were performed by univariable and adjusted multivariable methods. In none of the subgroups defined by type or severity of illness was a beneficial effect of early PN observed. The lowest dose of macronutrients was associated with the fastest recovery and any higher dose, administered parenterally or enterally, was associated with progressively more delayed recovery. The amount of proteins/amino acids rather than of glucose appeared to explain delayed recovery with early feeding., Conclusions: Early combined parenteral/enteral nutrition delayed recovery irrespective of severity of critical illness. No dose or type of macronutrient was found to be associated with improved outcome. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

Objective: Muscle weakness often complicates critical illness and is associated with increased risk of morbidity, mortality, and limiting functional outcome even years later. To assess the presence of muscle weakness and to examine the effects of interventions, objective and reliable muscle strength measurements are required. The first objective of this study is to determine interobserver reliability of handheld dynamometry. Secondary objectives are to quantify muscle weakness, to evaluate distribution of muscle weakness, and to evaluate gender-related differences in muscle strength., Design: Cross-sectional observational study., Setting: The surgical and medical intensive care units of a large, tertiary referral, university hospital., Patients: A cross-sectional, randomly selected sample of awake and cooperative critically ill patients., Interventions: None., Measurements and Main Results: Handheld dynamometry was performed in critically ill patients who had at least a score of 3 (movement against gravity) on the Medical Research Council scale. Three upper limb and three lower limb muscle groups were tested at the right-hand side. Patients were tested twice daily by two independent raters. Fifty-one test-retests were performed in 39 critically ill patients. Handheld dynamometry demonstrated good interobserver agreement with intraclass correlation coefficients >0.90 in four of the muscle groups tested (range, 0.91-0.96) and somewhat less for hip flexion (intraclass correlation coefficient, 0.80) and ankle dorsiflexion (intraclass correlation coefficient, 0.76). Limb muscle strength was considerably reduced in all muscle groups as shown by the median z-score (range, -1.08 to -3.48 sd units). Elbow flexors, knee extensors, and ankle dorsiflexors were the most affected muscle groups. Loss of muscle strength was comparable between men and women., Conclusions: Handheld dynamometry is a tool with a very good interobserver reliability to assess limb muscle strength in awake and cooperative critically ill patients. Future studies should focus on the sensitivity of handheld dynamometry in longitudinal studies to evaluate predictive values toward patients' functional outcome.

Intensive-care-unit-acquired weakness is a major complication in critically ill patients. The paper by Hough and coworkers suggests that the current method of manual muscle strength testing with the Medical Research Council sum score is of limited value in the intensive care unit. However, their results raise a number of questions and provide important lessons for implementation of such evaluations in the intensive care unit.

Background: For critically ill patients treated in intensive care units (ICU), two feeding strategies are currently being advocated, one by American/Canadian and the other by European expert guidelines. These guidelines differ particularly in the timing of initiating parenteral nutrition (PN) in patients for whom enteral nutrition (EN) does not reach caloric targets., Methods/design: The EPaNIC trial is an investigator-initiated, non-commercial, multi-center, randomized, controlled, clinical trial with a parallel group design. This study compares early (European guideline) versus late (American/Canadian guideline) initiation of PN when EN fails to reach a caloric target. In the early PN group, PN is initiated within 24-48 hours after ICU admission to complete early enteral nutrition (EN) up to a calculated nutritional target. In the late PN group, PN completing EN is initiated when the target is not reached on day 8. In both groups, the same early EN protocol is applied. The study is designed to compare clinical outcome (morbidity and mortality) in the 2 study arms as well as to address several mechanistical questions. We here describe the EPaNIC study protocol and the statistical analysis plan for the primary report of the clinical results., Discussion: The study has been initiated as planned on august 01 2007. One interim analysis advised continuation of the trial. The study will be completed in February 2011., Trial Registration: ClinicalTrials (NCT): NCT00512122.

Critically ill patients frequently develop muscle weakness due to critical illness-related acute neuropathy and/or myopathy. This is a frequent disorder, with important short-term consequences that include difficulties in weaning from mechanical ventilation, associated prolonged intensive care unit and hospital stay, and increased mortality rates. In addition, many patients continue to suffer from decreased exercise capacity and quality of life for months to years after the acute event. Many different mechanisms seem to be involved in the development of this process. In this review, we will focus on the metabolic aspects of critical illness-related acute neuropathy and/or myopathy and, more specifically, on our clinical experience with achieving strict glycemic control using insulin. Our group has performed two randomized controlled trials in surgical and medical critically ill patients and studied the occurrence of critical illness-related acute neuropathy and/or myopathy and delayed weaning, one of its most important complications. Potential underlying mechanisms derived from experimental studies and from the analysis of biopsy samples harvested from critically ill patients or patients suffering from other catabolic states are discussed.

Introduction: Intensive insulin therapy (IIT) reduced the incidence of critical illness polyneuropathy and/or myopathy (CIP/CIM) and the need for prolonged mechanical ventilation (MV >or= 14 days) in two randomised controlled trials (RCTs) on the effect of IIT in a surgical intensive care unit (SICU) and medical intensive care unit (MICU). In the present study, we investigated whether these effects are also present in daily clinical practice when IIT is implemented outside of a study protocol., Methods: We retrospectively studied electrophysiological data from patients in the SICU and MICU, performed because of clinical weakness and/or weaning failure, before and after routine implementation of IIT. CIP/CIM was diagnosed by abundant spontaneous electrical activity on electromyography. Baseline and outcome variables were compared using Student's t-test, Chi-squared or Mann-Whitney U-test when appropriate. The effect of implementing IIT on CIP/CIM and prolonged MV was assessed using univariate analysis and multivariate logistic regression analysis (MVLR), correcting for baseline and ICU risk factors., Results: IIT significantly lowered mean (+/- standard deviation) blood glucose levels (from 144 +/- 20 to 107 +/- 10 mg/dl, p < 0.0001) and significantly reduced the diagnosis of CIP/CIM in the screened long-stay patients (125/168 (74.4%) to 220/452 (48.7%), p < 0.0001). MVLR identified implementing IIT as an independent protective factor (p < 0.0001, odds ratio (OR): 0.25 (95% confidence interval (CI): 0.14 to 0.43)). MVLR confirmed the independent protective effect of IIT on prolonged MV (p = 0.002, OR:0.40 (95% CI: 0.22-0.72)). This effect was statistically only partially explained by the reduction in CIP/CIM., Conclusions: Implementing IIT in routine daily practice in critically ill patients evoked a similar beneficial effect on neuromuscular function as that observed in two RCTs. IIT significantly improved glycaemic control and significantly and independently reduced the electrophysiological incidence of CIP/CIM. This reduction partially explained the beneficial effect of IIT on prolonged MV.

Objective: Most intensive care deaths beyond the first few days of critical illness are attributable to nonresolving organ failure, either due to or coinciding with sepsis. One of the mechanisms that is thought to contribute to the pathogenesis of organ failure is microvascular thrombosis. Recently, we reported significant improved survival and prevention of organ failure with the use of intensive insulin therapy to maintain normoglycemia for at least several days. We hypothesize that intensive insulin therapy also prevents severe coagulation abnormalities thereby contributing to less organ failure and better survival., Design: This was a preplanned subanalysis of a large randomized controlled study, conducted at a university hospital medical intensive care unit. The intervention was strict blood glucose control to normoglycemia with insulin., Results: Mortality of intensive insulin-treated patients was lower than that of conventionally treated patients for all classes of upon-admission disseminated intravascular coagulation (DIC) scores, except for those patients with overt DIC scores of 6 or higher (for DIC < 5, p = 0.003; for DIC > or = 5, p = 0.4). There was no effect of insulin therapy on any of the fibrinolytic, coagulation, or inflammatory parameters tested., Conclusions: This negative observation does not support a key role for these systems in explaining the clinical benefit of intensive insulin therapy, although a short-lived effect within 5 days of treatment cannot be excluded.

Rationale: Critical illness polyneuropathy/myopathy causes limb and respiratory muscle weakness, prolongs mechanical ventilation, and extends hospitalization of intensive care patients. Besides controlling risk factors, no specific prevention or treatment exists. Recently, intensive insulin therapy prevented critical illness polyneuropathy in a surgical intensive care unit., Objectives: To investigate the impact of intensive insulin therapy on polyneuropathy/myopathy and treatment with prolonged mechanical ventilation in medical patients in the intensive care unit for at least 7 days., Methods: This was a prospectively planned subanalysis of a randomized controlled trial evaluating the effect of intensive insulin versus conventional therapy on morbidity and mortality in critically ill medical patients. All patients who were still in intensive care on Day 7 were screened weekly by electroneuromyography. The effect of intensive insulin therapy on critical illness polyneuropathy/myopathy and the relationship with duration of mechanical ventilation were assessed., Measurements and Main Results: Independent of risk factors, intensive insulin therapy reduced incidence of critical illness polyneuropathy/myopathy (107/212 [50.5%] to 81/208 [38.9%], p = 0.02). Treatment with prolonged (> or = 14 d) mechanical ventilation was reduced from 99 of 212 (46.7%) to 72 of 208 (34.6%) (p = 0.01). This was statistically only partially explained by prevention of critical illness polyneuropathy/myopathy., Conclusion: In a subset of medical patients in the intensive care unit for at least 7 days, enrolled in a randomized controlled trial of intensive insulin therapy, those assigned to intensive insulin therapy had a reduced incidence of critical illness polyneuropathy/myopathy and were treated with prolonged mechanical ventilation less frequently.

Background: Intensive insulin therapy reduces morbidity and mortality in patients in surgical intensive care units (ICUs), but its role in patients in medical ICUs is unknown., Methods: In a prospective, randomized, controlled study of adult patients admitted to our medical ICU, we studied patients who were considered to need intensive care for at least three days. On admission, patients were randomly assigned to strict normalization of blood glucose levels (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) with the use of insulin infusion or to conventional therapy (insulin administered when the blood glucose level exceeded 215 mg per deciliter [12 mmol per liter], with the infusion tapered when the level fell below 180 mg per deciliter [10 mmol per liter]). There was a history of diabetes in 16.9 percent of the patients., Results: In the intention-to-treat analysis of 1200 patients, intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality (40.0 percent in the conventional-treatment group vs. 37.3 percent in the intensive-treatment group, P=0.33). However, morbidity was significantly reduced by the prevention of newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital. Although length of stay in the ICU could not be predicted on admission, among 433 patients who stayed in the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy. In contrast, among 767 patients who stayed in the ICU for three or more days, in-hospital mortality in the 386 who received intensive insulin therapy was reduced from 52.5 to 43.0 percent (P=0.009) and morbidity was also reduced., Conclusions: Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy. Further studies are needed to confirm these preliminary data. (ClinicalTrials.gov number, NCT00115479.), (Copyright 2006 Massachusetts Medical Society.)