Abstract

Muscle weakness is common in the surgical intensive care unit (ICU). Low muscle mass at ICU admission is a significant predictor of adverse outcomes. The consequences of ICU-acquired muscle weakness depend on the underlying mechanism. Temporary drug-induced weakness when properly managed may not affect outcome. Severe perioperative acquired weakness that is associated with adverse outcomes (prolonged mechanical ventilation, increases in ICU length of stay, and mortality) occurs with persistent (time frame: days) activation of protein degradation pathways, decreases in the drive to the skeletal muscle, and impaired muscular homeostasis. ICU-acquired muscle weakness can be prevented by early treatment of the underlying disease, goal-directed therapy, restrictive use of immobilizing medications, optimal nutrition, activating ventilatory modes, early rehabilitation, and preventive drug therapy. In this article, the authors review the nosology, epidemiology, diagnosis, and prevention of ICU-acquired weakness in surgical ICU patients.

Abstract

Muscle weakness is a common complication in the surgical intensive care unit. This complication is preventable. Early identification with the appropriate diagnostic methods and employment of preventative strategies can improve perioperative patient outcomes.

Muscle weakness occurs as frequently as low arterial blood pressure in the surgical intensive care unit (SICU).1–3  The incidence of sarcopenia (low skeletal muscle mass) in the intensive care unit (ICU) can be as high as 70%,4  depending on the age, presentation, and comorbidities of the patient, and preexsiting sarcopenia predicts adverse discharge disposition.5  Muscle mass decreases by approximately 2% per day as a consequence of patients’ acute disease and their ICU treatment.6–9 

The current interest in surgical ICU-acquired weakness (ICUAW) is because of the associated significant and potentially long-term adverse outcomes for patients as well as the substantial costs involved in caring for this complication and its consequences. Associated adverse outcomes include joint contractures, thromboembolic disease, insulin resistance, microvascular dysfunction, pressure ulcers, respiratory complications (atelectasis, pneumonia, weaning failure), and delirium, translating into increased ICU and hospital length of stay, impaired functional status and neuropsychologic impairment that can persist for up to and over a year after surgery, increased readmission rate, and mortality.10–20 

In this article, we review the nosology, epidemiology, diagnosis, and prevention of ICUAW in surgical ICU patients. We also highlight the potential for drug targets and gene therapy in the prevention of ICUAW.

Nosology: Classification of Diseases Related to Skeletal Muscle Weakness

Muscle weakness is difficult to reliably quantify—small differences in the clinical testing procedure lead to meaningful differences in results. In addition, ICU healthcare providers of different professions may have different beliefs regarding what constitutes a “weak patient,” and based on the nosologic misunderstandings, their management of the weak patient can vary widely.21  Precise use of the terminology will help better synchronize efforts of scientists, physicians, nurses, and physical therapists to eliminate ICU-acquired muscle weakness.

Sarcopenia (derived from Greek word σάρξ sarx meaning “flesh” and πενία penia meaning “poverty”) is the loss of skeletal muscle mass, which can be reliably quantified by muscle ultrasound in the ICU even in unconscious patients.5  Sarcopenia is a component of frailty, which is the status of decreased physical and cognitive reserve leading to an increased vulnerability to stressors. A diagnosis of frailty can be made by using validated instruments such as interviewing the patient regarding their baseline functional status with questions.5  Furthermore, assessment of mobility, muscle mass, nutritional status, strength, and endurance are all valid identifiers of clinically weak patients. Dynapenia is the frailty-associated loss of muscle strength that is not caused by neurologic or muscular diseases.

Muscle strength is defined as the amount of force that a muscle, or a group of muscles, can produce to overcome resistance with a single maximal effort.22  Several factors impact the amount of force generated, such as neural drive to the skeletal muscles, the number and size of muscle fibers, number and functionality of acetylcholine receptors, muscle length at the time of stimulation, and frequency of stimulation.22  The ability of a muscle to overcome resistance repetitively is called endurance. The main determinants of endurance are the maximal oxygen uptake and the rate of glycogen depletion.23  Lack of endurance promotes a reduction in the exercise-induced capacity to generate force over time,24  which is known as muscle fatigue. Muscle fatigue can be classified, based on the evoked response to repeated muscle stimulation, into two types: (1) low-frequency fatigue (relative loss of force at low frequencies of stimulation and a slow recovery over the course of hours or even days) and (2) high-frequency fatigue (excessive loss of force at high frequencies of stimulation and rapid recovery when the frequency is reduced).25  Fatigue and deficits in endurance impair muscle performance leading to lack of muscle strength or dynapenia.

The term ICUAW typically describes the bilateral and symmetrical neuromuscular sequelae of critical illness, which occurs during the ICU stay and not related to another specific etiology.26  ICUAW can be recognized through clinical manifestations such as difficult weaning from mechanical ventilation, flaccid tetraparesis or tetraplegia, hyporeflexia, and muscular atrophy,27  which affects limb, respiratory, and pharyngeal muscles.28 

Epidemiology of Postoperative Muscle Weakness

Many patients develop transient muscle weakness after surgery as a consequence of residual neuromuscular blockade, opioid therapy, or inflammation.29,30  The surgical site, the type of surgical technique (e.g., open vs. laparoscopic), and the pharmacokinetics of anesthetics and neuromuscular-blocking agents (NMBAs) determine the magnitude and the duration of postoperative muscle weakness. Open abdominal and thoracic surgical interventions are associated with prolonged impairment in respiratory function and an increased risk of postoperative complications.31  These complications can result in postoperative mechanical ventilation being required for longer than 24 h,32,33  which further increases the risk of muscle weakness and diaphragmatic atrophy.34  Conversely, laparoscopic surgeries are associated with a faster recovery of grip strength and inspiratory force as early as 2 to 3 h after emergence from anesthesia.31 

Severe muscle weakness can persist for over a year after surgery.14,35  The incidence of persistent weakness at 1 yr has been found to be around 20 to 30% for localized procedures such as modified radical mastectomy14  and knee arthroplasty35  and as high as 80% in patients after liver and renal transplants.11  Predisposing factors to long-term ICUAW include surgeries requiring long periods of postoperative bed rest or medical conditions that result in immobilization (e.g., obesity, medical devices).36  Other factors associated with persistent muscle weakness include older age, dementia, cancer diagnoses, malnutrition, social isolation, and preexisting functional immobility.37 

Table 1 summarizes incidences reported in 10 studies, distinguishing between medical and surgical/trauma settings.1,3,6,10,38–43  Most data derived from research in medical ICUs report an estimated ICUAW incidence of 25 to 31%. In the surgical ICU, 56 to 74% of patients acquire muscle weakness.3,6  The higher incidence in the surgical ICU compared with the medical ICU is believed to be a consequence of pain, surgical muscle trauma, posttraumatic inflammation, and the lingering effects of anesthetics and NMBAs.44 

Table 1.

Diagnostic Criteria and Incidence of ICU Muscle Weakness in Medical and Surgical ICUs

Diagnostic Criteria and Incidence of ICU Muscle Weakness in Medical and Surgical ICUs
Diagnostic Criteria and Incidence of ICU Muscle Weakness in Medical and Surgical ICUs

Etiology and Mechanisms of Muscle Weakness Acquired in the Surgical Intensive Care Unit

ICUAW is typically a symmetric disease that can be induced by different mechanisms. The resulting weakness may be either transitory or long lasting (fig. 1). Critical illness polyneuropathy (CIP) is an acute axonal sensorimotor polyneuropathy45  characterized by a reduction in the amplitudes of compound muscle action potentials and sensory nerve action potentials, with normal nerve conduction velocity.8,46  Clinical signs, sensory signs in particular, are often unreliable in the acute stages of critical illness to clearly identify this condition. Therefore, electrophysiologic tests remain the definitive-standard tool for diagnosis of CIP.47  CIP is most commonly associated with severe sepsis.15  The incidence of CIP in patients with multiorgan failure is almost five times higher than in patients without multiorgan failure.48 

Fig. 1.

Mechanisms of ICUAW can be subclassified into two main groups: ICUAW with electrophysiologic and histopathologic findings (CIP and CIM) and ICUAW with normal diagnostic studies. Muscle weakness in the ICU with normal electromyogram findings can be caused by many factors that produce a direct impairment of the muscle cell without necessarily affecting the neurogenic output. Activation of protein degradation with the ubiquitin–proteasome pathway, inflammatory mediators, and inactivity decrease muscle size and produce atrophy. Electrolyte and acid–base imbalances produce trophic effects and functional impairment of the muscle cell. Medications and delirium affect mental status and decrease cortical arousal promoting long periods of inactivity and muscle weakness. CIM = critical illness myopathy; CINM = critical illness neuromyopathy; CIP = critical illness polyneuropathy; CMAP = compound muscle action potential; ICU = intensive care unit; ICUAW = ICU–acquired weakness; IL = interleukin; IFN = interferon; NMBA = neuromuscular-blocking agent; TNF = tumor necrosis factor; SNAP = sensory nerve action potential.

Fig. 1.

Mechanisms of ICUAW can be subclassified into two main groups: ICUAW with electrophysiologic and histopathologic findings (CIP and CIM) and ICUAW with normal diagnostic studies. Muscle weakness in the ICU with normal electromyogram findings can be caused by many factors that produce a direct impairment of the muscle cell without necessarily affecting the neurogenic output. Activation of protein degradation with the ubiquitin–proteasome pathway, inflammatory mediators, and inactivity decrease muscle size and produce atrophy. Electrolyte and acid–base imbalances produce trophic effects and functional impairment of the muscle cell. Medications and delirium affect mental status and decrease cortical arousal promoting long periods of inactivity and muscle weakness. CIM = critical illness myopathy; CINM = critical illness neuromyopathy; CIP = critical illness polyneuropathy; CMAP = compound muscle action potential; ICU = intensive care unit; ICUAW = ICU–acquired weakness; IL = interleukin; IFN = interferon; NMBA = neuromuscular-blocking agent; TNF = tumor necrosis factor; SNAP = sensory nerve action potential.

Critical illness myopathy (CIM) is an acute primary myopathy not secondary to muscle denervation, with characteristic electrophysiologic and histologic features. Electrophysiologic studies typically report short duration, low-amplitude compound muscle action potentials with normal sensory nerve action potentials.8,49  The definitive-standard test for CIM is muscle biopsy that further subclassifies this entity into cachectic myopathy, thick filament myopathy, and necrotizing myopathy.8  The thick filament myopathy with loss of myosin filament can be a very early event occurring in the initial stage of critical illness.50 

CIM is generalized and involves both limb and respiratory muscles, causing muscle weakness and paralysis, which are both clinically indistinguishable from that caused by CIP. Moreover, CIP and CIM can coexist,51  a condition that has been called critical illness neuromyopathy (CINM).

Transitory Reductions in Muscle Strength

Transitory impairment of muscle strength occurs regularly in the perioperative period as a consequence of attempts of the anesthesiologist to improve surgical conditions. Anesthesia affects respiratory arousal through an impairment of diaphragmatic and upper airway muscle function along with an inability to protect the airway.52,53  Respiratory arousal is defined as the arousal from sleep and other drug-induced or endogenous alterations of the mental status because of cumulative and progressive increases in stimuli related to breathing.54  These stimuli are regulated by chemoreceptors that respond to changes in the partial pressures of oxygen and carbon dioxide,55  sensors in the upper airway responsive to negative pressure generated by the respiratory pump,56  and neural drive through cortical stimulation.57  During the perioperative period, respiratory arousal is dampened by sedation, anesthesia, opioids, and endogenous impairment of consciousness. Consequently, the total level of stimulation to respiratory muscles decreases, and the upper airway is more vulnerable to collapse and respiratory failure.54  Upper airway muscles are generally more affected by sleep, anesthetics, and sedatives than respiratory pump muscles.54 

Neuromuscular-blocking Agents, Anesthetics, and Opioids

In the surgical ICU, NMBAs are given to patients with increased intracranial pressure58  and are also used to reduce stress and strain on the lung in patients with severe acute respiratory distress syndrome (ARDS).59  The use of NMBAs in the ICU is associated with higher rates of delirium (67 to 73%),60  prolonged muscle weakness, and myopathy.29,33  The lingering effects of NMBAs after surgery can also result in residual neuromuscular blockade, which delays recovery from both anesthesia and surgery.29,30  Postoperative residual paralysis prolongs the impairment in function of respiratory and peripheral muscles61  and transiently increases the incidence and severity of symptoms of muscle weakness62  but does not increase the incidence of ICUAW as long as the NMBA is no longer given postoperatively in the ICU.

Continuous administration of NMBAs has similar effects on muscle physiology as denervation,63,64  which increases the risk of muscle atrophy (fig. 1). Mechanical ventilation is nearly universally accompanied by the administration of large doses of anesthetics65  that further increase the incidence of ICU-acquired delirium and weakness, especially in older surgical patients.39,66  Furthermore, patients with sepsis are particularly vulnerable to the weakness inducing effects of NMBAs. Sepsis itself is an independent predictor of CINM.67 

Prolonged use of aminosteroidal NMBAs can result in muscle weakness that lasts for up to 7 days after termination of administration.68  Preclinical data also indicate that aminosteroidal NMBAs can worsen ventilator-induced diaphragmatic injury.69  This may exacerbate weaning-related concerns in those with neurologic compromise.

Despite the negative outcomes associated with NMBA administration, it is important to consider that short-term infusion of NMBAs may facilitate protective mechanical ventilator treatment in patients with severe ARDS, without necessarily increasing the risk of ICUAW.41  Thus, short-term use of NMBAs may be considered as a lung-protective adjuvant in early ARDS if sedatives and opioids do not allow control of the excessive respiratory drive.67 

Procedural pain (e.g., extubation, chest tube insertion or removal, wound drain removal, and arterial or central venous line insertion) is common in the SICU and requires further analgesic interventions.35,70,71  Opioid analgesics are of particular importance to this discussion, because they are known to cause respiratory depression and can impair ventilation because of their effects on the respiratory muscles. Studies have shown that opioids increase pulmonary resistance via cholinergic effects on the smooth muscle,72  reduce chest wall compliance, and reduce phrenic nerve and diaphragmatic muscle activity.73–75  Together these effects reduce minute ventilation.76  This is not to say that opioids should not be used. Although opioids contribute to the development of muscle weakness, conversely, optimal pain management can improve pulmonary function,77  as severe postoperative pain results in shallow breathing, atelectasis, and delayed early mobilization of the patient.78  Thus, the authors advocate judicious use of opioid titrated to effect and regular review of the necessity for continued prescription in the interest of improving patient outcomes in the SICU.

Other Mechanisms of Transient Muscle Weakness in the ICU

Figure 1 shows additional factors known to contribute to transitory muscle weakness, including inflammatory mediators,79  delirium,80  electrolytes disorders (hypermagnesemia, hypokalemia, hypercalcemia, hypophosphatemia), and endocrine dysfunction.81–83  Hyperkalemia occurs frequently with rhabdomyolysis, propofol infusion syndrome, hyperthermic malignant syndromes, succinylcholine administration, and renal failure.84,85  Other electrolyte disorders such as hypophosphatemia with hypomagnesemia are also common with refeeding syndrome in a previously malnourished patient.86,87 

Endocrine abnormalities such as thyrotoxic periodic paralysis can cause paralysis associated with hypokalemia in absence of a deficit in total body potassium. The prevalence is low among Caucasians (0.1 to 0.2%), but 10 times greater in those of Asian origin.81  It is sporadic in 95% of cases and mainly associated not only with autoimmune thyrotoxicosis (Graves disease) but also with thyroid stimulating hormone–secreting pituitary tumors, amiodarone-induced thyrotoxicosis, lymphocytic thyroiditis, etc.81  In fact, any cause of thyrotoxicosis, including excessive thyroid hormone replacement therapy, can trigger paralysis in susceptible patients. Metabolic disorders such as acute intermittent porphyria can cause peripheral neuropathy, mostly motor in nature and resembling Guillain–Barré syndrome.88  Acute intermittent porphyria presents with severe abdominal pain, nausea, vomiting, constipation, and symptoms of ileus mimicking a surgical emergency.88  It can be triggered by exposure to porphyrinogenic drugs such as ketamine, thiopental, clonidine, propafenone, carbamazepine, phenytoin, clonazepam, ketorolac, quetiapine, fluconazole, clindamycin, and amiodarone.88 

Clinically Significant Muscle Weakness Leading to Impaired Functional Independence

There is a grey zone between temporary and persistent muscle weakness: long-term exposure to evoked temporary muscle weakness in the ICU translates to clinically meaningful ICUAW.

Mechanical Unloading

In the surgical ICU, mechanical and/or pharmacologic unloading refers to the reduction in physical activity of the peripheral skeletal, postural, and respiratory muscles as a result of bed rest, joint immobilization, limb suspension, microgravity, and mechanical ventilation.89  Mechanical unloading together with reduced neural activation result in the skeletal muscle wasting otherwise known as disuse.89,90  The loss of muscle mass and fiber cross-sectional area is well documented in both rodent and human models of mechanical unloading.90  The rate and extent of muscle loss seem to be dependent on both the muscle type and the degree of inactivity. In rodent models of hind limb immobilization, for example, muscle loss is generally greater in the extensor muscles of the ankle (soleus and gastrocnemius).91,92  This pattern of muscle loss is also seen in humans with lower limb immobilization after ankle fracture.93  Furthermore, in humans, there is a preferential loss of type I muscle fibers,94,95  the muscle type most used in activities of daily living, a finding particularly relevant when considering functional independence outcomes after ICU stay. This pattern may be exacerbated among those with central neurologic injury.96  A disruption to the equilibrium of protein synthesis and degradation underlies the pathophysiology of disuse atrophy resulting in a net loss of muscle protein.

Impairment of Protein Synthesis

Although there is evidence from human studies demonstrating that the basal rate of protein synthesis begins to decrease in the immediate period after disuse,97,98  the cellular mechanisms responsible for this reduction in protein synthesis are poorly understood.90  As such, several immobilization-associated pathways (glycogen synthase kinase-3β activity, the elongation factor 2 pathway, and ribosome biogenesis)90,99  are currently being explored in the context of ICUAW with limited investigation.

It is important to stress that the overall contribution of decreased protein synthesis on muscle atrophy in mechanical unloading is minimal, and reduced protein synthesis alone is generally considered to be an inadequate explanation for the mechanism of atrophy. In an excellent review of this topic, Sandri100  explains that the size of a postmitotic cell stems from a balance between protein synthesis and degradation and that a reduction in protein synthesis cannot be considered to be the sole mechanism behind muscle atrophy. Under conditions of protein synthesis inhibition, the total protein content of the cell is affected by protein half-life, which itself is dependent on basal protein degradation rates. Thus, in circumstances of reduced protein synthesis, which critically ill patients commonly experience,101  muscle cell size ultimately depends on proteolysis more than it does under conditions of normal protein synthesis.100  In early systemic inflammation, for example, the proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon-γ, and interleukin (IL)-1 increase ubiquitin gene transcripts and thus enhance skeletal muscle catabolism.102 

Promotion of Proteolysis

Activation of several proteolytic mechanisms occurs with mechanical unloading and as a consequence of critical illness as described in figure 1. Taken together, these processes complementarily lead to the breakdown of muscle proteins that leads to significant muscle atrophy in as little as 2 to 5 days after unloading.34,89,103 

The most prominent of these degenerative pathways is the ubiquitin–proteasome system (UPS).89,90  The changes in muscle activity stimulate the UPS system to remove sarcomeric proteins. Muscle disuse increases the expression of key gene products that regulate this pathway. Muscle atrophy occurs as a result of increased conjugation of ubiquitin to muscle proteins, increased proteasomal adenosine triphosphate–dependent activity, increased proteolysis, and up-regulation of transcripts encoding key components of the UPS pathway (e.g., ubiquitin, ubiquitin-ligases and proteasome subunits).100,104  MAFbx/atrogin1 and MuRF1 are two E3 ligases that are of particular interest, because they are up-regulated in all conditions of muscle wasting, including disuse atrophy.105  An increased expression of these gene products has been demonstrated in the diaphragms of mechanically ventilated rodents and humans106–108  and in the limb muscles of humans after bed rest, lower limb suspension, or knee immobilization.103,109–112  As expected, up-regulation of components of the ubiquitin pathway leads to increased conjugation between ubiquitin and muscle proteins in humans. This coupled with the finding that mechanical unloading increases the proteolytic activity of the 20S- and 26S-proteasome complexes results in an increased breakdown of ubiquitin-conjugated proteins.106,108,110  Furthermore, muscle proteases are activated under disuse conditions. In 2008, Levine et al.113  first discovered that caspase-3 mRNA expression is increased in human diaphragm muscles during mechanical ventilation, a finding that has since been corroborated in rodent diaphragm and limb muscles.114,115  Mechanical unloading has also been shown to induce up-regulation of another protease, calpain, in the both diaphragm and limb muscles.115–117 

Likewise, the autophagy–lysosomal system is emerging as an important pathway that is modulated by critical illness118,119  and muscle disuse.94,107,116  Autophagy is a constitutively active catabolic process in the skeletal muscle, which is up-regulated under conditions of fasting, oxidative stress, and denervation, leading to muscle protein degradation.120,121  Studies have demonstrated that lysosomal degradation contributes to protein breakdown in denervated muscle,122  and there is a significant up-regulation of lysosomal proteases, such as cathepsin L, under conditions of atrophy.123  Myofiber atrophy resulting from in vivo overexpression of a constitutively active FoxO3 (a transcription factor that promotes cell death), for example, is dependent on autophagy, while siRNA knockdown of LC3 (a protein that is involved in autophagosome development) has been shown to partially prevent this FoxO3-mediated muscle atrophy.118,124  Genetic models have also confirmed the role of autophagy in muscle atrophy.118  Oxidative stress induced by a muscle-specific mutant superoxide dismutase protein (SOD1G93A) has been shown to cause muscle loss as a result of autophagy, whereas attenuation of autophagy by knockdown of LC3 in SOD1G93A transgenic mice results in maintenance of muscle mass.

Although autophagy is a catabolic process involved in the breakdown of cells, recent studies suggest that it may be important in the maintenance of muscle mass in critically ill patients because autophagy also plays a crucial role in cellular homeostasis by ensuring the removal of damaged and dysfunctional intracellular proteins and organelles.125  The essential role autophagy in muscle homeostasis is exemplified by the phenotypes of mice with muscle-specific inactivation of genes encoding autophagy-related proteins.118  Ablation of Atg7, a crucial component in autophagosome formation, results in disorganized sarcomeres that lead to myofiber degeneration.126  This manifests as muscle atrophy and weakness in Atg7-null mice. Moreover, fasting- and denervation-induced atrophy was exacerbated in Atg7-null mice.127  This beneficial effect of autophagy has also been observed in humans. Autophagy is induced by both endurance and resistance exercise.100,128,129  Autophagy also mediates the metabolic beneficial effects of exercise on glucose homeostasis.100,130  This activation of autophagy during exercise is believed to be an adaptive response for the removal of proteins and organelles damaged by exercise or a mechanism to provide energy for sustained muscle contraction.100  These favorable effects of autophagy have even been shown to benefit critically ill patients. In a large subanalysis of the EPaNIC trial, Hermans et al.131  found that critically ill patients receiving early parenteral nutrition were more likely to develop muscle weakness within 9 days of randomization than those receiving late parenteral nutrition. In 58 patients with muscle weakness, a significant inverse association between autophagy and the development of ICUAW was identified.131,132 

Sepsis

Muscle weakness may be clinically apparent on admission to the ICU, but because clinical assessments require patient arousal and collaboration, the diagnosis is often delayed in patients with sepsis133  as the appropriate initial management of sepsis is rightly prioritized.134  Patients with sepsis experience skeletal and respiratory muscle wasting and weakness more frequently than patients without sepsis.44,79,135–137  This weakness results from the effects of inflammatory markers; immobilization; impaired oxygen delivery; and effects of sedation, opioids, and neuromuscular blockade. Furthermore, septic encephalopathy often renders patients immobile, thus compounding the risk of developing ICUAW.135 

Proinflammatory cytokines have both direct and indirect effects on signaling pathways that regulate muscle mass.138,139  TNF-α, interferon-γ, and IL-1 increase ubiquitin gene transcripts and thus enhance the skeletal muscle catabolism.102  IL-6 has drawn particular interest because of its pleiotropic effects140  and as such has been dubbed the “double-edged sword” in relation to acquired muscle weakness. On one hand, IL-6 is a proinflammatory cytokine, traditionally associated with control and coordination of immune responses.141  In IL-6 deficient mice, for example, the inflammatory acute phase response after infection is severely blunted.142  Animal models of inflammation and tumor-induced cachexia provided early experimental evidence of the negative effects of IL-6. Inhibition of the increased IL-6 levels that exist in these models was shown to have a protective effect on weight loss and muscle wasting.143,144  High doses of IL-6 or prolonged exposure have been shown to increase muscle catabolism.145  Moreover, transgenic mice overexpressing human IL-6 show severe muscle atrophy by the age of 10 weeks, along with an increased activation of myofiber lysosomal enzymes and proteasomal subunit expression, suggesting that these mice have increased basal rates of protein degradation.146  Inhibition of IL-6 by neutralizing antibodies in these transgenic mice resulted in a complete reversal of the muscular atrophy.147  However, other studies have found no association between IL-6 levels and muscle atrophy,148,149  suggesting that it is the combination of IL-6 with other endogenous mediators, such as TNF-α and IL-1,that produces this catabolic response in the muscles under conditions of sepsis.102 

Interestingly, in contrast to the findings mentioned in Sepsis (paragraph 2), recent studies have identified IL-6 as a myokine that promotes muscle growth and regeneration.140,150  The discovery of IL-6 as a myokine was an incidental finding after the observation that it increased exponentially and proportionally in response to exercise and the amount of muscle mass engaged in exercise.140,151  IL-6 produced after an acute stimulus—without previous increase in TNF-α152 —has a positive impact on the proliferative capacity of muscle progenitor cells.140  It promotes muscle hypertrophy by activating satellite cells and by stimulating myoblast differentiation and fusion.153  Confirming that IL-6 plays a role in muscle hypertrophy, IL-6 knockout mice have been shown to have an impaired hypertrophic response to muscle overloading.150  This hypertrophic effect of IL-6 in response to overloading has also been confirmed in human muscle and electrically stimulated human myocytes.151,154  Therefore, transient production of IL-6 after mechanical loading in critically ill patients may actually facilitate muscle regeneration and hypertrophy in contrast to the catabolic effects of sustained IL-6 production seen in sepsis.140 

Mechanical Ventilation

Prolonged mechanical ventilation can lead to barotrauma, volutrauma, and atelectrauma, as well as ventilator-induced diaphragmatic injury.155  Diaphragmatic atrophy that can be apparent in as little as 48 h, as the work of breathing is assumed by a ventilator,34  and the magnitude of ventilator-induced diaphragmatic injury is associated with the level of support provided by the ventilator: preclinical data show that volume control compared with pressure support ventilation leads to more severe diaphragmatic weakness. On the biochemical level, unloading of the respiratory muscles by mechanical ventilation promotes crosstalk and up-regulation of the calpain, caspase-3, and UPSs that contribute to proteolysis that results in weakness and atrophy.89,90,156,157 

Nutrition

Critically ill patients commonly have a poor nutritional status that predicts adverse outcome. Functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery.5,158  Poor nutritional status has long been associated with greater morbidity and mortality, particularly in the surgical population.159  Malnutrition is associated with impaired immune function, reduced ventilatory drive, weakened respiratory muscles, and prolonged ventilator dependence.160  Critical illness induces a catabolic state in which an imbalance between protein synthesis and degradation leads to cellular death and muscle atrophy, otherwise known as sarcopenia, which in turn is associated with poor nutritional status.5,137  The consequences of poor nutritional status in ICU patients are more severe compared with the catabolic state induced by fasting in healthy persons because this calorific debt is often superimposed on inflammatory and endocrine responses as well as immobilization.161 

Although adequate nutrition in critically ill patients is important in the long term to negate the deleterious effects of a severe calorific debt, multiple studies have demonstrated that outcomes are also influenced by the mode of feeding and timing of feed initiation. Some studies indicate that early parenteral feeding may in fact promote greater levels of muscle wasting possibly because of inhibition of autophagy.101,131,162  In a subanalysis of the EPaNIC trial, for example, the authors found a greater expression of markers of autophagy in the late parenteral nutrition group.131  This suggests that the caloric restriction induced by late parenteral nutrition optimizes autophagic recycling of proteins with removal of toxic proteins and damaged cell organelles that may improve cell functioning.132,163  Mitophagy induced by late parenteral nutrition may thus optimize cellular conditions in the muscle cells for effective muscle contraction and strength generation, possibly explaining the increased strength seen in the late parenteral nutrition group.132  It is important to note that the EPaNIC study studied mostly cardiac surgery patients, of whom 50% stayed in the ICU for less than 3 days. In more severely ill patients, optimized energy supplementation with parenteral nutrition can reduce nosocomial infections, antibiotic usage, and time on mechanical ventilation.164 

Steroids

Approximately 31% of ICU patients exposed to steroids develop ICUAW.165  The association between steroid therapy and long-term functional impairment seems to be dose-dependent.12  Large multicenter studies have identified both corticosteroid administration1  and mean daily corticosteroid dose as strong predictors of ICUAW.166  In a randomized controlled trial (RCT) of 180 patients with persistent ARDS, methylprednisolone treatment was found to improve cardiopulmonary parameters but also resulted in a higher rate of neuromuscular weakness.167 

There is conflicting evidence regarding whether short-term use of steroids increases the risk of ICUAW in critically ill patients. Some data suggest that even a short-term steroid treatment in the ICU can lead to functional impairment.166  Stipulated mechanisms include impairment of the muscle membrane causing lack of excitability and promotion of muscle catabolism resulting in an imbalance between protein synthesis and loss.168–170 

There are equivocal data on the effects of steroids in septic shock on mortality. Although low-dose steroids do not affect mortality,171,172  there is some evidence suggesting that disease entity–based subgroups of patients with septic shock may benefit from corticosteroids.171  A recent retrospective cohort study demonstrated that a short course of methylprednisolone decreased treatment failure (defined as development of shock, need for mechanical ventilation, and death within 120 days) in patients with severe pneumonia.171 

Corticosteroid treatment in critically ill patients should therefore be tailored to the presentation and disease severity. Short-term administration in the most critically ill patients may improve outcomes in certain critically ill populations; however, long-term administration can increase the risk of ICUAW.

Other Mechanisms Implicated in the Development of Muscle Weakness

Central Melanocortin System.

The central melanocortin system plays a significant role in the pathogenesis of cachexia.173  Stimulation of the melanocortin-4 receptor, which is expressed mainly in the brain, results in anorexia, weight loss, and an increased metabolic rate,173  opening this pathway as a potential target in the prevention and treatment of muscle weakness.

Myostatin.

Myostatin, a member of the transforming growth factor-β family, is known to inhibit muscle cell growth and differentiation as well as decrease protein synthesis.174  These effects make myostatin an important target in the treatment and prevention of sarcopenia. Furthermore, myostatin gene mutations have been associated with increased muscle mass in humans.175 

Vitamin D.

The prevalence of low vitamin D levels is high among ICU patients.176  A growing body of evidence suggests that low 25-hydroxy vitamin D levels are associated with a host of negative outcomes in critically ill patients, including increased rates of infection and longer duration of hospital stay and mortality.177  Of particular relevance to our discussion, low vitamin D levels are associated with sarcopenia. In fact, a recent surgical ICU study found that vitamin D levels are inversely associated with the duration of mechanical ventilation, which in itself is a marker of muscle weakness.176 

Renin–Angiotensin System.

The renin–angiotensin system (RAS) has extracardiac effects, some of which impact skeletal muscle. Angiotensin-converting enzyme (ACE) inhibitors are believed to have a beneficial effect on the skeletal muscle by limiting the effects of angiotensin II on the inflammatory response and the growth hormone/insulin-like growth factor (IGF)-1 axis.173 

Critically ill patients are often hypotensive, which activates RAS. The activation of the RAS results in an increase in proinflammatory cytokines,178  which in turn results in muscle protein degradation.179  In humans, angiotensin II is known to induce IL-6180  and matrix metalloproteinase secretion.181  ACE inhibitors reverse these effects in vitro and in vivo.173 

The RAS also has effects on the growth hormone/IGF-1 axis. IGF-1 is an anabolic hormone that increases protein synthesis in existing muscle fibers while also stimulating myogenesis.173,182,183  Angiotensin II has been shown to be decrease IGF-1 levels, which leads to skeletal muscle wasting and reduced lean muscle mass.183 

Functional Capacity and Outcomes.

The frail phenotype is characterized by changes in mobility, muscle mass, nutritional status, strength, and endurance.184  Frail patients may have a lower functional capacity and decreased ability to mobilize at baseline. Thus, they are vulnerable against severe physiologic stressors, predisposing them to functional dependence at discharge and death.

Sarcopenia is a key element of frailty, which translates to higher healthcare utilization and mortality. Sarcopenia in critically ill trauma patients as assessed by computed tomography (CT) is associated with mortality, ICU utilization, and loss of functional independence.185  In a recent observational study, Puthucheary and Hart185  found that muscle mass as assessed by abdominal CT scan was a significant predictor of outcome and discharge location after ICU admission. Further studies exploring this association are needed to identify whether the measurement of muscle mass on admission to the ICU can lead to better patient management as well as a more efficient allocation of healthcare resources. Thus, taking steps to identify and prevent ICUAW can improve functional outcomes on discharge, thus reducing the risk of subsequent readmission and improving outcomes during subsequent readmissions should they occur.

Future studies will demonstrate whether patients with and without impaired functional capacity at admission need to be treated differently to avoid acute care readmissions18,20  and loss of functional independence after discharge.

Clinical Diagnosis of Muscle Weakness in the Surgical ICU

Figure 2 provides decision support for the differential diagnosis of ICUAW. The first step is a clinical examination at the bedside.22  First, the patient’s ability to cooperate with examination should be assessed, because the most valuable test to assess muscle strength depend on the patient’s level of arousal and attention (fig. 3).186 

Fig. 2.

Diagnosis of ICU-acquired muscles weakness. On daily clinical examination in the ICU, cognitive function needs to be assessed. Glasgow coma scale (GCS) should be assessed on admission of trauma patients; sedation and agitation level should be evaluated, and delirium screening should be conducted. In patients able to follow commands, manual muscle testing should be conducted, and a normal score (of ≥ 48 using the medical research council scale, 0 to 5, six muscle groups, bilateral testing) and absence of a focal motor deficit confirm the absence of ICU-acquired muscle weakness. Impaired mental status or a low MRC score dictate additional diagnostic workup for ICU-acquired muscle weakness that includes blood tests, point-of-care testing (train-of-four ratio), as well as a spontaneous awakening trial. Persistent neurologic deficit triggers advances imaging of the brain, and electrophysiologic testing (EMG, measurement of nerve conduction velocity) may be considered in patients with persistent, severe muscle weakness of unclear mechanism. CAM = Confusion Assessment Method; CT= computed tomography; EMG = electromyogram; ICU = intensive care unit; MRC = Medical Research Council scale; NMBA = neuromuscular-blocking agent.

Fig. 2.

Diagnosis of ICU-acquired muscles weakness. On daily clinical examination in the ICU, cognitive function needs to be assessed. Glasgow coma scale (GCS) should be assessed on admission of trauma patients; sedation and agitation level should be evaluated, and delirium screening should be conducted. In patients able to follow commands, manual muscle testing should be conducted, and a normal score (of ≥ 48 using the medical research council scale, 0 to 5, six muscle groups, bilateral testing) and absence of a focal motor deficit confirm the absence of ICU-acquired muscle weakness. Impaired mental status or a low MRC score dictate additional diagnostic workup for ICU-acquired muscle weakness that includes blood tests, point-of-care testing (train-of-four ratio), as well as a spontaneous awakening trial. Persistent neurologic deficit triggers advances imaging of the brain, and electrophysiologic testing (EMG, measurement of nerve conduction velocity) may be considered in patients with persistent, severe muscle weakness of unclear mechanism. CAM = Confusion Assessment Method; CT= computed tomography; EMG = electromyogram; ICU = intensive care unit; MRC = Medical Research Council scale; NMBA = neuromuscular-blocking agent.

Fig. 3.

Bias to clinical assessment of muscle strength. Clinical assessment of muscle strength is a volition-dependent examination, which requires adequate training of the examiner and consideration of perioperative barriers such as drug effects, pain, and medical devices. (Modified from the study by Waak et al.186  Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.) NMBA = neuromuscular-blocking agent.

Fig. 3.

Bias to clinical assessment of muscle strength. Clinical assessment of muscle strength is a volition-dependent examination, which requires adequate training of the examiner and consideration of perioperative barriers such as drug effects, pain, and medical devices. (Modified from the study by Waak et al.186  Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.) NMBA = neuromuscular-blocking agent.

In patients who cannot participate in volitional tests, drug effects (NMBAs, sedatives, opioids, and neuroleptics) and delirium need to be considered as possible mechanisms of muscle weakness. The Richmond agitation-sedation score, Glasgow coma score, and Confusion Assessment Method–ICU are useful tools to screen for cognitive impairments. A train-of-four ratio of more than or equal to 0.9 excludes a clinically significant impairment of neuromuscular transmission.30,187 

In patients able to reliably participate in the process of manual muscle testing, a total Medical Research Council Scale for muscle strength (MRC) score of less than or equal to 48 suggests ICUAW.3  Manual muscle testing—a subjective examination—has proven reliable in critically ill patients provided that strict guidelines on adequacy and standardized test procedures and positions are followed.188  In contrast, grip strength testing is inferior to manual muscle testing in predicting morbidity and increased healthcare utilization related to ICUAW. Global muscle strength but not grip strength predicts mortality and length of stay in a general population in a surgical ICU.189  As such, many experts perform manual muscle testing to identify patients with ICUAW in their clinical practices.190 

An MRC score of less than 48 suggests the presence of ICUAW. Patients with altered mental status or with the evidence of ICUAW should undergo further workup to identify and correct the underlying disorder that may include the etiologies mentioned in figure 1. If the attempts to correct such disorders fail initially, imaging studies such as CT scan should be considered, especially in cases where focal neurologic symptoms are present or in persistent sepsis-associated encephalopathy.

The last resource that could be considered in cases of persistent muscle weakness is electrophysiologic testing (EPS; compound action potentials, nerve conduction velocity, electromyogram). EPS alone can specify the mechanism of ICUAW better than clinical examinations, but muscle biopsies may ultimately be required to specify the nosology of an underlying myopathy.

EPS and histopathology reports have shown that up to 100% of ICU patients exhibit the signs of CIP or CIM.27,38,40,51,131,191–195  A systematic review reported CINM in 46% of patients; of these, CIP was present in 20% and CIM in 13%, whereas underlying pathology was unknown in 77.6%.194  Our group found that in the SICU, CIP, CIM, and CINM were the cause of muscle weakness in only 38% of patients with sepsis.133 

Electrophysiologic testing is limited by its predictive value for long-term outcomes.196  The examination requires expert examiners, is time consuming, and can cause considerable discomfort to the awake patient.190,196  However, the peroneal nerve test can be easily implemented in the ICU, and the results can almost be used interchangeably compared with complete electromyographic investigation for making diagnosis CIP/CIM.48,197  Some data suggest that identification of the underlying pathophysiology of persistent ICUAW is important, because CIP is a marker of persistent disability and delayed recovery, whereas CIM may lead to a better prognosis and a faster recovery than CIP.198,199  A recent study has even suggested that early electrophysiologic testing in critical illness can predict long-term functional outcomes198 ; however, further research is required to ascertain whether this is feasible and worthwhile.

Prevention of ICU-acquired Muscle Weakness in SICU

Persistent muscle weakness can be prevented by using the multimodal approach illustrated in figure 4. The authors believe that to prevent an impairment of functional independence from ICUAW, muscle function should be evaluated and measured regularly as a part of the daily patient assessment. Recently, we proposed some strategies to prevent the development of acquired muscle weakness.44 Table 2 breaks down these individual strategies and provides a summary of the strongest evidence and recommendations for each one.

Table 2.

Recommendations for Prevention of ICU-acquired Muscle Weakness

Recommendations for Prevention of ICU-acquired Muscle Weakness
Recommendations for Prevention of ICU-acquired Muscle Weakness
Fig. 4.

Prevention of ICU-acquired muscle weakness. Early and aggressive sepsis treatment requires adequate diagnostic procedures to identify its mechanism, as well as early treatment with antibiotics, fluid resuscitation, and in the surgical ICU often a surgical intervention to drain the focus. It is imperative to optimize the drive to the skeletal muscles; both inactivity and excessive drive to the skeletal muscles can lead to muscle weakness by atrophy and injury. Metabolic derangement needs to be prevented to provide an optimal homeostasis for the muscle to recovery during the highest acuity levels of critical illness. Future studies will address the effectiveness of pharmacologic pathways to prevent ICU-acquired muscle weakness.186  ACE = angiotensin-converting enzyme; ICU = intensive care unit; NMBA = neuromuscular-blocking agent; PGC = PPAR Gamma Coactivator; SOMS = surgical optimal mobilization score.

Fig. 4.

Prevention of ICU-acquired muscle weakness. Early and aggressive sepsis treatment requires adequate diagnostic procedures to identify its mechanism, as well as early treatment with antibiotics, fluid resuscitation, and in the surgical ICU often a surgical intervention to drain the focus. It is imperative to optimize the drive to the skeletal muscles; both inactivity and excessive drive to the skeletal muscles can lead to muscle weakness by atrophy and injury. Metabolic derangement needs to be prevented to provide an optimal homeostasis for the muscle to recovery during the highest acuity levels of critical illness. Future studies will address the effectiveness of pharmacologic pathways to prevent ICU-acquired muscle weakness.186  ACE = angiotensin-converting enzyme; ICU = intensive care unit; NMBA = neuromuscular-blocking agent; PGC = PPAR Gamma Coactivator; SOMS = surgical optimal mobilization score.

Treat Sepsis as Early and Aggressively as Possible

The Surviving Sepsis campaign233  popularized the concept of early goal-directed therapy in sepsis, including the early use of antibiotics and fluid resuscitation to maintain an adequate central venous pressure, mean arterial pressure, urine output, and mixed venous saturation. Studies demonstrated that this approach reduced mortality, days of mechanical ventilation, and ICU233  and hospital stay.201,203  Although the recent Protocolized Care for Early Septic Shock (ProCESS)134  and the Australasian Resuscitation in Sepsis Evaluation (ARISE)204  have called into question the evidence for early goal-directed therapy in the management of sepsis, it is clear that early identification and appropriate treatment with antibiotics are the most important elements in the treatment of patients with sepsis.234  Early treatment of sepsis may reduce the incidence of muscle weakness by preventing the development of inflammatory-mediated direct and indirect muscle damage and prompting an earlier return to physical activity and ambulation.134,204  Furthermore, lung-protective ventilation with relatively low tidal volumes should be considered in patients with sepsis to reduce organ dysfunction and diminish the inflammatory response associated with atelectasis and ARDS.200,202 

Optimize the Muscular Load

Mobilizing patients postoperatively is an important part of the recovery process. Point prevalence studies suggest that as few as 24% of mechanically ventilated patients and only 8% of patients with an endotracheal tube in the ICU are mobilized out of bed as a part of routine care.235  Outcome studies in the medical ICU indicate that goal-directed early mobilization may lead to shorter duration of delirium, less mechanical ventilation time, fewer days in the ICU, reduced hospital length of stay, and better functional independence at hospital discharge.9,44,205  Physical therapy with ergometry during ICU stay, for example, has been shown to improve functional outcomes as assessed by the 6-min walking distance and the isometric force of the lower limbs muscles206  at hospital discharge. Despite these encouraging findings, currently available evidence that physical therapy improves outcomes in the surgical ICU is of low quality.190  Therefore, the American Thoracic Society has made strong recommendations for RCTs examining this intervention to provide strong evidence to guide healthcare professionals responsible for the care of critically ill patients who are currently underway.36 

The ABCDE bundle is an evidence-based, multidisciplinary, multifaceted approach that seeks to reduce the risk of delirium and ICUAW by using a structured systematic approach that promotes awakening (reduce sedation), ventilator “liberation,” delirium monitoring, and early mobilization.236  This bundle promotes an interprofessional approach in the ICU that can reduce duration of ventilator dependence, hospital and ICU length of stay, incidence of ICUAW, and even mortality.19,66 

Both excessive muscular contractions and inactivity can be associated with the morbidity of surgical ICU patients (fig. 5). Muscle homeostasis in critical illness requires a fine balance between therapeutic activity and inactivity. Muscle disuse promotes atrophy, impaired functional status, and joint contractures, as well as having extramuscular effects such as thromboembolic disease, impaired respiratory mechanics, insulin resistance, and orthostatic hypotension. Immobility associated with muscle disease increases the risk of delirium. Conversely, muscle overuse predisposes patients to traumatic sequelae including pneumothorax and surgical wound pain, as well as risk for malposition of attached drains and medical devices. Moreover, excessive oxygen consumption triggers the production of lactate, and lactic acidosis can further affect the muscle function.

Fig. 5.

Optimize drive to the skeletal muscle in the surgical intensive care unit. To provide an ideal environment for muscle homeostasis in the surgical intensive care unit, muscle activation level needs to be optimized. Muscle overuse can lead to tissue trauma and excessive oxygen consumption. Immobilization is associated with muscular and extramuscular unwarranted effects.

Fig. 5.

Optimize drive to the skeletal muscle in the surgical intensive care unit. To provide an ideal environment for muscle homeostasis in the surgical intensive care unit, muscle activation level needs to be optimized. Muscle overuse can lead to tissue trauma and excessive oxygen consumption. Immobilization is associated with muscular and extramuscular unwarranted effects.

Addressing Muscular Inactivation

SOMS Score.

The surgical optimal mobilization score is a recently developed strategy for goal-directed early mobility after surgery that may help in conducting the needed trials.36  It allows healthcare providers to set safe and appropriate goals for mobilizing patients, in line with their condition postoperatively. The aim is to set mobilization goals appropriate to the patient’s condition early on in the postoperative period while minimizing the risk of patient harm that comes with muscle overuse (fig. 5). This may also decrease hospital costs through an efficient use of resources.21,237,238  Currently, there are no available data to determine whether utilization of this scoring algorithm improves outcomes on the SICU, although trials are currently underway.

Keep the Diaphragm Moving.

It is estimated that approximately 40% of patients in the ICU require mechanical ventilation239  and that weaning procedures account for up to 50% of the total time spent in the ICU.240  Controlled mechanical ventilation assumes the work of breathing from the respiratory muscles leading to the rapid development of diaphragmatic and other respiratory muscle weakness, which can occur in as little as 24 h.1,113 

Studies on mechanical ventilation in ARDS report that spontaneous ventilation improves oxygenation parameters including Pao2 and oxygen delivery,241,242  while also decreasing the global strain to the lung promoted by mechanical ventilation.34,243,244  Spontaneous breaths during mechanical ventilation also enhance cardiac preload and improve cardiovascular parameters208,241,245,246  and may decrease the need for paralysis and sedation.207,247  Furthermore, protective ventilation with lower tidal volumes improves hospital outcomes including shorter ICU and hospital stay and reduces the period of mechanical ventilation209–211  both of which can reduce the risk of ICUAW.

However, in patients with severe ARDS excessive spontaneous ventilation can increase transpulmonary pressure and lung strain. Yoshida et al.248  have reported that spontaneous breathing in mice with severe ARDS led to increased lung distress because of increased work of breathing with atelectasis, higher transpulmonary pressures, and increased airway driving pressures. Patients with severe ARDS and refractory hypoxemia may actually benefit from a short period of controlled mechanical ventilation where the drive to the respiratory pump muscles is pharmacologically controlled.41,59 

Regular Drug Review and Drug Holidays.

The cost/benefit ratio of maintaining or discontinuing these medications should be tailored to the clinical course of each patient. Constant reevaluation of the need for certain medications will promote judicious use in critically ill patients. Implementing “holiday” periods in care protocols, whereby the infusions of these medications are stopped temporarily,212,213  can decrease the duration of mechanical ventilation in surgical critically ill patients214  and the length of stay in the ICU without increasing adverse events such as self-extubation.212  However, it is important to bear in mind that not all patients will benefit from drug holidays; patients with increased intracranial pressure, for example, may not benefit from these drug holidays, but the sedation goal needs to be restrictively defined every day during rounds in all ICU patients.249 

Optimize Nutrition in the ICU

Critically ill patients require nutrients in the form of either enteral or parenteral nutrition to avoid an energy deficit that contributes to lean tissue wasting.250  It is estimated that the majority of patients in the ICU receive only 49 to 70% of calculated requirements.220,251,252  Although it is generally agreed that excessively hypocaloric (less than or equal to recommended daily caloric intake) or hypercaloric (≥ 125%) feeding should be avoided, there is still no consensus on what the daily targets should be.253  Higher average daily caloric energy intake is not necessarily associated with improved survival as shown in the RENAL trial,254  which reported that the mean caloric delivery in the ICU was low, but greater levels were not associated with improved outcomes. Studies suggest that overfeeding may in fact increase rate of infections, duration of mechanical ventilation, and mortality.162,255 

Enteral Nutrition.

Enteral administration of food, fluids, and nutrients is key to maintain gut integrity, but ICU patients are often not able to feed themselves.161  Meeting calorific requirements with enteral nutrition (EN) by means of tube feedings may improve the outcomes by preventing oxidative cell injury, attenuating the metabolic response to stress, and helping to maintain immune function.216,256 

EN can improve outcomes compared with no supplemental nutrition in critically ill patients. In a meta-analysis of 11 studies and 837 patients, Lewis et al.218  found a reduced incidence of infections and mortality, in addition to less hospitalization days in surgical and critical care patients with EN compared with patients kept “nil per mouth.” Studies have reported that early EN (less than 48 h after ICU admission) in surgical and trauma patients is associated with a significant reduction in mortality,223,257  infection rate,215,258,259  hospital and ICU length of stay,216,217,221,222,260  ventilator days,217,221,222,260  and costs258  compared with delayed EN. However, Puthucheary et al.101  have shown that the catabolic state and rapid muscle wasting induced by critical illness within the first week may be independent of EN. Contrary to expectations, high protein delivery through nasogastric tube in the first week of critical illness was actually associated with greater muscle wasting,101  thus challenging the notion that early enteral feeding is beneficial.

Interestingly, a recent RCT has demonstrated that there is no significant difference in the development of infectious complications or mortality between early enteral and parenteral feeding groups,224  thus shedding some light on the uncertainty that exists regarding the optimal feeding route in early nutrition. The challenge lies in identifying the appropriate levels and timing of nutritional supplementation that truly improve the functional outcomes in the ICU.

Parenteral Nutrition.

In patients for whom EN is not a feasible option because of the severity of their critical illness, parenteral nutrition may be considered; however, currently, the criteria and timing for initiation of parenteral nutrition are not well defined. A meta-analysis of seven RCTs involving a total of 798 patients showed that parenteral nutrition was associated with a higher rate of infection compared with no feeding.219  Furthermore, in a multicenter randomized study of 4,640 patients admitted to the ICU, late parenteral nutrition (8 days after admission) compared with early parenteral nutrition (initiated within 48 h of admission) has been shown to reduce rates of infection, mechanical ventilation days, and healthcare costs.162  The authors proposed that early parenteral nutrition (PN) suppressed cellular autophagic quality control impairing muscle integrity. Tolerating a macronutrient deficit for up to 1 week is believed to up-regulate this quality control and decrease the risk of muscle weakness.162  Hermans et al.131  corroborated these findings in a subanalysis of the EPaNIC trial, which found that the incidence of ICUAW as assessed by the MRC score was significantly lower in the group that received late PN (34%) compared with those receiving earlier PN (43%). The late PN group also recovered faster and had higher autophagy markers on muscle biopsy compared with the early PN group. Furthermore, late initiation of parenteral nutrition also resulted in a mean reduction of $1,600 in healthcare costs per patient.261 

In contrast to these studies, the Supplemental Parenteral Nutrition study found that parenteral nutrition given to patients unable to tolerate full enteral feeds on day 4 of ICU admission was associated with the reduced rates of nosocomial infections but did not improve overall mortality.164  Another large multicenter study assessing patients with a relative contraindication to parenteral nutrition found that parenteral nutrition actually reduced the duration of mechanical ventilation, thus potentially reducing the risk of muscle weakness.225  Thus, it remains unclear whether early parenteral nutrition is beneficial for patients who have an absolute and more prolonged contraindication to EN.161 

In summary, there seems to be continuous controversy regarding optimal energy provision and protein intake, particularly in the early phase of critical illness.262  Nutritional and healthcare status before ICU admission, patient’s age, admission diagnosis, and disease severity all influence individual requirements, and thus, nutritional strategies and goals should be personalized to the individual patient.233 

Glycemic Control.

Tight glycemic control also plays an important role in surgical ICU outcomes. Approximately 30% of critically ill patients suffer from hyperglycemia (more than 200 mg/dl).263  Hyperglycemia often correlates with disease severity. Stress hyperglycemia is known to be a compensatory mechanism to increase the availability of energy substrates in stressful situations such as trauma or surgical procedures. Although hyperglycemia is a physiologic response to stress, it can worsen patient outcomes. In patients with severe brain injury, for example, hyperglycemia of more than170 mg/dl is associated with longer duration of hospital stay, a worse neurologic status with higher intracranial pressures, and increased mortality.264  Trauma patients with persistent hyperglycemia (more than 200 mg/dl) also had a significantly greater degree of morbidity and mortality, as well as infectious complications.265  In a large RCT of 1,548 patients, strict glycemic control (blood sugar less than 110 mg/dl) was found to reduce the incidence of CIP, duration of mechanical ventilation, ICU length of stay, and mortality as well as improve functional outcomes in brain injury survivors at 1 yr.193  Subsequent studies have not reproduced these findings and on the contrary have shown that tight glucose control can be detrimental to critically ill patients, with some studies finding an association between tight glucose control and an increased risk of hypoglycemia and mortality.226,229–232  The NICE-SUGAR study found that tight blood glucose control (81 to 108 mg/dl) increased mortality among both medical and surgical ICU patients when compared with conventional blood glucose control (less than 180 mg/dl).229  However, this finding may be driven by medical ICU patients, because two meta-analyses showed that the increased mortality does not occur in the SICU population.227,228  As a result, the currently recommended target glycemic levels ranges between 110 and 180 mg/dl229,265  to promote earlier discharge from the ICU and to decrease the incidence of ICUAW.1 

Future Directions: Drug Targets and Gene Therapy

Potential Drug Targets.

Currently, there are no approved therapeutic strategies for sarcopenia. The anabolic and catabolic signals described in the pathogenesis of disuse atrophy are appealing potential drug and gene therapy targets. Accordingly, there is currently great interest in basic science research to characterize and exploit these pathways in the quest to find a successful preventative and therapeutic agent for muscle wasting.266  Herein, we focus on two interesting findings that have therapeutic potential.

Overexpression of a constitutively active mutant of Gαi2 has been shown to promote myotube growth, inhibit TNF-α–induced muscle atrophy via transcriptional down-regulation of MuRF1, enhance muscle regeneration, and stimulate a switch to oxidative fibers.267  This suggests that both lysophosphatidic acid and/or Gαi2 may be useful drug targets in the prevention and treatment of ICUAW.

Another approach exploits the role of mitochondria in the maintenance of muscle mass. Mitochondrial dysfunction has been shown to play an important role in disuse atrophy. PPAR Gamma Coactivator (PGC)-1α is a transcriptional coactivator with positive effects on mitochondrial biogenesis and respiration.268  Transgenic mice overexpressing PGC-1α have demonstrated resistance to muscle wasting because the overexpression of PGC-1α prevents the activation of the AMP-activated protein kinase pathway (stimulator of muscle catabolism); the expression of MuRF1, atrogin1, and autophagic factors (implicated in muscle protein catabolism); and also muscle atrophy secondary to mechanical unloading.269  Therefore, identifying compounds that induce and increase PGC-1α expression may be a novel and useful therapeutic strategy in the prevention of ICUAW in critically ill immobile patients.

Melanocortin-4 Receptor Antagonists.

Melanocortin-4 receptor antagonism has also been shown to prevent muscle wasting in rodent models of cancer270  and uremic/chronic kidney disease271  cachexia making this a promising potential intervention for ICU patients who commonly have these comorbidities. Results from human clinical trials are still pending.

Myostatin Inhibitiors.

Myostatin gene mutations have been associated with an increased muscle mass in humans.175  Antagonism of myostatin enhances muscle mass and strength272  by means of both muscle hypertrophy and hyperplasia.273  Myostatin antibody significantly attenuated the muscle atrophy and loss of functional capacity in mice models of disuse atrophy.274  A recently conducted phase I trial of a myostatin inhibitor in postmenopausal women proved to increase muscle mass even in these healthy subjects, with the drug seeming to be safe and well tolerated.275 

Reversal of Neuromuscular Blockade.

NMBAs are commonly used in the operating room (optimize surgical conditions) and ICU (mechanical ventilation) and can have the same effects on muscle physiology that denervation does,63,64  resulting in immobilization-associated muscle atrophy, especially with long-term use. The effects of lingering NMBAs can be rapidly and safely reversed by administration of a selectively binding reversal agent, such as Sugammadex (Merck Sharp and Dohme, USA) or Calabadion (Calabash Biotech Inc., USA).276  Currently, these agents are not licensed in the United States. A promising novel agent, Calabadion II is a broad-spectrum reversal agent that has been shown in rodents to promote faster recovery from neuromuscular blockade than Sugammadex.276  Moreover, Calabadion II has also been shown to successfully reverse the effects of both ketamine277  and etomidate278  in rodents, making this drug a unique and promising development in anesthesia reversal. The clinical introduction of these drugs may limit the impact of NMBAs on the development of muscle atrophy in surgical and critically ill patients in the future.

Vitamin D Supplementation.

Increased muscle strength has been reported in RCTs investigating vitamin D supplementation. In older institutionalized subjects, 6 months of vitamin D supplementation has been shown to significantly increase hip flexor and knee extensor strength by up to 25%.279  Furthermore, vitamin D supplementation seems to benefit the weakest at baseline the most.280  Vitamin D supplementation was also found to increase muscle fiber size281  and improve mitochondrial function resulting in reduced muscle fatigue.282  Further randomized controlled studies are needed to determine the clinical implications of vitamin D supplementation in critically ill patients.

ACE Inhibitors.

By limiting the conversion of angiotensin I to angiotensin II, ACE inhibitors up-regulate IGF-1 levels and as a result prevent muscle wasting.183,283  Observational studies have suggested that these findings may hold true in humans. Treatment of hypertensive subjects with an ACE inhibitor has been associated with increases in both locomotor muscle size and strength.284,285  Moreover, in a RCT of 95 elderly subjects who had self-reported mobility difficulties but who did not have heart failure, treatment with an ACE inhibitor significantly improved 6-min walk distance compared with placebo.286  Further studies are required to identify whether ACE inhibitors could benefit critically ill surgical patients.

Melatonin and Oxytocin.

Oxytocin and melatonin have immune modulatory and antiinflammatory properties in addition to their well-known effect on regulating circadian day–night rhythms and stimulating uterine smooth muscle contraction during labor and milk ejection during lactation. In animal model of cecal ligation and puncture,287  coadministration of oxytocin and melatonin abolished the nerve electrophysiologic alterations caused by sepsis and suppressed oxidative stress, lipid peroxidation, and TNF-α release.

Conclusion

Clinical analysis of muscle function should become a regular part of clinical examination in the ICU to allow appropriate identification and management of muscle weakness to prevent long-term morbidity and mortality and reduce healthcare costs. ICUAW weakness is a direct consequence of the patient’s systemic disease and its treatment. Aggressive treatment of the underlying disease is a key strategy to its prevention. Muscular inactivity and excessive load need to be prevented, and a metabolic environment that allows for optimal recovery should be created. Future studies will demonstrate whether drugs that prevent muscular atrophy can be used to prevent ICUAW.

Search Strategy and Selection Criteria

We searched PubMed for articles in English with the term “ICU acquired weakness” in the title from January 1, 1990, to December 1, 2014. We also searched for multiple combinations of the terms “muscle weakness AND ICU,” “early mobilization AND ICU,” “critical illness polyneuropathy,” “critical illness myopathy,” “critical illness neuromyopathy,” and “muscle weakness AND surgery.” We also retrieved relevant articles from the reference list of key articles. Whenever possible, we prioritized the articles published in the past 5 yr but cited older references when appropriate.

Acknowledgments

Support was provided solely from institutional and/or departmental sources, and by an unrestricted research grant provided by Jeffrey Buzen, Ph.D., and Judith Buzen.

Competing Interests

Dr. Eikermann holds an equity stake in Calabash Bioscience, Inc. (Wilmington, Delaware), which develops Calabadions for biomedical applications. The other authors declare no competing interests.

References

1.
De Jonghe
B
,
Sharshar
T
,
Lefaucheur
JP
,
Authier
FJ
,
Durand-Zaleski
I
,
Boussarsar
M
,
Cerf
C
,
Renaud
E
,
Mesrati
F
,
Carlet
J
,
Raphaël
JC
,
Outin
H
,
Bastuji-Garin
S
;
Groupe de Réflexion et d’Etude des Neuromyopathies en Réanimation
:
Paresis acquired in the intensive care unit: A prospective multicenter study.
JAMA
2002
;
288
:
2859
67
2.
Clark
BC
,
Manini
TM
:
Sarcopenia =/= dynapenia.
J Gerontol A Biol Sci Med Sci
2008
;
63
:
829
34
3.
Connolly
BA
,
Jones
GD
,
Curtis
AA
,
Murphy
PB
,
Douiri
A
,
Hopkinson
NS
,
Polkey
MI
,
Moxham
J
,
Hart
N
:
Clinical predictive value of manual muscle strength testing during critical illness: An observational cohort study.
Crit Care
2013
;
17
:
R229
4.
Moisey
LL
,
Mourtzakis
M
,
Cotton
BA
,
Premji
T
,
Heyland
DK
,
Wade
CE
,
Bulger
E
,
Kozar
RA
;
Nutrition and Rehabilitation Investigators Consortium (NUTRIC)
:
Skeletal muscle predicts ventilator-free days, ICU-free days, and mortality in elderly ICU patients.
Crit Care
2013
;
17
:
R206
5.
Mueller
N
,
Murthy
S
,
Tainter
CR
,
Lee
J
,
Richard
K
,
Fintelmann
FJ
,
Grabitz
SD
,
Timm
FP
,
Levi
B
,
Kurth
T
,
Eikermann
M
:
Can sarcopenia quantified by ultrasound of the rectus femoris muscle predict adverse outcome of surgical intensive care unit patients as well as frailty? A prosprective, observational cohort study.
Ann Surg
2015
6.
Kasotakis
G
,
Schmidt
U
,
Perry
D
,
Grosse-Sundrup
M
,
Benjamin
J
,
Ryan
C
,
Tully
S
,
Hirschberg
R
,
Waak
K
,
Velmahos
G
,
Bittner
EA
,
Zafonte
R
,
Cobb
JP
,
Eikermann
M
:
The surgical intensive care unit optimal mobility score predicts mortality and length of stay.
Crit Care Med
2012
;
40
:
1122
8
7.
Bolton
CF
:
Neuromuscular complications of sepsis.
Intensive Care Med
1993
;
19
(
suppl 2
):
S58
63
8.
Latronico
N
,
Bolton
CF
:
Critical illness polyneuropathy and myopathy: A major cause of muscle weakness and paralysis.
Lancet Neurol
2011
;
10
:
931
41
9.
Engel
HJ
,
Needham
DM
,
Morris
PE
,
Gropper
MA
:
ICU early mobilization: From recommendation to implementation at three medical centers.
Crit Care Med
2013
;
41
(
9
suppl 1
):
S69
80
10.
Ali
NA
,
O’Brien
JM
Jr
,
Hoffmann
SP
,
Phillips
G
,
Garland
A
,
Finley
JC
,
Almoosa
K
,
Hejal
R
,
Wolf
KM
,
Lemeshow
S
,
Connors
AF
Jr
,
Marsh
CB
;
Midwest Critical Care Consortium
:
Acquired weakness, handgrip strength, and mortality in critically ill patients.
Am J Respir Crit Care Med
2008
;
178
:
261
8
11.
Belle
SH
,
Porayko
MK
,
Hoofnagle
JH
,
Lake
JR
,
Zetterman
RK
:
Changes in quality of life after liver transplantation among adults. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database (LTD).
Liver Transpl Surg
1997
;
3
:
93
104
12.
Fan
E
,
Dowdy
DW
,
Colantuoni
E
,
Mendez-Tellez
PA
,
Sevransky
JE
,
Shanholtz
C
,
Himmelfarb
CR
,
Desai
SV
,
Ciesla
N
,
Herridge
MS
,
Pronovost
PJ
,
Needham
DM
:
Physical complications in acute lung injury survivors: A two-year longitudinal prospective study.
Crit Care Med
2014
;
42
:
849
59
13.
Ferrante
LE
,
Pisani
MA
,
Murphy
TE
,
Gahbauer
EA
,
Leo-Summers
LS
,
Gill
TM
:
Functional trajectories among older persons before and after critical illness.
JAMA Intern Med
2015
;
175
:
523
9
14.
Gerber
L
,
Lampert
M
,
Wood
C
,
Duncan
M
,
D’Angelo
T
,
Schain
W
,
McDonald
H
,
Danforth
D
,
Findlay
P
,
Glatstein
E
:
Comparison of pain, motion, and edema after modified radical mastectomy vs. local excision with axillary dissection and radiation.
Breast Cancer Res Treat
1992
;
21
:
139
45
15.
Gofton
TE
,
Young
GB
:
Sepsis-associated encephalopathy.
Nat Rev Neurol
2012
;
8
:
557
66
16.
Herridge
MS
:
Long-term outcomes after critical illness.
Curr Opin Crit Care
2002
;
8
:
331
6
17.
Hoyer
EH
,
Needham
DM
,
Atanelov
L
,
Knox
B
,
Friedman
M
,
Brotman
DJ
:
Association of impaired functional status at hospital discharge and subsequent rehospitalization.
J Hosp Med
2014
;
9
:
277
82
18.
Schneider
JC
,
Gerrard
P
,
Goldstein
R
,
DiVita
MA
,
Niewczyk
P
,
Ryan
CM
,
Kowalske
K
,
Zafonte
R
:
The impact of comorbidities and complications on burn injury inpatient rehabilitation outcomes.
PM R
2013
;
5
:
114
21
19.
Vasilevskis
EE
,
Ely
EW
,
Speroff
T
,
Pun
BT
,
Boehm
L
,
Dittus
RS
:
Reducing iatrogenic risks: ICU-acquired delirium and weakness—Crossing the quality chasm.
Chest
2010
;
138
:
1224
33
20.
Schneider
JC
,
Gerrard
P
,
Goldstein
R
,
Divita
MA
,
Niewczyk
P
,
Ryan
CM
,
Tan
WH
,
Kowalske
K
,
Zafonte
R
:
Predictors of transfer from rehabilitation to acute care in burn injuries.
J Trauma Acute Care Surg
2012
;
73
:
1596
601
21.
Garzon-Serrano
J
,
Ryan
C
,
Waak
K
,
Hirschberg
R
,
Tully
S
,
Bittner
EA
,
Chipman
DW
,
Schmidt
U
,
Kasotakis
G
,
Benjamin
J
,
Zafonte
R
,
Eikermann
M
:
Early mobilization in critically ill patients: Patients’ mobilization level depends on health care provider’s profession.
PM R
2011
;
3
:
307
13
22.
Bittner
EA
,
Martyn
JA
,
George
E
,
Frontera
WR
,
Eikermann
M
:
Measurement of muscle strength in the intensive care unit.
Crit Care Med
2009
;
37
(
10 suppl
):
S321
30
23.
Saltin
B
,
Henriksson
J
,
Nygaard
E
,
Andersen
P
,
Jansson
E
:
Fiber types and metabolic potentials of skeletal muscles in sedentary man and endurance runners.
Ann N Y Acad Sci
1977
;
301
:
3
29
24.
Vøllestad
NK
:
Measurement of human muscle fatigue.
J Neurosci Methods
1997
;
74
:
219
27
25.
Jones
DA
:
High-and low-frequency fatigue revisited.
Acta Physiol Scand
1996
;
156
:
265
70
26.
De Jonghe
B
,
Sharshar
T
,
Hopkinson
N
,
Outin
H
:
Paresis following mechanical ventilation.
Curr Opin Crit Care
2004
;
10
:
47
52
27.
Latronico
N
,
Guarneri
B
:
Critical illness myopathy and neuropathy.
Minerva Anestesiol
2008
;
74
:
319
23
28.
Mirzakhani
H
,
Williams
JN
,
Mello
J
,
Joseph
S
,
Meyer
MJ
,
Waak
K
,
Schmidt
U
,
Kelly
E
,
Eikermann
M
:
Muscle weakness predicts pharyngeal dysfunction and symptomatic aspiration in long-term ventilated patients.
Anesthesiology
2013
;
119
:
389
97
29.
Murphy
GS
,
Szokol
JW
,
Marymont
JH
,
Greenberg
SB
,
Avram
MJ
,
Vender
JS
:
Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit.
Anesth Analg
2008
;
107
:
130
7
30.
Alfille
PH
,
Merritt
C
,
Chamberlin
NL
,
Eikermann
M
:
Control of perioperative muscle strength during ambulatory surgery.
Curr Opin Anaesthesiol
2009
;
22
:
730
7
31.
Da Costa
ML
,
Qureshi
MA
,
Brindley
NM
,
Burke
PE
,
Grace
PA
,
Bouchier-Hayes
D
:
Normal inspiratory muscle strength is restored more rapidly after laparoscopic cholecystectomy.
Ann R Coll Surg Engl
1995
;
77
:
252
5
32.
Murphy
GS
,
Szokol
JW
,
Marymont
JH
,
Avram
MJ
,
Vender
JS
,
Rosengart
TK
:
Impact of shorter-acting neuromuscular blocking agents on fast-track recovery of the cardiac surgical patient.
Anesthesiology
2002
;
96
:
600
6
33.
Murphy
GS
,
Szokol
JW
,
Marymont
JH
,
Vender
JS
,
Avram
MJ
,
Rosengart
TK
,
Alwawi
EA
:
Recovery of neuromuscular function after cardiac surgery: Pancuronium versus rocuronium.
Anesth Analg
2003
;
96
:
1301
7
34.
Grosu
HB
,
Lee
YI
,
Lee
J
,
Eden
E
,
Eikermann
M
,
Rose
KM
:
Diaphragm muscle thinning in patients who are mechanically ventilated.
Chest
2012
;
142
:
1455
60
35.
Alnahdi
AH
,
Zeni
JA
,
Snyder-Mackler
L
:
Hip abductor strength reliability and association with physical function after unilateral total knee arthroplasty: A cross-sectional study.
Phys Ther
2014
;
94
:
1154
62
36.
Meyer
MJ
,
Stanislaus
AB
,
Lee
J
,
Waak
K
,
Ryan
C
,
Saxena
R
,
Ball
S
,
Schmidt
U
,
Poon
T
,
Piva
S
,
Walz
M
,
Talmor
DS
,
Blobner
M
,
Latronico
N
,
Eikermann
M
:
Surgical Intensive Care Unit Optimal Mobilisation Score (SOMS) trial: A protocol for an international, multicentre, randomised controlled trial focused on goal-directed early mobilisation of surgical ICU patients.
BMJ Open
2013
;
3
:
e003262
37.
Fukuse
T
,
Satoda
N
,
Hijiya
K
,
Fujinaga
T
:
Importance of a comprehensive geriatric assessment in prediction of complications following thoracic surgery in elderly patients.
Chest
2005
;
127
:
886
91
38.
De Jonghe
B
,
Cook
D
,
Sharshar
T
,
Lefaucheur
JP
,
Carlet
J
,
Outin
H
:
Acquired neuromuscular disorders in critically ill patients: A systematic review. Groupe de Reflexion et d’Etude sur les Neuromyopathies En Reanimation.
Intensive Care Med
1998
;
24
:
1242
50
39.
Schweickert
WD
,
Pohlman
MC
,
Pohlman
AS
,
Nigos
C
,
Pawlik
AJ
,
Esbrook
CL
,
Spears
L
,
Miller
M
,
Franczyk
M
,
Deprizio
D
,
Schmidt
GA
,
Bowman
A
,
Barr
R
,
McCallister
KE
,
Hall
JB
,
Kress
JP
:
Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomised controlled trial.
Lancet
2009
;
373
:
1874
82
40.
Sharshar
T
,
Bastuji-Garin
S
,
Stevens
RD
,
Durand
MC
,
Malissin
I
,
Rodriguez
P
,
Cerf
C
,
Outin
H
,
De Jonghe
B
;
Groupe de Réflexion et d’Etude des Neuromyopathies En Réanimation
:
Presence and severity of intensive care unit-acquired paresis at time of awakening are associated with increased intensive care unit and hospital mortality.
Crit Care Med
2009
;
37
:
3047
53
41.
Papazian
L
,
Forel
JM
,
Gacouin
A
,
Penot-Ragon
C
,
Perrin
G
,
Loundou
A
,
Jaber
S
,
Arnal
JM
,
Perez
D
,
Seghboyan
JM
,
Constantin
JM
,
Courant
P
,
Lefrant
JY
,
Guérin
C
,
Prat
G
,
Morange
S
,
Roch
A
;
ACURASYS Study Investigators
:
Neuromuscular blockers in early acute respiratory distress syndrome.
N Engl J Med
2010
;
363
:
1107
16
42.
Routsi
C
,
Gerovasili
V
,
Vasileiadis
I
,
Karatzanos
E
,
Pitsolis
T
,
Tripodaki
E
,
Markaki
V
,
Zervakis
D
,
Nanas
S
:
Electrical muscle stimulation prevents critical illness polyneuromyopathy: A randomized parallel intervention trial.
Crit Care
2010
;
14
:
R74
43.
Hermans
G
,
Van Mechelen
H
,
Clerckx
B
,
Vanhullebusch
T
,
Mesotten
D
,
Wilmer
A
,
Casaer
MP
,
Meersseman
P
,
Debaveye
Y
,
Van Cromphaut
S
,
Wouters
PJ
,
Gosselink
R
,
Van den Berghe
G
:
Acute outcomes and 1-year mortality of intensive care unit-acquired weakness. A cohort study and propensity-matched analysis.
Am J Respir Crit Care Med
2014
;
190
:
410
20
44.
Eikermann
M
,
Latronico
N
:
What is new in prevention of muscle weakness in critically ill patients?
Intensive Care Med
2013
;
39
:
2200
3
45.
Latronico
N
,
Peli
E
,
Botteri
M
:
Critical illness myopathy and neuropathy.
Curr Opin Crit Care
2005
;
11
:
126
32
46.
Bolton
CF
,
Gilbert
JJ
,
Hahn
AF
,
Sibbald
WJ
:
Polyneuropathy in critically ill patients.
J Neurol Neurosurg Psychiatry
1984
;
47
:
1223
31
47.
Leijten
FS
,
Poortvliet
DC
,
de Weerd
AW
:
The neurological examination in the assessment of polyneuropathy in mechanically ventilated patients.
Eur J Neurol
1997
;
4
:
124
9
48.
Latronico
N
,
Bertolini
G
,
Guarneri
B
,
Botteri
M
,
Peli
E
,
Andreoletti
S
,
Bera
P
,
Luciani
D
,
Nardella
A
,
Vittorielli
E
,
Simini
B
,
Candiani
A
:
Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: The Italian multi-centre CRIMYNE study.
Crit Care
2007
;
11
:
R11
49.
Lacomis
D
,
Giuliani
MJ
,
Van Cott
A
,
Kramer
DJ
:
Acute myopathy of intensive care: Clinical, electromyographic, and pathological aspects.
Ann Neurol
1996
;
40
:
645
54
50.
Wollersheim
T
,
Woehlecke
J
,
Krebs
M
,
Hamati
J
,
Lodka
D
,
Luther-Schroeder
A
,
Langhans
C
,
Haas
K
,
Radtke
T
,
Kleber
C
,
Spies
C
,
Labeit
S
,
Schuelke
M
,
Spuler
S
,
Spranger
J
,
Weber-Carstens
S
,
Fielitz
J
:
Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness.
Intensive Care Med
2014
;
40
:
528
38
51.
Latronico
N
,
Fenzi
F
,
Recupero
D
,
Guarneri
B
,
Tomelleri
G
,
Tonin
P
,
De Maria
G
,
Antonini
L
,
Rizzuto
N
,
Candiani
A
:
Critical illness myopathy and neuropathy.
Lancet
1996
;
347
:
1579
82
52.
Kress
JP
,
Hall
JB
:
Sedation in the mechanically ventilated patient.
Crit Care Med
2006
;
34
:
2541
6
53.
Kumar
GV
,
Nair
AP
,
Murthy
HS
,
Jalaja
KR
,
Ramachandra
K
,
Parameshwara
G
:
Residual neuromuscular blockade affects postoperative pulmonary function.
Anesthesiology
2012
;
117
:
1234
44
54.
Sasaki
N
,
Meyer
MJ
,
Eikermann
M
:
Postoperative respiratory muscle dysfunction: Pathophysiology and preventive strategies.
Anesthesiology
2013
;
118
:
961
78
55.
Pattinson
KT
:
Opioids and the control of respiration.
Br J Anaesth
2008
;
100
:
747
58
56.
Lo
YL
,
Jordan
AS
,
Malhotra
A
,
Wellman
A
,
Heinzer
RA
,
Eikermann
M
,
Schory
K
,
Dover
L
,
White
DP
:
Influence of wakefulness on pharyngeal airway muscle activity.
Thorax
2007
;
62
:
799
805
57.
Jordan
AS
,
Eckert
DJ
,
Wellman
A
,
Trinder
JA
,
Malhotra
A
,
White
DP
:
Termination of respiratory events with and without cortical arousal in obstructive sleep apnea.
Am J Respir Crit Care Med
2011
;
184
:
1183
91
58.
Prielipp
RC
,
Robinson
JC
,
Wilson
JA
,
MacGregor
DA
,
Scuderi
PE
:
Dose response, recovery, and cost of doxacurium as a continuous infusion in neurosurgical intensive care unit patients.
Crit Care Med
1997
;
25
:
1236
41
59.
Kacmarek
RM
,
Villar
J
:
Management of refractory hypoxemia in ARDS.
Minerva Anestesiol
2013
;
79
:
1173
9
60.
Pandharipande
P
,
Cotton
BA
,
Shintani
A
,
Thompson
J
,
Pun
BT
,
Morris
JA
Jr
,
Dittus
R
,
Ely
EW
:
Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients.
J Trauma
2008
;
65
:
34
41
61.
Eikermann
M
,
Groeben
H
,
Hüsing
J
,
Peters
J
:
Predictive value of mechanomyography and accelerometry for pulmonary function in partially paralyzed volunteers.
Acta Anaesthesiol Scand
2004
;
48
:
365
70
62.
Murphy
GS
,
Szokol
JW
,
Avram
MJ
,
Greenberg
SB
,
Shear
T
,
Vender
JS
,
Gray
J
,
Landry
E
:
Postoperative residual neuromuscular blockade is associated with impaired clinical recovery.
Anesth Analg
2013
;
117
:
133
41
63.
Berg
DK
,
Hall
ZW
:
Increased extrajunctional acetylcholine sensitivity produced by chronic acetylcholine sensitivity produced by chronic post-synaptic neuromuscular blockade.
J Physiol
1975
;
244
:
659
76
64.
Chang
CC
,
Chuang
ST
,
Huang
MC
:
Effects of chronic treatment with various neuromuscular blocking agents on the number and distribution of acetylcholine receptors in the rat diaphragm.
J Physiol
1975
;
250
:
161
73
65.
Brattebø
G
,
Hofoss
D
,
Flaatten
H
,
Muri
AK
,
Gjerde
S
,
Plsek
PE
:
Effect of a scoring system and protocol for sedation on duration of patients’ need for ventilator support in a surgical intensive care unit.
BMJ
2002
;
324
:
1386
9
66.
Girard
TD
,
Kress
JP
,
Fuchs
BD
,
Thomason
JW
,
Schweickert
WD
,
Pun
BT
,
Taichman
DB
,
Dunn
JG
,
Pohlman
AS
,
Kinniry
PA
,
Jackson
JC
,
Canonico
AE
,
Light
RW
,
Shintani
AK
,
Thompson
JL
,
Gordon
SM
,
Hall
JB
,
Dittus
RS
,
Bernard
GR
,
Ely
EW
:
Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): A randomised controlled trial.
Lancet
2008
;
371
:
126
34
67.
Price
D
,
Kenyon
NJ
,
Stollenwerk
N
:
A fresh look at paralytics in the critically ill: Real promise and real concern.
Ann Intensive Care
2012
;
2
:
43
68.
Segredo
V
,
Caldwell
JE
,
Matthay
MA
,
Sharma
ML
,
Gruenke
LD
,
Miller
RD
:
Persistent paralysis in critically ill patients after long-term administration of vecuronium.
N Engl J Med
1992
;
327
:
524
8
69.
Testelmans
D
,
Maes
K
,
Wouters
P
,
Gosselin
N
,
Deruisseau
K
,
Powers
S
,
Sciot
R
,
Decramer
M
,
Gayan-Ramirez
G
:
Rocuronium exacerbates mechanical ventilation-induced diaphragm dysfunction in rats.
Crit Care Med
2006
;
34
:
3018
23
70.
Puntillo
KA
:
Dimensions of procedural pain and its analgesic management in critically ill surgical patients.
Am J Crit Care
1994
;
3
:
116
22
71.
Puntillo
KA
,
Max
A
,
Timsit
JF
,
Vignoud
L
,
Chanques
G
,
Robleda
G
,
Roche-Campo
F
,
Mancebo
J
,
Divatia
JV
,
Soares
M
,
Ionescu
DC
,
Grintescu
IM
,
Vasiliu
IL
,
Maggiore
SM
,
Rusinova
K
,
Owczuk
R
,
Egerod
I
,
Papathanassoglou
ED
,
Kyranou
M
,
Joynt
GM
,
Burghi
G
,
Freebairn
RC
,
Ho
KM
,
Kaarlola
A
,
Gerritsen
RT
,
Kesecioglu
J
,
Sulaj
MM
,
Norrenberg
M
,
Benoit
DD
,
Seha
MS
,
Hennein
A
,
Periera
FJ
,
Benbenishty
JS
,
Abroug
F
,
Aquilina
A
,
Monte
JR
,
An
Y
,
Azoulay
E
:
Determinants of procedural pain intensity in the intensive care unit. The Europain® study.
Am J Respir Crit Care Med
2014
;
189
:
39
47
72.
Ruiz Neto
PP
,
Auler Júnior
JO
:
Respiratory mechanical properties during fentanyl and alfentanil anaesthesia.
Can J Anaesth
1992
;
39
(
5 pt 1
):
458
65
73.
Lui
PW
,
Lee
TY
,
Chan
SH
:
Involvement of coerulospinal noradrenergic pathway in fentanyl-induced muscular rigidity in rats.
Neurosci Lett
1990
;
108
:
183
8
74.
Campbell
C
,
Weinger
MB
,
Quinn
M
:
Alterations in diaphragm EMG activity during opiate-induced respiratory depression.
Respir Physiol
1995
;
100
:
107
17
75.
Jung
B
,
Nougaret
S
,
Conseil
M
,
Coisel
Y
,
Futier
E
,
Chanques
G
,
Molinari
N
,
Lacampagne
A
,
Matecki
S
,
Jaber
S
:
Sepsis is associated with a preferential diaphragmatic atrophy: A critically ill patient study using tridimensional computed tomography.
Anesthesiology
2014
;
120
:
1182
91
76.
Koo
CY
,
Eikermann
M
:
Effects of opioids in perioperative medicine.
Open Anesthesiol J
2011
;
5
:
23
4
77.
Richardson
J
,
Sabanathan
S
,
Shah
RD
,
Clarke
BJ
,
Cheema
S
,
Mearns
AJ
:
Pleural bupivacaine placement for optimal postthoracotomy pulmonary function: A prospective, randomized study.
J Cardiothorac Vasc Anesth
1998
;
12
:
166
9
78.
Needham
DM
,
Korupolu
R
,
Zanni
JM
,
Pradhan
P
,
Colantuoni
E
,
Palmer
JB
,
Brower
RG
,
Fan
E
:
Early physical medicine and rehabilitation for patients with acute respiratory failure: A quality improvement project.
Arch Phys Med Rehabil
2010
;
91
:
536
42
79.
Baldwin
CE
,
Bersten
AD
:
Alterations in respiratory and limb muscle strength and size in patients with sepsis who are mechanically ventilated.
Phys Ther
2014
;
94
:
68
82
80.
Banerjee
A
,
Girard
TD
,
Pandharipande
P
:
The complex interplay between delirium, sedation, and early mobility during critical illness: Applications in the trauma unit.
Curr Opin Anaesthesiol
2011
;
24
:
195
201
81.
Liu
YC
,
Tsai
WS
,
Chau
T
,
Lin
SH
:
Acute hypercapnic respiratory failure due to thyrotoxic periodic paralysis.
Am J Med Sci
2004
;
327
:
264
7
82.
Chhabra
A
,
Patwari
AK
,
Aneja
S
,
Chandra
J
,
Anand
VK
,
Ahluwalia
TP
:
Neuromuscular manifestations of diarrhea related hypokalemia.
Indian Pediatr
1995
;
32
:
409
15
83.
Varsano
S
,
Shapiro
M
,
Taragan
R
,
Bruderman
I
:
Hypophosphatemia as a reversible cause of refractory ventilatory failure.
Crit Care Med
1983
;
11
:
908
9
84.
Kang
TM
:
Propofol infusion syndrome in critically ill patients.
Ann Pharmacother
2002
;
36
:
1453
6
85.
Racca
F
,
Mongini
T
,
Wolfler
A
,
Vianello
A
,
Cutrera
R
,
Del Sorbo
L
,
Capello
EC
,
Gregoretti
C
,
Massa
R
,
De Luca
D
,
Conti
G
,
Tegazzin
V
,
Toscano
A
,
Ranieri
VM
:
Recommendations for anesthesia and perioperative management of patients with neuromuscular disorders.
Minerva Anestesiol
2013
;
79
:
419
33
86.
Byrnes
MC
,
Stangenes
J
:
Refeeding in the ICU: An adult and pediatric problem.
Curr Opin Clin Nutr Metab Care
2011
;
14
:
186
92
87.
Skipper
A
:
Refeeding syndrome or refeeding hypophosphatemia: A systematic review of cases.
Nutr Clin Pract
2012
;
27
:
34
40
88.
Dhand
UK
:
Clinical approach to the weak patient in the intensive care unit.
Respir Care
2006
;
51
:
1024
40
89.
Reid
MB
,
Judge
AR
,
Bodine
SC
:
CrossTalk opposing view: The dominant mechanism causing disuse muscle atrophy is proteolysis.
J Physiol
2014
;
592
(
pt 24
):
5345
7
90.
Bodine
SC
:
Disuse-induced muscle wasting.
Int J Biochem Cell Biol
2013
;
45
:
2200
8
91.
Ohira
Y
,
Yoshinaga
T
,
Nomura
T
,
Kawano
F
,
Ishihara
A
,
Nonaka
I
,
Roy
RR
,
Edgerton
VR
:
Gravitational unloading effects on muscle fiber size, phenotype and myonuclear number.
Adv Space Res
2002
;
30
:
777
81
92.
Zhong
H
,
Roy
RR
,
Siengthai
B
,
Edgerton
VR
:
Effects of inactivity on fiber size and myonuclear number in rat soleus muscle.
J Appl Physiol
2005
;
99
:
1494
9
93.
Psatha
M
,
Wu
Z
,
Gammie
FM
,
Ratkevicius
A
,
Wackerhage
H
,
Lee
JH
,
Redpath
TW
,
Gilbert
FJ
,
Ashcroft
GP
,
Meakin
JR
,
Aspden
RM
:
A longitudinal MRI study of muscle atrophy during lower leg immobilization following ankle fracture.
J Magn Reson Imaging
2012
;
35
:
686
95
94.
Brocca
L
,
Cannavino
J
,
Coletto
L
,
Biolo
G
,
Sandri
M
,
Bottinelli
R
,
Pellegrino
MA
:
The time course of the adaptations of human muscle proteome to bed rest and the underlying mechanisms.
J Physiol
2012
;
590
(
pt 20
):
5211
30
95.
Fitts
RH
,
Trappe
SW
,
Costill
DL
,
Gallagher
PM
,
Creer
AC
,
Colloton
PA
,
Peters
JR
,
Romatowski
JG
,
Bain
JL
,
Riley
DA
:
Prolonged space flight-induced alterations in the structure and function of human skeletal muscle fibres.
J Physiol
2010
;
588
(
pt 18
):
3567
92
96.
Carda
S
,
Cisari
C
,
Invernizzi
M
:
Sarcopenia or muscle modifications in neurologic diseases: A lexical or patophysiological difference?
Eur J Phys Rehabil Med
2013
;
49
:
119
30
97.
Glover
EI
,
Phillips
SM
,
Oates
BR
,
Tang
JE
,
Tarnopolsky
MA
,
Selby
A
,
Smith
K
,
Rennie
MJ
:
Immobilization induces anabolic resistance in human myofibrillar protein synthesis with low and high dose amino acid infusion.
J Physiol
2008
;
586
(
pt 24
):
6049
61
98.
Paddon-Jones
D
,
Sheffield-Moore
M
,
Cree
MG
,
Hewlings
SJ
,
Aarsland
A
,
Wolfe
RR
,
Ferrando
AA
:
Atrophy and impaired muscle protein synthesis during prolonged inactivity and stress.
J Clin Endocrinol Metab
2006
;
91
:
4836
41
99.
Urso
ML
,
Scrimgeour
AG
,
Chen
YW
,
Thompson
PD
,
Clarkson
PM
:
Analysis of human skeletal muscle after 48 h immobilization reveals alterations in mRNA and protein for extracellular matrix components.
J Appl Physiol
2006
;
101
:
1136
48
100.
Sandri
M
:
Protein breakdown in muscle wasting: Role of autophagy-lysosome and ubiquitin-proteasome.
Int J Biochem Cell Biol
2013
;
45
:
2121
9
101.
Puthucheary
ZA
,
Rawal
J
,
McPhail
M
,
Connolly
B
,
Ratnayake
G
,
Chan
P
,
Hopkinson
NS
,
Phadke
R
,
Padhke
R
,
Dew
T
,
Sidhu
PS
,
Velloso
C
,
Seymour
J
,
Agley
CC
,
Selby
A
,
Limb
M
,
Edwards
LM
,
Smith
K
,
Rowlerson
A
,
Rennie
MJ
,
Moxham
J
,
Harridge
SD
,
Hart
N
,
Montgomery
HE
:
Acute skeletal muscle wasting in critical illness.
JAMA
2013
;
310
:
1591
600
102.
Llovera
M
,
Carbó
N
,
López-Soriano
J
,
García-Martínez
C
,
Busquets
S
,
Alvarez
B
,
Agell
N
,
Costelli
P
,
López-Soriano
FJ
,
Celada
A
,
Argilés
JM
:
Different cytokines modulate ubiquitin gene expression in rat skeletal muscle.
Cancer Lett
1998
;
133
:
83
7
103.
Wall
BT
,
Dirks
ML
,
Snijders
T
,
Senden
JM
,
Dolmans
J
,
van Loon
LJ
:
Substantial skeletal muscle loss occurs during only 5 days of disuse.
Acta Physiol (Oxf)
2014
;
210
:
600
11
104.
Lecker
SH
,
Goldberg
AL
,
Mitch
WE
:
Protein degradation by the ubiquitin-proteasome pathway in normal and disease states.
J Am Soc Nephrol
2006
;
17
:
1807
19
105.
Bodine
SC
,
Latres
E
,
Baumhueter
S
,
Lai
VK
,
Nunez
L
,
Clarke
BA
,
Poueymirou
WT
,
Panaro
FJ
,
Na
E
,
Dharmarajan
K
,
Pan
ZQ
,
Valenzuela
DM
,
DeChiara
TM
,
Stitt
TN
,
Yancopoulos
GD
,
Glass
DJ
:
Identification of ubiquitin ligases required for skeletal muscle atrophy.
Science
2001
;
294
:
1704
8
106.
DeRuisseau
KC
,
Kavazis
AN
,
Deering
MA
,
Falk
DJ
,
Van Gammeren
D
,
Yimlamai
T
,
Ordway
GA
,
Powers
SK
:
Mechanical ventilation induces alterations of the ubiquitin-proteasome pathway in the diaphragm.
J Appl Physiol
2005
;
98
:
1314
21
107.
Hussain
SN
,
Mofarrahi
M
,
Sigala
I
,
Kim
HC
,
Vassilakopoulos
T
,
Maltais
F
,
Bellenis
I
,
Chaturvedi
R
,
Gottfried
SB
,
Metrakos
P
,
Danialou
G
,
Matecki
S
,
Jaber
S
,
Petrof
BJ
,
Goldberg
P
:
Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy.
Am J Respir Crit Care Med
2010
;
182
:
1377
86
108.
Levine
S
,
Biswas
C
,
Dierov
J
,
Barsotti
R
,
Shrager
JB
,
Nguyen
T
,
Sonnad
S
,
Kucharchzuk
JC
,
Kaiser
LR
,
Singhal
S
,
Budak
MT
:
Increased proteolysis, myosin depletion, and atrophic AKT-FOXO signaling in human diaphragm disuse.
Am J Respir Crit Care Med
2011
;
183
:
483
90
109.
de Boer
MD
,
Selby
A
,
Atherton
P
,
Smith
K
,
Seynnes
OR
,
Maganaris
CN
,
Maffulli
N
,
Movin
T
,
Narici
MV
,
Rennie
MJ
:
The temporal responses of protein synthesis, gene expression and cell signalling in human quadriceps muscle and patellar tendon to disuse.
J Physiol
2007
;
585
(
pt 1
):
241
51
110.
Abadi
A
,
Glover
EI
,
Isfort
RJ
,
Raha
S
,
Safdar
A
,
Yasuda
N
,
Kaczor
JJ
,
Melov
S
,
Hubbard
A
,
Qu
X
,
Phillips
SM
,
Tarnopolsky
M
:
Limb immobilization induces a coordinate down-regulation of mitochondrial and other metabolic pathways in men and women.
PLoS One
2009
;
4
:
e6518
111.
Gustafsson
T
,
Osterlund
T
,
Flanagan
JN
,
von Waldén
F
,
Trappe
TA
,
Linnehan
RM
,
Tesch
PA
:
Effects of 3 days unloading on molecular regulators of muscle size in humans.
J Appl Physiol
2010
;
109
:
721
7
112.
Jones
SW
,
Hill
RJ
,
Krasney
PA
,
O’Conner
B
,
Peirce
N
,
Greenhaff
PL
:
Disuse atrophy and exercise rehabilitation in humans profoundly affects the expression of genes associated with the regulation of skeletal muscle mass.
FASEB J
2004
;
18
:
1025
7
113.
Levine
S
,
Nguyen
T
,
Taylor
N
,
Friscia
ME
,
Budak
MT
,
Rothenberg
P
,
Zhu
J
,
Sachdeva
R
,
Sonnad
S
,
Kaiser
LR
,
Rubinstein
NA
,
Powers
SK
,
Shrager
JB
:
Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans.
N Engl J Med
2008
;
358
:
1327
35
114.
Ferreira
R
,
Vitorino
R
,
Neuparth
MJ
,
Appell
HJ
,
Duarte
JA
,
Amado
F
:
Proteolysis activation and proteome alterations in murine skeletal muscle submitted to 1 week of hindlimb suspension.
Eur J Appl Physiol
2009
;
107
:
553
63
115.
Talbert
EE
,
Smuder
AJ
,
Min
K
,
Kwon
OS
,
Powers
SK
:
Calpain and caspase-3 play required roles in immobilization-induced limb muscle atrophy.
J Appl Physiol
2013
;
114
:
1482
9
116.
Andrianjafiniony
T
,
Dupré-Aucouturier
S
,
Letexier
D
,
Couchoux
H
,
Desplanches
D
:
Oxidative stress, apoptosis, and proteolysis in skeletal muscle repair after unloading.
Am J Physiol Cell Physiol
2010
;
299
:
C307
15
117.
Nelson
WB
,
Smuder
AJ
,
Hudson
MB
,
Talbert
EE
,
Powers
SK
:
Cross-talk between the calpain and caspase-3 proteolytic systems in the diaphragm during prolonged mechanical ventilation.
Crit Care Med
2012
;
40
:
1857
63
118.
Bonaldo
P
,
Sandri
M
:
Cellular and molecular mechanisms of muscle atrophy.
Dis Model Mech
2013
;
6
:
25
39
119.
Derde
S
,
Vanhorebeek
I
,
Güiza
F
,
Derese
I
,
Gunst
J
,
Fahrenkrog
B
,
Martinet
W
,
Vervenne
H
,
Ververs
EJ
,
Larsson
L
,
Van den Berghe
G
:
Early parenteral nutrition evokes a phenotype of autophagy deficiency in liver and skeletal muscle of critically ill rabbits.
Endocrinology
2012
;
153
:
2267
76
120.
Bechet
D
,
Tassa
A
,
Taillandier
D
,
Combaret
L
,
Attaix
D
:
Lysosomal proteolysis in skeletal muscle.
Int J Biochem Cell Biol
2005
;
37
:
2098
114
121.
Zhao
J
,
Brault
JJ
,
Schild
A
,
Cao
P
,
Sandri
M
,
Schiaffino
S
,
Lecker
SH
,
Goldberg
AL
:
FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells.
Cell Metab
2007
;
6
:
472
83
122.
Furuno
K
,
Goodman
MN
,
Goldberg
AL
:
Role of different proteolytic systems in the degradation of muscle proteins during denervation atrophy.
J Biol Chem
1990
;
265
:
8550
7
123.
Deval
C
,
Mordier
S
,
Obled
C
,
Bechet
D
,
Combaret
L
,
Attaix
D
,
Ferrara
M
:
Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting.
Biochem J
2001
;
360
(
pt 1
):
143
50
124.
Mammucari
C
,
Milan
G
,
Romanello
V
,
Masiero
E
,
Rudolf
R
,
Del Piccolo
P
,
Burden
SJ
,
Di Lisi
R
,
Sandri
C
,
Zhao
J
,
Goldberg
AL
,
Schiaffino
S
,
Sandri
M
:
FoxO3 controls autophagy in skeletal muscle in vivo.
Cell Metab
2007
;
6
:
458
71
125.
Levine
B
,
Kroemer
G
:
Autophagy in the pathogenesis of disease.
Cell
2008
;
132
:
27
42
126.
Masiero
E
,
Agatea
L
,
Mammucari
C
,
Blaauw
B
,
Loro
E
,
Komatsu
M
,
Metzger
D
,
Reggiani
C
,
Schiaffino
S
,
Sandri
M
:
Autophagy is required to maintain muscle mass.
Cell Metab
2009
;
10
:
507
15
127.
Masiero
E
,
Sandri
M
:
Autophagy inhibition induces atrophy and myopathy in adult skeletal muscles.
Autophagy
2010
;
6
:
307
9
128.
Jamart
C
,
Benoit
N
,
Raymackers
JM
,
Kim
HJ
,
Kim
CK
,
Francaux
M
:
Autophagy-related and autophagy-regulatory genes are induced in human muscle after ultraendurance exercise.
Eur J Appl Physiol
2012
;
112
:
3173
7
129.
Jamart
C
,
Francaux
M
,
Millet
GY
,
Deldicque
L
,
Frère
D
,
Féasson
L
:
Modulation of autophagy and ubiquitin-proteasome pathways during ultra-endurance running.
J Appl Physiol
2012
;
112
:
1529
37
130.
He
C
,
Bassik
MC
,
Moresi
V
,
Sun
K
,
Wei
Y
,
Zou
Z
,
An
Z
,
Loh
J
,
Fisher
J
,
Sun
Q
,
Korsmeyer
S
,
Packer
M
,
May
HI
,
Hill
JA
,
Virgin
HW
,
Gilpin
C
,
Xiao
G
,
Bassel-Duby
R
,
Scherer
PE
,
Levine
B
:
Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis.
Nature
2012
;
481
:
511
5
131.
Hermans
G
,
Casaer
MP
,
Clerckx
B
,
Güiza
F
,
Vanhullebusch
T
,
Derde
S
,
Meersseman
P
,
Derese
I
,
Mesotten
D
,
Wouters
PJ
,
Van Cromphaut
S
,
Debaveye
Y
,
Gosselink
R
,
Gunst
J
,
Wilmer
A
,
Van den Berghe
G
,
Vanhorebeek
I
:
Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: A subanalysis of the EPaNIC trial.
Lancet Respir Med
2013
;
1
:
621
9
132.
Latronico
N
,
Nisoli
E
,
Eikermann
M
:
Muscle weakness and nutrition in critical illness: Matching nutrient supply and use.
Lancet Respir Med
2013
;
1
:
589
90
133.
Eikermann
M
,
Koch
G
,
Gerwig
M
,
Ochterbeck
C
,
Beiderlinden
M
,
Koeppen
S
,
Neuhäuser
M
,
Peters
J
:
Muscle force and fatigue in patients with sepsis and multiorgan failure.
Intensive Care Med
2006
;
32
:
251
9
134.
Yealy
DM
,
Kellum
JA
,
Huang
DT
,
Barnato
AE
,
Weissfeld
LA
,
Pike
F
,
Terndrup
T
,
Wang
HE
,
Hou
PC
,
LoVecchio
F
,
Filbin
MR
,
Shapiro
NI
,
Angus
DC
;
ProCESS Investigators
:
A randomized trial of protocol-based care for early septic shock.
N Engl J Med
2014
;
370
:
1683
93
135.
Llano-Diez
M
,
Renaud
G
,
Andersson
M
,
Marrero
HG
,
Cacciani
N
,
Engquist
H
,
Corpeño
R
,
Artemenko
K
,
Bergquist
J
,
Larsson
L
:
Mechanisms underlying ICU muscle wasting and effects of passive mechanical loading.
Crit Care
2012
;
16
:
R209
136.
Mendez-Tellez
PA
,
Needham
DM
:
Early physical rehabilitation in the ICU and ventilator liberation.
Respir Care
2012
;
57
:
1663
9
137.
Griffiths
RD
,
Hall
JB
:
Intensive care unit-acquired weakness.
Crit Care Med
2010
;
38
:
779
87
138.
Aversa
Z
,
Alamdari
N
,
Castillero
E
,
Muscaritoli
M
,
Rossi Fanelli
F
,
Hasselgren
PO
:
CaMKII activity is reduced in skeletal muscle during sepsis.
J Cell Biochem
2013
;
114
:
1294
305
139.
Gordon
BS
,
Kelleher
AR
,
Kimball
SR
:
Regulation of muscle protein synthesis and the effects of catabolic states.
Int J Biochem Cell Biol
2013
;
45
:
2147
57
140.
Muñoz-Cánoves
P
,
Scheele
C
,
Pedersen
BK
,
Serrano
AL
:
Interleukin-6 myokine signaling in skeletal muscle: A double-edged sword?
FEBS J
2013
;
280
:
4131
48
141.
Haddad
F
,
Zaldivar
F
,
Cooper
DM
,
Adams
GR
:
IL-6-induced skeletal muscle atrophy.
J Appl Physiol
2005
;
98
:
911
7
142.
Kopf
M
,
Baumann
H
,
Freer
G
,
Freudenberg
M
,
Lamers
M
,
Kishimoto
T
,
Zinkernagel
R
,
Bluethmann
H
,
Köhler
G
:
Impaired immune and acute-phase responses in interleukin-6-deficient mice.
Nature
1994
;
368
:
339
42
143.
Strassmann
G
,
Fong
M
,
Kenney
JS
,
Jacob
CO
:
Evidence for the involvement of interleukin 6 in experimental cancer cachexia.
J Clin Invest
1992
;
89
:
1681
4
144.
Oldenburg
HS
,
Rogy
MA
,
Lazarus
DD
,
Van Zee
KJ
,
Keeler
BP
,
Chizzonite
RA
,
Lowry
SF
,
Moldawer
LL
:
Cachexia and the acute-phase protein response in inflammation are regulated by interleukin-6.
Eur J Immunol
1993
;
23
:
1889
94
145.
Goodman
MN
:
Interleukin-6 induces skeletal muscle protein breakdown in rats.
Proc Soc Exp Biol Med
1994
;
205
:
182
5
146.
Tsujinaka
T
,
Ebisui
C
,
Fujita
J
,
Kishibuchi
M
,
Morimoto
T
,
Ogawa
A
,
Katsume
A
,
Ohsugi
Y
,
Kominami
E
,
Monden
M
:
Muscle undergoes atrophy in association with increase of lysosomal cathepsin activity in interleukin-6 transgenic mouse.
Biochem Biophys Res Commun
1995
;
207
:
168
74
147.
Tsujinaka
T
,
Fujita
J
,
Ebisui
C
,
Yano
M
,
Kominami
E
,
Suzuki
K
,
Tanaka
K
,
Katsume
A
,
Ohsugi
Y
,
Shiozaki
H
,
Monden
M
:
Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice.
J Clin Invest
1996
;
97
:
244
9
148.
Ebisui
C
,
Tsujinaka
T
,
Morimoto
T
,
Kan
K
,
Iijima
S
,
Yano
M
,
Kominami
E
,
Tanaka
K
,
Monden
M
:
Interleukin-6 induces proteolysis by activating intracellular proteases (cathepsins B and L, proteasome) in C2C12 myotubes.
Clin Sci
1995
;
89
:
431
9
149.
Williams
A
,
Wang
JJ
,
Wang
L
,
Sun
X
,
Fischer
JE
,
Hasselgren
PO
:
Sepsis in mice stimulates muscle proteolysis in the absence of IL-6.
Am J Physiol
1998
;
275
(
6 pt 2
):
R1983
91
150.
Spangenburg
EE
,
Booth
FW
:
Leukemia inhibitory factor restores the hypertrophic response to increased loading in the LIF(-/-) mouse.
Cytokine
2006
;
34
:
125
30
151.
Fischer
CP
:
Interleukin-6 in acute exercise and training: What is the biological relevance?
Exerc Immunol Rev
2006
;
12
:
6
33
152.
Nieman
DC
,
Nehlsen-Cannarella
SL
,
Fagoaga
OR
,
Henson
DA
,
Utter
A
,
Davis
JM
,
Williams
F
,
Butterworth
DE
:
Influence of mode and carbohydrate on the cytokine response to heavy exertion.
Med Sci Sports Exerc
1998
;
30
:
671
8
153.
Baeza-Raja
B
,
Muñoz-Cánoves
P
:
p38 MAPK-induced nuclear factor-kappaB activity is required for skeletal muscle differentiation: Role of interleukin-6.
Mol Biol Cell
2004
;
15
:
2013
26
154.
Broholm
C
,
Laye
MJ
,
Brandt
C
,
Vadalasetty
R
,
Pilegaard
H
,
Pedersen
BK
,
Scheele
C
:
LIF is a contraction-induced myokine stimulating human myocyte proliferation.
J Appl Physiol
2011
;
111
:
251
9
155.
Eikermann
M
,
Vidal Melo
MF
:
Therapeutic range of spontaneous breathing during mechanical ventilation.
Anesthesiology
2014
;
120
:
536
9
156.
Chambers
MA
,
Moylan
JS
,
Reid
MB
:
Physical inactivity and muscle weakness in the critically ill.
Crit Care Med
2009
;
37
(
10 suppl
):
S337
46
157.
Shanely
RA
,
Zergeroglu
MA
,
Lennon
SL
,
Sugiura
T
,
Yimlamai
T
,
Enns
D
,
Belcastro
A
,
Powers
SK
:
Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative injury and increased proteolytic activity.
Am J Respir Crit Care Med
2002
;
166
:
1369
74
158.
Reisinger
KW
,
van Vugt
JL
,
Tegels
JJ
,
Snijders
C
,
Hulsewé
KW
,
Hoofwijk
AG
,
Stoot
JH
,
Von Meyenfeldt
MF
,
Beets
GL
,
Derikx
JP
,
Poeze
M
:
Functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery.
Ann Surg
2015
;
261
:
345
52
159.
Dempsey
DT
,
Mullen
JL
,
Buzby
GP
:
The link between nutritional status and clinical outcome: Can nutritional intervention modify it?
Am J Clin Nutr
1988
;
47
(
2 suppl
):
352
6
160.
Goiburu
ME
,
Goiburu
MM
,
Bianco
H
,
Díaz
JR
,
Alderete
F
,
Palacios
MC
,
Cabral
V
,
Escobar
D
,
López
R
,
Waitzberg
DL
:
The impact of malnutrition on morbidity, mortality and length of hospital stay in trauma patients.
Nutr Hosp
2006
;
21
:
604
10
161.
Casaer
MP
,
Van den Berghe
G
:
Nutrition in the acute phase of critical illness.
N Engl J Med
2014
;
370
:
2450
1
162.
Casaer
MP
,
Mesotten
D
,
Hermans
G
,
Wouters
PJ
,
Schetz
M
,
Meyfroidt
G
,
Van Cromphaut
S
,
Ingels
C
,
Meersseman
P
,
Muller
J
,
Vlasselaers
D
,
Debaveye
Y
,
Desmet
L
,
Dubois
J
,
Van Assche
A
,
Vanderheyden
S
,
Wilmer
A
,
Van den Berghe
G
:
Early versus late parenteral nutrition in critically ill adults.
N Engl J Med
2011
;
365
:
506
17
163.
Vanhorebeek
I
,
Gunst
J
,
Derde
S
,
Derese
I
,
Boussemaere
M
,
Güiza
F
,
Martinet
W
,
Timmermans
JP
,
D’Hoore
A
,
Wouters
PJ
,
Van den Berghe
G
:
Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patients.
J Clin Endocrinol Metab
2011
;
96
:
E633
45
164.
Heidegger
CP
,
Berger
MM
,
Graf
S
,
Zingg
W
,
Darmon
P
,
Costanza
MC
,
Thibault
R
,
Pichard
C
:
Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: A randomised controlled clinical trial.
Lancet
2013
;
381
:
385
93
165.
Brunello
AG
,
Haenggi
M
,
Wigger
O
,
Porta
F
,
Takala
J
,
Jakob
SM
:
Usefulness of a clinical diagnosis of ICU-acquired paresis to predict outcome in patients with SIRS and acute respiratory failure.
Intensive Care Med
2010
;
36
:
66
74
166.
Needham
DM
,
Wozniak
AW
,
Hough
CL
,
Morris
PE
,
Dinglas
VD
,
Jackson
JC
,
Mendez-Tellez
PA
,
Shanholtz
C
,
Ely
EW
,
Colantuoni
E
,
Hopkins
RO
;
National Institutes of Health NHLBI ARDS Network
:
Risk factors for physical impairment after acute lung injury in a national, multicenter study.
Am J Respir Crit Care Med
2014
;
189
:
1214
24
167.
Steinberg
KP
,
Hudson
LD
,
Goodman
RB
,
Hough
CL
,
Lanken
PN
,
Hyzy
R
,
Thompson
BT
,
Ancukiewicz
M
;
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network
:
Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.
N Engl J Med
2006
;
354
:
1671
84
168.
Aare
S
,
Radell
P
,
Eriksson
LI
,
Akkad
H
,
Chen
YW
,
Hoffman
EP
,
Larsson
L
:
Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model.
Physiol Genomics
2013
;
45
:
312
20
169.
Massa
R
,
Carpenter
S
,
Holland
P
,
Karpati
G
:
Loss and renewal of thick myofilaments in glucocorticoid-treated rat soleus after denervation and reinnervation.
Muscle Nerve
1992
;
15
:
1290
8
170.
Bolton
CF
:
Neuromuscular manifestations of critical illness.
Muscle Nerve
2005
;
32
:
140
63
171.
Funk
D
,
Doucette
S
,
Pisipati
A
,
Dodek
P
,
Marshall
JC
,
Kumar
A
;
Cooperative Antimicrobial Therapy of Septic Shock Database Research Group
:
Low-dose corticosteroid treatment in septic shock: A propensity-matching study.
Crit Care Med
2014
;
42
:
2333
41
172.
Moreno
R
,
Sprung
CL
,
Annane
D
,
Chevret
S
,
Briegel
J
,
Keh
D
,
Singer
M
,
Weiss
YG
,
Payen
D
,
Cuthbertson
BH
,
Vincent
JL
:
Time course of organ failure in patients with septic shock treated with hydrocortisone: Results of the Corticus study.
Intensive Care Med
2011
;
37
:
1765
72
173.
Rolland
Y
,
Onder
G
,
Morley
JE
,
Gillette-Guyonet
S
,
Abellan van Kan
G
,
Vellas
B
:
Current and future pharmacologic treatment of sarcopenia.
Clin Geriatr Med
2011
;
27
:
423
47
174.
Artaza
JN
,
Bhasin
S
,
Magee
TR
,
Reisz-Porszasz
S
,
Shen
R
,
Groome
NP
,
Meerasahib
MF
,
Fareez
MM
,
Gonzalez-Cadavid
NF
:
Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells.
Endocrinology
2005
;
146
:
3547
57
175.
Schuelke
M
,
Wagner
KR
,
Stolz
LE
,
Hübner
C
,
Riebel
T
,
Kömen
W
,
Braun
T
,
Tobin
JF
,
Lee
SJ
:
Myostatin mutation associated with gross muscle hypertrophy in a child.
N Engl J Med
2004
;
350
:
2682
8
176.
Quraishi
SA
,
McCarthy
C
,
Blum
L
,
Cobb
JP
,
Camargo
CA
Jr
:
Plasma 25-hydroxyvitamin D levels at initiation of care and duration of mechanical ventilation in critically ill surgical patients.
JPEN J Parenter Enteral Nutr
2015
[Epub ahead of print]
177.
Quraishi
SA
,
Bittner
EA
,
Blum
L
,
McCarthy
CM
,
Bhan
I
,
Camargo
CA
Jr
:
Prospective study of vitamin D status at initiation of care in critically ill surgical patients and risk of 90-day mortality.
Crit Care Med
2014
;
42
:
1365
71
178.
Han
Y
,
Runge
MS
,
Brasier
AR
:
Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors.
Circ Res
1999
;
84
:
695
703
179.
Solomon
AM
,
Bouloux
PM
:
Modifying muscle mass—The endocrine perspective.
J Endocrinol
2006
;
191
:
349
60
180.
Kranzhöfer
R
,
Schmidt
J
,
Pfeiffer
CA
,
Hagl
S
,
Libby
P
,
Kübler
W
:
Angiotensin induces inflammatory activation of human vascular smooth muscle cells.
Arterioscler Thromb Vasc Biol
1999
;
19
:
1623
9
181.
Browatzki
M
,
Larsen
D
,
Pfeiffer
CA
,
Gehrke
SG
,
Schmidt
J
,
Kranzhofer
A
,
Katus
HA
,
Kranzhofer
R
:
Angiotensin II stimulates matrix metalloproteinase secretion in human vascular smooth muscle cells via nuclear factor-kappaB and activator protein 1 in a redox-sensitive manner.
J Vasc Res
2005
;
42
:
415
23
182.
Musarò
A
,
McCullagh
KJ
,
Naya
FJ
,
Olson
EN
,
Rosenthal
N
:
IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1.
Nature
1999
;
400
:
581
5
183.
Brink
M
,
Price
SR
,
Chrast
J
,
Bailey
JL
,
Anwar
A
,
Mitch
WE
,
Delafontaine
P
:
Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I.
Endocrinology
2001
;
142
:
1489
96
184.
Fried
LP
,
Tangen
CM
,
Walston
J
,
Newman
AB
,
Hirsch
C
,
Gottdiener
J
,
Seeman
T
,
Tracy
R
,
Kop
WJ
,
Burke
G
,
McBurnie
MA
;
Cardiovascular Health Study Collaborative Research Group
:
Frailty in older adults: Evidence for a phenotype.
J Gerontol A Biol Sci Med Sci
2001
;
56
:
M146
56
185.
Puthucheary
ZA
,
Hart
N
:
Skeletal muscle mass and mortality—But what about functional outcome?
Crit Care
2014
;
18
:
110
186.
Waak
K
,
Zaremba
S
,
Eikermann
M
:
Muscle strength measurement in the intensive care unit: Not everything that can be counted counts.
J Crit Care
2013
;
28
:
96
8
187.
Murphy
GS
,
Szokol
JW
,
Avram
MJ
,
Greenberg
SB
,
Marymont
JH
,
Vender
JS
,
Gray
J
,
Landry
E
,
Gupta
DK
:
Intraoperative acceleromyography monitoring reduces symptoms of muscle weakness and improves quality of recovery in the early postoperative period.
Anesthesiology
2011
;
115
:
946
54
188.
Vanpee
G
,
Hermans
G
,
Segers
J
,
Gosselink
R
:
Assessment of limb muscle strength in critically ill patients: A systematic review.
Crit Care Med
2014
;
42
:
701
11
189.
Lee
JJ
,
Waak
K
,
Grosse-Sundrup
M
,
Xue
F
,
Lee
J
,
Chipman
D
,
Ryan
C
,
Bittner
EA
,
Schmidt
U
,
Eikermann
M
:
Global muscle strength but not grip strength predicts mortality and length of stay in a general population in a surgical intensive care unit.
Phys Ther
2012
;
92
:
1546
55
190.
Fan
E
,
Cheek
F
,
Chlan
L
,
Gosselink
R
,
Hart
N
,
Herridge
MS
,
Hopkins
RO
,
Hough
CL
,
Kress
JP
,
Latronico
N
,
Moss
M
,
Needham
DM
,
Rich
MM
,
Stevens
RD
,
Wilson
KC
,
Winkelman
C
,
Zochodne
DW
,
Ali
NA
;
ATS Committee on ICU-acquired Weakness in Adults; American Thoracic Society
:
An official American Thoracic Society Clinical Practice guideline: The diagnosis of intensive care unit-acquired weakness in adults.
Am J Respir Crit Care Med
2014
;
190
:
1437
46
191.
Hough
CL
,
Lieu
BK
,
Caldwell
ES
:
Manual muscle strength testing of critically ill patients: Feasibility and interobserver agreement.
Crit Care
2011
;
15
:
R43
192.
Garnacho-Montero
J
,
Amaya-Villar
R
,
García-Garmendía
JL
,
Madrazo-Osuna
J
,
Ortiz-Leyba
C
:
Effect of critical illness polyneuropathy on the withdrawal from mechanical ventilation and the length of stay in septic patients.
Crit Care Med
2005
;
33
:
349
54
193.
Van den Berghe
G
,
Schoonheydt
K
,
Becx
P
,
Bruyninckx
F
,
Wouters
PJ
:
Insulin therapy protects the central and peripheral nervous system of intensive care patients.
Neurology
2005
;
64
:
1348
53
194.
Stevens
RD
,
Dowdy
DW
,
Michaels
RK
,
Mendez-Tellez
PA
,
Pronovost
PJ
,
Needham
DM
:
Neuromuscular dysfunction acquired in critical illness: A systematic review.
Intensive Care Med
2007
;
33
:
1876
91
195.
Tennilä
A
,
Salmi
T
,
Pettilä
V
,
Roine
RO
,
Varpula
T
,
Takkunen
O
:
Early signs of critical illness polyneuropathy in ICU patients with systemic inflammatory response syndrome or sepsis.
Intensive Care Med
2000
;
26
:
1360
3
196.
Latronico
N
,
Smith
M
:
Introducing simplified electrophysiological test of peripheral nerves and muscles in the ICU: Choosing wisely.
Intensive Care Med
2014
;
40
:
746
8
197.
Latronico
N
,
Nattino
G
,
Guarneri
B
,
Fagoni
N
,
Amantini
A
,
Bertolini
G
;
GiVITI Study Investigators
:
Validation of the peroneal nerve test to diagnose critical illness polyneuropathy and myopathy in the intensive care unit: The multicentre Italian CRIMYNE-2 diagnostic accuracy study.
F1000Res
2014
;
3
:
127
198.
Koch
S
,
Wollersheim
T
,
Bierbrauer
J
,
Haas
K
,
Mörgeli
R
,
Deja
M
,
Spies
CD
,
Spuler
S
,
Krebs
M
,
Weber-Carstens
S
:
Long-term recovery in critical illness myopathy is complete, contrary to polyneuropathy.
Muscle Nerve
2014
;
50
:
431
6
199.
Guarneri
B
,
Bertolini
G
,
Latronico
N
:
Long-term outcome in patients with critical illness myopathy or neuropathy: The Italian multicentre CRIMYNE study.
J Neurol Neurosurg Psychiatry
2008
;
79
:
838
41
200.
Ranieri
VM
,
Suter
PM
,
Tortorella
C
,
De Tullio
R
,
Dayer
JM
,
Brienza
A
,
Bruno
F
,
Slutsky
AS
:
Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: A randomized controlled trial.
JAMA
1999
;
282
:
54
61
201.
Rivers
E
,
Nguyen
B
,
Havstad
S
,
Ressler
J
,
Muzzin
A
,
Knoblich
B
,
Peterson
E
,
Tomlanovich
M
;
Early Goal-Directed Therapy Collaborative Group
:
Early goal-directed therapy in the treatment of severe sepsis and septic shock.
N Engl J Med
2001
;
345
:
1368
77
202.
Eisner
MD
,
Thompson
T
,
Hudson
LD
,
Luce
JM
,
Hayden
D
,
Schoenfeld
D
,
Matthay
MA
;
Acute Respiratory Distress Syndrome Network
:
Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome.
Am J Respir Crit Care Med
2001
;
164
:
231
6
203.
Trzeciak
S
,
Dellinger
RP
,
Abate
NL
,
Cowan
RM
,
Stauss
M
,
Kilgannon
JH
,
Zanotti
S
,
Parrillo
JE
:
Translating research to clinical practice: A 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department.
Chest
2006
;
129
:
225
32
204.
ARISE Investigators; ANZICS Clinical Trials Group
Peake
SL
,
Delaney
A
,
Bailey
M
,
Bellomo
R
,
Cameron
PA
,
Cooper
DJ
,
Higgins
AM
,
Holdgate
A
,
Howe
BD
,
Webb
SA
,
Williams
P
;
ARISE Investigators; ANZICS Clinical Trials Group
:
Goal-directed resuscitation for patients with early septic shock.
N Engl J Med
2014
;
371
:
1496
506
205.
Kangas
J
,
Pajala
A
,
Siira
P
,
Hämäläinen
M
,
Leppilahti
J
:
Early functional treatment versus early immobilization in tension of the musculotendinous unit after Achilles rupture repair: A prospective, randomized, clinical study.
J Trauma
2003
;
54
:
1171
80
206.
Burtin
C
,
Clerckx
B
,
Robbeets
C
,
Ferdinande
P
,
Langer
D
,
Troosters
T
,
Hermans
G
,
Decramer
M
,
Gosselink
R
:
Early exercise in critically ill patients enhances short-term functional recovery.
Crit Care Med
2009
;
37
:
2499
505
207.
Rathgeber
J
,
Schorn
B
,
Falk
V
,
Kazmaier
S
,
Spiegel
T
,
Burchardi
H
:
The influence of controlled mandatory ventilation (CMV), intermittent mandatory ventilation (IMV) and biphasic intermittent positive airway pressure (BIPAP) on duration of intubation and consumption of analgesics and sedatives. A prospective analysis in 596 patients following adult cardiac surgery.
Eur J Anaesthesiol
1997
;
14
:
576
82
208.
Putensen
C
,
Zech
S
,
Wrigge
H
,
Zinserling
J
,
Stüber
F
,
Von Spiegel
T
,
Mutz
N
:
Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury.
Am J Respir Crit Care Med
2001
;
164
:
43
9
209.
Amato
MB
,
Barbas
CS
,
Medeiros
DM
,
Magaldi
RB
,
Schettino
GP
,
Lorenzi-Filho
G
,
Kairalla
RA
,
Deheinzelin
D
,
Munoz
C
,
Oliveira
R
,
Takagaki
TY
,
Carvalho
CR
:
Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome.
N Engl J Med
1998
;
338
:
347
54
210.
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network.
N Engl J Med
2000
;
342
:
1301
8
211.
Maxwell
RA
,
Green
JM
,
Waldrop
J
,
Dart
BW
,
Smith
PW
,
Brooks
D
,
Lewis
PL
,
Barker
DE
:
A randomized prospective trial of airway pressure release ventilation and low tidal volume ventilation in adult trauma patients with acute respiratory failure.
J Trauma
2010
;
69
:
501
10
212.
Kress
JP
,
Pohlman
AS
,
O’Connor
MF
,
Hall
JB
:
Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation.
N Engl J Med
2000
;
342
:
1471
7
213.
Robinson
BR
,
Mueller
EW
,
Henson
K
,
Branson
RD
,
Barsoum
S
,
Tsuei
BJ
:
An analgesia-delirium-sedation protocol for critically ill trauma patients reduces ventilator days and hospital length of stay.
J Trauma
2008
;
65
:
517
26
214.
Mehta
S
,
Burry
L
,
Cook
D
,
Fergusson
D
,
Steinberg
M
,
Granton
J
,
Herridge
M
,
Ferguson
N
,
Devlin
J
,
Tanios
M
,
Dodek
P
,
Fowler
R
,
Burns
K
,
Jacka
M
,
Olafson
K
,
Skrobik
Y
,
Hébert
P
,
Sabri
E
,
Meade
M
;
SLEAP Investigators; Canadian Critical Care Trials Group
:
Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: A randomized controlled trial.
JAMA
2012
;
308
:
1985
92
215.
Singh
G
,
Ram
RP
,
Khanna
SK
:
Early postoperative enteral feeding in patients with nontraumatic intestinal perforation and peritonitis.
J Am Coll Surg
1998
;
187
:
142
6
216.
Marik
PE
,
Zaloga
GP
:
Early enteral nutrition in acutely ill patients: A systematic review.
Crit Care Med
2001
;
29
:
2264
70
217.
Minard
G
,
Kudsk
KA
,
Melton
S
,
Patton
JH
,
Tolley
EA
:
Early versus delayed feeding with an immune-enhancing diet in patients with severe head injuries.
JPEN J Parenter Enteral Nutr
2000
;
24
:
145
9
218.
Lewis
SJ
,
Egger
M
,
Sylvester
PA
,
Thomas
S
:
Early enteral feeding versus “nil by mouth” after gastrointestinal surgery: Systematic review and meta-analysis of controlled trials.
BMJ
2001
;
323
:
773
6
219.
Braunschweig
CL
,
Levy
P
,
Sheean
PM
,
Wang
X
:
Enteral compared with parenteral nutrition: A meta-analysis.
Am J Clin Nutr
2001
;
74
:
534
42
220.
Heyland
DK
,
Schroter-Noppe
D
,
Drover
JW
,
Jain
M
,
Keefe
L
,
Dhaliwal
R
,
Day
A
:
Nutrition support in the critical care setting: Current practice in canadian ICUs—Opportunities for improvement?
JPEN J Parenter Enteral Nutr
2003
;
27
:
74
83
221.
Dvorak
MF
,
Noonan
VK
,
Bélanger
L
,
Bruun
B
,
Wing
PC
,
Boyd
MC
,
Fisher
C
:
Early versus late enteral feeding in patients with acute cervical spinal cord injury: A pilot study.
Spine
2004
;
29
:
E175
80
222.
Peck
MD
,
Kessler
M
,
Cairns
BA
,
Chang
YH
,
Ivanova
A
,
Schooler
W
:
Early enteral nutrition does not decrease hypermetabolism associated with burn injury.
J Trauma
2004
;
57
:
1143
8
223.
Artinian
V
,
Krayem
H
,
DiGiovine
B
:
Effects of early enteral feeding on the outcome of critically ill mechanically ventilated medical patients.
Chest
2006
;
129
:
960
7
224.
Harvey
SE
,
Parrott
F
,
Harrison
DA
,
Bear
DE
,
Segaran
E
,
Beale
R
,
Bellingan
G
,
Leonard
R
,
Mythen
MG
,
Rowan
KM
;
CALORIES Trial Investigators
:
Trial of the route of early nutritional support in critically ill adults.
N Engl J Med
2014
;
371
:
1673
84
225.
Doig
GS
,
Simpson
F
,
Sweetman
EA
,
Finfer
SR
,
Cooper
DJ
,
Heighes
PT
,
Davies
AR
,
O’Leary
M
,
Solano
T
,
Peake
S
;
Early PN Investigators of the ANZICS Clinical Trials Group
:
Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: A randomized controlled trial.
JAMA
2013
;
309
:
2130
8
226.
Brunkhorst
FM
,
Engel
C
,
Bloos
F
,
Meier-Hellmann
A
,
Ragaller
M
,
Weiler
N
,
Moerer
O
,
Gruendling
M
,
Oppert
M
,
Grond
S
,
Olthoff
D
,
Jaschinski
U
,
John
S
,
Rossaint
R
,
Welte
T
,
Schaefer
M
,
Kern
P
,
Kuhnt
E
,
Kiehntopf
M
,
Hartog
C
,
Natanson
C
,
Loeffler
M
,
Reinhart
K
;
German Competence Network Sepsis (SepNet)
:
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med
2008
;
358
:
125
39
227.
Wiener
RS
,
Wiener
DC
,
Larson
RJ
:
Benefits and risks of tight glucose control in critically ill adults: A meta-analysis.
JAMA
2008
;
300
:
933
44
228.
Griesdale
DE
,
de Souza
RJ
,
van Dam
RM
,
Heyland
DK
,
Cook
DJ
,
Malhotra
A
,
Dhaliwal
R
,
Henderson
WR
,
Chittock
DR
,
Finfer
S
,
Talmor
D
:
Intensive insulin therapy and mortality among critically ill patients: A meta-analysis including NICE-SUGAR study data.
CMAJ
2009
;
180
:
821
7
229.
Finfer
S
,
Chittock
DR
,
Su
SY
,
Blair
D
,
Foster
D
,
Dhingra
V
,
Bellomo
R
,
Cook
D
,
Dodek
P
,
Henderson
WR
,
Hébert
PC
,
Heritier
S
,
Heyland
DK
,
McArthur
C
,
McDonald
E
,
Mitchell
I
,
Myburgh
JA
,
Norton
R
,
Potter
J
,
Robinson
BG
,
Ronco
JJ
;
NICE-SUGAR Study Investigators
:
Intensive versus conventional glucose control in critically ill patients.
N Engl J Med
2009
;
360
:
1283
97
230.
Preiser
JC
,
Devos
P
,
Ruiz-Santana
S
,
Mélot
C
,
Annane
D
,
Groeneveld
J
,
Iapichino
G
,
Leverve
X
,
Nitenberg
G
,
Singer
P
,
Wernerman
J
,
Joannidis
M
,
Stecher
A
,
Chioléro
R
:
A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: The Glucontrol study.
Intensive Care Med
2009
;
35
:
1738
48
231.
Marik
PE
,
Preiser
JC
:
Toward understanding tight glycemic control in the ICU: A systematic review and metaanalysis.
Chest
2010
;
137
:
544
51
232.
Kansagara
D
,
Fu
R
,
Freeman
M
,
Wolf
F
,
Helfand
M
:
Intensive insulin therapy in hospitalized patients: A systematic review.
Ann Intern Med
2011
;
154
:
268
82
233.
Dellinger
RP
,
Levy
MM
,
Rhodes
A
,
Annane
D
,
Gerlach
H
,
Opal
SM
,
Sevransky
JE
,
Sprung
CL
,
Douglas
IS
,
Jaeschke
R
,
Osborn
TM
,
Nunnally
ME
,
Townsend
SR
,
Reinhart
K
,
Kleinpell
RM
,
Angus
DC
,
Deutschman
CS
,
Machado
FR
,
Rubenfeld
GD
,
Webb
S
,
Beale
RJ
,
Vincent
JL
,
Moreno
R
;
Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup
:
Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2012.
Intensive Care Med
2013
;
39
:
165
228
234.
Marik
PE
:
The demise of early goal-directed therapy for severe sepsis and septic shock.
Acta Anaesthesiol Scand
2015
;
59
:
561
7
235.
Nydahl
P
,
Ruhl
AP
,
Bartoszek
G
,
Dubb
R
,
Filipovic
S
,
Flohr
HJ
,
Kaltwasser
A
,
Mende
H
,
Rothaug
O
,
Schuchhardt
D
,
Schwabbauer
N
,
Needham
DM
:
Early mobilization of mechanically ventilated patients: A 1-day point-prevalence study in Germany.
Crit Care Med
2014
;
42
:
1178
86
236.
Morandi
A
,
Brummel
NE
,
Ely
EW
:
Sedation, delirium and mechanical ventilation: The ‘ABCDE’ approach.
Curr Opin Crit Care
2011
;
17
:
43
9
237.
Mah
JW
,
Staff
I
,
Fichandler
D
,
Butler
KL
:
Resource-efficient mobilization programs in the intensive care unit: Who stands to win?
Am J Surg
2013
;
206
:
488
93
238.
Lord
RK
,
Mayhew
CR
,
Korupolu
R
,
Mantheiy
EC
,
Friedman
MA
,
Palmer
JB
,
Needham
DM
:
ICU early physical rehabilitation programs: Financial modeling of cost savings.
Crit Care Med
2013
;
41
:
717
24
239.
Esteban
A
,
Anzueto
A
,
Alía
I
,
Gordo
F
,
Apezteguía
C
,
Pálizas
F
,
Cide
D
,
Goldwaser
R
,
Soto
L
,
Bugedo
G
,
Rodrigo
C
,
Pimentel
J
,
Raimondi
G
,
Tobin
MJ
:
How is mechanical ventilation employed in the intensive care unit? An international utilization review.
Am J Respir Crit Care Med
2000
;
161
:
1450
8
240.
Jubran
A
:
Critical illness and mechanical ventilation: Effects on the diaphragm.
Respir Care
2006
;
51
:
1054
61
241.
Putensen
C
,
Mutz
NJ
,
Putensen-Himmer
G
,
Zinserling
J
:
Spontaneous breathing during ventilatory support improves ventilation-perfusion distributions in patients with acute respiratory distress syndrome.
Am J Respir Crit Care Med
1999
;
159
(
4 pt 1
):
1241
8
242.
Sydow
M
,
Burchardi
H
,
Ephraim
E
,
Zielmann
S
,
Crozier
TA
:
Long-term effects of two different ventilatory modes on oxygenation in acute lung injury. Comparison of airway pressure release ventilation and volume-controlled inverse ratio ventilation.
Am J Respir Crit Care Med
1994
;
149
:
1550
6
243.
Picard
M
,
Jung
B
,
Liang
F
,
Azuelos
I
,
Hussain
S
,
Goldberg
P
,
Godin
R
,
Danialou
G
,
Chaturvedi
R
,
Rygiel
K
,
Matecki
S
,
Jaber
S
,
Des Rosiers
C
,
Karpati
G
,
Ferri
L
,
Burelle
Y
,
Turnbull
DM
,
Taivassalo
T
,
Petrof
BJ
:
Mitochondrial dysfunction and lipid accumulation in the human diaphragm during mechanical ventilation.
Am J Respir Crit Care Med
2012
;
186
:
1140
9
244.
Reber
A
,
Nylund
U
,
Hedenstierna
G
:
Position and shape of the diaphragm: Implications for atelectasis formation.
Anaesthesia
1998
;
53
:
1054
61
245.
Downs
JB
,
Douglas
ME
,
Sanfelippo
PM
,
Stanford
W
,
Hodges
MR
:
Ventilatory pattern, intrapleural pressure, and cardiac output.
Anesth Analg
1977
;
56
:
88
96
246.
Henzler
D
,
Dembinski
R
,
Bensberg
R
,
Hochhausen
N
,
Rossaint
R
,
Kuhlen
R
:
Ventilation with biphasic positive airway pressure in experimental lung injury. Influence of transpulmonary pressure on gas exchange and haemodynamics.
Intensive Care Med
2004
;
30
:
935
43
247.
Kaplan
LJ
,
Bailey
H
,
Formosa
V
:
Airway pressure release ventilation increases cardiac performance in patients with acute lung injury/adult respiratory distress syndrome.
Crit Care
2001
;
5
:
221
6
248.
Yoshida
T
,
Uchiyama
A
,
Matsuura
N
,
Mashimo
T
,
Fujino
Y
:
The comparison of spontaneous breathing and muscle paralysis in two different severities of experimental lung injury.
Crit Care Med
2013
;
41
:
536
45
249.
Helbok
R
,
Kurtz
P
,
Schmidt
MJ
,
Stuart
MR
,
Fernandez
L
,
Connolly
SE
,
Lee
K
,
Schmutzhard
E
,
Mayer
SA
,
Claassen
J
,
Badjatia
N
:
Effects of the neurological wake-up test on clinical examination, intracranial pressure, brain metabolism and brain tissue oxygenation in severely brain-injured patients.
Crit Care
2012
;
16
:
R226
250.
Alberda
C
,
Gramlich
L
,
Jones
N
,
Jeejeebhoy
K
,
Day
AG
,
Dhaliwal
R
,
Heyland
DK
:
The relationship between nutritional intake and clinical outcomes in critically ill patients: Results of an international multicenter observational study.
Intensive Care Med
2009
;
35
:
1728
37
251.
De Jonghe
B
,
Appere-De-Vechi
C
,
Fournier
M
,
Tran
B
,
Merrer
J
,
Melchior
JC
,
Outin
H
:
A prospective survey of nutritional support practices in intensive care unit patients: What is prescribed? What is delivered?
Crit Care Med
2001
;
29
:
8
12
252.
Rice
TW
,
Swope
T
,
Bozeman
S
,
Wheeler
AP
:
Variation in enteral nutrition delivery in mechanically ventilated patients.
Nutrition
2005
;
21
:
786
92
253.
Stapleton
RD
,
Jones
N
,
Heyland
DK
:
Feeding critically ill patients: What is the optimal amount of energy?
Crit Care Med
2007
;
35
(
9 suppl
):
S535
40
254.
Bellomo
R
,
Cass
A
,
Cole
L
,
Finfer
S
,
Gallagher
M
,
Lee
J
,
Lo
S
,
McArthur
C
,
McGuinness
S
,
Myburgh
J
,
Norton
R
,
Scheinkestel
C
,
Su
S
;
RENAL Study Investigators
:
Calorie intake and patient outcomes in severe acute kidney injury: Findings from the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study trial.
Crit Care
2014
;
18
:
R45
255.
Weijs
PJ
,
Looijaard
WG
,
Beishuizen
A
,
Girbes
AR
,
Oudemans-van Straaten
HM
:
Early high protein intake is associated with low mortality and energy overfeeding with high mortality in non-septic mechanically ventilated critically ill patients.
Crit Care
2014
;
18
:
701
256.
McClave
SA
,
Martindale
RG
,
Vanek
VW
,
McCarthy
M
,
Roberts
P
,
Taylor
B
,
Ochoa
JB
,
Napolitano
L
,
Cresci
G
;
ASPEN Board of Directors; American College of Critical Care Medicine; Society of Critical Care Medicine
:
Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.).
JPEN J Parenter Enteral Nutr
2009
;
33
:
277
316
257.
Heyland
DK
,
Dhaliwal
R
,
Drover
JW
,
Gramlich
L
,
Dodek
P
;
Canadian Critical Care Clinical Practice Guidelines Committee
:
Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients.
JPEN J Parenter Enteral Nutr
2003
;
27
:
355
73
258.
Moore
EE
,
Jones
TN
:
Benefits of immediate jejunostomy feeding after major abdominal trauma—A prospective, randomized study.
J Trauma
1986
;
26
:
874
81
259.
Chiarelli
A
,
Enzi
G
,
Casadei
A
,
Baggio
B
,
Valerio
A
,
Mazzoleni
F
:
Very early nutrition supplementation in burned patients.
Am J Clin Nutr
1990
;
51
:
1035
9
260.
Kompan
L
,
Vidmar
G
,
Spindler-Vesel
A
,
Pecar
J
:
Is early enteral nutrition a risk factor for gastric intolerance and pneumonia?
Clin Nutr
2004
;
23
:
527
32
261.
Vanderheyden
S
,
Casaer
MP
,
Kesteloot
K
,
Simoens
S
,
De Rijdt
T
,
Peers
G
,
Wouters
PJ
,
Coenegrachts
J
,
Grieten
T
,
Polders
K
,
Maes
A
,
Wilmer
A
,
Dubois
J
,
Van den Berghe
G
,
Mesotten
D
:
Early versus late parenteral nutrition in ICU patients: Cost analysis of the EPaNIC trial.
Crit Care
2012
;
16
:
R96
262.
Preiser
JC
,
van Zanten
AR
,
Berger
MM
,
Biolo
G
,
Casaer
MP
,
Doig
GS
,
Griffiths
RD
,
Heyland
DK
,
Hiesmayr
M
,
Iapichino
G
,
Laviano
A
,
Pichard
C
,
Singer
P
,
Van den Berghe
G
,
Wernerman
J
,
Wischmeyer
P
,
Vincent
JL
:
Metabolic and nutritional support of critically ill patients: Consensus and controversies.
Crit Care
2015
;
19
:
35
263.
Farrokhi
F
,
Smiley
D
,
Umpierrez
GE
:
Glycemic control in non-diabetic critically ill patients.
Best Pract Res Clin Endocrinol Metab
2011
;
25
:
813
24
264.
Jeremitsky
E
,
Omert
LA
,
Dunham
CM
,
Wilberger
J
,
Rodriguez
A
:
The impact of hyperglycemia on patients with severe brain injury.
J Trauma
2005
;
58
:
47
50
265.
Laird
AM
,
Miller
PR
,
Kilgo
PD
,
Meredith
JW
,
Chang
MC
:
Relationship of early hyperglycemia to mortality in trauma patients.
J Trauma
2004
;
56
:
1058
62
266.
Palus
S
,
von Haehling
S
,
Springer
J
:
Muscle wasting: An overview of recent developments in basic research.
Int J Cardiol
2014
;
176
:
640
4
267.
Minetti
GC
,
Feige
JN
,
Rosenstiel
A
,
Bombard
F
,
Meier
V
,
Werner
A
,
Bassilana
F
,
Sailer
AW
,
Kahle
P
,
Lambert
C
,
Glass
DJ
,
Fornaro
M
:
Gαi2 signaling promotes skeletal muscle hypertrophy, myoblast differentiation, and muscle regeneration.
Sci Signal
2011
;
4
:
ra80
268.
Austin
S
,
St-Pierre
J
:
PGC1α and mitochondrial metabolism—Emerging concepts and relevance in ageing and neurodegenerative disorders.
J Cell Sci
2012
;
125
(
pt 21
):
4963
71
269.
Cannavino
J
,
Brocca
L
,
Sandri
M
,
Grassi
B
,
Bottinelli
R
,
Pellegrino
MA
:
The role of alterations in mitochondrial dynamics and PGC-1α over-expression in fast muscle atrophy following hindlimb unloading.
J Physiol
2015
;
593
:
1981
95
270.
Dallmann
R
,
Weyermann
P
,
Anklin
C
,
Boroff
M
,
Bray-French
K
,
Cardel
B
,
Courdier-Fruh
I
,
Deppe
H
,
Dubach-Powell
J
,
Erb
M
,
Haefeli
RH
,
Henneböhle
M
,
Herzner
H
,
Hufschmid
M
,
Marks
DL
,
Nordhoff
S
,
Papp
M
,
Rummey
C
,
Santos
G
,
Schärer
F
,
Siendt
H
,
Soeberdt
M
,
Sumanovski
LT
,
Terinek
M
,
Mondadori
C
,
Güven
N
,
Feurer
A
:
The orally active melanocortin-4 receptor antagonist BL-6020/979: A promising candidate for the treatment of cancer cachexia.
J Cachexia Sarcopenia Muscle
2011
;
2
:
163
74
271.
Cheung
WW
,
Mak
RH
:
Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease.
Am J Physiol Renal Physiol
2012
;
303
:
F1315
24
272.
Haidet
AM
,
Rizo
L
,
Handy
C
,
Umapathi
P
,
Eagle
A
,
Shilling
C
,
Boue
D
,
Martin
PT
,
Sahenk
Z
,
Mendell
JR
,
Kaspar
BK
:
Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors.
Proc Natl Acad Sci USA
2008
;
105
:
4318
22
273.
Rodino-Klapac
LR
,
Haidet
AM
,
Kota
J
,
Handy
C
,
Kaspar
BK
,
Mendell
JR
:
Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease.
Muscle Nerve
2009
;
39
:
283
96
274.
Murphy
KT
,
Cobani
V
,
Ryall
JG
,
Ibebunjo
C
,
Lynch
GS
:
Acute antibody-directed myostatin inhibition attenuates disuse muscle atrophy and weakness in mice.
J Appl Physiol
2011
;
110
:
1065
72
275.
Attie
KM
,
Borgstein
NG
,
Yang
Y
,
Condon
CH
,
Wilson
DM
,
Pearsall
AE
,
Kumar
R
,
Willins
DA
,
Seehra
JS
,
Sherman
ML
:
A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers.
Muscle Nerve
2013
;
47
:
416
23
276.
Farhan
H
,
Moreno-Duarte
I
,
McLean
D
,
Eikermann
M
:
Residual paralysis: Does it influence outcome after ambulatory surgery?
Curr Anesthesiol Rep
2014
;
4
:
290
302
277.
Haerter
F
,
Nimeh
T
,
Simons
J
,
Zhang
B
,
Zaremba
S
,
Ayata
C
,
Moreno Duarte
I
,
Eikermann-Haerter
K
,
Isaacs
L
,
Eikermann
M
:
Acyclic cucurbit[n]uril-type molecular containers bind ketamine in vitro and reverse ketamine anesthesia and associated side-effects in rats.
ASA Abstract
2013
, pp
LBB05
278.
Diaz-Gil
D
,
Moreno-Duarte
I
,
Cotten
J
,
Seidel
J
,
Ganapati
S
,
Zhang
B
,
Simons
J
,
Ayata
C
,
Isaacs
L
,
M.
E
:
Acyclic cucurbit[n]uril-type molecular containers bind etomidate in vitro and reverse etomidate anesthesia in rats dose-dependently.
ASA Abstract
2014
, pp
BOS01
279.
Moreira-Pfrimer
LD
,
Pedrosa
MA
,
Teixeira
L
,
Lazaretti-Castro
M
:
Treatment of vitamin D deficiency increases lower limb muscle st