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Critical illness myopathy
Abstract
Acute myopathy is a common problem in intensive care units. Those at highest risk for developing critical illness myopathy are exposed to intravenous corticosteroids and paralytic agents during treatment of various illnesses. Diffuse weakness and failure to wean from mechanical ventilation are the most common clinical manifestations. Serum creatine kinase levels are variable. Electrodiagnostic studies reveal findings of a myopathic process, often with evidence of muscle membrane inexcitability. Based on animal model studies, the loss of muscle membrane excitability may be related to inactivation of sodium channels at the resting potential. In addition, human and animal pathologic studies reveal characteristic loss of myosin with relative preservation of other structural proteins. In some patients, there is also upregulation of proteolytic pathways, involving calpain and ubiquitin, in conjunction with increased apoptosis. Fortunately, the disorder is reversible, but there may be considerable morbidity.
... This quadriplegia was considered a consequence of the modern practice of anaesthesiology and intensive care, and subsequent studies have shown that this quadriplegia is associated with a preferential myosin loss (Sher et al. 1979;Hirano et al. 1992). This complication of modern intensive care was originally given the name acute quadriplegic myopathy (AQM) and a number of different descriptive names have been given this disorder since then, such as critical illness myopathy, thick filament myosin myopathy, acute myopathy of severe asthma, myopathy of intensive care etc. (for references seeHirano et al. 1992;Lacomis et al. 2000). For many years, the AQM diagnosis was lumped together with muscle paralyses of neurogenic origin, such as the critical illness polyneuropathy and Guillain–Barré syndrome; however, AQM is a disorder of muscle, not nerve. ...
... In the clinical setting, AQM is still frequently lumped together with neuropathies, due to either co-existence between the two conditions or the use of diagnostic techniques with poor precision. While acute quadriplegia in the ICU was initially thought to be a rare event, we now know that neuromuscular dysfunction is found in up to 30% of the general ICU population and 70–80% of certain sub-groups (Leijten et al. 1995;Lacomis et al. 2000;De Jonghe et al. 2002;Friedrich et al. 2005). AQM is a potentially lethal complication that prolongs the recovery of critical care patients, increasing the median ICU treatment costs 3-fold (Rudis et al. 1996;Seneff et al. 2000). ...
The muscle wasting and impaired muscle function in critically ill intensive care unit (ICU) patients delay recovery from the primary disease, and have debilitating consequences that can persist for years after hospital discharge. It is likely that, in addition to pernicious effects of the primary disease, the basic life support procedures of long-term ICU treatment contribute directly to the progressive impairment of muscle function. This study aims at improving our understanding of the mechanisms underlying muscle wasting in ICU patients by using a unique experimental rat ICU model where animals are mechanically ventilated, sedated and pharmacologically paralysed for duration varying between 6 h and 14 days. Results show that the ICU intervention induces a phenotype resembling the severe muscle wasting and paralysis associated with the acute quadriplegic myopathy (AQM) observed in ICU patients, i.e. a preferential loss of myosin, transcriptional down-regulation of myosin synthesis, muscle atrophy and a dramatic decrease in muscle fibre force generation capacity. Detailed analyses of protein degradation pathways show that the ubiquitin proteasome pathway is highly involved in this process. A sequential change in localisation of muscle-specific RING finger proteins 1/2 (MuRF1/2) observed during the experimental period is suggested to play an instrumental role in both transcriptional regulation and protein degradation. We propose that, for those critically ill patients who develop AQM, complete mechanical silencing, due to pharmacological paralysis or sedation, is a critical factor underlying the preferential loss of the molecular motor protein myosin that leads to impaired muscle function or persisting paralysis.
... Two weeks later, further electrophysiological investigation of limbs and respiratory system showed significant changes of the motor unit action potentials and especially at proximal, intercostal muscles and diaphragm, suggesting a myopathic phenomenon without neurogenic cause. Muscle enzymes were not increased and biopsy of the quadriceps muscle showed diffuse muscle fiber atrophy with myofibrillar disintegration and loss of myosin filaments, characteristic of acute quadriplegic myopathy [1]. After 3 weeks, the myopathy started to regress and, after a tracheotomy was performed, the patient was weaned from the ventilator on day 35. ...
... Proximal myopathy has been reported once in a similar setting [3]. While polyneuropathy in critically ill patients is a possible cause of dependence on a ventilator, the weaning problems in the present case were clearly related to acute quadriplegic myopathy developing within a few days [1,4,5]. The patient did not present sepsis or multiple organ failure and was also not exposed to corticosteroids or to neuromuscular blocking agents. ...
... It is unclear what cumulative long-term effects these opposing processes would have on the hematological system in a zero-gravity environment. Muscular deconditioning, atrophy, myopathy, and osteopenia are complications faced by both astronauts and ICU patients (31,37,69). Stasis while hypothermic in zero gravity may compound these issues. ...
Suspended animation for deep-space travelers is moving out of the realm of science fiction. Two approaches are considered: the first elaborates the current medical practice of therapeutic hypothermia; the second invokes the cascade of metabolic processes naturally employed by hibernators. We explore the basis and evidence behind each approach and argue that mimicry of natural hibernation will be critical to overcome the innate limitations of human physiology for long-duration space travel.
... The term CINM was first described by Bolton et al. [2] in 1986 and has been reported sporadically thereafter in the setting of ICU on the way of managing a critical illness [3][4][5]. For the diagnosis, muscle biopsy remains the method of choice [1,6,7]. ...
... CINM is associated with sepsis, systemic inflammation, poor glycemic control, steroids, neuromuscular blocking agents, immobility, and malnutrition. [20] CINM presents as flaccid quadriparesis with hypo or areflexia and confirmed by nerve conduction and electromyography studies. [11,21] Optimal therapy for this condition is unknown. ...
Invasive mechanical ventilation (IMV) for management of chronic obstructive pulmonary disease (COPD) associated respiratory failure is increasing in Intensive Care Units. However, IMV is not without its own complications. Hence, aim of managing such patients is to get them off the ventilator as early as possible. This bridging process from IMV to extubation is called weaning in which mechanical ventilation is gradually withdrawn and the patient resumes spontaneous breathing. Many objective parameters have been defined for weaning success. Many of these patients are difficult-to-wean because of various pathophysiologic mechanisms that are of particular relevance to patients of COPD. The following review focuses on these mechanisms and how to troubleshoot patients who are difficult-to-wean.
... Bu hastalarda sarkolemmada sodyum kanalı sayısı azalmakta, normalde bulunan Nav1.4 kanallarına ek olarak daha inaktif olan Nav1.5'lerinde eksprese edilmekte ve membranın istirahatteki depolarizasyon düzeyi derinleşmektedir [6] . Yani elektrofizyolojik olarak ortaya konulabilecek olan fonksiyon bozukluğu daha yapısal hasar meydana gelmeden çok önce çıkar [22] . Bunun sepsise bağlı genel düşük enerji mevcudiyetine karşı adaptif bir fenomen olduğu iddia edilmiştir [13] . ...
... Bu hastalarda sarkolemmada sodyum kanalı sayısı azalmakta, normalde bulunan Nav1.4 kanallarına ek olarak daha inaktif olan Nav1.5'lerinde eksprese edilmekte ve membranın istirahatteki depolarizasyon düzeyi derinleşmektedir [6] . Yani elektrofizyolojik olarak ortaya konulabilecek olan fonksiyon bozukluğu daha yapısal hasar meydana gelmeden çok önce çıkar [22] . Bunun sepsise bağlı genel düşük enerji mevcudiyetine karşı adaptif bir fenomen olduğu iddia edilmiştir [13] . ...
... CIM is characterized by reduced muscle membrane excitability and a preferential loss of the molecular motor protein myosin. A number of different descriptive names have been given to this disorder, such as acute quadriplegic myopathy, thick filament myosin myopathy, acute myopathy of severe asthma and myopathy of intensive care [1,2]. In 1977, Macfarlane and Rosenthal [3] first reported a case of acute quadriplegia, affecting spinal nerve-innervated muscles, with intact sensory, cognitive and craniofacial muscle function [3]. ...
The muscle wasting and loss of specific force associated with Critical Illness Myopathy (CIM) is, at least in part, due to a preferential loss of the molecular motor protein myosin. This acquired myopathy is common in critically ill immobilized and mechanically ventilated intensive care patients (ICU). There is a growing understanding of the mechanisms underlying CIM, but the role of nutritional factors triggering this serious complication of modern intensive care remains unknown. This study aims at establishing the effect of nutritional status in the pathogenesis of CIM. An experimental ICU model was used where animals are mechanically ventilated, pharmacologically paralysed post-synaptically and extensively monitored for up to 14 days. Due to the complexity of the experimental model, the number of animals included is small. After exposure to this ICU condition, animals develop a phenotype similar to patients with CIM. The results from this study show that the preferential myosin loss, decline in specific force and muscle fiber atrophy did not differ between low vs. eucaloric animals. In both experimental groups, passive mechanical loading had a sparing effect of muscle weight independent on nutritional status. Thus, this study confirms the strong impact of the mechanical silencing associated with the ICU condition in triggering CIM, overriding any potential effects of caloric intake in triggering CIM. In addition, the positive effects of passive mechanical loading on muscle fiber size and force generating capacity was not affected by the nutritional status in this study. However, due to the small sample size these pilot results need to be validated in a larger cohort.
... In fact, functional limitations were shown to persist in the majority of patients as late as 2 years post-AQM, which was largely a result of muscle wasting and weakness [17,18]. The rapid muscle wasting in patients with AQM has been suggested to be associated with the activation of the ubiquitin–proteasome, cytoplasmic (calpain), and lysosomal (cathepsin) proteolytic pathways [11,192021222324. The muscle atrophy in AQM also is distinguished from neurogenic atrophy by the activation of the MAPK signaling cascade, including the proapoptotic transforming growth factor (TGF)-β and RAS cascades, as demonstrated by Di Giovanni and co-workers [19]. ...
The dramatic muscle wasting, preferential loss of myosin and impaired muscle function in intensive care unit (ICU) patients with acute quadriplegic myopathy (AQM) have traditionally been suggested to be the result of proteolysis via specific proteolytic pathways. In this study we aim to investigate the mechanisms underlying the preferential loss of thick vs. thin filament proteins and the reassembly of the sarcomere during the recovery process in muscle samples from ICU patients with AQM. Quantitative and qualitative analyses of myofibrillar protein and mRNA expression were analyzed using SDS-PAGE, confocal microscopy, histochemistry and real-time PCR. The present results demonstrate that the transcriptional regulation of myofibrillar protein synthesis plays an important role in the loss of contractile proteins, as well as the recovery of protein levels during clinical improvement, myosin in particular, presumably in concert with proteolytic pathways, but the mechanisms are specific to the different thick and thin filament proteins studied.
... Based on animal model studies the loss of muscle membrane excitability may be related to inactivation of sodium channels at the resting potential [40]. In critical illness myopathy, there is also upregulation of proteolytic pathways, involving calpain and ubiquitin, in conjunction with increased apoptosis [41]. Brealy et al. [42] have shown an association between mitochondrial dysfunction and severity and outcome of septic shock. ...
Neuromuscular disorders in the background of critical illness are under diagnosed. Standardized screening for weakness in the intensive care unit (ICU) setting is uncommon and persistent weakness as a sequel of critical illness is usually not recognized by physicians in the ICU for whom survival from acute illness is the primary outcome. The spectrum of illness ranges from isolated nerve entrapment with focal pain or weakness, to disuse muscle atrophy with mild weakness, and to severe myopathy or neuropathy with associated severe, prolonged weakness. This update focuses on neuromuscular disorders occurring in the critical care set up associated with diffuse and severe weakness.
Twenty-five years ago, the standard measure for outcomes after critical illness was the 28-day all-cause mortality. Long-term outcomes were a nascent field of investigation; the first organized report of 1-year outcomes after acute respiratory distress syndrome (ARDS) was published in the year 2003 [1]. In the past decade, the expanding armamentarium of therapies for critical illness and refinements in understanding its pathophysiology have led to improved survival rates but have created an increasing number of survivors that suffer from the long-term sequelae of critical illness. Manifestations of these long-term outcomes span a constellation of physical, cognitive, and mental domains and are collectively termed post-intensive care syndrome (PICS). Caregivers of survivors may be overwhelmed with this drastic life-changing event and can become affected with mood disorders, a phenomenon known as PICS-Family (PICS-F) [2, 3].
Older patients with critical illness comprise almost one-half of ICU admissions and represent a vulnerable patient subgroup in terms of incremental functional and neuropsychological disability sustained as a result of their critical illness [1]. We know that most patients who survive an episode of critical illness will have compromised physical function secondary to Intensive Care Unit-Acquired Weakness (ICUAW) and other physical disabilities [2–6]. Disability may be permanent [6], and the constellation of muscle, nerve and brain dysfunction [4, 7–12] may permanently alter disposition for those who were previously independent, may impose an additional healthcare cost burden [2, 6, 13, 14], and erode the reserve of family members [15–18]. Older patients may come to their episode of critical illness with less organ reserve than their younger counterparts, and the superimposed physical dysfunction associated with their illness may result in new disability. However, this literature suffers from selection bias in terms of who among the elderly is admitted to an ICU, the survivorship bias associated with high ICU and post-discharge mortality, and the challenges of long-term follow-up in this population. There remains a lingering uncertainty about the benefit of critical care in this vulnerable group.
Histopathological analysis of 52 muscle biopsies from 43 adult critically ill patients was performed to determine the differential diagnosis and course of neuromuscular involvement in critically ill patients suffering from critical illness polyneuropathy or myopathy. The first histopathological examination in all 43 patients revealed signs of neuropathy in 2 biopsies, myopathy in 19 biopsies, and neuromyopathy in 18, including type 2 fibre atrophy. A repeat study of 9 patients showed that the histopathological features changed in all cases. A second biopsy performed several months or years after the first revealed that myopathic features had regressed and either recovery to normal histopathological findings had occurred or evidence of a persistent neurogenic lesion was found. The results indicate that muscle involvement in critically ill patients is reversible.
Following the first part (Gisler, 2010) with overview, pathogenesis, and classification, this second part will discuss muscular dysbalance and dysharmony in theory and with practical examples.
Objective:
To describe the clinical course, diagnostic findings, medical and surgical treatments, and outcome in a dog with spontaneous pneumothorax secondary to necrotizing pneumonia thought to be a delayed complication of heatstroke.
Case summary:
A 1.5-year-old Labrador Retriever developed spontaneous pneumothorax 12 days after an episode of exertional heat stroke. Computed tomography was performed and showed bilateral pneumothorax and multifocal pulmonary consolidation, especially at the lung periphery. A median sternotomy was performed, and multifocal, well-demarcated areas of consolidated pulmonary tissue with purple discoloration were identified and resected from the right middle, right caudal, and accessory lung lobes. Histologic examination of the resected pulmonary tissue indicated necrotizing pneumonia, and bacteriologic culture of the tissue resulted in growth of Pseudomonas aeruginosa. Examination of tissue from a pectoral muscle biopsy performed at this time showed necrotizing myopathy. The dog was discharged 7 days after surgery and made a full recovery.
New or unique information provided:
This case report describes pneumothorax and multifocal necrotizing pneumonia as a delayed complication of heatstroke, and provides the first description of the computed tomography appearance of histologically confirmed necrotizing pneumonia in a dog. Multifocal necrotizing pneumonia with or without pneumothorax should be considered in dogs that develop respiratory distress following severe systemic illness.
Las alteraciones neuromusculares que tienen lugar en el paciente crítico han sido atribuidas a factores como la situación séptica, la liberación de mediadores inflamatorioso el empleo de fármacos que afectan desfavorablemente a la función neuro-muscular. El papel de factores metabólicos y nutricionales en el desarrollo de esta patología ha recibido poca atención. En la actualidad, el empleo de protocolos de control intensivo de la glucemia podría tener gran interés en la prevención de las alteraciones neuro-musculares de los pacientes críticos. Los mecanismos exactos de la implicación de la hiperglucemia en esta patología son, todavía, desconocidos, aunque la evidencia de los datos procedentes de la investigación es importante. La miopatía caquectizante (atrofia muscular) tiene lugar de manera habitual como consecuencia de los cambios obligados por la respuesta metabólica al estrés. El efecto del aporte de nutrientes sobre la ganancia de masa muscular es muy limitado, por lo que deben estudiarse otras acciones dirigidas a recuperar, de manera más rápida, la masa muscular perdida. Deben evitarse pautas agresivas de renutrición con objeto de prevenir el síndrome de realimentación y el consiguiente mayor deterioro de la función muscular. El aporte de substratos específicos, como la glutamina, podría tener un efecto beneficioso en la recuperación de las alteraciones neuro-musculares del paciente crítico. No obstante, no existen aún datos para justificar su empleo si el único objetivo es la recuperación de la función neuro-muscular.
Advances in critical care have resulted in improved intensive care unit (ICU) mortality. However, improved ICU survival has resulted in a growing number of ICU survivors living with long-term sequelae of critical illness, such as impaired physical function and quality of life (QOL). In addition to critical illness, prolonged bed rest and immobility may lead to severe physical deconditioning and loss of muscle mass and muscle weakness. ICU-acquired weakness is associated with increased duration of mechanical ventilation and weaning, longer ICU and hospital stay, and increased mortality. These physical impairments may last for years after ICU discharge. Early Physical Medicine and Rehabilitation (PM&R) interventions in the ICU may attenuate or prevent the weakness and physical impairments occurring during critical illness. This article reviews the evidence regarding safety, feasibility, barriers, and benefits of early PM&R interventions in ICU patients and discusses the limited existing data on early PM&R in the neurological ICU and future directions for early PM&R in the ICU.
Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are complications causing weakness of respiratory and limb muscles in critically ill patients. As an important differential diagnosis of Guillain-Barré syndrome (GBS), CIP and CIM should be diagnosed with caution, after a complete clinical and laboratory examination. Although not uncommon in ICU, CIP and CIM as severe complications of percutaneous nephrostolithotomy (PNL) have not been documented in literature.
A 48-year-old Chinese woman was referred to our hospital, complaining of occasional pain in the right lower back for one month. Lithiasis was diagnosed by ultrasonographical and radiological examinations on the urinary system. PNL was indicated and performed. The patient developed CIP and CIM on the fourth day after PNL. Early recognition and treatment of the severe complications contributed to a satisfactory recovery of the patient.
This case expands our understanding of the complications of PNL and underscores the importance of differentiating CIP/CIM from GBS in case of such patients developing weakness after the treatment. Clinical characteristics and examination results should be carefully evaluated to make the diagnosis of CIP or CIM. Both anti-septic prophylaxis and control of hyperglycemia might be effective for the prevention of CIP or CIM; aggressive treatment on sepsis and multiple organ failure is considered to be the most effective measure to reduce the incidence of CIP/CIM.
IntroductionIn the intensive care unit (ICU) patients sometimes develop diffuse neuromuscular deficit resulting in flaccid tetraparesia with a more or less severe prognosis.State of the art ICU-acquired neuromuscular disorders have various possible origins, including necrotic or catabolic myopathies and sensori-motor axonal neuropathies. Electrophysiological testing determines these pathophysiological mechanisms better than clinical examination. The technique of direct muscle stimulation has been proposed, in addition to conventional electroneuromyographic methods, to improve the reliability of electrodiagnosis in ICU, but has been rarely studied. Using this technique, we recently showed that a majority of ICU-acquired pareses are of myopathic origin.Perspectives The technique of direct muscle stimulation could be fruitfully associated with usual electroneuromyographic methods to differentiate myopathic from neuropathic involvement at the origin of any severe weakness in ICU.Conclusion The contribution of myopathic processes in ICU-acquired paresis is probably underestimated. Direct muscle stimulation enables better understanding of the mechanisms underlying acquired motor deficit in ICU patients. However, it remains to be determined whether this refinement could have a significant impact on prognosis and treatment.
Intermittent positive pressure breathing (IPPB) is used in non-intubated patients to increase lung volume and to enhance coughing. Alpha 200 (Salvia Lifetec, Kronberg, Germany) is a specific IPPB device. CoughAssist (Respironics France, Carquefou, France) is a mechanical insufflator-exsufflator used to remove secretions in patients with inefficient cough. Both can also be used for intubated or tracheotomized patients. We assessed the impact of various artificial airways on the ability of the Alpha 200 and CoughAssist to generate insufflated volume.
We measured the insufflated volume and pressure at the airway opening in a lung model under 2 conditions of compliance (30 or 60 mL/cm H(2)O) at single resistance of 5 cm H(2)O/L/s. The devices were used at 2 set pressures: 30 and 40 cm H(2)O. The Alpha 200 was set at 2 inflation flows: 0.5 and 1 L/s, whereas CoughAssist was set at its highest value of 10 L/s. Measurements were done without (control) and with different size endotracheal tubes and tracheostomy cannulae. The relationships between insufflated volume and measured pressure were analyzed using linear regressions.
The slopes and intercepts of the control relationship between insufflated volume and pressure were significantly greater with Alpha 200 at each set flow than with CoughAssist. As artificial airways were used, the insufflated volume did not differ from the control with CoughAssist, while with Alpha 200 it increased at each flow setting and for all mechanical conditions. The largest differences in insufflated volume between the 2 devices were observed for the largest endotracheal tubes and tracheostomy cannulas and for the lowest inflation flow setting in Alpha 200. These results can be explained in terms of how the devices function, as CoughAssist adapts by increasing flow, while Alpha 200 adapts by increasing inspiratory time.
This bench study has shown that in the presence of artificial airways the value of the insufflated volume generated by the CoughAssist device was significantly lower than that generated by the Alpha 200 device.
Intensive care unit-acquired weakness (ICUAW) is a severe complication in critically ill patients which has been increasingly recognized over the last two decades. By definition ICUAW is caused by distinct neuromuscular disorders, namely critical illness polyneuropathy (CIP) and critical illness myopathy (CIM). Both CIP and CIM can affect limb and respiratory muscles and thus complicate weaning from a ventilator, increase the length of stay in the intensive care unit and delay mobilization and physical rehabilitation. It is controversially discussed whether CIP and CIM are distinct entities or whether they just represent different organ manifestations with common pathomechanisms. These basic pathomechanisms, however, are complex and still not completely understood but metabolic, inflammatory and bioenergetic alterations seem to play a crucial role. In this respect several risk factors have recently been revealed: in addition to the administration of glucocorticoids and non-depolarizing muscle relaxants, sepsis and multi-organ failure per se as well as elevated levels of blood glucose and muscular immobilization have been shown to have a profound impact on the occurrence of CIP and CIM. For the diagnosis, careful physical and neurological examinations, electrophysiological testing and in rare cases nerve and muscle biopsies are recommended. Nevertheless, it appears to be difficult to clearly distinguish between CIM and CIP in a clinical setting. At present no specific therapy for these neuromuscular disorders has been established but recent data suggest that in addition to avoidance of risk factors early active mobilization of critically ill patients may be beneficial.
Unlabelled:
The prognostic and predictive value of the epidermal growth factor receptor (EGFR) expression and some genetic alterations in an EGFR signal pathway, such as the EGFR amplification, the EGFR activating tyrosine kinase domain mutations or the k-ras gene mutation were investigated in our study. The aim of the research was to evaluate the occurrence of the above-mentioned biomarkers in correlation with a therapeutic response and survival in patients with locoregionally advanced spinocellular head and neck cancers.
Keywords:
Head and neck cancer, EGFR, predictive marker, k-ras, EGFR amplification, EGFR tyrosine kinase domain mutation.
Patients in the intensive care unit commonly develop muscle weakness. In part, this reflects loss of mechanical loading due to physical inactivity, bed rest, or immobilization. Mechanical unloading stimulates a complex adaptive response that results in muscle atrophy and loss of specific force. One element of this response is slowing of protein synthesis, which is regulated by signaling pathways downstream of mammalian target of rapamycin and insulin-like growth factor-1. In parallel, protein degradation is accelerated via three coordinate processes: calcium-dependent proteolysis, adenosine triphosphate-dependent proteolysis, and lysosomal proteolysis. Finally, unloading stimulates apoptosis of a subset of myonuclei within multinucleated muscle fibers. This helps to stabilize the relationship between nuclear number and cell volume during atrophy. Each of these responses is promoted by concurrent development of oxidative stress caused by increased production of reactive oxygen species in unloaded muscle fibers. Countermeasures that lessen the effects of unloading include physical activity, nutritional supplements, hormone therapy, and antioxidant administration. Targeted research is needed to define the role of mechanical unloading in intensive care unit-associated weakness and develop countermeasures to preserve muscle function, lessen illness, and hasten the recovery of critically ill patients.
The processes that trigger severe muscle atrophy and loss of myosin in critical illness myopathy (CIM) are poorly understood. It has been reported that muscle disuse alters Ca(2+) handling by the sarcoplasmic reticulum. Since inactivity is an important contributor to CIM, this finding raises the possibility that elevated levels of the proteins involved in Ca(2+) handling might contribute to development of CIM. CIM was induced in 3- to 5-mo-old rats by sciatic nerve lesion and infusion of dexamethasone for 1 wk. Western blot analysis revealed increased levels of ryanodine receptor (RYR) isoforms-1 and -2 as well as the dihydropyridine receptor/voltage-gated calcium channel type 1.1 (DHPR/Ca(V) 1.1). Immunostaining revealed a subset of fibers with elevation of RYR1 and Ca(V) 1.1 that had severe atrophy and disorganization of sarcomeres. These findings suggest increased Ca(2+) release from the sarcoplasmic reticulum may be an important contributor to development of CIM. To assess the endogenous functional effects of increased intracellular Ca(2+) in CIM, proteolysis of α-fodrin, a well-known target substrate of Ca(2+)-activated proteases, was measured and found to be 50% greater in CIM. There was also selective degradation of myosin heavy chain relative to actin in CIM muscle. Taken together, our findings suggest that increased Ca(2+) release from the sarcoplasmic reticulum may contribute to pathology in CIM.
Die Critical-lllness-Polyneuropathie (CIP), eine Erkrankung des peripheren Nervensystems nach einer schweren intensivmedizinisch behandlungspflichtigen Erkrankung, ist bereits seit dem 19. Jahrhundert bekannt und lässt sich nur sehr schwer von einer Critical-Illness- Myopathie, die im gleichen Kontext auftreten kann, unterscheiden. Erschwert wird die Situation dadurch, dass beide Funktionsstörungen kombiniert auftreten können. Auf Grund der Weiterentwicklung in der Medizin ist in den letzten 2 Jahrzehnten eine Häufigkeitssteigerung zu verzeichnen mit der Forderung geeignete Maßnahmen zu finden, die häufig schwerwiegenden Folgeerscheinungen zu mindern. Mit Entwicklung eines bestimmten neurorehabilitativen Behandlungsregimes ergeben sich die Fragen, welche CIP Patienten profitieren, ergeben sich prognoserelevante Faktoren und welche Art und Dauer der Neurorehabilitation vorgehalten werden muss. In der vorliegenden Arbeit wurden retrospektiv die Entlassungsbriefe der Patienten mit einer CIP der Abteilung für neurologisch-neurochirurgisch Frührehabilitation der Jahre 2004-2008 ausgewertet. Die Beurteilung der Fähigkeitsstörungen erfolgte mit dem Frührehabilitations-Barthel-Index nach Schönle, dem Barthel-Index sowie dem FIM und das Handicap wurde mit der 8-stufigen Glasgow-Outcome-Scale bewertet. Zusätzliche Parameter waren das Alter und Geschlecht, die Ursache der CIP, die Zeit von Erkrankungsbeginn bis zur Aufnahme, die Behandlungsdauer, Komplikationen sowie die Entlassungsart. 200 Patienten, 67,5% Männer und 32,5% Frauen konnten ausgewertet werden. Eine Häufung des Erkrankungsbildes fand sich bei Patienten ab dem 60. Lebensjahr. Eine Ursachenpräferenz fand sich nicht, wobei im Wesentlichen kardiale, respiratorische und gastrointestinale Erkrankungen vorgefunden worden waren. Alle Patienten konnten, nach einer durchschnittlichen Behandlungsdauer von 40 Tagen, von der Frührehabilitationsbehandlung profitieren. So konnten 34% in weiterführende rehabilitative Behandlungsstufen und 17,5% der Patienten gebessert nach Hause entlassen werden. Die Sterblichkeit mit 11% muss der besonderen Schwere des Krankheitsbildes angelastet werden. Dies wird durch die Feststellung gestützt, dass die Komplikationsrate mit über 60% während der rehabilitativen Behandlung sehr hoch lag. Hervorzuheben ist, dass sich herausarbeiten ließ, dass sich eine längere Behandlung positiv auf die Behandlungsergebnisse, auch bei schwer Betroffenen auswirkte. Die auslösende Ursache scheint keinen wesentlichen Einfluss auf das outcome zu haben. Männer profitieren bei der Wiedererlangung motorischer Fähigkeiten etwas besser als Frauen. Die älteren Patienten zeigen gute Verbesserungen bei körperlichen Funktionsstörungen. Bezogen auf die kognitiven Fähigkeiten muss aber das Alter als negativer Prädiktor angesehen werden. Der Grad der Behinderung hat einen deutlichen Einfluss auf die Behandlungsdauer und Behandlungsergebnisse. Demgegenüber stellt eine primäre Intensivpflicht einen negativen Prädiktor, auch wenn auch diese Patienten von der Rehabilitation profitieren. The Critical-lllness-Polyneuropathie (CIP) is an illness of the peripheral nervous system after a severe illness with intensive care treatment. It is known since the 19th century and cannot be distinguished easyly from the Critical Illness Myopathie which can appear in the same context. The situation is complicated by the fact that both dysfunctions can appear combined. Because of the advances in the medicine the frequency of the CIP has increased in the last 2 decades. The question is which patients profits from a certain neurorehabilitativen treatment, which factors are relevant for the prognosis and which kind and duration of the neurorehabilitation must be reproached.
A syndrome of generalized weakness, areflexia, and difficulty with weaning from a ventilator is a common clinical presentation in the critically ill patient, especially in the setting of sepsis, multiorgan failure, and hyperglycemia. At first believed to be a manifestation of nerve (critical illness neuropathy, CIN) or muscle (critical illness myopathy, CIM) dysfunction, our current conceptualization is as a spectrum (critical illness neuromuscular abnormalities, CINMA) that varies in extent and site(s) of involvement, but often a similar clinical presentation. Signs and symptoms of CINMA must be identified early to foster recovery and limit morbidity and mortality. The medical history is crucial in excluding preexisting neuromuscular conditions and electrodiagnostic testing helps to establish the diagnosis and prognostication. A stepwise approach to the management of a patient with CINMA is outlined, but avoiding potential medications, and ensuring supportive care are the primary interventions to consider. Recently intensive insulin therapy for hyperglycemia has been shown to lower the risk of CINMA and decrease the time of ventilatory support, but with a greater risk of hypoglycemia. Future therapeutic interventions will require a better understanding of disease pathogenesis, but may target proinflammatory cytokine and free-radical pathways, muscle gene expression, ion channel function, or proteolytic muscle protein mechanisms. Rehabilitation is an equally essential component in a patient's management. Although prognosis depends on the extent of the underlying muscle and nerve damage, mild persistent deficits are common and severe disability may be persistent.
The present study examined the effects of an isolated sepsis with E. coli bacteria on neuromuscular transmission and the expression of acetylcholin receptors in rats. Serum level of a1-acid glycoprotein increased over the time course of sepsis. Body weight gain, muscle weight and force generating capacity decreased compared to time matched controls.There was no significant difference in acetylcholine receptor expression. General catabolism is, therefore, a major factor for the muscle dysfunction seen during sepsis.
Acute quadriplegic myopathy (AQM; also called "critical illness myopathy") shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber-specific ubiquitin/proteosome pathways (eg, atrogin-1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF)-beta/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF-beta receptors, p38 MAPK, c-jun, and c-myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF-beta pathway in myofibers. The acute stimulation of the TGF-beta/MAPK pathway, coupled with the inactivity-induced atrogin-1/proteosome pathway, leads to the acute muscle loss seen in AQM patients.
To evaluate aspiration needle muscular biopsy as an alternative to surgical open biopsy, so we focus on its results and tolerance.
We studied 150 patients with muscular pathology of every kind, and aged between 10 and 86 years, using a modified Allendale/Liverpool needle which by our indication has a built-in lateral funnel that provides faultless aspiration in 100% of cases. Percutaneous biopsy neuromuscular disorders study with modified aspiration Allendale needle: use and advantages over surgical biopsy.
The biopsy, which was very well tolerated by the patients, children in particular, left no scar and produced fine samples for standard, immunohistochemical, ultrastructural, biochemical and genetic investigation. In children beyond 10 years of age no general anesthetics was required and in many 4-10 years neither. A number of unsuspected cases of mitochondrial or inflammatory myopathy were detected. Patients with cramps or unclearly defined clinical picture did, however, show frequent morphological pathology. In just three cases samples were defective; all others produced changes of diagnostic or prognostic value with 8% without morphologically abnormal changes.
Modified aspiration needle biopsy is the choice method to study muscle. The samples are of excellent quality allowing for any kind of morphological, biochemical or genetic investigation. The procedure is routinely very well tolerated by patients so is very superior to open surgical biopsy, that we still use for infants in selected cases.
Critical illness, more precisely defined as the systemic inflammatory response syndrome (SIRS), occurs in 20%-50% of patients who have been on mechanical ventilation for more than 1 week in an intensive care unit. Critical illness polyneuropathy (CIP) and myopathy (CIM), singly or in combination, occur commonly in these patients and present as limb weakness and difficulty in weaning from the ventilator. Critical illness myopathy can be subdivided into thick-filament (myosin) loss, cachectic myopathy, acute rhabdomyolysis, and acute necrotizing myopathy of intensive care. SIRS is the predominant underlying factor in CIP and is likely a factor in CIM even though the effects of neuromuscular blocking agents and steroids predominate in CIM. Identification and characterization of the polyneuropathy and myopathy depend upon neurological examination, electrophysiological studies, measurement of serum creatine kinase, and, if features suggest a myopathy, muscle biopsy. The information is valuable in deciding treatment and prognosis.
Muscle-fiber loss is a characteristic of many progressive neuromuscular disorders. Over the past decade, identification of a growing number of apoptosis-associated factors and events in pathological skeletal muscle provided increasing evidence that apoptotic cell-death mechanisms account significantly for muscle-fiber atrophy and loss in a wide spectrum of neuromuscular disorders. It became obvious that there is not one specific pathway for muscle fibers to undergo apoptotic degradation. In contrast, certain neuromuscular diseases seem to involve characteristic expression patterns of apoptosis-related factors and pathways. Furthermore, there are some characteristics of muscle-fiber apoptosis that rely on the muscle fiber itself as an extremely specified cell type. Multinucleated muscle fibers with successive muscle-fiber segments controlled by individual nuclei display some specifics different from apoptosis of mononucleated cells. This review focuses on the expression patterns of apoptosis-associated factors in different primary and secondary neuromuscular disorders and gives a synopsis of current knowledge.
The pathogenesis of myopathies occurring in critically ill patients (critical illness myopathy, CIM) is poorly understood. Both local and systemic responses to sepsis and other severe insults to the body are presumed to be involved but the precise mechanisms by which muscle function is impaired are far from clear. To elucidate such mechanisms we investigated the effects of blood serum fractions (5 kDa to 100 kDa molecular weight cut-off, MWCO) from patients with CIM and from control persons on membrane and contractile functions in intact mammalian single skeletal muscle fibres and chemically skinned fibre bundles. In intact fibres, resting membrane potentials were less negative when exposed to CIM serum fractions compared with control serum fractions. Half-width and maximum rise time of action potentials (AP) were smaller in CIM serum low MWCO fractions vs. control serum. Peak amplitudes of fast inward sodium currents (I(Na)) were increased by low MWCO-CIM fractions compared with control sera fractions. Additionally, voltage dependent inactivation of I(Na) was shifted towards more positive potentials by high MWCO fractions of CIM sera. In skinned fibres, pCa-force relations were similar in CIM and control serum fractions but peak force of Ca2+ induced force transients was decreased by low MWCO-CIM vs. control serum fractions. Our results (i) provide the first evidence that serum from CIM patients affects membrane excitability and the excitation-contraction coupling process at the level of the sarcoplasmic reticulum Ca2+ release of mammalian muscle fibres and (ii) also show that even control serum fractions "per se" alter the response to important physiological membrane and contractility parameters compared with physiological saline.
Acquired diffuse paresis in an intensive care unit (ICU) can result from critical illness myopathy or polyneuropathy. Clinical examination and conventional neurophysiological techniques may not distinguish between these entities.
To assess the value of direct muscle stimulation (DMS) to differentiate myopathic from neuropathic process in critically ill patients with diffuse severe muscle weakness.
30 consecutive patients with ICU acquired diffuse motor weakness were studied. Responses of the right deltoid and tibialis anterior muscles to DMS and to motor nerve stimulation (MNS) were studied and compared with results of conventional nerve conduction studies and concentric needle electromyography (EMG). An original algorithm was used for differential diagnosis, taking into account first the amplitude of the responses to DMS, then the MNS to DMS amplitude ratio, and finally the amplitude of the sensory nerve action potentials recorded at the lower limbs.
Evidence of neuropathy and myopathy was found in 57% and 83% of the patients, respectively. Pure or predominant myopathy was found in 19 patients. Other results were consistent with neuromyopathy (n = 5) and pure or predominant neuropathy (n = 2). Four patients had normal results with stimulation techniques, but spontaneous EMG activity and raised plasma creatine kinase suggesting necrotic myopathy.
A neurophysiological approach combining DMS and conventional techniques revealed myopathic processes in a majority of ICU patients. Reduced muscle fibre excitability may be a leading cause for this. The diagnosis of myopathy in ICU acquired paralysis can be established by a combination of DMS, needle EMG, and plasma creatine kinase.
Critical care myopathy (CCM) is an important, often unrecognized cause of weakness in the intensive care unit (ICU). We report a child who developed severe myopathy in the ICU. Our patient was newly diagnosed to have autoimmune hepatitis that may have predisposed her to toxicity from corticosteroids and neuromuscular-blocking agents, but she recovered her strength completely. Risk factors that may have predisposed this patient to CCM include underlying liver dysfunction, presence of acute lung injury, use of corticosteroids, and use of neuromuscular blockade. Given the apparent prevalence and underreporting of CCM in the ICU, it is important for rheumatology consultants to include this entity in their differential diagnosis of weakness in critically ill children and adults, and to recommend appropriate evaluation.
Neuromuscular pathology in the critically ill patient develops within two settings: primary neurological diseases that require admission in the Intensive Care Medicine Unit for close monitoring or mechanical ventilation, and peripheral nervous system manifestations secondary to critical systemic diseases. The most frequent conditions in the first group are Guillain-Barré syndrome and Myasthenia Gravis, and in the second group, polyneuropathy and myopathy of the critically ill patient. The most commonly shared clinical pattern is the development of severe weakness and quadriplegia which most typical manifestation is the need for assisted ventilation and/or weaning difficulty/impossibility. Triggering factors considered are multiorgan failure and sepsis in polyneuropathy, and steroids and neuromuscular blockers in myopathy, with malnutrition, particularly hypoalbuminemia, and hyperglycemia being co-adjuvant in both conditions. Considering that neuropathic and myopathic conditions may frequently coexist, the term polyneuromyopathy of the critically ill patient has been coined. Both Guillain-Barré syndrome and polyneuropathy of the critically ill patient involve peripheral nerves, so that the differential diagnosis has to be made between both. The presenting picture is different, since the former is an acute pathology that motivates ICU admission, whereas the latter is a polyneuropathy acquired during hospitalization. In the former, involvement of the autonomous nervous system and CSF albumin-cytology dissociation are common, which do not occur in polyneuropathy. Electrophysiological studies show demyelinating signs with decreased conduction velocity and normal amplitude of motor potentials in Guillain-Barré syndrome versus normal conduction velocity and reduced amplitude of motor potentials in axonal polyneuropathy. Myasthenic crisis affects the neuromuscular junction and its diagnosis tends to be easier since in most of the cases a previous diagnosis of myasthenia gravis exists. Muscle weakness increases during repeated activity (muscle fatigue) and improves on resting. Diagnostic confirmation is done by means of edrophonium test and by repeated nerve stimulation, which leads to a rapid decrease by 10-15% of the amplitude of evoked responses. Myopathy of the critically ill patient involves the muscle and provokes a generalized weakness with quadriplegia, very similar to that from polyneuropathy, which prevents or delays weaning from mechanical ventilation, and which may lead to CPK and myoglobin increase in more advanced stages, together with changes in neurophysiological examination. The findings of neurophysiological examination are difficult to differentiate from those encountered in polyneuropathy, although normal sensitive action potentials and reduction of motor action potentials with direct muscle stimulation may help in the differentiation. The functional prognosis of primary muscle impairments tends to be quite good, but both polyneuropathy and myopathy resolve very slowly along weeks or months, with the possibility of an important residual deficit within two years in the most severe cases.
Use of corticosteroids for adrenal supplementation and attenuation of the inflammatory and immune response is widespread in acute critical illness. The study hypothesis was that exposure to corticosteroids influences the mortality and morbidity in acute critical illness.
This case-control retrospective study was performed in a single multidisciplinary intensive care unit at a tertiary care institution and consisted of 10,285 critically ill patients admitted between 1 January 1999 and 31 December 2004. Demographics, comorbidities, acute illness characteristics including severity measured by Sequential Organ Failure Assessment, concurrent medications, therapeutic interventions and incidence of infections were obtained from electronic medical records, were examined with multiple regression analysis and were adjusted for propensity of corticosteroid exposure. The primary outcome was hospital death, and the secondary outcome was transfer to a care facility at hospital discharge.
Corticosteroid exposure in 2,632 (26%) patients was characterized by younger age, more females, higher Charlson comorbidity and maximal daily Sequential Organ Failure Assessment scores compared with control patients. Corticosteroids potentiated metabolic and neuromuscular sequels of critical illness with increased requirements for diuretics, insulin, protracted weaning from mechanical ventilation, need for tracheostomy and discharge to a care facility. Early exposure to corticosteroids predisposed to recurrent and late onset of polymicrobial and fungal hospital-acquired infections. Corticosteroids increased the risk for death or disability after adjustments for comorbidities and acute illness characteristics.
Corticosteroids increased the risk for death or disability in critical illness. Hospital-acquired infections and metabolic and neuromuscular sequels of critical illness were exacerbated by corticosteroids. Careful appraisal of the indications for use of corticosteroids is necessary to balance the benefits and risks from exposure in acute critical illness.
Critically-ill patients who receive nondepolarizing neuromuscular blocking drugs (NMBDs) may be at risk of developing profound muscle weakness that may last for months after the NMBD is discontinued, especially when large cumulative doses of NMBDs and corticosteroids are co-administered to septic, mechanically ventilated patients. This review focuses on the etiology and clinical features of critical illness myopathy (CIM), summarizes specific risk factors for its development, and discusses strategies that might be used to attenuate or even prevent the development of this potentially devastating syndrome.
The etiology of CIM is unknown. Whether it can develop in at-risk patients who undergo lengthy operations during which they receive NMBDs is also unknown. In some patients following exposure to NMBDs their motor systems are impaired secondary to loss of thick (myosin) filaments that render the muscle unexcitable to direct electrical stimulation, while the sensory system is spared. Management of patients who develop NMBD myopathy is supportive, consisting of nutritional support, physical therapy, and daily trials of decreased ventilatory support.
Recent guidelines recommend that NMBDs be used in critically ill patients only when absolutely necessary, that the depth of muscle paralysis be monitored to avoid overdosing and metabolite accumulation, and that drug administration be curtailed periodically to allow interruption of sustained NMBD effect.
In the intensive care unit (ICU) patients sometimes develop diffuse neuromuscular deficit resulting in flaccid tetraparesia with a more or less severe prognosis.
ICU-acquired neuromuscular disorders have various possible origins, including necrotic or catabolic myopathies and sensori-motor axonal neuropathies. Electrophysiological testing determines these pathophysiological mechanisms better than clinical examination. The technique of direct muscle stimulation has been proposed, in addition to conventional electroneuromyographic methods, to improve the reliability of electrodiagnosis in ICU, but has been rarely studied. Using this technique, we recently showed that a majority of ICU-acquired pareses are of myopathic origin.
The technique of direct muscle stimulation could be fruitfully associated with usual electroneuromyographic methods to differentiate myopathic from neuropathic involvement at the origin of any severe weakness in ICU.
The contribution of myopathic processes in ICU-acquired paresis is probably underestimated. Direct muscle stimulation enables better understanding of the mechanisms underlying acquired motor deficit in ICU patients. However, it remains to be determined whether this refinement could have a significant impact on prognosis and treatment.
Critical illness polyneuromyopathy, a complication of critical illness, is a primary axonal degeneration of motor and sensory fibers that leads to skeletal muscle weakness. It significantly contributes to the unexplained difficulty in weaning from mechanical ventilation and to their prolonged rehabilitation and poor quality of life after discharge. This article will discuss the diagnosis of critical illness polyneuromyopathy, identify risk factors, review several pathomechanisms that have been proposed, and discuss the implications for practice.
Recent studies have demonstrated acquired muscle inexcitability in critical illness myopathy (CIM) and have used direct muscle stimulation (DMS) techniques to distinguish neuropathy from myopathy as a cause of weakness in the critically ill. The mechanisms underlying weakness in CIM are incompletely understood and DMS is only semiquantitative. We report results from a series of 32 patients with CIM and demonstrate significant slowing of muscle-fiber conduction velocity (MFCV) and muscle-fiber conduction block during the acute phase of CIM, which correlates with prolonged compound muscle action potential (CMAP) duration, clinical severity, and course. We also used a paired stimulation technique to explore the excitability of individual muscle fibers in vivo. We demonstrate altered muscle-fiber excitability in CIM patients. Serial studies help define the course of these pathophysiological changes. Parallels are made between CIM and hypokalemic periodic paralysis. Our findings provide further evidence for muscle membrane dysfunction being the principal underlying abnormality in CIM.
Despite the recent and marked improvement in short-term mortality after critical illness, significant morbidities persist for many patients following hospital discharge. This article discusses the risk factors for muscle, nerve, and brain dysfunction after critical illness and preliminary basic science data to support possible pathophysiologic mechanisms mediating this disability. Additionally, it presents a roadmap outlining future directions in this area of research.
Critical illness polyneuropathy (CIP) is a recognized cause of muscle weakness and failure of weaning from a ventilator. In
order to characterize the features of CIP, we have examined 28 consecutive surgical patients with severe sepsis using bedside
electrophysiology. Of the 28 patients (median APACHE II score 31), 20 developed moderate to severe CIP, as shown by the presence
of moderate to severe denervation activity on resting EMG. The median nerve compound muscle action potential (CMAP) amplitudes
were reduced to 3.24 (SEM 0.48) mV, while sensory nerve action potential (SNAP) amplitudes obtained from the same nerve were
normal (13.1 (1.9) microV). In approximately 50% of these patients, the reduction in CMAP exceeded 50% of the lower limit
of normal. Similar results were obtained from stimulation of the ulnar nerve. We conclude that CIP is a major complication
in patients with severe sepsis and prolonged artificial ventilation. It predominantly involves motor fibres and thus markedly
interferes with weaning from the ventilator.
Acute quadriplegic myopathy is a rare condition associated with the use of nondepolarizing muscle-blocking agents and corticosteroids in the course of severe systemic illness. A 17-month-old boy underwent liver transplantation for fulminant hepatitis. He was intubated for 24 days and treated with vecuronium bromide and high-dose methylprednisolone. The child was weaned from the ventilator and presented extreme weakness in the upper limbs and total paralysis of the lower limbs. Serum creatine kinase level was normal and electromyography showed myopathic abnormalities. Muscle biopsy showed severe type-1 fiber atrophy and selective loss of myosin thick filaments was seen on electron microscopy. Scattered regenerating fetal myosin-positive fibers were present, mu calpain was absent, while m calpain was diffusely expressed. Physical therapy was immediately started and the child recovered even though corticosteroids were not discontinued. The pathogenesis of acute quadriplegic myopathy is still unknown. We suggest that it could be due to abnormal protein turnover in the muscle. Several independent factors, such as corticosteroid treatment, immobilization, or cytokines, could take part in a cascade of events that leads to an excessive yet selective degradation of proteins involving myosin thick filaments and possibly components of sarcolemma, causing muscle inexcitability.
MyoD regulates skeletal muscle differentiation (SMD) and is essential for repair of damaged tissue. The transcription factor
nuclear factor kappa B (NF-κB) is activated by the cytokine tumor necrosis factor (TNF), a mediator of skeletal muscle wasting
in cachexia. Here, the role of NF-κB in cytokine-induced muscle degeneration was explored. In differentiating C2C12 myocytes,
TNF-induced activation of NF-κB inhibited SMD by suppressing MyoD mRNA at the posttranscriptional level. In contrast, in differentiated
myotubes, TNF plus interferon-γ (IFN-γ) signaling was required for NF-κB–dependent down-regulation of MyoD and dysfunction
of skeletal myofibers. MyoD mRNA was also down-regulated by TNF and IFN-γ expression in mouse muscle in vivo. These data elucidate
a possible mechanism that may underlie the skeletal muscle decay in cachexia.
Severe weakness with respiratory failure is a serious and common complication of critically ill patients in the intensive care unit setting. Recent studies have elucidated 2 entities characterized by severe weakness that occur as a result of these circumstances: critical illness neuropathy and critical illness myopathy. Both are the result of a serious illness, in contrast to weakness arising from a primary neurological disorder that results in admission to an intensive care unit (eg, myasthenic crisis, Guillain-Barre syndrome, rhabdomyolysis, or botulism). Critical illness neuropathy and myopathy are difficult to distinguish from each other on purely clinical grounds, although certain clues may make one more likely. Nerve conduction studies, needle electromyography, and muscle biopsy are often necessary to make a firm diagnosis.
Nineteen patients developed polyneuropathy complicating critical illness. They had been admitted to a critical care unit following intubation for cardiac or pulmonary disease and had developed sepsis and multiple organ failure. Approximately one month following intubation, failure to wean from the ventilator and limb weakness prompted neurological referral. Examination disclosed weakness and wasting of muscles and impaired tendon reflexes in most, but not all, patients. Electrophysiological studies in 17 patients revealed attenuated compound muscle and sensory nerve action potential amplitudes and widespread denervation on needle electromyography. Autopsy in 9 patients who died of their critical illness revealed widespread primary axonal degeneration of motor and sensory fibres, with extensive denervation atrophy of limb and respiratory muscles. Survivors recovered from the polyneuropathy three to six months following discharge.
Seventeen of the patients were segregated by electrophysiological criteria into mild (8) and severe (9) polyneuropathy categories. An analysis of these two groups failed to reveal putative metabolic, drug, nutritional or toxic factors that might be responsible for the polyneuropathy. Our studies suggest that the mechanism may be a fundamental defect, still unknown, which causes dysfunction of all organ systems in this syndrome.
The spectrum of neuromuscular disorders among intensive care unit (ICU) patients has shifted toward disorders acquired within the ICU and away from “traditional” neuromuscular disorders that lead to ICU admission. We sought to assess this spectrum by determining the causes and relative frequencies of neuromuscular disorders that led to electromyography (EMG) examinations in our ICU population. Ninety-two patients were studied over a 4½-year period. Twenty-six (28%) had neuromuscular disorders (mainly Guillain–Barré syndrome, myopathy, and motor neuron disease) that led to ICU admission. Among patients who developed weakness in the ICU, there was a predominance of organ transplant patients and patients with the systemic inflammatory response syndrome and multiorgan dysfunction. Thirty-nine (42%) developed acute myopathy (consistent with critical illness myopathy in most), and 13% developed acute axonal sensorimotor polyneuropathy (mainly critical illness polyneuropathy). Patients with acute myopathy and acute axonal sensorimotor polyneuropathy had similar functional outcomes. We conclude that among patients who underwent EMG in our ICU population, acute myopathy is three times as common as acute axonal polyneuropathy, and the outcomes from acute myopathy and acute axonal polyneuropathy may be similar. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:610–617, 1998.
Neuromuscular disorders developing m critically ill patients often result in increased morbidity and prolonged intensive care hospitalization Detection and assessment of affected patients are frequently hindered by the severe nature of the underlying medical illness. The various syndromes have overlapping clinical and electrodiagnostic features, presenting further obstacles to prompt classification. Nonetheless, an accurate diagnosis can usually be attained through an organized approach to the evaluation and management of critically ill patients with acquired weakness.
The muscle relaxant vecuronium is sometimes administered to facilitate mechanical ventilation. Neuromuscular paralysis lasting up to seven days may occur after the termination of long-term administration (i.e., more than two days) of vecuronium in critically ill patients. We investigated the role of clinical factors and plasma concentrations of vecuronium and its metabolite in causing this prolonged neuromuscular blockade.
We studied 16 critically ill adult patients (8 women and 8 men) who had received vecuronium to facilitate mechanical ventilation for at least two consecutive days. Clinical factors and plasma concentrations of vecuronium and 3-desacetylvecuronium, the active metabolite of vecuronium, were compared in patients with and without prolonged neuromuscular blockade. In addition, we performed detailed pharmacokinetic studies in the patients without prolonged neuromuscular blockade.
Seven of the 16 patients had prolonged neuromuscular blockade, lasting from six hours to more than seven days, after the termination of vecuronium therapy. These seven patients, six of whom were women, had higher plasma magnesium concentrations and lower arterial blood pH values than the nine patients without prolonged neuromuscular blockade. They also had higher plasma concentrations of 3-desacetylvecuronium and a higher frequency of renal failure (seven of seven patients vs. four of nine patients, P less than 0.03). In the patients without prolonged neuromuscular blockade, the mean (+/- SD) plasma clearance, elimination half-life, and volume of distribution of vecuronium were 2.5 +/- 1.0 ml per kilogram of body weight per minute, 299 +/- 154 minutes, and 1.1 +/- 0.6 liters per kilogram, respectively.
Prolonged neuromuscular blockade after the termination of long-term treatment with vecuronium is associated with metabolic acidosis, elevated plasma magnesium concentrations, female sex, and probably more important, the presence of renal failure and high plasma concentrations of 3-desacetylvecuronium.
Myopathy complicating the therapy of severe asthma has been recently described in several case reports. Twenty-five consecutive patients admitted to the intensive care unit (ICU) at this hospital for mechanical ventilation for severe asthma were studied for the incidence of creatine kinase (CK) enzyme rise and for the development of clinical myopathy. Pharmacologic therapy was standardized, every patient receiving corticosteroids and aminophylline intravenously and salbutamol both nebulized and intravenously. Twenty-two patients received muscle relaxant therapy with vecuronium. In 19 of 25 (76%) of patients there was elevation of CK levels to a median of 1,575 U/L (range, 66 to 7,430) occurring 3.6 +/- 1.5 days after admission. In nine patients there was clinically detectable myopathy. The presence of either myopathy or CK enzyme rise was associated with a significant prolongation of ventilation time. Arterial blood gas measurements on admission to the ICU revealed a pH (mean +/- SD) of 7.07 +/- 0.21, a PaCO2 of 87.2 +/- 32.7, and a PaO2 (with a high FIO2) of 129 +/- 97 mm Hg; however, no correlation was found between the severity of initial metabolic disturbance and the subsequent development of myopathy. There was no association between the type of corticosteroid administered and the subsequent development of myopathy. Patients with myopathy had received a significantly higher total dose of vecuronium when compared with those who did not develop myopathy (p < 0.001, Kruskal Wallis test). We have therefore found a surprisingly high incidence of CK enzyme rise and myopathy in this group of mechanically ventilated patients with severe asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
Denervation of rat soleus muscle and simultaneous administration of high doses of corticosteroids for 7 days caused marked muscle fiber atrophy and selective loss of thick myofilaments from many muscle fibers by light and electron microscopy. Myosin heavy chain/actin ratios were greatly reduced on polyacrylamide gel electrophoresis. Nerve crush instead of cut permitted reinnervation after 2 weeks and demonstrated the reversibility of the muscle changes within a week after reinnervation. There was formation of new thick filaments and their reintegration into myofibrils without further breakdown, although large areas of Z-disc streaming appeared. The mechanism of A-band breakdown remains obscure, but it presumably starts with limited proteolysis and continues with disaggregation of myosin molecules. This is consistent with our observation that the muscle fibers retain a relatively good reactivity to antibodies against myosin heavy chain 1 week after denervation and corticosteroid administration. A syndrome recalling these experiments is seen in severely asthmatic patients receiving corticosteroids and pharmacologically paralyzed for mechanical respiration.
In one hospital over a 15-month period, four out of nine patients ventilated for acute severe asthma developed acute hydrocortisone myopathy. All patients had received less than 1.0 g day-1 hydrocortisone. Affected patients had severe generalized weakness which recovered over 1-6 weeks. When myopathic and unaffected subjects were compared, there was no clearcut difference with respect to age, sex, types of drug used, serum potassium levels, duration of ventilation and muscle paralysis, total dose of vecuronium bromide, or mean daily doses of hydrocortisone. The main difference between the two groups was in the total doses of hydrocortisone. The myopathic patients all received greater than 5.0 g hydrocortisone (range 5.4-10.2 g) and the others less than 4.0 g (range 0.9-3.5 g). The possibility that neuromuscular blockade might predispose to the development of myopathy is discussed. Hydrocortisone myopathy can occur when less than 1.0 g day-1 is used, and even with as little as 5.4 g given over 6 days.
An association between the use of parenteral corticosteroids in acute asthma and the development of an acute myopathy was first reported in 1977. We report 2 further cases that contribute significantly to our knowledge of this rare complication of the treatment of acute asthma. These cases demonstrate that the acute myopathy is not just a complication of the use of parenteral hydrocortisone in patients requiring ventilatory support during an episode of acute asthma. The acute myopathy can occur with several parenteral corticosteroids, may be severe (with rhabdomyolysis and myoglobinuria), and may have protracted morbidity. Prospective follow-up allowed demonstration of histopathology, electrophysiology, and also the contribution of various pharmacologic agents. Careful analysis of the evidence strongly implicates corticosteroids as the causative agent.
The combined effects of dexamethasone treatment (1 mg/Kg/day) plus denervation (DEX-DEN), were studied at 7, 13, and 28 days by microscopic, biochemical, and physiological techniques in plantaris and soleus muscles of adult rats. The results were compared with corresponding dexamethasone-treated (DEX) and denervated (DEN) muscles and appropriate controls. There was a significantly more marked atrophy of all fiber types in the DEX-DEN plantares at 7 and 13 days than in either DEX or DEN muscles. The degree of atrophy was greatest in type 2B fibers in DEX-DEN plantares. Electron microscopy revealed a severe preferential depletion of thick myofilaments in DEX-DEN plantares and solei but not in DEX or DEN muscles. The thick myofilament depletion in DEX-DEN muscles occurred in addition to a severe overall reduction of myofibrillar caliber. Gel electrophoresis showed a marked preferential decrease of myosin heavy chain in DEX-DEN plantares and solei, but not in either DEX or DEN muscles. Myosin light chains were also markedly reduced in DEX-DEN plantares and solei. In vitro physiological studies showed a marked reduction of the denervation-induced twitch potentiation in DEX-DEN solei. Maximal tetanic tension (20 Hz stimulation) per gram weight of muscle as well as the twitch-tetanus ratio was significantly reduced only in DEX-DEN solei in relation to controls. Myosin depletion in DEX-DEN muscles may be due to a severe preferential inhibition of its synthesis coupled with an accelerated catabolism.
Nineteen patients developed polyneuropathy complicating critical illness. They had been admitted to a critical care unit following intubation for cardiac or pulmonary disease and had developed sepsis and multiple organ failure. Approximately one month following intubation, failure to wean from the ventilator and limb weakness prompted neurological referral. Examination disclosed weakness and wasting of muscles and impaired tendon reflexes in most, but not all, patients. Electrophysiological studies in 17 patients revealed attenuated compound muscle and sensory nerve action potential amplitudes and widespread denervation on needle electromyography. Autopsy in 9 patients who died of their critical illness revealed widespread primary axonal degeneration of motor and sensory fibres, with extensive denervation atrophy of limb and respiratory muscles. Survivors recovered from the polyneuropathy three to six months following discharge. Seventeen of the patients were segregated by electrophysiological criteria into mild (8) and severe (9) polyneuropathy categories. An analysis of these two groups failed to reveal putative metabolic, drug, nutritional or toxic factors that might be responsible for the polyneuropathy. Our studies suggest that the mechanism may be a fundamental defect, still unknown, which causes dysfunction of all organ systems in this syndrome.
A series of recent reports have identified cases of a quadriplegic myopathy characterized by myofiber necrosis and loss of myosin filaments associated with the use of nondepolarizing muscle blocking agents and glucocorticoids. We report electrophysiological findings in 7 intensive care unit patients who developed evidence of an acute myopathy in association with the use of nondepolarizing muscle blocking agents. Several important features were identified: (i) a neuromuscular transmission deficit was observed in 3 patients up to 7 days following withdrawal of vecuronium; (ii) motor M potentials were of low amplitude, there was mild abnormal spontaneous activity on needle electromyography, and sensory conduction was relatively preserved; (iii) not all patients received glucocorticoids or were asthmatic; (iv) 2 patients given vecuronium had very high creatine kinase levels and developed acute renal failure associated with myoglobinuria; and (v) rises in motor M potentials accompanied clinical recovery. This complication of intensive care may be severe, but is reversible and possibly avoidable. Our findings implicate nondepolarizing muscle blocking agents in the development of the myopathy. Electrophysiological studies provide important prognostic guidance.
We directly stimulated muscle in three patients with acute quadriplegic myopathy to determine whether paralyzed muscle in this syndrome is electrically excitable. Two of the patients had been treated with neuromuscular blocking agents and corticosteroids, and one patient had been treated with corticosteroids alone. We found that paralyzed muscle is electrically inexcitable in affected patients. Muscle regained electrical excitability over weeks to months. The recovery of muscle excitability paralleled the clinical recovery of patients, suggesting that paralysis in this syndrome is secondary to electrical inexcitability of muscle membrane.
Patients who undergo mechanical ventilation for severe asthma are at risk of developing diffuse muscle weakness because of acute myopathy. The relative importance of corticosteroids and neuromuscular paralysis in causing the myopathy is controversial, and it is uncertain whether the chemical structure of the drug used to induce paralysis influences the risk of myopathy. Using a retrospective cohort study design, we evaluated 107 consecutive episodes of mechanical ventilation for severe asthma to assess (1) the incidence of clinically significant weakness in patients treated with corticosteroids alone versus corticosteroids with neuromuscular paralysis, (2) the influence of the duration of paralysis on the incidence of muscle weakness, and (3) the relative risk of weakness in patients paralyzed with the nonsteroidal drug atracurium versus an aminosteroid paralytic agent (pancuronium, vecuronium). The use of corticosteroids and a neuromuscular blocking agent was associated with a much higher incidence of muscle weakness as compared with the use of corticosteroids alone (20 of 69 versus O of 38, p < 0.001). The 20 weak patients were paralyzed significantly longer than the 49 patients who received a neuromuscular blocking agent without subsequent weakness (3.4 +/- 2.4 versus 0.6 +/- 0.7 d, p < 0.001). Eighteen of the 20 weak patients had been paralyzed for more than 24 h. The incidence of weakness was not reduced when paralysis was achieved with atracurium as opposed to an aminosteroid neuromuscular blocking agent. In conclusion, corticosteroid-treated patients with severe asthma who undergo prolonged neuromuscular paralysis are at significant risk for the development of muscle weakness, and the risk of weakness is not reduced by use of atracurium.
Critically ill patients may develop muscle weakness or paralysis during the course of sepsis and multiple-organ failure. We studied peripheral nerve and muscle disorders (NMD) in comatose patients.
Comatose patients who developed paralysis associated with absent deep-tendon reflexes had electroneuromyography (ENMG) and muscle-nerve biopsy specimens taken. Onset and duration of sepsis, multiple-organ dysfunction and failure, biochemical alterations, and drugs potentially interfering with nerve-muscle function were recorded.
24 patients became quadriparetic or quadriplegic; muscle changes were found in 23. Axonal neuropathy was found in eight of 22 patients examined. All patients had prolonged sepsis and multiple-organ dysfunction, but only 14 had multiple-organ failure. Drugs such as steroids, neuromuscular-blocking agents, and aminoglycosides were not responsible for paresis, and the part played by hyperglycaemia and hypoalbuminaemia is uncertain. Attending physicians predicted a fatal outcome in all cases, although six of seven survivors fully recovered within 115-210 days from the onset of paralysis.
Comatose patients may become completely paralysed because of NMD. The diagnosis is important to avoid unnecessary investigations and unreasonably pessimistic prognosis. ENMG is essential for the diagnosis and for planning further clinical management. Biopsy needs to be done only when it is necessary to properly classify NMD.
An acute myopathy of intensive care occurs in critically ill patients treated with intravenous corticosteroids and neuromuscular junction-blocking agents. The full clinicopathological spectrum is uncertain. We evaluated the clinical, electrodiagnostic, and histopathological features of 14 patients who developed acute myopathy of intensive care after organ transplantation or during treatment of severe pulmonary disorders and sepsis. Patients received high-dose intravenous corticosteroids, usually in conjunction with relatively low to moderate doses of neuromuscular junction-blocking agents. After discontinuation of the latter drugs, most had diffuse, flaccid weakness with failure to wean from mechanical ventilation. Electrodiagnostic findings were consistent with a necrotizing myopathy. Muscle histopathology revealed myopathy with loss of thick filaments in 79%, mild myopathic changes in 14%, and atrophy of type 1 and type 2 fibers in 7%. Loss of thick filaments was identified in muscle biopsy specimens obtained 30 +/- 11 days (mean +/- standard deviation) after intravenous corticosteroid treatment but not in those obtained earlier (12 +/- 2 days). Critically ill patients, including those receiving organ transplants, may develop acute myopathy of intensive care after exposure to intravenous corticosteroids and neuromuscular junction-blocking agents, although the exposure to the latter drugs may be minimal. Selective loss of thick filaments is common in acute myopathy of intensive care, especially if the muscle biopsy specimen is obtained 2 weeks or more after intravenous corticosteroid exposure.
Immunocytochemical analysis of muscle specimens from 5 patients with acute quadriplegic myopathy indictes that depletion of either fast or slow myosin occurs in this disorder. The initial lesion consists of focal myosin loss in nonatrophic fibers. Other structural proteins (actin, titin, nebulin) are spared or affected only at an advanced stage of the disease. Attempts at regeneration, evidenced by expression of fetal myosin and desmin, occur in some fibers. Calpain expression is markedly enhanced in the affected fibers, implicating an altered calcium homeostasis in the evolution of the pathologic process. By contrast, cathepsin B and ubiquitin expressions are only minimally affected. The history of 1 of our patients indicates that severe systemic illness in and of itself can cause acute quadriplegic myopathy.
We have previously found that muscle is electrically inexcitable in severe acute quadriplegic myopathy (AQM). In contrast, muscle retains normal electrical excitability in peripheral neuropathy. To study the relationship between muscle electrical excitability and all types of flaccid weakness occurring in the intensive care unit, we identified 14 critically ill, weak patients and measured the amplitude of compound muscle action potentials (CMAPs) obtained with direct muscle stimulation (dmCMAP) and with nerve stimulation (neCMAP). In 11 of 14 patients dmCMAP amplitudes were reduced and the ratio of the neCMAP amplitude to the dmCMAP amplitude (nerve/muscle ratio) was indicative of loss of muscle electrical excitability. In 2 other patients, the nerve/muscle ratio indicated neuropathy. Direct muscle stimulation may allow differentiation of AQM from neuropathy even in comatose or encephalopathic critically ill patients. AQM may be more common than has previously been appreciated.
To study the temporal course and the relationship between autonomic failure and motor weakness in Guillain-Barré syndrome (GBS), a total of 164 autonomic function tests were serially applied for up to 1 year in 13 consecutive patients. Results were compared with those obtained in 25 healthy volunteers and 13 patients with other neurological diseases. Parasympathetic function tests comprised heart rate responses to Valsalva maneuver, deep breathing, and active change of posture, whereas sympathetic vasomotor function was assessed by blood pressure responses to handgrip and standing. At the height of the disease, subclinical autonomic involvement of both parasympathetic and sympathetic arms was revealed in the vast majority of patients. Abnormalities of autonomic function tests improved gradually over time, paralleling the recovery of motor function, but were only partially related to clinically significant autonomic dysfunction. Correlation analysis suggested that tachycardia in the context of GBS might be caused by a reduction of sympathetically mediated peripheral vascular tone rather than by vagal failure.
Prolonged neuromuscular weakness has been identified after neuromuscular blockade in intensive care unit patients on mechanical ventilation. Previously reported electromyographic studies in these patients documented both neurogenic features and features consistent with a myopathy. We recorded sequential electrophysiological parameters during recovery from neuromuscular blockade in 5 patients with clinical weakness. An evolving pattern was identified. The early features were in keeping with previous reports of neurogenic changes, and this evolved into features consistent with a primary myopathy. Several potential underlying mechanisms are discussed.
Acute myopathy is a cause of weakness and additional morbidity in a variety of critically ill patients, including transplant recipients. We report the incidence of and risk factors associated with acute myopathy after orthotopic liver transplantation (OLTx). One hundred consecutive adult patients were prospectively assessed for muscle weakness after OLTx. Electrodiagnostic studies and muscle biopsies were performed on consenting affected patients. Potential risk factors for myopathy were evaluated in patients with myopathy versus control subjects. Seven patients developed acute persistent weakness after OLTx. Electrodiagnostic studies were consistent with a necrotizing myopathy. Histopathologic evaluation in five revealed a necrotizing myopathy with loss of myosin thick filaments. A higher initial index of illness severity, dialysis requirement, and higher doses of glucocorticoids were associated with development of myopathy. Patients with myopathy subsequently remained in the intensive care unit (ICU) longer than unaffected patients. In conclusion, acute substantial weakness was a source of additional morbidity in 7% of patients after OLTx. Most had myopathy with loss of myosin thick filaments. Patients with greater severity of illnesses and renal failure requiring dialysis were more likely to be affected. The effect of reducing exposure to corticosteroids in high-risk patients warrants further investigation.
In rats treated with high-dose corticosteroids, skeletal muscle that is denervated in vivo (steroid-denervated [S-D]) develops electrical inexcitability similar to that seen in patients with acute quadriplegic myopathy. In studies of affected muscles in vitro, the majority of S-D fibers failed to generate action potentials in response to intracellular stimulation although the average resting potential of these fibers was no different from that of control denervated muscle. The downregulation of membrane chloride conductance (G[Cl]) seen in normal muscle after denervation did not occur in S-D muscle. Although block of chloride channels in S-D muscle produced high specific membrane resistance, comparable to similarly treated control denervated muscle, and partially restored excitability in many fibers, action potential amplitude was still reduced in S-D fibers, suggesting a concomitant reduction in sodium current. 3H-saxitoxin binding measurements revealed a reduction in the density of the adult muscle sodium channel isoform in S-D muscle, suggesting that a decrease in the number of sodium channels present may play a role in the reduction of sodium current, although altered properties of channels may also contribute. The weakness seen in S-D muscle may involve the interaction of a number of factors that modify membrane excitability, including membrane depolarization, persistence of G(Cl), and reduced voltage-gated sodium currents.
Acute myopathy occurs in critically ill patients, receiving neuromuscular blocking agents or corticosteroids during intensive care hospitalisation. We report three patients with acute quadriplegic myopathy, two of whom were not exposed to corticosteroids or neuromuscular blocking agents. The first of these latter two patients had a history of generalised anoxia with coma related to surgery, complicated by multiple organ failure and sepsis. The second patient, suffering from acute leukaemia, developed sepsis and acute respiratory distress syndrome with the need for mechanical ventilation in the intensive care unit. Electrophysiological studies and muscle biopsy findings were consistent with the diagnosis of critical illness myopathy with loss of myosin filaments. Selective loss of myosin was confirmed by biochemical analysis of muscle. These findings demonstrate that acute myopathy with loss of myosin filaments may occur in patients with severe systemic illness without exposure to corticosteroids or neuromuscular blocking agents.
In the last few years, rare cases of acute quadriplegic myopathy (AQM*) with myosin-deficient muscle fibres occurring after solid organ transplantation has been reported. The aim of the present study was to review all cases of AQM with myosin deficient fibres seen at our institution among a large series of patients after orthotopic liver transplants (OLT), with special attention to clinical aspects and associated risk factors. Additionally, an extensive review of all ultrastructurally demonstrated cases of AQM in transplant recipients is also included.
Among patients involved in 281 consecutive liver transplant procedures performed in a 4-year period, 3 men and 1 woman developed an arreflexic, flaccid quadriplegia in the immediate postoperative period of OLT. After ruling out other causes of weakness, a muscle biopsy was performed and a loss of thick (myosin) filaments was confirmed by ultrastructural analysis in all cases. Accurate clinical, epidemiological, and evolutive data were recorded.
Corticosteroids had been used at usual dosage given to liver transplant recipients; all four patients had several intra- and postoperative complications leading to receiving significantly higher amounts of hemoderivates, to develop renal failure in all cases, and to require a significantly higher number of reoperations within a few days after transplantation than our contemporaneous global series of liver transplant recipients. AQM patients required a significantly longer intensive care unit and hospital stay. Muscular recovery was the rule, but currently a mild myopathic gait remains in three patients. These and other reported cases of AQM do not histologically and clinically differ from AQM seen in other critically ill patients who have not had transplants.
Patients with a complicated intra- and postoperative course of OLT who develop newly acquired acute muscle weakness should be suspected as having acute AQM with myosin-deficient muscle fibres. In this setting, differential diagnosis with other causes of weakness should be carried out, because the prognosis of this myopathy is good with early muscle rehabilitation therapy.
In rats treated with high-dose corticosteroids, skeletal muscle that is denervated in vivo (steroid-denervated) develops electrical inexcitability similar to that seen in patients with acute quadriplegic myopathy. To determine whether changes in muscle gene transcription might underlie inexcitability of steroid-denervated muscle we performed RNase protection assays to quantitate adult (SkM1) and embryonic (SkM2) sodium channel isoforms and chloride channel (CLC-1) mRNA levels in control, denervated, steroid-innervated, and steroid-denervated skeletal muscle. While SkM1 mRNA levels were relatively unaffected by denervation or steroid treatment, SkM2 mRNA levels were increased by both. These effects were synergistic and high levels of SkM2 mRNA were expressed in denervated muscle exposed to corticosteroids. Skeletal muscle CLC-1 mRNA levels were decreased by denervation. To better understand the marked upregulation of SkM2 in steroid-denervated muscle we examined changes in myogenin and glucocorticoid receptor mRNA levels. However, changes in these mRNA levels cannot account for the upregulation of SkM2 in steroid-denervated muscle.
In a longitudinal prospective study a muscle biopsy was taken from 30/32 (33%) of the 98 patients who developed critical illness polyneuropathy and myopathy (CIPNM). Neuropathic changes were found in 37%, myopathic in 40%, and a combination in 23% of the biopsies. The immunohistopathology showed macrophages and Th-cells in 40% and 60% of the muscle biopsies respectively. Small mainly perivascular infiltrates contained macrophages and Th-cells. ICAM-1, VCAM and MAC were found on the vascular endothelium in 58%, 53% and 79% respectively. In all biopsies there was an upregulation of both HLA-I and HLA-DR. Proinflammatory cytokines and TNFalphaR75 were also produced locally (IL-1beta in 71%, IFN-gamma in 40%, IL-12 in 73%, TNFalphaR75 in 90%). The anti-inflammatory cytokine IL-10 was simultaneously expressed in 96% of the biopsies. HLA-DR, TNFalphaR75 and IL-10 differed significantly when compared with control muscle biopsies. Our data provide evidence that small numbers of activated leukocytes producing both pro- and anti-inflammatory cytokines infiltrate skeletal muscle of CIPNM patients. We propose that the local balance of leukocyte activities is of importance in the pathophysiology of muscle weakness in CIPNM.
We investigated the changes of muscle proteins in acute quadriplegic myopathy (AQM) using immunohistochemistry and stoichiometry. Cases of AQM were observed in which it was difficult to type muscle fibers with adenosine triphosphatase staining in biopsied muscle. Well-defined typing of these cases was possible by performing immunofluorescent staining using slow and fast skeletal troponin I (TnI) antibodies. By this means, small angular fibers were shown to be fast skeletal muscle, and myosin was absent from these muscle fibers. Actin and tropomyosin were maintained. Muscle protein ratios were determined by stoichiometry following sodium dodecyl sulfate-polyacrylamide gel electrophoresis of AQM myofibril specimens from four subjects. The myosin heavy chain/actin ratio was significantly decreased compared with a normal control group and other neuromuscular diseases. These pathologic findings returned to normal during recovery from AQM. Thus, myosin selectively decreases, whereas actin and regulatory proteins located above it are maintained during AQM.
To investigate the role of apoptosis in acute quadriplegic myopathy.
Acute quadriplegic myopathy is a muscular disease characterized by diffuse flaccid weakness occurring in patients with severe systemic illness and exposure to corticosteroids or neuroblocking agents. Myofiber atrophy and thick filament loss are the distinguishing pathologic features on muscle biopsy. Increased calpains expression and lysosomal and nonlysosomal proteolytic pathways have been claimed as possible pathogenic factors. Nevertheless, the mechanisms leading to myofiber atrophy and thick filament loss need further investigation.
The expression of ubiquitin and proapoptotic proteases as well as DNA fragmentation in muscle biopsies from three patients with acute quadriplegic myopathy were studied.
All patients exhibited an important overexpression of caspases, calpain, cathepsin B, and ubiquitin, and the presence of numerous apoptotic nuclei in over 70% of myofibers.
These data suggest that apoptosis mediated by proteolytic proteases may play a role in the pathogenesis of acute quadriplegic myopathy.
MyoD regulates skeletal muscle differentiation (SMD) and is essential for repair of damaged tissue. The transcription factor nuclear factor kappa B (NF-kappaB) is activated by the cytokine tumor necrosis factor (TNF), a mediator of skeletal muscle wasting in cachexia. Here, the role of NF-kappaB in cytokine-induced muscle degeneration was explored. In differentiating C2C12 myocytes, TNF-induced activation of NF-kappaB inhibited SMD by suppressing MyoD mRNA at the posttranscriptional level. In contrast, in differentiated myotubes, TNF plus interferon-gamma (IFN-gamma) signaling was required for NF-kappaB-dependent down-regulation of MyoD and dysfunction of skeletal myofibers. MyoD mRNA was also down-regulated by TNF and IFN-gamma expression in mouse muscle in vivo. These data elucidate a possible mechanism that may underlie the skeletal muscle decay in cachexia.
Acute myopathy is a common problem in intensive care units. Those at highest risk for developing critical illness myopathy are exposed to intravenous corticosteroids and paralytic agents during treatment of various illnesses. Diffuse weakness and failure to wean from mechanical ventilation are the most common clinical manifestations. Serum creatine kinase levels are variable. Electrodiagnostic studies reveal findings of a myopathic process, often with evidence of muscle membrane inexcitability. Based on animal model studies, the loss of muscle membrane excitability may be related to inactivation of sodium channels at the resting potential. In addition, human and animal pathologic studies reveal characteristic loss of myosin with relative preservation of other structural proteins. In some patients, there is also upregulation of proteolytic pathways, involving calpain and ubiquitin, in conjunction with increased apoptosis. Fortunately, the disorder is reversible, but there may be considerable morbidity.
We previously demonstrated that muscle fibers become unable to fire action potentials in both patients and an animal model of acute quadriplegic myopathy (AQM). In the animal model, skeletal muscle is denervated in rats treated with high-dose corticosteroids (steroid-denervated; SD), and muscle fibers become inexcitable despite resting potentials and membrane resistances similar to those of control denervated fibers that remain excitable. We show here that unexcitability of SD fibers is due to increased inactivation of sodium channels at the resting potential of affected fibers. A hyperpolarizing shift in the voltage dependence of inactivation in combination with the depolarization of the resting potential induced by denervation results in inexcitability. Our findings suggest that paralysis in the animal model of AQM is the result of an abnormality in the voltage dependence of sodium channel inactivation.
Unexplained weakness in critically ill patients is recognized with increasing frequency. However, it is debated whether the condition is a peripheral neuropathy or a myopathy. Diagnostic difficulties can arise from multiple sources that are not generally a factor in other neuromuscular conditions. Conventional electrodiagnostic techniques may provide only non-specific data, clinical examination is often hampered, and muscle biopsy is not a practical screening tool.
To improve diagnostic yield, we studied 22 consecutive patients with critical illness associated weakness with additional electrodiagnostic techniques, including direct muscle stimulation, quantitative electromyography, and motor unit number estimation.
The applied techniques supported an underlying myopathy in all the patients examined. The diagnosis was confirmed by muscle biopsy in 9 patients. Additional lesser features of neuropathy were concomitantly present in one patient who also underwent sural nerve biopsy.
The study suggests that myopathy is much more common than polyneuropathy in critical illness. Suspicion of this entity should be high in this setting even without exposure to corticosteroids or non-depolarizing blocking agents.
Sepsis may cause not only failure of parenchymal organs but can also cause damage to peripheral nerves and skeletal muscles. It is now recognized that sepsis-mediated disorders of the peripheral nerves and the muscle, called critical illness polyneuropathy (CIP) and critical illness myopathy, are responsible for weakness and muscle atrophy occurring de novo in intensively treated patients. CIP represents an acute axonal neuropathy that develops during treatment of severely ill patients and remits spontaneously, once the critical condition is under control. The course is monophasic and self-limiting. Among the critical illness myopathies, three main types have been identified: a non-necrotizing "cachectic" myopathy (critical illness myopathy in the strict sense), a myopathy with selective loss of myosin filaments ("thick filament myopathy") and an acute necrotizing myopathy of intensive care. Clinical manifestations of both critical illness myopathies and CIP include delayed weaning from the respirator, muscle weakness, and prolonging of the mobilization phase. The pathogenesis of these neuromuscular complications of sepsis is not understood in detail but most authors assume that the inflammatory factors that mediate systemic inflammatory response and multiple organ failure are closely involved. In thick filament myopathy and acute necrotizing myopathy, administration of steroids and neuromuscular blocking agents may act as triggers. Specific therapies have not been discovered. Stabilization of the underlying critical condition and elimination of sepsis appear to be of major importance. Steroids and muscle relaxants should be avoided or administered at the lowest dose possible.
Apoptotic features accompany acute quadriplegic myopathy The authors studied proteolytic pathways and apoptosis in three patients with critical illness myopathy. They suggest that these pathways may play a pathogenic role
- Di S Giovanni
- D M Mirabella
- A Amico
Analysis of muscle proteins in acute quadriplegic myopathy Immunohistochemistry and stoichiometry were used to identify and quantitate myosin loss and maintenance of actin and regulatory proteins in four patients with critical illness myopathy
- N Matsumoto
- T Nakamura
- Y Yasui
- J Torll
Inflammatory myopathy in intensive care patients [abstract]
- P Bazzi
- M Moggio
- A Prelle
Myopathy associated with heavy chain loss in rats with intramuscular botulinum toxin and high dose parenteral corticosteroids
- V V Vedanarayanan
- Pjs Vig
- N Lawson
- VV Vedanarayanan
The authors studied proteolytic pathways and apoptosis in three patients with critical illness myopathy
- Di Giovanni
- D Amico
- S Di Giovanni
Critical illness polyneuropathy: a complication of sepsis and multiple organ failure
- D W Zochodne
- C F Bolton
- G A Wells
- DW Zochodne
An immunohistopathologic study from a mixed group of intensive care unit patients with acute myopathy and neuropathy. The authors suggest that activated leukocytes may have a
- M A De Letter
- P A Van Doorn
- H F Savelkoul
- MA De Letter
of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis