Long-term recovery In critical illness myopathy is complete, contrary to polyneuropathy.

INTRODUCTION: Muscle weakness in critically ill patients after discharge varies. It is not known whether the electrophysiological distinction between critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) during the early part of a patient's stay in the intensive care unit (ICU) predicts long-term prognosis. METHODS: This was a prospective cohort study of mechanically ventilated ICU patients undergoing conventional nerve conduction studies and direct muscle stimulation in addition to neurological examination during their ICU stay and 1 year after ICU discharge. RESULTS: Twenty-six patients (7 ICU controls, 8 CIM patients, and 11 CIM/CIP patients) were evaluated 1 year after discharge from the ICU. Eighty-eight percent (n = 7) of CIM patients recovered within 1 year compared with 55% (n = 6) of CIM/CIP patients. Thirty-six percent (n = 4) of CIM/CIP patients still needed assistance during their daily routine (P = 0.005). CONCLUSIONS: Early electrophysiological testing predicts long-term outcome in ICU survivors. CIM has a significantly better prognosis than CIM/CIP.

Critical illness myopathy and GLUT4: significance of insulin and muscle contraction.

RATIONALE: Critical illness myopathy (CIM) has no known cause and no treatment. Immobilization and impaired glucose metabolism are implicated. OBJECTIVES: We assessed signal transduction in skeletal muscle of patients at risk for CIM. We also investigated the effects of evoked muscle contraction. METHODS: In a prospective observational and interventional pilot study, we screened 874 mechanically ventilated patients with a sepsis-related organ-failure assessment score greater than or equal to 8 for 3 consecutive days in the first 5 days of intensive care unit stay. Thirty patients at risk for CIM underwent euglycemic-hyperinsulinemic clamp, muscle microdialysis studies, and muscle biopsies. Control subjects were healthy. In five additional patients at risk for CIM, we performed corresponding analyses after 12-day, daily, unilateral electrical muscle stimulation with the contralateral leg as control. MEASUREMENTS AND MAIN RESULTS: We performed successive muscle biopsies and assessed systemic insulin sensitivity and signal transduction pathways of glucose utilization at the mRNA and protein level and glucose transporter-4 (GLUT4) localization in skeletal muscle tissue. Skeletal muscle GLUT4 was trapped at perinuclear spaces, most pronounced in patients with CIM, but resided at the sarcolemma in control subjects. Glucose metabolism was not stimulated during euglycemic-hyperinsulinergic clamp. Insulin signal transduction was competent up to p-Akt activation; however, p-adenosine monophosphate-activated protein kinase (p-AMPK) was not detectable in CIM muscle. Electrical muscle stimulation increased p-AMPK, repositioned GLUT4, locally improved glucose metabolism, and prevented type-2 fiber atrophy. CONCLUSIONS: Insufficient GLUT4 translocation results in decreased glucose supply in patients with CIM. Failed AMPK activation is involved. Evoked muscle contraction may prevent muscle-specific AMPK failure, restore GLUT4 disposition, and diminish protein breakdown. Clinical trial registered with http://www.controlled-trials.com (registration number ISRCTN77569430).

Early type II fiber atrophy in intensive care unit patients with nonexcitable muscle membrane.

OBJECTIVE: Intensive care unit-acquired weakness indicates increased morbidity and mortality. Nonexcitable muscle membrane after direct muscle stimulation develops early and predicts intensive care unit-acquired weakness in sedated, mechanically ventilated patients. A comparison of muscle histology at an early stage in intensive care unit-acquired weakness has not been done. We investigated whether nonexcitable muscle membrane indicates fast-twitch myofiber atrophy during the early course of critical illness. DESIGN: Prospective observational study. SETTING: Two intensive care units at Charité University Medicine, Berlin. PATIENTS: Patients at increased risk for development of intensive care unit-acquired weakness, indicated by Sepsis-related Organ Failure Assessment scores ≥8 on 3 of 5 consecutive days within their first week in the intensive care unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Electrophysiological compound muscle action potentials after direct muscle stimulation and muscle biopsies were obtained at median days 7 and 5, respectively. Patients with nonexcitable muscle membranes (n = 15) showed smaller median type II cross-sectional areas (p < .05), whereas type I muscle fibers did not compared with patients with preserved muscle membrane excitability (compound muscle action potentials after direct muscle stimulation ≥3.0 mV; n = 9). We also observed decreased mRNA transcription levels of myosin heavy chain isoform IIa and a lower densitometric ratio of fast-to-slow myosin heavy chain protein content. CONCLUSION: We suggest that electrophysiological nonexcitable muscle membrane predicts preferential type II fiber atrophy in intensive care unit patients during early critical illness.

Critical illness myopathy is frequent: accompanying neuropathy protracts ICU discharge.

OBJECTIVES: Neuromuscular dysfunction in critically ill patients is attributed to either critical illness myopathy (CIM) or critical illness polyneuropathy (CIP) or a combination of both. However, it is unknown whether differential diagnosis has an impact on prognosis. This study investigates whether there is an association between the early differentiation of CIM versus CIP and clinical prognosis. METHODS: The authors included mechanically ventilated patients who featured a Simplified Acute Physiology Score II (SAPS-II) ≥ 20 on three consecutive days within the first week after intensive care unit (ICU) admission. Fifty-three critically ill patients were enrolled and examined by conventional nerve-conduction studies and direct muscle stimulation (184 examinations in total). The first examination was conducted within the first week after admission to the ICU. RESULTS: In this cohort of critically ill patients, CIM was more frequent (68%) than CIP (38%). Electrophysiological signs of CIM preceded electrophysiological signs of CIP (median at day 7 in CIM patients vs day 10 in CIP patients, p<0.001). Most patients with CIP featured concomitant CIM. At discharge from ICU, 25% of patients with isolated CIM showed electrophysiological signs of recovery and significantly lower degrees of weakness. Recovery could not be observed in patients with combined CIM/CIP, even though the ICU length of stay was significantly longer (mean 35 days in CIM/CIP vs mean 19 days in CIM, p<0.001). CONCLUSION: Prognoses of patients differ depending on electrophysiological findings during early critical illness: early electrophysiological differentiation of ICU acquired neuromuscular disorder enhances the evaluation of clinical prognosis during critical illness.

[Insulin resistance and protein catabolism in critically ill patients]. / Insulinresistenz: Bedeutung in Anästhesie und Intensivmedizin - Insulinresistenz und Proteinkatabolie bei kritisch Kranken.

Hyperglycemia is a frequently observed phenomenon in critically ill patients, affecting numerous patients without a history of impaired glucose tolerance or diabetes. During critical illness, hyperglycemia may result from decreased peripheral glucose uptake and/or utilisation in presence of normal or elevated plasma insulin levels (peripheral insulin resistance) as well as an increase in hepatic glucose production due to augmented glycogenolysis and gluconeogenesis resulting from stress and/or central (hepatic) insulin resistance. As there are a number of factors that cause or aggravate hyperglycemia / insulin resistance during the intensive care unit (ICU) stay, a multifactorial etiology is likely. Furthermore, animal models of sepsis suggest a decrease in anabolic insulin signalling within skeletal muscle.

Critical illness polyneuropathy in ICU patients is related to reduced motor nerve excitability caused by reduced sodium permeability.

BACKGROUND: Reduced motor and sensory nerve amplitudes in critical illness polyneuropathy (CIP) are characteristic features described in electrophysiological studies and due to dysfunction of voltage-gated sodium channels. Yet, faulty membrane depolarization as reported in various tissues of critically ill patients may cause reduced membrane excitability as well. The aim of this study was to compare the pathophysiological differences in motor nerve membrane polarization and voltage-gated sodium channel function between CIP patients and critically ill patients not developing CIP during their ICU stay (ICU controls). METHODS: ICU patients underwent electrophysiological nerve conduction studies and were categorized as either ICU controls or CIP patients. Subsequently, excitability parameters were recorded as current-threshold relationship, stimulus-response behavior, threshold electrotonus, and recovery of excitability from the abductor pollicis brevis following median nerve stimulation. RESULTS: Twenty-six critically ill patients were enrolled and categorized as 12 ICU controls and 14 CIP patients. When compared to 31 healthy subjects, the ICU controls exhibited signs of membrane depolarization as shown by reduced superexcitability (p = 0.003), depolarized threshold electrotonus (p = 0.007), increased current-threshold relationship (p = 0.03), and slightly prolonged strength-duration time constant. In contrast, the CIP patients displayed a significantly reduced strength-duration time constant (p < 0.0001), which indicates an increased inactivation of voltage-gated sodium channels. CONCLUSIONS: Abnormal motor nerve membrane depolarization is a general finding in critically ill patients whereas voltage-gated sodium channel dysfunction is a characteristic of CIP patients.

Intensive care unit-acquired weakness (ICUAW) and muscle wasting in critically ill patients with severe sepsis and septic shock.

Sepsis presents a major health care problem and remains one of the leading causes of death within the intensive care unit (ICU). Therapeutic approaches against severe sepsis and septic shock focus on early identification. Adequate source control, administration of antibiotics, preload optimization by fluid resuscitation and further hemodynamic stabilisation using vasopressors whenever appropriate are considered pivotal within the early-golden-hours of sepsis. However, organ dysfunction develops frequently in and represents a significant comorbidity of sepsis. A considerable amount of patients with sepsis will show signs of severe muscle wasting and/or ICU-acquired weakness (ICUAW), which describes a frequently observed complication in critically ill patients and refers to clinically weak ICU patients in whom there is no plausible aetiology other than critical illness. Some authors consider ICUAW as neuromuscular organ failure, caused by dysfunction of the motor unit, which consists of peripheral nerve, neuromuscular junction and skeletal muscle fibre. Electrophysiologic and/or biopsy studies facilitate further subclassification of ICUAW as critical illness myopathy, critical illness polyneuropathy or critical illness myoneuropathy, their combination. ICUAW may protract weaning from mechanical ventilation and impede rehabilitation measures, resulting in increased morbidity and mortality. This review provides an insight on the available literature on sepsis-mediated muscle wasting, ICUAW and their potential pathomechanisms.

A possible new diagnostic biomarker in early diagnosis of Alzheimer's disease.

Early diagnosis in patients with Alzheimer's disease (AD) is of great importance since only a sufficient treatment in early stages of this disease helps to keep patients in an autonomous state for as long as possible. Until now, there is no single diagnostic biomarker for AD derived from material routinely obtained. In this study, proton nuclear magnetic resonance (1H-NMR) spectra of the cerebrospinal fluid (CSF) of AD patients were compared with 1H-NMR spectra of the CSF of healthy control subjects using a metabonomic approach. The 1H-NMR spectra of CSF of AD patients showed specific multiplets at 2.15 ppm and 2.45 ppm, which could not be detected in the majority (59.3% and 70.4%, respectively) of healthy control subjects (positive likelihood ratio (+LR) 2.33, 95% CI [1.46, 3.72], p<0.01; +LR 3.22, 95% CI [1.78, 5.78], p<0.01). Moreover, CSF 1H-NMR spectra of AD patients showed specific resonances at 7.03 ppm (+LR 3.38, 95% CI [1.60, 7.14], p<0.05), 7.19 ppm (+LR 2.89, 95% CI [1.46, 5.74], p<0.05), 7.43 ppm (+LR 3.15, 95% CI [1.47, 6.75], p<0.05), and at 7.91 ppm (+LR 3.38, 95% CI [1.60, 7.14], p<0.01). CSF 1H-NMR spectroscopy is obviously a capable method for detection and quantification of substances in the CSF of AD patients even without the knowledge of molecular structures. These substances can be used as a biomarker in the early diagnosis of AD. We assume that this biomarker will simplify the diagnosis of AD, especially in early stages of the disease.

Smoking and structural brain deficits: a volumetric MR investigation.

Growing evidence from animal studies indicates brain-damaging properties of nicotine exposure. Investigations in humans found a wide range of functional cerebral effects of nicotine and cigarette smoking, but studies focusing on brain damage are sparse. In 22 smokers and 23 never-smokers possible differences of the cerebral structures were investigated using magnetic resonance imaging and voxel-based morphometry. Significantly smaller grey matter volume and lower grey matter density (P = 0.05, corrected) were observed in the frontal regions (anterior cingulate, prefrontal and orbitofrontal cortex), the occipital lobe and the temporal lobe including parahippocampal gyrus, in smokers than in never-smokers. Group differences of either grey matter volume or grey matter density were also found in the thalamus, cerebellum and substantia nigra, among other regions. Smokers did not show greater volumes than never-smokers in any cerebral region. Magnitude of lifetime exposure to tobacco smoke (pack-years) was inversely correlated with volume of frontal and temporal lobes and cerebellum (P = 0.001, uncorrected). The data indicate structural deficits of several cortical and subcortical regions in smokers relative to never-smokers. The topographic profile of the group differences show some similarities to brain networks known to mediate drug reinforcement, attention and working memory processing. The present findings may explain in part the frequently reported cognitive dysfunctions in chronic cigarette consumers.