Longitudinal Assessment of Blood-Based Inflammatory, Neuromuscular, and Neurovascular Biomarker Profiles in Intensive Care Unit-Acquired Weakness: A Prospective Single-Center Cohort Study.

BACKGROUND: The diagnosis of intensive care unit (ICU)-acquired weakness (ICUAW) and critical illness neuromyopathy (CINM) is frequently hampered in the clinical routine. We evaluated a novel panel of blood-based inflammatory, neuromuscular, and neurovascular biomarkers as an alternative diagnostic approach for ICUAW and CINM. METHODS: Patients admitted to the ICU with a Sequential Organ Failure Assessment score of ≥ 8 on 3 consecutive days within the first 5 days as well as healthy controls were enrolled. The Medical Research Council Sum Score (MRCSS) was calculated, and motor and sensory electroneurography (ENG) for assessment of peripheral nerve function were performed at days 3 and 10. ICUAW was defined by an MRCSS < 48 and CINM by pathological ENG alterations, both at day 10. Blood samples were taken at days 3, 10, and 17 for quantitative analysis of 18 different biomarkers (white blood cell count, C-reactive protein, procalcitonin, C-terminal agrin filament, fatty-acid-binding protein 3, growth and differentiation factor 15, syndecan 1, troponin I, interferon-γ, tumor necrosis factor-α, interleukin-1α [IL-1α], IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-13, and monocyte chemoattractant protein 1). Results of the biomarker analysis were categorized according to the ICUAW and CINM status. Clinical outcome was assessed after 3 months. RESULTS: Between October 2016 and December 2018, 38 critically ill patients, grouped into ICUAW (18 with and 20 without) and CINM (18 with and 17 without), as well as ten healthy volunteers were included. Biomarkers were significantly elevated in critically ill patients compared to healthy controls and correlated with disease severity and 3-month outcome parameters. However, none of the biomarkers enabled discrimination of patients with and without neuromuscular impairment, irrespective of applied classification. CONCLUSIONS: Blood-based biomarkers are generally elevated in ICU patients but do not identify patients with ICUAW or CINM. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02706314.

[Intensive care unit-acquired weakness-Diagnostic value of neuromuscular ultrasound]. / Intensive Care Unit-Acquired Weakness ­ diagnostischer Stellenwert des neuromuskulären Ultraschalls.

Intensive care unit-acquired weakness (ICUAW) is one of the most common neuromuscular complications in intensive care medicine. The clinical diagnosis and assessment of the severity using established diagnostic methods (e.g., clinical examination using the Medical Research Council Sum Score or electrophysiological examination) can be difficult or even impossible, especially in sedated, ventilated and delirious patients. Neuromuscular ultrasound (NMUS) has increasingly been investigated in ICUAW as an easy to use noninvasive and mostly patient compliance-independent diagnostic alternative. It has been shown that NMUS appears to be a promising tool to detect ICUAW, to assess the severity of muscular weakness and to monitor the clinical progression. Further studies are needed to standardize the methodology, to evaluate the training effort and to optimize outcome predication. The formulation of an interdisciplinary neurological and anesthesiological training curriculum is warranted to establish NMUS as a complementary diagnostic method of ICUAW in daily clinical practice.

Neuromuscular Ultrasound in Intensive Care Unit-Acquired Weakness: Current State and Future Directions.

Intensive care unit-acquired weakness (ICUAW) is one of the most common causes of muscle atrophy and functional disability in critically ill intensive care patients. Clinical examination, manual muscle strength testing and monitoring are frequently hampered by sedation, delirium and cognitive impairment. Many different attempts have been made to evaluate alternative compliance-independent methods, such as muscle biopsies, nerve conduction studies, electromyography and serum biomarkers. However, they are invasive, time-consuming and often require special expertise to perform, making them vastly impractical for daily intensive care medicine. Ultrasound is a broadly accepted, non-invasive, bedside-accessible diagnostic tool and well established in various clinical applications. Hereby, neuromuscular ultrasound (NMUS), in particular, has been proven to be of significant diagnostic value in many different neuromuscular diseases. In ICUAW, NMUS has been shown to detect and monitor alterations of muscles and nerves, and might help to predict patient outcome. This narrative review is focused on the recent scientific literature investigating NMUS in ICUAW and highlights the current state and future opportunities of this promising diagnostic tool.

Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review.

Mitochondria are key structures providing most of the energy needed to maintain homeostasis. They are the main source of adenosine triphosphate (ATP), participate in glucose, lipid and amino acid metabolism, store calcium and are integral components in various intracellular signaling cascades. However, due to their crucial role in cellular integrity, mitochondrial damage and dysregulation in the context of critical illness can severely impair organ function, leading to energetic crisis and organ failure. Skeletal muscle tissue is rich in mitochondria and, therefore, particularly vulnerable to mitochondrial dysfunction. Intensive care unit-acquired weakness (ICUAW) and critical illness myopathy (CIM) are phenomena of generalized weakness and atrophying skeletal muscle wasting, including preferential myosin breakdown in critical illness, which has also been linked to mitochondrial failure. Hence, imbalanced mitochondrial dynamics, dysregulation of the respiratory chain complexes, alterations in gene expression, disturbed signal transduction as well as impaired nutrient utilization have been proposed as underlying mechanisms. This narrative review aims to highlight the current known molecular mechanisms immanent in mitochondrial dysfunction of patients suffering from ICUAW and CIM, as well as to discuss possible implications for muscle phenotype, function and therapeutic approaches.

The Effect of Early Application of Synthetic Peptides 19-2.5 and 19-4LF to Improve Survival and Neurological Outcome in a Mouse Model of Cardiac Arrest and Resuscitation.

The synthetic antimicrobial peptides (sAMPs) Pep19-2.5 and Pep19-4LF have been shown in vitro and in vivo to reduce the release of pro-inflammatory cytokines, leading to the suppression of inflammation and immunomodulation. We hypothesized that intervention with Pep19-2.5 and Pep19-4LF immediately after cardiac arrest and resuscitation (CA-CPR) might attenuate immediate systemic inflammation, survival, and long-term outcomes in a standardized mouse model of CA-CPR. Long-term outcomes up to 28 days were assessed between a control group (saline) and two peptide intervention groups. Primarily, survival as well as neurological and cognitive parameters were assessed. In addition, systemic inflammatory molecules and specific biomarkers were analyzed in plasma as well as in brain tissue. Treatment with sAMPs did not provide any short- or long-term benefits for either survival or neurological outcomes, and no significant benefit on inflammation in the CA-CPR animal model. While no difference was found in the plasma analysis of early cytokines between the intervention groups four hours after resuscitation, a significant increase in UCH-L1, a biomarker of neuronal damage and blood-brain barrier rupture, was measured in the Pep19-4LF-treated group. The theoretical benefit of both sAMPs tested here for the treatment of post-cardiac arrest syndrome could not be proven.

A Global Survey on Diagnostic, Therapeutic and Preventive Strategies in Intensive Care Unit-Acquired Weakness.

Background and Objectives: Intensive care unit-acquired weakness (ICU-AW) is one of the most frequent neuromuscular complications in critically ill patients. We conducted a global survey to evaluate the current practices of diagnostics, treatment and prevention in patients with ICU-AW. Materials and Methods: A pre-survey was created with international experts. After revision, the final survey was endorsed by the European Society of Intensive Care Medicine (ESICM) using the online platform SurveyMonkey®. In 27 items, we addressed strategies of diagnostics, therapy and prevention. An invitation link was sent by email to all ESICM members. Furthermore, the survey was available on the ESICM homepage. Results: A total of 154 healthcare professionals from 39 countries participated in the survey. An ICU-AW screening protocol was used by 20% (28/140) of participants. Forty-four percent (62/141) of all participants reported performing routine screening for ICU-AW, using clinical examination as the method of choice (124/141, 87.9%). Almost 63% (84/134) of the participants reported using current treatment strategies for patients with ICU-AW. The use of treatment and prevention strategies differed between intensivists and non-intensivists regarding the reduction in sedatives (80.0% vs. 52.6%, p = 0.002), neuromuscular blocking agents (76.4% vs. 50%, p = 0.004), corticosteroids (69.1% vs. 37.2%, p < 0.001) and glycemic control regimes (50.9% vs. 23.1%, p = 0.002). Mobilization and physical activity are the most frequently reported treatment strategies for ICU-AW (111/134, 82.9%). The availability of physiotherapists (92/134, 68.7%) and the lack of knowledge about ICU-AW within the medical team (83/134, 61.9%) were the main obstacles to the implementation of the strategies. The necessity to develop guidelines for the screening, diagnosing, treatment and prevention of ICU-AW was recognized by 95% (127/133) of participants. Conclusions: A great heterogeneity regarding diagnostics, treatment and prevention of ICU-AW was reported internationally. Comprehensive guidelines with evidence-based recommendations for ICU-AW management are needed.

Sonographic Evaluation of Muscle Echogenicity for the Detection of Intensive Care Unit-Acquired Weakness: A Pilot Single-Center Prospective Cohort Study.

Qualitative assessment by the Heckmatt scale (HS) and quantitative greyscale analysis of muscle echogenicity were compared for their value in detecting intensive care unit-acquired weakness (ICU-AW). We performed muscle ultrasound (MUS) of eight skeletal muscles on day 3 and day 10 after ICU admission. We calculated the global mean greyscale score (MGS), the global mean z-score (MZS) and the global mean Heckmatt score (MHS). Longitudinal outcome was defined by the modified Rankin scale (mRS) and Barthel index (BI) after 100 days. In total, 652 ultrasound pictures from 38 critically ill patients (18 with and 20 without ICU-AW) and 10 controls were analyzed. Patients with ICU-AW had a higher MHS on day 10 compared to patients without ICU-AW (2.6 (0.4) vs. 2.2 (0.4), p = 0.006). The MHS was superior to ROC analysis (cut-off: 2.2, AUC: 0.79, p = 0.003, sensitivity 86%, specificity 60%) in detecting ICU-AW compared to MGS and MZS on day 10. The MHS correlated with the Medical Research Council sum score (MRC-SS) (r = -0.45, p = 0.004), the mRS (r = 0.45; p = 0.007) and BI (r = -0.38, p = 0.04) on day 100. Qualitative MUS analysis seems superior to quantitative greyscale analysis of muscle echogenicity for the detection of ICU-AW.

[Intensive Care Unit-Acquired Weakness : A nationwide survey on diagnostics, monitoring and treatment strategies on German intensive care units]. / "Intensive Care Unit-Acquired Weakness" : Eine bundesweite Umfrage zu Diagnostik, Monitoring und Therapiestrategien auf deutschen Intensivstationen.

BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is one of the most frequent causes of neuromuscular dysfunction in intensive care medicine. To date no evidence-based recommendations exist for the diagnostics, monitoring or further intensive care treatment. OBJECTIVE: To evaluate the current clinical practice of diagnostics, monitoring and treatment strategies of ICU-AW on intensive care units in Germany. MATERIAL AND METHODS: We conducted an online survey with a self-designed questionnaire and invited 448 members of the Scientific Working Group for Intensive Care Medicine (WAKI) and the Scientific Working Group for Neuroanesthesia (WAKNA) to participate. RESULTS: A total of 68/448 (15.2%) questionnaires were analyzed. Of the participants 13.4% (9/67) stated that a structured diagnostic approach for the detection of ICU-AW is applied in their units. The clinical examination was the preferred method for screening (60/68; 88.2%) and follow-up (57/65; 87.7%). Scores, such as the Medical Research Council sum score (MRC-SS) seem to be less important for the screening (7/68; 10.3%) and follow-up assessment (7/65; 10.8%). Mobilization with physiotherapy (45/68; 66.2%) is the most common strategy applied to treat ICU-AW. A lack of physiotherapists (64/68; 94.1%) and intensive care nurses (57/68; 83.8%) are the main deficits identified in the care of patients with ICU-AW. The majority of the study participants (62/68; 91.2%) would welcome evidence-based guidelines for diagnostics, monitoring and treatment approaches in ICU-AW. DISCUSSION: To date comprehensive recommendations for diagnostics, monitoring, prevention and treatment of ICU-AW are still lacking in German intensive care units. The introduction of new diagnostic approaches could help to detect ICU-AW and therefore to initiate earlier preventive and treatment approaches.

A novel ex vivo model for critical illness neuromyopathy using freshly resected human colon smooth muscle.

Patients suffering from critical illness are at risk to develop critical illness neuromyopathy (CINM). The underlying pathophysiology is complex and controversial. A central question is whether soluble serum factors are involved in the pathogenesis of CINM. In this study, smooth muscle preparations obtained from the colon of patients undergoing elective surgery were used to investigate the effects of serum from critically ill patients. At the time of blood draw, CINM was assessed by clinical rating and electrophysiology. Muscle strips were incubated with serum of healthy controls or patients in organ baths and isometric force was measured. Fifteen samples from healthy controls and 98 from patients were studied. Ratios of responses to electric field stimulation (EFS) before and after incubation were 118% for serum from controls and 51% and 62% with serum from critically ill patients obtained at day 3 and 10 of critical illness, respectively (p = 0.003, One-Way-ANOVA). Responses to carbachol and high-K+ were equal between these groups. Ratios of post/pre-EFS responses correlated with less severe CINM. These results support the existence of pathogenic, i.e. neurotoxic factors in the serum of critically ill patients. Using human colon smooth muscle as a bioassay may facilitate their future molecular identification.

A case series on the value of tau and neurofilament protein levels to predict and detect delirium in cardiac surgery patients.

BACKGROUND: Delirium following cardiac surgery is a relevant complication in the majority of elderly patients but its prediction is challenging. Cardiopulmonary bypass, essential for many interventions in cardiac surgery, is responsible for a severe inflammatory response leading to neuroinflammation and subsequent delirium. Neurofilament light protein (NfL) and tau protein (tau) are specific biomarkers to detect neuroaxonal injury as well as glial fibrillary acidic protein (GFAP), a marker of astrocytic activation. METHODS: We thought to examine the perioperative course of these markers in a case series of each three cardiac surgery patients under off-pump cardiac arterial bypass without evolving delirium (OPCAB-NDEL), patients with a procedure under cardio-pulmonary bypass (CPB) without delirium (CPB-NDEL) and delirium after a CPB procedure (CPB-DEL). Delirium was diagnosed by the Confusion Assessment Method for the ICU and chart reviews. RESULTS: We observed increased preoperative levels of tau in patients with later delirium, whereas values of NfL and GFAP did not differ. In the postoperative course, all biomarkers increased multi-fold. NfL levels sharply increased in patients with CPB reaching the highest levels in the CPB-DEL group. CONCLUSION: Tau and NfL might be of benefit to identify patients in cardiac surgery at risk for delirium and to detect patients with the postoperative emergence of delirium.

Acetylcholine Neurotransmitter Receptor Densities in the Striatum of Hemiparkinsonian Rats Following Botulinum Neurotoxin-A Injection.

Cholinergic neurotransmission has a pivotal function in the caudate-putamen, and is highly associated with the pathophysiology of Parkinson's disease. Here, we investigated long-term changes in the densities of the muscarinic receptor subtypes M1, M2, M3 (mAchRs) and the nicotinic receptor subtype α4ß2 (nAchRs) in the striatum of the 6-OHDA-induced hemiparkinsonian (hemi-PD) rat model using quantitative in vitro receptor autoradiography. Hemi-PD rats exhibited an ipsilateral decrease in striatal mAchR densities between 6 and 16%. Moreover, a massive and constant decrease in striatal nAchR density by 57% was found. A second goal of the study was to disclose receptor-related mechanisms for the positive motor effect of intrastriatally injected Botulinum neurotoxin-A (BoNT-A) in hemi-PD rats in the apomorphine rotation test. Therefore, the effect of intrastriatally injected BoNT-A in control and hemi-PD rats on mAchR and nAchR densities was analyzed and compared to control animals or vehicle-injected hemi-PD rats. BoNT-A administration slightly reduced interhemispheric differences of mAchR and nAchR densities in hemi-PD rats. Importantly, the BoNT-A effect on striatal nAchRs significantly correlated with behavioral testing after apomorphine application. This study gives novel insights of 6-OHDA-induced effects on striatal mAchR and nAchR densities, and partly explains the therapeutic effect of BoNT-A in hemi-PD rats on a cellular level.