Critical Illness Myopathy: Diagnostic Approach and Resulting Therapeutic Implications.

Purpose of review Critical illness myopathy (CIM) is a common neuro-muscular complication of intensive care treatment associated with increased morbidity and mortality. The current guidelines for diagnosis include clinical and electrophysiological criteria as well as a muscle biopsy, and allow diagnosis only at an advanced stage of the disease. To date, there is no treatment for CIM available, apart from symptomatic and rehabilitative interventions. In this review, we discuss different diagnostic approaches and describe new treatment possibilities for CIM. Recent findings Of the diagnostic approaches evaluated, a new electrophysiological technique for measuring muscle excitability has the greatest potential to allow earlier diagnosis of CIM than the current guidelines do and thereby may facilitate the conduction of future pathophysiological and therapeutic studies. Although clinical trials are still lacking, in animal models, BGP-15, vamorolone, and ruxolitinib have been shown to have anti-inflammatory effects, to reduce muscle wasting and to improve muscle function and survival. Summary In recent years, promising methods for early and confirmatory diagnosis of CIM have been developed, but still need validation. Experimental studies on novel pharmacological interventions show promising results in terms of preventive CIM treatments, but future clinical studies will be needed to study the effectiveness and safety of these drugs

Standardized visual EEG features predict outcome in patients with acute consciousness impairment of various etiologies.

Early prognostication in patients with acute consciousness impairment is a challenging but essential task. Current prognostic guidelines vary with the underlying etiology. In particular, electroencephalography (EEG) is the most important paraclinical examination tool in patients with hypoxic ischemic encephalopathy (HIE), whereas it is not routinely used for outcome prediction in patients with traumatic brain injury (TBI). Data from 364 critically ill patients with acute consciousness impairment (GCS ≤ 11 or FOUR ≤ 12) of various etiologies and without recent signs of seizures from a prospective randomized trial were retrospectively analyzed. Random forest classifiers were trained using 8 visual EEG features-first alone, then in combination with clinical features-to predict survival at 6 months or favorable functional outcome (defined as cerebral performance category 1-2). The area under the ROC curve was 0.812 for predicting survival and 0.790 for predicting favorable outcome using EEG features. Adding clinical features did not improve the overall performance of the classifier (for survival: AUC = 0.806, p = 0.926; for favorable outcome: AUC = 0.777, p = 0.844). Survival could be predicted in all etiology groups: the AUC was 0.958 for patients with HIE, 0.955 for patients with TBI and other neurosurgical diagnoses, 0.697 for patients with metabolic, inflammatory or infectious causes for consciousness impairment and 0.695 for patients with stroke. Training the classifier separately on subgroups of patients with a given etiology (and thus using less training data) leads to poorer classification performance. While prognostication was best for patients with HIE and TBI, our study demonstrates that similar EEG criteria can be used in patients with various causes of consciousness impairment, and that the size of the training set is more important than homogeneity of ACI etiology

Traumatic brain injury in the elderly after a skiing accident: A retrospective cohort study in a level 1 emergency department in Switzerland.

BACKGROUND Skiing is a very popular sport worldwide, with increasing trends over the past decades. This study aimed to evaluate the importance of traumatic brain injury (TBI), especially in the elderly, after a ski accident, and to describe its short-term repercussions. METHODOLOGY Patients were analyzed who were admitted to our neurotrauma center from 2012-2018 after a head trauma while skiing. Three different age groups were differentiated and analyzed for the severity of TBI depending on the initial Glasgow Coma Scale as the primary outcome and as secondary outcomes need and type of surgery, Glasgow Outcome Score, preexisting use of anticoagulant or antiplatelet drugs, time to presentation, and pattern of brain injury. TBI severity was adjusted to the time to initial medical consultation. RESULTS No significant difference in TBI severity was found when comparing the middle (>29-54) and older (≥54) age groups to the reference group <30 years (OR:0.45, p = 0.127; OR:0.46, p = 0.17). Acute subdural hemorrhage was present in 21.2% of the ≥55 group and 14.5% of the 30-54 age group, compared to 12.8% of the youngest group (p = <0.001). Overall, 39.4% of the patients in the ≥55 group and 8.1% of the 30-54 age group presented with chronic subdural hemorrhage, whereas none of the youngest patients did (p = <0.001). CONCLUSION No differences were observed in terms of TBI severity between age groups after acute trauma. Nonetheless, a different pattern of head injury after TBI in older patients was demonstrated. Accordingly, the management differs for these TBIs compared to those of younger patients

How much space is needed for decompressive surgery in malignant middle cerebral artery infarction: Enabling single-stage surgery.

INTRODUCTION Decompressive hemicraniectomy (DCE) is routinely performed for intracranial pressure control after malignant middle cerebral artery (MCA) infarction. Decompressed patients are at risk of traumatic brain injury and the syndrome of the trephined until cranioplasty. Cranioplasty after DCE is itself associated with high complication rates. Single-stage surgical strategies may eliminate the need for follow-up surgery while allowing for safe brain expansion and protection from environmental factors. RESEARCH QUESTION Assess the volume needed for safe expansion of the brain to enable single-stage surgery. MATERIALS AND METHODS We performed a retrospective radiological and volumetric analysis of all patients that had DCE in our clinic between January 2009 and December 2018 and met inclusion criteria. We investigated prognostic parameters in perioperative imaging and assessed clinical outcome. RESULTS Of 86 patients with DCE, 44 fulfilled the inclusion criteria. Median brain swelling was 75.35 mL (8.7-151.2 mL). Median bone flap volume was 113.3 mL (73.34-146.1 mL). Median brain swelling was 1.62 mm below the previous outer rim of the skull (5.3 mm to -2.19 mm). In 79.6% of the patients, the volume of removed bone alone was equivalent to or larger than the additional intracranial volume needed for brain swelling. DISCUSSION AND CONCLUSION The space provided by removal of the bone alone was sufficient to match the expansion of the injured brain after malignant MCA infarction in the vast majority of our patientsA subgaleal space-expanding flap with a minimal offset can provide protection from trauma and atmospheric pressure without compromising brain expansion

Tolerability of COVID-19 mRNA vaccines in patients with postural tachycardia syndrome: a cross-sectional study [version 1; peer review: 2 approved]

Background: Postural tachycardia syndrome (POTS) is a form of autonomic dysregulation. There is increasing evidence that the etiology may be immune-mediated in a subgroup of patients. Patients with POTS often experience an exacerbation of their symptoms associated with (viral) infections and often fear the same symptom aggravation after vaccination. In this report we describe the tolerability of messenger ribonucleic acid (mRNA) vaccines against coronavirus disease 19 (COVID-19) and the consequences of a COVID-19 infection on POTS symptoms in our cohort of patients with neuropathic POTS. Methods: We conducted a standardized, checklist-based interview with 23 patients and recorded the acute side effects of mRNA vaccination, acute symptoms of COVID-19 infection as well as the effects of vaccination and COVID-19 infection on POTS symptoms. Results: Of all included patients, 20 patients received two mRNA vaccines without having had a previous COVID-19 infection, and five patients in total had suffered a COVID-19 infection. Of these, three had COVID-19 without and two after being vaccinated. No increased frequency of side effects after both doses of mRNA vaccines was observed. Six patients reported a mild and short-term aggravation of their POTS symptoms beyond the duration of acute vaccine side effects. All five patients who suffered a COVID-19 infection subsequently reported a pronounced and persistent exacerbation of POTS symptoms. Conclusions: Our observations suggest that mRNA vaccines are not associated with a higher frequency of acute side effects in patients with POTS. Symptom exacerbation as a consequence of mRNA vaccination seems to be less frequent and of shorter duration compared to patients who suffered a COVID-19 infection

Muscular myostatin gene expression and plasma concentrations are decreased in critically ill patients.

BACKGROUND The objective was to investigate the role of gene expression and plasma levels of the muscular protein myostatin in intensive care unit-acquired weakness (ICUAW). This was performed to evaluate a potential clinical and/or pathophysiological rationale of therapeutic myostatin inhibition. METHODS A retrospective analysis from pooled data of two prospective studies to assess the dynamics of myostatin plasma concentrations (day 4, 8 and 14) and myostatin gene (MSTN) expression levels in skeletal muscle (day 15) was performed. Associations of myostatin to clinical and electrophysiological outcomes, muscular metabolism and muscular atrophy pathways were investigated. RESULTS MSTN gene expression (median [IQR] fold change: 1.00 [0.68-1.54] vs. 0.26 [0.11-0.80]; p = 0.004) and myostatin plasma concentrations were significantly reduced in all critically ill patients when compared to healthy controls. In critically ill patients, myostatin plasma concentrations increased over time (median [IQR] fold change: day 4: 0.13 [0.08/0.21] vs. day 8: 0.23 [0.10/0.43] vs. day 14: 0.40 [0.26/0.61]; p < 0.001). Patients with ICUAW versus without ICUAW showed significantly lower MSTN gene expression levels (median [IQR] fold change: 0.17 [0.10/0.33] and 0.51 [0.20/0.86]; p = 0.047). Myostatin levels were directly correlated with muscle strength (correlation coefficient 0.339; p = 0.020) and insulin sensitivity index (correlation coefficient 0.357; p = 0.015). No association was observed between myostatin plasma concentrations as well as MSTN expression levels and levels of mobilization, electrophysiological variables, or markers of atrophy pathways. CONCLUSION Muscular gene expression and systemic protein levels of myostatin are downregulated during critical illness. The previously proposed therapeutic inhibition of myostatin does therefore not seem to have a pathophysiological rationale to improve muscle quality in critically ill patients. TRIAL REGISTRATION ISRCTN77569430 -13th of February 2008 and ISRCTN19392591 17th of February 2011

Development and early diagnosis of critical illness myopathy in COVID-19 associated acute respiratory distress syndrome.

BACKGROUND The COVID-19 pandemic has greatly increased the incidence and clinical importance of critical illness myopathy (CIM), because it is one of the most common complications of modern intensive care medicine. Current diagnostic criteria only allow diagnosis of CIM at an advanced stage, so that patients are at risk of being overlooked, especially in early stages. To determine the frequency of CIM and to assess a recently proposed tool for early diagnosis, we have followed a cohort of COVID-19 patients with acute respiratory distress syndrome and compared the time course of muscle excitability measurements with the definite diagnosis of CIM. METHODS Adult COVID-19 patients admitted to the Intensive Care Unit of the University Hospital Bern, Switzerland requiring mechanical ventilation were recruited and examined on Days 1, 2, 5, and 10 post-intubation. Clinical examination, muscle excitability measurements, medication record, and laboratory analyses were performed on all study visits, and additionally nerve conduction studies, electromyography and muscle biopsy on Day 10. Muscle excitability data were compared with a cohort of 31 age-matched healthy subjects. Diagnosis of definite CIM was made according to the current guidelines and was based on patient history, results of clinical and electrophysiological examinations as well as muscle biopsy. RESULTS Complete data were available in 31 out of 44 recruited patients (mean [SD] age, 62.4 [9.8] years). Of these, 17 (55%) developed CIM. Muscle excitability measurements on Day 10 discriminated between patients who developed CIM and those who did not, with a diagnostic precision of 90% (AUC 0.908; 95% CI 0.799-1.000; sensitivity 1.000; specificity 0.714). On Days 1 and 2, muscle excitability parameters also discriminated between the two groups with 73% (AUC 0.734; 95% CI 0.550-0.919; sensitivity 0.562; specificity 0.857) and 82% (AUC 0.820; CI 0.652-0.903; sensitivity 0.750; specificity 0.923) diagnostic precision, respectively. All critically ill COVID-19 patients showed signs of muscle membrane depolarization compared with healthy subjects, but in patients who developed CIM muscle membrane depolarization on Days 1, 2 and 10 was more pronounced than in patients who did not develop CIM. CONCLUSIONS This study reports a 55% prevalence of definite CIM in critically ill COVID-19 patients. Furthermore, the results confirm that muscle excitability measurements may serve as an alternative method for CIM diagnosis and support its use as a tool for early diagnosis and monitoring the development of CIM

Inhaled Nitric Oxide Treatment for Aneurysmal SAH Patients With Delayed Cerebral Ischemia

BACKGROUND: We demonstrated experimentally that inhaled nitric oxide (iNO) dilates hypoperfused arterioles, increases tissue perfusion, and improves neurological outcome following subarachnoid hemorrhage (SAH) in mice. We performed a prospective pilot study to evaluate iNO in patients with delayed cerebral ischemia after SAH. METHODS: SAH patients with delayed cerebral ischemia and hypoperfusion despite conservative treatment were included. iNO was administered at a maximum dose of 40 ppm. The response to iNO was considered positive if: cerebral artery diameter increased by 10% in digital subtraction angiography (DSA), or tissue oxygen partial pressure (PtiO(2)) increased by > 5 mmHg, or transcranial doppler (TCD) values decreased more than 30 cm/sec, or mean transit time (MTT) decreased below 6.5 secs in CT perfusion (CTP). Patient outcome was assessed at 6 months with the modified Rankin Scale (mRS). RESULTS: Seven patients were enrolled between February 2013 and September 2016. Median duration of iNO administration was 23 h. The primary endpoint was reached in all patients (five out of 17 DSA examinations, 19 out of 29 PtiO(2) time points, nine out of 26 TCD examinations, three out of five CTP examinations). No adverse events necessitating the cessation of iNO were observed. At 6 months, three patients presented with a mRS score of 0, one patient each with an mRS score of 2 and 3, and two patients had died. CONCLUSION: Administration of iNO in SAH patients is safe. These results call for a larger prospective evaluation

Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (Pinteraction=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION URL: https://clinicaltrials.gov; Unique identifier: NCT02866838

Etiology, 3-Month Functional Outcome and Recurrent Events in Non-Traumatic Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce. METHODS We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). RESULTS We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031). CONCLUSIONS Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage