Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial.

PURPOSE: Methylene blue (MB) has been tested as a rescue therapy for patients with refractory septic shock. However, there is a lack of evidence on MB as an adjuvant therapy, its' optimal timing, dosing and safety profile. We aimed to assess whether early adjunctive MB can reduce time to vasopressor discontinuation in patients with septic shock. METHODS: In this single-center randomized controlled trial, we assigned patients with septic shock according to Sepsis-3 criteria to MB or placebo. Primary outcome was time to vasopressor discontinuation at 28 days. Secondary outcomes included vasopressor-free days at 28 days, days on mechanical ventilator, length of stay in ICU and hospital, and mortality at 28 days. RESULTS: Among 91 randomized patients, forty-five were assigned to MB and 46 to placebo. The MB group had a shorter time to vasopressor discontinuation (69 h [IQR 59-83] vs 94 h [IQR 74-141]; p < 0.001), one more day of vasopressor-free days at day 28 (p = 0.008), a shorter ICU length of stay by 1.5 days (p = 0.039) and shorter hospital length of stay by 2.7 days (p = 0.027) compared to patients in the control group. Days on mechanical ventilator and mortality were similar. There were no serious adverse effects related to MB administration. CONCLUSION: In patients with septic shock, MB initiated within 24 h reduced time to vasopressor discontinuation and increased vasopressor-free days at 28 days. It also reduced length of stay in ICU and hospital without adverse effects. Our study supports further research regarding MB in larger randomized clinical trials. Trial registration ClinicalTrials.gov registration number NCT04446871 , June 25, 2020, retrospectively registered.

Advanced Nanomaterials-Based Electrochemical Biosensors for Catecholamines Detection: Challenges and Trends.

Catecholamines, including dopamine, epinephrine, and norepinephrine, are considered one of the most crucial subgroups of neurotransmitters in the central nervous system (CNS), in which they act at the brain's highest levels of mental function and play key roles in neurological disorders. Accordingly, the analysis of such catecholamines in biological samples has shown a great interest in clinical and pharmaceutical importance toward the early diagnosis of neurological diseases such as Epilepsy, Parkinson, and Alzheimer diseases. As promising routes for the real-time monitoring of catecholamine neurotransmitters, optical and electrochemical biosensors have been widely adopted and perceived as a dramatically accelerating development in the last decade. Therefore, this review aims to provide a comprehensive overview on the recent advances and main challenges in catecholamines biosensors. Particular emphasis is given to electrochemical biosensors, reviewing their sensing mechanism and the unique characteristics brought by the emergence of nanotechnology. Based on specific biosensors' performance metrics, multiple perspectives on the therapeutic use of nanomaterial for catecholamines analysis and future development trends are also summarized.

Spinal Anesthesia in Hemodynamic Instability: A Case Report.

Anesthetic dilemmas are not rare in daily practice. Frequently, patients present with comorbid conditions that make general anesthesia risky (e.g., difficult airway and severe pulmonary dysfunction) and contraindications to neuraxial anesthesia at the same time. Reports on the successful anesthetic management of these patients can provide useful information. We report a case of a patient with severe hemodynamic instability who underwent spinal anesthesia for surgical hip debridement. General anesthesia and airway manipulation were avoided because the patient had recently recovered from SARS-CoV-2 pneumonia amid the first wave of the coronavirus disease 2019 (COVID-19) pandemic when very little was known about the disease and no ventilators were available for postoperative care. We explain in detail the continuous spinal anesthesia technique using a conventional epidural catheter and prophylactic norepinephrine when cardiovascular instability was the major concern.

Antidepressant use and risk of intubation or death in hospitalized patients with COVID-19: A retrospective cohort study of clinical effectiveness.

Initial controlled trials of the serotonergic antidepressant fluvoxamine showed promise for treatment of mild to moderate COVID-19 in outpatients, although more recent outpatient data have been less encouraging. Turning to studies of hospitalized patients, a retrospective cohort study by Hoertel and associates in 2021 found a markedly reduced risk of intubation or death among patients hospitalized with COVID-19 who were receiving serotonergic antidepressants at the time of admission vs. those not receiving antidepressants. In an attempt to replicate these latter findings, we performed a similarly designed study of 500 individuals hospitalized with COVID-19 in a large academic hospital system who were taking a serotonergic antidepressant at the time of admission compared with two groups (N = 573 and N = 593) not receiving an antidepressant. In analyses controlling for demographic and clinical variables, we found no significant difference in effect between the antidepressant group and either of the two comparison groups [hazard ratios (95% CI) for intubation or death 1.1 (0.83-1.5) and 1.1 (0.86-1.5); and for death alone 1.3 (0.93-1.8) and 1.1 (0.85-1.7)]. Examining the results of our study, along with those of Hoertel et al. and three additional retrospective cohort studies in inpatients published in the interim, the data permit only very limited conclusions, with the findings on the effect of serotonergic antidepressants ranging from a strongly protective effect to no effect. Although there are numerous threats to validity that might account for this wide range of findings, we could not identify any principal factor or set of factors that could clearly explain the differences.

Treatment of depression from both biological and psychological aspects

Depression was common before COVID-19 and became the top 25 burdens of disease in 2019 according to the annual Global Burden of Disease Study. With the continued spreading of COVID-19, researchers predict that depression may increase larger in the future. With the development in both neuroscience and psychology, the major depressive disorder can be released by different kinds of methods. From the medical aspect, most of the antidepressants which are widely used can be divided into 4 types: Tetracyclic Antidepressants (TeCAs), Tricyclic Antidepressants (TCAs) ， Selective Serotonin Reuptake Inhibitors (SSRIs), and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). The advantages of them involve high efficiency and can be absorbed easily. However, the main drawback of these medications is the side effects that they can cause ranging from somnolence to drowsiness after starting treatment. Research shows that some level of sexual dysfunction may occur in 40 to 65 percent of people who use SSRIs due to the sexual side effects. In this way, some of the psychological methods were explored including cognitive behavior therapy (CBT) and interpersonal psychotherapy (IPT) which focus on changing the mind or opinions of the patients to achieve goals. The content of this article not only focuses on different methods to treat depression but also compares their advantages and disadvantages of them. It may provide some pieces of evidence and viewpoints for clinical decision-making. © 2022 SPIE. All rights reserved.

The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion.

ARNSTEN, A.F.T., M.K.P. Joyce and A.C. Roberts. The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion. NEUROSCI BIOBEHAV REV XXX-XXX, 2022. The symptoms of major-depressive-disorder include psychic pain and anhedonia, i.e. seeing the world through an "aversive lens". The neurobiology underlying this shift in worldview is emerging. Here these data are reviewed, focusing on how activation of subgenual cingulate (BA25) induces an "aversive lens", and how higher prefrontal cortical (PFC) areas (BA46/10/32) provide top-down regulation of BA25 but are weakened by excessive dopamine and norepinephrine release during stress exposure, and dendritic spine loss with chronic stress exposure. These changes may generate an attractor state, which maintains the brain under the control of BA25, requiring medication or neuromodulatory treatments to return connectivity to a more flexible state. In line with this hypothesis, effective anti-depressant treatments reduce the activity of BA25 and restore top-down regulation by higher circuits, e.g. as seen with SSRI medications, ketamine, deep brain stimulation of BA25, or rTMS to strengthen dorsolateral PFC. This research has special relevance in an era of chronic stress caused by the COVID19 pandemic, political unrest and threat of climate change.

The effect of selective serotonin and norepinephrine reuptake inhibitors on clinical outcome of COVID-19 patients: A systematic review and meta-analysis.

Background and Aim: Due to the high social and economic burden and also mortality and morbidity caused by coronavirus disease 2019 (COVID-19) in the past few years, researchers have aimed at finding solutions to suppressing the severity of infection. Recently, selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRI) have been investigated as an adjuvant treatment for COVID-19. The aim of the current study was to investigate the impact of SSRI/SNRIs on outcomes of COVID-19 patients. Methods: In this systematic review and meta-analysis, a comprehensive search strategy consisting of relevant words was performed by two researchers in PubMed, Scopus and EMBASE libraries. Studies reporting the effect of SSRI and/or SNRI use in COVID-19 patients' outcome were included. Hospitalization, mortality, hospitalization event, and length of hospital stay were considered as main outcomes of this study. Analysis was carried out using Comprehensive Meta-Analysis (CMA-version 2) and final data were reported as odds ratio (OR) and 95% confidence interval (CI). Results: Our search led to the final selection of 9 articles including 15,287 patients. The effect of fluvoxamine, fluoxetine, and the overall effect of SSRI/SNRI use on mortality of COVID-19 patients were investigated in 3, 2, and 7 articles, respectively. The results of our analyses showed that these medications could significantly decrease mortality of COVID-19 patients (OR and 95% [CI]: 0.595 [0.467-0.758], 0.620 [0.469-0.821], and 0.596 [0.437-0.813]). The effect of SSRI/SNRIs on hospitalization events of COVID-19 patients was not significant (OR: 0.240% and 95% CI: 0.041-1.4). Also, length of hospital stay was longer in patients who administrated SSRIs. Conclusion: According to this study's results, SSRI/SNRIs may be effective in reducing mortality of COVID-19 patients, suggesting the superiority of fluvoxamine to fluoxetine. The safety profile and affordable cost of SSRI/SNRIs for a short-term use may be other reasons to propose them as beneficial medications in preventing mortality in COVID-19.

Neuroimaging a cytokine storm by transducing IL-1α to hippocampal cornu ammonis: COVID-19 SARS-CoV-2

Concerning the matter of depression, its full understanding pushes the envelope beyond clinical psychology and moves the subject further into the areas of Neuropsychopharmacology and Neuromolecular Imaging (NMI). Here, we studied, with the BRODERICK PROBE® acute and chronic stress-induced depression via the hypothalamic-pituitary-adrenal (HPA) axis. The “axis” is responsible for the emission of glucocorticoids during sympathetic nervous system activation. Negative feedback systems within areas of the hippocampus (HPC) and prefrontal cortex (PFC) prevent excessive amounts of glucocorticoids in the neurochemical environment and regulate the HPA axis production of these hormones. In depression, whether or not stress-induced, an increased concentration of glucocorticoids is present. In fact, when released by psychological or physical insult, glucocorticoids are accompanied by cytokines. The purpose of this work is to neuroimage a cytokine storm in the brain as it relates to COVID-19 SARS-CoV-2 patients. The advanced sensor nanobiotechnology, BRODERICK PROBE® transduced a small, protein cytokine, interleukin 1 alpha (IL-1α) to hippocampal Cornu Ammonis (CA-1) in two groups of animal subjects who are walking during neurotransmitter signaling. One genetically normal group was devoid of comorbidity to depression and indeed was also bred without viruses. The other genetic group was bred genetically depressed having platelet storage pool deficiency of the neurotransmitter, serotonin (5-HT);this group presented with Chediak-Higashi Syndrome and are Fawn-Hooded. Microdosing the pro-inflammatory IL-1α showed inherent neuroprotection of the hippocampal cytokine storm during real-time video tracking in Cornu Ammonis neurons in both nondepressed and depressed freely moving and walking subjects. The depressed subjects showed that the cytokine-induced storm began earlier than in nondepressed subjects while walking was increased in addition to enhanced stereotypy. Longer term studies in the same freely moving, walking subjects showed that the nondepressed were adapted to this cytokine brainstorm according to reliable sensor signaling signatures whereas the depressed subjects remained depressed. Thus, at the same time that we watched the brain immune derived cytokine storm directly coming to us online from HPC (CA-1) neurons, we monitored these motor skills with infrared photocell beams. Stereotypic grooming, nasopharyngeal systems were carefully assessed. These skills are important as they are related to respiratory SARS-CoV-2 insults and trauma. We watched online as the feared “hippocampal cytokine storm” was imaged in the depressed subject while immune T cell ratio CD4/CD8 was reversed. Tracking cytokine neuroinflammation transduced to HPC CA-1 neurons directly online while the subject is walking enables direct extrapolation to immune brain dysfunction in SARS-CoV-2 virus (Covid 19) patient data. © 2021 Elsevier Inc. All rights reserved.

Role of Microglial Activation and Norepinephrine Transporter Abnormalities in Pathogenesis of MS-Related Fatigue

This proposal addresses the Biology and Measurement of MS symptoms focus area of FY18 MSRP Exploration Hypothesis Development Award. The overarching aim of this proposal is to assess the role of microglial activation and norepinephrine transporter binding in pathogenesis of MS-related fatigue, using novel Positron Emission Tomography (PET) radiotracers. [F-18]PBR06 and [C-11]MRB. The major developments in the progress of this project have been the following: 1. We received permission to resume recruitment of subjects on July 15, 2020. 2. We are pleased to report that we have recruited and obtained informed consent from 10 eligible subjects already (greater than 80 percent of the target sample size). 3 of these subjects have completed all the study related procedures (25 percent of the target sample size). Based on our preliminary data about the role of neuroinflammation in pathogenesis of MS-related fatigue, we had a manuscript published in the journal Neurology: Neuroimmunology and Neuroinflammation in September, 2020. The title of the manuscript is T Singhal, S Cicero, H Pan, K Carter, S Dubey, R Chu, B Glanz, S Hurwitz, S Tauhid, Mi-Ae Park, M Kijewski, E Stern, R Bakshi, D Silbersweig, and HL Weiner. Regional Microglial Activation in Substantia Nigra is linked with Fatigue in Multiple Sclerosis. (PMID 32769103)

Year 2021 in review - Anaesthesiology in obstetrics

The article highlights and discusses several current topics that have been published in the field of anaesthesiology in obstetrics in the Czech Republic and abroad last year. It summarizes the influence of COVID-19 pandemia on anaesthesiological praxis in obstetrics. It also presents new developments in systemic and neuroaxial obstetric analgesia, Caesarean Section anaesthesia and emergencies in peripartum period.

New Serotonin-Norepinephrine Reuptake Inhibitors and Their Anesthetic and Analgesic Considerations.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the presynaptic neuronal uptake of serotonin and norepinephrine and prolong the effects of the monoamines in the synaptic cleft within the central nervous system, leading to increased postsynaptic receptor activation and neuronal activities. Serotonin-norepinephrine reuptake inhibitors can have multiple clinical indications, including as the first-line agents for the management of depression and anxiety, and as analgesics in the treatment of chronic pain. The effects of reuptake inhibition of norepinephrine and serotonin are often dose-dependent and agent-dependent. There are five FDA-approved serotonin-norepinephrine reuptake inhibitors (desvenlafaxine, duloxetine, levomilnacipran, milnacipran and sibutramine) currently being marketed in the United States. As the COVID-19 pandemic significantly increased the incidence and prevalence of anxiety and depression across the country, there are significantly increased prescriptions of these medications perioperatively. Thus, anesthesiologists are more likely than ever to have patients administered with these agents and scheduled for elective or emergency surgical procedures. A thorough understanding of these commonly prescribed serotonin-norepinephrine reuptake inhibitors and their interactions with commonly utilized anesthetic agents is paramount. There are two potentially increased risks related to the continuation of SNRIs through the perioperative period: intraoperative bleeding and serotonin syndrome. SNRIs have some off-label uses, more new indications, and ever-increasing new applications in perioperative practice. This article aims to review the commonly prescribed serotonin-norepinephrine reuptake inhibitors and the current clinical evidence regarding their considerations in perioperative anesthesia and analgesia.

Early Effects of Passive Leg-Raising Test, Fluid Challenge, and Norepinephrine on Cerebral Autoregulation and Oxygenation in COVID-19 Critically Ill Patients.

Background: Coronavirus disease 2019 (COVID-19) patients are at high risk of neurological complications consequent to several factors including persistent hypotension. There is a paucity of data on the effects of therapeutic interventions designed to optimize systemic hemodynamics on cerebral autoregulation (CA) in this group of patients. Methods: Single-center, observational prospective study conducted at San Martino Policlinico Hospital, Genoa, Italy, from October 1 to December 15, 2020. Mechanically ventilated COVID-19 patients, who had at least one episode of hypotension and received a passive leg raising (PLR) test, were included. They were then treated with fluid challenge (FC) and/or norepinephrine (NE), according to patients' clinical conditions, at different moments. The primary outcome was to assess the early effects of PLR test and of FC and NE [when clinically indicated to maintain adequate mean arterial pressure (MAP)] on CA (CA index) measured by transcranial Doppler (TCD). Secondary outcomes were to evaluate the effects of PLR test, FC, and NE on systemic hemodynamic variables, cerebral oxygenation (rSo2), and non-invasive intracranial pressure (nICP). Results: Twenty-three patients were included and underwent PLR test. Of these, 22 patients received FC and 14 were treated with NE. The median age was 62 years (interquartile range = 57-68.5 years), and 78% were male. PLR test led to a low CA index [58% (44-76.3%)]. FC and NE administration resulted in a CA index of 90.8% (74.2-100%) and 100% (100-100%), respectively. After PLR test, nICP based on pulsatility index and nICP based on flow velocity diastolic formula was increased [18.6 (17.7-19.6) vs. 19.3 (18.2-19.8) mm Hg, p = 0.009, and 12.9 (8.5-18) vs. 15 (10.5-19.7) mm Hg, p = 0.001, respectively]. PLR test, FC, and NE resulted in a significant increase in MAP and rSo2. Conclusions: In mechanically ventilated severe COVID-19 patients, PLR test adversely affects CA. An individualized strategy aimed at assessing both the hemodynamic and cerebral needs is warranted in patients at high risk of neurological complications.

Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches.

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

Physiologic Response to Angiotensin II Treatment for Coronavirus Disease 2019-Induced Vasodilatory Shock: A Retrospective Matched Cohort Study.

OBJECTIVES: To assess the early physiologic response to angiotensin-II treatment in patients with coronavirus disease 2019-induced respiratory failure and distributive shock. DESIGN: Retrospective consecutive-sample cohort study. SETTING: Three medical ICUs in New York during the coronavirus disease 2019 outbreak. PATIENTS: All patients were admitted to the ICU with respiratory failure and were receiving norepinephrine for distributive shock. INTERVENTIONS: The treatment groups were patients who received greater than or equal to 1 hour of angiotensin-II treatment. Time-zero was the time of angiotensin-II initiation. Controls were identified using a 2:1 hierarchical process that matched for 1) date and unit of admission; 2) specific organ support modalities; 3) age; 4) chronic lung, cardiovascular, and kidney disease; and 5) sex. Time-zero in the control group was 21 hours post vasopressor initiation, the mean duration of vasopressor therapy prior to angiotensin-II initiation in the treated group. MEASUREMENTS AND MAIN RESULTS: Main outcomes were trajectories of vasopressor requirements (in norepinephrine-equivalent dose) and mean arterial pressure. Additionally assessed trajectories were respiratory (Pao2/Fio2, Paco2), metabolic (pH, creatinine), and coagulation (d-dimer) dysfunction indices after time-zero. We also recorded adverse events and clinical outcomes. Trajectories were analyzed using mixed-effects models for immediate (first 6 hr), early (48 hr), and sustained (7 d) responses. Twenty-nine patients (n = 10 treated, n = 19 control) were identified. Despite matching, angiotensin-II-treated patients had markedly greater vasopressor requirements (mean: 0.489 vs 0.097 µg/kg/min), oxygenation impairment, and acidosis at time-zero. Nonetheless, angiotensin-II treatment was associated with an immediate and sustained reduction in norepinephrine-equivalent dose (6 hr model: ß = -0.036 µg/kg/min/hr; 95% CI: -0.054 to -0.018 µg/kg/min/hr, p interaction=0.0002) (7 d model: ß = -0.04 µg/kg/min/d, 95% CI: -0.05 to -0.03 µg/kg/min/d; p interaction = 0.0002). Compared with controls, angiotensin-II-treated patients had significantly faster improvement in mean arterial pressure, hypercapnia, acidosis, baseline-corrected creatinine, and d-dimer. Three thrombotic events occurred, all in control patients. CONCLUSIONS: Angiotensin-II treatment for coronavirus disease 2019-induced distributive shock was associated with rapid improvement in multiple physiologic indices. Angiotensin-II in coronavirus disease 2019-induced shock warrants further study.