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Coralsnakes (Micrurus spp.) are the only elapids found throughout the Americas. They are recognized for their highly neurotoxic venom, which is comprised of a wide variety of toxins, including the stable, low-mass toxins known as three-finger toxins (3FTx). Due to difficulties in venom extraction and availability, research on coralsnake venoms is still very limited when compared to that of other Elapidae snakes like cobras, kraits, and mambas. In this study, two previously described 3FTx from the venom of M. corallinus, NXH1 (3SOC1_MICCO), and NXH8 (3NO48_MICCO) were characterized. Using in silico, in vitro, and ex vivo experiments, the biological activities of these toxins were predicted and evaluated. The results showed that only NXH8 was capable of binding to skeletal muscle cells and modulating the activity of nAChRs in nerve-diaphragm preparations. These effects were antagonized by anti-rNXH8 or antielapidic sera. Sequence analysis revealed that the NXH1 toxin possesses eight cysteine residues and four disulfide bonds, while the NXH8 toxin has a primary structure similar to that of non-conventional 3FTx, with an additional disulfide bond on the first loop. These findings add more information related to the structural diversity present within the 3FTx class, while expanding our understanding of the mechanisms of the toxicity of this coralsnake venom and opening new perspectives for developing more effective therapeutic interventions.

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Rationale: Hypoxemia during mechanical ventilation might be worsened by expiratory muscle activity, which reduces end-expiratory lung volume through lung collapse. A proposed mechanism of benefit of neuromuscular blockade in acute respiratory distress syndrome (ARDS) is the abolition of expiratory efforts. This may contribute to the restoration of lung volumes. The prevalence of this phenomenon, however, is unknown. Objectives: To investigate the incidence and amount of end-expiratory lung impedance (EELI) increase after the administration of neuromuscular blocking agents (NMBAs), clinical factors associated with this phenomenon, its impact on regional lung ventilation, and any association with changes in pleural pressure. Methods: We included mechanically ventilated patients with ARDS monitored with electrical impedance tomography (EIT) who received NMBAs in one of two centers. We measured changes in EELI, a surrogate for end-expiratory lung volume, before and after NMBA administration. In an additional 10 patients, we investigated the characteristic signatures of expiratory muscle activity depicted by EIT and esophageal catheters simultaneously. Clinical factors associated with EELI changes were assessed. Measurements and Main Results: We included 46 patients, half of whom showed an increase in EELI of >10% of the corresponding Vt (46.2%; IQR, 23.9-60.9%). The degree of EELI increase correlated positively with fentanyl dosage and negatively with changes in end-expiratory pleural pressures. This suggests that expiratory muscle activity might exert strong counter-effects against positive end-expiratory pressure that are possibly aggravated by fentanyl. Conclusions: Administration of NMBAs during EIT monitoring revealed activity of expiratory muscles in half of patients with ARDS. The resultant increase in EELI had a dose-response relationship with fentanyl dosage. This suggests a potential side effect of fentanyl during protective ventilation.

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Coralsnakes (Micrurus spp.) are the only elapids found throughout the Americas. They are recognized for their highly neurotoxic venom, which is comprised of a wide variety of toxins, including the stable, low-mass toxins known as three-finger toxins (3FTx). Due to difficulties in venom extraction and availability, research on coralsnake venoms is still very limited when compared to that of other Elapidae snakes like cobras, kraits, and mambas. In this study, two previously described 3FTx from the venom of M. corallinus, NXH1 (3SOC1_MICCO), and NXH8 (3NO48_MICCO) were characterized. Using in silico, in vitro, and ex vivo experiments, the biological activities of these toxins were predicted and evaluated. The results showed that only NXH8 was capable of binding to skeletal muscle cells and modulating the activity of nAChRs in nerve–diaphragm preparations. These effects were antagonized by anti-rNXH8 or antielapidic sera. Sequence analysis revealed that the NXH1 toxin possesses eight cysteine residues and four disulfide bonds, while the NXH8 toxin has a primary structure similar to that of non-conventional 3FTx, with an additional disulfide bond on the first loop. These findings add more information related to the structural diversity present within the 3FTx class, while expanding our understanding of the mechanisms of the toxicity of this coralsnake venom and opening new perspectives for developing more effective therapeutic interventions.

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In this work, we examined the neuromuscular blockade caused by venoms from four South-American coralsnakes (Micrurus altirostris - MA, M. corallinus - MC, M. spixii - MS, and M. dumerilii carinicauda - MDC) and the ability of varespladib (VPL), a phospholipase A2 (PLA2) inhibitor, to attenuate this blockade. PLA2 activity was determined using a colorimetric assay and a fixed amount of venom (10 µg). Neurotoxicity was assayed using a single concentration of venom (10 µg/ml) in mouse phrenic nerve-diaphragm (PND) preparations mounted for myographic recordings and then subjected to histological analysis. All venoms showed PLA2 activity, with MS and MA venoms having the highest (15.53 ± 1.9 A425 nm/min) and lowest (0.23 ± 0.14 A425 nm/min) activities, respectively. VPL (292 and 438 µM) inhibited the PLA2 activity of all venoms, although that of MA venom was least affected. All venoms caused neuromuscular blockade, with MS and MDC venoms causing the fastest and slowest 100% blockade [in 40 ± 3 min and 120 ± 6 min (n = 4), respectively]; MA and MC produced complete blockade within 90-100 min. Preincubation of venoms with 292 µM VPL attenuated the blockade to varying degrees: the greatest inhibition was seen with MDC venom and blockade by MS venom was unaffected by this inhibitor. These results indicate that PLA2 has a variable contribution to coralsnake venom-induced neuromuscular blockade in vitro, with the insensitivity of MS venom to VPL suggesting that blockade by this venom is mediated predominantly by post-synaptically-active α-neurotoxins.

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STUDY OBJECTIVE: The current study tested the hypothesis that magnesium sulfate after reversal with sugammadex causes recurarization. DESIGN: A single-center, prospective, randomized, double-blind, controlled trial. SETTING: Terciary care hospital in Rio de Janeiro, Brazil. PATIENTS: Included 60 patients undergoing for elective otolaryngological surgery. INTERVENTIONS: All patients received total intravenous anesthesia and a single dose of rocuronium (0.6 mg/kg). In 30 patients, the neuromuscular blockade was reversed with sugammadex (4 mg/kg) at the reappearance of one or two posttetanic counts (deep-blockade series). In 30 other patients, sugammadex (2 mg/kg) was administered at the reappearance of the second twitch of the train-of-four (moderate-blockade series). After the normalized train-of-four ratio recovered to ≥0.9, the patients in each series were randomized to receive intravenous magnesium sulfate (60 mg/kg) or placebo for 10 min. Neuromuscular function was measured by acceleromyography. MEASUREMENTS: The primary outcome was the number of patients who exhibited recurarization (normalized train-of-four ratio < 0.9). The secondary outcome was rescue with an additional dose of sugammadex after 60 min. MAIN RESULTS: In the deep-blockade series, a normalized train-of-four ratio < 0.9 occurred in 9/14 (64%) patients receiving magnesium sulfate and 1/14 (7%) receiving placebo, RR 9.0 (95% CI: 62-1.30), and (p = 0.002), with four rescues with sugammadex. In the moderate-blockade series, neuromuscular blockade recurred in 11/15 (73%) patients receiving magnesium sulfate and in 0/14 (0%) receiving placebo (p < 0.001), with two rescues. The absolute differences in recurarization were 57% and 73% in the deep-blockade and moderate-blockade, respectively. CONCLUSIONS: Single-dose magnesium sulfate led to a normalized train-of-four ratio < 0.9, 2 min after recovery from rocuronium-induced deep and moderate neuromuscular blockade using sugammadex. Additional sugammadex reversed prolonged recurarization.

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BACKGROUND: Reliable devices that quantitatively monitor the level of neuromuscular blockade after neuromuscular blocking agents' administration are crucial. Electromyography and acceleromyography are two monitoring modalities commonly used in clinical practice. The primary outcome of this study is to compare the onset of neuromuscular blockade, defined as a Train-Of-Four Count (TOFC) equal to 0, as measured by an electromyography-based device (TetraGraph) and an acceleromyography-based device (TOFscan). The secondary outcome was to compare intubating conditions when one of these two devices reached a TOFC equal to 0. METHODS: One hundred adult patients scheduled for elective surgery requiring neuromuscular blockade were enrolled. Prior to induction of anesthesia, TetraGraph electrodes were placed over the forearm of patients' dominant/non-dominant hand based on randomization and TOFscan electrodes placed on the contralateral forearm. Intraoperative neuromuscular blocking agent dose was standardized to 0.5 mg.kg-1 of rocuronium. After baseline values were obtained, objective measurements were recorded every 20 seconds and intubation was performed using video laryngoscopy once either device displayed a TOFC = 0. The anesthesia provider was then surveyed about intubating conditions. RESULTS: Baseline TetraGraph train-of-four ratios were higher than those obtained with TOFscan (Median: 1.02 [0.88, 1.20] vs. 1.00 [0.64, 1.01], respectively, p < 0.001). The time to reach a TOFC = 0 was significantly longer when measured with TetraGraph compared to TOFscan (Median: 160 [40, 900] vs. 120 [60, 300] seconds, respectively, p < 0.001). There was no significant difference in intubating conditions when either device was used to determine the timing of endotracheal intubation. CONCLUSIONS: The onset of neuromuscular blockade was longer when measured with TetraGraph than TOFscan, and a train-of-four count of zero in either device was a useful indicator for adequate intubating conditions. CLINICAL TRIAL NUMBER AND REGISTRY: URL NCT05120999, https://clinicaltrials.gov/ct2/show/NCT05120999.

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BACKGROUND: Sedation in intensive care is fundamental for optimizing clinical outcomes. For many years the world has been facing high rates of opioid use, and to combat the increasing opioid addiction plans at both national and international level have been implemented.1 The COVID-19 pandemic posed a major challenge for health systems and also increased the use of sedatives and opioid analgesia for prolonged periods of time, and at high doses, in a significant proportion of patients. In our institutions, the shortage of many drugs for intravenous (IV) analgosedation forces us to alternatives to replace out-of-stock drugs or to seek sedation goals, which are difficult to obtain with traditional drugs at high doses.2 METHODS: This was an analytical retrospective cohort study evaluating the follow-up of subjects with inclusion criteria from ICU admission to discharge (alive or dead). Five end points were measured: need for high-dose opioids (≥ 200 µg/h), comparison of inhaled versus IV sedation of opioid analgesic doses, midazolam dose, need for muscle relaxant, and risk of delirium. RESULTS: A total of 283 subjects were included in the study, of whom 230 were administered IV sedation and 53 inhaled sedation. In the inhaled sedation group, the relative risks (RRs) were 0.5 (95% CI 0.4-0.8, P = .045) for need of high-dose fentanyl, 0.3 (95% CI 0.20-0.45, P < .001) for need of muscle relaxant, and 0.8 (95% CI 0.61-1.15, P = .25) for risk of delirium. The median difference of fentanyl dose between the inhaled sedation and IV sedation groups was 61 µg/h or 1,200 µg/d (2.2 ampules/d, P < .001), and that of midazolam dose was 5.7 mg/h. CONCLUSIONS: Inhaled sedation was associated with lower doses of opioids, benzodiazepines, and muscle relaxants compared to IV sedation. This therapy should be considered as an alternative in critically ill patients requiring prolonged ventilatory support and where IV sedation is not possible, always under adequate supervision of ICU staff.

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Abstract Background Reliable devices that quantitatively monitor the level of neuromuscular blockade after neuromuscular blocking agents' administration are crucial. Electromyography and acceleromyography are two monitoring modalities commonly used in clinical practice. The primary outcome of this study is to compare the onset of neuromuscular blockade, defined as a Train-Of-Four Count (TOFC) equal to 0, as measured by an electromyography-based device (TetraGraph) and an acceleromyography-based device (TOFscan). The secondary outcome was to compare intubating conditions when one of these two devices reached a TOFC equal to 0. Methods One hundred adult patients scheduled for elective surgery requiring neuromuscular blockade were enrolled. Prior to induction of anesthesia, TetraGraph electrodes were placed over the forearm of patients' dominant/non-dominant hand based on randomization and TOFscan electrodes placed on the contralateral forearm. Intraoperative neuromuscular blocking agent dose was standardized to 0.5 mg.kg−1 of rocuronium. After baseline values were obtained, objective measurements were recorded every 20 seconds and intubation was performed using video laryngoscopy once either device displayed a TOFC = 0. The anesthesia provider was then surveyed about intubating conditions. Results Baseline TetraGraph train-of-four ratios were higher than those obtained with TOFscan (Median: 1.02 [0.88, 1.20] vs. 1.00 [0.64, 1.01], respectively, p < 0.001). The time to reach a TOFC = 0 was significantly longer when measured with TetraGraph compared to TOFscan (Median: 160 [40, 900] vs. 120 [60, 300] seconds, respectively, p < 0.001). There was no significant difference in intubating conditions when either device was used to determine the timing of endotracheal intubation. Conclusions The onset of neuromuscular blockade was longer when measured with TetraGraph than TOFscan, and a train-of-four count of zero in either device was a useful indicator for adequate intubating conditions. Clinical trial number and registry URL NCT05120999, https://clinicaltrials.gov/ct2/show/NCT05120999.

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Abstract: Introduction: Among the patients infected with SARS-CoV-2, 14.6% were admitted to intensive care unit. this 29 to 75% required invasive mechanical ventilation with an associated mortality of 12 to 81%. Acute respiratory distress syndrome (ARDS) is the most serious form of presentation. The pathophysiology of ARDS secondary to SARS-CoV-2 differs from conventional causes. It presents dysregulation in hypoxic pulmonary vasoconstriction, secondary acute pulmonary hypertension and microthrombotic phenomena. The development of refractory severe hypoxemia (PaO2 < 60 mmHg or PaO2/FiO2 < 100 mmHg, with FiO2 80 to 100%, with PEEP > 10 to 20 cmH2O for at least 10 to 12 hours) constitutes the scenario of maximum severity with an associated mortality of 71 to 94%. The use of rescue strategies that impact on the specific pathophysiology of this entity such as the use of inhaled nitric oxide, neuromuscular blockade and prone ventilation have emerged as therapeutic targets of interest. Protective mechanical ventilation (plateau pressure [Pplat] < 27 cmH2O and driving pressure [DP] < 15 cmH2O) continues to be the cornerstone of the management. Objectives: To determine whether there is an association between the use of inhaled nitric oxide and prone ventilation with ventilatory mechanics in patients with severe refractory hypoxemia secondary to SARS-CoV-2 infection. Material and methods: A historical, retrospective, descriptive, comparative and retrolective cohort study was carried out. Data from the records of patients admitted to the Respiratory ICU of the ABC Medical Center with a diagnosis of ARDS secondary to SARS-CoV-2 infection who required iNO and mechanical ventilation in prone from April 1 to December 31, 2020 were analyzed. A univariate analysis was performed, the statistical analysis was performed in SPSS v 21, measures of trend, dispersion were analyzed as well as the analysis of risk factors with Student's t test and χ2. Results: A total of 108 patients were analyzed, of which 54 received iNO, neuromuscular blockade and prone and 54 only neuromuscular blockade and prone ventilation. 81.5% (n = 88) were men. The most common comorbidity was diabetes mellitus in 51.9% (n = 56). The increase in oxygenation (delta PaO2/FiO2) was with a median of 31.9 ± 15.2 mmHg in the iNO group and 52.9 ± 16.74 mmHg in the control group (p = 0.001). The postintervention Pplat in the iNO group was 26.3 ± 3 and 34.5 ± 1.9 cmH2O in the control group (p = 0.792). The preintervention DP in the iNO group was 17.2 ± 3.9 and 13.4 ± 2.8 cmH2O in control group vs 13.1 ± 1.29 and 12 ± 1.92 cmH2O after the intervention (p = 0.001). Conclusions: The use of iNO in patients with severe hypoxemia refractory to prone ventilation and neuromuscular blockade did not produce a statistically significant improvement in oxygenation, however it allowed to reprogram the ventilatory support to keep the patient in goals of alveolar protection.

Resumo: Introdução: 14.6% dos pacientes infectados com SARS-CoV-2 são internados em terapia intensiva. Destes, 29 a 75% necessitam de ventilação mecânica invasiva com mortalidade associada de 12 a 81%. A síndrome do desconforto respiratório agudo (SDRA) é a forma mais grave de apresentação. A fisiopatologia da SDRA secundária ao SARS-CoV-2 difere das causas convencionais. Apresenta desregulação na vasoconstrição pulmonar hipóxica, hipertensão pulmonar aguda secundária e fenômenos microtrombóticos. O desenvolvimento de hipoxemia grave refratária (PaO2 < 60 mmHg ou PaO2/FiO2 < 100 mmHg, com FiO2 de 80 a 100%, PEEP > 10 a 20 cmH2O por pelo menos 10 a 12 horas) constitui o cenário mais grave com mortalidade associada de 71 a 94%. O uso de estratégias de resgate que impactam na fisiopatologia específica dessa entidade, como o uso de óxido nítrico inalatório (NOi), bloqueio neuromuscular e ventilação prona, surgiram como alvos terapêuticos de interesse. A ventilação mecânica protetora (Pressão de Platô [PPLAT] < 27 cmH2O e Pressão de Condução [CP] < 15 cmH2O) continua sendo a base de seu manejo. Objetivo: Determinar se existe associação entre o uso de óxido nítrico inalatório e ventilação prona prolongada com mecânica ventilatória em pacientes com hipoxemia refratária grave secundária à infecção por SARS-CoV-2. Material e métodos: Realizou-se um estudo de coorte histórico, retrospectivo, descritivo, comparativo e retroletivo. Analisaram-se dados dos prontuários de pacientes internados na UTI Respiratória do Centro Médico ABC com diagnóstico de SDRA secundária à infecção por SARS-CoV-2 que necessitaram de óxido nítrico inalatório e ventilação mecânica prona no período de 1o de abril a 31 de dezembro de 2020. Realizou-se uma análise univariada , a análise estatística foi realizada no SPSS v 21, foram analisadas as medidas de tendência e dispersão, assim como a análise dos fatores de risco com teste t de Student e χ2. Resultados: Analisaram-se 108 pacientes, dos quais 54 receberam NOi, bloqueio neuromuscular e prono e 54 apenas bloqueio neuromuscular e ventilação prona. 81.5% (n = 88) eram homens. A comorbidade mais comum foi diabetes mellitus em 51.9% (n = 56). O aumento da oxigenação (Delta PaO2/FiO2) foi com mediana de 31.9 ± 15.2 mmHg no grupo NOi e 52.9 ± 16.74 mmHg no grupo controle (p = 0.001). A PPLAT após a intervenção no grupo NOi foi de 26.3 ± 3 e 34.5 ± 1.9 cmH2O no grupo controle (p = 0.792). A PC antes da intervenção no grupo NOi foi de 17.2 ± 3.9 e 13.4 ± 2.8 cmH2O no grupo controle vs 13.1 ± 1.29 e 12 ± 1.92 cmH2O após a intervenção (p = 0.001). Conclusões: O uso de NOi em pacientes com hipoxemia grave refratária à ventilação em pronação e bloqueio neuromuscular não produziu melhora estatisticamente significativa na oxigenação, porém permitiu que o suporte ventilatório fosse reprogramado para manter as metas de proteção alveolar do paciente.

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The use of sugammadex for reversal of rocuronium-induced neuromuscular blockade after caesarean section is nowadays common practice, but concerns exist about its use in pregnant women undergoing non-obstetric surgery. We report six cases of pregnant women submitted to general anesthesia for non-obstetric surgery in which neuromuscular blockade was reversed with sugammadex. We followed the outcome of both mother and baby during and after delivery. Sugammadex seemed to be a safe option for both mother and baby but more reports are necessary to fill the evidence gap and increase the global knowledge about its safety in this special group of patients.

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