Adjuvant Wilms' tumour 1-specific dendritic cell immunotherapy complementing conventional therapy for paediatric patients with high-grade glioma and diffuse intrinsic pontine glioma: protocol of a monocentric phase I/II clinical trial in Belgium.

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) and paediatric high-grade glioma (pHGG) are aggressive glial tumours, for which conventional treatment modalities fall short. Dendritic cell (DC)-based immunotherapy is being investigated as a promising and safe adjuvant therapy. The Wilms' tumour protein (WT1) is a potent target for this type of antigen-specific immunotherapy and is overexpressed in DIPG and pHGG. Based on this, we designed a non-randomised phase I/II trial, assessing the feasibility and safety of WT1 mRNA-loaded DC (WT1/DC) immunotherapy in combination with conventional treatment in pHGG and DIPG. METHODS AND ANALYSIS: 10 paediatric patients with newly diagnosed or pretreated HGG or DIPG were treated according to the trial protocol. The trial protocol consists of leukapheresis of mononuclear cells, the manufacturing of autologous WT1/DC vaccines and the combination of WT1/DC-vaccine immunotherapy with conventional antiglioma treatment. In newly diagnosed patients, this comprises chemoradiation (oral temozolomide 90 mg/m2 daily+radiotherapy 54 Gy in 1.8 Gy fractions) followed by three induction WT1/DC vaccines (8-10×106 cells/vaccine) given on a weekly basis and a chemoimmunotherapy booster phase consisting of six 28-day cycles of oral temozolomide (150-200 mg/m2 on days 1-5) and a WT1/DC vaccine on day 21. In pretreated patients, the induction and booster phase are combined with best possible antiglioma treatment at hand. Primary objectives are to assess the feasibility of the production of mRNA-electroporated WT1/DC vaccines in this patient population and to assess the safety and feasibility of combining conventional antiglioma treatment with the proposed immunotherapy. Secondary objectives are to investigate in vivo immunogenicity of WT1/DC vaccination and to assess disease-specific and general quality of life. ETHICS AND DISSEMINATION: The ethics committee of the Antwerp University Hospital and the University of Antwerp granted ethics approval. Results of the clinical trial will be shared through publication in a peer-reviewed journal and presentations at conferences. TRIAL REGISTRATION NUMBER: NCT04911621.

Remimazolam Pilot for Office-Based Dental Sedation: Adverse Events, Awareness and Outcomes.

In recent years, remimazolam has gained approval for use in adult procedural sedation in both the United Kingdom and the United States, potentially offering an alternative to conventional sedatives like propofol and midazolam for procedural sedation. However, there is a limited body of literature that systematically reviews the outcomes of a remimazolam-alfentanil combination protocol for routine office-based dental procedures. The primary objective of this pilot study was to assess the occurrence of significant adverse events associated with the use of a remimazolam-alfentanil sedation protocol for adult dental procedures. Secondary outcomes included evaluating physiological responses, sedation effectiveness, patient and clinician satisfaction and the incidence of intraprocedural awareness. Notably, no significant adverse events were reported among the 25 adult subjects who received remimazolam and alfentanil, and all dental procedures were successfully completed. Patients and clinicians expressed high levels of satisfaction, and patients did not report any distressing memories associated with the dental procedure. These findings suggest that in a limited cohort, the remimazolam-alfentanil regimen appears to be well tolerated and effective for office-based dental procedures in adult patients, with a low risk of adverse events, acceptable hemodynamic effects, rapid onset and recovery and minimal intraoperative awareness. This study provides valuable insights into the potential use of the remimazolam-alfentanil combination in dental sedation practice.

Respiratory muscle activity after spontaneous, neostigmine- or sugammadex-enhanced recovery of neuromuscular blockade: a double blind prospective randomized controlled trial.

BACKGROUND: The use of neostigmine after neuromuscular blockade (NMB) has been associated with postoperative respiratory complications. In previous studies, we found lower diaphragmatic activity after neostigmine reversal of NMB, compared to sugammadex. It is still unclear whether the adequate use of neostigmine guarantees normal respiratory muscle function after NMB. In this study, we wanted to assess the effect of commonly used degrees of NMB and their possible reversal strategies on respiratory muscle activity after the return of normal neuromuscular transmission. METHODS: This is a randomized, controlled, parallel-group, single-centre, double-blind study in patients scheduled for intracranial surgery at a tertiary academic hospital in Belgium. All participants received target controlled propofol/remifentanil anesthesia and were randomized into one of five groups, receiving either a shallow NMB with no reversal (shallow/saline), a shallow NMB with sugammadex reversal (shallow/sugammadex), a moderate NMB with neostigmine reversal (moderate/neostigmine), a moderate NMB with sugammadex reversal (moderate/sugammadex), or a deep NMB with sugammadex reversal (deep/sugammadex). Primary and secondary outcome parameters were diaphragm and intercostal electromyographic (EMG) activity at the moment of resumed spontaneous breathing activity, defined as a maximal interval of 10 min after the first spontaneous breath. RESULTS: For the five groups, a total of 55 patients could be included in the final analysis. Median time of spontaneous breathing analyzed was 5 min (IQR 3-9.5 min). Both the moderate/sugammadex and the moderate/neostigmine groups had lower levels of diaphragm EMG compared to the shallow/sugammadex group. The moderate/neostigmine group had lower levels of intercostal EMG activity compared to the shallow/saline group. CONCLUSIONS: In this study, the depth of neuromuscular blockade and type of reversal strategy impacts respiratory muscle activity at the moment of resumed spontaneous breathing and recovery of neuromuscular blockade. Both groups that received moderate NMB had lower levels of diaphragm EMG, compared to the shallow NMB group with sugammadex reversal. Compared to the shallow NMB group with no reversal, the moderate NMB with neostigmine reversal group had lower intercostal EMG activity. TRIAL REGISTRATION: Clinicaltrials.gov NCT01962298 on October 9, 2013 and EudraCT 2013-001926-25 on October 10, 2013.

Perioperative Care of Patients With Obstructive Sleep Apnea Undergoing Upper Airway Surgery: A Review and Consensus Recommendations.

IMPORTANCE: To date, no consensus exists regarding optimal perioperative care of patients with obstructive sleep apnea (OSA) undergoing upper airway (UA) surgery. These patients are at risk related to anesthesia and postoperative analgesia, among other risks associated with difficult airway control, and may require intensified perioperative management. OBJECTIVE: To provide a consensus-based guideline by reviewing available literature and collecting expert opinion during an international consensus meeting with experts from relevant speciliaties. EVIDENCE REVIEW: In a consensus meeting conducted on April 4, 2018, a total of 47 questions covering preoperative, intraoperative, and postoperative care were formulated by 12 international experts with extensive clinical experience in the field of UA surgery for OSA. Systematic literature searches were performed by an independent information specialist and 6 researchers according to the Oxford and GRADE systems, and 164 articles published on or before December 31, 2011, were included in the analysis. Two moderators chaired the meeting according to the Amsterdam Delphi Method, including iteration of literature conclusions, expert discussion, and voting rounds. Consensus was reached when there was 70% or more agreement among experts. FINDINGS: Of 47 questions, 35 led to a recommendation or statement. The remaining 12 questions provided no additional information and were excluded in the judgment of experts. Consensus was reached for 32 recommendations. For 1 question there was less than 70% agreement among experts; therefore, consensus was not achieved. Highlights of these recommendations include (1) postoperative bleeding is a complication described for all types of UA surgery; (2) OSA is a relative risk factor for difficult mask ventilation and intubation, and plans for difficult airway management should be considered and implemented; (3) safe perioperative care should be provided, with aspects such as OSA severity, adherent use of positive airway pressure, type of surgery, and comorbidities taken into account; (4) although there is no direct evidence to date, in patients undergoing UA surgery, preoperative treatment with positive airway pressure may reduce the risk of postoperative airway complications; and (5) alternative pain management options perioperatively to reduce opioid use should be considered. CONCLUSIONS AND RELEVANCE: This consensus contains 35 recommendations and statements on the perioperative care of patients with OSA undergoing UA surgery and may be used as a guideline in daily practice.

Functional respiratory imaging after neostigmine- or sugammadex-enhanced recovery from neuromuscular blockade in the anesthetised rat: a randomised controlled pilot study / Imagem funcional da respiração após aceleração da recuperação do bloqueio neuromuscular com neostigmina ou sugamadex em ratos anestesiados: estudo piloto controlado e randomizado

Abstract Objectives Reductions in diaphragm activity are associated with the postoperative development of atelectasis. Neostigmine reversal is also associated with increased atelectasis. We assessed the effects of neostigmine, sugammadex, and spontaneous reversal on regional lung ventilation and airway flow. Methods Six Sprague-Dawley rats were paralysed with rocuronium and mechanically ventilated until recovery of the train-of-four ratio to 0.5. We administered neostigmine (0.06 mg.kg-1), sugammadex (15 mg.kg-1), or saline (n = 2 per group). Computed tomography scans were obtained during the breathing cycle. Three-dimensional models of lung lobes were generated using functional respiratory imaging technology, and lobar volumes were calculated during the breathing cycle. The diaphragmatic surface was segmented for the end-expiratory and end-inspiratory scans. The total change in volume was reported by the lung volume change from the end-expiratory scan to the end-inspiratory scan. Chest wall movement was defined as the lung volume change minus the volume change that resulted from diaphragm excursion. Results The two rats that received neostigmine exhibited a smaller relative contribution of diaphragm movement to the total change in lung volume compared with the two rats that received sugammadex or saline (chest wall contribution (%): 26.69 and 25.55 for neostigmine; -2.77 and 15.98 for sugammadex; 18.82 and 10.30 for saline). Conclusion This pilot study in rats demonstrated an increased relative contribution of chest wall expansion after neostigmine compared with sugammadex or saline. This smaller relative contribution of diaphragm movement may be explained by a neostigmine-induced decrease in phrenic nerve activity or by remaining occupied acetylcholine receptors after neostigmine.

Resumo Objetivos As reduções da atividade do diafragma estão associadas ao desenvolvimento de atelectasia no período pós-operatório. A reversão com neostigmina também está associada ao aumento de atelectasia. Avaliamos os efeitos de neostigmina, sugamadex e da reversão espontânea sobre a ventilação pulmonar regional e o fluxo aéreo. Métodos Seis ratos Sprague-Dawley foram paralisados com rocurônio e mecanicamente ventilados até a recuperação da sequência de quatro estímulos atingir relação 0,5. Administramos neostigmina (0,06 mg.kg-1), sugamadex (15 mg.kg-1) ou solução salina (n = 2 por grupo). As tomografias foram feitas durante o ciclo respiratório. Modelos tridimensionais dos lobos pulmonares foram gerados com a tecnologia de imagem funcional respiratória e os volumes lobares foram calculados durante o ciclo respiratório. A superfície diafragmática foi segmentada para as varreduras expiratória final e inspiratória final. A alteração total no volume foi relatada pela alteração do volume pulmonar da varredura expiratória final para a varredura inspiratória final. O movimento da parede torácica foi definido como a variação do volume pulmonar menos a alteração no volume resultante da excursão do diafragma. Resultados Os dois ratos que receberam neostigmina apresentaram uma contribuição relativa menor do movimento do diafragma para a alteração total do volume pulmonar em comparação com os dois ratos que receberam sugamadex ou solução salina (contribuição da parede torácica (%): 26,69 e 25,55 para neostigmina; -2,77 e 15,98 para sugamadex; 18,82 e 10,30 para solução salina). Conclusão Este estudo piloto com ratos demonstrou uma contribuição relativa aumentada de expansão da parede torácica após neostigmina em comparação com sugamadex ou solução salina. Essa contribuição relativa menor de movimento do diafragma pode ser explicada por uma redução induzida por neostigmina na atividade do nervo frênico ou por receptores de acetilcolina permanecerem ocupados após a administração de neostigmina.

[Functional respiratory imaging after neostigmine- or sugammadex-enhanced recovery from neuromuscular blockade in the anesthetised rat: a randomised controlled pilot study]. / Imagem funcional da respiração após aceleração da recuperação do bloqueio neuromuscular com neostigmina ou sugamadex em ratos anestesiados: estudo piloto controlado e randomizado.

OBJECTIVES: Reductions in diaphragm activity are associated with the postoperative development of atelectasis. Neostigmine reversal is also associated with increased atelectasis. We assessed the effects of neostigmine, sugammadex, and spontaneous reversal on regional lung ventilation and airway flow. METHODS: Six Sprague-Dawley rats were paralysed with rocuronium and mechanically ventilated until recovery of the train-of-four ratio to 0.5. We administered neostigmine (0.06mg.kg-1), sugammadex (15mg.kg-1), or saline (n=2 per group). Computed tomography scans were obtained during the breathing cycle. Three-dimensional models of lung lobes were generated using functional respiratory imaging technology, and lobar volumes were calculated during the breathing cycle. The diaphragmatic surface was segmented for the end-expiratory and end-inspiratory scans. The total change in volume was reported by the lung volume change from the end-expiratory scan to the end-inspiratory scan. Chest wall movement was defined as the lung volume change minus the volume change that resulted from diaphragm excursion. RESULTS: The two rats that received neostigmine exhibited a smaller relative contribution of diaphragm movement to the total change in lung volume compared with the two rats that received sugammadex or saline (chest wall contribution (%): 26.69 and 25.55 for neostigmine; -2.77 and 15.98 for sugammadex; 18.82 and 10.30 for saline). CONCLUSION: This pilot study in rats demonstrated an increased relative contribution of chest wall expansion after neostigmine compared with sugammadex or saline. This smaller relative contribution of diaphragm movement may be explained by a neostigmine-induced decrease in phrenic nerve activity or by remaining occupied acetylcholine receptors after neostigmine.

Antihyperalgesic activity of nucleoside transport inhibitors in models of inflammatory pain in guinea pigs.

BACKGROUND AND METHODS: The role of the endogenous purine nucleoside, adenosine, in nociception is well established. Inhibition of the equilibrative nucleoside transporter (ENT1) prevents adenosine uptake into cells, and could therefore enhance the antinociceptive properties of adenosine. The effects of ENT1 inhibition were studied in two animal models of inflammatory pain. Analgesic activity was assessed in a complete Freund's adjuvant (CFA)-induced and carrageenan-induced mechanical and thermal hyperalgesia model in the guinea pig. RESULTS: Draflazine, dipyridamole, dilazep, lidoflazine, soluflazine, and KF24345 showed efficacy in the CFA thermal hyperalgesia model. Draflazine, the most potent compound in this test, was further characterized in the CFA model of mechanical hyperalgesia and the carrageenan inflammation model of thermal and mechanical hyperalgesia, where it completely reversed the hypersensitivity. The antihyperalgesic effects of draflazine (10 mg/kg, administered subcutaneously) were attenuated by the A1 receptor antagonist, cyclopentyltheophylline (5-40 mg/kg, administered intraperitoneally), by the nonselective adenosine antagonist, caffeine (10-40 mg/kg intraperitoneally), and by the A2 antagonist, DMPX (10 mg/kg administered intraperitoneally). CONCLUSION: ENT1 inhibition is an effective way of reversing mechanical and thermal inflammatory hyperalgesia in the guinea pig, and these effects are mediated by enhancement of endogenous adenosine levels. Both A1 and A2 adenosine receptor subtypes are likely to be involved.