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This 2023 Clinical Practice Guideline provides the biomedical definition of death based on permanent cessation of brain function that applies to all persons, as well as recommendations for death determination by circulatory criteria for potential organ donors and death determination by neurologic criteria for all mechanically ventilated patients regardless of organ donation potential. This Guideline is endorsed by the Canadian Critical Care Society, the Canadian Medical Association, the Canadian Association of Critical Care Nurses, Canadian Anesthesiologists’ Society, the Canadian Neurological Sciences Federation (representing the Canadian Neurological Society, Canadian Neurosurgical Society, Canadian Society of Clinical Neurophysiologists, Canadian Association of Child Neurology, Canadian Society of Neuroradiology, and Canadian Stroke Consortium), Canadian Blood Services, the Canadian Donation and Transplantation Research Program, the Canadian Association of Emergency Physicians, the Nurse Practitioners Association of Canada, and the Canadian Cardiovascular Critical Care Society. Supplementary Information The online version contains supplementary material available at 10.1007/s12630-023-02431-4.

5-HT3A receptors select among permeant ions based on size and charge. The membrane-associated (MA) helix lines the portals into the channel’s cytoplasmic vestibule in the 4-Å resolution structure of the homologous acetylcholine receptor. 5-HT3A MA helix residues are important determinants of single-channel conductance. It is unknown whether the portals into the cytoplasmic vestibule also determine the size selectivity of permeant ions. We sought to determine whether the portals form the size selectivity filter. Recently, we showed that channels functioned when the entire 5-HT3A M3–M4 loop was replaced by the heptapeptide M3–M4 loop sequence from GLIC, a bacterial Cys-loop neurotransmitter gated ion channel homologue from Gloebacter violaceus. We used homomeric 5-HT3A receptors with either a wild-type (WT) M3–M4 loop or the chimeric heptapeptide (5-HT3A–glvM3M4) loop, i.e., with or without portals. In Na+-containing buffer, the WT receptor current–voltage relationship was inwardly rectifying. In contrast, the 5-HT3A–glvM3M4 construct had a negative slope conductance region at voltages less than −80 mV. Glutamine substitution for the heptapeptide M3–M4 loop arginine eliminated the negative slope conductance region. We measured the relative permeabilities and conductances of a series of inorganic and organic cations ranging from 0.9 to 4.5 Å in radius (Li+, Na+, ammonium, methylammonium, ethanolammonium, 2-methylethanolammonium, dimethylammonium, diethanolammonium, tetramethylammonium, choline, tris [hydroxymethyl] aminomethane, and N-methyl-d-glucamine). Both constructs had measurable conductances with Li+, ammonium, and methylammonium (size range of 0.9–1.8-Å radius). Many of the organic cations >2.4 Å acted as competitive antagonists complicating measurement of conductance ratios. Analysis of the permeability ratios by excluded volume theory indicates that the minimal pore radius for 5-HT3A and 5-HT3–glvM3M4 receptors was similar, ∼5 Å. We infer that the 5-HT3A size selectivity filter is located in the transmembrane channel and not in the portals into the cytoplasmic vestibule. Thus, the determinants of size selectivity and conductance are located in physically distinct regions of the channel protein.

5-HT3A receptors are pentameric neurotransmitter-gated ion channels in the Cys-loop receptor family. Each subunit contains an extracellular domain, four transmembrane segments (M1, M2, M3, M4) and a 115 residue intracellular loop between M3 and M4. In contrast, the M3M4 loop in prokaryotic homologues is <15 residues. To investigate the limits of M3M4 loop length and composition on channel function we replaced the 5-HT3A M3M4 loop with two to seven alanine residues (5-HT3A-An = 2–7). Mutants were expressed in Xenopus laevis oocytes and characterized using two electrode voltage clamp recording. All mutants were functional. The 5-HT EC50's were at most 5-fold greater than wild-type (WT). The desensitization rate differed significantly among the mutants. Desensitization rates for 5-HT3A-A2, 5-HT3A-A4, 5-HT3A-A6, and 5-HT3A-A7 were similar to WT. In contrast, 5-HT3A-A3 and 5-HT3A-A5 had desensitization rates at least an order of magnitude faster than WT. The one Ala loop construct, 5-HT3A-A1, entered a non-functional state from which it did not recover after the first 5-HT application. These results suggest that the large M3M4 loop of eukaryotic Cys-loop channels is not required for receptor assembly or function. However, loop length and amino acid composition can effect channel expression and desensitization. We infer that the cytoplasmic ends of the M3 and M4 segments may undergo conformational changes during channel gating and desensitization and/or the loop may influence the position and mobility of these segments as they undergo gating-induced conformational changes. Altering structure or conformational mobility of the cytoplasmic ends of M3 and M4 may be the basis by which phosphorylation or protein binding to the cytoplasmic loop alters channel function.

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Objectives/Hypothesis Assess the risks and benefits of adenotonsillectomy (AT) for obstructive sleep apnea (OSA) in children with cerebral palsy (CP). Study Design Systematic review. Methods We conducted a systematic review of Medline, Embase, and Cochrane Central Registry from 1946 to 2021. Broad search concepts included cerebral palsy, pediatric, tonsillectomy/adenoidectomy, and sleep. Additional articles were identified by searching reference lists. Studies on the safety and efficacy of AT for OSA management in children with CP were included. Results Fifteen articles met inclusion criteria. Articles were classified into one or more of four themes: intraoperative risk (n = 1), postoperative risk (n = 3), postoperative care requirements (n = 6), and surgical outcomes (n = 7). No intraoperative anesthetic complications were reported. Postoperatively, respiratory complications including pneumonia were common and necessitated additional airway management. Following AT, children with CP required close postoperative observation, experienced increased lengths of stay, and had increased odds of unplanned intensive care unit (ICU) admission. Benefits following AT were improvement in OSA as measured by a reduction in obstructive apnea‐hypopnea index (OAHI) as well as improved quality of life in some; however, many patients went on to require tracheostomy due to persistent OSA. Conclusions Children with CP who undergo AT have a significant risk of developing a postoperative respiratory complication. Realistic counseling of families around increased perioperative risks in this population is imperative and close postoperative monitoring is critical. Many children will obtain a reduction in OAHI, but additional surgical management is often required, including tracheostomy. Further research is needed to determine the best management strategy for OSA in children with CP. Laryngoscope, 132:687–694, 2022

IMPORTANCE Button batteries (BBs) are commonly found in many household items and present a risk of severe injury to children if ingested. The direct apposition of the trachea and recurrent laryngeal nerves with the esophagus puts children at risk of airway injury secondary to the liquefactive necrotic effects of BB impactions.OBJECTIVE To review airway injuries, including long-term sequelae, after BB ingestion in children.EVIDENCE REVIEW For this systematic review, a comprehensive strategy was designed to search MEDLINE, Embase, Cochrane Database of Systematic Reviews, Web of Science, and CINAHL (Cumulative Index of Nursing and Allied Health Literature) from inception to July 31, 2021, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Additional cases were identified from the National Capital Poison Center BB registry. Individual authors were contacted for additional information. Studies with pediatric patients (<18 years) who developed airway injuries after BB ingestion were included. A total of 195 patients were included in the analysis; 95 were male. The mean (SD) age at BB ingestion was 17.8 (10.2) months. The mean (SD) time from BB ingestion to removal was 5.8 (9.0) days. The 2 most common airway sequelae observed in our series were 155 tracheoesophageal fistulae and 16 unilateral vocal cord paralyses. Twentythree children had bilateral vocal cord paralysis. The mean (SD) duration of ingestion leading to vocal cord paralysis was shorter than that of the general cohort (17.8 [22.5] hours vs 138.7 [216.7] hours, respectively). Children presenting with airway symptoms were likely to have a subsequent tracheoesophageal fistula or vocal cord paralysis.CONCLUSIONS AND RELEVANCE Airway injuries are a severe consequence of BB ingestion, occurring more often in younger children. This systematic review found that tracheoesophageal fistulae and vocal cord paralyses were the 2 most common airway injuries, often requiring tracheostomy. Vocal cord injury occurred after a shorter BB exposure time than other airway injuries. Continued efforts should be directed toward prevention strategies to avoid the devastating sequelae of BB-associated airway injury.

Ischemic long-term potentiation (iLTP) is a form of synaptic plasticity that occurs in acute brain slices following oxygen-glucose deprivation. In vitro, iLTP can occlude physiological LTP (pLTP) through saturation of plasticity mechanisms. We used our murine cardiac arrest and cardiopulmonary resuscitation (CA/CPR) model to produce global brain ischemia and assess whether iLTP is induced in vivo, contributing to the functionally relevant impairment of pLTP. Adult male mice were subjected to CA/CPR, and slice electrophysiology was performed in the hippocampal CA1 region 7 or 30 days later. We observed increased miniature excitatory postsynaptic current amplitudes, suggesting a potentiation of postsynaptic AMPA receptor function after CA/CPR. We also observed increased phosphorylated GluR1 in the postsynaptic density of hippocampi after CA/CPR. These data support the in vivo induction of ischemia-induced plasticity. Application of a low-frequency stimulus (LFS) to CA1 inputs reduced excitatory postsynaptic potentials in slices from mice subjected to CA/CPR, while having no effects in sham controls. These results are consistent with a reversal, or depotentiation, of iLTP. Further, depotentiation with LFS partially restored induction of pLTP with theta burst stimulation. These data provide evidence for iLTP following in vivo ischemia, which occludes pLTP and likely contributes to network disruptions that underlie memory impairments.