Mechanism of Antidepressant Action of (2R,6R)-6-Hydroxynorketamine (HNK) and Its Compounds: Insights from Proteomic Analysis.

The effects of HNK, I5, and I6 on the expression of protein in hippocampus of depressed mice were studied by isobaric tags for relative and absolute quantitation (iTRAQ) to explore the mechanism of their antidepressant action. HNK, I5, and I6 were administered intragastric administration once a day in the morning for 7 days. The drug was subsequently discontinued for 7 days (without any treatment). On the 15th day, mice in each group were given the drug (1.0, 10.0, 30.0 mg/kg) intragastric stimulation and mouse hippocampal tissues were taken to perform iTRAQ to identify differentially expressed proteins, and bioinformatics was used to analyze the functional enrichment of the differentially expressed proteins. Compared with Ctr group, the number of differentially expressed proteins in HNK, I5, and I6 treatment groups was 158, 88, and 105, respectively. The three groups shared 29 differentially expressed proteins. In addition, compared with HNK group, the number of differentially expressed proteins in I5 and I6 groups was 201 and 203, respectively. A total of 47 and 56 differentially expressed proteins were co-expressed in I5 and I6 groups. Bioinformatics analysis showed that these differentially expressed proteins mainly had the functions of binding, biocatalysis, and transport, and mainly participated in cellular process, biological regulation process, biological metabolism process, and stress reaction process. GO and KEGG pathway analysis found that these differentially expressed proteins were involved long-term potentiation, G13 pathway, platelet activation pathway, and MAPK signaling pathway. HNK, I5, and I6 antidepressants are closely related to sudden stress sensitivity, stress resistance, neurotransmitter, and metabolic pathways. This study provides a scientific basis to further elucidate the mechanism and clinical application of HNK, I5, and I6 antidepressants.

General anesthesia but not conscious sedation improves functional outcome in patients receiving endovascular thrombectomy for acute ischemic stroke: A meta-analysis of randomized clinical trials and trial sequence analysis.

Background: This study aimed at comparing the difference in prognostic outcomes between patients receiving general anesthesia (GA) and conscious sedation (CS) for endovascular thrombectomy after acute ischemic stroke. Methods: Databases from Medline, Embase, Google scholar, and Cochrane library were searched for randomized controlled studies (RCTs) comparing patients undergoing GA and CS for endovascular thrombectomy following anterior circulation ischemic stroke. The primary outcome was frequency of 90-day good functional outcome [defined as modified Rankin Scale score of ≤ 2], while secondary outcomes included successful recanalization rate (SRR) [i.e., modified thrombolysis in cerebral infarction = 2b or 3], mortality risk, symptomatic intracranial hemorrhage (ICH), procedure-related complications, hypotension, pneumonia, neurological outcome at post-procedure 24-48 h, and puncture-to-recanalization time. Results: Six RCTs including 883 patients published between 2016 and 2022 were included. Merged results revealed a higher SRR [risk ratio (RR) = 1.11, 95% CI: 1.03-1.2, p = 0.007; I 2 = 29%] and favorable neurological outcomes at 3-months (RR = 1.2, 95% CI: 1.01-1.41, p = 0.04; I 2 = 8%) in the GA group compared to CS group, without difference in the risk of mortality (RR = 0.88), symptomatic ICH (RR = 0.91), procedure-related complications (RR = 1.05), and pneumonia (RR = 1.9) as well as post-procedure neurological outcome (MD = -0.21) and successful recanalization time (MD = 3.33 min). However, GA was associated with a higher risk of hypotension compared with that of CS. Conclusion: Patients with acute anterior circulation ischemic stroke receiving GA were associated with a higher successful recanalization rate as well as a better 3-month neurological outcome compared to the use of CS. Further investigations are warranted to verify our findings. Systematic review registration: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022342483, identifier: CRD42022342483.

Association of peripheral nerve blocks with patient-reported quality of recovery in female patients receiving breast cancer surgery: a systematic review and meta-analysis of randomized controlled studies.

PURPOSE: This systematic review and meta-analysis investigated the impact of peripheral nerve blocks (PNBs) on patient-reported quality of recovery (QoR) following breast cancer surgery. SOURCE: Medline, EMBASE, Cochrane Library, and Google scholar databases were searched for randomized controlled trials (RCTs) comparing the QoR with or without PNBs in patients receiving breast cancer surgery from inception to September 2021. Using a random effects model, the primary outcome was total scores of postoperative QoR scales (i.e., QoR-15 and QoR-40). PRINCIPAL FINDINGS: Eight RCTs (QoR-15, n = 4; QoR-40, n = 4) involving 653 patients published from 2018 to 2021 were included. For the QoR-40 scale, pooled results revealed a significantly higher total score (mean difference [MD], 12.8 [8.2%]; 95% confidence interval [CI], 10.6 to 14.9; I2 = 59%; five RCTs; n = 251) and scores on all subscales, except psychological support, in the PNB group than in controls at 24 hr after surgery. For the QoR-15 scale, pooled results also showed favorable QoR (MD, 7.7 [5.2%]; 95% CI, 4.9 to 10.5; I2 = 75%; four RCTs; n = 402) in the PNB group at 24 hr after surgery. Sensitivity analysis showed no effect on the QoR-40 score and the difference in total QoR-15 score was no longer significant when a single trial was omitted. The use of PNBs was associated with a significantly lower opioid consumption and risk of postoperative nausea and vomiting without significant differences in the pain score between the two groups. CONCLUSION: Our results verified the efficacy of PNBs for enhancing postoperative QoR using two validated patient-reported tools in female patients receiving breast cancer surgery under general anesthesia. STUDY REGISTRATION: PROSPERO (CRD42021272575); first submitted 9 August 2021.

RéSUMé: OBJECTIF: Cette revue systématique et méta-analyse a étudié l'impact des blocs nerveux périphériques (BNP) sur la qualité de récupération (QoR) rapportée par les patientes après une chirurgie du cancer du sein. SOURCES: Les bases de données Medline, EMBASE, Cochrane Library et Google Scholar ont été analysées pour en tirer les études randomisées contrôlées (ERC) comparant la QoR avec ou sans BNP chez les patientes bénéficiant d'une chirurgie de cancer du sein, de leur création jusqu'en septembre 2021. À l'aide d'un modèle à effets aléatoires, le critère d'évaluation principal était les scores totaux sur les échelles de QoR postopératoire (c.-à-d. QoR-15 et QoR-40). CONSTATATIONS PRINCIPALES: Huit ERC (QoR-15, n = 4; QoR-40, n = 4) impliquant 653 patientes publiées de 2018 à 2021 ont été incluses. Pour l'échelle QoR-40, les résultats regroupés ont révélé un score total (différence moyenne [DM], 12,8 [8,2 %]; intervalle de confiance [IC] à 95 %, 10,6 à 14,9; I2 = 59 %; cinq ECR; n = 251) et des scores sur toutes les sous-échelles significativement plus élevés, à l'exception du soutien psychologique, dans le groupe BNP que dans le groupe témoin 24 heures après la chirurgie. Pour l'échelle QoR-15, les résultats groupés ont également montré un QoR favorable (DM, 7,7 [5,2 %]; IC 95 %, 4,9 à 10,5; I2 = 75 %; quatre ECR; n = 402) dans le groupe BNP 24 heures après la chirurgie. L'analyse de sensibilité n'a montré aucun effet sur le score de QoR-40 et la différence dans le score total de QoR-15 n'était plus significative lorsqu'une seule étude était omise. L'utilisation de BNP a été associée à une consommation d'opioïdes significativement plus faible et à un risque de nausées et vomissements postopératoires sans différences significatives dans le score de douleur entre les deux groupes. CONCLUSION: Nos résultats ont confirmé l'efficacité des BNP pour améliorer la QoR postopératoire à l'aide de deux outils validés rapportés par les patientes recevant une chirurgie du cancer du sein sous anesthésie générale. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42021272575); soumis pour la première fois le 9 août 2021.

Viable Allogeneic Mitochondria Transplantation Improves Gas Exchange and Alveolar-Capillary Permeability in Rats with Endotoxin-Induced Acute Lung Injuries.

Background: Acute lung injuries (ALI) cause disruption of the alveolar-capillary barrier and is the leading cause of death in critically ill patients. This study tested the hypothesis that the administration of freshly isolated viable allogeneic mitochondria can prevent alveolar-capillary barrier injuries at the endothelial level, as mitochondrial dysfunction of the pulmonary endothelium is a critical aspect of ALI progression. Methods: ALI was induced by intratracheal lipopolysaccharide instillation (LPS, 1mg/kg) in anesthetized rats. Mitochondria (100 µg) were isolated from the freshly harvested soleus muscles of naïve rats and stained with a green fluorescence MitoTracker™ dyne. A mitochondria or placebo solution was randomly administered into the jugular veins of the rats at 2 h and 4 h after ALI induction. An arterial blood gas analysis was done 20 h later. The animals were then sacrificed and lung tissues were harvested for analysis. Results: An IVIS Spectrum imaging system was used to obtain ex vivo heart-lung block images and track the enhancement of MitoTracker™ fluorescence in the lungs. Mitochondria transplantation significantly improved arterial oxygen contents (PaO2 and SaO2) and reduced CO2 tension in rats with ALI. Animals with mitochondrial transplants had significantly higher ATP concentrations in their lung tissues. Allogeneic mitochondria transplantation preserved alveolar-capillary barrier function, as shown by a reduction in protein levels in the bronchoalveolar lavage fluid and decreased extravasated Evans blue dyne and hemoglobin content in lung tissues. In addition, relaxation responses to acetylcholine and eNOS expression were potentiated in injured pulmonary arteries and inflammatory cells infiltration into lung tissue was reduced following mitochondrial transplantation. Conclusions: Transplantation of viable mitochondria protects the integrity of endothelial lining of the alveolar-capillary barrier, thereby improving gas exchange during the acute stages of endotoxin-induced ALI. However, the long-term effects of mitochondrial transplantation on pulmonary function recovery after ALI requires further investigation.

Conscious sedation/monitored anesthesia care versus general anesthesia in patients undergoing transcatheter aortic valve replacement: A meta-analysis.

Background: To compare the merits and safety between conscious sedation/monitored anesthesia (CS/MAC) and general anesthesia (GA) for patients receiving transcatheter aortic valve replacement (TAVR). Measurements: Databases including EMBASE, MEDLINE, and the Cochrane Library databases were searched from inception to October 2022 to identify studies investigating the impact of CS/MAC on peri-procedural and prognostic outcomes compared to those with GA. The primary outcome was the association of CS/MAC with the risk of 30-day mortality, while secondary outcomes included the risks of adverse peri-procedural (e.g., vasopressor/inotropic support) and post-procedural (e.g., stroke) outcomes. Subgroup analysis was performed based on study design [i.e., cohort vs. matched cohort/randomized controlled trials (RCTs)]. Main results: Twenty-four studies (observational studies, n = 22; RCTs, n = 2) involving 141,965 patients were analyzed. Pooled results revealed lower risks of 30-day mortality [odd ratios (OR) = 0.66, p < 0.00001, 139,731 patients, certainty of evidence (COE): low], one-year mortality (OR = 0.72, p = 0.001, 4,827 patients, COE: very low), major bleeding (OR = 0.61, p = 0.01, 6,888 patients, COE: very low), acute kidney injury (OR = 0.71, p = 0.01, 7,155 patients, COE: very low), vasopressor/inotropic support (OR = 0.25, p < 0.00001, 133,438 patients, COE: very low), shorter procedure time (MD = -12.27 minutes, p = 0.0006, 17,694 patients, COE: very low), intensive care unit stay (mean difference(MD) = -7.53 h p = 0.04, 7,589 patients, COE: very low), and hospital stay [MD = -0.84 days, p < 0.00001, 19,019 patients, COE: very low) in patients receiving CS/MAC compared to those undergoing GA without significant differences in procedure success rate, risks of cardiac-vascular complications (e.g., myocardial infarction) and stroke. The pooled conversion rate was 3.1%. Results from matched cohort/RCTs suggested an association of CS/MAC use with a shorter procedural time and hospital stay, and a lower risk of vasopressor/inotropic support. Conclusion: Compared with GA, our results demonstrated that the use of CS/MAC may be feasible and safe in patients receiving TAVR. However, more evidence is needed to support our findings because of our inclusion of mostly retrospective studies. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022367417.

The preconditioning pulmonary protective effect of volatile isoflurane in acute lung injury is mediated by activation of endogenous iNOS.

PURPOSE: There is still a lack of evidence to support the use of specific anesthetic agents during major operations that could affect the development of postoperative acute lung injury (ALI). This study determined the protective effect of inhaled isoflurane in a rat model of endotoxin-induced ALI. METHODS: Rats were exposed to volatile isoflurane (1.5 % in oxygen) or pure oxygen via a facemask for 2 h. After a 3-h recovery period, rats were reanesthetized and ALI was induced by intratracheal instillation of lipopolysaccharide (LPS, 1 mg/kg in 0.5 ml saline). In some animals, a specific inducible nitric oxide synthase (iNOS) inhibitor, 1400W, (10 mg/kg, i.p.) was administered before exposure to isoflurane. Animals were sacrificed 12 h later for analysis. Pulmonary artery vasomotor function and alveolocapillary permeability were assessed. Expression of iNOS and CD11b, and activity of myeloperoxidase in the lung were analyzed. RESULTS: The maximal relaxation response to acetylcholine was significantly potentiated in rats pretreated with isoflurane. Lung wet-to-dry ratio was reduced in the lung of isoflurane-treated animals. Expression of iNOS and CD11b were attenuated in the lung tissue obtained from rats receiving isoflurane. Furthermore, enzymatic activity of myeloperoxidase was also reduced in the lung preexposed to isoflurane. However, these pulmonary protective effects of isoflurane were significantly abolished by pretreatment with 1400W. CONCLUSION: Pretreatment with volatile isoflurane attenuated inflammatory process in the lung tissue of rats with LPS-induced ALI, and this preconditioning pulmonary protective effect was mainly mediated by activation of endogenous iNOS in the lung.

Suxamethonium-induced hyperkalaemia in a patient with a normal potassium level before rapid-sequence intubation.

The use of suxamethonium (succinylcholine) for rapid-sequence intubation may be limited by hyperkalaemia. Modest pre-induction hyperkalaemia is usually disregarded. We present a patient who underwent emergency surgery for a perforated peptic ulcer after being bedbound for 26 days because of a head injury. Serum potassium level was 4.0 mmol/L. The patient was intubated after injection of sedative and suxamethonium and, about 3 minutes later, developed ventricular arrhythmia. Blood tests during resuscitation showed a serum potassium level of 8.8 mmol/L. Immobilisation, denervation and intra-abdominal infection were risk factors for hyperkalaemia in this patient. This report reinforces the need to identify risk factors for hyperkalaemia before administration of suxamethonium, even when serum potassium levels are normal.