Ferritinophagy-Mediated Hippocampus Ferroptosis is Involved in Cognitive Impairment in Immature Rats Induced by Hypoxia Combined with Propofol.

Propofol is a clinically common intravenous general anesthetic and is widely used for anesthesia induction, maintenance and intensive care unit (ICU) sedation in children. Hypoxemia is a common perioperative complication. In clinical work, we found that children with hypoxemia who received propofol anesthesia experienced significant postoperative cognitive changes. To explore the causes of this phenomenon, we conducted the study. In this study, our in vivo experiments found that immature rats exposed to hypoxia combined with propofol (HCWP) could develop cognitive impairment. We performed the RNA-seq analysis of its hippocampal tissues and found that autophagy and ferroptosis may play a role in our model. Next, we verified the participation of the two modes of death by detecting the expression of autophagy-related indexes Sequestosome 1 (SQSTM1) and Beclin1, and ferroptosis-related indicators Fe2+, reactive oxygen species (ROS) and glutathione peroxidase 4 (GPX4). Meanwhile, we found that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, could improve cognitive impairment in immature rats caused by HCWP. In addition, we found that nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, which acted as a key junction between autophagy and ferroptosis, was also involved. Finally, our in vitro experiments concluded that autophagy activation was an upstream factor in HCWP-induced hippocampus ferroptosis through the intervention of autophagy inhibitor 3-methyladenine (3-MA). Our study was expected to provide an attractive therapeutic target for cognitive impairment that occurred after HCWP exposures.

The median effective concentration of ropivacaine for ultrasound-guided caudal block in children: a dose-finding study.

PURPOSE: To determine the 50% minimum effective concentration (MEC50) and the 95% effective concentration (MEC95) of ropivacaine for ultrasound-guided caudal block during hypospadias repair surgery of pediatric patients. METHODS: Children were enrolled with the American Society of Anesthesiologists (ASA) physical status I-II undergoing elective hypospadias repair surgery. Children were grouped into two age groups: toddlerhood (1-3 years old) and preschool (3-6 years old). We measured The MEC50 using Dixon's up-and-down method. The first children received the caudal block with 1.0 mL/kg of 0.15% ropivacaine. We determined each subsequent patient's concentration based on the previous patient's response and adjusted the concentration in intervals of 0.015%. Meanwhile, the probit regression analysis obtains 95% effective concentration (MEC95). In addition, we recorded the general condition, adverse events, and postoperative pain of each child. RESULTS: 46 children undergoing elective hypospadias repair surgery were included in this study, 22 in the toddlerhood group and 24 in the preschool group. Of the total number of patients, the caudal block was successful in 25 (54%) and failed in 21 (46%). The MEC50 of 1 ml/kg ropivacaine was 0.102% (95% CI 0.099%, 0.138%) in the toddlerhood group and 0.129% (95% CI 0.124%, 0.138%) in the preschool group. The MEC95 of 1 ml/kg ropivacaine was 0.148% (95% CI 0.131%, 0.149%) in the toddlerhood group and 0.162% (95% CI 0.134%, 0.164%) in the preschool group. Our results showed that ropivacaine concentration was statistically different between preschool children and toddlers (P < 0.001). None of the adverse events occurred. CONCLUSIONS: This study showed that children in the preschool group required higher concentrations of ropivacaine than children in the toddler group during ultrasound-guided sacral block combined with non-intubated general anesthesia. At the same time, this method of anesthesia is safe and effective for children undergoing surgery for hypospadias.

Median effective volume of 0.2% ropivacaine for ultrasound-guided supraclavicular brachial plexus block in children aged 1-6 years: a prospective dose-finding study.

Objective: To determine the median effective volume (EV50) of 0.2% ropivacaine for ultrasound-guided supraclavicular brachial plexus block (SC-BPB) in children aged 1-6 years. Methods: Children aged from 1 to 6 years with an American Society of Anaesthesiologists (ASA) physical status I-II who were scheduled for unilateral upper extremity surgery at the Children's Hospital of Chongqing Medical University were recruited. All patients underwent surgery under general anaesthesia combined with brachial plexus block. SC-BPB was guided by ultrasound after anaesthesia induction, and 0.2% ropivacaine was given after localization. In the study, we used Dixon's up-and-down approach with an initial dose of 0.50 ml/kg. Considering the effect of the previous block, a successful or failed block could produce a 0.05 ml/kg decrement or increment in volume, correspondingly. The experiment was stopped when there were 7 inflection points. Using isotonic regression and bootstrapping algorithms, the EV50, the 95% effective volume (EV95) and the 95% confidence interval (CI) were calculated. The patients' general information, postoperative pain scores, and adverse events were also recorded. Results: Twenty-seven patients were involved in this study. The EV50 of 0.2% ropivacaine was 0.150 ml/kg (95% CI, 0.131-0.169 ml/kg) and the EV95 (secondary metric) was 0.195 ml/kg (95% CI, 0.188-0.197 ml/kg). No adverse events occurred during the research study. Conclusions: For ultrasound-guided SC-BPB in children aged 1-6 years undergoing unilateral upper extremity surgery, the EV50 of 0.2% ropivacaine was 0.150 ml/kg (95% CI, 0.131-0.169 ml/kg).

Scale ultrasound-guided radial artery cannulation in infant: A randomized controlled trial.

BACKGROUND: Cannulation of the radial artery can be extremely challenging in infants. Scale ultrasound can provide accurate arterial location and guidance for operators. We hypothesized that scale ultrasound helps increase the initial success rate of radial artery cannulation in this population. METHOD: Seventy-six infants aged 0-3 months who needed arterial puncture after general anesthesia were randomly divided into two groups (1:1 ratio): the scale ultrasound group and the traditional ultrasound group. The primary endpoints were the success rate of the first attempt and the total success rate of arterial cannulation. The secondary endpoints were the time during arterial puncture and the incidence of vascular complications. RESULTS: The success rate of the first attempt and the total success rate of arterial cannulation were 92.1% (35/38) versus 50% (19/38) and 100% (38/38) versus 86.8% (33/38) in the scale ultrasound and traditional ultrasound group (p < 0.005), respectively. The median time to ultrasound location, needle entry into the radial artery, and successful cannulation in the scale ultrasound group were significantly shorter than those in the traditional ultrasound group: 10 (8.0, 17.2) s, 15 (11.7, 20) s, and 65 (53.8, 78.5) s vs 30 (26.5, 43.5) s, 35 (23, 51) s, and 224.5 (123.5, 356) s (p < 0.001), respectively. The incidence of hematoma was higher in the traditional group (p < 0.005). CONCLUSIONS: Scale ultrasound-guided radial arterial cannulation can significantly improved initial success rate and overall success rate, shorten puncture time in infant, compared with that achieved with the use of traditional ultrasound guidance.

Median effective dose of 0.2% ropivacaine for ultrasound-guided median nerve block in young children.

OBJECTIVE: To determine the median effective dose (ED50) and the 95% effective dose (ED95) of 0.2% ropivacaine for ultrasound-guided lower forearm median nerve block in paediatric patients. METHODS: Eligible children were American Society of Anesthesiologists (ASA) status I-II scheduled to have elective open surgery for trigger thumb repair. Patients were stratified into two age groups: 1- to 3-year-olds and 3- to 6-year-olds. The ED50 was determined by Dixon's up-and-down method. The first patient received an ultrasound-guided median nerve block by injection of 2 mL of 0.2% ropivacaine. Each subsequent patient's dose was determined by the response of the previous patient, the doses being adjusted in intervals of 0.2 mL. In addition, the 95% effective dose (ED95) was obtained using a probit regression approach. The patients' general condition, postoperative pain scores, and adverse events were recorded. RESULTS: A total of 52 children who were scheduled to undergo open surgery for trigger thumb were included in this study: 28 in the 1- to 3-year-olds group and 24 in the 3- to 6-year-olds group. The ED50 (95% confidence interval) values were 0.9 (0.44-1.36) mL in 1- to 3-year-olds and 1.4 (1.14-1.66) mL in 3- to 6-year-olds. The ED95 (95% confidence interval) values were 1.5 (0.98-1.58) mL in 1- to 3-year-olds and 1.7 (1.54-1.78) mL in 3- to 6-year-olds. No adverse events occurred. CONCLUSIONS: A single dose of ropivacaine was an effective agent for young children requiring ultrasound-guided lower forearm median nerve block in open surgery for trigger thumb. The ED50 (95% confidence interval) values were 0.9 (0.44-1.36) mL in 1- to 3-year-olds and 1.4 (1.14-1.66) mL in 3- to 6-year-olds. The ED95 (95% confidence interval) values were 1.5 (0.98-1.58) mL in 1- to 3-year-olds and 1.7 (1.54-1.78) mL in 3- to 6-year-olds.

The 90% minimum effective volume and concentration of ropivacaine for ultrasound-guided median nerve block in children aged 1-3 years: A biased-coin design up-and-down sequential allocation trial.

BACKGROUND: Median nerve block can provide excellent analgesia during open surgery for trigger thumb in children. However, no data on the 90% minimum effective volume (MEV90) and concentration (MEC90) of ropivacaine for ultrasound-guided median nerve block in pediatric patients have been reported. DESIGN: A prospective two-phase study with an up-and-down sequential allocation trial using a biased coin design. PATIENTS: Children aged 1-3 years are experiencing open surgery for trigger thumb. INTERVENTION: This study has 2 parts, one for MEV90 and subsequently studied MEC90 from the former part of the study. The MEV90 and MEC90 of ropivacaine for each subsequent patient were determined by the response of the previous patient, with the biased coin design up-and-down sequential allocation trial. The interval of -volume or concentration was -0.1 ml or 0.01%, respectively. MEASUREMENTS: The MEV90 and MEC90 of ropivacaine for ultrasound-guided median nerve block in pediatric patients, were then used to estimate the 99% minimum effective volume (MEV99) and concentration (MEC99). The patient's general condition, postoperative pain, and adverse events. MAIN RESULTS: A total of one hundred and eighteen children were enrolled for the study, and 56 and 62 patients were enrolled for the MEV90 and MEC90 studies, respectively. The MEV90 of 0.2% ropivacaine was 1.44 ml (95% CI 1.043 ml, 1.466 ml), and the MEC90 of 1.5 ml ropivacaine was 0.195% (95% CI 0.159%, 0.197%). There were no adverse events that occurred. CONCLUSION: For ultrasound-guided median nerve block in children aged 1-3 years old with trigger finger undergoing open surgery, the MEV90 of 0.2% ropivacaine is 1.44 ml (95% CI 1.043 ml, 1.466 ml), and the MEC90 of 1.5 ml of ropivacaine is 0.195% (95% CI 0.159%, 0.197%).

The 90% effective dose of intranasal dexmedetomidine for procedural sedation in children with congenital heart disease before and after surgery: A biased-coin design up-and-down sequential allocation trial.

BACKGROUND: Intranasal dexmedetomidine can provide adequate sedation during short procedures. However, there are few reports investigating the effective dose of intranasal dexmedetomidine for sedation in children with congenital heart disease (CHD) before and after surgery. METHODS: Children aged 13-36 months with acyanotic CHD requiring trans-thoracic echocardiography before cardiac surgery were recruited for this study. One month after the cardiac surgery, the same children were studied again. The 90% effective dose was established using a biased-coin design up-and-down sequential method. Onset time, examination time, wake-up time and adverse effects were measured. Safety was evaluated in terms of changes in vital signs. RESULTS: A total of fifty-eight subjects were recruited for this study. The 90% effective dose of intranasal dexmedetomidine for sedation was 2.13 µg/kg (95% CI, 1.73-2.34 µg/kg) in children with CHD before cardiac surgery and 3.51 µg/kg (95% CI, 2.99-3.63 µg/kg) after cardiac surgery (P < .01). There were no differences between the groups in terms of demographic variables, onset time, examination time, wake-up time or adverse effects. CONCLUSIONS: The 90% effective dose of intranasal dexmedetomidine for sedation in children with CHD was 2.13 µg/kg before cardiac surgery and 3.51 µg/kg after cardiac surgery.

[Comparison of ED50 of intranasal dexmedetomidine sedation in children with acyanotic congenital heart disease before and after cardiac surgery].

OBJECTIVE: To compare the median effective dose (ED50) of intranasal dexmedetomidine for procedural sedation in uncooperative pediatric patients with acyanotic congenital heart disease before and after cardiac surgery. METHODS: We prospectively recruited 47 children (22 in preoperative group and 25 in postoperative group) who needed sedation for transthoracic echocardiography (TTE). A modified up-and-down sequential study design was employed to determine dexmedetomidine dose for each patient with a starting dose of 2 µg/kg in both groups; dexmedetomidine doses for subsequent subjects were determined according to the responses from the previous subject using the up-and-down method at a 0.25 µg/kg interval. The ED95 was determined using probit regression. The onset time, examination time, wake-up time and adverse effects were measured, and the safety was evaluated in terms of changes in vital signs every 5 min. RESULTS: The ED50 value of intranasal dexmedetomidine for sedation was 1.84 µg/kg (95% CI: 1.68-2.00 µg/kg) in children with congenital heart disease before cardiac surgery, and 3.38 µg/kg (95% CI: 3.21-3.54 µg/kg) after the surgery. No significant difference was found between the two groups in the demographic variables, onset time, examination time, wake-up time, or adverse effects. CONCLUSIONS: In children with acyanotic congenital heart disease, the ED50 of intranasal dexmedetomidine for TTE sedation increases to 3.38 µg/ kg after cardiac surgery from the preoperative value of 1.84 µg/kg.

TRPV1 Contributes to the Neuroprotective Effect of Dexmedetomidine in Pilocarpine-Induced Status Epilepticus Juvenile Rats.

To investigate the antiepileptic and neuroprotective effects of dexmedetomidine (Dex) in pilocarpine- (Pilo-) induced status epilepticus (SE) juvenile rats, rats were randomly assigned to the following six groups (n = 20): normal, normal+Dex, SE, SE+Cap, SE+Dex, and SE+Dex+Cap. The rats were treated with either diazepam (i.p., an antiepileptic drug) or Dex after the onset of SE. The Morris water maze was used to assess rat cognitive behavior. Flow cytometry was used to detect the concentrations of Ca2+, mitochondrial membrane potential, and reactive oxygen species. Transmission electron microscopy was performed to evaluate specimens of brain tissue. The levels of caspase 3 and TRPV1 were examined by western blot and immunohistochemistry (IHC). Treatment with Dex significantly decreased the escape latency of the SE rats (P < 0.05). Capsaicin, a TRPV1 agonist, delivery aggravated the performance of SE rats. Pathological changes in SE rat were attenuated by Dex and deteriorated by capsaicin. Swollen mitochondria and abnormal endoplasmic reticulum were found in SE rats and were then aggravated by capsaicin and reversed by Dex. Moreover, our data showed that Dex significantly restrained calcium overload, ROS production, and mitochondrial membrane potential loss, all of which were induced by Pilo and capsaicin (P < 0.05). Dex decreased the apoptotic rate in the Model SE group (P < 0.05) and TRPV1 and caspase 3 expression in the Dex treatment group (P < 0.05). Interestingly, all these effects of Dex were partially counteracted by the TRPV1 agonist, capsaicin (P < 0.05). Our study showed that Dex exerted a neuroprotective effect in Pilo-induced SE rats by inhibiting TRPV1 expression and provided information for therapy to SE patients.

A Comparison of Intranasal Dexmedetomidine and Dexmedetomidine-Ketamine Combination Sedation for Transthoracic Echocardiography in Pediatric Patients With Congenital Heart Disease: A Randomized Controlled Trial.

OBJECTIVES: To compare the effects of intranasal dexmedetomidine (DEX) and DEX-ketamine (KET) on hemodynamics and sedation quality in children with congenital heart disease. DESIGN: A randomized controlled, double-blind, prospective trial. SETTING: A tertiary care teaching hospital. PARTICIPANTS: The study comprised 60 children undergoing transthoracic echocardiography (TTE). INTERVENTIONS: Patients were randomly allocated into the DEX group (group D [n = 30]) or the DEX-KET group (group D-K [n = 30]). Group D received 2 µg/kg of intranasal DEX; group D-K received 2 µg/kg of DEX and 1 mg/kg of KET intranasally. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in hemodynamics, measured using mean arterial pressure (MAP) and heart rate (HR). Secondary outcomes were onset time, wake-up time, and discharge time. No differences were found in mean arterial pressure or heart rate. The onset time was significantly shorter in group D-K than in group D (9.6 ± 2.9 minutes v 14.3 ± 3.4 minutes; p = 0.031). The wake-up time was longer in group D-K than in group D (52 ± 14.7 minutes v 39.6 ± 12.1 minutes; p = 0.017). The discharge time was longer in group D-K than in group D (61.33 ± 11.59 minutes v 48.17 ± 8.86 minutes; p < 0.001). No differences in hemodynamics were found between the 2 groups. Intranasal DEX was found to be as effective for TTE sedation as intranasal DEX-KET, with longer onset time and shorter recovery and discharge times. CONCLUSION: No differences in hemodynamics were found between the 2 groups. Intranasal DEX was found to be as effective for TTE sedation as is intranasal DEX-KET, with longer onset time and shorter recovery and discharge times.

The effects of repeated propofol anesthesia on spatial memory and long-term potentiation in infant rats under hypoxic conditions.

Propofol is widely used as an intravenous drug for induction and maintenance in general anesthesia. Hypoxemia is a common complication during perianesthesia. We want to know the effect of propofol on spatial memory and LTP (Long-term potentiation) under hypoxic conditions. In this study, 84 seven-day-old Sprague-Dawley rats were randomly assigned into six groups (n = 14)-four control groups: lipid emulsion solvent + 50% oxygen (CO), lipid emulsion solvent + room air (CA), lipid emulsion solvent + 18% oxygen (CH), and propofol + 50% oxygen (propofol-oxygen, PO); and two experiment groups: propofol + room air (propofol-air, PA), and propofol + 18% oxygen (propofol-hypoxia, PH). After receiving propofol (50 mg/kg) or the same volume of intralipid intraperitoneal (5.0 ml/kg), injected once per day for seven consecutive days, the rats were exposed to 18% oxygen, 50% oxygen and air, until recovery of the righting reflex. We found that the apoptotic index and activated caspase-3 increased in the PH group (P < 0.05) compared with the PA group, fEPSP (field excitatory postsynaptic) potential and success induction rate of LTP reduced in all propofol groups (P < 0.05). Compared with the PO group, the fEPSP and success induction rate of LTP reduced significantly in the PA and PH groups (P < 0.05). Moreover, compared with CH group, the average time of escape latency was longer, and the number of platform location crossings was significantly reduced in the PH group (P < 0.05). Thus, we believe that adequate oxygen is very important during propofol anesthesia.

Intranasal dexmedetomidine is an effective sedative agent for electroencephalography in children.

BACKGROUND: Intranasal dexmedetomidine (DEX), as a novel sedation method, has been used in many clinical examinations of infants and children. However, the safety and efficacy of this method for electroencephalography (EEG) in children is limited. In this study, we performed a large-scale clinical case analysis of patients who received this sedation method. The purpose of this study was to evaluate the safety and efficacy of intranasal DEX for sedation in children during EEG. METHODS: This was a retrospective study. The inclusion criteria were children who underwent EEG from October 2016 to October 2018 at the Children's Hospital affiliated with Chongqing Medical University. All the children received 2.5 µg·kg- 1 of intranasal DEX for sedation during the procedure. We used the Modified Observer Assessment of Alertness/Sedation Scale (MOAA/S) and the Modified Aldrete score (MAS) to evaluate the effects of the treatment on sedation and resuscitation. The sex, age, weight, American Society of Anesthesiologists physical status (ASAPS), vital signs, sedation onset and recovery times, sedation success rate, and adverse patient events were recorded. RESULTS: A total of 3475 cases were collected and analysed in this study. The success rate of the initial dose was 87.0% (3024/3475 cases), and the success rate of intranasal sedation rescue was 60.8% (274/451 cases). The median sedation onset time was 19 mins (IQR: 17-22 min), and the sedation recovery time was 41 mins (IQR: 36-47 min). The total incidence of adverse events was 0.95% (33/3475 cases), and no serious adverse events occurred. CONCLUSIONS: Intranasal DEX (2.5 µg·kg- 1) can be safely and effectively used for EEG sedation in children.

The 95% effective dose of intranasal dexmedetomidine sedation for pulmonary function testing in children aged 1-3 years: A biased coin design up-and-down sequential method.

STUDY OBJECTIVE: Intranasal dexmedetomidine (DEX) can provide adequate sedation during short examinations in children. However, we found no data regarding the 95% effective dose (ED95) of intranasal DEX for children's pulmonary function testing (PFT). DESIGN: Prospective study and a biased coin design up-and-down sequential method. SETTING: Sedation center of Children's Hospital of Chongqing Medical University. PATIENTS: Children aged 1-3 years undergoing pulmonary function testing. INTERVENTION: The dose of DEX for each subsequent patient was determined by the response of the previous patient with the biased coin design up-and-down sequential method with an interval of 0.25 µg∙kg-1. MEASUREMENTS: Children aged 1-3 years who received pulmonary function testing were involved in this dose-finding trial. Intranasal DEX started at a dose of 2 µg∙kg-1 on the first patient. The dose of DEX for each subsequent patient was determined by the response of the previous patient with the biased coin design up-and-down sequential method with an interval of 0.25 µg∙kg-1. The sedation was assessed by the Modified Observer Assessment of Alertness and Sedation (MOAA/S) scale, and recovery was assessed by the modified Aldrete recovery score. The ED95 was calculated using isotonic regression. Other variables, including the sedation onset time, examination time, wake-up time, blood pressure (BP), heart rate (HR), respiratory rate (RR), and oxyhaemoglobin desaturation (SpO2), were recorded. Adverse events such as hypotension, bradycardia, respiration depression, oxyhaemoglobin desaturation, regurgitation and vomiting were recorded. MAIN RESULTS: A total of 68 children were enrolled for the study; 62 children had successful sedation, and 6 had failed sedation. The ED95 of intranasal DEX was estimated to be 2.64 µg∙kg-1 [95% confidence interval (CI), 2.49-2.87 µg∙kg-1]. The sedation onset time for all patients was 15.0 (12.3-19.0) min. The sedation onset time of successful sedation patients was 15.0 (12.0-19.0) min, the sedation onset time of failed sedation patients was 16.0 (15.0-27.8) min, the examination time was 8 (7-10) min, and the wake-up time was 40 (35-43) min. There were no adverse events during the whole procedure. CONCLUSION: The ED95 of intranasal DEX sedation in children aged 1-3 years undergoing PFT was 2.64 µg∙kg-1.

Fifty Percent Effective Dose of Intranasal Dexmedetomidine Sedation for Transthoracic Echocardiography in Children With Cyanotic and Acyanotic Congenital Heart Disease.

OBJECTIVES: To determine the 50% and 95% effective dose of intranasal dexmedetomidine sedation for transthoracic echocardiography in children with cyanotic and acyanotic congenital heart disease. DESIGN: A prospective, nonrandomized study. SETTING: A tertiary care teaching hospital. PARTICIPANTS: Patients younger than 18 months with known or suspected congenital heart disease scheduled for transthoracic echocardiography with sedation. INTERVENTIONS: Patients were divided into a cyanotic group (blood oxygen saturation <85%) or an acyanotic group (blood oxygen saturation ≥85%). This study used Dixon's up-and-down method sequential allocation design. In both groups, the initial dose of intranasal dexmedetomidine was 2 µg/kg and the gradient of increase or decrease was 0.25 µg/kg. MEASUREMENTS AND MAIN RESULTS: The 50% effective dose (95% confidence interval) of intranasal dexmedetomidine sedation for transthoracic echocardiography was 3.2 (2.78-3.55) µg/kg and 1.9 (1.69-2.06) µg/kg in the cyanotic and acyanotic groups, respectively. None of the patients experienced significant adverse events. CONCLUSION: The 50% (95% confidence intervals) effective doses of intranasal dexmedetomidine sedation for transthoracic echocardiography were 3.2 (2.78-3.55) µg/kg and 1.9 (1.69-2.06) µg/kg in children with cyanotic and acyanotic congenital heart disease, respectively.

The therapeutic effect of controlled reoxygenation on chronic hypoxia-associated brain injury.

Cardiopulmonary bypass (CPB) is the most general technique applied in congenital heart disease (CHD). However, standard CPB poses a specific pathologic condition for patients during surgery: exposure to reoxygenation. When surgery is performed on cyanotic infants, standard CPB is usually initiated at a high concentration of oxygen without consideration of cytotoxic effects. Controlled reoxygenation is defined as using normoxic CPB with a pump primed to the PO2 (oxygen tension in the blood), which is matched to the patient's preoperative saturation. The aim of this study was to determine whether controlled reoxygenation could avoid standard reoxygenation injury and also to clarify the molecular signaling pathways during hypoxia. We successfully reproduced the abnormal brain observed in mice with chronic hypoxia during early postnatal development - equivalent to the third trimester in human. Mice were treated with standard reoxygenation and controlled reoxygenation after hypoxia for 24 h. We then assessed the brain tissue of these mice. In standard reoxygenation-treated hypoxia mice, the caspase-3-dependent neuronal apoptosis was enhanced by increasing concentration of oxygen. Interestingly, controlled reoxygenation inhibited neuron and glial cell apoptosis through suppressing cleavage of caspase-3 and PARP. We also found that controlled reoxygenation suppressed LCN2 expression and inflammatory cytokine (including TNF-α, IL-6, and CXCL10) production, in which the JAK2/STAT3 signaling pathway might participate. In conclusion, our findings propose the novel therapeutic potential of controlled reoxygenation on CPB during CHD.

Determination of the 90% effective dose of intranasal dexmedetomidine for sedation during electroencephalography in children.

BACKGROUND: The intranasal route of dexmedetomidine (DEX) administration is becoming increasingly popular for providing adequate sedation during short examinations in infants and children. However, data on the 90% effective dose (ED90) of intranasal DEX are rare in children under 3 years old. METHODS: This is a double-blind trial using a biased coin design up-and-down sequential method (BCD-UDM). Fifty-three children aged under 3 years old requiring DEX for EEG were included in our study. The first patient received 2.5 µg kg-1 DEX, and the dose of DEX administered to the subsequent patient was determined by the response of the previous patient. The patient responses were recorded and analysed to calculate the ED90 by isotonic regression. The 95% confidence interval (CI) was estimated using a bootstrapping method. RESULTS: Fifty-three patients were included in our study, of which 45 patients were successfully sedated, and the 8 instances of failed sedation were rescued using sevoflurane inhalation, allowing the completion of the procedure. The 90% effective dose of DEX was calculated to be 3.28 µg kg-1 , and the 95% CI was 2.74 ~ 3.39 µg kg-1 . No significant adverse events occurred in any of the patients. CONCLUSION: The 90% effective dose of intranasal DEX sedation for EEG was 3.28 µg kg-1 in children under 3 years old.

Anticonvulsant and Neuroprotective Effects of Dexmedetomidine on Pilocarpine-Induced Status Epilepticus in Rats Using a Metabolomics Approach.

BACKGROUND Status epilepticus (SE) is the most extreme form of seizure. It is a medical and neurological emergency that requires prompt and appropriate treatment and early neuroprotection. Dexmedetomidine (DEX) is mainly used for its sedative, analgesic, anxiolytic, and neuroprotective effects with light respiratory depression. The purpose of this study was to comprehensively analyze the metabolic events associated with anticonvulsion and neuroprotection of DEX on pilocarpine-induced status epilepticus rats by LC-MS/MS-based on metabolomics methods combined with histopathology. MATERIAL AND METHODS In this research, rats were divided into 3 groups: a normal group, an SE group, and an SE+DEX group. Hippocampus of rats from each group were collected for further LC-MS/MS-based metabolomic analysis. We collected brains for HE staining and Nissl staining. Multivariate analysis and KEGG enrichment analysis were performed. RESULTS Results of metabolic profiles of the hippocampus tissues of rats proved that dexmedetomidine relieved rats suffering from the status epilepticus by restoring the damaged neuromodulatory metabolism and neurotransmitters, reducing the disturbance in energy, improving oxidative stress, and alleviating nucleic acid metabolism and amino acid in pilocarpine-induced status epilepticus rats. CONCLUSIONS This integral metabolomics research provides an extremely effective method to access the therapeutic effects of DEX. This research will further development of new treats for status epilepticus and provide new insights into the anticonvulsive and neuroprotective effects of DEX on status epilepticus.

Analysis of 17 948 pediatric patients undergoing procedural sedation with a combination of intranasal dexmedetomidine and ketamine.

BACKGROUND: Intranasal procedural sedation using dexmedetomidine is well described in the literature. The combination of intranasal dexmedetomidine and ketamine is a novel approach for which there are little data on the rate of successful sedation or adverse events. OBJECTIVES: The aim of this study is to evaluate the rate of successful sedation and adverse events of intranasal procedural sedation using a combination of dexmedetomidine and ketamine for diagnostic examination in children. METHODS: This was a retrospective study and data were collected after ethics approval. A total of 17 948 pediatric patients (7718 females, 10 230 males) in a tertiary hospital in China were evaluated. Patients received a combination of 2 µg kg-1 of dexmedetomidine and 1 mg kg-1 of ketamine intranasally for procedural sedation. The level of sedation and recovery was assessed by the Modified Observer Assessment of Alertness/Sedation scale and the Modified Aldrete Score. RESULTS: The rate of intranasal sedation success was 93% (16691/17948), intranasal sedation rescue was 1.8% (322/17948), and intranasal sedation failure was 5.2% (935/17948). Sedation success was defined as successful completed the diagnostic examination and obtained adequate diagnostic-quality images and reports. Intranasal sedation success, rescue and failure were respectively defined as sedation success with intranasal a single dose, additional bolus dose and the need for intravenous (IV) medications/inhalation agents. Median sedation time was 62 min (interquartile range: 55-70 min), median time for onset of sedation was 15 min (interquartile range: 15-20 min), and median sedation recovery time was 45 min (interquartile range: 38-53 min). Incidence of adverse events was low (0.58%; 105/17948), with major and minor adverse event being reported in 0.02% (4/17948) and 0.56% (101/17948) patients, respectively. Postoperative nausea and vomiting was the most common (0.3%; 53/17948) minor adverse event. CONCLUSION: Procedural sedation using a combination of intranasal dexmedetomidine and ketamine is associated with acceptable effectiveness and low rates of adverse events.

[Propofol combined with hypoxia induces cognitive dysfunction in immature rats via p38 pathway].

OBJECTIVE: To investigate the effects of propofol combined with hypoxia on cognitive function of immature rats and the possible role of p38 pathway and tau protein in mediating such effects. METHODS: Ninety 7-day-old (P7) SD rats were randomized for daily intraperitoneal injection of propofol (50 mg/kg) or lipid emulsion (5.0 mL/kg) for 7 consecutive days. After each injection, the rats were placed in a warm box (38 ℃) with an oxygen concentration of 18% (hypoxia), 21% (normal air), or 50% (oxygen) until full recovery of the righting reflex. Another 90 P7 rats were similarly grouped and received intraperitoneal injections of p-p38 blocker (15 mg/kg) 30 min before the same treaments. The phosphorylated tau protein, total tau protein and p-p38 content in the hippocampus were detected using Western blotting. The spatial learning and memory abilities of the rats were evaluated with Morris water maze test. RESULTS: Compared with lipid emulsion, propofol injection resulted in significantly increased levels of p-p38, phosphorylated tau and total tau proteins in rats with subsequent hypoxic or normal air treatment (P < 0.05), but propofol with oxygen and injections of the blocker before propofol did not cause significant changes in the proteins. Without subsequent oxygenation, the rats receiving injections of propofol, with and without prior blocker injection, all showed significantly prolonged latency time and reduced platform-crossing times and third quadrant residence time compared with the corresponding lipid emulsion groups (P < 0.05). With oxygen treatment, the rats in propofoland blocker-treated groups showed no significant difference in the performance in Morris water maze test from the corresponding lipid emulsion group. The results of Morris water maze test differed significantly between blocker-propofol group and propofol groups irrespective of exposures to different oxygen levels (P < 0.05), but not between the lipid emulsion and blocker group pairs with exposures to different oxygen levels. CONCLUSIONS: Propofol combined with hypoxia can affect the expression of tau protein through p38 pathway to impair the cognitive function of immature rats, in which oxygen plays a protective role.