Comparison of Efficacy and Safety of Midazolam versus Nitrous Oxide as Sedative Agents during Paediatric Dental Treatment: A Systematic Review / Comparison of Efficacy and Safety of Midazolam versus Nitrous Oxide as Sedative Agents during Paediatric Dental Treatment: A Systematic Review

ABSTRACT Objective: To identify and study the existing literature on the efficacy and safety of midazolam compared to inhalation of nitrous oxide in children undergoing dental treatment. Material and Methods: Electronic resources such as PubMed Central, Cochrane Database of Systematic Reviews, Lilacs, Science Direct, and SIGLE were thoroughly searched. The title scan was used to find randomised controlled trials reviewed for inclusion by reading the abstract. Studies comparing the sedative, behavioural, and anxiolytic effects and safety in children undergoing dental treatment under midazolam and nitrous oxide inhalation were included. The Cochrane Reviews system software, Revman 5.4.1, was used to assess the quality of the included studies. Results: 11328 articles were identified by screening the electronic databases, of which 10906 were eliminated after titles were read and duplicates were removed. Ten full-text articles were examined, of which three were excluded as they did not match the eligibility criteria. Hence, a total of 7 studies were included. Midazolam and nitrous oxide inhalation were not statistically different in terms of the success of treatment and behaviour modification. However, midazolam showed a deeper level of sedation and resulted in amnesia in more children when compared to nitrous oxide sedation. All of the included studies were found to have a high risk of bias. Conclusion: Though all the studies included showed an increased risk of bias, midazolam and nitrous oxide inhalation seem equally effective sedative agents for controlling behaviour in children undergoing dental treatment. Midazolam shows a deeper sedation level when given orally and produces a higher rate of anterograde amnesia.

Effects of the timing of satisfactory sedation with preoperative oral midazolam on anesthesia induction and recovery in children undergoing adenotonsillectomy / 中国临床药理学与治疗学

AIM: To investigate the effect of the timing of satisfactory sedation with preoperative oral midazolam on anesthesia induction and recovery in children undergoing adenotonsillectomy. METHODS: A total of 147 children undergoing elective adenotonsillectomy, with ASA physical status orⅡ, aged 2-7 years were selected from November 2022 to June 2023 in the Second Affiliated Hospital of Wenzhou Medical University. The children were orally administered 0.5 mg/kg midazolam in preoperative waiting area and were divided into 10-20 min (rapid onset, M1 group) and 21-30 min (slow onset, M2 group) based on the satisfactory sedation time, or equal volume of sugar pear drink orally (blank control group, C group). Children in all three groups received a general anesthesia method of propofol+fentanyl combined with sevoflurane induction and sevoflurane maintenance. The primary outcome measures were the induction compliance checklist (ICC) score and the pediatric anesthesia emergence delirium (PAED) score in the post-anesthesia care unit (PACU) to assess the occurrence of emergence agitation (EA), and the secondary outcome measures included the parental separation anxiety scale (PSAS), sedation Ramsay score, surgery duration, recovery time, PACU stay time, discharge time, the incidence of perioperative respiratory adverse events (PRAE) and other adverse events in the ward. RESULTS: 147 children were included in the result analysis, with 49 cases in each group. The proportion of perfect induction (ICC=0) were significantly higher in two M groups than that in group C (95.9% vs. 91.8% vs. 61.2%, P=0.001). The maximum and average PAED score in PACU in group M1 showed a significantly higher (6.4±5.0 vs. 4.4 ± 4.1, P=0.029; 5.2 ± 4.5 vs. 3.4 ± 3.6, P=0.030), and the incidence of EA was significantly higher than those in group C (10.2% vs. 30.6%, P=0.022), and increased compared to the group M2 (OR= 0.581, 95%CI 0.231-1.463, P=0.354). There was no statistically significant difference in the maximum and average PAED scores, incidence of EA between group M2 and group C (P>0.05). The Ramsay score and PSAS score in two M groups were higher, PACU stay time and recovery time was longer than those in group C (P0.05). CONCLUSION: Preoperative oral midazolam can improve the ICC and PSAS scores of children during induction, but it also leads to prolonged recovery time and PACU retention time. The rapid onset of midazolam did not result in better induction and recovery quality, but instead increased the incidence of EA and postoperative pain score.

Meta-analysis of efficacy and safety of sedative therapy with midazolam and dexmedetomidine/propofol in critically ill patients undergoing mechanical ventilation / 中国药房

OBJECTIVE To systematically evaluate the efficacy and safety of midazolam and dexmedetomidine/propofol for the sedation of critically ill patients undergoing mechanical ventilation， and to provide evidence-based reference for clinical treatment. METHODS Retrieved from PubMed， Embase， Web of Science， Cochrane Library， Clinical trials. gov， China Journal Full Text Database， Chinese Science and Technology Journal Database， Wanfang database and China Biomedical Literature Database， the data on the efficacy and safety of midazolam and dexmetomidine/propofol for the sedation of critically ill patients undergoing mechanical ventilation were collected from the establishment of the database to March 31， 2023. After extracting data from clinical studies that met the inclusion criteria， the meta-analysis was conducted by using the RevMan 5.3 statistical software. RESULTS A total of 31 literature were included， with a total of 2 765 patients. Results of meta-analysis showed that the mechanical ventilation time [MD＝14.13， 95%CI （13.75， 14.52）， P＜0.000 01] and the length of hospitalization in the intensive care unit [MD＝0.92， 95%CI （0.54， 1.30）， P＜0.000 01] of patients in the midazolam group was longer than dexmedetomidine/ propofol group. The incidence of bradycardia in midazolam group was lower dexmedetomidine/propofol group [OR＝0.60， 95%CI （0.41， 0.90）， P＝0.01]， but there was no statistically significant difference in the incidence of hypotension between the two groups [OR＝0.69， 95%CI （0.47， 1.01）， P＝0.06]. The incidence of delirium [OR＝3.88， 95%CI （2.74， 5.49）， P＜0.000 01]， ventilator- associated pneumonia [OR＝2.32， 95%CI （1.19， 4.51）， P＝0.01]， and respiratory depression [OR＝5.70， 95%CI （3.09， 10.52）， P＜0.000 01] in midazolam group were higher than dexmedetomidine/propofol group. CONCLUSIONS Compared with dexmedetomidine/propofol， midazolam increases patients’ mechanical ventilation time and the length of hospitalization in the intensive care unit in terms of efficacy， and increases the risk of delirium and pulmonary complications in terms of safety， but has a smaller cardiovascular impact.

Evaluation of Cardiovascular Parameters of ASA I and ASA II Patients Undergoing Dental Implant Surgery Under Intravenous Sedation with Midazolam: A Retrospective Analysis

The purpose of this research was to compare the vital signs of ASA II patients undergoing dental implant surgery under intravenous anesthesia to those of ASA I patients. From a specialist course in Implant Dentistry, 41 medical records (22 ASA I and 19 ASA II patients) were analyzed. Age, gender, ASA classification, blood pressure, heart rate, and oxygen saturation were all measured. Pre-surgery, following the onset of local anesthetic, at the end of the initial implant insertion, and at the end of surgery were all used to collect vital signs. Student's t-test (p<0.05) was used to determine inter- and intra-group data associations. The crossing of operative moments pre-surgical and installation of the first implant in both systolic (p<=0.01) and diastolic (p<=0.03) pressure was statistically significant in ASA I patients. In contrast, there was only a statistical difference in the verification of peripheral oxygen saturation data at preoperative and local anesthesia times in ASA II patients (p<=0.04). When comparing the time of installation of the first implant (p<=0.03) and at the end of surgery (p<=0.02), with respect to systolic pressure, ASA II presented statistically higher, while variable oxygen saturation at the beginning of local anesthesia in ASA I was statistically higher (p<=0.04). It is proposed that intravenous sedation acts in a compensatory manner in patients with systemic disease, leading both groups' behavior to be similar.

El propósito de esta investigación fue comparar los signos vitales de pacientes ASA II sometidos a cirugía de implante dental bajo anestesia intravenosa con los de pacientes ASA I. Se analizaron 41 historias clínicas de un curso de especialista en Implantología (22 pacientes ASA I y 19 ASA II). Se midieron la edad, el sexo, la clasificación ASA, la presión arterial, la frecuencia cardíaca y la saturación de oxígeno. Se tomarn los signos vitales antes de la cirugía, después del inicio de la anestesia local, al final de la inserción inicial del implante y al final de la cirugía. Se utilizó la prueba t de Student (p<0,05) para determinar las asociaciones de datos entre e intragrupos. El cruce de los momentos operatorios prequirúrgicos y de instalación del primer implante tanto en la presión sistólica (p<=0,01) como en la diastólica (p<=0,03) fue estadísticamente significativo en los pacientes ASA I. En contraste, solo hubo diferencia estadística en la verificación de los datos de saturación periférica de oxígeno en el momento preoperatorio y de anes- tesia local en los pacientes ASA II (p<=0,04). Al comparar el tiempo de instalación del primer implante (p<=0,03) y al final de la cirugía (p<=0,02), con respecto a la presión sistólica, el ASA II se presentó estadísticamente mayor, mientras que la variable saturación de oxígeno al inicio de la anestesia local en El ASA I fue estadísticamente mayor (p<0,4). Se propone que la sedación intravenosa actúa de forma compensatoria en pacientes con enfermedad sistémica, lo que hace que el comportamiento de ambos grupos sea similar.

Premedication with midazolam in low-risk surgery in children does not reduce postoperative delirium. Prospective cohort study

Introduction: Pediatric postoperative delirium is a frequent complication for which preventive pharmacological measures have been suggested. The use of midazolam as a prophylactic strategy has not yet been thoroughly assessed. Notwithstanding the fact that it is used in pediatric presurgical separation anxiety, its role in delirium is yet to be established. Objective: To quantify the incidence of pediatric postoperative delirium in patients undergoing low risk surgical interventions, exposed to oral midazolam-based premedication and to explore the protective and risk factors associated with the development of delirium. Methods: Prospective, analytical observational study with a cohort design. Children were conveniently selected in accordance with the daily list of surgical procedures in the operating rooms. The inclusion criteria were children between 2 and 10 years old, ASA I-II, undergoing low risk surgeries. Concurrent and longitudinal follow-up was then conducted upon admission to the post-anesthesia care unit (PACU) for the first hour. Results: A total of 518 children were included. The overall incidence of delirium was 14.4 % (95 % CI: 11.4 %-17.5 %). In the subgroup exposed to midazolam, 178 children were analyzed, with an incidence of delirium of 16.2% (95% CI of 10,8 %-21,7). These patients exhibited a higher tendency to delirium with the use of sevoflurane or fentanyl, and/orwhen presenting with severe postoperative pain. Patients exposed to propofol and/or remifentanil showed lower incidences. Conclusions: No reduction in the incidence of emergency pediatric delirium associated with the use of pre-surgical oral midazolam in low risk surgical procedures. Prospective controlled trials and additional research are required to study the effectiveness and safety of this intervention.

Introducción: El delirio pediátrico posoperatorio es una complicación frecuente para la cual se han sugerido medidas farmacológicas de prevención. El uso de midazolam como estrategia profiláctica aún no ha sido suficientemente evaluado. A pesar de que se emplea para la ansiedad de separación pediátrica prequirúrgica, su papel en delirio aún no se ha establecido. Objetivo: Cuantificar la incidencia de delirio pediátrico posoperatorio en pacientes sometidos a cirugías de bajo riesgo quirúrgico, expuestos a premedicación basada en midazolam oral y adicionalmente, explorar los factores protectores y de riesgo asociados a la ocurrencia. Materiales y métodos: Estudio observacional analítico prospectivo con un diseño de cohorte. Se seleccionaron niños por conveniencia de acuerdo con la lista quirúrgica diaria en salas de cirugía. Como criterios de inclusión se tomaron sujetos entre 2 y 10 años de edad, ASA 1-11, sometidos a cirugías de bajo riesgo quirúrgico. Posteriormente se realizó seguimiento concurrente y longitudinal al ingreso a la unidad de recuperación posanestésica (UCPA) durante la primera hora de estancia. Resultados: Se incluyeron 518 niños. La incidencia global de delirio fue del 14,4 % (IC 95 %;11,4 %-17,5 %). En el subgrupo expuesto a midazolam se analizaron 178 niños, quienes presentaron una incidencia de delirio del 16,2 % (IC 95 %;10,8 %-21,7 %). Estos pacientes presentaron una mayor tendencia a delirio con el uso de sevofluorano o fentanilo, y/o cuando presentaron dolor severo posoperatorio. Pacientes con exposición a propofol y/o remifentanilo exhibieron incidencias inferiores. Conclusiones: No se encontró una reducción en la incidencia de delirio pediátrico de emergencia asociada al empleo de midazolam oral prequirúrgico en cirugías de bajo riesgo. Se requieren estudios prospectivos controlados e investigación adicional para el estudio de la efectividad y seguridad de esta intervención.

Comparison between oral midazolam versus oral ketamine plus midazolam as preanesthetic medication in autism spectrum disorder: double-blind randomized clinical trial

Abstract Background: Conventional dental care is often impossible in patients with Autism Spectrum Disorder (ASD). Non-collaborative behaviors, sometimes associated with aggressiveness, are usual justifications for premedication in this population. Thereby, this research focuses on the effects of oral midazolam versus oral ketamine plus midazolam as preanesthetic medication in ASD. Methods: The sample included 64 persons with ASD, aged 2-59 years, scheduled for dental care under general anesthesia. The primary objective of this study was to compare degrees of sedation between two parallel, double-blinded, equally proportional groups randomized to receive oral midazolam (0.5 mg.kg−1, maximum 15 mg) or oral midazolam (0.5 mg.kg−1) associated with oral S(+)-ketamine (3 mg.kg−1, maximum 300 mg). The secondary outcomes were the need of physical stabilization to obtain intravenous line, awakening time, and occurrence of adverse events. Results: According to the dichotomous analysis of sedation level (Ramsay score 1 and 2 versus Ramsay ≥ 3), oral association of S(+)-ketamine and midazolam improved sedation, with increased probability of Ramsay ≥ 3, Relative Risk (RR) = 3.2 (95% Confidence Interval [95% CI] = 1.32 to 7.76) compared to midazolam alone. Combined treatment also made it easier to obtain venous access without physical stabilization, RR = 2.05 (95% CI = 1.14 to 3.68). There were no differences between groups regarding awakening time and the occurrence of adverse events. Conclusion: The association of oral S(+)-ketamine with midazolam provides better preanesthetic sedation rates than midazolam alone and facilitates intravenous line access in patients with autism.

Comparison of intranasal midazolam-fentanyl with dexmedetomidine–fentanyl as pre-medication in the paediatric age group

Background & objectives: Intranasal midazolam-fentanyl is commonly used as pre-medication in paediatric patients, but there is a risk of respiratory depression with this combination. Dexmedetomidine is a drug that preserves respiratory function. The objective of this study was to compare the efficacy of intranasal midazolam-fentanyl and dexmedetomidine-fentanyl in paediatric patients undergoing elective surgeries. Methods: Hundred children in the age group of 3-8 yr of American Society of Anaesthesiologists physical status grade 1 were randomized into two groups- group A received intranasal midazolam (0.2 mg/kg)-fentanyl (2 ?g/kg) and group B received intranasal dexmedetomidine (1 ?g/kg)-fentanyl (2 ?g/kg) 20 min before induction of general anaesthesia. Heart rate and SpO2 were monitored. Sedation score, parental separation and response to intravenous cannulation were seen after 20 min. Children were monitored for 2 h for post-operative analgesia by Oucher’s Facial Pain Scale. Results: Sedation scores were satisfactory in both groups, although children in group A were more sedated than in group B. Parental separation and response to intravenous cannulation were comparable in both the groups. The two groups were also haemodynamically comparable intraoperatively. Post-operative heart rate was also comparable at all-time intervals in both the groups except for heart rate at 100 and 120 min which were more in group A. Group A experienced more post-operative pain as assessed by Oucher’s Facial Pain Scale as compared to group B. Children receiving intranasal dexmedetomidine- fentanyl had better post-operative analgesia as compared to those who received intranasal midazolam-fentanyl. Interpretation & conclusions: Both intranasal midazolam with fentanyl and intranasal dexmedetomidine with fentanyl provided satisfactory sedation. Both groups were comparable in separation reaction and response to intravenous cannulation with better post-operative analgesia in children receiving intranasal dexmedetomidine-fentanyl.

Efficacy and Safety of Oral Midazolam Sedation Compared with its Combination with Hydroxyzine Use in Pediatric Dentistry: A Systematic Review

ABSTRACT Objective: To assess the efficacy and safety of the use of midazolam as monotherapy, compared to the associated use of midazolam and hydroxyzine for minimum and moderate sedation of children in dental offices, using data obtained from clinical trials. Material and Methods: A systematic review protocol was developed and registered on PROSPERO (CR42020208633). An electronic search was carried out in Pubmed, Lilacs, Science Direct, Open Gray, Web of Science, and central Cochrane Library. No language restrictions were included. Clinical trials were carried out with children aged 0-12 years, using midazolam as monotherapy compared to the use of midazolam associated with hydroxyzine to verify the effectiveness and safety of oral sedation. The quality of the studies was individually assessed and grouped using the RoB 2 (Revised Cochrane risk-of-bias tool for randomized trials) and GRADE (Grading of Recommendations Assessment, Development and Evaluation) systems, respectively. Results: A total of 749 studies were found. After analyzing the inclusion and removal of duplicates, two studies were analyzed for the quality of evidence. Through this analysis, it was possible to verify the very low level of scientific evidence on the superiority of the efficacy and safety of the combined use of midazolam and hydroxyzine for oral sedation in children in dental offices. Conclusion: The conflicting results and limitations of the studies enabled to establish that there is insufficient evidence to support the use of these drugs combined. There is only evidence for the use of midazolam as monotherapy.

Child Stress and Behaviour During Restorative Treatment under Non-Pharmacological Techniques and Sedation: A Case Series

ABSTRACT Objective: To evaluate the behaviour and stress of children undergoing restorative treatment with and without sedation. Material and Methods: Participants were 14 healthy children aged between 2.5 and 6 years and with a history of dental behavioural management problems. In the dental treatment visit, the child was treated with non-pharmacological techniques, and in the second, moderate sedation was added. The child received the same procedure performed by a paediatric dentist in both visits: composite resin restoration using local anaesthesia and rubber dam isolation. In both visits, saliva was collected at the children's arrival at the dental clinic, during local anaesthesia and at the end of treatment. The visits were filmed for later analysis of behaviour according to the Ohio State University Behavioural Rating Scale. Results: About 78.5% of children improved their behaviour from the first to the second visit. The salivary cortisol curve of the first visit was maintained in the second visit for 21.4% of children but varied in the remaining participants. Conclusion: Most children presented better behaviour and less stress when sedation was added to non-pharmacological techniques during dental care.

Oral preanesthetic medication in children - comparison between midazolam alone and in combination with ketamine: a systematic review and meta-analysis

Abstract Background Up to 60% of pediatric surgical patients develop high levels of preoperative anxiety. This study compared the effects of oral combinations of midazolam and ketamine with oral midazolam alone for pediatric preanesthetic medication. Methods The study protocol was registered in PROSPERO as CRD42020172920. A systematic literature search was conducted using Medline, Cochrane, EMBASE, CENTRAL, and Web of Science for randomized controlled trials comparing oral combinations of midazolam and ketamine with midazolam alone as preanesthetic medication in elective surgical pediatric patients. Meta-analyses included the following outcomes: anxiety and sedation levels, child's behavior during separation from parents, face mask acceptance, and venipuncture. The quality of evidence was assessed using GRADE criteria. Results Twenty studies were included. The following effects (RR (95% CI)) were observed for combinations of ketamine and midazolam relative midazolam alone: anxiolysis (1.2 (0.94-1.52); p= 0.15; I2 = 80%; GRADE = very low); satisfactory sedation (1.2 ( 1.10-1.31); p< 0.001; I2 = 71%; GRADE = very low); behavior during parental separation (1.2 (1.06-1.36); p= 0.003; I2 = 88%; GRADE = very low); facial mask acceptance (1.13 (1.04-1.24); p= 0.007; I2 = 49%; GRADE = very low); behavior during venipuncture (1.32 (1.11-1.57); p= 0.002; I2 = 66%; GRADE = very low). Conclusions While similar probabilities of obtaining anxiolysis were found, adequate sedation, calm behavior during child's separation from parents, low levels of fear during face mask adaptation, and cooperative behavior during peripheral venous cannulation were more likely with midazolam-ketamine combinations.

Effect of combined sedation using multiple drugs on inflammatory cytokines in patients with acute respiratory distress syndrome

Abstract he innate immune response plays an important role in the pathophysiology of acute respiratory distress syndrome (ARDS); however, no drug has been proven to be beneficial in the management of ARDS. Therefore, the aim of this study was to investigate the effects of using combined sedatives on systemic inflammatory responses in patients with ARDS. A total of 90 patients with ARDS and an intubation time of > 120 h were randomly divided into the propofol group (group P), midazolam group (group M), and combined sedation group (group U). Patients in groups P and M were sedated with propofol and midazolam, respectively, whereas patients in group U were sedated with a combination of propofol, midazolam, and dexmedetomidine. The dosage of sedatives and vasoactive drugs, duration of mechanical ventilation, and incidence of sedative adverse reactions were documented. The dosage of sedatives and vasoactive drugs, as well as the incidence of sedative adverse reactions in group U, was significantly lower than those in groups P and M. Similarly, the duration of mechanical ventilation in group U was significantly shorter than that in groups P and M. Hence, inducing sedation through a combination of multiple drugs can significantly reduce their adverse effects, improve their sedative effect, inhibit systemic inflammatory responses, and improve oxygenation in patients with ARDS

Effects of midazolam combined with propofol on recovery of patients with laparoscopic cholecystectomy / 药学实践杂志

Objective To explore the effect midazolam combination with propofol on postoperative recovery in patients undergoing laparoscopic cholecystectomy. Methods A total of 162 patients who were admitted to the hospital for laparoscopic cholecystectomy from April 2019 to January 2021 were selected. According to different anesthesia methods, they were divided into control group (midazolam anesthesia) and observation group (midazolam combined with propofol anesthesia), with 81 cases in each group. The stress index levels before and after operation, MoCA scores before operation (T0), 24 h after operation (T1) and 48 h after operation (T2), sleep quality at T0, the first day after operation (T3) and the second day after operation (T4), the perioperative recovery were compared between the two groups. Results The levels of Cor and NE, the recovery time of eyes opening, extubation, orientation, and the incidence of adverse reactions in the observation group were lower than those in the control group (P<0.05). Observation group MMSE score when T1, T2, T3, T4 sleep quality score were higher than control group (P<0.05). Conclusion Midazolam combined with propofol was safe and had good postoperative recovery in patients undergoing laparoscopic cholecystectomy.

Role of Nrf2/GPX4 signaling pathway-mediated ferroptosis in midazolam-induced reduction of HIBD in neonatal rats / 中华麻醉学杂志

Objective:To evaluate the role of nuclear factor-erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase-4 (GPX4) signaling pathway-mediated ferroptosis in midazolam-induced reduction of hypoxic-ischemic brain damage (HIBD) in neonatal rats.Methods:Ninety healthy 7-day-old neonatal rats, weighing 16-20 g, were divided into 6 groups ( n=15 each) using the random number table method: sham operation group (Sham group), HIBD group, low-dose midazolam (10 mg/kg) group (group L), medium-dose midazolam (20 mg/kg) group (group M), high-dose midazolam (40 mg/kg) group (group H), and Nrf2 inhibitor ML385 group (group I). The HIBD model was developed by ligating the left carotid artery and exposing to a hypoxic condition for 2 h in anesthetized animals. Starting from 2nd day after developing the model, the corresponding doses of midazolam were intraperitoneally injected in midazolam groups, the equal volume of normal saline was intraperitoneally injected in Sham and HIBD groups, midazolam 40 mg/kg and Nrf2 inhibitor ML385 30 mg/kg were intraperitoneally injected once a day for 8 consecutive days in group I. The rats were weighed and subjected to the Morris water maze test after the end of administration. Blood samples were taken from the abdominal aorta after the end of the Morris water maze test, and then the animals were sacrificed to remove the brain for determination of the concentrations of serum iron, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (by enzyme-linked immunosorbent assay), contents of iron and GSH in hippocampal tissues (by ultraviolet spectrophotometry and micro method), the number of Nrf2/neuronal nuclear antigen (NeuN) and GPX4/NeuN positive cells (by immunofluorescent staining), and expression of Nrf2, GPX4, and 4-hydroxynonaenoic acid (4-HNE) in hippocampal tissues and for microscopic examination of the pathological changes of hippocampal neurons in brain tissues (after HE staining and Nissl staining). Results:Compared with Sham group, the first time to arrival at platform was significantly prolonged, the number of crossing the origional platform was reduced, and the time of staying at the target quadrant was shortened, the iron content in the hippocampal tissues was increased, the content of GSH and the number of Nrf2/NeuN and GPX4/NeuN positive cells were decreased, the expression of Nrf2 and GPX4 was down-regulated, the expression of 4-HNE was up-regulated, the concentrations of serum iron, IL-6 and TNF-α were increased, and the injury to hippocampal neurons was marked in HIBD group ( P<0.05). Compared with HIBD group, the first time to arrival at platform was significantly shortened, the number of crossing the origional platform was increased, and the time of staying at the target quadrant was prolonged, the iron content in the hippocampus tissues was decreased, the content of GSH and the number of Nrf2/NeuN and GPX4/NeuN positive cells were increased, the expression of Nrf2 and GPX4 was up-regulated, the expression of 4-HNE was down-regulated, the concentrations of serum iron, IL-6 and TNF-α were decreased ( P<0.05), and the injury to hippocampal neurons was significantly reduced in H, M and L groups. Compared with group H, the first time to arrival at platform was significantly prolonged, the number of crossing the origional platform was reduced, and the time of staying at the target quadrant was shortened, the iron content in the hippocampus tissue was increased, the content of GSH and the number of Nrf2/NeuN and GPX4/NeuN positive cells were decreased, the expression of Nrf2 and GPX4 was down-regulated, the expression of 4-HNE was up-regulated, the concentrations of serum iron, IL-6 and TNF-α were increased ( P<0.05), and the injury to hippocampal neurons was aggravated in group I. Conclusions:The mechanism by which midazolam reduces HIBD may be related to activation of the Nrf2/GPX4 signaling pathway and inhibition of hippocampal neuronal ferroptosis in neonatal rats.

Comparison of the effects of remimazolam besylate and midazolam on postoperative cognitive function in patients undergoing gynecologic laparoscopic surgery under general anesthesia / 中国医师杂志

Objective:To investigate the effects of remimazolam besylate and midazolam on postoperative cognitive function of patients undergoing gynecologic laparoscopic surgery under general anesthesia.Methods:From May 2019 to January 2021, 120 patients with gynecological laparoscopic surgery under general anesthesia in Haikou Maternal and Child Health Hospital were selected and divided into control group (60 cases) and observation group (60 cases) by random number table. The control group was given 0.05 mg/kg midazolam and 0.50 μg/kg sufentanil and 0.15 mg/kg vecuronium bromide were used for anesthesia induction. Patients in the observation group were given 0.3 mg/kg remimazolam besylate and 0.50 μg /kg sufentanil and 0.15 mg/kg vecuronium were used for anesthesia induction. The levels of hemodynamic indexes before anesthesia (T 0), during anesthesia (T 1), and after intubation (T 2) as well as the levels of postoperative anesthesia recovery indexes were compared between the two groups. The Visual Analogue Scale (VAS) score and Mini-Mental State Examination (MMSE) scores were recorded and compared before surgery, 24 h, 72 h after surgery. The total incidence of adverse reactions after surgery was recorded and compared between the two groups. Results:The heart rate (HR) at T 1 and T 2 in the two groups was higher than that at T 0, the oxygen saturation (SpO 2) at T 1 and T 2 was lower than that at T 0, the mean arterial pressure (MAP) at T 1 was lower than that at T 0, and the MAP at T 2 was higher than that at T 0, with statistically significant difference (all P<0.05); The HR and MAP at T 1 and T 2 in the observation group were lower than those in the control group, and SpO 2 was higher than those in the control group (all P<0.05); The recovery time of spontaneous respiration, eye opening time and extubation time in the observation group were significantly shorter than those in the control group (all P<0.05); The MMSE score at 24 h and 72 h after operation was lower than that before operation, and the VAS score at 24 h was higher than that before operation in both groups (all P<0.05); The MMSE scores in the observation group at 24 h and 72 h after operation were significantly higher than those in the control group (all P<0.05), and there was no significant difference in the VAS scores at 24 h and 72 h after operation between the two groups ( P>0.05); There was no significant difference in the total incidence of adverse reactions between the two groups (all P>0.05). Conclusions:Remimazolam besylate has little effect on cognitive function of patients undergoing gynecologic laparoscopic surgery under general anesthesia, with fast recovery and high safety, which is worthy of clinical promotion.

Role and mechanism of PKCs in midazolam-induced relaxation of aortic smooth muscle in spontaneously hypertensive rats / 中国药理学通报

Aim To investigate the effect of protein kinase C (PKCs) on midazolam-induced relaxation of aortic smooth muscle in spontaneously hypertensive rats (SHR) and the underlying mechanism. Methods U-sing the isolated vessel tension measurement system, the relaxant effect of midazolam on aortic smooth muscle of SHR and Wistar-Kyoto (WKY) rats was observed. After preincubation with GF109203X (GF, a broad-spectrum inhibitor of PKCs), LY333531 (LY, PKCp2 specific inhibitor) and PKC6 pseudo-substrate inhibitor (PPS), the changes of midazolam-induced relaxation amplitude were observed. Western blot was used to detect the effect of midazolam on the phosphorylation level of PKC [32 in SHR aortic smooth muscle. The effect of midazolam, LY, GF and PPS on the phosphorylation level of the key proteins (CPI-17/ MYPT1/MLC) in calcium sensitization pathway in SHR aortic smooth muscle was also examined. Results Midazolam concentration-dependently relaxed aortic smooth muscle in SHR and WKY. GF significantly inhibited midazolam-induced relaxation amplitude of SHR and WKY aortic smooth muscle. LY and PPS had no significant effect on midazolam-induced relaxation amplitude of WKY aortic smooth muscle. In contrast, LY markedly inhibited midazolam-induced relaxation amplitude of SHR aortic smooth muscle. Midazolam significantly inhibited the phosphorylation level of PKC [32 enhanced by NE in SHR aortic smooth muscle. Midazolam, LY and GF all evidently inhibited the phosphorylation level of the key proteins in calcium sensitization pathway enhanced by NE in SHR aortic smooth muscle. Conclusions Midazolam induces excessive relaxation of SHR aortic smooth muscle by inhibiting calcium sensitization pathway mediated by PKC [32.

Factors Requiring Midazolam in Addition to Systemic Opioids to Control Dyspnea in Cancer Patients at the End of Life

Background: Factors requiring midazolam in addition to systemic opioids to control dyspnea in cancer patients have yet to be evaluated. Methods: We retrospectively analyzed data for cancer patients who received systemic opioids to relieve dyspnea from April 2019 to July 2021 in Wakayama Medical University Hospital, Japan. Patients were divided into an opioid-alone group and an opioid plus midazolam group, according to the treatment of dyspnea. Results: The total of 107 patients included 85 patients (79.4%) in the opioid alone group and 22 patients (20.6%) in the opioid plus midazolam group. Age<60 years (p=0.004) and male sex (p=0.034) was significantly associated with the addition of midazolam. Multivariate analysis found age <60 years (OR=5.34, 95%CI: 1.66–17.21; p=0.005) was associated with the addition of midazolam. Conclusion: Age <60 years is factor requiring midazolam in addition to systemic opioids to control dyspnea in cancer patients.

Comparative Evaluation of Midazolam and Ketamine with Midazolam Alone as Oral Premedication in Children

Introduction: The main aims of preanesthetic medication in children are to reduce anxiety associated with the unfamiliar environment, facilitate the separation of the child from their parent and allow smooth induction of anesthesia. Both oral midazolam and oral ketamine fulfil many of these characteristics and are useful. Method: As 48 patients of ASA grade 1 and 2, aged between 2-10 years undergoing elective surgery were allocated to one of two study groups using random numbers: Group 1 received midazolam 0.5mg/kg and group 2 received midazolam 0.25 mg/kg with ketamine 3 mg/kg. The medications were prepared and mixed with 25% dextrose up to a maximum volume of 0.3 ml/kg. Result: Uniform and acceptable sedation scores were seen in both the groups, without any serious side effects. However, the combination offered significantly more children in an awake, calm and quiet state, who were easily separated from their parents. The induction scores, Recovery room characteristics and time to achieve satisfactory Aldrete score were also comparable between the two groups. Conclusion: Oral midazolam alone and a combination of midazolam with ketamine provide equally effective anxiolysis and separation characteristics. However, the combination provided more Benefits.

Dose-effect relationship of alfentanil inhibiting cardiovascular responses to endotracheal intubation when combined with midazolam and etomidate / 中华麻醉学杂志

Objective:To investigate the dose-effect relationship of alfentanil inhibiting cardiovascular responses to tracheal intubation when combined with midazolam and etomidate.Methods:American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ patients of either sex, aged 18-64 yr, with body mass index<32 kg/m 2, undergoing elective operation under general anesthesia with endotracheal intubation, were enrolled in this study.Midazolam 0.025 mg/kg was intravenously injected for adequate sedation, and 5 min later mean arterial pressure and heart rate were recorded for 3 consecutive times at an interval of 3 min, and the mean value was calculated and served as the baseline value.Etomidate 0.3 mg/kg was intravenously injected, and alfentanil and rocuronium 0.6 mg/kg were intravenously injected when bispectral index value < 60, and then 1.4 min later tracheal intubation was performed.The dose of alfentanil was determined by the Dixon′s up-and-down method.The initial dose of alfentanil was set at 20 μg/kg.The dose of alfentanil in the next patient was determined according to the development of cardiovascular responses to tracheal intubation, and the ratio between the two successive doses was 1.0∶1.1.The cardiovascular response was defined as as positive when the maximum value of mean arterial pressure or heart rate increased by ≥20% of the baseline value within 2 min after endotracheal intubation.Probit method was used to determine the ED 50, ED 95 and 95% confidence interval of alfentanil inhibiting cardiovascular responses to tracheal intubation. Results:When combined with midazolam and etomidate, the ED 50 (95% confidence interval) of alfentanil inhibiting cardiovascular responses to tracheal intubation was 21.343 (19.105-24.516) μg/kg, and the ED 95 (95% confidence interval) was 25.043 (22.983-48.983) μg/kg. Conclusions:When combined with midazolam and etomidate, the ED 50 and ED 95 of alfentanil inhibiting cardiovascular responses to tracheal intubation are 21.343 and 25.043 μg/kg, respectively.

Dose-response relationship of alfentanil in combination with midazolam-etomidate inhibiting cardiovascular responses to laryngeal mask airway implantation in elderly patients / 中华麻醉学杂志

Objective:To evaluate the dose-response relationship of alfentanil in combination with midazolam-etomidate inhibiting cardiovascular responses to laryngeal mask airway implantation in elderly patients.Methods:American Society of Anesthesiologists Physical Status Ⅰ or Ⅱ patients of either sex, aged 65-85 yr, with body mass index of 20-30 kg/m 2, undergoing elective operation under general anesthesia, were enrolled in this study.Midazolam 0.025 mg/kg was intravenously injected for adequate sedation, 5 min later mean arterial pressure and heart rate were recorded for 3 consecutive times at 3-min interval, the mean value was collected and considered as the baseline value.Etomidate 0.2 mg/kg was intravenously injected, and alfentanil and rocuronium 0.6 mg/kg were intravenously injected when bispectral index value < 60.A laryngeal mask airway was inserted at 1.4 min after intravenous injection of alfentanil, and mechanical ventilation was performed.The dose of alfentanil was determined by the Dixon′s up-and-down method.The initial dose of alfentanil was set at 6.83 μg/kg.The dose of alfentanil in the next patient was determined according to the development of cardiovascular response to laryngeal mask airway placement.If the cardiovascular response to laryngeal mask airway placement occurred, the dose was increased for the next patient, and if cardiovascular response to laryngeal mask airway placement did not occur, the dose was decreased, and the ratio between the two successive doses was 1.0∶1.1.The cardiovascular response to laryngeal mask airway placement was defined as increase in maximum mean arterial pressure or maximum heart rate by≥20% of baseline values within 2 min after laryngeal mask airway placement.The median effective dose (ED 50), 95% effective dose (ED 95) and 95% confidence interval (95% CI) of alfentanil inhibiting cardiovascular responses to laryngeal mask airway placement in elderly patients were calculated by the Probit method. Results:When combined with midazolam and etomidate, the ED 50 (95% CI) of alfentanil inhibiting the cardiovascular responses to laryngeal mask airway placement in elderly patients were 5.605 (5.036-6.082) μg/kg, and the ED 95 (95% CI) were 6.625 (6.125-9.763) μg/kg. Conclusions:When combined with midazolam and etomidate, the ED 50 and ED 95 of alfentanil inhibiting the cardiovascular responses to laryngeal mask airway placement are 5.605 and 6.625 μg/kg, respectively, in elderly patients.

Uma análise de custo-efetividade de propofol versus midazolam para sedação de pacientes adultos admitidos à unidade de terapia intensiva / A cost-effectiveness analysis of propofol versus midazolam for the sedation of adult patients admitted to the intensive care unit

RESUMO Objetivo: Construir um modelo de custo-efetividade para comparar o uso de propofol com o de midazolam em pacientes críticos adultos sob uso de ventilação mecânica. Métodos: Foi construído um modelo de árvore decisória para pacientes críticos submetidos à ventilação mecânica, o qual foi analisado sob a perspectiva do sistema privado de saúde no Brasil. O horizonte temporal foi o da internação na unidade de terapia intensiva. Os desfechos foram custo-efetividade por hora de permanência na unidade de terapia intensiva evitada e custo-efetividade por hora de ventilação mecânica evitada. Foram obtidos os dados do modelo a partir de metanálise prévia. Assumiu-se que o custo da medicação estava incluído nos custos da unidade de terapia intensiva. Conduziram-se análises univariada e de sensibilidade probabilística. Resultados: Pacientes mecanicamente ventilados em uso de propofol tiveram diminuição de sua permanência na unidade de terapia intensiva e na duração da ventilação mecânica, respectivamente, em 47,97 horas e 21,65 horas. Com o uso de propofol, ocorreu redução média do custo de U$2.998,971 em comparação ao uso do midazolam. A custo-efetividade por hora de permanência na unidade de terapia intensiva evitada e por hora de ventilação mecânica evitada foi dominante, respectivamente, em 94,40% e 80,8% do tempo. Conclusão: Ocorreu diminuição significante do custo associado ao uso de propofol, no que se refere à permanência na unidade de terapia intensiva e à duração da ventilação mecânica para pacientes críticos adultos.

ABSTRACT Objective: To build a cost-effectiveness model to compare the use of propofol versus midazolam in critically ill adult patients under mechanical ventilation. Methods: We built a decision tree model for critically ill patients submitted to mechanical ventilation and analyzed it from the Brazilian private health care system perspective. The time horizon was that of intensive care unit hospitalization. The outcomes were cost-effectiveness per hour of intensive care unit stay avoided and cost-effectiveness per hour of mechanical ventilation avoided. We retrieved data for the model from a previous meta-analysis. We assumed that the cost of medication was embedded in the intensive care unit cost. We conducted univariate and probabilistic sensitivity analyses. Results: Mechanically ventilated patients using propofol had their intensive care unit stay and the duration of mechanical ventilation decreased by 47.97 hours and 21.65 hours, respectively. There was an average cost reduction of US$ 2,998.971 for propofol when compared to midazolam. The cost-effectiveness per hour of intensive care unit stay and mechanical ventilation avoided were dominant 94.40% and 80.8% of the time, respectively. Conclusion: There was a significant reduction in costs associated with propofol use related to intensive care unit stay and duration of mechanical ventilation for critically ill adult patients.