Comparison of the effects of ketamine via nebulization versus different pharmacological approaches in pediatric sedation: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Nebulized drug delivery is commonly used in pediatric clinical practice. The growing number of literatures have reported the application of nebulized ketamine in pediatric sedation in recent years. This meta-analysis of randomized controlled trials comparing the efficacy and safety of nebulized ketamine versus different pharmacological approaches was conducted to estimate the effects of this technique in pediatric sedation. METHODS: We searched PubMed, Embase, and Cochrane Library from inception to Feb 2023. All randomized controlled trials used nebulized ketamine as presurgical and pre-procedural sedatives in children were included. Sedative effects and various adverse events were considered as the outcomes. RESULTS: Ten studies with 727 pediatric patients were enrolled. Compared to nebulized dexmedetomidine, using of ketamine via nebulization showed similar sedation satisfaction (54.79% vs. 60.69%, RR = 0.88, with 95%CI [0.61, 1.27]), success rate of parental separation (57.27% vs. 73.64%, RR = 0.81, with 95%CI [0.61, 1.08]), and mask acceptability (37.27% vs. 52.73%, RR = 0.71, with 95%CI [0.45, 1.10]). However, the using of combination of two medications (nebulized ketamine plus nebulized dexmedetomidine) was associated with better sedative satisfaction (33.82% vs. 68.11%, RR = 0.50, with 95%CI [0.27, 0.92]) and more satisfactory mask acceptance (45.59% vs. 71.01%, RR = 0.69, with 95%CI [0.56, 0.86]). Compared with nebulized ketamine, using of nebulized dexmedetomidine was associated with less incidence of emergence agitation (18.18% vs. 3.33%, RR = 4.98, with 95%CI [1.88, 13.16]). CONCLUSIONS: Based on current evidences, compared to nebulized dexmedetomidine, nebulized ketamine provides inconspicuous advantages in pediatric sedation, and it has a relatively high incidence of emergence agitation. Combination of nebulized ketamine and dexmedetomidine might be considered as one preferred option in pediatric sedation as it can provide more satisfactory sedative effects. However, there is insufficient evidence regarding nebulized ketamine versus ketamine administered through other routes and nebulized ketamine versus other sedatives. The overall low or moderate quality of evidence evaluated by the GRADE system also calls for more high-quality studies with larger sample sizes in future. RESEARCH REGISTRATION: The protocol of present study was registered with PROSPERO (CRD42023403226).

Efficacy and safety of oral versus intranasal midazolam as premedication in children: a systematic review and meta-analysis.

INTRODUCTION: Midazolam hydrochloride is a widely accepted benzodiazepine for premedication in pediatric patients. However, there is no consistent conclusion regarding which route of administration is best. We performed a meta-analysis to assess the efficacy and safety of oral versus intranasal midazolam premedication in children. EVIDENCE ACQUISITION: The PubMed, Embase, Cochrane Library, and Google Scholar databases were searched from inception to June 2022, for randomized controlled trials comparing oral versus intranasal midazolam. Primary outcomes included satisfactory mask acceptance for induction and satisfactory sedation at separation from parents. Secondary outcomes included the incidence of postoperative nausea and vomiting, incidence of nasal irritation, postoperative recovery time, and hemodynamic changes. EVIDENCE SYNTHESIS: Data from 14 studies involving a total of 901 children were obtained. The results indicated that intranasal and oral midazolam premedication in children provided similar satisfactory mask acceptance for induction (RR, 1.02; 95% CI, 0.93-1.13; P=0.64; I2=0%), satisfactory sedation at separation from parents (RR, 0.99; 95% CI, 0.89-1.10; P=0.90; I2=57%), and postoperative recovery time (WMD, -8.01; 95% CI, -20.16-4.14; P=0.20; I2=85%). Additionally, intranasal midazolam premedication was associated with lower incidence of postoperative nausea and vomiting (RR, 0.70; 95% CI, 0.51-0.96; P=0.03; I2=0%) and shorter onset time. CONCLUSIONS: Differences between intranasal and oral midazolam in satisfactory mask acceptance for induction, satisfactory sedation at separation from parents, and postoperative recovery time were not significant. Intranasal midazolam premedication was associated with shorter onset time and higher incidence of nasal irritation.

Efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients: a meta-analysis of randomized controlled trials.

BACKGROUND: Intranasal midazolam and ketamine have been widely used as sedative premedication in children. It is difficult to determine which one yields better sedative effects for clinical practice. We conducted the present meta-analysis by summarizing the evidences to evaluate the efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients. METHODS: We searched PubMed, Embase, and Cochrane Library from inception to April 2022. All randomized controlled trials (RCTs) used intranasal midazolam and ketamine as sedatives in children were enrolled. The risk of bias in RCTs was assessed by Cochrane risk of bias tool. Condition of parental separation, anesthesia induction or facemask acceptance, sedation level, different hemodynamic parameters and adverse events were considered as the outcomes in our study. RESULTS: A total of 16 studies with 1066 patients were enrolled. Compared with midazolam, administration of intranasal ketamine might be associated with severer changes in hemodynamics parameters including mean blood pressure (SMD = -0.53, with 95% CI [-0.93, -0.13]) and heart rate (HR) (SMD = -1.39, with 95% CI [-2.84, 0.06]). Meanwhile, administration of intranasal midazolam was associated with more satisfactory sedation level (61.76% vs 40.74%, RR = 1.53, with 95%CI [1.28, 1.83]), more rapid onset of sedation (SMD = -0.59, with 95%CI [-0.90, -0.28]) and more rapid recovery (SMD = -1.06, with 95%CI [-1.83, -0.28]). Current evidences also indicated that the differences of various adverse effects between two groups were not significant. CONCLUSIONS: Given that administration of midazolam via intranasal route provides more satisfactory sedative level with less fluctuation of hemodynamics parameters and more rapid onset and recovery, it might be considered as the preferred sedative premedication for pediatric patients compared to ketamine. However, the widespread evidences with low or moderate quality indicated that superiority of intranasal midazolam in pediatric sedation needs to be confirmed by more studies with high quality and large sample size in future. TRIAL REGISTRATION: The protocol of present study was registered with PROSPERO (CRD42022321348).

Efficacy and safety of sugammadex for neuromuscular blockade reversal in pediatric patients: an updated meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: A recent survey revealed that extensive off-label use of sugammadex in pediatric anesthesia deserved particular attention. The present study with trial sequential analysis (TSA) aimed to evaluate the effects of sugammadex for antagonizing neuromuscular blockade (NMB) in pediatric patients, and to investigate whether the findings achieved the required information size to draw conclusions. METHODS: PubMed, Embase, Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched from inception to April 2021. All randomized controlled trials used sugammadex as reversal agent in pediatric patients were enrolled. Time from NMB reversal to recovery of the train-of-four ratio (TOFr) to 0.9 and extubation time were considered as co-primary outcomes, and incidences of adverse events were considered as secondary outcomes. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to rate the quality of evidences. RESULTS: Data from 18 studies involving 1,065 pediatric patients were acquired. The results revealed that use of sugammadex was associated with shorter duration from administration of reversal agents to TOFr > 0.9 (MD = -14.42, with 95% CI [-17.08, -11.75]) and shorter interval from reversal from NMB to extubation (MD = -13.98, with 95% CI [-16.70, -11.26]) compared to control groups. TSA also indicated that the current sample sizes were sufficient with unnecessary further trials. Analysis of secondary outcomes indicated that administration of sugammadex was associated with less incidence of postoperative nausea and vomiting (PONV), bradycardia, and dry mouth compared to control groups. CONCLUSION: Considering of satisfactory and rapid neuromuscular blockade reversal with low incidences of adverse events, sugammadex might be considered as the preferred option for children in clinical anesthesia practice compared to acetylcholinesterase inhibitors. However, overall low-quality evidences in present study rated by GRADE system indicated that superiority of sugammadex employed in pediatric patients needs to be confirmed by more studies with high quality and large sample size in future.

The Impact of Two-Invoice System on Pharmaceutical Manufacturers' Selling Expenses in China: A Difference-in-Differences Approach.

A perennial question for the pharmaceutical industry has been excessive drug prices. To alleviate patients' burden of expensive medical bills and increase the affordability of medicines, China adopted the Two-Invoice System (TIS) in drug procurement for public medical institutions in 2017. In this paper, we study the impact of the TIS on pharmaceutical manufacturers' selling expenses. Using a Difference-in-Differences (DID) methodology and a sample of the A-share pharmaceutical manufacturing firms listed on the Shanghai Stock Exchange and Shenzhen Stock Exchange from the years 2014 to 2020, we find that the TIS leads to a significant increase in pharmaceutical manufacturers' selling expenses but gradually weakens over time. In addition, we further explore whether the impact of the TIS on pharmaceutical manufacturers' selling expenses is affected by the pharmaceutical manufacturers' previous drug circulation mode. The results indicate that the TIS could significantly increase the pharmaceutical manufacturers' selling expenses in the agency mode group. However, there is no evidence to support the TIS having the same effect in the direct sales office model group.

Will the Volume-Based Procurement Policy Promote Pharmaceutical Firms' R&D Investment in China? An Event Study Approach.

Innovation is the key to the development of the pharmaceutical industry. The pilot program of China's "4 + 7" volume-based procurement policy ("4 + 7" procurement policy) brings the drug price back to a reasonable level through trading procurement quantities for lower drug prices. The policy manages to reduce the burden of the health care system, improve efficiency, and push the pharmaceutical industry to transform and update from the era of high gross profit of generic drugs to innovative drugs. So far, few studies have investigated the influence of the volume-based procurement policy on the innovation of pharmaceutical firms. By combining the event study and Difference-in-Difference (DiD) methodology, this study finds that the abnormal return (AR) of firms with high R&D intensity is lower than that of firms with low R&D intensity during the event window period. Moreover, further analysis identifies the moderating effect of firm size and firm type. Specifically, the results show that the negative influence of high R&D intensity on abnormal return (AR) during the announcement of the "4 + 7" procurement policy is stronger in large firms and innovative pharmaceutical firms. Finally, we discuss the policy implications of our study.

Genetic Algorithm in Data Mining of Colorectal Images.

There is currently no effective analytical method in colorectal image analysis, which leads to certain errors in colorectal image analysis. In order to improve the accuracy of colorectal imaging detection, this study used a genetic algorithm as the data mining algorithm and combined it with image processing technology to perform image analysis. At the same time, combined with the actual requirements of image detection, the gray theory model is used as the basic theory of image processing, and the image detection prediction model is constructed to predict the data. In addition, in order to study the effectiveness of the algorithm, the experiment is carried out to analyze the validity of the data of the study, and the predicted value is compared with the actual value. The research shows that the proposed algorithm has certain accuracy and can provide theoretical reference for subsequent related research.

Opioids for the Prevention of Post-dural Puncture Headache in Obstetrics: A Systematic Review and Meta-analysis of Efficacy and Safety.

BACKGROUND: Post-dural puncture headache (PDPH), or spinal headache, is the most common serious complication resulting from iatrogenic puncture of the dura during epidural or spinal anesthesia and cerebrospinal fluid (CSF) leak in pregnant women. OBJECTIVE: To analyze the effectiveness and safety of opioids as a prophylaxis approach in treating obstetric patients who underwent unintentional dural puncture during the initiation of neuraxial anesthesia. STUDY DESIGN: A systematice review and meta-analysis. SETTING: No restriction regarding study type. METHODS: PubMed, Embase, and the Cochrane library were searched for available papers published up to September 2020. RESULTS: According to the eligibility criteria, 10 studies were included with post-dural puncture headache (PDPH) incidence as the primary outcome and the number of epidural blood patch (EBP) required as the second outcome. The risk estimates of each study were reported as odds ratios (ORs). The results showed morphine does not decrease the incidence of PDPH (OR = 0.45, 95% CI: 0.15 - 1.34, P = 0.153, I2 = 74.4%, Pheterogeneity = 0.004) and the use of EBP (OR = 0.40, 95% CI: 0.08 - 1.95, P = 0.259, I2=73.7%, Pheterogeneity = 0.004). Fentanyl does not decrease the incidence of PDPH (OR = 0.35, 95% CI: 0.01-13.77, P = 0.576, I2 = 81.0%, Pheterogeneity = 0.022). LIMITATIONS: The small number of included studies, high heterogeneity, and variety in study designs. CONCLUSIONS: Exposure to opioids for any reason after the diagnosis of unintentional dural puncture is not associated with a reduced risk of PDPH and does not decrease the need for therapeutic EBP.

A comparative evaluation of dexmedetomidine and midazolam in pediatric sedation: A meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: The present study with trial sequential analysis (TSA) was conducted to evaluate comprehensively the efficacy and safety of dexmedetomidine and midazolam in pediatric sedation, and to investigate whether the outcomes achieved the required information size to draw the conclusions. METHODS: PubMed, Embase, and Cochrane Library were searched from inception to October 2019. All randomized controlled trials used dexmedetomidine and midazolam in pediatric sedation were enrolled. Sedative efficacy, postoperative analgesic effect, and incidence of emergence agitation were considered as the co-primary outcomes. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was applied to rate the quality of evidences. RESULTS: We acquired data from 34 studies involving 2281 pediatric patients. The results indicated that administration of dexmedetomidine was associated with less incidence of emergence agitation (RR = 0.78, with 95% CI [0.65, 0.92]) and more satisfactory sedation at parental separation (RR = 0.31, with 95% CI [0.24, 0.41]) compared to midazolam, and the current sample sizes were sufficient with unnecessary further trials. Two groups did not differ significantly in sedation level at mask induction (RR = 0.86, with 95% CI [0.74, 1.00]). And using of dexmedetomidine was associated with less incidence of postoperative analgesic rescue (RR = 0.57, with 95% CI [0.35, 0.93]), but the number of patients was too few to achieve the required information size and to draw reliable conclusions. Premedication of dexmedetomidine was associated with significant less value of SBP, heart rate, increased incidence of bradycardia, and a lower rate of shivering. And there were no differences about onset of sedation and recovery time between two groups. CONCLUSIONS: Given that more satisfactory sedation at separation from parents and less incidence of emergence agitation, dexmedetomidine is preferred for pediatric sedation. However, compared with midazolam, the superiority of dexmedetomidine in providing adequate sedation at mask induction and postoperative analgesic effects has not yet been defined.

Comparison of effects and safety in providing controlled hypotension during surgery between dexmedetomidine and magnesium sulphate: A meta-analysis of randomized controlled trials.

BACKGROUND: Effectiveness of controlled hypotension has been proven in alleviating intraoperative bleeding. Many recent studies emphasized the efficacy of dexmedetomidine and magnesium in providing controlled hypotension during various surgeries. The present meta-analysis of randomized controlled trials (RCTs) was performed to evaluate comprehensively the effects and safety of these two medications. METHODS: Literature search was performed in four databases from inception to April 2019. All RCTs that used dexmedetomidine and magnesium as hypotensive agents were enrolled. The outcomes contained bleeding condition of surgical site, hemodynamic parameters, duration of surgeries, number of patients requiring opioid/analgesia administration, recovery period, and adverse events emerged during surgeries. RESULTS: Ten studies with 663 patients met with our inclusion criteria. The results indicated that both bleeding score and values of mean arterial pressure (MAP) and heart rate (HR) were significantly lower in patients receiving dexmedetomidine (SMD 1.65 with 95% CI [0.90,2.41], P<0.00001) compared to the patients receiving magnesium. The effect in decreasing the necessity of using opioid/analgesia was affirmative in dexmedetomidine group (29.13% with magnesium vs 10.78% with dexmedetomidine), and the condition was more favorable in magnesium group in reducing recovery period (SMD -1.98 with 95% CI [-4.27,0.30], P = 0.09). Compared with magnesium, using of dexmedetomidine was associated with higher incidence of bradycardia but lower incidence of nausea and vomiting. CONCLUSION: Compared with magnesium, dexmedetomidine is more effective to provide promising surgical field condition, favorable controlled hypotension, and less necessity of opioid or analgesia administration. But long recovery period and high-probability bradycardia should be deliberated.

Aortocaval compression resulting in sudden loss of consciousness and severe bradycardia and hypotension during cesarean section in a patient with subvalvular aortic stenosis.

BACKGROUND: Maternal cardiac arrest during cesarean section (CS) is an extremely rare but devastating complication. Preventing emergency events from developing into maternal cardiac arrest is one of the most challenging clinical scenarios. CASE PRESENTATION: A 35-year-old pregnant woman with subvalvular aortic stenosis who was scheduled for elective CS under epidural anesthesia, and experienced devastating supine hypotensive syndrome, but was successfully resuscitated after delivery. CONCLUSIONS: The performance of tilt position strictly or high-quality continue manual left uterine displacement (LUD) should be performed until the fetus is delivered, otherwise timely delivery of the fetus may be the best way to optimize the deadly condition.

A quality analysis of clinical anaesthesia study protocols from the Chinese clinical trials registry according to the SPIRIT statement.

OBJECTIVE: To learn about the overall quality of clinical anaesthesia study protocols from the Chinese Clinical Trials Registry and to discuss the way to improve study protocol quality. METHODS: We defined completeness of each sub-item in SPIRIT as N/A (not applicable) or with a score of 0, 1, or 2. For each protocol, we calculated the proportion of adequately reported items (score = 2 and N/A) and unreported items (score = 0). Protocol quality was determined according to the proportion of reported items, with values >50% indicating high quality. Protocol quality was determined according to the proportion of reported items. For each sub-item in SPIRIT, we calculated the adequately reported rate (percentage of all protocols with score 2 and NA on one sub-item) as well as the unreported rate (percentage of all protocols with score 0 on one sub-item). RESULTS: Total 126 study protocols were available for assessment. Among these, 88.1% were assessed as being of low quality. By comparison, the percentage of low-quality protocols was 88.9% after the publication of the SPIRIT statement. Among the 51 SPIRIT sub-items, 18 sub-items had an unreported rate above 90% while 16 had a higher adequately reported rate than an unreported rate. CONCLUSIONS: The overall quality of clinical anaesthesia study protocols registered in the ChiCTR was poor. A mandatory protocol upload and self-check based on the SPIRIT statement during the trial registration process may improve protocol quality in the future.

ET-26 hydrochloride (ET-26 HCl) has similar hemodynamic stability to that of etomidate in normal and uncontrolled hemorrhagic shock (UHS) rats.

OBJECTIVE: ET-26 HCl is a promising sedative-hypnotic anesthetic with virtually no effect on adrenocortical steroid synthesis. However, whether or not ET-26 HCl also has a sufficiently wide safety margin and hemodynamic stability similar to that of etomidate and related compounds remains unknown. In this study, the effects of ET-26 HCl, etomidate and propofol on therapeutic index, heart rate (HR), mean arterial pressure (MAP), maximal rate for left ventricular pressure rise (Dmax/t), and maximal rate for left ventricular pressure decline (Dmin/t) were investigated in healthy rats and a rat model of uncontrolled hemorrhagic shock (UHS). METHODS: 50% effective dose (ED50) and 50% lethal dose (LD50) were determined after single bolus doses of propofol, etomidate, or ET-26 HCl using the Bliss method and the up and down method, respectively. All rats were divided into either the normal group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group) or the UHS group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group). In the normal group, after preparation for hemodynamic and heart-function monitoring, rats were administered a dose of one of the test agents twofold-higher than the established ED50, followed by hemodynamic and heart-function monitoring. Rats in the UHS group underwent experimentally induced UHS with a target arterial pressure of 40 mmHg for 1 hour, followed by administration of an ED50 dose of one of the experimental agents. Blood-gas analysis was conducted on samples obtained during equilibration with the experimental setup and at the end of the experiment. RESULTS: In the normal group, no significant differences in HR, MAP, Dmax/t and Dmin/t (all P > 0.05) were observed at any time point between the etomidate and ET-26 HCl groups, whereas HR, MAP and Dmax/t decreased briefly and Dmin/t increased following propofol administration. In the UHS group, no significant differences in HR, MAP, Dmax/t and Dmin/t were observed before and after administration of etomidate or ET-26 HCl at ED50 doses (all P > 0.05). Administration of propofol resulted in brief, statistically significant reductions in HR and Dmax/t, with a brief increase in Dmin/t (P ˂ 0.05), while no significant differences in MAP were observed among the three groups. The blood-lactate concentrations of rats in the ET-26 HCl group were significantly lower than those in etomidate and propofol groups (P ˂ 0.05). CONCLUSIONS: ET-26 HCl provides a similar level of hemodynamic stability to that obtained with etomidate in both healthy rats, and rat models of UHS. ET-26 HCl has the potential to be a novel induction anesthetic for use in critically ill patients.