Sedation Research Articles

Management of analgosedation during noninvasive respiratory support: an expert Delphi consensus document developed by the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI)

BackgroundDiscomfort can be the cause of noninvasive respiratory support (NRS) failure in up to 50% of treated patients. Several studies have shown how analgosedation during NRS can reduce the rate of delirium, endotracheal intubation, and hospital length of stay in patients with acute respiratory failure. The purpose of this project was to explore consensus on which medications are currently available as analgosedatives during NRS, which types of patients may benefit from analgosedation while on NRS, and which clinical settings might be appropriate for the implementation of analgosedation during NRS.MethodsThe Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) selected a panel of experts and asked them to define key aspects of the use of analgesics and sedatives during NRS treatment. The methodology applied is in line with the principles of the modified Delphi and RAND-UCLA methods. The experts developed statements and supportive rationales which were then subjected to blind votes for consensus.ResultsThe use of an analgosedation strategy in adult patients with acute respiratory failure of different origins may be useful where there is a need to manage discomfort. This strategy should be considered after careful assessment of other potential factors associated with respiratory failure or inappropriate noninvasive respiratory support settings, which may, in turn, be responsible for NRS failure. Several drugs can be used, each of them specifically targeted to the main component of discomfort to treat. In addition, analgosedation during NRS treatment should always be combined with close cardiorespiratory monitoring in an appropriate clinical setting.ConclusionsThe use of analgosedation during NRS has been studied in several clinical trials. However, its successful application relies on a thorough understanding of the pharmacological aspects of the sedative drugs used, the clinical conditions for which NRS is applied, and a careful selection of the appropriate clinical setting.

γ-Aminobutyric acid type A receptor β1 subunit gene polymorphisms are associated with the sedative and amnesic effects of midazolam

Midazolam is widely used for intravenous sedation. However, wide interindividual variability is seen in the sensitivity to midazolam. The association between genetic factors and interindividual differences in midazolam sensitivity remains unclear. The present study explored the association between common genetic variants and sedative and amnesic effects of midazolam. This prospective study included patients who were scheduled to undergo dental procedures under intravenous sedation. The sedative effect was evaluated using the Ramsay sedation scale 5 min after midazolam (0.05 mg/kg) administration. We employed two parallel approaches in this study: genome-wide approach and candidate gene approach. The γ-aminobutyric acid type A receptor subunit genes were selected as candidate genes. Multivariate linear regression analyses were performed to investigate the association between the Ramsay sedation scale and genetic variants. We also analyzed the association between the presence of anterograde amnesia and genetic variants using multivariate binominal logistic regression analyses. The analyses were adjusted for potential confounding factors. A total of 191 patients were included in the analyses. In the genome-wide association analyses, no significant association was found between the genetic variants and Ramsay scores. In the candidate gene analyses, the rs73247636 (dominant model: β = 0.72 [95% confidence interval, 0.34 to 1.10], P < 0.001) and rs56278524 (dominant model: β = 0.73 [0.37 to 1.10], P < 0.001) polymorphisms of the GABRB1 gene were significantly associated with Ramsay scores. Additionally, the rs73247636 (dominant model: odds ratio [OR] = 8.39 [2.36 to 29.85], P = 0.001) and rs56278524 (dominant model: OR = 15.26 [3.42 to 68.07], P < 0.001) polymorphisms were also significantly associated with the presence of anterograde amnesia. The rs73247636 and rs56278524 single-nucleotide polymorphisms of GABRB1 were associated with the sedative and amnesic effects of midazolam.

Evaluation of Oral Pregabalin as a Preemptive Adjuvant for Postoperative Pain in Patients Undergoing Coronary Artery Bypass Grafting With General Anesthesia and High Thoracic Epidural: A Randomized Controlled Study.

Aim This study aimed to evaluate the effectiveness of oral pregabalin as a preventive supplement in managing postoperative pain in patients undergoing coronary artery bypass grafting (CABG) with a combination of general anesthesia and high thoracic epidural anesthesia. Material and methods This 18-month randomized controlled study at a tertiary hospital's anesthesiology department included 62 American Society of Anesthesiologists (ASA) II or III patients aged 35-75 with left ventricular ejection fraction >35%. Placebo (Group B, n = 31) or pregabalin (Group A, n = 31) was randomly allocated. Group A got 150 mg of pregabalin the night before surgery and 75 mg on postoperative days 0 and 1, whereas Group B received a placebo. Postoperative pain was evaluated using the Verbal Numerical Scale and Visual Analogue Scale, while sedation was assessed with the Ramsay Sedation Scale. Statistical analysis was performed using SPSS for Windows, Version 16.0 (Released 2007; SPSS Inc., Chicago). Results In this study, pregabalin significantly reduced postoperative pain on Day 0 and Day 1 (p < 0.001) compared to the placebo. The pregabalin group exhibited higher sedation scores on Day 0 (p < 0.001), but there were no significant differences on Day 1. Inotrope requirements were similar between both groups. Conclusions CABG patients' postoperative pain was greatly reduced by pregabalin without impacting sedation or inotrope needs. These data imply that pregabalin was a useful supplementary analgesic for CABG patients' multimodal pain treatment.

Eucalyptus essential oil exerted a sedative-hypnotic effect by influencing brain neurotransmitters and gut microbes via the gut microbiota-brain axis.

Sleep disorders are becoming more and more common, leading to many health problems. However, most of current available medications to treat sleep disorders are addictive and even impair cognitive abilities. Therefore, it is important to find a natural and safe alternative to treat sleep disorders. In this study, twenty-four 8-week-old male ICR mice (25 ± 2g) were equally divided into three groups: the control group (gavage of 0.9% saline), the eucalyptus essential oil (EEO) group (10mg/kg B.W.), and the diazepam group (1mg/kg B.W.). Firstly, open field test and sleep induction test were used to determine the sedative-hypnotic effect of EEO. Secondly, the effect of EEO on neurotransmitters in the mice brain was determined. Finally, based on the gut microbiota-brain axis (GMBA), the effect of EEO on the intestinal flora of mice was explored. It was found that EEO significantly reduce the activity and prolong the sleep duration of mice, exhibiting a good sedative-hypnotic effect. In the brain, EEO could increase the levels of sleep-promoting neurotransmitters, such as glutamine, Gamma-aminobutyric acid (GABA), glycine, tryptophan, N-acetylserotonin, and 5-hydroxyindoleacetic acid (5-HIAA). In the intestine, EEO was found to increase the diversity of gut microbes, the abundance of short chain fatty acid (SCFA) producing flora, and the abundance of functional flora synthesizing GABA and glycine neurotransmitters. These studies suggested that EEO exerted a sedative-hypnotic effect by acting on gut microbes and neurotransmitters in the brain. EEO has the potential to become a natural and safe alternative to traditional hypnotic sedative drugs.

Dexmedetomidine vs. Fentanyl for Awake Fiberoptic Intubation Among Adults in Tamil Nadu - A Randomized Control Trial.

Background: Dexmedetomidine and fentanyl are often administered medications for inducing conscious sedation, a technique employed for performing awake fibreoptic intubation. However, there is a scarcity of literature that directly compares the effects of these drugs when administered at equivalent doses. This study sought to assess the effectiveness and safety of using dexmedetomidine and fentanyl in adult patients undergoing Awake Fiberoptic Intubation (AFOI). Methodology: The current research study undertaken was a randomized controlled trial conducted among adult patients at A hospital providing specialized medical services in Salem, Tamil Nadu. There were 60 study participants, 30 participants in each group. A group received the drug dexmedetomidine 1-µg/kg while B group received fentanyl l-µg/kg intravenously. Primary outcomes measured were the efficacy of both drugs for sedation, patients’ comfort and compliance during AFOI, cough score, BP, HR, post-intubation score, and the Ramsay sedation score and SpO2 for 15 minutes intraoperatively. Results: The study found that 80% of study participants in A group had cough score below 2, compared to only 6.7% in group B. Post-intubation cooperation was also higher in group A, with 83.3% of patients showing cooperation. The Ramsay sedation score showed significant differences between the groups. Intubation length was shorter in group A, while group B experienced HR increased, SBP, and oxygen saturation. These findings highlight the importance of individualized care in patient care. Conclusion: Dexmedetomidine is superior to fentanyl for AFOI. Regarding the provision of heightened sedation, enhanced intubating circumstances, and increased tolerance to intubation, and greater hemodynamic stability, all within a shorter duration for intubation.

Association between duration of action of benzodiazepine hypnotic drugs and blepharospasm: A disproportionality analysis study using FDA Adverse Events Reporting System.

Association between duration of action of benzodiazepine hypnotic drugs and blepharospasm: A disproportionality analysis study using FDA Adverse Events Reporting System.

A Comparison of the Use of Propofol versus Midazolam for Pediatric Magnetic Resonance Imaging Sedation: Retrospective Cohort Study.

The aim of the present study was to do a comparison of the recovery profiles and airway-related adverse events of pediatric magnetic resonance imaging (MRI) sedation patients who received propofol alone to those who received midazolam alone. This retrospective cohort study was approved by the Mutah University Ethical Approval Committee (No. 2378). A search of the patients' medical records was performed between September 2021 and April 2022 to identify children aged 4 months-11 years who received propofol or midazolam for MRI sedation. The patients were subdivided into two groups: Those who had propofol alone (propofol group) and those who received midazolam (midazolam group) for pediatric MRI sedation. In propofol group, a 1-2 mg/kg of propofol bolus was given to have a deep sedation (Ramsay Sedation Scale score of 5). Patients in midazolam group received 0.05 mg/kg of midazolam. During the maintenance state of sedation, the patient received 150 µg/kg/min of propofol, and the infusion rate was adjusted in 25 μg/kg/min increments up or down at the discretion of the anesthesiologists to maintain a state of deep sedation. The major targets of this study were recovery profiles (time to awake and time to discharge) and airway-related intervention ratios in pediatric MRI sedation patients. Patient demographics, MRI sedation, and recovery data, including propofol induction dose, airway intervention, and sedation-related adverse events from the pediatric sedation recovery unit were also collected. The mean (standard deviation [SD]) propofol induction dose was higher compared to midazolam group (2.4 [0.7] mg vs. 1.3 [0.5] mg; mean difference, 1.1 mg; P < 0.001). The mean (SD) infusion rate was higher in propofol group compared to midazolam group (161.3 [37.6] μg/min/kg vs. 116.2 [25.6] μg/min/kg; mean difference 45.1 μg/min/kg; P < 0.001). The mean (SD) propofol total dose was higher in propofol group compared to midazolam group (236.3 [102.4] mg vs. 180.7 [80.9] mg; mean difference, 155.4 mg; P < 0.001). The mean (SD) time to awake was longer in midazolam group compared to propofol group (21.2 [5.6] min vs. 23.0 [7.1] min; mean difference, 1.8 min; P < 0.001). The mean (SD) time to discharge was longer in midazolam group compared to propofol group (34.5 [6.9] min vs. 38.6 [9.4] min; mean difference, 4.1 min; 95% confidence interval, 3.0-5.1; P < 0.001). The administration of midazolam during pediatric MRI sedation can decrease the frequency of airway complications without prolonging the clinically significant recovery profile.

Novel neuropharmacological activity of citrus lime (Citrus aurantifolia): A standardized lime peel supplement enhances non-rapid eye movement sleep by activating the GABA type A receptor

Polyphenols have been well-established to exert sedative-hypnotic effects in psychopharmacology. Lime (Citrus aurantifolia) peel is rich in biologically active polyphenols; however, the effects of lime peel extract on sleep have not yet been demonstrated. A comparison was conducted in mice, between the sleep-promoting effects of a standardized lime peel supplement (SLPS) and a well-known hypnotic drug, zolpidem, and its hypnotic mechanism was investigated using in vivo and in vitro assays. The effects of SLPS on sleep were assessed using a pentobarbital-induced sleep test and sleep architecture analysis based on recording electroencephalograms and electromyograms. Additionally, a GABAA receptor binding assay, electrophysiological measurements, and in vivo animal models were used to elucidate the hypnotic mechanism. SLPS (200 and 400 mg/kg) was found to significantly decrease sleep latency and increase the amount of non-rapid eye movement sleep without altering delta activity. The hypnotic effects of SLPS were attributed to its flavonoid-rich ethyl acetate fraction. SLPS had a binding affinity to the GABA-binding site of the GABAA receptor and directly activated the GABAA receptors. The hypnotic effects and GABAA receptor activity of SLPS were completely blocked by bicuculline, a competitive antagonist of the GABAA receptor, in both in vitro and in vivo assays. To the best of our knowledge, this study is the first to demonstrate the hypnotic effects of SLPS, which acts via the GABA-binding site of the GABAA receptor. Our results suggest that lime peel, a by-product abundantly generated during juice processing, can potentially be used as a novel sedative-hypnotic.

Depression of cortical neuronal activity after a low-dose fentanyl in preterm infants.

Opioids might be harmful to the developing brain and dosing accuracy is important. We aimed at investigating fentanyl effects on cortical activity in infants using computational re-analysis of bedside recorded EEG signals. Fifteen infants born at median 26.4 gestational weeks (range 23.3-34.1), with a birth weight 740 grams (530-1420) and postnatal age 7 days (5-11) received fentanyl 0.5 or 2 μg/kg intravenously before a skin-breaking procedure or tracheal intubation, respectively. Cortical activity was continuously recorded using amplitude-integrated electroencephalography (aEEG). Analyses using three computational EEG features representing cortical synchrony and signal power, were conducted five minutes pre- and 10 minutes post the drug administration. Visual assessment of trends displayed from the EEG metrics did not indicate systematic changes. However, the magnitude of the changes in the parietal and right hemisphere signals after the dose was significantly correlated (ρ < -0.5, p < 0.05) to the EEG amplitude and frequency power level before drug administration. This effect started after 3-4 min. Fentanyl, even in small doses, may affect cortical activity in the preterm brain. The effect is robustly related to the state of cortical activity prior to drug treatment, which must be taken into account when analysing the effects of sedative drugs.

Dexmedetomidine versus Ketofol for Moderate Sedation in Endoscopic Retrograde Cholangiopancreatography.

To compare the efficacy of dexmedetomidine versus ketofol for moderate sedation in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Randomised controlled trial. Place and Duration of the Study: Department of Anaesthesia, SICU and Pain Management, Sindh Institute of Urology and Transplantation, Karachi, Paksitan, from December 2021 to June 2022. Sixty-two patients aged 20-60 years of any gender scheduled for elective ERCP were included. Patients were randomly divided into Dexmedetomidine group (2ml ampule of 100ug/ml diluted in 18ml of normal saline) and Ketofol group (2ml ketamine and 10ml of propofol 1% diluted in 8ml of normal saline) for sedation. The mean difference in time to achieve Ramsay Sedation Scale (RSS) score of 4 and Modified Aldrete's Score (MAS) of 9 were noted as outcomes in each group. In addition, complications during the procedure and recovery were also noted. The mean age was 39.15 ± 9.82 years. There were 33 (53.2%) males and 29 (46.8%) females. The mean time to achieve RSS 4 was significantly lower in patients who were treated with Dexmedetomidine as compared to Ketofol, i.e., 11.84 ± 1.77 minutes vs. 13.10 ± 1.64 minutes respectively (p-value 0.005, 95% CI -2.12 to -0.39). Similarly, the mean time to achieve MAS score 9 was significantly lower in patients who were treated with Dexmedetomidine as compared to Ketofol, i.e., 11.19 ± 1.72 minutes vs. 12.23 ± 1.84 minutes, respectively (p-value 0.026, 95% CI -1.94 to -0.13). Dexmedetomidine proved to be more effective than Ketofol for sedation in ERCP, achieving faster sedation and quicker recovery. Dexmedetomidine, Ketofol, Sedation, Endoscopic Retrograde Cholangiopancreatography.

Efficacy and Safety of General Anesthesia Induction with Ciprofol in Hip Fracture Surgery of Elderly Patients: A Randomized Controlled Trial.

Ciprofol is a new intravenous sedative / anesthetic drug. In recent years, many clinical studies have also confirmed the sedative effect of ciprofol. However, more clinical research is still needed on its clinical application characteristics in special populations. The aim of this study was to compare the clinical effects of ciprofol and propofol in general anesthesia induction of elderly patients. 60 elderly (aged ≥ 75 years) patients underwent hip fracture surgery were randomly into two groups of a 1:1 ratio. Group C (ciprofol group): 0.3mg/kg ciprofol was infused. Group P (propofol group): 1.5mg/kg propofol was infused. The observation period was from the infusion of test drug to 5 min after endotracheal intubation. The primary outcomes included the incidence of severe hypotension and hypotension during the observation period. The secondary outcomes were as follows: the success rate of general anesthesia induction, the number of additional sedation, the time of loss of consciousness (LOC), Δ MAP, Δ HR, adverse events and the frequency of vasoactive drugs used. Finally, 60 subjects completed the study. Compared with Group P, the incidence of severe hypotension in Group C was lower (26.7% vs 53.3%, P = 0.035), the incidence of hypotension was also lower (36.7% vs 63.3%, P = 0.037), Δ MAP in Group C was significantly lower (31.4 ± 11.4 vs 39.6 ± 15.7, P = 0.025), the frequency of ephedrine used and the incidence of injection pain in Group C were also significantly lower. Ciprofol showed similar efficacy to propofol when used for general anesthesia induction in elderly patients underwent hip fracture surgery and could maintain more stable blood pressure.

Initial experience with transcatheter aortic valve replacement before and after lung transplant

ObjectivesPatients with end-stage lung disease and lung transplant (LTx) recipients are high-risk candidates for surgical aortic valve replacement (AVR). Transcatheter AVR (TAVR) is an established treatment for aortic stenosis. Experience with TAVR in the LTx population is limited. We sought to report our experience in patients who underwent TAVR before or after LTx. MethodsSingle-center, retrospective analysis, including all patients who underwent TAVR pre- or post-LTx from 2000 to 2020. Indications, mode of anesthesia, timing of TAVR, and procedural outcomes were reviewed. ResultsIn total, 10 LTx patients underwent TAVR. Aortic stenosis was the indication for TAVR in all patients: 5 had TAVR pre-LTx, and 5 post-LTx. All 10 TAVRs were performed with transfemoral access, and 9 out of 10 with intravenous sedation and monitored anesthesia care; only 1 required general anesthesia. In the TAVR pre-LTx group, mean age was 62 years and 4 patients were men. Four TAVR valves were balloon-expandable and 1 self-expanding. Median time from TAVR to transplant was 7.4 months (range, 1.7-36 months), and median length of stay after TAVR 4 days (range, 2-36 days). The only TAVR-related complication was a pacemaker for heart block (1 out of 5). All 5 subsequently underwent successful double LTx (1 with concurrent liver transplant). In the TAVR post-LTx group, mean age was 66 years and 2 patients were men. Four TAVR valves were balloon-expandable and 1 was self-expanding. Median time from LTx to TAVR was 5 years (range, 2.6-7.6 years), and median length of stay post-TAVR was 2 days (range, 1-17 days). The only TAVR-related complication in this group was heart block requiring pacemaker (1 out of 5). In both groups, there were no intraprocedural mortality or conversion to surgical AVR. No patients required post-TAVR surgical intervention during study follow-up. ConclusionsOur initial experience suggests that TAVR is safe and feasible for treatment of aortic stenosis in patients with end-stage lung disease awaiting LTx, and in patients who have undergone LTx. Overall TAVR-related complications included need for pacemaker. TAVR should be considered for treatment of aortic stenosis in patients with end-stage lung disease awaiting transplant, and for post-LTx patients as an alternative to surgical aortic valve replacement.

Ni/Cu Dual-Catalyzed Propargylation for the Stereodivergent Synthesis of Methohexital.

The development of efficient methodologies for the controlled manufacture of specific stereoisomers bearing quaternary stereocenters has prompted advances in a variety of scientific disciplines including pharmaceutical chemistry, materials science, and chemical biology. However, complete control of the absolute and relative stereochemical configurations of alkyne derivatives remains an unmet synthetic challenge. Herein, a Ni/Cu dual-catalyzed asymmetric propargylic substitution reaction is presented to produce propargylated products with all-carbon quaternary stereocenters in high yields with significant diastereo- and enantioselectivities (up to >20:1 dr, >99% ee). The synthesis of all stereochemical variants of methohexital, a widely used sedative-hypnotic drug, exemplifies the efficacy of dual-catalyzed stereodivergent propargylation.

Comparison of Hemodynamic and Recovery Profile Between Segmental Thoracic Spinal and General Anesthesia in Upper Abdominal and Breast Surgeries: A Systematic Review and Meta-Analysis.

Segmental thoracic spinal anesthesia (STSA) has been described primarily as case reports for performing upper abdominal and thoracic surgeries in significant respiratory comorbid patients. A few comparative studies have recently evaluated the technique as an advantageous alternative to general anesthesia (GA). However, there is no systematic evaluation and comparison of the techniques. The present systematic review evaluated the hemodynamic, comfort, and satisfaction of patients undergoing abdominal and thoracic surgeries under STSA and GA. PubMed, CENTRAL, Google Scholar Advanced, and citation tracking were performed to find suitable articles that compared STSA and GA. The primary objective-related data were hypotension and bradycardia. The secondary objective-related data in the context of postoperative nausea vomiting (PONV), pain, rescue analgesics, sedation requirement, satisfaction, and comfort were assessed. Meta-analysis was performed for dichotomous data on hypotension, bradycardia, and PONV; odds ratio (OR) and 95% confidence interval (CI) were reported. Data of 394 patients from six studies were evaluated. Patients undergoing upper abdominal and breast surgeries under STSA had significantly higher odds of hypotension (Fixed-Effect Model OR 12.23, 95% CI 2.81-53.28; I2 =0%, and the Random Effects Model OR 12.01, 95% CI 2.75-52.52; I2 =0%) and bradycardia (Fixed-Effect Model OR 10.95, 95% CI 2.94-40.74, I2 =0%, and the Random Effects Model OR 9.97, 95% CI 2.61-38.08; I2 =0%) but lower odds of PONV (Fixed-Effect Model OR 0.24, 95% CI 0.13-0.43; I2 =0%, and the Random Effects Model OR 0.24, 95% CI 0.13-0.45; I2 =0%). Most of the patients undergoing STSA were given intravenous sedation to overcome anxiety and discomfort. Overall, patient satisfaction was on par with GA. However, few surgeons were unenthusiastic about the technique while performing axillary clearances due to bothering twitches from cautery. STSA led to early post-anesthesia care unit (PACU) discharge and provided better pain control, lowering the need for rescue analgesics and opioid consumption in the first 24-hour postoperative period. STSA is associated with very high odds of hypotension and bradycardia as compared to GA. On the other hand, STSA demonstrated superior pain control, reduced opioid requirements, shorter PACU stays, and significantly reduced risk of PONV. Nevertheless, STSA patients mostly require sedation to make the patient comfortable.

Postoperative Sedation in Free Microvascular Tissue Transfer in Head and Neck Cancer: A Comparison of Fentanyl and Morphine

Background and Aims: Head-and-neck cancer surgeries with microvascular free flap reconstruction require endotracheal tube retention for 24–48 h postoperatively. Many regimes have been used for analgesia and sedation. The efficacy of fentanyl and morphine for post-operative analgosedation was compared by evaluating the need for additional sedatives to achieve optimum sedation scores. The secondary objective included analgesia, haemodynamic stability and a re-exploration rate. Methods: This was an open-label prospective study. A sample size of 36 was calculated in each group with α = 0.05 and a power of 80% to detect a 50% difference between the groups. Ninety adult patients were allocated to receive either fentanyl (Group F) or morphine (Group M). The Richmond agitation sedation score, Behavioural pain scale score, requirement of rescue hypnotic drug, pulse rate, systolic and diastolic blood pressures and re-explorations were recorded postoperatively. Haemodynamic parameters and sedation were analysed by two-way repeated measures of analysis variances. Pain scores were analysed using the Chi-square test. Results: When titrating to optimal sedation, in Group M, more patients needed intravenous midazolam boluses (n = 42, 93.3%) as compared to Group F (n = 33, 73.3%) (P = 0.011). More subjects in Group M required propofol infusion (n = 15, 33.3%) than in Group F (n = 4, 8.9%) (P = 0.009). Mean behavioural pain scores were significantly higher in Group M (score 1: P = 0.005 and score 2: P =0.001). The difference in the mean systolic, diastolic blood pressure, pulse rate, respiratory rate and re-exploration rate between the two groups was statistically insignificant. Conclusion: For analgesia-based sedation of spontaneously breathing intubated patients after head-and-neck cancer reconstructive surgeries, fentanyl is more effective than morphine in terms of ease of titration, sedation quality and analgesia. Both are safe for post-operative sedation regarding haemodynamic stability, tube retention and maintenance of spontaneous respiration.

Monitoring and modulation of respiratory drive in patients with acute hypoxemic respiratory failure in spontaneous breathing.

Non-invasive respiratory support, namely, non-invasive ventilation, continuous positive airway pressure, and high-flow nasal cannula, has been increasingly used worldwide to treat acute hypoxemic respiratory failure, giving the benefits of keeping spontaneous breathing preserved. In this scenario, monitoring and controlling respiratory drive could be helpful to avoid patient self-inflicted lung injury and promptly identify those patients that require an upgrade to invasive mechanical ventilation. In this review, we first describe the physiological components affecting respiratory drive to outline the risks associated with its hyperactivation. Further, we analyze and compare the leading strategies implemented for respiratory drive monitoring and discuss the sedative drugs and the non-pharmacological approaches used to modulate respiratory drive during non-invasive respiratory support. Refining the available techniques and rethinking our therapeutic and monitoring targets can help critical care physicians develop a personalized and minimally invasive approach.

Comparing the Efficacy of “Spray as You Go” Technique Versus Combined Airway Nerve Block and “Spray as You Go” as Topical Anesthesia During Flexible Bronchoscopy; a Double-Blinded Randomized Clinical Trial

Flexible bronchoscopy is employed to diagnose a range of respiratory disorders. Local airway anesthesia is mandatory to facilitate tracheal intubation. It is commonly done by injection of diluted lidocaine through working channel of bronchoscope via Spray-as-you-go (SAYGO) method. Other methods such as airway nerve block (ANB) by direct injection of lidocaine are also used to increase patient comfort. The aim of this study was to compare patient and physician satisfaction during bronchoscopy in two groups receiving SAGO alone versus combination of SAYGO and ANB. In a double-blinded randomized clinical trial, 68 patients undergoing bronchoscopy were divided into two groups. The first group received local anesthesia solely through the SAYGO method, while the second group received a combination of SAYGO and ANB. Both groups received intravenous sedation. The anesthesia level was assessed using Ramsay score. Patient and physician satisfaction with bronchoscopy was evaluated on a numeric scale of 1 to 5. Combination of ANB and SAYGO resulted in significantly higher satisfaction score both in physician [3.4±1.6 and 4.6±0.8] and patients [3.5±1.3 and 4.9±0.4] (P&lt;0.001). Thirteen individuals (38.2%) in the SAYGO and four individuals (11.8%) in SAYGO+ANB experienced a drop in oxygen levels (P=0.023). Additionally, sedation levels (Ramsay sedation scale score) were significantly higher in the first group (4) compared to the second group (3) (P=0.001). Combining ANB with SAYGO resulted in higher patient and physician comfort during bronchoscopy in comparison to SAYGO alone with no increase in complications.

Toward Model-Informed Precision Dosing for Remimazolam: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Remimazolam, widely used for procedural sedation and general anesthesia, is a new ultra short-acting benzodiazepine for intravenous sedation and anesthesia. We aim to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of remimazolam and its metabolite CNS 7054 in healthy Chinese volunteers using population analysis and suggest an optimal dosing regimen for sedation therapy. Data were collected from a single-center, placebo-controlled, randomized, and dose-escalation clinical pharmacology study. Forty-six healthy volunteers received a single infusion dose of remimazolam, while nine healthy subjects received a continuous infusion of remimazolam. A population PK/PD model was established and RxODE and Shiny in R were used to design the remimazolam dosing regimens. A three-compartment model best described the PK of remimazolam and a two-compartment model with one transit compartment was adopted for CNS 7054. The relationship between exposure and the bispectral index was best described using an effect compartment model with an inhibitory sigmoid model. Additionally, a web-based dashboard was developed to provide individualized dosing regimens, complemented by a graphical illustration of the PK/PD profiles of the proposed dosing regimen. The established population PK/PD model characterized the dose-exposure-response relationship of remimazolam well, which could be applied to optimize individual dosing regimens.

Biopharmaceutical studies of a novel sedative sublingual lozenge based on glycine and tryptophan: A rationale for mucoadhesive agent selection

Effective sedative drugs are in great demand due to increasing incidence of nervous disorders. The present work was aimed to develop a novel sublingual sedative drug based on glycine and L-tryptophan amino acids. Carbopol and different hydroxypropyl methylcellulose species were alternatively tested as mucoadhesive agents intended to prolong tryptophan sublingual release time. A model lipid medium of fully hydrated L-α-dimyristoylphosphatidylcholine was used for optimal mucoadhesive agents selection. Simultaneous processes of drug release and diffusion in lipid medium were first investigated involving both experimental and theoretical approaches. Individual substances, their selected combinations as well as different drug formulations were consecutively examined. Application of kinetic differential scanning calorimetry method allowed us to reveal a number of specific drug-excipient effects. Lactose was found to essentially facilitate tryptophan release and provide its ability to get into the bloodstream simultaneously with glycine, which is necessary to achieve glycine-tryptophan synergism. Introduction of a mucoadhesive agent into the formulation was shown to change kinetics of drug-membrane interactions variously depending on viscosity grade. Among the mucoadhesive agents, hydroxypropyl methylcellulose species K4M and E4M were shown to further accelerate drug release, therefore they were selected as optimal. Thus, effectiveness of the novel sedative drug was provided by including some excipients, such as lactose and the selected mucoadhesive agent species. A dynamic mathematical model was developed properly describing release and diffusion in lipid medium of various drug substances. Our study clearly showed applicability of a lipid medium to meet challenges such as drug-excipient interactions and optimization of drug formulations.

Volatile Sedation in Neurointensive Care Patients After Aneurysmal Subarachnoid Hemorrhage: Effects on Delayed Cerebral Ischemia, Cerebral Vasospasm, and Functional Outcome

Volatile anesthetics have shown neuroprotective effects in preclinical studies, but clinical data on their use after aneurysmal subarachnoid hemorrhage (aSAH) are limited. This study aimed to analyze whether the use of volatile anesthetics for neurocritical care sedation affects the incidence of delayed cerebral ischemia (DCI), cerebral vasospasm (CVS), DCI-related infarction or functional outcome. Data were retrospectively collected for ventilated aSAH patients (2016-2022), who received sedation for at least 180 hours. For comparative analysis patients were assigned to a control and a study group according to the sedation used (intravenous vs. volatile sedation). Logistic regression analysis was performed to identify independent predictors of DCI, CVS, DCI-related infarction, and functional outcome. 99 patients with a median age of 58 years (IQR 52-65 years) were included. 47 patients (47%) received intravenous sedation, while 52 patients (53%) received (additional) volatile sedation with isoflurane (n=30, 58%) or sevoflurane (n=22, 42%) for a median duration of 169 hours (range 5-298 hours). There were no significant differences between the two groups regarding the occurrence of DCI, angiographic CVS, DCI-related infarction, or functional outcome. In a multivariable logistic regression analysis, the use of volatile anesthetics had no impact on the incidence of DCI-related infarction or the patients' functional outcome. Volatile sedation in aSAH patients is not associated with the incidence of DCI, CVS, DCI-related infarction or functional outcome. Although we could not demonstrate neuroprotective effects of volatile anesthetics, our results suggest that volatile sedation after aSAH has no negative effect on patient's outcome.