Sclareol antagonizes the sedative effect of diazepam in thiopental sodium-induced sleeping animals: In vivo and in silico studies.

BACKGROUND: Sclareol (SCL), a labdane diterpene compound found in Salvia sclarea L., exhibited therapeutic effects. This study investigated the potential interaction between SCL and diazepam (DZP) in modulating sedation in the thiopental sodium-induced sleeping animal model, supported by in-silico molecular docking analysis. METHODS: The control, sclareol (5, 10 and 20 mg/kg), and the reference drugs [diazepam: 3 mg/kg and Caffeine (CAF): 10 mg/kg] were used in male albino mice. Then, sodium thiopental (40 mg/kg, i.p.) was administrated to induce sleep. The latent period, percentage of sleep incidence and modulation of latency were measured. Further, homology modeling of human γ-aminobutyric acid (GABA) was conducted examine the binding mode of GABA interaction with SCL, DZP, and CAF compounds RESULTS: SCL (low dose) slightly increased the sleep latency, while the higher dose significantly prolonged sleep latency. DZP, a GABAA receptor agonist, exhibited strong sleep-inducing properties, reducing sleep latency, and increasing sleeping time. Caffeine (CAF) administration prolonged sleep latency and reduced sleeping time, consistent with its stimulant effects. The combination treatments involving SCL, DZP, and CAF showed mixed effects on sleep parameters. The molecular docking revealed good binding affinities of SCL, DZP, and CAF for GABAA receptor subunits A2 and A5. CONCLUSIONS: Our findings highlighted the complex interplay between SCL, DZP, and CAF in regulating sleep behaviors and provided insights into potential combination therapies for sleep disorders.

Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations.

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Quercetin increases the antidepressant-like effects of sclareol and antagonizes diazepam in thiopental sodium-induced sleeping mice: A possible GABAergic transmission intervention.

Quercetin is the most common polyphenolic flavonoid present in fruits and vegetables demonstrating versatile health-promoting effects. This study aimed to examine the effects of quercetin (QR) and sclareol (SCL) on the thiopental sodium (TS)-induced sleeping and forced swimming test (FST) mouse models. SCL (1, 5, and 10 mg/kg, p.o.) or QR (50 mg/kg, p.o.) and/or diazepam (DZP) (3 mg/kg, i.p.) were employed. After 30 min of TS induction, individual or combined effects on the animals were checked. In the FST test, the animals were subjected to forced swimming after 30 min of administration of the test and/or controls for 5 min. In this case, immobility time was measured. In silico studies were conducted to evaluate the involvement of GABA receptors. SCL (5 and 10 mg/kg) significantly increased the latency and decreased sleeping time compared to the control in the TS-induced sleeping time study. DZP (3 mg/kg) showed a sedative-like effect in animals in both sleeping and FST studies. QR (50 mg/kg) exhibited a similar pattern of activity as SCL. However, its effects were more prominent than those of SCL groups. SCL (10 mg/kg) altered the DZP-3-mediated effects. SCL-10 co-treated with QR-50 significantly (p < 0.05) increased the latency and decreased sleep time and immobility time, suggesting possible synergistic antidepressant-like effects. In silico studies revealed that SCL and QR demonstrated better binding affinities with GABAA receptor, especially α2, α3, and α5 subunits. Both compounds also exhibited good ADMET and drug-like properties. In animal studies, the both compounds worked synergistically to provide antidepressant-like effects in a slightly different fashion. As a conclusion, the combined administration of SCL and QR may be used in upcoming neurological clinical trials, according to in vivo and in silico findings. However, additional investigation is necessary to verify this behavior and clarify the potential mechanism of action.

In vivo study of the utility of selective intra-arterial injection of thiopental for neuroprotection in reversible cerebral ischemia.

BACKGROUND: Neuroprotective agents are needed to reduce cerebral damage during surgical or neurointerventional procedures including stroke patients. PURPOSE: To evaluate if thiopental can be used as a neuroprotective agent when injected intra-arterially in a transient ischemia model. MATERIAL AND METHODS: In total, 24 rabbits were studied as four groups of six animals. Group 1 served as the control group. In group 2, transient ischemia was obtained by intracarotid administration of degradable starch microspheres (DSM). Group 3 was administered thiopental intra-arterially via the carotid artery. Group 4 (experimental group) received both thiopental and DSM intra-arterially. DSM and thiopental were administered through a microcatheter placed into the common carotid artery via the central ear artery access. After sacrifice, apoptotic cells in the cerebral tissues of the animals were evaluated in H&E and TUNEL stained slides. RESULTS: There was a significant increase in the number of apoptotic glial or neuronal cells in group 2 compared to the control group and group 3. The mean number of both the apoptotic neuronal cells (6.8 ± 2.1 vs. 2.5 ± 1.3, P < 0.001) and the apoptotic glial cells (9.4 ± 3.1 vs. 4.6 ± 1.6, P < 0.001) were higher in group 2 compared to group 4. In addition, a higher level of neurological improvement was observed in group 4 compared to group 2 based on neurological assessment score. CONCLUSION: The intra-arterial administration of thiopental has a protective effect on both glial and neuronal cells during temporary cerebral ischemia in low doses.

Histological Alterations in the Internal Organs of Wistar Han Rats (Rattus norvegicus) Euthanized by Five Different Methods.

Selecting a method of euthanasia is an important step in designing research studies that use animals; euthanasia methods must be humane, cause minimal pain and suffering to the animal, and preserve the tissue architecture of the organs of interest. In this study, we evaluated the histomorphology of the internal organs (lung, spleen, heart, kidney, liver, brain, and adrenal gland) of rats submitted to five different methods of euthanasia, with the goal of determining which protocol caused the least alteration of histomorphology. Twenty adult Wistar Han rats (Rattus norvegicus) were divided into 5 groups of 4 rats each (2 females and 2 males) and were euthanized by CO2 or isoflurane inhalation, sodium thiopental or xylazine plus ketamine overdose, or decapitation. All euthanasia was performed in accordance with published guidelines and local legal require- ments. Necropsy was performed immediately after euthanasia. Specific internal organs were removed and placed in formalin and submitted for routine histologic processing. Histomorphological examination of hematoxylin and eosin-stained tissues revealed circulatory alterations in multiple organs, predominantly congestion in multiple tissues, pulmonary hemorrhage, and hepatic degeneration. The euthanasia methods that induced the most severe alterations were exposure to CO2 and anesthetic overdose with xylazine plus ketamine or sodium thiopental. Euthanasia by overexposure to isoflurane caused less damage, and the alterations were of minimal severity. Decapitation resulted in the lowest incidence of lesions in multiple organs but due its traumatic nature, it caused the highest incidence of pulmonary hemorrhage. In selecting a method of euthanasia, factors to consider are the species of animal, the purpose of the research, and the practical ability to perform the procedure to achieve maximal animal welfare without iatrogenic changes that could compromise the outcome and reproducibility of the study.

The dosage of thiopental as pharmacological cerebral protection during non-shunt carotid endarterectomy: A retrospective study.

Background: Thiopental has been used as a pharmacological cerebral protection strategy during carotid endarterectomy surgeries. However, the optimal dosage required to induce burst suppression on the electroencephalogram (EEG) remains unknown. This retrospective study aimed to determine the optimal dosage of thiopental required to induce burst suppression during non-shunt carotid endarterectomy. Methods: The Neurological Institute of Thailand Review Board approved the study. Data were collected from 2009 to 2019 for all non-shunt carotid endarterectomy patients who received thiopental for pharmacological cerebral protection and had intraoperative EEG monitoring. Demographic information, carotid stenosis severity, intraoperative EEG parameters, thiopental dosage, carotid clamp time, intraoperative events, and patient outcomes were abstracted. Results: The study included 57 patients. Among them, 24 patients (42%) achieved EEG burst suppression pattern with a thiopental dosage of 26.3±10.1 mg/kg/hr. There were no significant differences in perioperative events between patients who achieved burst suppression and those who did not. After surgery, 33.3% of patients who achieved burst suppression were extubated and awakened. One patient in the non-burst suppression group experienced mild neurological deficits. No deaths occurred within one month postoperative. Conclusions: The optimal dosage of thiopental required to achieve burst suppression on intraoperative EEG during non-shunt carotid endarterectomy was 26.3±10.1 mg/kg/hr.

Urgent first-step screening method for ketamine, phenobarbital, zopiclone, zolpidem, phenytoin and thiopental in adulterated soft drink.

Date-rape drugs given to victims through drinks without their knowledge in drug-facilitated sexual assaults and thefts (money, property and body organs), are important threats for the public. Detection in beverage residues gains importance, since some of them can be quickly eliminated from the body, till the victim understands what he/she has experienced, goes to the hospital and gives a urine sample for analysis. Here, date-rape drugs; ketamine, thiopental, phenobarbital, zolpidem, phenytoin and zopiclone were analyzed simultaneously in 1.00mL caffeine-based carbonated beverage residue, through direct injection, using a modified, economical emergency first-step screening method with high performance liquid chromatography-diode array detector (elution time: 11 minutes). Screening power of the method was qualitatively observed in sour cherry juice, sweet soda and beer with some additional experiments. Caffeine in caffeine-based carbonated beverage could also be detected simultaneously. LODs and LOQs were between 0.02-1.79 and 0.08-5.60µgmL-1. Repeatability and reproducibility values were <9.91%. HorRat values were between 0.184-0.500. As the first screening and quantitative study on the simultaneous analysis of these drugs in a beverage, it's important for solving the crimes committed using drugs in caffeine-based carbonated beverage residues found at the crime scene, when the use of these drugs is suspected after anamnesis and inspection.

General intravenous anesthetics - pharmacodynamics, pharmacokinetics and chiral properties.

In continuation of our published review on general inhalational anesthetics, the current article presents a survey of intravenous agents for general anaesthesia. From chemical point of view these compounds belong to structurally diverse categories, such as barbiturates - thiopental (Sodium pentothal®, Trapanal®, Pentothal®), methohexital (Brevital®), and hexobarbital (Evipan®, Hexenal®, Citopan®, Tobinal®); non-barbiturate derivatives - ketamine (Ketalar® Ketaset®), esketamine (Ketanest®), and etomidate (Amidate®, Hypnomidate®), phenolic derivatives - propofol (Diprivan®); steroid derivatives - mixture of alfadolone and alfaxalone (Althesin® in human and Saffan® in veterinary anesthesia); and derivatives of phenylacetic acid - propanidid (Epontol®, Sombrevin®). Most of these compounds are chiral, with the exception of propofol and propanidid. Apart from etomidate and esketamine, they are used in the form of their racemates. Besides their characteristics and mechanism of action, attention is centred also on their chiral properties.

ANTIOXIDANT-PROOXIDANT BALANCE OF THE KIDNEYS IN RATS OF DIFFERENT AGES UNDER CONDITIONS OF EXPERIMENTAL CRANIOSKELETAL TRAUMA.

OBJECTIVE: The aim: To determine the peculiarities of the antioxidant-prooxidant balance in the kidney of rats of different ages under conditions of experimental cranioskeletal trauma (CST). PATIENTS AND METHODS: Materials and methods: The experiments involved 147 male white Wistar rats of different age groups. The first experimental group included immature animals aged 100-120 days. The second group included sexually mature animals aged 6-8 months. The third group included old animals aged 19-23 months. In all experimental groups, CST was modelled under thiopental-sodium anaesthesia. The control groups of rats was only injected with thiopental-sodium anaesthesia. The animals were withdrawn from the experiments under anaesthesia after 1, 3, 7, 14, 21 and 28 days by total bleeding from the heart. The content of reagents to thiobarbituric acid and catalase activity was determined in a 10 % kidney homogenate extract, and the antioxidant-prooxidant index (API) was calculated from the ratio of these two parameters. RESULTS: Results: As a result of the application of CST in rats of different age groups, a decrease in the value of renal API was observed with a maximum in immature rats - after 7 days, in mature and old rats - after 14 days. By day 28, the index increased in all experimental groups, but did not reach the control level. The degree of decrease in renal API in old rats under the influence of CCT was significantly higher than in other experimental groups. In immature rats, the impairment of renal API after the application of CST was less, indicating higher reserve capacity of the renal antioxidant defence system in this age group of rats. CONCLUSION: Conclusions: Simulation of CST in rats of different age groups is accompanied by a decrease in the value of API, which by day 28 does not reach the control level in any of the experimental groups. The degree of decrease in renal API value statistically significantly increases with increasing age of rats at all times of the post-traumatic period.

Thiopental and decompressive craniectomy as last-tier ICP-treatments in aneurysmal subarachnoid hemorrhage: is functional recovery within reach?

The study aimed to investigate the indication and functional outcome after barbiturates and decompressive craniectomy (DC) as last-tier treatments for elevated intracranial pressure (ICP) in aneurysmal subarachnoid hemorrhage (aSAH). This observational study included 891 aSAH patients treated at a single center between 2008 and 2018. Data on demography, admission status, radiology, ICP, clinical course, and outcome 1-year post-ictus were collected. Patients treated with thiopental (barbiturate) and DC were the main target group.Thirty-nine patients (4%) were treated with thiopental alone and 52 (6%) with DC. These patients were younger and had a worse neurological status than those who did not require these treatments. Before thiopental, the median midline shift was 0 mm, whereas basal cisterns were compressed/obliterated in 66%. The median percentage of monitoring time with ICP > 20 mmHg immediately before treatment was 38%, which did not improve after 6 h of infusion. Before DC, the median midline shift was 10 mm, and the median percentage of monitoring time with ICP > 20 mmHg before DC was 56%, which both significantly improved postoperatively. At follow-up, 52% of the patients not given thiopental or operated with DC reached favorable outcome, whereas this occurred in 10% of the thiopental and DC patients.In summary, 10% of the aSAH cohort required thiopental, DC, or both. Thiopental and DC are important integrated last-tier treatment options, but careful patient selection is needed due to the risk of saving many patients into a state of suffering.

Thiopental sodium attenuates hypoxia/reoxygenation-induced injury in osteoblasts by modulating AKT signaling.

Thiopental sodium (TPTS) is a barbiturate general anesthetic, while its effects on hypoxia/reoxygenation (H/R)-induced injury are still unclear. This study aimed to investigate whether TPTS exerts protective effects against the H/R-induced osteoblast cell injury and explore the underlying mechanisms. Osteoblast cell injury model was induced by the H/R condition, which was treated with or without TPTS. Cell viability and lactate dehydrogenase (LDH) release were determined by the corresponding commercial kits. The levels of oxidative stress were determined in the experimental groups. Cell apoptosis and Caspase-3 activities were determined by propidium iodide staining and substrate-based assay, respectively. Western blotting and qRT-PCR were performed to measure the mRNA and protein levels, respectively. Treatment with TPTS was able to increase cell viability and reduce LDH release in H/R-induced osteoblasts. Additionally, TPTS regulated oxidative stress in H/R-induced osteoblasts by suppressing malondialdehyde (MDA) and reactive oxygen species (ROS) as well as boosting superoxide dismutase (SOD). TPTS was able to suppress cell apoptosis by suppressing Caspase-3 activity and cleavage. TPTS exerted protective effects against cell injury and apoptosis induced by the H/R conditions, which were associated with its regulation of Akt signaling. Moreover, TPTS induced osteoblast differentiation under the H/R condition. In summary, TPTS attenuates H/R-induced injury in osteoblasts by regulating AKT signaling.

Decompressive craniectomy as a second/third-tier intervention in traumatic brain injury: A multicenter observational study.

OBJECTIVES: RESCUEicp studied decompressive craniectomy (DC) applied as third-tier option in severe traumatic brain injury (TBI) patients in a randomized controlled setting and demonstrated a decrease in mortality with similar rates of favorable outcome in the DC group compared to the medical management group. In many centers, DC is being used in combination with other second/third-tier therapies. The aim of the present study is to investigate outcomes from DC in a prospective non-RCT context. METHODS: This is a prospective observational study of 2 patient cohorts: one from the University Hospitals Leuven (2008-2016) and one from the Brain-IT study, a European multicenter database (2003-2005). In thirty-seven patients with refractory elevated intracranial pressure who underwent DC as a second/third-tier intervention, patient, injury and management variables including physiological monitoring data and administration of thiopental were analysed, as well as Extended Glasgow Outcome score (GOSE) at 6 months. RESULTS: In the current cohorts, patients were older than in the surgical RESCUEicp cohort (mean 39.6 vs. 32.3; p < 0.001), had higher Glasgow Motor Score on admission (GMS < 3 in 24.3% vs. 53.0%; p = 0.003) and 37.8% received thiopental (vs. 9.4%; p < 0.001). Other variables were not significantly different. GOSE distribution was: death 24.3%; vegetative 2.7%; lower severe disability 10.8%; upper severe disability 13.5%; lower moderate disability 5.4%; upper moderate disability 2.7%, lower good recovery 35.1%; and upper good recovery 5.4%. The outcome was unfavorable in 51.4% and favorable in 48.6%, as opposed to 72.6% and 27.4% respectively in RESCUEicp (p = 0.02). CONCLUSION: Outcomes in DC patients from two prospective cohorts reflecting everyday practice were better than in RESCUEicp surgical patients. Mortality was similar, but fewer patients remained vegetative or severely disabled and more patients had a good recovery. Although patients were older and injury severity was lower, a potential partial explanation may be in the pragmatic use of DC in combination with other second/third-tier therapies in real-life cohorts. The findings underscore that DC maintains an important role in managing severe TBI.

Rapidly, sensitive quantitative assessment of thiopental via forced stability indicating validated RP-HPLC method and its in-use stability activities.

Thiopental sodium (Tho) is an intravenous anesthetic. The current study aimed to find a rapid RP-HPLC method of Tho analysis with high linearity, repeatability, sensitivity, selectivity, and inexpensive. In our developed method, there is no need to use special chemical reagents, a high percentage of organic solvent, a high flow rate, or a further guard column. The chromatographic system consists of an ODS column (150 mm × 4.6 mm × 5 µm). The mobile phase was prepared by mixing KH2PO4 solution: methanol (40:60) with a flow rate of 1.2 mL/min at a detection wavelength of 230 nm, at room temperature using an injection volume of 10 µL. The method manifested a satisfied linearity regression R2 (0.9997) with a good repeatability precision range (0.16-0.47%) with LOD and LOQ; 14.4 µg/mL and 43.6 µg/mL respectively. Additionally, the method proved its efficiency via system suitability achievement in robustness and ruggedness, according to the validation guidelines. The shorter analysis time makes the method very valuable in quality control to quantify the commercial Tho in pharmaceutical preparations. This improved HPLC method has been successfully applied for Tho analysis for Thiopental UP Pharma 500 mg vials and Thiopental Eipico 1.0 g vials in our routine finished and stability studies testing laboratories. Additionally, the detection limit of Tho has been tested in our quality control lab to detect the smallest amount of traces that may be present after the cleaning process of the production machines for cephalosporins preparations. The method has shown positive results for Tho in low-level raw materials and pharmaceutical formulations.

The effects of thiopental on cold ischemic injury in renal transplantation.

INTRODUCTION: One of the most important factors influencing post-transplant success in kidney transplantation is preserving the viability of the organ from removal to transfer into the recipient. AIM: This study aimed to reduce the energy requirement with thiopental doses administered before organ transplantation, and to increase the organ viability by minimizing the tissue damage during the cold ischemia process. MATERIALS AND METHODS: Twenty female Wistar albino rats were divided into two groups: control group (group C), and thiopental group (group T). In group C, a midline incision was performed, and the renal artery was isolated under ketamine and xylazine anesthesia. A standard organ storage solution (cooled to +4°C) was used for kidney perfusion. Nephrectomy was applied, and the removed kidneys were placed into +4°C standard organ storage solution and stored at +4°C for 12 hours. Animals in group T were subjected to the procedures explained above under 85 mg/kg thiopental sodium anesthesia. After 12-hour storage, samples from the kidney tissues were fixed in 10% neutral buffered formalin. Histopathological evaluation and apoptosis detection via TUNEL method were performed. RESULTS: Tubular necrosis was more extensive in group C compared with that in group T and this difference was statistically significant. Similarly, vacuolization was widely observed in group C, and this increase was also statistically significant. For the 'dilatation of Bowman's space' parameter, a significant decrease was observed in group T compared with group C. When the apoptotic index values of both groups were examined, it was seen that they were lower in group T than those in group C. This result was statistically significant. CONCLUSIONS: These data suggest that thiopental provides protection to the kidney tissue during the cold storage process. Thiopental has been shown to decrease the number of apoptotic cells in the kidney tissue when administered to the donor before organ transplantation, increasing the organ viability.

Comparison of Low and High Doses of Pentobarbital or Thiopental for Euthanasia of Isoflurane-anesthetized Pigs.

Barbiturate overdose is a common method for euthanizing pigs. However, barbiturates can cause tissue damage and may affect experimental results, so the minimal dose should be used. The minimal dose of barbiturate for euthanasia in pigs under isoflurane anesthesia has not yet been determined. In this study, we compared the effect of low and high doses of 2 barbiturates (pentobarbital, 30 or 60 mg/kg; thiopental, 20 and 40 mg/kg) on hemodynamic parameters and time to cardiac arrest in female pigs maintained on isoflurane. Acute decreases in blood pressure and end-tidal CO2 occurred in all pigs shortly after administration of the barbiturate. However, these changes were not different between either of the high- and low dose groups. Cardiac arrest occurred significantly faster for high dose as compared with low dose thiopental groups, but this parameter was different between the 2 pentobarbital groups. The bispectral index fell immediately after dosing, in all pigs, but no significant differences were observed in the time needed to achieve 0 for the high or low-doses of either drug. In pigs maintained on isoflurane, a low dose of barbiturates is adequate for euthanasia and may result in less tissue damage.

Comparison of cytotoxic, reactive oxygen species (ROS) and apoptotic effects of propofol, thiopental and dexmedetomidine on liver cells at accumulative doses (AML12).

OBJECTIVE: Propofol, thiopental and dexmedetomidine are hypnotic, sedative, antiepileptic and analgesic agents used in general anesthesia and intensive care. There are many known and yet unknown side effects. Our aim in this study was to examine and compare the cytotoxic, reactive oxygen species (ROS) and apoptotic effects of propofol, thiopental and dexmedetomidine drugs, which are widely used in anesthesia, on liver cells (AML12) in vitro. MATERIALS AND METHODS: The half-maximum inhibitory concentration (IC50) doses of the three drugs on AML12 cells were determined using the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide (MTT) method. Then at two different doses of each of the three drugs, apoptotic effects were determined by the Annexin-V method, morphological examinations were determined by acridine orange ethidium bromide method and intracellular reactive oxygen species (ROS) levels were determined by flow cytometry. RESULTS: The IC50 thiopental, propofol and dexmedetomidine doses were found to be 255.008, 254.904 and 34.501 µgr/mL, respectively (p<0.001). The highest cytotoxic effect on liver cells was found in the lowest dose of dexmedetomidine (34.501 µgr/mL) compared to the control group. This was followed by thiopental and propofol, respectively. CONCLUSIONS: In this study, propofol, thiopental and dexmedetomidine drugs on AML12 cells were found to have toxic effects by increasing intracellular ROS at two different concentrations higher than clinical doses. It was determined that cytotoxic doses caused an increase in ROS and induced apoptosis in cells. We believe that the toxic effects of these drugs can be prevented by examining the values obtained from this study and the results of future studies.

Propofol and thiopental for intravenous induction in neonates: Study protocol for a dose-finding trial.

BACKGROUND: Propofol and thiopental are commonly used induction agents in neonatal anesthesia. Even though both hypnotics have been used off-label for many years, pharmacological knowledge regarding these agents is scarce in neonates. The significant variability in neonates' body composition, organ function, and maturation makes pharmacological studies highly relevant albeit challenging. As a result, there is currently limited data about the anesthetic induction dose of thiopental and propofol in neonates. In addition, a knowledge gap exists concerning the pharmacodynamics of induction doses. OBJECTIVE: To determine the median effective anesthetic induction dose of propofol and thiopental in neonatal patients of different gestational and postnatal ages and evaluate the pharmacodynamics of the anesthesia induction doses on the neonatal systemic and cerebral hemodynamics. METHODS: This is a single-center, prospective, open-label, interventional, dose-finding study, including neonatal patients from birth up to 28 postnatal days undergoing general anesthesia for surgical or diagnostic procedures. The patients will be stratified according to their gestational and postnatal age and allocated to one of the two trial arms: anesthesia induction with propofol or anesthesia induction with thiopental. We will use Dixon's up-and-down method to estimate the median effective anesthesia induction dose of both agents in neonates of different gestational and postnatal ages. In addition, we will study the relationship between anesthesia induction doses and changes in systemic and cerebral hemodynamics. DISCUSSION: Alterations in the systemic and cerebral regional hemodynamics secondary to anesthesia induction may be harmful in neonates, especially premature and critically ill newborns, due to their immature organ systems, reduced physiological reserves, and impaired cerebral autoregulation. Perfusion homeostasis is considered one of the significant and modifiable determinants of anesthesia-related neurocognitive outcomes. Therefore, dose-finding and safety pharmacological studies of the anesthetic induction agents in neonates are urgently needed and acknowledged as a high priority by the European Medicine Agency. Estimating adequate induction doses to ensure optimal depth of anesthesia while avoiding systemic and cerebral hemodynamic disturbances will help ensure safe anesthesia and potentially improve anesthesia-related outcomes in this group of patients. TRIAL REGISTRATION: EudraCT (EudraCT Identifier: 2019-001534-34), 05.07.2022.

Differences in Cognitive Adverse Effects and Seizure Parameters Between Thiopental and Propofol Anesthesia for Electroconvulsive Therapy.

INTRODUCTION: Electroconvulsive therapy (ECT) is a well-established treatment option in case of severe and treatment-resistant psychiatric conditions. In this retrospective study, we compared the 2 anesthetics propofol and thiopental in terms of seizure quality, cognitive adverse effects, and clinical outcome. METHODS: Data collection was performed retrospectively by a chart review, including patient files and medical records. A total of 64 patients (female = 60.9%) treated with ECT within the period of February 2019 to March 2020 were included. Of these, 35 (54.7%) received thiopental for ECT narcosis and 29 (45.3%) were treated with propofol. RESULTS: Six hundred sixteen ECT treatments (mean number per case, 9.6) were performed in total. The mean electroencephalogram seizure duration (38.3 vs 28.1 seconds, t = 3.534, degrees of freedom [ df ] = 62, P < 0.001) and motor seizure duration (21.5 vs 12.0, t = 4.336, df = 62, P < 0.001) as well as postictal suppression index and heart rate increase were significantly higher in the thiopental group. Mean stimulation energy needed per session was higher in the propofol group (88.6% vs 73.0%, Mann-Whitney U test, P = 0.042). The ECT series was more likely to be interrupted due to cognitive adverse effects in the thiopental group ( P = 0.001, Pearson χ 2 = 10.514, df = 1). Number of patients achieving remission was significantly higher in the thiopental group (31.4% vs 6.9%, P = 0.015, χ 2 = 5.897, df = 1). CONCLUSIONS: Thiopental led to better seizure duration and quality and was associated with a higher rate of remission. As a downside, thiopental was also associated with a greater risk of cognitive adverse effects.