-
Indian Journal of Critical Care... May 2024Survey of treatment practices and adherence to pediatric status epilepticus (PSE) management guidelines in India.
AIM
Survey of treatment practices and adherence to pediatric status epilepticus (PSE) management guidelines in India.
METHODS
This eSurvey was conducted over 35 days (15th October to 20th November 2023) and included questions related to hospital setting; antiseizure medications (ASMs); ancillary treatment; facilities available; etiology; and adherence to PSE management guidelines.
RESULTS
A total of 170 respondents participated, majority of them were working in tertiary level hospitals (94.1%) as pediatric intensivists (56.5%) and pediatricians (19.4%), and were in clinical practice for 2-10 years (46.5%). Majority use intravenous (IV) midazolam and levetiracetam as first- and second-line ASMs (67.1 and 51.2%, respectively). In cases with refractory status epilepticus (RSE), the most commonly used ASM is midazolam infusion (92.4%). For super-refractory status epilepticus (SRSE), the commonly used third-line ASMs include midazolam infusion (34.1%), thiopentone infusion (26.5%), high dose phenobarbitone (18.2%), and ketamine infusion (15.3%). Overall, in cases with SRSE, 44.7% respondents use ketamine infusion, 42.5% use add-on oral topiramate, and 34.7% use high-dose phenobarbitone (1-3 mg/kg/hour) infusion. Most respondents targeted both clinical and EEG seizure control (48.8%). Ancillary treatment used for SRSE included IV pyridoxine (57.1%), methylprednisolone (45.3%), IVIG (42.4%), ketogenic diet (40.6%), and second-line immunomodulation (33.5%). Most common causes were febrile SE, viral encephalitis, and febrile illness-related epilepsy syndrome (60.6%, 52.4%, and 37.1%, respectively). Facilities available included pediatric intensive care units (PICU) (97.1%), mechanical ventilation (98.2%), pediatric neurologist (68.8%), MRI brain (86.5%), EEG (69.4%), and viral PCR (58.2%). The compliance with guidelines for timing of initiation of ASM ranged from 63.5 to 88.8%.
CONCLUSION
Intravenous midazolam bolus/es, levetiracetam, and midazolam infusion are commonly used first-, second-, and third-line ASMs, respectively. There were wide variations in use of ASMs for RSE and SRSE, ancillary treatment, and compliance to PSE management guidelines.
HOW TO CITE THIS ARTICLE
Suthar R, Angurana SK, Nallasamy K, Bansal A, Muralidharan J. Survey of Pediatric Status Epilepticus Treatment Practices and Adherence to Management Guidelines (Pedi-SPECTRUM e-Survey). Indian J Crit Care Med 2024;28(5):504-510.
PubMed: 38738206
DOI: 10.5005/jp-journals-10071-24707 -
Journal of Anxiety Disorders Jun 2024Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure... (Meta-Analysis)
Meta-Analysis
Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.
Topics: Propranolol; Animals; Fear; Extinction, Psychological; Rats; Humans; Adrenergic beta-Antagonists; Male; Memory; Midazolam; Adult; Bayes Theorem; Female; Conditioning, Classical; Young Adult
PubMed: 38733644
DOI: 10.1016/j.janxdis.2024.102870 -
Drug Metabolism and Disposition: the... May 2024The CYP3A7 enzyme accounts for ~50% of the total CYP content in fetal and neonatal livers and is the predominant CYP involved in neonatal xenobiotic metabolism....
The CYP3A7 enzyme accounts for ~50% of the total CYP content in fetal and neonatal livers and is the predominant CYP involved in neonatal xenobiotic metabolism. Additionally, it is a key player in healthy birth outcomes through the oxidation of dehydroepiandrosterone (DHEA) and DHEA-S (sulfate). The amount of the other hepatic CYP3A isoforms, CYP3A4 and CYP3A5, expressed in neonates is low, but highly variable, and therefore the activity of individual CYP3A isoforms is difficult to differentiate due to their functional similarities. Consequently, a better understanding of the contribution of CYP3A7 to drug metabolism is essential to identify the risk drugs may pose to neonates and developing infants. To distinguish CYP3A7 activity from CYP3A4/5, we sought to further characterize the selectivity of the specific CYP3A inhibitors CYP3cide, clobetasol, and azamulin. We utilized three substrate probes, dibenzylfluorescein, luciferin-PPXE, and midazolam, to determine the IC and metabolism-dependent inhibition (MDI) properties of the CYP3A inhibitors. Probe selection had a significant effect on the IC values and CYP inactivation across all inhibitory compounds and enzymes. CYP3cide and azamulin were both identified as MDIs and were most specific for CYP3A4. Contrary to previous reports, we found that CP was not an MDI of CYP3A5, but was more selective for CYP3A5 over CYP3A4/7. We further investigated CYP3cide and CP's ability to differentiate CYP3A7 activity in an equal mixture of recombinant CYP3A4, CYP3A5, and CYP3A7 and our results provide confidence of CYP3cide's and CP's ability to distinguish CYP3A7 activity in the presence of the other CYP3A isoforms. These findings provide valuable insight regarding testing conditions to investigate the metabolism of new drug candidates and help determine drug safety in neonates. The results presented here also clearly demonstrate the effect probe selection may have on CYP3A P450 inhibition studies.
PubMed: 38702193
DOI: 10.1124/dmd.124.001598 -
Clinical and Translational Science May 2024St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and...
St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.
Topics: Humans; Hypericum; Blood-Brain Barrier; Phloroglucinol; Plant Extracts; Male; Adult; Positron-Emission Tomography; Terpenes; Female; Young Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B; Bridged Bicyclo Compounds; Terfenadine; Cytochrome P-450 Enzyme System; Healthy Volunteers
PubMed: 38700454
DOI: 10.1111/cts.13804 -
Clinical and Translational Science May 2024This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational... (Randomized Controlled Trial)
Randomized Controlled Trial
This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.
Topics: Humans; Midazolam; Ethinyl Estradiol; Female; Adult; Male; Young Adult; Contraceptives, Oral, Combined; Levonorgestrel; Drug Interactions; Drug Combinations; Healthy Volunteers; Adolescent; Cytochrome P-450 CYP3A; Middle Aged; Area Under Curve; Cytochrome P-450 CYP3A Inducers
PubMed: 38700236
DOI: 10.1111/cts.13791 -
Intensive & Critical Care Nursing Aug 2024To create a nomogram for early delirium detection in pediatric patients following cardiopulmonary bypass. (Observational Study)
Observational Study
OBJECTIVES
To create a nomogram for early delirium detection in pediatric patients following cardiopulmonary bypass.
RESEARCH METHODOLOGY/DESIGN
This prospective, observational study was conducted in the Cardiac Intensive Care Unit at a Children's Hospital, enrolling 501 pediatric patients from February 2022 to January 2023. Perioperative data were systematically collected through the hospital information system. Postoperative delirium was assessed using the Cornell Assessment of Pediatric Delirium (CAPD). For model development, Least Absolute Shrinkage and Selection Operator (LASSO) regression was employed to identify the most relevant predictors. These selected predictors were then incorporated into a multivariable logistic regression model to construct the predictive nomogram. The performance of the model was evaluated by Harrell's concordance index, receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis. External validity of the model was confirmed through the C-index and calibration plots.
RESULTS
Five independent predictors were identified: age, SpO levels, lymphocyte count, diuretic use, and midazolam administration, integrated into a predictive nomogram. This nomogram demonstrated strong predictive capacity (AUC 0.816, concordance index 0.815) with good model fit (Hosmer-Lemeshow test p = 0.826) and high accuracy. Decision curve analysis showed a significant net benefit, and external validation confirmed the nomogram's reliability.
CONCLUSIONS
The study successfully developed a precise and effective nomogram for identifying pediatric patients at high risk of post-cardiopulmonary bypass delirium, incorporating age, SpO2 levels, lymphocyte counts, diuretic use, and midazolam medication.
IMPLICATIONS FOR CLINICAL PRACTICE
This nomogram aids early delirium detection and prevention in critically ill children, improving clinical decisions and treatment optimization. It enables precise monitoring and tailored medication strategies, significantly contributes to reducing the incidence of delirium, thereby enhancing the overall quality of patient care.
Topics: Humans; Prospective Studies; Nomograms; Male; Female; Cardiopulmonary Bypass; Child, Preschool; Child; Infant; Delirium; Postoperative Complications; ROC Curve; Adolescent; Risk Factors
PubMed: 38692080
DOI: 10.1016/j.iccn.2024.103717 -
European Journal of Drug Metabolism and... Jul 2024Cytochrome P450 (CYP) enzymes play a central role in the elimination of approximately 80% of all clinically used drugs. Differences in CYP enzyme activity between... (Review)
Review
Cytochrome P450 (CYP) enzymes play a central role in the elimination of approximately 80% of all clinically used drugs. Differences in CYP enzyme activity between individuals can contribute to interindividual variability in exposure and, therefore, treatment outcome. In vivo CYP enzyme activity could be determined with phenotyping. Currently, (sub)therapeutic doses are used for in vivo phenotyping, which can lead to side effects. The use of microdoses (100 µg) for in vivo phenotyping for CYP enzymes could overcome the limitations associated with the use of (sub)therapeutic doses of substrates. The aim of this review is to provide a critical overview of the application of microdosing for in vivo phenotyping of CYP enzymes. A literature search was performed to find drug-drug interaction studies of CYP enzyme substrates that used microdoses of the respective substrates. A substrate was deemed sensitive to changes in CYP enzyme activity when the pharmacokinetics of the substrate significantly changed during inhibition and induction of the enzyme. On the basis of the currently available evidence, the use of microdosing for in vivo phenotyping for subtypes CYP1A2, CYP2C9, CYP2D6, and CYP2E1 is not recommended. Microdosing can be used for the in vivo phenotyping of CYP2C19 and CYP3A. The recommended microdose phenotyping test for CYP2C19 is measuring the omeprazole area-under-the-concentration-time curve over 24 h (AUC) after administration of a single 100 µg dose. CYP3A activity could be best determined with a 0.1-75 µg dose of midazolam, and subsequently measuring AUC extrapolated to infinity (AUC) or clearance. Moreover, there are two metrics available for midazolam using a limited sampling strategy: AUC over 10 h (AUC) and AUC from 2 to 4 h (AUC).
Topics: Humans; Cytochrome P-450 Enzyme System; Phenotype; Drug Interactions; Pharmaceutical Preparations; Animals; Dose-Response Relationship, Drug; Cytochrome P-450 Enzyme Inhibitors
PubMed: 38689161
DOI: 10.1007/s13318-024-00896-2 -
Indian Journal of Pharmacology Mar 2024Sedative agents used in bronchoscopy require trained personnel to administer and monitor the patient. This increases the procedure cost, duration, and inpatient stay.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sedative agents used in bronchoscopy require trained personnel to administer and monitor the patient. This increases the procedure cost, duration, and inpatient stay. Inhalational administration of sedative agents can be a practical solution to the issue. Dexmedetomidine in the inhalational form could give results similar to the intravenous form without significant adverse events.
MATERIALS AND METHODS
The study is prospective, randomized, and double-blinded study. Patients needing bronchoscopy were randomized to receive the nebulized form of either dexmedetomidine or saline (0.9%) before bronchoscopy. The study parameters are assessed and recorded before, during, and after bronchoscopy. Data collected are analyzed using the SPSS software.
DISCUSSION
The side effects limit using commonly administered sedation agents in bronchoscopy, such as midazolam, fentanyl, and dexmedetomidine. The nebulized dexmedetomidine is safe with proven efficacy when compared to the placebo. Proceduralist-administered conscious sedation reduces the overall cost and shortens inpatient stays. Attenuation of hemodynamic parameters by dexmedetomidine could be an advantage for the physician in reducing an untoward cardiac event.
CONCLUSION
Dexmedetomidine in the nebulized form improves the comfort of patients during the procedure. It blunts the pressure response during bronchoscopy and could be a safer and cost-effective agent in its nebulized form for conscious sedation in bronchoscopy. The study is approved by the institutional ethics committee (IEC KMC MLR 10-2021-310).
Topics: Dexmedetomidine; Humans; Bronchoscopy; Conscious Sedation; Hypnotics and Sedatives; Double-Blind Method; India; Male; Female; Nebulizers and Vaporizers; Prospective Studies; Middle Aged; Adult; Administration, Inhalation
PubMed: 38687314
DOI: 10.4103/ijp.ijp_160_23 -
Cureus Mar 2024Anesthesiologists often use benzodiazepines (BZDs) due to their remarkable amnestic and anxiolytic capabilities. Because of this, they are perfect for use during the... (Review)
Review
Anesthesiologists often use benzodiazepines (BZDs) due to their remarkable amnestic and anxiolytic capabilities. Because of this, they are perfect for use during the perioperative phase, when patients' anxiety levels are already high. Remimazolam has replaced certain commonly used intravenous (IV) anesthetics due to its excellent safety profile, rapid onset of action, and short half-life. The four classes of BZDs, 2-keto-benzodiazepines, 3-hydroxy-benzodiazepines, triazolobenzodiazepines, and 7-nitro-benzodiazepines based on chemical structure, provide various levels of drowsiness, forgetfulness, and anxiolysis. Based on their elimination half-life, short-acting BZDs typically have a half-life ranging from one to 12 hours, e.g., oxazepam; intermediate-acting BZDs have an average elimination half-life of 12 to 40 hours, e.g., alprazolam; and long-acting BZDs have an average elimination half-life of more than 40 hours, e.g., diazepam. The chloride ion channel is conformationally shifted by the benzodiazepine molecule resulting in central nervous system (CNS) inhibition and hyperpolarization. Each type of benzodiazepine has a favored use. For example, diazepam is used to treat anxiety. Midazolam is used for its anxiolytic and anterograde amnestic effects during the perioperative phase. Anxiety and epilepsy are two conditions that lorazepam effectively treats. There are now phase II and III clinical studies investigating remimazolam. It is not sensitive to alterations in its surroundings and has a brief half-life so that it may be removed rapidly, even after extensive infusion. Being a soft drug means the body easily breaks it down via metabolism, which explains many features. Remimazolam is hydrolyzed into methanol and its carboxylic acid metabolite CNS 7054 by esterase metabolism. Therefore, remimazolam has a shorter onset time and faster recovery than other BZDs. Remimazolam is metabolized independently of any particular organ. Patients with hepatic and renal problems will not see any changes in metabolism or excretion since the drug's ester moiety makes it a substrate for general tissue esterase enzymes. Like its predecessor, midazolam, it has a high potential for addiction. Some side effects that could occur during infusion include headaches and drowsiness. In clinical trials, hypotension, respiratory depression, and bradycardia were noted in participants. BZDs are helpful when used in conjunction with anesthesia. Remimazolam stands out, thanks to its unique pharmacokinetics, pharmacodynamics, safety profile, and potential medical applications. Its desirable properties make it a potential surgical premedication and sedative in the critical care unit. Anesthesiologists and other doctors could have access to more consistent and safer medication. However, additional comprehensive clinical trials are necessary to understand remimazolam's advantages and disadvantages.
PubMed: 38686236
DOI: 10.7759/cureus.57260 -
BMC Pediatrics Apr 2024This study aimed to compare the efficacy of neurally adjusted ventilatory assist (NAVA) to synchronized intermittent mandatory ventilation (SIMV) in preterm infants... (Comparative Study)
Comparative Study
Comparison of neurally adjusted ventilatory assist and synchronized intermittent mandatory ventilation in preterm infants after patent ductus arteriosus ligation: a retrospective study.
OBJECTIVE
This study aimed to compare the efficacy of neurally adjusted ventilatory assist (NAVA) to synchronized intermittent mandatory ventilation (SIMV) in preterm infants requiring mechanical ventilation after patent ductus arteriosus (PDA) ligation.
METHODS
A retrospective analysis was conducted on intubated preterm infants who underwent PDA ligation at our hospital from July 2021 to January 2023. Infants were divided into NAVA or SIMV groups based on the ventilation mode after surgery.
RESULTS
Fifty preterm infants were included. During treatment, peak inspiratory pressure (PIP) and mean airway pressure (MAP) were lower with NAVA compared to SIMV (PIP: 19.1 ± 2.9 vs. 22.4 ± 3.6 cmHO, P < 0.001; MAP: 9.1 ± 1.8 vs. 10.9 ± 2.7 cmHO, P = 0.002). PaO and PaO/FiO were higher with NAVA (PaO: 94.0 ± 11.7 vs. 84.8 ± 15.8 mmHg, P = 0.031; PaO/FiO: 267 [220-322] vs. 232 [186-290] mmHg, P = 0.025). Less sedation was required with NAVA (midazolam: 1.5 ± 0.5 vs. 1.1 ± 0.3 μg/kg/min, P < 0.001).
CONCLUSION
Compared to SIMV, early use of NAVA post PDA ligation in preterm infants was associated with decreased PIP and MAP. Early NAVA was also associated with reduced sedation needs and improved oxygenation. However, further studies are warranted to quantify the benefits of NAVA ventilation.
Topics: Humans; Ductus Arteriosus, Patent; Retrospective Studies; Infant, Newborn; Male; Female; Infant, Premature; Ligation; Interactive Ventilatory Support; Intermittent Positive-Pressure Ventilation; Respiratory Distress Syndrome, Newborn
PubMed: 38678190
DOI: 10.1186/s12887-024-04727-w