Development of a pharmacokinetic and pharmacodynamic model for intranasal administration of midazolam in older adults: a single-site two-period crossover study.

BACKGROUND: Intranasal midazolam can produce procedural sedation in frail older patients with dementia who are unable to tolerate necessary medical or dental procedures during domiciliary medical care. Little is known about the pharmacokinetics and pharmacodynamics of intranasal midazolam in older (>65 yr old) people. The aim of this study was to understand the pharmacokinetic/pharmacodynamic properties of intranasal midazolam in older people with the primary goal of developing a pharmacokinetic/pharmacodynamic model to facilitate safer domiciliary sedation care. METHODS: We recruited 12 volunteers: ASA physical status 1-2, aged 65-80 yr, and received midazolam 5 mg intravenously and 5 mg intranasally on two study days separated by a 6 day washout period. Concentrations of venous midazolam and 1'-OH-midazolam, Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score, bispectral index (BIS), arterial pressure, ECG, and respiratory parameters were measured for 10 h. RESULTS: Time to peak effect of intranasal midazolam for BIS, MAP, and SpO2 were 31.9 (6.2), 41.0 (7.6), and 23.1 (3.0) min, respectively. Intranasal bioavailability was lower compared with intravenous administration (Fabs 95%; 95% confidence interval: 89-100%). A three-compartment model best described midazolam pharmacokinetics following intranasal administration. A separate effect compartment linked to the dose compartment best described an observed time-varying drug-effect difference between intranasal and intravenous midazolam, suggesting direct nose-to-brain transport. CONCLUSIONS: Intranasal bioavailability was high and sedation onset was rapid, with maximum sedative effects after 32 min. We developed a pharmacokinetic/pharmacodynamic model for intranasal midazolam for older persons and an online tool to simulate changes in MOAA/S, BIS, MAP, and SpO2 after single and additional intranasal boluses. CLINICAL TRIAL REGISTRATION: EudraCT (2019-004806-90).

Moderate-to-Deep Sedation Using Target-Controlled Infusions of Propofol and Remifentanil: Adverse Events and Risk Factors: A Retrospective Cohort Study of 2937 Procedures.

BACKGROUND: In the University Medical Center Groningen in Groningen, the Netherlands, moderate-to-deep sedation is provided by nursing staff trained and supervised by the anesthesia department using protocol-based target-controlled infusions (TCIs) of propofol and remifentanil. The aim of this retrospective cohort study was to investigate the incidence of events with potential adverse health consequences within this service model and the risk factors for the occurrence of these events. METHODS: We retrospectively interrogated a database containing the computerized anesthetic records of 2937 procedures where moderate-to-deep sedation was provided using TCI administration of propofol and remifentanil between May 2014 and October 2017. The primary outcome measures were the incidence of sedation-related events with potential adverse health consequences and risk factors for the occurrence of such events. The events under investigation were unplanned intensive care unit (ICU) admission, need for cardiopulmonary resuscitation (CPR), death on the day of the procedure due to sedation-related events, cardiovascular events (arrhythmias, hypertension, and hypotension), pulmonary events (aspiration, desaturation, unplanned tracheal intubation), anaphylactic or allergic reactions, and the termination of the procedure due to sedation-related events. Cardiovascular and pulmonary events were classified as severe, significant, or moderate. Events were identified by using computer algorithms to search the computerized records from all included procedures. RESULTS: Data from 2937 procedures were analyzed. No patients suffered catastrophic events (death, need for CPR, or unplanned ICU admission). Thirty-two severe sedation-related events occurred in 32 procedures. Severe desaturation (0.6%; 95% confidence interval [CI], 0.4-0.9) and severe hypertension (0.2%; 95% CI, 0.04-0.37) were the most common severe events. Significant hypotension (8.8%; 95% CI, 7.73-9.77) and significant desaturation (1.6%; 95% CI, 1.12-2.02) were found to be the most common events with potential adverse health consequences. No patient suffered lasting health consequences. Average mean and maximum targeted effect-site concentrations (Cet) for propofol were 2.6 ± 0.83 and 3.3 ± 1.09 µg·mL, respectively, and for remifentanil 0.84 ± 0.18 and 0.99 ± 0.22 ng·mL, respectively. Maximum Cets of propofol were lower among patients with higher body mass index (BMI) and were higher among patients of younger age. Higher BMI was a risk factor for desaturation. Increased age and lower BMI were risk factors for hypotension. Longer procedure time was a risk factor for both desaturation and hypotension. CONCLUSIONS: Moderate-to-deep sedation by propofol and remifentanil TCI has a low incidence of catastrophic and severe events.

Intranasal dexmedetomidine in elderly subjects with or without beta blockade: a randomised double-blind single-ascending-dose cohort study.

BACKGROUND: The aim of this double-blind, placebo-controlled, single-ascending-dose study was to determine the safety and tolerability of intranasal dexmedetomidine in the elderly. METHODS: We randomly assigned 48 surgical patients ≥65 yr of age to receive single intranasal doses of dexmedetomidine or placebo (5:1 ratio) in four sequential dose cohorts: 0.5, 1.0, 1.5, and 2.0 µg kg-1. Each dose cohort comprised two groups of six subjects: a group of subjects using ß-blockers and a group not taking ß-blockers. Vital signs and sedation depth (Modified Observer's Assessment of Alertness and Sedation [MOAA/S] and bispectral index) were measured for 2 h after administration. Blood samples were taken to determine dexmedetomidine plasma concentrations. RESULTS: One subject (1.0 µg kg-1) had acute hypotension requiring ephedrine. Systolic arterial BP decreased >30% in 15 of 40 subjects (37.5%) receiving dexmedetomidine, lasting longer than 5 min in 11 subjects (27.5%). The MAP decreased >30% (>5 min) in 10%, 20%, 50%, and 30% of subjects receiving dexmedetomidine 0.5, 1.0, 1.5, and 2.0 µg kg-1, respectively, irrespective of ß-blocker use. HR decreased 10-26%. MOAA/S score ≤3 occurred in 18 (45%) subjects; eight (20%) subjects receiving dexmedetomidine showed no signs of sedation. Tmax was 70 min. Cmax was between 0.15 ng ml-1 (0.5 µg kg-1) and 0.46 ng ml-1 (2.0 µg kg-1). CONCLUSIONS: Intranasal dexmedetomidine in elderly subjects had a sedative effect, but caused a high incidence of profound and sustained hypotension irrespective of ß-blocker use. The technique is unsuitable for routine clinical use. CLINICAL TRIAL REGISTRATION: NTR5513 (The Netherlands Trial Registry 5513).