Adaptation of non-linear mixed amount with zero amount response surface model for analysis of concentration-dependent synergism and safety with midazolam, alfentanil, and propofol sedation

Liou, Jing-Yang; Ting, Chien‐Kun; Teng, Wei-Nung; Mandell, M. Susan; Tsou, Mei-Yung

doi:10.1016/j.bja.2018.01.041

Cited by 16 publications

(31 citation statements)

References 33 publications

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“…The combination of a sedative and an opioid is frequently used in sedation and general anesthesia, and synergism between them has been shown 10 11 . Several preclinical and clinical studies indicate a reduction in dose as a result of the synergism between a sedative and an opioid, and the level of effect differs between combinations 12 13 14 . The lower requirement for fentanyl observed in the remimazolam group suggest that remimazolam might have stronger synergism with fentanyl than does midazolam.…”

Section: Discussionmentioning

confidence: 99%

“…The combination of a sedative and an opioid is frequently used in sedation and general anesthesia, and synergism between them has been shown [10,11]. Several preclinical and clinical studies indicate a reduction in dose as a result of the synergism between a sedative and an opioid, and the level of effect differs between combinations [12][13][14]…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy of remimazolam versus midazolam for procedural sedation: post hoc integrated analyses of three phase 3 clinical trials

Schippers¹,

Stöhr

Dao

2022

Endosc Int Open

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Background and study aims Remimazolam is an ultra-short acting, fast onset/fast offset benzodiazepine for intravenous use in procedural sedation, general anesthesia, and Intensive Care Unit sedation. The aim of this work was to compare the efficacy of remimazolam versus midazolam dosed according to medical practice (real-world midazolam) and midazolam dosed according to US prescribing information (on-label midazolam) for procedural sedation. Patients and methods This post hoc analysis was performed using integrated data from three randomized, placebo, and active (midazolam) controlled, phase 3 clinical trials in patients undergoing colonoscopy and bronchoscopy. Statistical comparisons between treatment groups, without adjustment for potential confounding factors, were exploratory and observational in nature. Results The mean ± SD dose of midazolam in the real-world midazolam group was 6.2 ± 3.1 mg, compared with 3.5 ± 1.5 mg in the on-label midazolam group. remimazolam showed significantly shorter time from first dose to start of procedure (median 3 minutes) compared to on-label midazolam (median 8 minutes). Recovery time from end of procedure to fully alert was significantly shorter for remimazolam (median 6 minutes) than real-world midazolam (median 14 minutes), enabling earlier transfer of patients from the procedure room to the recovery area with a lower requirement for patient monitoring. The onset and recovery times with remimazolam showed significantly less inter-patient variability than with on-label midazolam and real-world midazolam, respectively. Patients treated with remimazolam received significantly less fentanyl for analgesia (78.2 ± 28.4 µg) than did those treated with real-world midazolam (113.6 ± 60.1 µg) and on-label midazolam (92.5 ± 40.0 µg). Conclusions Remimazolam offers advantages over midazolam in terms of faster recovery and less fentanyl requirement, which may facilitate increased procedural throughput in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Efficacy of remimazolam versus midazolam for procedural sedation: post hoc integrated analyses of three phase 3 clinical trials

Schippers¹,

Stöhr

Dao

2022

Endosc Int Open

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“…No additional midazolam or alfentanil was permitted for the remainder of the procedure. Propofol was initiated via target controlled infusion (TCI) (Agilia, SB Medica SRL, Italy) at 1 mcg ml −1 and was titrated throughout the procedure by the in charge anaesthesiologist to maintain moderate to deep sedation [25]. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score was assessed every 30 seconds by the anaesthesiologist in charge, beginning after initial drug dose administration and continuing until the patient recovered.…”

Section: Methodsmentioning

confidence: 99%

High-Flow Nasal Cannula and Mandibular Advancement Bite Block Decrease Hypoxic Events during Sedative Esophagogastroduodenoscopy: A Randomized Clinical Trial

Teng

Ting

Wang

et al. 2019

BioMed Research International

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During sedated endoscopic examinations, upper airway obstruction occurs. Nasal breathing often shifts to oral breathing during open mouth esophagogastroduodenoscopy (EGD). High-flow nasal cannula (HFNC) which delivers humidified 100% oxygen at 30 L min−1 may prevent hypoxemia. A mandibular advancement (MA) bite block with oxygen inlet directed to both mouth and nose may prevent airway obstruction during sedated EGD. The purpose of this study was to evaluate the efficacy of these airway devices versus standard management. One hundred and eighty-nine patients were assessed for eligibility. One hundred and fifty-three were enrolled. This study randomly assigned eligible patients to three arms: the standard bite block and standard nasal cannula, HFNC, and MA bite block groups. EGD was performed after anaesthetic induction. The primary endpoint was the oxygen desaturation area under curve at 90% (AUCDesat). The secondary endpoints were percentage of patients with hypoxic, upper airway obstruction, and apnoeic and rescue events. One hundred and fifty-three patients were enrolled. AUCdesat was significantly lower for HFNC and MA bite blocks versus the standard management (p= 0.019). The HFNC reduced hypoxic events by 18% despite similar airway obstruction and apnoeic events as standard group. The MA bite block reduced hypoxic events by 12% and airway obstructions by 32%. The HFNC and MA groups both showed a 16% and 14% reduction in the number of patients who received rescue intervention, respectively, compared to the standard group. The HFNC and MA bite block may both reduce degree and duration of hypoxemia. HFNC may decrease hypoxemic events while maintaining nasal patency is crucial during sedative EGD. The MA bite block may prevent airway obstruction and decrease the need for rescue intervention.

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“…Details of the patients and sedation management for the modeling group were described in an earlier publication. [3] In brief, ASA class I or II adult patients (20 to 80 years of age) undergoing gastrointestinal endoscopy sedation were enrolled. Sedation was performed with propofol, midazolam and alfentanil in every patient.…”

Section: Study Group (Modeling)mentioning

confidence: 99%

“…The nonlinear mixed amount with zero amount (NLMAZ) model was used. [3,16] Patient response was reprocessed into binary data (1 if MOAA/S is 0 to 3, and 0 if MOAA/S is 4 to 5) for modeling. The formula is as follows…”

Section: Pharmacodynamic Response Surface Modelingmentioning

confidence: 99%

Pharmacodynamic modeling of moderate sedation and rationale for dosing using midazolam, propofol and alfentanil

Liou

Kuo

Chang

et al. 2022

Preprint

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Purpose:Regulations have broadened to allow moderate sedation administration for gastrointestinal endoscopy by non-anesthesia personnel. The line between moderate and deep sedation is ambiguous. Deep sedation offers patient comfort as well as greater safety concerns. Unintended deep sedation can occur if drug interactions are overlooked. We present a pharmacodynamic model for moderate sedation using midazolam, alfentanil and propofol. The model is suitable for training and devising rationales for appropriate dosing.Methods:The study consists of two parts: modeling and validation. In modeling, patients scheduled for esophagogastroduodenoscopy (EGD) or colonoscopy sedation are enrolled. The modified observer’s assessment of alertness/sedation (MOAA/S) score < 4 is defined as loss of response to represent moderate sedation. Two patient groups receiving bronchoscopy or endoscopic retrograde cholangiopancreatography (ERCP) are used for validation. Model performance is assessed by receiver operating characteristic (ROC) curves and area under the curve (AUC). Simulations are performed to demonstrate how the model is used to rationally determine drug regimen for moderate sedation.Results:Interaction between propofol and alfentanil is stronger than the other pairwise combinations. Additional synergy is observed with three drugs. ROC AUC is 0.83 for the modeling group, and 0.96 and 0.93 for ERCP and bronchoscopy groups respectively. Model simulation suggests that 1mg midazolam, 250μg alfentanil and propofol maximally benefits from drug interactions and suitable for moderate sedation.Conclusion:We demonstrate the accurate prediction of a three-drug response surface model for moderate sedation and simulation suggests a rational dosing strategy for moderate sedation with midazolam, alfentanil and propofol.

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Adaptation of non-linear mixed amount with zero amount response surface model for analysis of concentration-dependent synergism and safety with midazolam, alfentanil, and propofol sedation

Cited by 16 publications

References 33 publications

Efficacy of remimazolam versus midazolam for procedural sedation: post hoc integrated analyses of three phase 3 clinical trials

Efficacy of remimazolam versus midazolam for procedural sedation: post hoc integrated analyses of three phase 3 clinical trials

High-Flow Nasal Cannula and Mandibular Advancement Bite Block Decrease Hypoxic Events during Sedative Esophagogastroduodenoscopy: A Randomized Clinical Trial

Pharmacodynamic modeling of moderate sedation and rationale for dosing using midazolam, propofol and alfentanil

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