Understanding Research Methods: Up-and-down Designs for Dose-finding

Oron, Assaf P.; Souter, Michael J.; Flournoy, Nancy

doi:10.1097/aln.0000000000004282

Cited by 20 publications

(29 citation statements)

References 68 publications

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“…The sample size was calculated according to the stop rule of the up-and-down sequential methodology, in each group, at least six cross overs are needed for accurate EC 50 calculation, and anesthesia trials using Dixon’s up and down method typically have 20–40 patients ( Pace and Stylianou, 2007 ; Feng et al, 2020 ; Oron et al, 2022 ; Zheng et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

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The median effective concentration of propofol in combination with different doses of esketamine during gastrointestinal endoscopy in adults

et al. 2022

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We designed a four-arm randomized controlled trial to investigate the median effective concentration (EC50) of propofol in combination with different doses of esketamine inducing appropriate depth of anaesthesia during gastrointestinal endoscopy in adults. One hundred patients aged 18–65 years planning for gastrointestinal endoscopy were divided into four groups randomly: esketamine 0, 0.15, 0.25 and 0.5 mg/kg groups (n = 25). Propofol doses followed the Dixon and Massey up-and-down method with different starting between groups. The primary endpoint was the EC50 of propofol. Secondary outcomes included the cumulative dose of propofol, the duration of the procedure, recovery time, and adverse effects. The EC50 (median, 95% confidence interval) of propofol was significantly less in the esketamine 0.5 mg/kg group compared with the esketamine 0, 0.15, and 0.25 mg/kg groups [1.34 (1.15, 1.54) vs. 3.48 (3.25, 3.71), 2.82 (2.58, 3.07), and 2.36 (2.11, 2.61), respectively; p < 0.001]. The total dose of propofol (mean ± SD) required for the whole procedure was significantly less in the esketamine 0.5 mg/kg group compared with the esketamine 0, 0.15, and 0.25 mg/kg groups [95.5 ± 43.1 vs. 277.4 ± 49.0, 207.8 ± 31.6, and 135.1 ± 27.7, respectively; p < 0.001]. The recovery time was significantly longer in esketamine 0 and 0.5 mg/kg group compared with other two groups (p < 0.001). More patients in the esketamine 0.5 mg/kg group experienced visual disturbance compared with the other groups (p = 0.016). Additionally, the incidence of hypotensionin the esketamine 0 mg/kg group after inducation was higher compared with other groups (p < 0.001). In summary, the administration of esketamine significantly and dose-dependently reduced the dose of propofol required to accomplish procedures.

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Section: Methodsmentioning

confidence: 99%

“…Frontiers in Pharmacology frontiersin.org trials using Dixon's up and down method typically have 20-40 patients (Pace and Stylianou, 2007;Feng et al, 2020;Oron et al, 2022;Zheng et al, 2022).…”

Section: Groupmentioning

confidence: 99%

The median effective concentration of propofol in combination with different doses of esketamine during gastrointestinal endoscopy in adults

et al. 2022

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“…The use of this methodology for dose determination is well established. 15 However, our primary aim was to evaluate whether there exists a dose-response relationship for oxytocin infusion when used as a weight-based regimen. We thus explored whether there was an escalating response with increase in weight-based doses in various groups, and if present, evaluate the ED90 as well.…”

Section: Resultsmentioning

confidence: 99%

“…To further determine the precise ED90 when using weight‐based oxytocin, future studies employing the up‐and‐down sequential allocation method may be conducted. The use of this methodology for dose determination is well established 15 . However, our primary aim was to evaluate whether there exists a dose–response relationship for oxytocin infusion when used as a weight‐based regimen.…”

Section: Discussionmentioning

confidence: 99%

Weight‐based oxytocin infusion for preventing uterine atony during caesarean delivery in non‐labouring patients: A dose–response study

Tyagi

Salhotra

et al. 2023

Clin Exp Pharma Physio

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Postpartum haemorrhage remains a significant cause of maternal morbidity and mortality with the commonest reason being uterine atony. For prevention of uterine atony during caesarean delivery, oxytocin is advocated as a first line drug. There is however no published data regarding utility of a weight-based oxytocin infusion. The present study evaluated dose-response relationship for oxytocin infusion when used as weight-based regimen. A total of 55 non-labouring patients without risk factors for uterine atony and scheduled for caesarean delivery under spinal anaesthesia were enrolled. Randomization was done to receive oxytocin infusion in a dose of 0.1, 0.15, 0.2, 0.25 or 0.3 IU kg À1 h À1 (n = 11 each), initiated at the time of cord clamping and continued until the end of surgery.Successful outcome was defined as attaining an adequate uterine response at 4 min of initiation of infusion and maintained till end of surgery. Oxytocin associated hypotension, tachycardia, ST-T changes, nausea/vomiting, flushing and chest pain were also observed. A significant linear trend for adequate intraoperative uterine tone was seen with increasing dose of weight-based oxytocin infusion (P < 0.001). The effective dose in 90% population (ED90) was 0.29 IU kg À1 h À1 (95% CI = 0.25-0.42). Amongst the oxytocin associated side effects, a significant linear trend was seen between increasing dose of oxytocin infusion and hypotension as well as nausea/vomiting (p = 0.016 and 0.023 respectively). Thus, oxytocin infusion during caesarean delivery may be used as per the patient's body weight.

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“…Normally distributed continuous variables were compared using the least signifcant diference t-test (LSD-t) or Mann-Whitney U test for nonnormally distributed continuous variables. ED 50 (90% CI) of each group and diferences between groups were calculated with the centered isotonic regression R Language package [14]. A P < 0.05 was considered statistically signifcant.…”

Section: Discussionmentioning

confidence: 99%

Median Effective Dose of an Etomidate-Propofol Mixture with Dezocine in Inhibiting the Response to Gastroscope Insertion: Gender Differences in a Randomized Controlled Study Using Dixon’s Up-and-Down Method

Tang

Zhang

Zheng

et al. 2023

Journal of Clinical Pharmacy and Therapeutics

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What Is Known and Objective. Appropriate doses of sedatives are crucial for a successful, painless upper gastrointestinal endoscopy. Hence, we conducted a randomized controlled study to explore the effects of dezocine on the median effective dose (ED50) of the etomidate-propofol (E-P) mixture in prohibiting response to gastroscope insertion in patients of different genders. Methods. Patients aged 18–65 years enrolled in the study of the American Society of Anesthesiologists (ASA) with physical status I or II undergoing elective gastroscopy were included. Patients were randomly assigned to the male normal saline group (MS group), male dezocine group (MD group), female normal saline group (FS group), and female dezocine group (FD group). All patients were anesthetized with an E-P mixture of 1 : 1. The FD and MD groups were intravenously injected (i.v.) 50 µg/kg dezocine 5 min before anesthesia, while the FS and MS groups were injected with an equal volume of normal saline 5 min before anesthesia. According to the preexperiment, the initial dose of the E-P mixture for the FD and MD groups was 0.4 and 0.3 mL/kg for the FS and MS groups. The variation proportion was set as 0.9 between dosages. Dixon’s up-and-down method was adopted to confirm the dose of the E-P mixture for the next patient, which was reduced if the insertion was performed successfully; otherwise, the dose was increased. Centered isotonic regression was employed to determine the ED50 and 90% confidence interval (CI) values of the E-P mixture in the four groups. The total amount of E-P mixture consumed was recorded as well as the adverse events of patients. Results. The ED50 and 90% CI of the MS, MD, FS, and FD groups were 0.315 (0.285–0.349), 0.206 (0.175–0.237), 0.329 (0.305–0.355), and 0.207 (0.188–0.227) mL/kg, respectively. The MD group was <MS group ( P ≤ 0.001 ), and the FD group was <FS group ( P ≤ 0.001 ); no statistical difference was observed between the MS and FS groups and MD and FD groups. Dezocine reduced the total amount of E-P mixture consumed and the overall incidence of adverse events. What Is New and Conclusion. Dezocine significantly decreased the ED50 of the E-P mixture in inhibiting the response of patients to gastroscope insertion and the occurrence rate of adverse events. Further, gender had no impact on the ED50 of the E-P mixture.

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Understanding Research Methods: Up-and-down Designs for Dose-finding

Cited by 20 publications

References 68 publications

The median effective concentration of propofol in combination with different doses of esketamine during gastrointestinal endoscopy in adults

The median effective concentration of propofol in combination with different doses of esketamine during gastrointestinal endoscopy in adults

Weight‐based oxytocin infusion for preventing uterine atony during caesarean delivery in non‐labouring patients: A dose–response study

Median Effective Dose of an Etomidate-Propofol Mixture with Dezocine in Inhibiting the Response to Gastroscope Insertion: Gender Differences in a Randomized Controlled Study Using Dixon’s Up-and-Down Method

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