Advances in and limitations of up-and-down methodology - A precis of clinical use, study design, and dose estimation in anesthesia research

Department of Anesthesiology, University of Utah, Salt Lake City, Utah 84132-2304, USA.
Anesthesiology (Impact Factor: 5.88). 08/2007; 107(1):144-52. DOI: 10.1097/01.anes.0000267514.42592.2a
Source: PubMed


Sequential design methods for binary response variables exist for determination of the concentration or dose associated with the 50% point along the dose-response curve; the up-and-down method of Dixon and Mood is now commonly used in anesthesia research. There have been important developments in statistical methods that (1) allow the design of experiments for the measurement of the response at any point (quantile) along the dose-response curve, (2) demonstrate the risk of certain statistical methods commonly used in literature reports, (3) allow the estimation of the concentration or dose-the target dose-associated with the chosen quantile without the assumption of the symmetry of the tolerance distribution, and (4) set bounds on the probability of response at this target dose. This article details these developments, briefly surveys current use of the up-and-down method in anesthesia research, reanalyzes published reports using the up-and-down method for the study of the epidural relief of pain during labor, and discusses appropriate inferences from up-and-down method studies.

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    • "The upper concentration was limited to 3.0 ng/mL due to concerns for patient safety after extubation.8,14 The stopping rule, which required at least six pairs of failure/success, necessitated the recruitment of more than 20 patients.22 This up-and-down method was conducted independently for each sex. "
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    ABSTRACT: Target-controlled infusion (TCI) of remifentanil can suppress coughing during emergence from general anesthesia; nevertheless, previous studies under different clinical conditions recommend significantly different effective effect-site concentrations (effective Ce) of remifentanil for 50% of patients (EC₅₀). The differences among these studies include type of surgery and patient sex. In recent years, study of sex differences in regards to anesthetic pharmacology has drawn greater interest. Accordingly, we attempted to determine the effective Ce of remifentanil for preventing cough for each sex under the same clinical conditions. Twenty female and 25 male ASA physical status I-II grade patients between the ages of 20 and 46 years who were undergoing thyroidectomy were enrolled in this study. The effective Ce of remifentanil for preventing cough was determined for each sex using the isotonic regression method with a bootstrapping approach, following Dixon's up-and-down method. Isotonic regression with a bootstrapping approach revealed that the estimated EC₅₀ of remifentanil for preventing coughing during emergence was significantly lower in females {1.30 ng/mL [83% confidence interval (CI), 1.20-1.47 ng/mL]} than in males [2.57 ng/mL (83% CI, 2.45-2.70 ng/mL)]. Mean EC₅₀ in females was also significantly lower than in males (1.23±0.21 ng/mL vs. 2.43±0.21 ng/mL, p<0.001). Mean arterial pressure, heart rate, and respiratory rate over time were not significantly different between the sexes. When using remifentanil TCI for cough prevention during anesthetic emergence, patient sex should be a considered for appropriate dosing.
    Yonsei medical journal 05/2014; 55(3):807-14. DOI:10.3349/ymj.2014.55.3.807 · 1.29 Impact Factor
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    • "Recent discussions and implementation recommendations for U&D can be found in refs. Pace and Stylianou (2007) and (Oron, 2007, Ch. 2-3). "
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    ABSTRACT: Novel dose-finding designs for Phase I cancer clinical trials, using estimation to assign the best estimated Maximum Tolerated Dose (MTD) at each point in the experiment, most prominently via Bayesian techniques, have been widely discussed and promoted since 1990. To examine the small-sample behavior of these 'Bayesian Phase I' designs, and also of non-Bayesian designs sharing the same main 'Long-Memory' traits of using likelihood estimation and assigning the estimated MTD to the next patient. Data from several recently published experiments are presented and discussed, and Long-Memory designs' operating principles are explained. Simulation studies compare the small-sample behavior of Long-Memory designs with short-memory 'Up-and-Down' designs. In simulation, Long-Memory and Up-and-Down designs achieved similar success rates in finding the MTD. However, for all Long-Memory designs examined, the number n (*) of cohorts treated at the true MTD was highly variable between simulated experiments drawn from the same toxicity-threshold distribution. Further investigation using the same set of thresholds in permuted order indicates that this Long-Memory behavior is driven by sensitivity to the order in which participants enter the experiment. This sensitivity is related to Long-Memory designs' 'winner-takes-all' dose-assignment rule, which grants the early cohorts a disproportionately large influence, and causes many experiments to settle early on a specific dose. Additionally for the Bayesian Long-Memory designs, the prior-predictive distribution over the dose levels has a substantial impact upon MTD-finding performance, long into the experiment. While the numerical evidence for Long-Memory designs' order sensitivity is broad, and plausible explanations for it are provided, we do not present a theoretical proof of the phenomenon. Method developers, analysts, and practitioners should be aware of Long-Memory designs' order sensitivity and related phenomena. In particular, they should be informed that settling on a single dose does not guarantee that this dose is the MTD. Presently, Up-and-Down designs offer a simpler and more robust alternative for the sample sizes of 10-40 patients used in most Phase I trials. Future designs might benefit from combining the two approaches. We also suggest that the field's paradigm change from dose-selection to dose-estimation.
    Clinical Trials 01/2013; 10(1):63-80. DOI:10.1177/1740774512469311 · 1.93 Impact Factor
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    • "Simulation studies have demonstrated that performing an experiment to characterize the EC50 by obtaining a fully specified tolerance distribution is almost always less efficient than a sequential design to estimate only the EC50 [5]. In this study, EC50 or EC95 levels of remifentanil were investigated to determine the level that would blunt hemodynamic changes provoked by head holder pinning by means of UDM. "
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    ABSTRACT: During neuroanesthesia, head holder pinning commonly results in sympathetic stimulation manifested by hemodynamic changes, such as increased heart rate and arterial blood pressure. Remifentanil has been used successfully to control acute autonomic responses during neurosurgical procedures. The objective of this study was to determine effect-site concentration of remifentanil for suppressing the hemodynamic response to head holder pinning with the probability of 50% (EC(50)). Forty-one ASA physical status I or II patients, between the ages of 20-70, who were scheduled for neurosurgery were recruited into this study. After arrival in the operating room, standard monitoring was applied throughout the study, which included a bispectral index monitor. Both propofol and remifentanil were administered by Target-control infusion device. The Dixon "up-and-down" sequential allocation method was used to determine the EC(50) of remifentanil. The EC(50) of remifentanil was 2.19 ± 0.76 ng/ml by the turning point estimate (TPE). In probit analysis, EC(50) was 2.42 ng/ml (95% CI : -0.62-4.66) and EC(95) was 5.70 ng/ml (95% CI : 4.02-67.53). The EC(50) estimator comes from isotonic regression is 2.90 ng/ml (95% CI : 1.78-3.65). The EC(95) estimator comes from isotonic regression is 4.28 ng/ml (95% CI : 3.85-4.41). This study showed that EC(50) of remifentanil was 2.19 ± 0.76 ng/ml by TPE. EC(50) was 2.42 ng/ml (95% CI -0.62-4.66) in probit analysis, as back up analysis. The EC(50) estimator comes from isotonic regression is 2.90 ng/ml (95% CI : 1.78-3.65).
    Korean journal of anesthesiology 10/2012; 63(4):327-33. DOI:10.4097/kjae.2012.63.4.327
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