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Predicting the Best Fit: A Comparison of Response Surface Models for Midazolam and Alfentanil Sedation in Procedures With Varying Stimulation

Liou, Jing-Yang MD; Ting, Chien-Kun MD, PhD; Mandell, M. Susan MD, PhD; Chang, Kuang-Yi MD, PhD; Teng, Wei-Nung MD; Huang, Yu-Yin MD; Tsou, Mei-Yung MD, PhD

doi: 10.1213/ANE.0000000000001299
Ambulatory Anesthesiology: Original Clinical Research Report

BACKGROUND: Selecting an effective dose of sedative drugs in combined upper and lower gastrointestinal endoscopy is complicated by varying degrees of pain stimulation. We tested the ability of 5 response surface models to predict depth of sedation after administration of midazolam and alfentanil in this complex model. The procedure was divided into 3 phases: esophagogastroduodenoscopy (EGD), colonoscopy, and the time interval between the 2 (intersession).

METHODS: The depth of sedation in 33 adult patients was monitored by Observer Assessment of Alertness/Scores. A total of 218 combinations of midazolam and alfentanil effect-site concentrations derived from pharmacokinetic models were used to test 5 response surface models in each of the 3 phases of endoscopy. Model fit was evaluated with objective function value, corrected Akaike Information Criterion (AICc), and Spearman ranked correlation. A model was arbitrarily defined as accurate if the predicted probability is <0.5 from the observed response.

RESULTS: The effect-site concentrations tested ranged from 1 to 76 ng/mL and from 5 to 80 ng/mL for midazolam and alfentanil, respectively. Midazolam and alfentanil had synergistic effects in colonoscopy and EGD, but additivity was observed in the intersession group. Adequate prediction rates were 84% to 85% in the intersession group, 84% to 88% during colonoscopy, and 82% to 87% during EGD. The reduced Greco and Fixed alfentanil concentration required for 50% of the patients to achieve targeted response Hierarchy models performed better with comparable predictive strength. The reduced Greco model had the lowest AICc with strong correlation in all 3 phases of endoscopy. Dynamic, rather than fixed, γ and γalf in the Hierarchy model improved model fit.

CONCLUSIONS: The reduced Greco model had the lowest objective function value and AICc and thus the best fit. This model was reliable with acceptable predictive ability based on adequate clinical correlation. We suggest that this model has practical clinical value for patients undergoing procedures with varying degrees of stimulation.

Published ahead of print May 17, 2016

From the *Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan; Department of Anesthesiology, University of Colorado Hospital, Aurora, Colorado; and Department of Anesthesiology, Cheng Hsin General Hospital, Taipei City, Taiwan.

Accepted for publication January 31, 2016.

Published ahead of print May 17, 2016

Funding: Taiwan National Science Council, Taipei City, Taiwan: National Science Council Grant NSC 102-2314-B-075-078 and NSC 103-2314-B-075-030.

The authors declare no conflicts of interest.

Jing-Yang Liou and Chien-Kun Ting contributed equally to this work.

Reprints will not be available from the authors.

Address correspondence to Mei-Yung Tsou, MD, PhD, Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, No. 201, Sec. 2, Shipai Rd, Beitou District, Taipei, Taiwan 11217, People’s Republic of China. Address e-mail to

© 2016 International Anesthesia Research Society