A pharmacodynamic model of respiratory rate and end-tidal carbon dioxide values during anesthesia in children

Authors: Ji-Hyun Lee1, Pyo-Yoon Kang1, Young-Eun Jang1, Eun-Hee Kim1, Jin-Tae Kim2, Hee-Soo Kim2
1 Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Korea
2 Department of Anesthesiology and Pain Medicine, College of Medicine, Seoul National University, Seoul, Korea
Correspondence to: Hee-Soo Kim:,
DOI: 10.1038/s41401-018-0156-x
Received: 23 April 2018
Accepted: 20 July 2018
Advance online: 30 August 2018


It is essential to monitor the end-tidal carbon dioxide (ETCO2) during general anesthesia and adjust the tidal volume and respiratory rate (RR). For the purpose of this study, we used a population pharmacodynamic modeling approach to establish the relationship between RR versus ETCO2 data during general anesthesia in children, and to identify the clinical variables affecting this relationship. A prospective observational study was designed to include 51 patients (aged ≤ 12 years), including users of antiepileptic drugs (levetiracetam, valproic, or phenobarbital (n = 21)) and non-users (n = 30), scheduled to receive general anesthesia during elective surgery. When the ETCO2 was at 40 mmHg, the RR was adjusted 1 breath per every 2 min until the ETCO2 was 30 mmHg and recovered to 40 mmHg. Pharmacodynamic analysis using a sigmoid Emax model was performed to assess the RR-ETCO2 relationship. As RR varied from 3 to 37 breaths per minute, the ETCO2 changed from 40 to 30 mmHg. Hysteresis between the RR and ETCO2 was observed and accounted for when the model was developed. The Ce50 (RR to achieve 50% of maximum decrease in ETCO2; i.e. 35 mmHg) was 20.5 in non-users of antiepileptic drugs and 14.9 in those on antiepileptic drug medication. The values of γ (the steepness of the concentration-response relation curve) and keo (the first-order rate constant determining the equilibration between the RR and ETCO2) were 7.53 and 0.467 min-1, respectively. The Ce50 and ETCO2 data fit to a sigmoid Emax model. In conclusion, the RR required to get the target ETCO2 was much lower in children patients taking antiepileptic drugs than that of non-user children patients during the general anesthesia.
Keywords: pediatric anesthesia; end-tidal carbon dioxide; respiratory rate; population pharmacodynamic modeling; antiepileptic drugs

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