Population pharmacodynamic modelling of midazolam induced sedation in terminally ill adult patients

Abstract

Introduction

Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. A previous pharmacokinetic (PK) study showed that variability between patients could be partly explained by renal function and inflammatory status. The goal of this study was to combine this PK information with pharmacodynamic (PD) data, to evaluate the variability in response to midazolam and to find clinically relevant covariates that may predict PD response.

Method

A population pharmacodynamic analysis using nonlinear mixed effect models was performed with data from 43 terminally ill patients. PK profiles were predicted by a previously described PK model and depth of sedation was measured using the Ramsay sedation score. Patient and disease characteristics were evaluated as possible covariates. The final model was evaluated using a visual predictive check (VPC).

Results

The effect of midazolam on the sedation level was best described by a differential odds model including a baseline probability, Emax model and inter individual variability (IIV) on the overall effect. The EC50 value was 68.7 ug/L for a Ramsay score of 3-5 and 117.1 ug/L for a Ramsay score of 6. Co-medication with haloperidol was the only significant covariate. The VPC of the final model showed good model predictability.

Conclusion

We were able to accurately describe the clinical response to midazolam. As expected there was large variability in response to midazolam. The use of haloperidol was associated with a lower probability of sedation. This may be a result of confounding by indication as haloperidol was used to treat delirium, and deliria has been linked to a more difficult sedation procedure.

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