Table 3. Variables Considered in the Investigation and Restrictions Given for Direct Search
When identifying a new combination in the optimization procedure, a minimum increase in morphine and ketamine concentrations in patient-controlled analgesia solution was defined to avoid an increase in the dose produced by the optimization model that would be so small that a high number of steps would be necessary to reach the endpoint of the procedure. The maximum increase aimed at preventing an excessive increase in the drug doses with possible occurrence of side effects. The increase/decrease is defined as the difference between the new calculated value and the average of the values of ‘good’ combinations (centroid G, see Appendix) for each variable investigated.
* For lockout interval, no limits in increase were defined. As an extreme, decrease of 2 min was defined in order to avoid an excessive decrease in the interval between two doses with possible drug accumulation.