PulmCrit Wee - Loading infusion auto-titration (LIAT) for infused medications with intermediate half-lives

Let's talk about starting patients on milrinone.

Milrinone is part of a group of medications that I would regard as quasi-titratable. They have an awkward half-life of roughly ~0.5-3 hours. Other medications in this group might include diltiazem, labetalol, and perhaps nicardipine. These drugs can be given as a continuous infusion, but they're not easy to titrate. When infused at a fixed rate, they will tend to accumulate over several hours (yes diltiazem, I'm looking at YOU, we both know what you did). This post is directed at milrinone, but it's potentially applicable to any drug with this sort of pharmacokinetics.

LIAT: loading infusion auto-titration

OK, getting back to milrinone: A loading bolus would be a logical approach to initiating the infusion. However, this can precipitate severe hypotension, so it's often avoided. Guessing the optimal loading dose is a bit awkward and messy. Alternatively, giving several serial loading doses is a lot of work (this may be done in the operating room by a cardiac anesthetist who is paired 1:1 with the patient, but it's rarely done in an ICU).

A commonly encountered approach is to start at a low dose and titrate upwards. However, given the half-life of >2 hours, true titration can only be performed at time increments of >6-8 hours (to allow for reaching a steady state before adjusting the infusion). There are two problems with this strategy:

This can take forever. If you start the patient on a tiny dose of milrinone and work upwards, the milrinone concentration will likely lie within a homeopathic range for several hours or even days.
The milrinone level sometimes reaches a steady state during the middle of the night. This may cause hemodynamic decompensation when nobody is paying close attention.

A more logical strategy is loading infusion auto-titration (LIAS). This works as follows:

[1] A milrinone infusion is initiated at the upper end of the dosing range (e.g., 0.75 ug/kg/min). This will cause milrinone levels to rise in a steady and controlled fashion (as shown in the graph above). Although the infusion is continued at a fixed rate, milrinone levels will accumulate, causing the drug to auto-titrate itself.
[2] Hemodynamics are meticulously monitored to determine when a therapeutic effect is achieved.
[3] As soon as a satisfactory effect is seen, the infusion rate is dropped down to a maintenance infusion. The rate of the maintenance infusion can be calculated based on how long it takes to reach a therapeutic effect, as follows:

During the loading infusion, drug concentration increases according to the following formula:

The concentration at steady state will be proportional to the infusion rate. Therefore, once we know how long the loading infusion requires to reach a desirable therapeutic effect, we can calculate the optimal maintenance infusion rate as follows:

For example, let's say that we start a milrinone loading infusion at 0.75 mcg/kg/min. After 1.2 hours, a satisfactory therapeutic result is seen. The patient has normal renal function, so we can approximate the half-life of milrinone at 2.4 hours. In this case, the optimal infusion rate can be calculated as follows:

accelerated weaning

OK, now let's suppose that the patient has recovered and we're ready to wean milrinone. The long half-life is, once again, an impediment to weaning. If we wean down in a stepwise fashion, we must wait more than ~6-8 hours between each step in order to allow milrinone to reach a steady-state concentration. This may take forever.

To accelerate this process, we can essentially run the above process in reverse:

[1] We start out with a patient on a baseline infusion rate of milrinone.
[2] Milrinone is shut off completely.
[3] Hemodynamics are meticulously monitored to evaluate for any deterioration.
[4] If deterioration occurs, milrinone may be resumed at a reduced dose corresponding to the latest time point when hemodynamics were adequate. This reduced infusion rate may be calculated using the following equation:

For example, let's imagine that the patient was doing well with milrinone at an infusion of 0.375 ug/kg/min. A weaning trial was performed during which milrinone was discontinued. Hemodynamics were stable for 4 hours and then deteriorated after 4.5 hours. The milrinone may be resumed at the following dose: