Tuning key_reads in MySQL

Question

We are trying to tune our MySQL database (Myisam, 5.1.73) which is getting busy.

We investigated Key_reads:

$ mysqladmin ext -ri10 | grep Key_reads

During a normal load we have the following values (average):

Key_reads          40      (per 10 seconds)
Key_read_requests  350000  (per 10 seconds)

But sometimes, during a few dozens of minutes, we see values like this:

Key_reads          1000    (per 10 seconds)
Key_read_requests  350000  (per 10 seconds)

We have increased Key_buffer_size to 512 (which is bigger than the total of our indexes). We still have 16Gb of free RAM.

Should Key_reads be low or null?

Are these peacks normal or avoidable?