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Personally, if I have the time and energy to micromanage, I watch my players carefully and rest anyone who falls below 100% in fatigue status.
If you don't occasionally rotate your players, it seems that they are much more injury prone. And a player who is at 96% won't be tired, but his chances of sustaining an injury seem to increase.
If your players are rated as durable for injuries, then there is less risk in playing them until they're tired. But I would try to rotate players who are rated normal and especially those who might be rated fragile. In those cases, I set the depth chart grid rotate them at least once every four to 10 games, depending on the differences between the starter and the backup along with what the rest of the lineup will look like for a given game.
Sometimes it's good to use your depth charts to occasionally get some better righty vs. lefty matchups. If one of your players is fairly weak against one or the other, you might consider using his backup every few games to get a better matchup against the starting pitcher. This assumes that the backup isn't good enough to start normally against a lefty or righty.
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