signs that tubes need to be replaced

I have a pair of Cary Audio Six pacs which i bought used about a year ago. They mate well with my tube preamp and i couldn't be more pleased with the setup i have.  I dont know the number of hours on the EL 34s that came with the amps. The previous owner may have replaced them at one time since they look like they were sourced from Tubeco.I have them biased at the recommended 220 ma. and put about 300 hrs/yr on them. Question is, what should I be looking for (sonically) besides obvious tube failure that would signify the tubes are nearing the end of their useful life? Will inability to maintain bias be any indication?

No, there really is no reliable way of telling in advance. If the tubes are used a very long time they can sometimes simply get weaker. Dynamics and extension suffer. But these changes can be so small and gradual over such a long period of time you may not even notice.  

If you are concerned at all then the smart thing to do is just order another set of tubes. Put the new ones in and if it turns out sure enough the old ones were shot you will know it right away. Save the old set for backup. Or if they sound about the same do whatever you want. If it was me I'd run the old ones as long as they last, maybe comparing them against the new ones every once in a while, until either one goes or they start to sound weak. Either way you keep your backups so you're never SOL waiting for tubes to come.
Drifting bias is a sure sign however that could also be caused by an out of spec bias resistor.    I had a matched quad of  EL34 power tubes that were about 8 months old.  One had "fire in the bottle" so to speak.  Literally arcs and sparks in one tube... it was scary.  Fortunately Quicksilver amps are robust and it only took out the mains fuse.   That was during play , it was sounding great and then all of a sudden horrible cracking noise through my speakers, I look up and fire....   I was lucky.  That said, I always try to replace before failure.  I have a set of KT88 that have a lot of miles on them and have been my spare a few times.  They still sound ok and hold bias but I'm nervous due to hours on them

I have a new quad of Gold Lion  KT77 on the way.  Hopefully they are as rugged and long lasting as they say
Look here for additional signs...

Interested in your update after you fully burn in the Genelex GL KT77s in your QS amps.  I'm recommending them to a friend for his QS mono 60 apmps in place of the stock JJ KT88s.  
My PrimaLuna DiaLogue Premium told me when I had a bad KT88 via the "Bad Tube Indicator" feature.  When a power tube goes bad, the amp goes into protection mode, sound cuts off, and a red LED indicates which tube is the culprit .

I knew about this feature when I bought the amp - and wondered if it really worked.  It does and now I'm a believer.  I don't know if this feature is available on other brands, but I'm glad I've got it on my amp.
No highs no bass and crappy sound this is why i only have tubes(12ax7,6dj8) in my TW phone stage only.Good luck!!
When the silver getter flashes start turning brown at the edges! Eventually all the silver will turn to brown. That is the sign of "old age" - even though the tube will still work!
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The same exact same Ruby EL34-BSTR (formerly Shuguang Factory made for Ruby batches), same tubes in the Cary SixPacs were also used in my Cary V12R amp.

Don’t underestimate these particular -bstr tubes due to the lower price point. These amps were designed and voiced with them and actually sounded fantastic! Similar reports over the years from friends with same amps. Grab ’em if you can find them, supply was kinda drying up on the BSTR version Ruby’s for a while. Did a search today, fewer carrying them as before. Look for the -bstr version. Snatch up three quads.. good luck.

When output tubes are difficult to bias then is a good time to replace. That will happen before losing dynamics, highs, bass and sounding muddy. You know that end of service life is close and it is better to have a spare set to check it. Better safe than leave them on till last moment. Visual check is not always the best guide but if the getters are not shiny any more and the silver layer at top of glass has gone off is a sign for replacement.
Sorry for the delay... those tubes didn't wow me at all at first.   I also was waiting for input and driver tubes before any real judgment 

So amps are freshly re tubed with over 100 hours and they sound great.   The bass is probably better than any other tube and it is balanced JUST RIGHT.   They sound great.   Think EL34 on steroids

I just pulled some tired KT88 out and these to me are better sounding in the QS Mids.   I think I just prefer EL34. Its almost like a hybrid of the best of EL34 and 6L6