Lingering Injuries, Frail Constitution, Festering Scars

These three modifiers all decrease the amount of HP you'll have to work with during the run. The good news is that this literally doesn't matter unless you take damage. If you perfect every fight, it's free instability. Realistically, you'll probably take at least a bit of damage here and there, but even with all of these maxed out, you should have enough wiggle room to handle a few hits here and there. You can avoid maxing these if you tend to struggle with perfecting, but as you become more skilled these will be the foundation of every impossible+ run.

One For All

While this modifier is a little different, it's the same in that it does nothing if you perfect your fights. It's actually even easier to mitigate in that you only need to perfectly block on a few turns to negate the effect, and you might not even have vulnerable application.

Take It Or Leave It

This one is free if you never skip an elite artifact (why would you do that anyway?) and never destroy a cursed item. Often enough, you won't be pathing to a cursed item, and if you are, you'll often want to take or drain it anyway. Even if you actually path to one and don't want to take or drain it, you're only missing out on 3 souls, which is a pretty small price to pay.

Collapsing Hallways

This one is free if you never pass through an empty tile. This can be a little annoying with Hidden who wants empty tiles to power up his starter relic, but it's generally not worth going out of your way to hit empty tiles at the cost of other tiles anyway, so this will usually only cost you on Hidden if it causes you to avoid an empty tile that wouldn't otherwise alter your pathing. In terms of HP, this will usually cost you 0-10. Also, be aware that the damage effect cannot cause you to go below 1 HP.

Tight Pockets

Now we reach modifiers with truly notable impacts. You'll definitely feel the price hike with this one maxed out, but 9 instability is worth it. Smart pathing will do a lot to mitigate this one: avoid visiting too many tiles with essence costs and you can make up for lost purchasing power by getting value in other tiles.

Imperfect Works

Even though you should be getting tons of perfects, don't feel too bad about losing out on your perfect bonus. Tight Pockets already devalues the essence you'd be earning significantly. This modifier also has a nice psychological bonus by making missed perfects feel less bad.

Soulless Greed

With this modifier, praying for greed is pretty bad, and when Tight Pockets is also devaluing the essence you'd earn, praying for greed is essentially worthless. For 2 instability, it's an acceptable loss of resources, and praying for health can make up for missing health you start with from Lingering Injuries or any damage you took to Collapsing Hallways.

The Damned

This is the last modifier to affect your soul count. If you have them all enabled, you'll earn about enough souls for one big purchase at the soul collector/queen event, one small purchase at those events or an offering of souls to the dark idol, and a little smidgen left to release on floor 3. Timing your visits to these tiles properly becomes key, but with smart pathing you should be able to buy the stuff you really need.

The modifiers from this point become significantly more challenging to handle, so I'll stop going by category and look individually at the remaining ones.

This is the first modifier I would recommend using without maxing. There are two main ways I would suggest trying to handle this one. What I usually do is start with 2 Voids and aim to hit the first available shrine and cleanse them. Alternatively, you can start with 1 Void and aim to grab another at a cursed item or deadly sins event, and cleanse the both after that. I strongly prefer starting with 2 since this allows for an efficient cleanse with minimal pathing requirements, but if you get a lucky map spawn, starting with 1 will be a lot easier (although you will have to make up the instability elsewhere). If you don't mind losing runs early and restarting, 1 becomes a bit better since you can retry until the map generation co-operates. 3 Voids is basically never worth it, since you'll be crippled in early fights and have your pathing heavily restricted by needing to cleanse twice while picking up another void somewhere along the way if you want to be efficient. Ultimately, as bad as having starting Voids is, the instability is worth it given that after a cleanse (which should happen early on), the remainder of the run is unaffected.

This one isn't that bad, but ranks low due to the low instability it offers. The little bit of extra block needed per turn is usually not a huge deal. The biggest issue comes when it forces you to block on a turn that would otherwise have been damage-less. Even this is not so bad, especially on Enlightened (who often has extra delay block) and Daughter (who is often already accounting for soultithe).

This is one is interesting in that in can be almost free or brutal, based on your character and what sort of deck you end up with. The issue comes from the fact that you don't really know how much you'll rely on debuffs before the run begins. This modifier is at its best when you are applying many stacks of a debuff, such as bleed, since the amount lost is relatively small. On the other hand, losing an extra stack of a debuff like slow will hurt a lot more, since it is more difficult to apply in the first place. If you want to take this modifier, you may as well max out since you are already rolling the dice a bit and it's worth a big chunk of instability. Notably, since the Void already causes debuffs to tick down by 3 instead of 1, the jump up to 4 with this modifier active often does nothing in that particular fight.

This is another modifier that can vary, as some loot the dead bonuses provide a nice immediate boost (such as a free void stone) while others provide more long term value (such as bonus essence). If you died early on the previous run, you'll know that you didn't miss out on anything huge. However, if the previous run made it far enough to unlock the stronger loot the dead options, you could be losing something that would help out when you need it most (while you deck has those pesky Voids and your cardpool is limited).

Remember how I just said that a free void stone at the start of a run is really good? Well that's why this modifier is really bad. Not only is your starting void stone a very timely resource, but more stones total over the course of a run also means you're more likely to find the stones you want most.

This drawback feels even worse than a lost void stone, but you get less instability for it. The starting uncommon you get is usually helpful early on and also helps guide the deck in towards a more defined build. If you have access to the mastery reroll, odds are very good that you'll have a good uncommon to start. I strongly suggest avoiding this one.

This modifier will frequently change the turn on which you are able to kill enemies, especially when aiming for synchronized kills. This can turn what would have been an easy perfect into a close call or much worse. It is worth a lot of instability, and doesn't change the most important/difficult fights, but you will absolutely feel the pain of this modifier if you take it.

Vault guardians are obviously among the hardest fights in a run, so having to do more of them is rough. Any lost HP from extra fights makes the Void that much harder if you don't have enough health potions to offset it. Specific guardians can also counter certain decks pretty hard, and even though you see them at the start of a run, you can easily end up in a rough spot based on the ones chosen and what sort of cards you are offered (for example, if both the spiders and star council spawn, you'll have a very hard time building a deck that can handle both well). One stack is tolerable, but for two stacks the instability offered is just not worth it.

This modifier makes turn 1 really hard by robbing you of two of your strongest defensive options: preemptive damage mitigation via debuffs, delay block, or just killing enemies, and the ability to retain block cards from turn to turn. With just 5 draws, you'll somewhat often end up staring down damage that you simply cannot avoid no matter what. No free turn to start the fight also makes it much harder to get buffs in play. Despite being worth such an enormous amount of instability, it's too dangerous to use in most runs (although it can make for a fun challenge).

The absolute worst modifier, bar none. Pathing is fundamental in this game. Building a good deck, securing your important upgrades, spending resources efficiently, and so much more depends on you having a good path. Even one rank of this modifier cripples your ability to plan a path well. Do not take it.

A fairly typical I30 set up for me looks something like this:

• Collapsing Hallways
  
• Take It Or Leave It
  
• 3 Tight Pockets
  
• 2 Lingering Injuries
  
• One For All
  
• 2 Frail Constitution
  
• 3 Festering Scars

Here is the copyable code for this set up:

MSwyLDUsMywyLDIsMTAsMSw2LDEsOSwxLDEyLDMs

If you aren't ready for this many HP modifiers, I would suggest dropping stacks of Lingering Injuries and/or Frail Constitution. Here is a code for a setup which replaces all Lingering Injuries and Frail Constituion stacks with Soulless Greed, The Damned, 1 Imperfect Works, and 1 Eroding Sanity:

NSwzLDEwLDEsNiwxLDksMSwxMiwzLDgsMSw3LDEsMTEsMSwxNiwxLA==

A fairly typical I50 set up for me looks something like this:

• 2 Original Sin
  
• Collapsing Hallways
  
• Take It Or Leave It
  
• 3 Tight Pockets
  
• 3 Adaptation
  
• 2 Lingering Injuries
  
• One For All
  
• Imperfect Works
  
• 2 Frail Constitution
  
• 3 Festering Scars
  
• Soulless Greed
  
• 3 Eroding Sanity

Here is the copyable code for this set up:

MSwyLDIsMiw1LDMsOSwxLDYsMSwwLDIsMTIsMywxMCwxLDgsMSwxMSwzLDE4LDMsMTYsMSw=

Hitting 50 requires so many modifiers that there isn't a whole lot of room to pick and choose. The biggest flex point here is Adaptation. If you plan to skip Adaptation, I'd suggest replacing it with Knew I Forgot Something, The Damned, and one Praetorian Guard.

Hopefully this is helpful for anyone wishing to climb instability!