Well our party is onto the 5th book in Serpent skull and we don't use the hero points system.
There have been some deaths,(my character 2x) nothing unrecoverable though, and no TPK's.
As long as the party has a good range of skills it works fine, someone with the knowledge skills, someone to be face, someone with survival ETC.
DBH
The Hero Point system works fine with this, but is not necessary. Just stress to your players to read the Player's Guide and take that advice to heart.
The only really important skill here is diplomacy. The first module rewards you really quickly for having it, so most players will keep it high hopefully. If your party doesn't have a couple of people with darkvision, your trip into the Shiv in book 1 can end really quickly though. The ghoul combat is a real killer, and my party only survived due to the quick thinking druid summoning earth elementals. Later on knowledge checks and such make the game more fun story wise, but really diplomacy is the only must have. There should be lots of friendly NPCS to massage the story forward with those knowledge checks.
When I described this AP to the group, I used Tomb Raider meets Indiana Jones as the best descriptor - to prep them for the kind of thing needed. As Glutton mentioned, diplomacy is an indispensable skill, and will be useful throughout the AP. Knowledge Arcana, History, and Religion are going to be inordinately useful as well. Linguistics will come in handy especially if your players are more self-motivating rather than sitting back and letting the story sweep them forward. Survival is a must (and a barbarian, druid or ranger will find themselves really useful).
Read and get comfortable with environmental rules about heat, diease and so on.
The first installment the PCs have their gear and whatever they and their fellow castaways can scavenge or hunt.
Be ready to handle a lot of NPCs... Some are quite compelling. You may want to look at some of the NPC posts in this forum, including the one on leadership.
In the third part of the AP is very much a sandbox, and you will either need curious PCs who actually want to explore the city or will have to motivate them to do so. The magic item finds are not really "good" until the 4th installment - you may need to remind the PCs that they need to sell stuff to their expedition backers and equip up that way.
That is as far as I have read deeply enough to actually comment upon. We are just starting Smuggler's Shiv ourselves.
The high skill DCs are there so these things are a tough challenge and players and PCs have to think hard how to accomplish those tasks. To include hero points would render that moot.
I'm running book 5 by now and just be warned that this path is as much of a meat grinder as its reputation suggests. My group loves this, but it's not for everyone's taste.
First book is excellent, but be sure to include the rules about heat and disease and so on to get the survival/Lost feeling going. Module itself is a giant sandbox with a lot of rewarding stuff to be found beyond the main plot.
Second book, after a brief intermission in a city (which will come to your players as a relief after weeks/months on a desert island), is a railroad with some interesting encounters along the way and a nice change of pace before it gets sandboxy again. Make sure your players know what they are getting into or you'll have a few yawns around the table.
The third book will definitely need some work if your group wants some really political/power struggle flavor in here. You get the basic tools from the module as written but you'll have to work out the details yourself. Can be very rewarding. Make sure your players don't start killing everything and everyone as they will need some of the city's denizens as allies later on in the path.
The fourth book is a series of short dungeon crawls with an out-of-place celebrity cameo in the middle. You might want to emphasize the Midnight Spores part or the repetitive dungeon delving could get a little bland.
Only two short sessions in the fifth book so far, but I like what I see. The main story, which is kind of non-existent and only hinted at until here, really takes off now!
Hope this is of any help to you.
EDIT: And one more thing, use the Faction Guide! You will find yourself in a lot of situations where PCs will ask their faction for favors and if you don't want to worry about balance, the Faction rules give a nice and easy framework to handle these things.