5. I've found the last few seasons to really blur the lines around killing monsters & saving people. For instance, there's no real agonizing about stabbing a demon's vessel, which is a person. But Dean just committed "can't-explain-it-away-even-though-he-has-the-mark-of-Cain" MURDER x 4. How do the brothers deal with that? How does the audience?
Nate: The show's been running on protagonist-centered morality for so long I wonder if the audience will even react, though don't forget he did commit similar murder last season in #THINMAN, though it was just 1 person. And don't forget the body count of soulless!Sam. I would HOPE that this moment leads to the brothers realizing why they had a "no kill human" rule no matter how problematic it might get for them and a return to their classic form and morals. Based on experience... I'm not betting on it.
Bardicvoice: I hope the brothers DO address it directly and consciously decide to strive to return to the "don't kill people, don't kill non-killers" standard they used to have. I'll note that rule was always weaker for Dean than for Sam -- look at Dean's arguments for action in Faith and Nightmare, for example -- because he translated anything "evil" into "monster," but what he did here was monstrous and he knows it. Even without the MoC, the danger for hunters has always been slipping over the line into becoming in practice as bad or worse than what they hunt, with no defensible moral line remaining: remember Travis from Metamorphosis, for example. What the brothers do has always involved moral conflict and ambiguity; I think it's time for another piece of the soul-searching that used to feature prominently in their action assessments, such as Dean's anguished questioning in Bloodlust of the "kill all monsters" hunter ethos he'd absorbed from John. If the brothers and all of us aren't questioning their actions, we are all losing our humanity.
Metamorphic Rocks: I think it was actually x 5 (Dean killed the four thugs plus Randy). I have often been bothered that the brothers no longer even mention the humans that die when they stab a demon's meatsuit (that specific point was in an article I wrote last season). It seems like it's done to save time with the storytelling, but I would love for the boys to make a statement here and there regarding their regret in killing a human being; Or better yet, let them do some more exorcisms - that would be fun to see again.
Because they have killed so many humans in the past (especially Soulless Sam, as Nate pointed out), I'm not sure that Sam or Castiel won't just explain it away with the infamous "it wasn't you." Also, Dean was in danger, as he was outnumbered 4 to 1 (I think Randy was still tied to the chair), and he had just been kicked in the face by the loan shark, so he most likely started out defending himself and lost control. So, I think there are ways for the brothers to justify it to an extent, but clearly the Mark issue needs to be addressed in an urgent way. The point is, I don't think it's something that Dean can't come back from, judging by the show's history with killing humans.
As for the audience, because we've seen it so often, I think we may be desensitized to the human casualties of demonic and angelic possession. Also, these were criminals who were going to hurt Dean (and one who tried to assault Claire), so the "they had it coming" philosophy is in play here. I don't believe the audience will judge Dean too harshly.
Pragmatic Dreamer: I got nothing except maybe Gavin being alive in 2014 will somehow cause a ripple in the time/space continuum and it will be like this never happened!