The Catalan, though, is hoping De Bruyne can still play a part in the final weeks of the campaign.
The Belgian left the field after 28 minutes with an unspecified knock and the City boss has confirmed he will miss the Manchester derby.
“I don’t think so,” said Pep when asked about De Bruyne’s chances of playing.
“I don’t know (exactly what the issue is). It’s a muscular problem we will see in next few days how he will do, but tomorrow, no.
“Muscular problems - he had two or three this season, but normally this kind of competition in England we don’t have time for an operation - we have to more attention in little details.
“We will see if he can play one or two more games this season and next season take care of him.
“He has a lovely family, his life is well organised with family, training, rest, next game.
“We are going to speak with him, docs physios to make sure he is safe and fit. That’s what we are trying to do from now on.”
In regards to other potential injury issues, Pep responded: “Yeah, there are some problems with some players, but almost everyone is good for tomorrow.”
The City boss also said that United, who have lost six of their last eight matches in all competitions, will be dangerous opponents regardless of the heavy defeat at Goodison Park on Sunday.
Asked if the loss to Everton makes this task even harder for City, Pep said: “A little bit yeah, but the confidence will be high, it’s a derby - derbies played in Spain and Germany they’re special games or the fans for the club.
“I saw what these games do - it’s a different game - the one against Everton is over and the only one that matters is tomorrow.
“We have four games left so we have to win all four to retain title.
“It’s not easy place to go but at same time it’s a nice place to go. We know exactly what we have to do. We’re going to go there to do a good game.”