De Bruyne was forced off at half time with a hip injury in Man City's 0-0 draw with Inter Milan at the Etihad on matchday one, and has not featured since, failing a late fitness test ahead of their clash with Newcastle United on Saturday.
Against weaker opposition though, it is unlikely manager Pep Guardiola will risk the Belgian midfielder here, as they may hold him back to be ready in time to face Fulham at the weekend.
That could allow Phil Foden to make just a second start of the season, with Guardiola holding the England international back so far, being reluctant to use him from the beginning after a few weeks out in August and September.
Foden was only a sub against Inter Milan, Arsenal and Newcastle, but started in the EFL Cup win over Watford last midweek, meaning he could be drafted into the starting XI again here.
Rodri's ACL tear was confirmed by the club last week, with Guardiola stating he will not feature again this season, leaving a huge hole in the Man City midfield which they could struggle to fill.
Youngster Rico Lewis plugged the void at the weekend, but Guardiola may use this fixture as an opportunity to give Matheus Nunes some minutes in the side, alongside Mateo Kovacic in the engine room.
Elsewhere on the treatment table, Nathan Ake is set to remain out until after the October international break, while Oscar Bobb will not be seen until the end of the year at the earliest.
With an expensively-assembled squad, Guardiola will likely make quite a few changes here, and after sitting out the draw at St James' Park, both Jeremy Doku and Savinho could start out wide.
Backup goalkeeper Stefan Ortega has played five Champions League games since joining City and may be handed a start in the Slovakian capital, while John Stones could also get a rare start after only making the bench again on Saturday.
One player who never seems to be the victim of Guardiola's heavy rotation is Erling Haaland, and he will look to end something of a barren run in this competition of late, as the City number nine has scored just once in his last five Champions League games, but that does not have much of an impact on his incredible record of 45 goals in 46 UCL appearances.
Manchester City possible starting lineup:
Ortega; Lewis, Stones, Akanji, Gvardiol; Matheus Nunes, Kovacic; Savinho, Foden, Doku; Haaland