Van Nistelrooy decided in the 50th minute to send on Jonny Evans and Alejandro Garnacho and they came on for Diogo Dalot and Marcus Rashford seven minutes later.
Evans slotted in at centre back and Noussair Mazraoui switched from left back to right back as Lisandro Martinez shifted to left back.
Garnacho was a straight swap for Rashford on the left wing.
Dalot has started in all 18 of United's matches this season as specialist left backs Luke Shaw and Tyrell Malacia have remained sidelined.
Rashford has only started on the bench twice this term and has gone eight games without a goal.
Garnacho curled in his seventh goal of the season and his second during Van Nistelrooy's four-game interim spell.
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