Karlsson said he was held out for precautionary reasons and because the Senators were losing by five goals. He said he could have returned if necessary.
The Senators lost 7-0 against the Penguins, who lead the best-of-7 series 3-2 and can advance to the Stanley Cup Final with another victory in Ottawa on Tuesday (8 p.m. ET; NBCSN, CBC, TVA Sports).
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"The score was not what we wanted, and not only me but we decided to shorten down minutes a bit and move on and get ready for the next game," said Karlsson, who is the Senators captain.
In addition, center Derick Brassard and defenseman Cody Ceci did not return for the third period. Senators coach Guy Boucher said it was rest for all of them and they could have come back if necessary.
Karlsson, who has been playing with two hairline fractures in his left heel, had the same thing happen to him in Game 4 against the New York Rangers in the second round. Ottawa was losing 3-0 after 40 minutes and the Senators decided against bringing Karlsson back out for the third.