The Norris Trophy winner last season as the NHL's top defenceman, Karlsson was cut by Penguins forward Matt Cooke's skate blade as the two tangled along the boards.
Karlsson leads NHL defencemen with six goals, scoring three times in his previous four games. He had a short-handed goal to help the Senators beat Buffalo 2-0 on Tuesday night.
"It's a tough blow," Senators captain Daniel Alfredsson said. "Obviously, the way he's playing, and how much he means to our team, it feels terrible and I feel really bad for him."
Karlsson immediately fell to the ice and was in visible pain. He needed help getting back to the bench and showed frustration, throwing his stick against the boards before disappearing down the runway.
"You knew right away there was an issue," Senators goalie Craig Anderson said. "He's a player who is irreplaceable. It's unfortunate, but there are no words that can explain what we're feeling."
Cooke has been suspended several times for hits, some of them involving head shots that injured opposing players. In 2011, Cooke was suspended for the Penguins' final 10 regular-season games and the first round of the Stanley Cup Playoffs after an elbow to the head of New York Rangers defenceman Ryan McDonagh.
"We all know who's involved in it," Senators coach Paul MacLean said. "That's just the way it is. The injury to Erik was unfortunate, and it happens on a nothing play that could've potentially been whistled down."
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