Gareth Bale looks set to miss Wales' Nations League clash with the Republic of Ireland in Dublin next Tuesday.
The Real Madrid star sat out a 4-1 friendly defeat at the hands of a ruthless Spain team due to what Wales manager Ryan Giggs described as "muscle fatigue."
And Giggs has admitted he is unlikely to have him back in the mix when Wales look to dust themselves down from a Principality Stadium pummelling.
"Gareth is struggling for Tuesday," Giggs said. "Ethan (Ampadu) just extended his knee a little bit in the second half, and we will assess it and see how it is, and Chris Mepham got a little knock in training yesterday.
"We will take care of the lads the best we can over the next couple of days and get ready for Tuesday.
"We will make a decision (on Bale) in the next couple of days. We will make it sooner, rather than later."
Asked if it looked at the moment that Wales would be without their headline performer, Giggs said: "Yes, it does."
Luis Enrique's stylish side strolled to an emphatic victory ahead of tackling Nations League opponents England in Seville in four days' time after Paco Alcacer, with a brace, and Sergio Ramos scored inside 29 minutes, before substitute Marc Bartra added a fourth.
Sam Vokes headed a consolation a minute from time, but it was a sobering evening for Giggs' side prior to tackling Ireland as they suffered a heaviest defeat since a 6-1 thrashing away to Serbia in 2012.
"It is disappointing," Giggs added. "Against average teams you have to do the basics right. Against a very good team, if you don't do the basics, you get punished, and that's what happened.
"The build-up was magnificent. Coming into the stadium on the coach (it was Wales' first game at the Prinicpality Stadium for seven years), you could feel the buzz and it's something different. Unfortunately, we couldn't perform on the pitch, which is obviously disappointing.
"We brush ourselves down, take it on the chin. The last time we were in Cardiff we won 4-1 and were magnificent. Tonight, we were disappointing.
"The good thing about football is you have always got the next game, and that can't come quickly enough.
"We got taught a lesson in many aspects, but the main thing we were taught tonight was to do the basics right.
"You have to give them (Spain) credit. They are fantastic players, they are all playing at the top level, and they showed that tonight. It was a lesson for us, it was a lesson for a lot of the players, and one that we will learn from. We will be better on Tuesday."
It was a third successive victory for Spain under Enrique - they have also scored 12 goals in that time - and he said: "The team were very involved from the first minute and had an almost perfect attitude.
"Yes, there are (selection) clues (for the England game) in terms of those who have not played tonight, but you won't be able to guess more than four or five (of the team). It was an intense game tonight, and I loved watching my team.
"Their attitude lasted 90 minutes and we went into the game looking to create chances, put Wales under pressure and to prevent them from coming out, and it went well."