Novak Djokovic struggled with the heat and humidity as he fell to a shock defeat by Argentina’s Thiago Tirante.

The 24-time Grand Slam champion dropped on to his hands and knees and took a medical timeout during the second set before eventually losing 2-6 6-4 6-4 to the South American, who is ranked 50th in the world.

“It was not an enjoyable match for me, for sure,” Djokovic said. “The way I felt. Not the first and I guess not the last time, but it is what it is.”

Djokovic, 39, the world number five, was making his first appearance since losing to Jannik Sinner in the semi-finals at Wimbledon in July.

The Serbian had never failed to reach at least the last 32 of the tournament in Ohio since making his debut in it in 2005.

However, despite claiming the first set, Djokovic toiled badly after winning an 18-minute third game in the second set and appeared to vomit twice.

A physio and a doctor provided on-court assistance and both players returned to the dressing rooms after the second set.

When play resumed Djokovic dropped serve in the ninth game of the third set and Tirante was able see out the match.

Djokovic said he is dealing with an underlying health condition.

“It’s just a condition that I have, health wise, that has been bothering me for the past couple of years,” Djokovic added. “[It causes] a lot of issues, especially when it is humid and it is hot.”

Tirante called the victory the “best win of my career”, adding: “I managed the nerves of playing a legend like Novak. It was all so much pressure.”