NHS chiefs have warned four days of strikes by junior doctors will cause "unparalleled levels of disruption".
Floundering Health Secretary Steve Barclay is under pressure to resolve the dispute, with the British Medical Association (BMA) saying a "credible offer" would end plans for a strike starting on Tuesday.
But Mr Barclay instead doubled down, branding their demands "unrealistic" and describing the union as "militant".
England's national medical director Professor Sir Stephen Powis said hospitals could face up to 100 hours without half their workforce.
He said: "This next round of strikes will see unparalleled levels of disruption, and we are very concerned about the potential severity of impact on patients and services across the country.
"This time the action immediately follows a four-day bank holiday weekend, which is already difficult as many staff are taking much-needed holiday, and it will be more extensive than ever before with hospitals facing nearly 100 hours without up to half of the NHS medical workforce."
Experts warn the walkout could result in a quarter of a million postponed appointments and operations.
According to The Observer, hospital trusts are also speeding up the discharge of patients and have cancelled leave for non-striking doctors in desperate measures to stem the disruption.
Dr Layla McCay, director of policy at the NHS Confederation, said NHS bosses were more concerned about the impact of this strike than any other strike so far amid fears over patient safety.
She told the BBC: "In the last junior doctors' strike we saw about 175,000 appointments and operations having to be postponed.
"In terms of the disruption that we're anticipating this time, we reckon it could be up to about a quarter of a million so that is a huge amount of impact for patients up and down the country."
She added: "What we're hearing from our members who are health leaders across the whole system is that they are more concerned about this than they have been about about any other strike.
"They think that the impact is going to be so significant that this one is likely to have impact on patient safety and that is a huge concern for every healthcare leader."
But the appeals have fallen on deaf ears, with the Health Secretary writing in the Sunday Telegraph that calls for a 35% increase is an "unrealistic position".
"This demand is widely out of step with pay settlements in other parts of the public sector at a time of considerable economic pressure on our country," he wrote.
"A salary hike of this size would see some junior doctors receiving more than an extra £20,000 a year.
"I recognise their hard work and dedication. But it is deeply disappointing that this industrial action has been timed by the British Medical Association (BMA) Junior Doctors Committee to cause maximum disruption to both patients and other NHS staff."
Mr Barclay said he remains "determined" to find a fair offer that benefits junior doctors but also halve inflation.
"I value the important work these doctors do every day, and I want to see a fair deal that increases their pay. But I think the public also expects that any deal will be fair to taxpayers and not put our efforts to tackle inflation at risk."
Dr Mike Greenhalgh, deputy co-chair of the BMA's Junior Doctors Committee, said: "It's hard to negotiate when only one side is doing it and we're not getting anything back from the Government on that front."
