A nurses' strike beginning at 8pm on Sunday is "the most worrying so far" and could lead to "increased risk to patients", NHS leaders have warned.
Members of the Royal College of Nursing (RCN) union will walk out until 11.59pm on Monday after voting to reject the government's latest pay offer.
This will be the first time that nurses will be walking out of critical services including intensive care, prompting fears that hospital wards will become overwhelmed and that patients will be put at risk.
Some NHS trusts have been granted local exemptions, allowing them to receive emergency staff, but many others are worried about inadequate staffing levels.
This includes Great Ormond Street Hospital after it expressed "serious concerns" about strike impact and declared an official "incident".
Health secretary Steve Barclay said the lack of national exemptions "risks patient safety", adding: "These strikes will put more pressure on the NHS and will be incredibly disruptive for patients."
Julian Hartley, from NHS Providers, which represents health managers, said the latest round of strikes is "the most worrying so far".
"Some say they are struggling to find enough staff for specialist areas including children's services," he said.
"Trust leaders and staff will do everything they can to minimise disruption and keep patients safe but it's piling on the pressure on an overstretched NHS now into its sixth consecutive month of industrial action.
"That's resulted in more than 531,000 appointments and procedures being rescheduled – not just in hospitals but across mental health and community services too."
Nick Hulme, chief executive of the East Suffolk and North Essex NHS Foundation Trust, told BBC Breakfast: "I am concerned. I'm sure that we will be able to provide safe services - the public can be assured that they'll be safe - but there will be significant disruption."
Despite the concerns, RCN general secretary Pat Cullen has said nurses have worked "tirelessly" with NHS England to make sure the strike is safe for patients.
On Sunday, she rejected the health secretary's claims and insisted there were some national exemptions in place for "those really acute urgent services".
She argued that patients' lives were already at risk in the health service due to chronic staffing shortages - one of the main reasons nurses are striking in the first place.
“They're going on strike because patients' lives are being put at risk every single day,” Cullen told Sky News's Sophy Ridge On Sunday programme.
“And why? Because we have tens of thousands of vacant nursing posts.”
Nurses make up a quarter of NHS staff and are the biggest proportion of the health service workforce.
NHS England warned that staffing levels for some areas of the country will be "exceptionally low, lower than on previous strike days".
It added the number of rescheduled appointments due to strike action is set to hit half a million next week.
On Thursday, a High Court judge ruled it would be unlawful for the RCN strike to continue into Tuesday as originally planned, which is why it is now ending just before midnight on Monday.