The U.S. Air Force is narrowing its focus on new combinations of factors as it explores hypoxia events that claimed the life of one F-22 pilot and plagued the fleet for more than a year.

Service officials remain frustrated, that a “smoking gun” for the cause is still elusive despite an extraordinary effort to enlist scientists, the medical profession and fighter experts in a quest for answers.

The Lockheed Martin F-22 is the Air Force's premier, twin-engine, stealthy fighter. It cost more than $200 million per copy to produce, including R&D. It entered service in 2005, and the 188th and final unit was delivered on May 2.

The problem came to light after a November 2010 crash that claimed the life of a pilot. The fleet was grounded for four months last year as officials scrambled to find a cause; flights resumed in September. Since then, Air Combat Command (ACC) officials say there have been 11 hypoxic events. The unknown nature of the incidents has rattled the service. “There is no startling similarity [in the incidents] other than . . . hypoxic-like indications,” says Gen. Mike Hostage, ACC commander.

The extreme capabilities of the F-22 test the physical and mental stamina of pilots. It is the only fighter capable of sustained supercruise at Mach 1.5 without using afterburner and it can operate for long periods at 60,000 ft. Pilots also are exposed to extreme forces owing to the aircraft's ability to accelerate quickly, decelerate and execute intense maneuvers using thrust-vectored propulsion.

Service officials temporarily restricted the altitude of the aircraft. They once focused on whether a toxin was being introduced into the pilot's oxygen supply—powered by a Honeywell Onboard Oxygen Generating System. However, Maj. Gen. Charles Lyon, ACC's director of operations, says that investigations into filters placed on the pilot have not turned up any conclusive evidence. After analyzing hundreds of these filters and comparing them to ones not yet used in flight, Lyon declared that those not used showed higher rates of toxins. “This informed our thinking and research.” Though the toxin theory has not been fully rejected, it is not a central focus.

Initially, the study targeted the aircraft, says Lyon. Now the team is looking into the physiological-support equipment and exploring whether there are commonalities in the flight profiles—various altitudes and maneuvers—that could be common in the incidents. The majority have occurred at the end of a flight, Lyon says, prompting officials to wonder if there is a cumulative effect of some factors on the pilots.

This added scrutiny on the program comes at a challenging time; defense spending is shrinking. The Government Accountability Office, meanwhile, says the planned upgrades to expand the F-22's electronic protection, targeting geolocation and other ground-attack capabilities have more than doubled in price and now total $11.7 billion; and delivery of these capabilities has slipped to fiscal 2017 from 2011.

One potential link among the hypoxic incidents is not the standard physiological-support gear—a g-suit, helmet and vest (carrying emergency items in the event of a crash). The majority of incidents occurred with F-22s at Langley AFB, Va., or Joint Base Elmendorf-Richardson, Alaska. Many of these flights require additional equipment—cold-weather gear for the Alaska pilots and an anti-exposure suit for aviators flying out of Langley over the Atlantic. “That is what got me to thinking,” Lyon tells Aviation Week. In some cases, if the “fit is off by what would seem to be an insufficient amount,” it could impact physiological support for the pilot. “It could be things such as the gear we are wearing and how it is assembled.”

Air Force officials are confident enough of clearing the toxin cause that they are taking the filters out of the aircraft. However, they are researching whether better filters could be used to possibly uncover other types of elements in the cockpit air.

Additionally, pilots are wearing a pulse oximeter to monitor oxygen-saturation levels during flight; if it dips below 85%, they are required to return to base immediately (the data are downloaded after landing and not dispatched in real time).

Lyon acknowledges an impact on the training hours that pilots can achieve. Hostage adds that the incidents have prompted some pilots to decline flying the Raptor, though he says these incidents are the exception. He notes that any guidance, such as returning to base with a low oxygen-saturation level, can be waived in the event of an operational requirement for F-22 use.

In the meantime, the Air Force acknowledged first to Aviation Week that F-22s have been deployed to the Middle East. The aircraft are operating out of Al Dhafra Air Base in the United Arab Emirates.

“The whole point is everybody pays attention” when F-22s are deployed to a particular region, says Hostage. “Our friends are very reassured by its presence.”

The fighters are thought to be providing a presence to counter Iran's ambitions to destabilize the Middle East and build long-range ballistic missiles and nuclear weapons.