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Late-occurring signs of declining neurocognitive function proved to be highly specific and highly likely markers of impending death in patients with advanced-stage cancer, investigators reported.

Overall, eight physical signs had ≥95% specificity for predicting death within 3 days. All but one of the markers was neurologic, the most common being drooping of the nasolabial fold, which occurred in almost 80% of the patients who died during hospitalization. The only non-neurologic marker was upper gastrointestinal bleeding, which occurred infrequently but was highly specific for impending death.

The findings add to five previously identified markers of impending death, three of which also were neurologic, and should help inform end-of-life decision making, , of the University of Texas MD Anderson Cancer Center in Houston, and colleagues reported online in .

The current and previous study stand out from others in that the patients were evaluated prospectively on the basis of characteristics observed on admission and without knowledge of whether a patient was expected to survive.

"In the past, studies trying to understand the signs associated with impending death were conduced in people who were recognized as dying, so there's a potential bias built into this model," Hui said in a statement. "With our study, we observed a list of signs in patients from the time they were admitted to the palliative care unit. They were observed systematically, twice a day, without knowing if the patient would die or be discharged."

Historically, clinicians and families have had minimal clinical or scientific guidance to inform discharge to home or hospice, end-of-life care, and other issues relevant to patients with terminal illness. Last year, Hui and co-investigators at MD Anderson and in Brazil reported identifying that had strong associations with death within 3 days among hospitalized patients with advanced cancers.

The five characteristics were absence of pulse in the radial artery, decreased urine output, , mandibular movement during respiration, and . All five occurred very late after hospitalization and had 95% specificity for death within 3 days.

Hui and colleagues continued their investigation by analyzing the same data to identify additional markers of impending death, to determine how often each characteristic was observed, and to quantify the predictive association within impending death.

The study involved 357 patients with advanced cancers, all admitted to acute palliative care units at two tertiary-care hospitals. Each patient was evaluated twice daily for 62 signs related to functioning of neurologic, cardiovascular, respiratory, gastrointestinal, genitourinary, gynecologic, macular, and integumentary systems.

In the earlier study, investigators focused on 10 literature-defined signs. The follow-up study comprised the remaining 52 signs. At each 12-hour assessment, each of the 52 signs was documented as present or absent.

The primary objective of the analysis was to determine the frequency of each sign and its association with imminent death, defined as death within 3 days. The principal outcome measures of interest were specificity and positive likelihood ratio (LR) for death within 3 days. LRs of >5 to >10 reflect good and excellent discriminatory performance, the authors noted.

Subsequently, 203 of the 357 patients died after admission to the hospital. Many of the 52 signs appeared frequently in the 3 days before death but did not have significant associations with death within 3 days. Examples included heart rate >130 bpm (92%), oxygen saturation <90% (90%), decreased level of consciousness (97%), and delirium (89%).

The authors identified eight signs that occurred in 38% to 78% of patients within 3 days of death and also correlated significantly with death within that period of time:

• Decreased response to verbal stimuli (69%)
• Decreased response to visual stimuli (70%)
• Nonreactive pupils (38%)
• Drooping of nasolabial fold (78%)
• Hyperextension of neck (46%)
• In ability to close eyelids (57%)
• Grunting of vocal cords (54%)
• Upper gastrointestinal bleeding (5%)

The eight signs had a specificity for death within 3 days of 94.9% to >99%. LRs associated with signs ranged from 6.7 for decreased response to visual stimuli to 16.7 for nasolabial drooping.

"This study identified eight physical signs with high specificity and positive LRs for impending death within 3 days," Hui and co-authors concluded. "Upon further validation, the presence of these telltale signs would suggest that patients are actively dying.

"Taken together with the five physical signs identified earlier, these objective bedside signs may assist clinicians, family members, and researchers in recognizing when the patient has entered the final days of life."

The study added new information to a topic of longstanding interest by taking a detailed look at commonly observed findings in terminally ill patients, said , of Massachusetts General Hospital Cancer Center in Boston.

"What was novel about this study is that they came up with a long list of changes that we commonly see in patients who are getting close to the end of life and really studied them closely to figure out what would be best for that set of patients that will die within the next 3 days," Temel told MedPage Today.

Such information is "very helpful when families have an idea of how much longer a patient has to live," she added. "It can also help us figure out how to provide them the best medical care."

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