In a recently published study of patients with advanced cancer whose status was systematically documented twice a day, from the time of admission to a palliative care unit until death or discharge, investigators identified eight physical signs associated with death within 3 days. Taken together with five physical signs reported earlier, “these objective bedside signs may assist clinicians, family members, and researchers in recognizing when the patient has entered the final days of life,” David Hui, MD, MSc, and colleagues reported in Cancer.¹ That recognition, in turn, can inform physicians’ recommendations concerning continued treatment, as well as personal decisions by caregivers about maintaining a constant presence at the patient’s bedside and alerting others family members of the impending death.

The eight identified signs, including seven neurologic conditions and one bleeding complication, had 95% or higher specificity and likelihood ratios from 6.7 to 16.7 (with likelihood ratios > 5 suggesting good and > 10 suggesting excellent diagnostic value) for predicting death within 3 days. 

Dr. Hui told The ASCO Post that he had been contacted by several reporters and that the study has been the subject of several editorials and perspectives. Moreover, he expects other articles to evolve over time as the study is discussed in the context of end-of-life care in general. Dr. Hui is Assistant Professor, Department of Palliative Care and Rehabilitation Medicine and Department of General Oncology at The University of Texas MD Anderson Cancer Center, Houston.

Investigating the Process of Dying

The study reported in Cancer was a planned secondary analysis of the Investigating the Process of Dying study, a prospective, longitudinal, observational study that systematically documented an array of clinical signs every 12 hours among 357 consecutive patients with advanced cancer admitted to acute palliative care units at two tertiary care cancer centers—MD Anderson and Barretos Cancer Hospital in Brazil. The average age of the patients was 58; 55% were female, 65% were of Hispanic origin, and 28% had a diagnosis of gastrointestinal disorder. Of the 357 patients, 203 (57%) died at the end of the admission, the investigators reported.

The researchers compiled a list of 62 clinical signs, selecting 10 as target signs based on their prevalence in the literature. They had also previously identified five physical signs “that were highly diagnostic of impending death.” Based on their findings, which were published in The Oncologist² (and subsequently reviewed in The ASCO Post³), these five signs are pulselessness of the radial artery, decreased urine output, Cheyne-Stokes breathing, respiration with mandibular movement, and death rattle.

Powerful Predictors

The secondary analysis looked at the remaining 52 physical signs. “The 10 signs that we looked at initially were the more commonly cited signs that people were already pretty sure about, and for this study, we were looking into the things that we are not as sure about. We found that 8 of these 52 signs were quite powerful in predicting death,” Dr. Hui said in an interview with The ASCO Post.

The researchers explained:

To determine the diagnostic utility of each sign, we computed the sensitivity, specificity, positive [likelihood ratio], and negative [likelihood ratio] for death within 3 days. Positive [likelihood ratios] indicate how many times the sign of interest appeared in patients who died within 3 days in comparison with patients who did not die within 3 days. Positive [likelihood ratios] > 5 and > 10 suggest good and excellent discriminatory test performance, respectively. The last 3 days was chosen as the cutoff for impending death because our previous study showed the emergence of many of the signs of impending death during this period, and knowing a patient is within the last 3 days of life could affect many medical decisions such as hospital discharge, discontinuation of prescription medications, artificial nutrition, and use of life- support measures.

The eight physical signs identified as highly diagnostic of impending death “occurred in 5% to 78% of the patients within the last 3 days of life, had a late onset, and had a high specificity (> 95%) and a high positive [likelihood ratio] for death within 3 days,” the authors noted. Listed from high to low likelihood ratios, the 7 neurologic signs included nonreactive pupils (likelihood ratio = 16.7), inability to close eyelids (likelihood ratio = 13.6), grunting of vocal cords (likelihood ratio = 11.8), decreased response to verbal stimuli (likelihood ratio = 8.3), drooping of the nasolabial fold (likelihood ratio = 8.3), hyperextension of the neck (likelihood ratio = 7.3), and decreased response to visual stimuli (likelihood ratio = 6.7). In addition, upper gastrointestinal bleeding had a likelihood ratio of 10.3.

On multivariate analysis, two physical signs (ie, decreased response to verbal stimuli and drooping of the nasolabial fold) were identified as independently significant, according to the study report. “However, the other physical signs with high positive [likelihood ratios], when present, could still be helpful in the diagnosis of impending death. This is particularly true because patients often do not present with all the physical signs at the same time.”

It is important for clinicians to realize, Dr. Hui noted, that “if they don’t see the signs, it doesn’t mean that their patient won’t die in the next 3 days. These signs don’t always occur in patients. So the flip side is not always true.”

Systematic Examination From Day 1

Physicians have been aware of some of the signs of impending death, such as decreased level of consciousness, responsiveness, grunting of vocal chords, nonreactive pupils, Dr. Hui acknowledged, “but prior to this study, these signs had not really been examined systematically. What is important about this study is that this is the first time we have systematically examined patients for a large and comprehensive array of these signs in the largest population to date from the very first day they enter our unit. Twice a day, we monitored these signs, and we continued that monitoring until they either died or were discharged.”

Previous studies that have looked at signs of impending death “tended to start monitoring when people are already recognized as dying, and so there may be potential bias. That is why we started out from the very beginning to try to get an unselected and consecutive patient population to make sure that our findings are valid,” Dr. Hui added.

Signs Add Up to Higher Probability

In addition to the reported results, further analysis of the data showed that a “higher number of signs tends to be associated with a higher probability of death,” Dr. Hui said. “Just to put things in context, let’s say that when patients come into a palliative care unit, there is maybe a 30% to 40% chance that they would die over the next 3 days.” If a patient, however, displays one of the eight signs, and that sign has a likelihood ratio of 10, “it would increase the probability to about 80% to 90% that they would die in the next 3 days. Then, if another sign is added, the probability of death would rise above 90%,” Dr. Hui added.

Additional signs could raise the probability to 95% or 98%. “That is how we generally can use these signs,” Dr. Hui said. More signs can be confirmatory, but “even just one or two of these signs can be very informative.”

Next Generation of Studies

Dr. Hui and his colleagues cautioned that the results concerning the reliability of the eight signs to predict death within 3 days among patients with advanced cancer should be considered preliminary. “At this time, I would say that they provide good preliminary information, but, of course, I always want more confirmatory data,” Dr. Hui stated. “I do believe that this finding is at least applicable to the study population that we had, which was a unique population in the palliative care unit, as not too many hospitals have palliative care units.”

Further studies “are actively in the planning phase right now,” Dr. Hui said. “We are not enrolling patients yet, but based on the findings from both studies, we are crafting the next generation of studies to further confirm our findings.”

Whether the next round of studies will involve Dr. Hui’s study partners in Brazil or others “depends on funding opportunities,” he noted, “but we definitely want to expand into other populations, such as those in hospice care. A large proportion of people are under hospice care in the last days of life, and I think it is very important to see whether these signs hold outside of a hospital. Generally we believe they are universal in nature, but what distinguishes science from art is that we really want to get the numbers right by documenting things carefully.” ■

Disclosure: Dr. Hui reported no potential conflicts of interest.

References

1. Hui D, dos Santos R, Chisholm G, et al: Bedside clinical signs associated with impending death in patients with advanced cancer: Preliminary findings of a prospective, longitudinal cohort study. Cancer 121:960-967, 2015.

2. Hui D, dos Santos R, Chisholm G, et al: Clinical signs of impending death in cancer patients. Oncologist 19:681-687, 2014.

3. Piana R: Identifying impending death helps patients and caregivers. A conversation with David Hui, MD, MSc. ASCO Post, September 1, 2014.