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Symptom Management and Supportive Care
Clinical Signs of Impending Death in Cancer Patients
DAVID HUI,
a
RENATA DOS SANTOS,
c
GARY CHISHOLM,
b
SWATI BANSAL,
a
THIAGO BUOSI SILVA,
c
KELLY KILGORE,
a
CAMILA SOUZA CROVADOR,
c
XIAOYING YU,
d
MICHAEL D. SWARTZ,
d
PEDRO EMILIO PEREZ-CRUZ,
a,e
RAPHAEL DE ALMEIDA LEITE,
c
MARIA SALETE DE ANGELIS NASCIMENTO,
c
SURESH REDDY,
a
FABIOLA SERIACO,
c
SRIRAM YENNU,
a
CARLOS EDUARDO PAIVA,
c
RONY DEV,
a
STACY HALL,
a
JULIETA FAJARDO,
a
EDUARDO BRUERA
a
Departments of
a
Palliative Care and Rehabilitation Medicine and
b
Biostatistics, The University of Texas MD Anderson Cancer Center,
Houston,Texas, USA;
c
Department of Palliative Care,Barretos Cancer Hospital, Barretos, Brazil;
d
Division of Biostatistics, Universityof Texas
Health Science Center at Houston, Houston, Texas, USA;
e
Programa Medicina Paliativa, Facultad de Medicina, Pontificia Universidad
Catolica de Chile, Santiago, Chile
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Death xDiagnosis xNeoplasms xPalliative care xPhysical examination xSensitivity xSigns xSpecificity
ABSTRACT
Background. The physical signs of impending death have not
been well characterized in cancer patients. A better under-
standing of these signs may improve the ability of clinicians to
diagnose impending death. We examined the frequency
and onset of 10 bedside physical signs and their diagnostic
performance for impending death.
Methods. We systematically documented 10 physical signs
every 12 hours from admission to death or discharge in 357
consecutive patients with advanced cancer admitted to two
acute palliative care units. We examined the frequency and
median onset of each sign from death backward and calculated
their likelihood ratios (LRs) associated with death within 3 days.
Results. In total, 203 of 357 patients (52 of 151 in the U.S., 151
of 206 in Brazil) died. Decreased level of consciousness,
Palliative Performance Scale #20%, and dysphagia of liquids
appeared at high frequency and .3 days before death and had
low specificity (,90%) and positive LR (,5) for impending
death. In contrast, apnea periods, Cheyne-Stokes breathing,
death rattle, peripheral cyanosis, pulselessness of radial artery,
respiration with mandibular movement, and decreased urine
output occurred mostly in the last 3 days of life and at lower
frequency. Fiveof these signs had high specificity (.95%) and
positive LRs for death within 3 days, including pulselessness of
radial artery (positive LR: 15.6; 95% confidence interval [CI]:
13.7–17.4), respiration with mandibular movement (positive
LR: 10; 95% CI: 9.1–10.9), decreased urine output (positive LR:
15.2; 95% CI: 13.4–17.1), Cheyne-Stokes breathing (positive
LR: 12.4; 95% CI: 10.8–13.9), and death rattle (positive LR: 9;
95% CI: 8.1–9.8).
Conclusion. We identified highly specific physical signs asso-
ciated with death within 3 days among cancer patients. The
Oncologist 2014;19:681–687
Implications for Practice: In this prospective observational study, we identified 5 physical signs (pulselessness of radial artery,
respiration with mandibular movement, decreased urine output, Cheyne-Stokes breathing, and death rattle) that were associated
with a high likelihood of death within 3 days.The presence of these tell-tale signs may assist clinicians to make the diagnosis of
impending death, with implications for important decisions such as hospital discharges and enrollment onto a clinical care
pathway at the end of life.
INTRODUCTION
Cancer is a leading cause of death worldwide [1]. Timely and
accurate diagnosis of impending death (i.e., death within
days) is of utmost importance to clinicians, patients, and
families. Many important decisions related to the quality of
end-of-life care, such as discharge planning, hospice trans-
fers, and discontinuation of aggressive investigations and
treatments are dependent on a patient’s prognosis [2].
Currently, the utility of clinical care pathways at the end
of life (e.g., the Liverpool care pathway) is limited by clini-
cians’inability to accurately diagnose impending death [3].
Clinicians often overestimate survival [4, 5] and hesitate to
make the diagnosis of impending death without adequate
supporting evidence.
The trajectory of cancer has been examined in patients
with months and weeks of life expectancy [6–9]; however, the
physical signs that occur in the last days and hours of liferemain
poorly understood [10]. The frequency and onset of many
clinical signs associated with impending death have not been
systematically examined. A better understanding of the
frequency and onset of these signs and their diagnostic
Correspondence: David Hui, M.D., Department of Palliative Care and Rehabilitation Medicine, Unit 1414, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. Telephone: 713-606-3376; E-Mail: dhui@mdanderson.org Received
December 9, 2013; accepted for publication February 21, 2014; first published online in The Oncologist Express on April 23, 2014. ©AlphaMed
Press 1083-7159/2014/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2013-0457
The Oncologist 2014;19:681–687 www.TheOncologist.com ©AlphaMed Press 2014
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performance may assist clinicians with the diagnosis of
impending death. The primary objective of this prospective
observational study was to determine the frequency and
onset of 10 clinical signs associated with impending death
(i.e., apnea periods, Cheyne-Stokes breathing, death rattle,
dysphagia of liquids, decreased level of consciousness, Palliative
Performance Scale (PPS) #20%, peripheral cyanosis, pulseless-
ness of radial artery, respiration with mandibular movement,
and urine output over the last 12 hours ,100 mL) in cancer
patients admitted to acute palliative care units (APCUs). Our
secondary objective was to determine their diagnostic perfor-
mance for impending death in 3 days.
METHODS
Study Setting and Criteria
The Investigating the Process of Dying Study is a prospective
longitudinal observational study. We enrolled consecutive
patients with a diagnosis of advanced cancer who were $18
years of age and admitted to the APCUs at MD Anderson
Cancer Center (MDACC) in the U.S. between April 5, 2010, and
July 6, 2010, and at Barretos Cancer Hospital (BCH) in Brazil
between January 27, 2011, and July 1, 2011. The institutional
review boards at both institutions approved this study and
provided waiver of consent for patient participation. This ap-
proach was adopted to minimize distress during the con-
sent process and to ensure that we could collect data on an
inclusive sample. All clinicians who participated in this study
signed the informed consent prior to patient enrollment.
Patients with advanced cancer and severe distress were
admitted to APCUs for intensive symptom support and/or for
facilitating transitions relating to goals of care (e.g., palliative),
place of care (e.g., home), and teams of care (e.g., hospice).
Both the 12-bed APCU at MDACC and the 45-bed APCU at
BCH are situated within tertiary care cancer centers and pro-
vide comprehensive symptom management and psychosocial
support through an interdisciplinary team, active treatment
of various complications, and discharge planning for acutely ill
patients.Both APCUs have accessto full arrays of diagnostic and
therapeutic measures, such as computed tomography and
intravenous antibiotics. The historical in-hospital mortality rate
was 30% at MDACC and 70% at BCH [11].
Data Collection
To select clinical signs to be captured in this study, our research
team conducted a literature review of published articles
[10, 12–14] and educational materials [15] on the process
of dying. We subsequently discussed these signs with par-
ticipating palliative care physicians and nurses. The final list
of 10 targeted bedside signs were selected based on their
prevalence in the literature and included apnea periods,
Cheyne-Stokes breathing, death rattle, dysphagia of liquids,
decreased level of consciousness, decreased PPS, peripheral
cyanosis, pulselessness of radial artery, respiration with
mandibular movement, and decreased urine output.
Table 1 consists of a description of each sign and its coding.
The level of consciousness was documented using the
Richmond Agitation Sedation Scale (RASS), a validated 10-
point numeric rating scale that ranges from 25 (unarousable)
to 14 (very agitated), in which 0 denotes a calm and alert
patient [16, 17]. For study purposes, a RASS score of 22or
lower was considered as decreased level of consciousness.
The PPS is a validated 11-point scale ranging from 0% (death)
to 100% (completely asymptomatic) based on the patient’s
function [18, 19]. A score of #20% indicates that the patient
is completely bed bound and has limited survival [20].
We collected baseline patient demographics on admis-
sion. All nurses who participated in this study worked full time
in palliative care and were experienced in providing care at the
end of life. All nurses attended an orientation session to review
the study objectives and data collection forms. Moreover,
the principal investigators and charge nurses provided
Table 1. Definition of clinical signs
Physical sign Description Criteria for negative sign Criteria for positive sign
Apnea periods Prolonged pauses between each
breath
None ,30 seconds; 30–60 seconds;
.60 seconds
Cheyne-Stokes
breathing
Alternating periods of apnea and
hyperpnea with
a crescendo-decrescendo pattern
Absent Present
Death rattle Gurgling sound produced on
inspiration and/or expiration
related to airway secretions
None Audible if very close; audible at the
end of bed; audible .6 meters from
door of room
Dysphagia of liquids Difficulty with fluid intake Absent Present
Decreased level of
consciousness
Richmond Agitation Sedation Scale 21to4 22to25 (sedation)
Decreased
performance status
Palliative performance scale,
validated for assessing function
(0%–100%)
30%–100% #20% (bed bound, completely
dependent)
Peripheral cyanosis Bluish discoloration of extremities None Toes; feet; up to knees
Pulselessness of radial
artery
Inability to palpate radial pulse Normal Left; right; both
Respiration with
mandibular movement
Depression of jaw with inspiration Absent Present
Urine output Measured volume of urine over
a 12-hour period
.3,600 mL; 2,401–3,600 mL;
1,201–2,400 mL; #101–1,200 mL
#100 mL
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longitudinal support during the study by reviewing the forms
on a daily basis to ensure they were complete and accurate and
provided education to the nurses on an as needed basis. The
two study sites had weekly video conferences to ensure data
were collected systematically and accurately. The study forms
were translated into Portuguese to facilitate data collection in
Brazil and back-translated to ensure accuracy of translation.
Every 12 hours from admission to discharge or death, clinical
nurses completed standardized data collection forms in-
dependently of prior assessments. The 12-hour period was
chosen based on the duration of the nursing shift.
Survival from time of APCU admission was collected from
institutional databases and electronic health records.
Statistical Analysis
Our preplanned sample size was a combined total of 200
deaths in the two study sites. For signs with a prevalence of
10%, 30%, and 50%, the corresponding 95% confidence
intervals (CIs) were 4.2%, 6.4%, and 6.9%, respectively. This
sample size was able to provide a standard error of the Kaplan-
Meier estimate at a particular time of #0.025 using the
method described by Peto et al. [21, 22].
We summarized the baseline demographics using de-
scriptive statistics. We documented the frequency of each sign
and the median onset from death backward for all patients
who died in the APCUs. The median time of death after first
occurrence of each sign was estimated by the Kaplan-Meier
method, conditional on observation of that particular sign
or symptom. Patients were left censored if they entered the
APCU with the sign already present.
To determine the diagnostic performance of each sign, we
computed the sensitivity, specificity, positive likelihood ratio
(LR), and negative LR using a 2 32 diagnostic table with
random sampling, as described previously [23]. We used data
from all 357 patients, instead of only those 203 patients who
died, because it is the entire population in which the diag-
nostic test will be applied. We coded the diagnostic test
result by dichotomizing all the signs into “absent”or “present”
(Table 1). For each diagnostic test result, we then determined
whether the patient died in the next 3 days.We selected 3 days
as the cutoff for impending death because our data showed
emergence of many of these signs during this period, and
knowing a patient is in the last 3 days of lifecould have practical
implications for integrated care pathways and discharge de-
cisions. We subsequently constructed a 2 32 table with one
observation per patient based on the presence or absence of
change in a particular vital sign during a randomly sampled
nursing shift and whether that patient died within the next 3
days.To account for the multiple observations for each patient,
we resampled our data 100 times to obtain the average and
95% CI. Missing data were omitted from the analyses.
Positive LR provides an estimate of how many times more
or less likely patients who died within a given time period are to
have a particular physical sign than patients who did not die,
and it is commonly used in diagnostic studies [24]. Positive LRs
of .5 and .10 correspond to good and excellent discrimina-
tory test performance, respectively [24].
SAS version 9.2 (SAS Institute, Cary, NC, http://www.sas.
com) was used for statistical analysis. Urinary output was not
routinely collected at BCH.
RESULTS
Patient Characteristics
Consistent with our projection, 52 of 151 MDACC patients
(34%) and 151 of 206 BCH patients (73%) died in the APCU.
Table 2 shows the patient characteristics at APCU admission. At
the time of analysis, 46 (13%) remained alive, with a median
follow-up of 61 days.
Frequency and Onset of Clinical Signs
Table 3 shows the frequency of each clinical sign among the
patients who died in the APCU.Three signs (PPS #20%, RASS 2
2 or lower, and dysphagia of liquids) were documented in
a substantial proportion of patients over the last 7 days of life,
occurring in a majority of decedents 12 hours before death.
In contrast, seven other signs (apnea periods, Cheyne-
Stokes breathing, death rattle, peripheral cyanosis, pulseless-
ness of radial artery, respiration with mandibular movement,
and decreased urine output) were documented in fewer than
half of the patients, even in the last 12 hours of life.
The onset of the 10 clinical signs is shown in Figure 1A. The
median onset was 4 days, 4.5 days, and 7 days prior to death
for PPS #20%, RASS 22 or lower, and dysphagia of liquids,
respectively. In contrast, the seven other signs had a median
onset of 3 days or less before death. The average number of
these seven signs increased in the last 3 days of life (Fig. 1B).
Diagnostic Performance of Clinical Signs
Table 4 illustrates the diagnostic performance of the 10 clinical
signs. The seven signs that emerged in the last 3 days of life
had high specificity (.95%), low sensitivity (,60%), and high
positive LR for impending death in 3 days. Specifically, the
positive LRs were 15.6 (95% CI: 13.7–17.4) for pulselessness of
radial artery, 15.2 (95% CI: 13.4–17.1) for decreased urine
output, 12.4 (95% CI: 10.8–13.9) for Cheyne-Stokes breathing,
10 (95% CI: 9.1–10.9) for respiration with mandibular
movement, and 9 (95% CI: 8.1–9.8) for death rattle. In
contrast, PPS #20%, RASS 22 or lower, and dysphagia of
liquids had higher sensitivity, lower specificity, and lower
positive LR.
DISCUSSION
Despite the universality and fundamental nature of the dying
process, little is known about the frequency and onset of
clinical signs that occur in the last days of life [12, 14, 25, 26]. By
systematically examining the frequency and onset of 10 clinical
signs, we were able to divide them into two categories: early and
late signs. Early signs were observed relatively frequently and
include decreased performance status, decreased oral intake,
and decreased level of consciousness. Because of their low
specificity,these signs could not reliably predict impending death
in 3 days. In contrast, late signs emerged only in the last few
days of life in a smaller proportion of patients and had high
positive LR for impending death in 3 days. The use of late
physical signs may assist clinicians in making the diagnosis of
impending death.
Impending death is a diagnostic issue rather than a prog-
nostic phenomenon because these signs indicate the presence
of an irreversible physiologic process, similar to the diagnosis
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of a pregnancy or labor. The ability to make this diagnosis
confidently is of great significance because many critical
decisions such as enrollment into integrated care pathways
and discharge planning are based on this diagnosis. Although
some of the signs identified in this paper have been described
anecdotally in review articles and books [10, 12–14], this is the
first study to systematically characterize their frequencies,
onset, and LRs, allowing clinicians to differentiate their relative
importance and utilityfor the diagnosisof impendingdeath. Our
findings suggest that simple bedside physical findings may help
clinicians make the diagnosis of impending death.
Our findings also explain why it is difficult for clinicians to
diagnose impending death in advance. Although the presence
of late signs strongly suggest that death is imminent, these
signs are observed relatively infrequently and only in the last
few days of life. Importantly, their absence could not rule out
the possibility that the patient will die shortly, because their
sensitivity is low. In contrast, early signs are common, are
present early, and have only moderate positive LRs (,5) for
impending death in 3 days.
Kehl et al. conducted a systematic review of the signs and
symptoms and identified very few studies on the signs of
Table 2. Patient characteristics
Characteristics
All patients
(n5357)
a
Patients who were
alive at APCU
discharge (n5154)
a
Patients who
died in APCU
(n5203)
a
pvalue
Age, average (range) 58 (18–88) 57 (18–86) 58 (18–88) .21
b
Female sex, n(%) 195 (55) 96 (62) 99 (49) .01
c
Ethnicity, n(%) ,.001
d
White 98 (28) 60 (39) 38 (19)
Black 21 (6) 15 (10) 6 (3)
Hispanic 233 (65) 75 (49) 158 (78)
Others 5 (1) 4 (3) 1 (1)
Christian religion, n(%) 329 (93) 136 (89) 193 (96) .02
c
Married, n(%) 206 (58) 92 (61) 114 (57) .47
c
Education, n(%) .12
c
High school or lower 243 (76) 96 (71) 147 (80)
College 59 (18) 32 (24) 27 (15)
Advanced 17 (5) 7 (5) 10 (5)
Cancer, n(%) .13
c
Breast 40 (11) 20 (13) 20 (10)
Gastrointestinal 101 (28) 33 (21) 68 (33)
Genitourinary 37 (10) 16 (10) 21 (10)
Gynecological 41 (11) 25 (16) 16 (8)
Head and neck 26 (7) 10 (6) 16 (8)
Hematological 17 (5) 7 (5) 10 (5)
Others 44 (12) 21 (14) 23 (11)
Respiratory 51 (14) 22 (14) 29 (14)
Comorbidities, n(%)
Chronic obstructive
pulmonary disease
16 (4) 12 (8) 4 (2) .01
d
Heart failure 17 (5) 8 (5) 9 (4) .74
c
Coronary artery disease 13 (4) 9 (6) 4 (2) .08
d
Stroke 8 (2) 4 (3) 4 (2) .73
d
Chronic kidney disease 5 (1) 4 (3) 1 (0.5) .09
d
Diabetes 50 (14) 22 (14) 28 (14) .89
d
Months between cancer diagnosis
and palliative care unit
admission, median (IQR)
15 (6–34) 20 (9–46) 13 (4–31) .002
e
Duration of palliative care unit
admission, days, median (IQR)
6(4–9) 7 (5–9) 5 (2–9) ,.001
e
a
Unless otherwise specified.
b
ttest.
c
x
2
test.
d
Fisher exact test (expected cell count ,5).
e
Mann-Whitney test.
Abbreviations: APCU, acute palliative care unit; IQR, interquartile range.
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impending death [27]. The OPCARE9 project recently used a
Delphi survey by international experts to identify key clinical
signs associated with impending death [28]. They recommended
10 phenomena for further examination (e.g., degradation of
general condition, no fluid or food intake, conscious level
changes, death rattle, breathing pattern changes) that were
similar to our list of 10 signs chosen for this study.
Early signs are useful because they inform us that the
patient is deteriorating. Based on the literature, the presence
of these signs indicates a survival of weeks or less [11, 20, 29].
Seow et al. showed that PPS declined sharply 4–6 weeks
before death in a cohort of cancer patients [6]. Ourdata added
to this by demonstrating that both performance status and
level of consciousness continue to deteriorate rapidly in the
last week of life. A majority of patients present with these early
signs in the last days of life. Because of their lower specificity,
early signs cannot reliably inform us that death is imminent.
Late signs are important because their appearance sug-
gests that the patient likely has survival only in terms of days
or less. Interestingly, these signs occurred only in the last days
Figure 1. Frequency and onset of clinical signs among 203 patients who died in acute palliative care units. (A): The median time of onset
(95% confidence interval) is shown. The median onset was #3 days before death for seven of these signs. (B): The average number of the
seven late signs (apnea periods, Cheyne-Stokes breathing, death rattle, peripheral cyanosis, pulselessness of radial artery,respiration with
mandibular movement, and decreased urine output) are shown over time, with error bars indicating standard errors.
Table 3. Frequency of 10 clinical signs before death
Physical signs
Frequency of each sign before death, n/N (%)
a
Frequency
of sign in
last 3 days
of life,
n(%)
b
27.0
days
26.5
days
26.0
days
25.5
days
25.0
days
24.5
days
24.0
days
23.5
days
23.0
days
22.5
days
22.0
days
21.5
days
21.0
days
20.5
days
PPS #20% 23/65
(35)
24/70
(34)
26/75
(35)
28/81
(35)
29/90
(32)
36/98
(36)
47/110
(43)
50/124
(40)
64/133
(48)
76/147
(52)
93/164
(56)
105/179
(59)
143/195
(73)
166/203
(82)
169 (93)
RASS 22or
lower
14/65
(22)
12/70
(17)
19/75
(26)
22/81
(27)
30/90
(34)
31/98
(32)
47/110
(43)
41/124
(33)
59/133
(44)
62/147
(42)
79/164
(48)
91/179
(51)
121/195
(62)
151/203
(74)
159 (90)
Dysphagia of
liquids
20/61
(33)
23/66
(35)
26/69
(38)
25/70
(36)
28/77
(36)
29/87
(33)
37/91
(41)
39/103
(38)
37/104
(36)
47/115
(41)
53/125
(42)
49/121
(40)
50/108
(46)
41/76
(54)
100 (90)
Urine output
over last
12 hours
,100 mL
1/20
(5)
0/23
(0)
3/25
(12)
0/25
(0)
1/34
(3)
1/36
(3)
3/37
(8)
3/51
(6)
7/55
(13)
6/61
(10)
6/68
(9)
13/72
(18)
23/80
(29)
30/75
(40)
48 (72)
Death rattle 3/65
(5)
2/68
(3)
3/74
(4)
7/78
(9)
4/89
(4)
8/97
(8)
10/110
(9)
18/123
(15)
15/133
(11)
14/144
(10)
29/163
(18)
35/176
(20)
56/195
(29)
78/202
(39)
110 (66)
Apnea periods 2/65
(3)
4/69
(6)
3/74
(4)
5/78
(6)
6/89
(7)
5/97
(5)
6/109
(6)
7/123
(6)
13/133
(10)
12/145
(8)
18/164
(11)
30/177
(17)
37/194
(19)
66/201
(33)
71 (46)
Respiration
with
mandibular
movement
1/64
(2)
2/69
(3)
3/74
(4)
1/78
(1)
3/89
(3)
4/97
(4)
6/110
(5)
9/123
(7)
15/133
(11)
10/145
(7)
20/163
(12)
29/177
(16)
50/195
(26)
65/202
(32)
92 (56)
Peripheral
cyanosis
7/65
(11)
4/69
(6)
9/74
(12)
8/78
(10)
7/89
(8)
11/97
(11)
17/109
(16)
13/123
(11)
19/133
(14)
26/145
(18)
30/164
(18)
35/177
(20)
49/195
(25)
80/201
(40)
99 (59)
Cheyne-Stokes
breathing
3/65
(5)
3/69
(4)
1/74
(1)
0/78
(0)
2/89
(2)
4/97
(4)
3/110
(3)
5/123
(4)
7/133
(5)
7/145
(5)
14/164
(9)
20/177
(11)
23/194
(12)
46/202
(23)
61 (41)
Pulselessness
of radial artery
1/65
(2)
1/69
(1)
0/74
(0)
0/78
(0)
0/89
(0)
2/97
(2)
1/108
(1)
5/123
(4)
4/132
(3)
5/144
(3)
6/163
(4)
8/176
(5)
18/194
(9)
48/200
(24)
57 (38)
a
The nominator was the number of patients with a sign of interest,the denominator was the number of patients with data at the particular time point. The
number of patients in the denominator varied because of the different duration of hospitalization among patients and missing data. For instance,urinary
output was not routinely collected at Barretos Cancer Hospital.
b
Any occurrence of the sign of interest within the last 3 days of life among patients who died in the acute palliative care unit.
Abbreviations: PPS, Palliative Performance Scale; RASS, Richmond Agitation Sedation Scale.
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of life and at relatively low frequencies; for instance, only 54%
of patients had any of these seven signs in the last 12 hours
before death. The frequency of death rattle in our study (66%)
is consistent with others [14, 30–32]. Consequently, their
absence cannot rule out imminent death, but their presence
can be highly informative.The positive LRs for pulselessness of
radial artery, decreased urine output, Cheyne-Stokes breath-
ing, respiration with mandibular movement, and death rattle
were particularly high. Based on the pretest probability and
positive LR, the post-test probability for impending death can
be determined using either a nomogram or a formula: Prob
post
5
(Prob
pre
/[12Prob
pre
]3LR1)/(11[Prob
pre
/(12Prob
pre
)3
LR1]). For example, the pretest probability of dying within
3 days after admission to our APCUs was 38%. The presence
of respiration with mandibular movement (positive LR: 10) in
a patient results in a post-test probability of 86% ([0.38 / (1 2
0.38) 310] / [1 1(0.38 / (1 20.38) 310)]). Upon external
validation in larger samples, the use of these signs alone or in
combination could facilitate the diagnosis of impending death.
This study was powered based on the combined data.
Notably,the two APCUs had different mortality rates because
of different referral patterns and patient characteristics. When
analysis was conducted by site, we found comparable
specificities and sensitivities for the signs between the two
participating institutions, and this finding further strengthens
our results. Furthermore, because LRs are less dependent on
prevalence, they are particularly suited for this analysis.
This study has several limitations. First, we included only
cancer patients who were admitted to APCUs in the Americas,
where they received intensive symptom management and
interprofessional support [33]. Further studies are needed to
determine whether the process of dying is similar in other
settings and in noncancer illnesses. Second, we may have
underestimated the frequency of some signs because of active
interventions in the APCUs (e.g., death rattle); however, it
would have been unethical to withhold treatments. Third,
variations in the prevalence of some signs may be related to
patient differences, cancer diagnoses, and/or how they were
interpreted. The data were highly compatible when analyzed
by study site, demonstrating similar specificities and sensitiv-
ities for each sign. Fourth, we relied on highly trained nurses
instead of physicians to document the clinical signs because
they spend more time at patients’bedsides. All nurses received
an orientation before study initiation and support throughout
the study. Fifth, we did not assess the inter-rater reliability of
these signs. Further validation is needed. Sixth, this study
focused only on 10 physical signs; the frequency and diagnostic
performance for other bedside signs would need to be
examined. Finally, this study included only two centers with
relatively smallpatient populations,and the signs were collected
every 12 hours, which limited the resolution of data. Future
studies should examine the cardinal signs in greater detail.
CONCLUSION
We methodically documented the frequency, onset, and
diagnostic performance of 10 signs in cancer patients admitted
to APCUs. On further validation, the late signs may assist
clinicians in formulating the diagnosis of impending death,
help patients and families in preparing ahead, and support
researchers in further investigating the process of dying.
ACKNOWLEDGMENTS
We thank all the patients, clinical nurses, and physicians who
participated in this study and provided valuable data. We also
thank Dr. Maxine De La Cruz and Dr. Camila Zimmermann for
scientific input and Dr. Jing Ning for biostatistics advice. This
research is supported in part by a University of Texas MD
Anderson Cancer Center support grant (CA 016672), which
provided the funds for data collection at both study sites. E.B. is
supportedinpartbyNationalInstitutesofHealthGrants
R01NR010162-01A1, R01CA122292-01, and R01CA124481-01.
AUTHOR CONTRIBUTIONS
Conception/Design: David Hui, Stacy Hall, Julieta Fajardo, Eduardo Bruera
Table 4. Diagnostic performance of 10 target clinical signs (n5357)
Physical signs
Missing data,
n(%)
a
Sensitivity
b
(95% CI)
Specificity
b
(95% CI)
Negative LR
b
(95% CI)
Positive LR
b
(95% CI)
PPS #20% 120 (2.1) 64 (63.4–64.7) 81.3 (80.9–81.7) 0.44 (0.43–0.45) 3.5 (3.4–3.6)
RASS 22 or lower 90 (1.6) 50.5 (49.9–51.1) 89.3 (88.9–89.7) 0.6 (0.5–0.6) 4.9 (4.7–5)
Dysphagia of liquids 652 (11.7) 40.9 (40.1–41.7) 78.8 (78.3–79.2) 0.75 (0.74–0.76) 1.9 (1.9–2)
Urine output over last
12 hours ,100 mL
3262 (58) 24.2 (23.2–25.1) 98.2 (98–98.5) 0.77 (0.76–0.78) 15.2 (13.4–17.1)
Death rattle 101 (1.8) 22.4 (21.8–22.9) 97.1 (96.9–97.3) 0.8 (0.79–0.81) 9 (8.1–9.8)
Apnea periods 85 (1.5) 17.6 (17.1–18) 95.3 (95.1–95.6) 0.86 (0.86–0.87) 4.5 (3.7–5.2)
Respiration with mandibular
movement
86 (1.5) 22 (21.5–22.4) 97.5 (97.3–97.6) 0.8 (0.8–0.81) 10 (9.1–10.9)
Peripheral cyanosis 90 (1.6) 26.7 (26.1–27.3) 94.9 (94.7–95.2) 0.77 (0.77–0.78) 5.7 (5.4–6.1)
Cheyne-Stokes breathing 83 (1.5) 14.1 (13.6–14.5) 98.5 (98.4–98.7) 0.9 (0.9–0.9) 12.4 (10.8–13.9)
Pulselessness of radial artery 94 (1.7) 11.3 (10.9–11.8) 99.3 (99.2–99.5) 0.89 (0.89–0.9) 15.6 (13.7–17.4)
a
Urinary output was not routinely collected at Barretos Cancer Hospital.
b
We computed the sensitivity,specificity,positive LR, and negative LR for each sign for death within 3 days using data from all 357 patients.We constructed
a232 table with one observation per patient based on the presence or absence of a particular sign during a randomly sampled nursing shift and whether
that patient died within the next 3 days from that shift, and then we calculatedthe sensitivity, specificity, positive LR, and negativeLR. To account forthe
multiple observations for each patient, we resampled our data 100 times to obtain the average and 95% confidence interval for each statistic.
Abbreviations: CI, confidence interval; LR, likelihood ratio; PPS, Palliative Performance Scale; RASS, Richmond Agitation Sedation Scale.
©AlphaMed Press 2014
T
he
O
ncologist
®
686 Clinical Signs of Impending Death
CME
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Provision of study material or patients: David Hui, Renata dos Santos,
Thiago Buosi Silva, Camila Souza Crovador, Raphael de Almeida Leite, Maria
Salete de Angelis Nascimento, Suresh Reddy, Fabiola Seriaco, Sriram Yennu,
Carlos Edurado Paiva, Rony Dev, Stacy Hall, Julieta Fajardo, Eduardo Bruera
Collection and/or assembly of data: David Hui, Renata dos Santos, Swati
Bansal, Thiago Buosi Silva, Kelly Kilgore, Camila Souza Crovador, Raphael de
Almeida Leite, Maria Salete de Angelis Nascimento, Suresh Reddy, Fabiola
Seriaco, Sriram Yennu, Carlos Edurado Paiva, Rony Dev, Stacy Hall, Julieta
Fajardo, Eduardo Bruera
Data analysis and interpretation: David Hui, Gary Chisholm, Swati Bansal,
Xiaoying Yu, Michael D. Swartz, Pedro Emilio Perez-Cruz, Eduardo Bruera
Manuscript writing: David Hui, Renata dos Santos, Gary Chisholm, Swati
Bansal, Thiago Buosi Silva, Kelly Kilgore, Camila Souza Crovador, Xiaoying Yu,
Michael D. Swartz, Pedro Emilio Perez-Cruz, Raphael de Almeida Leite, Maria
Salete de Angelis Nascimento, Suresh Reddy, Fabiola Seriaco, Sriram Yennu,
Carlos Edurado Paiva, Rony Dev, Stacy Hall, Julieta Fajardo, Eduardo Bruera
Final approval of manuscript: David Hui, Renata dos Santos, Gary Chisholm,
Swati Bansal, Thiago Buosi Silva, Kelly Kilgore, Camila Souza Crovador,
Xiaoying Yu, Michael D. Swartz, PedroEmilio Perez-Cruz, Raphael de Almeida
Leite, Maria Salete de Angelis Nascimento, Suresh Reddy, Fabiola Seriaco,
Sriram Yennu, Carlos Edurado Paiva, Rony Dev, Stacy Hall, Julieta Fajardo,
Eduardo Bruera
DISCLOSURES
The authors indicated no financial relationships.
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