- Email: [email protected]
Variations in Vital Signs in the Last Days of Life in Patients With Advanced Cancer
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Journal of Pain and Symptom Management 1
Original Article
Variations in Vital Signs in the Last Days of Life in Patients With Advanced Cancer Sebastian Bruera, Gary Chisholm, MS, Renata Dos Santos, MD, Camila Crovador, RN, Eduardo Bruera, MD, and David Hui, MD, MSc Department of Palliative Care and Rehabilitation Medicine (S.B., E.B., D.H.) and Department of Biostatistics (G.C.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; and Department of Palliative Care (R.D.S., C.C.), Barretos Cancer Hospital, Barretos, Brazil
Abstract Context. Few studies have examined variation in vital signs in the last days of life. Objectives. We determined the variation of vital signs in the final two weeks of life in patients with advanced cancer and examined their association with impending death in three days. Methods. In this prospective, longitudinal, observational study, we enrolled consecutive patients admitted to two acute palliative care units and documented their vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation, and temperature) twice a day serially from admission to death or discharge. Results. Of 357 patients, 203 (55%) died in hospital. Systolic blood pressure (P < 0.001), diastolic blood pressure (P < 0.001), and oxygen saturation (P < 0.001) decreased significantly in the final three days of life, and temperature increased slightly (P < 0.04). Heart rate (P ¼ 0.22) and respiratory rate (P ¼ 0.24) remained similar in the last three days. Impending death in three days was significantly associated with increased heart rate (odds ratio [OR] ¼ 2; P ¼ 0.01), decreased systolic blood pressure (OR ¼ 2.5; P ¼ 0.004), decreased diastolic blood pressure (OR ¼ 2.3; P ¼ 0.002), and decreased oxygen saturation (OR ¼ 3.7; P ¼ 0.003) from baseline readings on admission. These changes had high specificity ($80%), low sensitivity (#35%), and modest positive likelihood ratios (#5) for impending death within three days. A large proportion of patients had normal vital signs in the last days of life. Conclusion. Blood pressure and oxygen saturation decreased in the last days of life. Clinicians and families cannot rely on vital sign changes alone to rule in or rule out impending death. Our findings do not support routine vital signs monitoring of patients who are imminently dying. J Pain Symptom Manage 2014;-:-e-. Ó 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Address correspondence to: David Hui, MD, MSc, Department of Palliative Care and Rehabilitation Medicine, Unit 1414, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Ó 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Boulevard, Houston, TX 77030, USA. E-mail: [email protected] Accepted for publication: October 30, 2013. 0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2013.10.019
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Key Words Blood pressure, diagnosis, death, heart rate, oxygen, physiologic phenomena, respiratory rate, temperature, impending death, neoplasms
Introduction The last days of life are characterized by a multitude of physiologic changes, such as muscle weakness, dysphagia, and altered level of consciousness. These signs become increasingly common as patients approach death and are highly predictive of a shortened survival.1e4 In addition to these physiologic changes, vital signs such as heart rate, blood pressure, respiratory rate, oxygen saturation, and temperature also may provide useful information on the patient’s health status. Vital signs are regularly measured and recorded in hospitalized patients, even among those who are imminently dying. Abrupt and marked changes in vital signs often signal cardiovascular instability and/or respiratory compromise, which could be related to potentially lifethreatening complications. There is a paucity of studies examining how vital signs vary in the last days of life.5,6 A better understanding of how vital signs change as patients approach the last days of life and the association between vital sign changes and impending death may improve the clinician’s diagnostic accuracy of impending death, thereby facilitating communication with patients and families to plan for the final stages of life.7 The primary objective of our study was to determine the variation in vital signs in the final two weeks of life among cancer patients who died in our acute palliative care units (APCUs). Our secondary objective was to determine the association between the changes in vital signs and impending death.
Methods Participants This was a prospective, longitudinal, observational study. Consecutive patients with advanced cancer who were 18 years or older and admitted to the APCU at either M. D. Anderson Cancer Center between April 5, 2010 and July 6, 2010 or Barretos Cancer Hospital between January 27, 2011 and June 1, 2011
were enrolled into this study.8 The institutional review boards at both M. D. Anderson Cancer Center and Barretos Cancer Hospital reviewed this protocol and granted waivers of informed consent because this study was purely observational in nature. Furthermore, informed consent may precluded us from enrolling consecutive patients, which could then have introduced selection bias if patients who were delirious or in distress were not consistently included. It is the policy of both APCUs to monitor vital signs routinely unless otherwise requested.
Data Collection We collected baseline demographics including age, sex, race, cancer diagnosis, and admission length. Vital signs including heart rate, blood pressure, respiratory rate, oxygen saturation, and temperature were routinely documented at both APCUs, once in the morning and once in the afternoon, by our nurses from admission until death or discharge. Patients who were nonresponsive and/or delirious still had their vital signs taken whenever feasible. Collection of vital signs may increase or decrease in frequency depending on any specific requests from the attending physician, patient, or family members. For patients with multiple documented vital signs throughout the day, the recordings made closest to 8 a.m. and 8 p.m. were used for data analyses. We collected survival data from institutional databases, electronic health records, and the Tumor Registry Vital Statistics Database.
Statistical Analysis We summarized the baseline demographics using descriptive statistics. To determine the pattern of vital signs in the last two weeks of life, we plotted the average value of each vital sign every 12 hours from death backward for patients who died at the end of the APCU stay. We fit a two-piece model to determine the slope, with the first piece from Day 14 to Day 4 and the second piece from Day 3
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to Day 1. A random effects variance components model was fit to each of the two pieces, with time included as a fixed effect and patient included as a random effect, resulting in two regression lines per plot. T-tests were performed to determine if the slopes of the vital across time variable differed significantly from zero. To determine the diagnostic performance of each vital sign, we computed the sensitivity, specificity, positive predictive value (PPV), negative predictive value, positive likelihood ratio (LR), and negative LR using a 2 2 diagnostic table. We used data from all 357 patients instead of only those 203 patients who died because it was the entire population in which the diagnostic test was applied. We first coded the diagnostic test result by dichotomizing the change in the vital sign of interest, which was based on its average change in the last three days of life in our cohort (e.g., 20 mm Hg decrease in systolic blood pressure). For each diagnostic test result, we then determined whether the patient died in the next three days. The last three days of life were chosen as the outcome for impending death because our data showed that vital signs often change abruptly during this period, and that knowing a patient in the last three days of life could have practical implications for integrated care pathways and discharge. We subsequently constructed a 2 2 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 three days. To account for the multiple observations for each patient, we resampled our data 100 times to obtain the average and 95% CI for each statistic. Sensitivity indicates how often a sign of interest is present among patients with the outcome of interest (i.e., true positive/[true positive þ false negative]). Specificity indicates how often a sign of interest is absent among patients without the outcome of interest (i.e., true negative/[true negative þ false positive]). Positive LR provides an estimate of how many times more or less likely patients who died within a given period had a particular physical sign than patients who did not die (i.e., sensitivity/[1 specificity]). We also examined the univariate odds ratios (ORs) using a similar resampling methodology with 100 repetitions, each with one randomly
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sampled observation per patient. The independent variable was the presence or absence of change in the vital sign of interest during a randomly sampled nursing shift, and the dependent variable was whether the patient died within the next three days. ORs are complementary to LRs because they provide an estimate of the association between impending death and the change in a vital sign. The Statistical Analysis System (SAS, version 9.2; SAS Institute, Cary, NC) was used for statistical analysis. A P-value of less than 0.05 was considered significant.
Results Patient Characteristics One hundred fifty-one patients were enrolled from M. D. Anderson Cancer Center and 206 were enrolled from Barretos Cancer Hospital. The average age was 58 years (range 18e88), and 195 of 357 patients (55%) were female. Most patients were of Hispanic origin (n ¼ 233, 65%). Gastrointestinal cancer (n ¼ 101, 28%) and lung cancer (n ¼ 51, 14%) were the most common malignancies. Among the 203 patients who died at the end of the APCU stay, the average age was 58 years (range 18e88), 99 (49%) were female, and 158 (78%) were Hispanic. Gastrointestinal cancer (n ¼ 68, 33%) and lung cancer (n ¼ 29, 14%) also were the most common cancer types.
Changes in Vital Signs in the Last Days of Life Fig. 1 demonstrates the changes in vital signs in the final two weeks of life. Systolic blood pressure (P < 0.001), diastolic blood pressure (P < 0.001), and oxygen saturation (P < 0.001) each showed a significant decrease in the final three days of life. Temperature showed a small but statistically significant increase (P < 0.04) in the final three days of life. In contrast, heart rate (P ¼ 0.22) and respiratory rate (P ¼ 0.24) remained similar. The percentage of patients with vital sign abnormalities in the final two weeks of life is shown in Table 1. The changes of proportion of patients with abnormal vital signs in the last few days of life are consistent with the curves seen in Fig. 1. Most patients had normal
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Fig. 1. Changes in vital signs in the final two weeks of life. P (Segment 1) represents the significance of change of vital signs in the final two weeks of life; P (Segment 2) represents the significance of change of vital signs in the final three days of life. a) Systolic blood pressure: a significant decrease is seen in both Segments 1 and 2. b) Diastolic blood pressure: a significant decrease is seen in both Segments 1 and 2. c) Heart rate: a significant increase is seen in Segment 1 but not 2. d) Respiratory rate: a significant change is seen in Segment 1 but not 2. e) Oxygen saturation: a significant decrease is seen in both Segments 1 and 2. f) Temperature: a significant increase is seen in both Segments 1 and 2.
diastolic blood pressure, respiratory rate, and temperature in the final days of life. Heart rate, systolic blood pressure, and oxygen saturation were abnormal in approximately half of our patients on the last day of life.
Association Between Vital Sign Changes and Impending Death As shown in Table 2, death in three days was significantly associated with increased heart rate (OR ¼ 2; P ¼ 0.01), decreased systolic blood pressure (OR ¼ 2.5; P ¼ 0.004), decreased diastolic blood pressure (OR ¼ 2.3, P ¼ 0.002); increased temperature (OR ¼ 1.8; P ¼ 0.01) and decreased oxygen saturation (OR ¼ 3.7; P ¼ 0.003) from baseline readings taken at admission. Respiratory rate (OR ¼ 1.9; P ¼ 0.08) showed no association. A decrease in systolic blood pressure of greater than 20 mm Hg, decrease in diastolic blood
pressure of greater than 10 mm Hg, decrease in respiratory rate of greater than 5, and decrease in oxygen saturation greater than 8% were highly specific but not sensitive to impending death within three days (Table 3). Furthermore, these changes had low PPVs and modest positive LRs (<5) for impending death within three days.
Discussion We conducted a prospective study to determine the variations in vital signs among patients with advanced cancer and their association with impending death. We found a significant decrease in blood pressure and oxygen saturation over time, most prominently in the final three days of life. Changes in these signs were highly specific for impending death; however, they only had a modest PPV, which limits their utility for the diagnosis of
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Table 1 Percent of Patients With Vital Sign Abnormalities From Admission to Deatha Vital Signs Heart rate Low (<60) Normal (60e100) High (>100) Systolic blood pressure Low (<100) Normal (100e140) High (>140) Diastolic blood pressure Low (<60) Normal (60e90) High (>90) Respiratory rate Low (<12) Normal (12e20) High (>20) Oxygen saturation Low (<85%) Low normal (85e90%) Normal (>90%) Temperature Low (<36) Normal (36e38.5) High (>38.5)
Day 14
Day 7
Day 6
Day 5
Day 4
Day 3
Day 2
Day 1
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
1 (3) 19 (66) 9 (31)
0 (0) 41 (63) 24 (37)
0 (0) 39 (53) 34 (47)
0 (0) 44 (51) 42 (49)
3 (3) 53 (50) 51 (48)
0 (0) 61 (48) 67 (52)
1 (1) 70 (44) 87 (55)
2 (1) 81 (45) 97 (54)
5 (18) 22 (79) 1 (4)
12 (19) 48 (75) 4 (6)
11 (15) 59 (82) 2 (3)
13 (16) 68 (82) 2 (2)
16 (15) 87 (81) 4 (4)
25 (20) 97 (78) 3 (2)
39 (25) 112 (71) 7 (4)
85 (47) 85 (47) 10 (6)
0 (0) 27 (96) 1 (4)
4 (6) 59 (92) 1 (2)
1 (1) 71 (99) 0 (0)
4 (5) 79 (95) 0 (0)
8 (7) 96 (90) 3 (3)
12 (10) 111 (90) 1 (1)
20 (13) 131 (83) 7 (4)
49 (27) 127 (71) 4 (2)
0 (0) 28 (100) 0 (0)
0 (0) 61 (94) 4 (6)
0 (0) 62 (86) 10 (14)
0 (0) 72 (87) 11 (13)
0 (0) 90 (84) 17 (16)
0 (0) 106 (84) 20 (16)
0 (0) 128 (81) 31 (19)
1 (1) 128 (70) 53 (29)
3 (10) 7 (24) 19 (66)
7 (11) 27 (42) 30 (47)
12 (17) 21 (29) 39 (54)
13 (16) 28 (34) 41 (50)
13 (12) 36 (34) 58 (54)
17 (14) 39 (31) 69 (55)
23 (15) 50 (33) 80 (52)
52 (30) 43 (25) 76 (44)
6 (21) 22 (79) 0 (0)
10 (16) 54 (84) 0 (0)
13 (18) 59 (82) 0 (0)
14 (17) 68 (83) 0 (0)
20 (19) 87 (81) 0 (0)
19 (15) 106 (83) 2 (2)
21 (13) 136 (86) 1 (1)
24 (13) 148 (81) 10 (5)
a The changes in proportion from Day 14 to Day 7 are limited. Because of this, Days 8 to 13 were omitted from the table for simplicity. Furthermore, the number of data points at each time point was limited by the duration of stay in the acute palliative care unit, with a greater number of observations closer to death.
impending death. Importantly, their low sensitivity suggests that the absence of vital sign changes does not rule out impending death. Our findings do not support universal vital signs monitoring in the last days of life. How vital signs vary at the end of life is a frequently asked question by health care professionals, patients, and families. To our knowledge, this is the first study to systematically record vital signs in a serial fashion and examine their variations in the final days of life. Gang et al.9 previously examined the heart rhythm changes among 26 patients who died with an implanted loop recorder and reported that ventricular tachyarrhythmias and bradyarrhythmias were common at the time of death. However, their study focused on patients who had an acute myocardial infarction and only examined the rhythm in the period immediately before death. In our cohort of patients with cancer, we found a small but significant decrease in systolic blood pressure, diastolic blood pressure, and oxygen saturation in the last two weeks of life, with an abrupt decrease in these vital signs in the final three days. Heart rate also increased steadily, whereas
the changes in respiratory rate and temperature were minimal. It is important to note that we cannot distinguish these vital sign changes as part of the natural process of dying, or whether they are related to major complications, such as sepsis, leading to hypotension, tachycardia, and fever. Remarkably, a large proportion of patients had normal vital signs in the final days of life. Our secondary objective was to investigate if the changes in vital signs in the last days of life can inform us about the diagnosis of Table 2 Association Between Vital Sign Changes and Death in Three Days Variables
OR (95% CI)
P-value
Heart rate increase >10 Systolic blood pressure decrease >20 mm Hg Diastolic blood pressure decrease >10 mm Hg Respiratory rate decrease >5 Oxygen saturation decrease >8% Temperature increase >0.5 C
2 (1.1e3.2) 2.5 (1.4e4.7)
0.01 0.0004
2.3 (1.4e4.3)
0.002
1.9 (0.8e5.3) 3.7 (2.1e10.8)
0.08 0.0003
2.1 (1.2e3.9)
0.002
OR ¼ odds ratio.
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Table 3 Vital Sign Changes and Respective Sensitivity, Specificity, PPV, NPV, Positive LR, and Negative LR for Death in Three Days Variables Heart rate increase >10 Systolic blood pressure decrease >20 mm Hg Diastolic blood pressure decrease >10 mm Hg Respiratory rate decrease >5 Oxygen saturation decrease >8% Temperature increase >0.5 C
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
Positive LR (95% CI)
Negative LR (95% CI)
34 (33e34) 23 (22e24)
80 (79e80) 90 (89e90)
39 (38e40) 48 (47e49)
75 (75e76) 74 (73e74)
1.68 (1.61e1.75) 2.3 (2.19e2.42)
0.84 (0.82e0.85) 0.86 (0.85e0.87)
26 (25e26)
88 (88e89)
47 (45e48)
75 (74e75)
2.24 (2.11e2.36)
0.84 (0.83e0.86)
7 (7e8) 15 (14e16)
96 (96e97) 95 (95e96)
43 (41e46) 57 (56e59)
72 (71e72) 73 (73e74)
2.15 (1.9e2.41) 3.61 (3.3e3.91)
0.97 (0.96e0.97) 0.89 (0.88e0.9)
30 (29e31)
83 (83e84)
43 (42e44)
74 (74e75)
1.86 (1.78e1.94)
0.84 (0.83e0.85)
PPV ¼ positive predictive value; NPV ¼ negative predictive value; LR ¼ likelihood ratio.
impending death. We decided to examine relative vital sign changes (i.e., changes from baseline values on admission, e.g., systolic blood pressure decrease >20 mm Hg from baseline) instead of absolute changes (e.g., systolic blood pressure below 80 mm Hg) because relative changes allowed us to control for each individual, and absolute changes have already been reported elsewhere. To date, only one study has investigated the relative changes in vital signs and their association with impending death. Hwang et al.10 conducted an observational prospective cohort study investigating signs and symptoms that were associated with impending death within 48 hours in a population of 181 patients in a palliative care unit. Consistent with our study, they found that decreased blood pressure and oxygen saturation were associated with impending death; however, they had higher PPVs (79% and 81%, respectively). This discrepancy can be explained by the different study populations, study settings, statistical analysis, and study outcomes. Huang et al. examined changes in the final 48 hours of life, whereas we examined the final 72 hours. They also defined decreased blood pressure as changes in either systolic or diastolic readings, whereas we investigated systolic and diastolic blood pressures separately. Furthermore, Huang et al. only recorded vital signs on patients who were recognized as imminently dying, whereas we recorded vital signs on unselected patients admitted to the APCU. Taken together, we believe that both our results support the weak association between impending death and changes in blood pressure and oxygen saturation. Prognostic models to date have mostly examined absolute abnormalities in vital signs
among patients with weeks of life expectancy.3,11e16 These studies showed that lower respiratory rate, lower blood pressure, lower oxygen saturation, and higher temperature on hospital admission were associated with a shortened survival. Our findings are generally consistent with the literature despite our different approach. Specifically, our serial data revealed the slight decrease in average blood pressure and oxygen saturation and slight increase in average heart rate and temperature even two weeks from death (Fig. 1). Because the magnitude of changes are small, variations in these vital signs may best be considered as potential risk factors for poor survival rather than definitive markers of impending death.
Implications for Clinical Practice Our findings have important implications for clinical practice. Health care professionals and family caregivers often follow vital signs closely in patients over time and often wonder whether vital sign changes can inform them that the patient will be dying soon. Our data clearly show a moderate association between changes in some vital signs (blood pressure and oxygen saturation) and impending death; however, the LR was not high enough to definitely inform us that death was imminent. At the same time, because a large proportion of patients had normal vital signs even in the last days of life, a normal vital sign cannot exclude the possibility of impending death either. Other beside signs, such as death rattle and respiration with mandibular movement, may be more informative in making the diagnosis of impending death.3,10 Taken together, the presence or absence of vital sign changes,
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when used on their own, cannot uniformly rule in or rule out impending death. This lack of utility, coupled with the potential risks of sleep disruption, agitation in delirious patients, and causing excessive worries among families, suggests that the current practice of universal vital sign monitoring in the last days of life may not be warranted.
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limited ability to rule in or rule out impending death, questioning the need to routinely monitor vital signs in patients who are clearly dying. Future research to examine other physiologic changes that happen in the last days of life may improve clinicians’ ability to recognize impending death, thereby facilitating communication with patients and families to optimize care planning.
Limitations There are certain limitations in our study. First, vital signs were recorded twice a day. It might be possible that more frequent readings would detect more subtle variations in vital signs, particularly in the last three days of life. Unlike patients in critical care units, our APCU patients are not monitored continuously with telemetry. We decided not to conduct more frequent measurements of vital signs in our patients to minimize study burden. Second, we only included cancer patients admitted APCUs, which could have limited the generalizability of our findings. Third, patients admitted to the APCUs often received antihypertensive medications, antipyretic agents (e.g., steroids, acetaminophen), and/or supplemental oxygen, which could affect vital sign changes. Thus, our data only reflect vital sign changes in patients treated in acute care facilities receiving standard medical interventions. Future studies should examine vital sign changes in other patient populations and other settings. Fourth, we made every attempt to document vital signs and were able to capture the majority. However, vital signs were sometimes missing because of occasional orders, family requests to discontinue monitoring, or patients were not present in their rooms. This represented only a small proportion of our cohort. Finally, the baseline vital signs obtained on APCU admission may not be reflective of the premorbid baseline because patients were acutely ill while in hospital.
Conclusion In summary, we examined, in a prospective study, the changes of vital signs in the last days of life and their association with impending death. We identified characteristic changes such as decreased blood pressure and oxygen saturation as patients approach death. However, these vital sign changes on their own have
Disclosures and Acknowledgments S. B. is supported in part by National Institutes of Health grants RO1NR010162-01A1, RO1CA122292-01, and RO1CA124481-01. D. H. is supported in part by an institutional startup grant (#18075582). This study is also supported by the M.D. Anderson Cancer Center Support Grant (CA 016672). The funding sources were not involved in the conduct of the study or development of the submission.
References 1. Morita T, Tsunoda J, Inoue S, Chihara S. Improved accuracy of physicians’ survival prediction for terminally ill cancer patients using the Palliative Prognostic Index. Palliat Med 2001;15:419e424. 2. Caraceni A, Nanni O, Maltoni M, et al. Impact of delirium on the short term prognosis of advanced cancer patients. Italian Multicenter Study Group on Palliative Care. Cancer 2000;89: 1145e1149. 3. Morita T, Tsunoda J, Inoue S, Chihara S. The Palliative Prognostic Index: a scoring system for survival prediction of terminally ill cancer patients. Support Care Cancer 1999;7:128e133. 4. Vigano A, Bruera E, Jhangri GS, et al. Clinical survival predictors in patients with advanced cancer. Arch Intern Med 2000;160:861e868. 5. Kao YH, Chen CN, Chiang JK, Chen SS, Huang WW. Predicting factors in the last week of survival in elderly patients with terminal cancer: a prospective study in southern Taiwan. J Formos Med Assoc 2009;108:231e239. 6. Plonk WM Jr, Arnold RM. Terminal care: the last weeks of life. J Palliat Med 2005;8:1042e1054. 7. Weeks JC, Cook EF, O’Day SJ, et al. Relationship between cancer patients’ predictions of prognosis and their treatment preferences. JAMA 1998;279: 1709e1714. 8. Hui D, Elsayem A, Palla S, et al. Discharge outcomes and survival of patients with advanced cancer admitted to an acute palliative care unit at a
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comprehensive cancer center. J Palliat Med 2010;13: 49e57.
admission criteria via the electronic medical record. Cancer 2013;119:2074e2080.
9. Gang UJ, Jons C, Jorgensen RM, et al. Heart rhythm at the time of death documented by an implantable loop recorder. Europace 2010;12: 254e260.
13. Pirovano M, Maltoni M, Nanni O, et al. A new palliative prognostic score: a first step for the staging of terminally ill cancer patients. Italian Multicenter and Study Group on Palliative Care. J Pain Symptom Manage 1999;17:231e239.
10. Hwang IC, Ahn HY, Park SM, Shim JY, Kim KK. Clinical changes in terminally ill cancer patients and death within 48 h: when should we refer patients to a separate room? Support Care Cancer 2013;21:835e840.
14. Chuang RB, Hu WY, Chiu TY, Chen CY. Prediction of survival in terminal cancer patients in Taiwan: constructing a prognostic scale. J Pain Symptom Manage 2004;28:115e122.
11. Yun YH, Heo DS, Heo BY, et al. Development of terminal cancer prognostic score as an index in terminally ill cancer patients. Oncol Rep 2001;8: 795e800. 12. Ramchandran KJ, Shega JW, Von Roenn J, et al. A predictive model to identify hospitalized cancer patients at risk for 30-day mortality based on
15. Chiang JK, Lai NS, Wang MH, Chen SC, Kao YH. A proposed prognostic 7-day survival formula for patients with terminal cancer. BMC Public Health 2009;9:365. 16. Bruera E, Miller MJ, Kuehn N, MacEachern T, Hanson J. Estimate of survival of patients admitted to a palliative care unit: a prospective study. J Pain Symptom Manage 1992;7:82e86.
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Journal of Pain and Symptom Management 1
Original Article
Variations in Vital Signs in the Last Days of Life in Patients With Advanced Cancer Sebastian Bruera, Gary Chisholm, MS, Renata Dos Santos, MD, Camila Crovador, RN, Eduardo Bruera, MD, and David Hui, MD, MSc Department of Palliative Care and Rehabilitation Medicine (S.B., E.B., D.H.) and Department of Biostatistics (G.C.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; and Department of Palliative Care (R.D.S., C.C.), Barretos Cancer Hospital, Barretos, Brazil
Abstract Context. Few studies have examined variation in vital signs in the last days of life. Objectives. We determined the variation of vital signs in the final two weeks of life in patients with advanced cancer and examined their association with impending death in three days. Methods. In this prospective, longitudinal, observational study, we enrolled consecutive patients admitted to two acute palliative care units and documented their vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation, and temperature) twice a day serially from admission to death or discharge. Results. Of 357 patients, 203 (55%) died in hospital. Systolic blood pressure (P < 0.001), diastolic blood pressure (P < 0.001), and oxygen saturation (P < 0.001) decreased significantly in the final three days of life, and temperature increased slightly (P < 0.04). Heart rate (P ¼ 0.22) and respiratory rate (P ¼ 0.24) remained similar in the last three days. Impending death in three days was significantly associated with increased heart rate (odds ratio [OR] ¼ 2; P ¼ 0.01), decreased systolic blood pressure (OR ¼ 2.5; P ¼ 0.004), decreased diastolic blood pressure (OR ¼ 2.3; P ¼ 0.002), and decreased oxygen saturation (OR ¼ 3.7; P ¼ 0.003) from baseline readings on admission. These changes had high specificity ($80%), low sensitivity (#35%), and modest positive likelihood ratios (#5) for impending death within three days. A large proportion of patients had normal vital signs in the last days of life. Conclusion. Blood pressure and oxygen saturation decreased in the last days of life. Clinicians and families cannot rely on vital sign changes alone to rule in or rule out impending death. Our findings do not support routine vital signs monitoring of patients who are imminently dying. J Pain Symptom Manage 2014;-:-e-. Ó 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Address correspondence to: David Hui, MD, MSc, Department of Palliative Care and Rehabilitation Medicine, Unit 1414, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Ó 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Boulevard, Houston, TX 77030, USA. E-mail: [email protected] Accepted for publication: October 30, 2013. 0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2013.10.019
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Key Words Blood pressure, diagnosis, death, heart rate, oxygen, physiologic phenomena, respiratory rate, temperature, impending death, neoplasms
Introduction The last days of life are characterized by a multitude of physiologic changes, such as muscle weakness, dysphagia, and altered level of consciousness. These signs become increasingly common as patients approach death and are highly predictive of a shortened survival.1e4 In addition to these physiologic changes, vital signs such as heart rate, blood pressure, respiratory rate, oxygen saturation, and temperature also may provide useful information on the patient’s health status. Vital signs are regularly measured and recorded in hospitalized patients, even among those who are imminently dying. Abrupt and marked changes in vital signs often signal cardiovascular instability and/or respiratory compromise, which could be related to potentially lifethreatening complications. There is a paucity of studies examining how vital signs vary in the last days of life.5,6 A better understanding of how vital signs change as patients approach the last days of life and the association between vital sign changes and impending death may improve the clinician’s diagnostic accuracy of impending death, thereby facilitating communication with patients and families to plan for the final stages of life.7 The primary objective of our study was to determine the variation in vital signs in the final two weeks of life among cancer patients who died in our acute palliative care units (APCUs). Our secondary objective was to determine the association between the changes in vital signs and impending death.
Methods Participants This was a prospective, longitudinal, observational study. Consecutive patients with advanced cancer who were 18 years or older and admitted to the APCU at either M. D. Anderson Cancer Center between April 5, 2010 and July 6, 2010 or Barretos Cancer Hospital between January 27, 2011 and June 1, 2011
were enrolled into this study.8 The institutional review boards at both M. D. Anderson Cancer Center and Barretos Cancer Hospital reviewed this protocol and granted waivers of informed consent because this study was purely observational in nature. Furthermore, informed consent may precluded us from enrolling consecutive patients, which could then have introduced selection bias if patients who were delirious or in distress were not consistently included. It is the policy of both APCUs to monitor vital signs routinely unless otherwise requested.
Data Collection We collected baseline demographics including age, sex, race, cancer diagnosis, and admission length. Vital signs including heart rate, blood pressure, respiratory rate, oxygen saturation, and temperature were routinely documented at both APCUs, once in the morning and once in the afternoon, by our nurses from admission until death or discharge. Patients who were nonresponsive and/or delirious still had their vital signs taken whenever feasible. Collection of vital signs may increase or decrease in frequency depending on any specific requests from the attending physician, patient, or family members. For patients with multiple documented vital signs throughout the day, the recordings made closest to 8 a.m. and 8 p.m. were used for data analyses. We collected survival data from institutional databases, electronic health records, and the Tumor Registry Vital Statistics Database.
Statistical Analysis We summarized the baseline demographics using descriptive statistics. To determine the pattern of vital signs in the last two weeks of life, we plotted the average value of each vital sign every 12 hours from death backward for patients who died at the end of the APCU stay. We fit a two-piece model to determine the slope, with the first piece from Day 14 to Day 4 and the second piece from Day 3
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to Day 1. A random effects variance components model was fit to each of the two pieces, with time included as a fixed effect and patient included as a random effect, resulting in two regression lines per plot. T-tests were performed to determine if the slopes of the vital across time variable differed significantly from zero. To determine the diagnostic performance of each vital sign, we computed the sensitivity, specificity, positive predictive value (PPV), negative predictive value, positive likelihood ratio (LR), and negative LR using a 2 2 diagnostic table. We used data from all 357 patients instead of only those 203 patients who died because it was the entire population in which the diagnostic test was applied. We first coded the diagnostic test result by dichotomizing the change in the vital sign of interest, which was based on its average change in the last three days of life in our cohort (e.g., 20 mm Hg decrease in systolic blood pressure). For each diagnostic test result, we then determined whether the patient died in the next three days. The last three days of life were chosen as the outcome for impending death because our data showed that vital signs often change abruptly during this period, and that knowing a patient in the last three days of life could have practical implications for integrated care pathways and discharge. We subsequently constructed a 2 2 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 three days. To account for the multiple observations for each patient, we resampled our data 100 times to obtain the average and 95% CI for each statistic. Sensitivity indicates how often a sign of interest is present among patients with the outcome of interest (i.e., true positive/[true positive þ false negative]). Specificity indicates how often a sign of interest is absent among patients without the outcome of interest (i.e., true negative/[true negative þ false positive]). Positive LR provides an estimate of how many times more or less likely patients who died within a given period had a particular physical sign than patients who did not die (i.e., sensitivity/[1 specificity]). We also examined the univariate odds ratios (ORs) using a similar resampling methodology with 100 repetitions, each with one randomly
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sampled observation per patient. The independent variable was the presence or absence of change in the vital sign of interest during a randomly sampled nursing shift, and the dependent variable was whether the patient died within the next three days. ORs are complementary to LRs because they provide an estimate of the association between impending death and the change in a vital sign. The Statistical Analysis System (SAS, version 9.2; SAS Institute, Cary, NC) was used for statistical analysis. A P-value of less than 0.05 was considered significant.
Results Patient Characteristics One hundred fifty-one patients were enrolled from M. D. Anderson Cancer Center and 206 were enrolled from Barretos Cancer Hospital. The average age was 58 years (range 18e88), and 195 of 357 patients (55%) were female. Most patients were of Hispanic origin (n ¼ 233, 65%). Gastrointestinal cancer (n ¼ 101, 28%) and lung cancer (n ¼ 51, 14%) were the most common malignancies. Among the 203 patients who died at the end of the APCU stay, the average age was 58 years (range 18e88), 99 (49%) were female, and 158 (78%) were Hispanic. Gastrointestinal cancer (n ¼ 68, 33%) and lung cancer (n ¼ 29, 14%) also were the most common cancer types.
Changes in Vital Signs in the Last Days of Life Fig. 1 demonstrates the changes in vital signs in the final two weeks of life. Systolic blood pressure (P < 0.001), diastolic blood pressure (P < 0.001), and oxygen saturation (P < 0.001) each showed a significant decrease in the final three days of life. Temperature showed a small but statistically significant increase (P < 0.04) in the final three days of life. In contrast, heart rate (P ¼ 0.22) and respiratory rate (P ¼ 0.24) remained similar. The percentage of patients with vital sign abnormalities in the final two weeks of life is shown in Table 1. The changes of proportion of patients with abnormal vital signs in the last few days of life are consistent with the curves seen in Fig. 1. Most patients had normal
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Fig. 1. Changes in vital signs in the final two weeks of life. P (Segment 1) represents the significance of change of vital signs in the final two weeks of life; P (Segment 2) represents the significance of change of vital signs in the final three days of life. a) Systolic blood pressure: a significant decrease is seen in both Segments 1 and 2. b) Diastolic blood pressure: a significant decrease is seen in both Segments 1 and 2. c) Heart rate: a significant increase is seen in Segment 1 but not 2. d) Respiratory rate: a significant change is seen in Segment 1 but not 2. e) Oxygen saturation: a significant decrease is seen in both Segments 1 and 2. f) Temperature: a significant increase is seen in both Segments 1 and 2.
diastolic blood pressure, respiratory rate, and temperature in the final days of life. Heart rate, systolic blood pressure, and oxygen saturation were abnormal in approximately half of our patients on the last day of life.
Association Between Vital Sign Changes and Impending Death As shown in Table 2, death in three days was significantly associated with increased heart rate (OR ¼ 2; P ¼ 0.01), decreased systolic blood pressure (OR ¼ 2.5; P ¼ 0.004), decreased diastolic blood pressure (OR ¼ 2.3, P ¼ 0.002); increased temperature (OR ¼ 1.8; P ¼ 0.01) and decreased oxygen saturation (OR ¼ 3.7; P ¼ 0.003) from baseline readings taken at admission. Respiratory rate (OR ¼ 1.9; P ¼ 0.08) showed no association. A decrease in systolic blood pressure of greater than 20 mm Hg, decrease in diastolic blood
pressure of greater than 10 mm Hg, decrease in respiratory rate of greater than 5, and decrease in oxygen saturation greater than 8% were highly specific but not sensitive to impending death within three days (Table 3). Furthermore, these changes had low PPVs and modest positive LRs (<5) for impending death within three days.
Discussion We conducted a prospective study to determine the variations in vital signs among patients with advanced cancer and their association with impending death. We found a significant decrease in blood pressure and oxygen saturation over time, most prominently in the final three days of life. Changes in these signs were highly specific for impending death; however, they only had a modest PPV, which limits their utility for the diagnosis of
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Table 1 Percent of Patients With Vital Sign Abnormalities From Admission to Deatha Vital Signs Heart rate Low (<60) Normal (60e100) High (>100) Systolic blood pressure Low (<100) Normal (100e140) High (>140) Diastolic blood pressure Low (<60) Normal (60e90) High (>90) Respiratory rate Low (<12) Normal (12e20) High (>20) Oxygen saturation Low (<85%) Low normal (85e90%) Normal (>90%) Temperature Low (<36) Normal (36e38.5) High (>38.5)
Day 14
Day 7
Day 6
Day 5
Day 4
Day 3
Day 2
Day 1
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
1 (3) 19 (66) 9 (31)
0 (0) 41 (63) 24 (37)
0 (0) 39 (53) 34 (47)
0 (0) 44 (51) 42 (49)
3 (3) 53 (50) 51 (48)
0 (0) 61 (48) 67 (52)
1 (1) 70 (44) 87 (55)
2 (1) 81 (45) 97 (54)
5 (18) 22 (79) 1 (4)
12 (19) 48 (75) 4 (6)
11 (15) 59 (82) 2 (3)
13 (16) 68 (82) 2 (2)
16 (15) 87 (81) 4 (4)
25 (20) 97 (78) 3 (2)
39 (25) 112 (71) 7 (4)
85 (47) 85 (47) 10 (6)
0 (0) 27 (96) 1 (4)
4 (6) 59 (92) 1 (2)
1 (1) 71 (99) 0 (0)
4 (5) 79 (95) 0 (0)
8 (7) 96 (90) 3 (3)
12 (10) 111 (90) 1 (1)
20 (13) 131 (83) 7 (4)
49 (27) 127 (71) 4 (2)
0 (0) 28 (100) 0 (0)
0 (0) 61 (94) 4 (6)
0 (0) 62 (86) 10 (14)
0 (0) 72 (87) 11 (13)
0 (0) 90 (84) 17 (16)
0 (0) 106 (84) 20 (16)
0 (0) 128 (81) 31 (19)
1 (1) 128 (70) 53 (29)
3 (10) 7 (24) 19 (66)
7 (11) 27 (42) 30 (47)
12 (17) 21 (29) 39 (54)
13 (16) 28 (34) 41 (50)
13 (12) 36 (34) 58 (54)
17 (14) 39 (31) 69 (55)
23 (15) 50 (33) 80 (52)
52 (30) 43 (25) 76 (44)
6 (21) 22 (79) 0 (0)
10 (16) 54 (84) 0 (0)
13 (18) 59 (82) 0 (0)
14 (17) 68 (83) 0 (0)
20 (19) 87 (81) 0 (0)
19 (15) 106 (83) 2 (2)
21 (13) 136 (86) 1 (1)
24 (13) 148 (81) 10 (5)
a The changes in proportion from Day 14 to Day 7 are limited. Because of this, Days 8 to 13 were omitted from the table for simplicity. Furthermore, the number of data points at each time point was limited by the duration of stay in the acute palliative care unit, with a greater number of observations closer to death.
impending death. Importantly, their low sensitivity suggests that the absence of vital sign changes does not rule out impending death. Our findings do not support universal vital signs monitoring in the last days of life. How vital signs vary at the end of life is a frequently asked question by health care professionals, patients, and families. To our knowledge, this is the first study to systematically record vital signs in a serial fashion and examine their variations in the final days of life. Gang et al.9 previously examined the heart rhythm changes among 26 patients who died with an implanted loop recorder and reported that ventricular tachyarrhythmias and bradyarrhythmias were common at the time of death. However, their study focused on patients who had an acute myocardial infarction and only examined the rhythm in the period immediately before death. In our cohort of patients with cancer, we found a small but significant decrease in systolic blood pressure, diastolic blood pressure, and oxygen saturation in the last two weeks of life, with an abrupt decrease in these vital signs in the final three days. Heart rate also increased steadily, whereas
the changes in respiratory rate and temperature were minimal. It is important to note that we cannot distinguish these vital sign changes as part of the natural process of dying, or whether they are related to major complications, such as sepsis, leading to hypotension, tachycardia, and fever. Remarkably, a large proportion of patients had normal vital signs in the final days of life. Our secondary objective was to investigate if the changes in vital signs in the last days of life can inform us about the diagnosis of Table 2 Association Between Vital Sign Changes and Death in Three Days Variables
OR (95% CI)
P-value
Heart rate increase >10 Systolic blood pressure decrease >20 mm Hg Diastolic blood pressure decrease >10 mm Hg Respiratory rate decrease >5 Oxygen saturation decrease >8% Temperature increase >0.5 C
2 (1.1e3.2) 2.5 (1.4e4.7)
0.01 0.0004
2.3 (1.4e4.3)
0.002
1.9 (0.8e5.3) 3.7 (2.1e10.8)
0.08 0.0003
2.1 (1.2e3.9)
0.002
OR ¼ odds ratio.
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Table 3 Vital Sign Changes and Respective Sensitivity, Specificity, PPV, NPV, Positive LR, and Negative LR for Death in Three Days Variables Heart rate increase >10 Systolic blood pressure decrease >20 mm Hg Diastolic blood pressure decrease >10 mm Hg Respiratory rate decrease >5 Oxygen saturation decrease >8% Temperature increase >0.5 C
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
Positive LR (95% CI)
Negative LR (95% CI)
34 (33e34) 23 (22e24)
80 (79e80) 90 (89e90)
39 (38e40) 48 (47e49)
75 (75e76) 74 (73e74)
1.68 (1.61e1.75) 2.3 (2.19e2.42)
0.84 (0.82e0.85) 0.86 (0.85e0.87)
26 (25e26)
88 (88e89)
47 (45e48)
75 (74e75)
2.24 (2.11e2.36)
0.84 (0.83e0.86)
7 (7e8) 15 (14e16)
96 (96e97) 95 (95e96)
43 (41e46) 57 (56e59)
72 (71e72) 73 (73e74)
2.15 (1.9e2.41) 3.61 (3.3e3.91)
0.97 (0.96e0.97) 0.89 (0.88e0.9)
30 (29e31)
83 (83e84)
43 (42e44)
74 (74e75)
1.86 (1.78e1.94)
0.84 (0.83e0.85)
PPV ¼ positive predictive value; NPV ¼ negative predictive value; LR ¼ likelihood ratio.
impending death. We decided to examine relative vital sign changes (i.e., changes from baseline values on admission, e.g., systolic blood pressure decrease >20 mm Hg from baseline) instead of absolute changes (e.g., systolic blood pressure below 80 mm Hg) because relative changes allowed us to control for each individual, and absolute changes have already been reported elsewhere. To date, only one study has investigated the relative changes in vital signs and their association with impending death. Hwang et al.10 conducted an observational prospective cohort study investigating signs and symptoms that were associated with impending death within 48 hours in a population of 181 patients in a palliative care unit. Consistent with our study, they found that decreased blood pressure and oxygen saturation were associated with impending death; however, they had higher PPVs (79% and 81%, respectively). This discrepancy can be explained by the different study populations, study settings, statistical analysis, and study outcomes. Huang et al. examined changes in the final 48 hours of life, whereas we examined the final 72 hours. They also defined decreased blood pressure as changes in either systolic or diastolic readings, whereas we investigated systolic and diastolic blood pressures separately. Furthermore, Huang et al. only recorded vital signs on patients who were recognized as imminently dying, whereas we recorded vital signs on unselected patients admitted to the APCU. Taken together, we believe that both our results support the weak association between impending death and changes in blood pressure and oxygen saturation. Prognostic models to date have mostly examined absolute abnormalities in vital signs
among patients with weeks of life expectancy.3,11e16 These studies showed that lower respiratory rate, lower blood pressure, lower oxygen saturation, and higher temperature on hospital admission were associated with a shortened survival. Our findings are generally consistent with the literature despite our different approach. Specifically, our serial data revealed the slight decrease in average blood pressure and oxygen saturation and slight increase in average heart rate and temperature even two weeks from death (Fig. 1). Because the magnitude of changes are small, variations in these vital signs may best be considered as potential risk factors for poor survival rather than definitive markers of impending death.
Implications for Clinical Practice Our findings have important implications for clinical practice. Health care professionals and family caregivers often follow vital signs closely in patients over time and often wonder whether vital sign changes can inform them that the patient will be dying soon. Our data clearly show a moderate association between changes in some vital signs (blood pressure and oxygen saturation) and impending death; however, the LR was not high enough to definitely inform us that death was imminent. At the same time, because a large proportion of patients had normal vital signs even in the last days of life, a normal vital sign cannot exclude the possibility of impending death either. Other beside signs, such as death rattle and respiration with mandibular movement, may be more informative in making the diagnosis of impending death.3,10 Taken together, the presence or absence of vital sign changes,
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when used on their own, cannot uniformly rule in or rule out impending death. This lack of utility, coupled with the potential risks of sleep disruption, agitation in delirious patients, and causing excessive worries among families, suggests that the current practice of universal vital sign monitoring in the last days of life may not be warranted.
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limited ability to rule in or rule out impending death, questioning the need to routinely monitor vital signs in patients who are clearly dying. Future research to examine other physiologic changes that happen in the last days of life may improve clinicians’ ability to recognize impending death, thereby facilitating communication with patients and families to optimize care planning.
Limitations There are certain limitations in our study. First, vital signs were recorded twice a day. It might be possible that more frequent readings would detect more subtle variations in vital signs, particularly in the last three days of life. Unlike patients in critical care units, our APCU patients are not monitored continuously with telemetry. We decided not to conduct more frequent measurements of vital signs in our patients to minimize study burden. Second, we only included cancer patients admitted APCUs, which could have limited the generalizability of our findings. Third, patients admitted to the APCUs often received antihypertensive medications, antipyretic agents (e.g., steroids, acetaminophen), and/or supplemental oxygen, which could affect vital sign changes. Thus, our data only reflect vital sign changes in patients treated in acute care facilities receiving standard medical interventions. Future studies should examine vital sign changes in other patient populations and other settings. Fourth, we made every attempt to document vital signs and were able to capture the majority. However, vital signs were sometimes missing because of occasional orders, family requests to discontinue monitoring, or patients were not present in their rooms. This represented only a small proportion of our cohort. Finally, the baseline vital signs obtained on APCU admission may not be reflective of the premorbid baseline because patients were acutely ill while in hospital.
Conclusion In summary, we examined, in a prospective study, the changes of vital signs in the last days of life and their association with impending death. We identified characteristic changes such as decreased blood pressure and oxygen saturation as patients approach death. However, these vital sign changes on their own have
Disclosures and Acknowledgments S. B. is supported in part by National Institutes of Health grants RO1NR010162-01A1, RO1CA122292-01, and RO1CA124481-01. D. H. is supported in part by an institutional startup grant (#18075582). This study is also supported by the M.D. Anderson Cancer Center Support Grant (CA 016672). The funding sources were not involved in the conduct of the study or development of the submission.
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