Está en la página 1de 8

ethics in cardiopulmonary medicine

Narcotic and Benzodiazepine Use After


Withdrawal of Life Support*
Association With Time to Death?
Jeannie D. Chan, PharmD, MPH; Patsy D. Treece, RN, MN;
Ruth A. Engelberg, PhD; Lauren Crowley, BA;
Gordon D. Rubenfeld, MD, MSc, FCCP; Kenneth P. Steinberg, MD, FCCP; and
J. Randall Curtis, MD, MPH, FCCP

Objective: To determine whether the dose of narcotics and benzodiazepines is associated with
length of time from mechanical ventilation withdrawal to death in the setting of withdrawal of
life-sustaining treatment in the ICU.
Design: Retrospective chart review.
Setting: University-affiliated, level I trauma center.
Patients: Consecutive critically ill patients who had mechanical ventilation withdrawn and
subsequently died in the ICU during two study time periods.
Results: There were 75 eligible patients with a mean age of 59 years. The primary ICU admission
diagnoses included intracranial hemorrhage (37%), trauma (27%), acute respiratory failure
(27%), and acute renal failure (20%). Patients died during a median of 35 min (range, 1 to 890
min) after ventilator withdrawal. On average, 16.2 mg/h opiates in morphine equivalents and
7.5 mg/h benzodiazepine in lorazepam equivalents were administered during the time period
starting 1 h before ventilator withdrawal and ending at death. There was no statistically
significant relationship between the average hourly narcotic and benzodiazepine use during the
1-h period prior to ventilator withdrawal until death, and the time from ventilator withdrawal to
death. The restriction of medication assessment in the last 2 h of life showed an inverse
association between the use of benzodiazepines and time to death. For every 1 mg/h increase in
benzodiazepine use, time to death was increased by 13 min (p ⴝ 0.015). There was no
relationship between narcotic dose and time to death during the last 2 h of life (p ⴝ 0.11).
Conclusions: We found no evidence that the use of narcotics or benzodiazepines to treat
discomfort after the withdrawal of life support hastens death in critically ill patients at our center.
Clinicians should strive to control patient symptoms in this setting and should document the
rationale for escalating drug doses. (CHEST 2004; 126:286 –293)

Key words: benzodiazepines; death; end-of-life care; ICU; mechanical ventilation; narcotics; withdrawing life support

Abbreviations: APACHE ⫽ acute physiology and chronic health evaluation; GCS ⫽ Glasgow coma scale

D espite remarkable advances in critical care tech-


nology and treatment, the mortality of patients
deaths in the ICU occurs in the context of withhold-
ing or withdrawing life-sustaining treatments.1,2 The
in the ICU remains high. A large proportion of Study to Understand Prognoses and Preferences for
Outcomes and Risks of Treatments3 showed that,
*From the Department of Epidemiology (Dr. Chan), School of according to seriously ill hospitalized patients and
Public Health and Community Medicine, University of Washing-
ton, Seattle; and Harborview Medical Center (Mss. Treece and
Crowley, and Drs. Engelberg, Rubenfeld, Steinberg, and Curtis), Reproduction of this article is prohibited without written permis-
Division of Pulmonary and Critical Care, Seattle, WA. sion from the American College of Chest Physicians (e-mail:
This project was funded by a grant from the Greenwall Founda- permissions@chestnet.org).
tion and the National Institute of Nursing Research (grant No. Correspondence to: Jeannie D. Chan, PharmD, MPH, Harbor-
R01NR/AG05226-03). view Medical Center, 325 Ninth Ave, Room GEH-74, Department
Manuscript received August 11, 2003; revision accepted Febru- of Pharmacy, Box 359885, Seattle, WA 98104; e-mail: jdchan@
ary 23, 2004. u.washington.edu

286 Ethics in Cardiopulmonary Medicine


their proxies, approximately 50% of patients were in length of time between the removal of mechanical
moderate or severe pain during the last 3 days of life. ventilation and death among ICU patients for whom
The study also suggested that patients with critical life-sustaining treatments were being withdrawn.
illness and those cared for by intensivists had equal
or worse symptom control than other seriously ill
hospitalized patients.4 The problem of symptom Materials and Methods
assessment in the ICU can be particularly challeng-
ing, because many patients have impaired cognition The data were collected as part of a hospital-wide quality
improvement project. A total of 2,250 patients were admitted to
and communication. A cohort study5 of cancer pa- the ICU of Harborview Medical Center over an 8-month period
tients suggested that between 55% and 75% of including June to August 2000 and July to November 2001. All
critically ill patients who could describe their symp- patients (178 patients) who died in the ICU during this 8-month
toms reported experiencing moderate-to-severe lev- time period were screened for eligibility for participation in the
els of pain, discomfort, anxiety, sleep disturbance, study. Eligible patients included those who had received me-
chanical ventilation within 1 week before death and had mechan-
unsatisfied hunger, or thirst while in the ICU. In one ical ventilation discontinued prior to death (137 patients). We
study6 of trauma patients receiving intensive care, excluded patients who received cardiopulmonary resuscitation
95% of physicians and 81% of nurses reported that immediately prior to death (22 patients) and those who had no
their patients had received adequate analgesia, documentation of life support withdrawal (2 patients). We also
whereas 74% of these patients rated their pain as attempted to exclude patients for whom the use of benzodiaz-
epines or narcotics after withdrawal of mechanical ventilation
moderate or severe. These studies suggested that would be unnecessary, such as those who were brain dead (29
ICU patients commonly experience distressing patients) and those who had a Glasgow coma scale (GCS) score
symptoms at levels of severity that are substantial of 3 and died within 24 h of ICU admission (9 patients). A total
and may be underestimated by caregivers. However, of 75 patients were included in the analysis. The institutional
despite the need to incorporate the principles of review board reviewed this study and determined it to be exempt
from requirements for written consent, because anonymous data
palliative care into practices in the ICU to provide were obtained from the previous hospital-wide quality improve-
better symptom control and end-of-life care, there is ment project such that patients and clinicians could not be
limited research to guide clinicians in understanding identified.
and improving practice in this area.7–10 Basic demographic characteristics (ie, age, gender, and race)
In addition to these documented shortcomings in and clinical information (ie, ICU diagnoses, GCS score, ICU
length of stay, and IV narcotic and sedative drugs used 24 h prior
symptom assessment and management, there are to death) had been abstracted previously from electronic chart
considerable discrepancies and variations among review as part of a quality improvement project. Based on a
health-care professionals in the way that life-sustain- relative potency scale for benzodiazepines and opiates used by a
ing therapy is withheld or withdrawn.2,11,12 Although previous study,17 doses of opiates (ie, fentanyl and morphine)
variation does not necessarily indicate poor quality of were compared according to a dose-equivalent conversion factor
of 15 ␮g fentanyl to 1 mg morphine. Lorazepam and midazolam
care, large degrees of variation suggest a lack of were compared based on a dose-equivalent conversion factor of
consensus in clinicians’ approaches to dying patients. 2.5 mg midazolam to 1 mg lorazepam. The cumulative amounts
Furthermore, critical care nurses report frustration of benzodiazepines and narcotics used were calculated during the
with the end-of-life care provided by physicians and following three stages of life support withdrawal: (1) the 24-h
cite as an example their impression that some phy- period before death; (2) the time period from 1 h prior to
ventilation withdrawal until the time of death; and (3) the 2-h
sicians are reluctant to use sedation for fear of period prior to death. In response to comments from reviewers,
hastening death.13,14 This impression is reinforced by we also examined the 4-h and the 8-h periods prior to death.
surveys of physicians that reflect concern about Cumulative medication use during these different time intervals
hastening death with the use of sedation in the was divided by the total amount of time in the interval and was
setting of withdrawing life-sustaining treatments.15,16 expressed as an average number of milligrams per hour admin-
istered over these time periods.
These studies raise the possibility that well-inten- We used multivariate linear regression modeling with robust
tioned but unskilled cessation of life-sustaining treat- variance estimates (a conservative approach that does not assume
ment may cause distressing symptoms, leading to equal variances of parameters in the model) to determine
significant and unnecessary suffering in the final whether the use of narcotics and sedatives during these time
hours of life. periods was associated with the length of time from the with-
drawal of mechanical ventilation to death. Our primary analysis
Given the lack of consistency in the delivery of was to test for an association between the predictor variables of
end-of-life care and reports from critical care nurses the narcotic and benzodiazepine doses used during the time
implying that some nurses may be using narcotics or period from 1 h prior to ventilator withdrawal until death and the
benzodiazepines to hasten death,13–16 concerns outcome variable of length of time from ventilator withdrawal to
about hastening death by oversedating patients are death. As secondary analyses, we also examined the predictor
variables of the doses of narcotics and benzodiazepines used
understandable. We therefore conducted a retro- during the last 2 h, 4 h, and 8 h of life in association with the same
spective study to determine whether the use of outcome variable. Hypothesis-driven linear regression models
narcotics or benzodiazepines is associated with the were constructed by placing a priori defined potential confound-

www.chestjournal.org CHEST / 126 / 1 / JULY, 2004 287


ers between medication use and time to death into the models Table 1—Characteristics of Study Subjects*
followed by the predictor variables of interest. These potential
confounders included age (years), gender, hospital admission Characteristics Values
diagnosis of an intracranial hemorrhage (yes or no), worst GCS
Age, yr 59 ⫾ 19† (16–91)
score in the 24 h prior to death as indicator for neurologic status,
Male gender, % 53
and ICU length of stay (days) as a surrogate marker for disease
Race, %
severity. Comparisons between average hourly medication dos-
Non-Hispanic white 77
ages at different stages of life support withdrawal were analyzed
African American 5
using the Student t test without equal variance assumption.
Asian 3
Differences were considered to be statistically significant for a
Hispanic 3
two-sided p value of ⬍ 0.05. Data analyses were performed using
Uncoded 8
a statistical software package (STATA, version 7.0; Stata Corpo-
Mean worst GCS score 24 h prior to death‡ 4 (3–10)
ration; College Station, TX).
Median ICU length of stay, d 4 (1–82)
Median time to death from ventilator 35 (1–890)
withdrawal, min
Results ICU admission diagnosis, %
Intracranial hemorrhage 37
The mean age of the study population was 59 years Respiratory arrest/failure 27
(age range, 16 to 91 years). The majority of the Trauma 27
patients were non-Hispanic whites. Intracranial Acute renal failure 20
hemorrhage was the most common primary ICU Myocardial infarction 12
admission diagnosis (37%), and neurologic status was Pneumonia 12
ARDS 9
poor in this study population, with a mean worst Sepsis/septic shock 9
GCS score of 4 in the 24 h prior to death. The other Coagulopathy 8
frequent ICU admission diagnoses were trauma Anoxic brain injury 7
(27%), acute respiratory failure (27%), and acute Congestive heart failure 7
renal failure (20%). The median length of ICU stay Stroke 7
GI bleed 5
in this study sample was 4 days. Once the process of Neoplasm 5
ventilator withdrawal was initiated, patients died Other 18
within a median of 35 min (25th percentile to 75th
*Values in parentheses are ranges; n ⫽ 75.
percentile, 16 to 146 min) [Table 1]. †Values given as mean ⫾ SD.
Medications were administered by both bolus and ‡Data available in 74 subjects.
continuous infusion during life support withdrawal.
A progressive increase in narcotic dosage was ob-
served starting 8 h prior to death, with the most
evident increase in dosage occurring during the last during the last 2 h of life. There was no statistically
4 h of life. Similarly, there was a steady increase in significant difference by demographic characteris-
benzodiazepine dosage noted throughout the last 8 h tics, primary ICU admission diagnosis, and ICU
of life (Fig 1). However, justifications for medication length of stay between users and nonusers of benzo-
dosage increase were not consistently documented diazepines, although users tended to have a margin-
using sedation or pain scores, and we therefore were ally higher GCS score (median GCS score, 5 vs 4,
not able to report patient comfort or sedation levels. respectively; p ⫽ 0.054). Among patients who re-
Overall, five patients did not receive any opiate or ceived these medications, morphine (90%) and
benzodiazepine during the 24-h period preceding lorazepam (80%) were the primary agents used
death. Narcotic medications were commonly used compared to other opiates and benzodiazepines,
during the two time periods (ie, 1 h before ventilator respectively.
withdrawal until death and the last 2 h of life) in 84% In this study population, an average of 4 mg/h
of patients (63 patients). Users and nonusers of narcotic (in morphine equivalents), and 1.6 mg/h
opiates were similar in demographic characteristics benzodiazepines (in lorazepam equivalents) were
and neurologic status as assessed by worst GCS administered during the last 24 h of life. Medication
score. However, those who received opiates were dosages were escalated when the initiation of life-
less likely to have trauma as a primary admission sustaining therapy withdrawal was anticipated. Dur-
diagnosis (p ⫽ 0.020) and tended to have longer ICU ing the time interval from 1 h prior to ventilator
lengths of stay (mean length of stay, 9.4 vs 3.7 days, withdrawal until death, average doses of 16.2 mg/h
respectively; p ⫽ 0.012) than did those who did not narcotics and 7.5 mg/h benzodiazepines were admin-
receive opiates. Benzodiazepine use was less fre- istered. These drug dosages represented marked
quent, with only 40% of the patients (30 patients) increases compared to the average hourly dosages of
receiving these sedatives during the time periods opiates and benzodiazepines used during the time
from 1 h before ventilator withdrawal until death and interval from the 24th h before death to 1 h prior to

288 Ethics in Cardiopulmonary Medicine


Figure 1. Mean dose of narcotic and sedative medication administered to study subjects over the final
24 h of life. For each patient receiving a narcotic or sedative drug corresponding to the particular hour
of “time to death,” the cumulative amount was calculated, and the average hourly dose was tabulated
based on the number of patients receiving a narcotic or sedative drug at that particular hour.

ventilator withdrawal, respectively (p ⬍ 0.001 for of time to death from ventilator discontinuation
both opiates and benzodiazepines). During the last (Table 3). However, there was a significant dose
2 h of life, average doses of 18.1 mg/h narcotics effect of hourly medication use in the last 2 h of life
and 9.2 mg/h benzodiazepines were administered that was associated with the time from ventilator
(Table 2). These medication dosages were signifi- withdrawal to death (Table 4). On average, every
cantly higher than the average hourly dosages of 1 mg/h increase in benzodiazepine use corresponded
opiates and benzodiazepines used during the 22 h to a statistically significant 13-min increase in the
before death after excluding the final 2 h of life, duration of time between ventilator withdrawal and
respectively (p ⬍ 0.001 for both opiates and benzo- death (p ⫽ 0.015). On the contrary, for every 1 mg/h
diazepines). increase in narcotic use, there was a 2-min reduction
Multivariate linear regression models examining in the time from ventilator withdrawal to death,
the association between narcotic and benzodiazepine although statistical significance was not achieved
medication used (expressed in milligrams per hour, (p ⫽ 0.11). Further analyses with the average hourly
the predictor variable) and the time from ventilator amount of medication used in the last 4 and 8 h of
withdrawal to death (the outcome variable) are life as the predictors of interest yielded similar
presented in Tables 3 and 4. Age, gender, and results, with no statistical association seen between
neurologic status did not appear to be predictive of narcotic use and time to death but with a trend
time to death after adjustment for the other covari- toward increased benzodiazepine use being associ-
ates, but ICU length of stay was inversely associated ated with an increased time to death (Table 4).
with time to death. Every 1-day increase in ICU stay
corresponded to an approximate 2.5-min reduction
from the time of ventilator withdrawal to death Discussion
(p ⱕ 0.03). Adjustment for baseline medication use
(defined as a narcotic or benzodiazepine received in The principle of double effect states that it is
the 24th h before death), extubation prior to death, acceptable for medications to be used that may have
and time periods of data collection (June to August the potential to hasten death in the setting of
2000 and July to November 2001) did not change terminal illness, provided that the purpose of the
these estimates appreciably (data not presented). medications is to relieve suffering. Although there is
Our results demonstrated no statistically signifi- some debate about the philosophy of this principle, it
cant relationship between either benzodiazepine or is generally well-accepted in the practice of palliative
narcotic dose during the time interval from 1 h prior medicine.18 Nonetheless, surveys of physicians show
to ventilator withdrawal until death and the outcome that a substantial minority of physicians withhold or

www.chestjournal.org CHEST / 126 / 1 / JULY, 2004 289


Table 2—Administration of Narcotic and Benzodiazepine Medications*

Variables Cumulative Amount Hourly Amount

Average medication usage 24 h before death


Morphine, mg 81.4 (2–1,052) 3.4 (0.1–44)
Fentanyl, ␮g 2267.0 (50–14,400) 94.5 (2–600)
Total narcotic in morphine equivalents,† mg 97.0 (2–1,052) 4.0 (0.1–44)
Lorazepam, mg 39.3 (1–379) 1.6 (0.04–16)
Midazolam, mg 34.3 (3–214) 1.4 (0.1–9)
Total benzodiazepine in lorazepam equivalents,‡ mg 37.3 (1–379) 1.6 (0.04–16)
Average medication usage 1 h before ventilator withdrawal to death
Morphine, mg 52.9 (2–399) 15.6 (1–106)
Fentanyl, ␮g 628.3 (25–3,054) 322.3 (25–1222)
Total narcotic in morphine equivalents,§ mg 51.7 (2–399) 16.2 (1–106)
Lorazepam, mg 37.3 (0.5–261) 8.6 (0.1–35)
Midazolam, mg 12.8 (2–28) 8.2 (1.6–18.6)
Total benzodiazepine in lorazepam equivalents,㛳 mg 30.9 (0.5–261) 7.5 (0.1–35)
Average medication usage 2 h before death
Morphine, mg 35.1 (2–286) 17.6 (1–143)
Fentanyl, ␮g 606.0 (25–2,554) 303.0 (13–1,277)
Total narcotic in morphine equivalents,§ mg 36.2 (2–286) 18.1 (1–143)
Lorazepam, mg 20.7 (1–72) 10.3 (0.5–36)
Midazolam, mg 14.8 (2–30) 7.4 (1–15)
Total benzodiazepine in lorazepam equivalents,㛳 mg 18.5 (1–72) 9.2 (0.4–36)
*Values in parentheses are ranges. Narcotic use is calculated based on the combined amount of morphine and fentanyl (fentanyl, 15 ␮g; morphine,
1 mg). Benzodiazepine use is calculated based on the combined amount of lorazepam and midazolam (midazolam, 2.5 mg; lorazepam, 1 mg).
†Calculation based on 70 patients.
‡Calculation based on 42 patients.
§Calculation based on 63 patients.
㛳Calculation based on 30 patients.

limit narcotics and benzodiazepines at the end of life benzodiazepines are not being used in ways that
out of fear that they will be perceived to be hastening significantly hasten death. This is consistent with the
death.15 In this context, it is useful to know whether results of a previous report19 stating that survival
narcotics and benzodiazepines are being used in a duration was unrelated to morphine dosage in pa-
way that hastens death. tients undergoing mechanical ventilation withdrawal
Our study suggested that in our ICU, after the as part of end-of-life care. Other non-ICU stud-
withdrawal of mechanical ventilation, narcotics and ies20 –23 also have documented the lack of relation-
ship between opiate and sedative use during end-of-
life care and time to death. In a prospective study of
Table 3—Dose-Response Relationship Between Average 120 patients with terminal cancer assisted by a home
Hourly Narcotic and Sedative Medication Use 1 h care team, there was no detectable survival differ-
Prior to Ventilator Withdrawal and Time From
ence between sedated and nonsedated patients.20
Ventilator Withdrawal to Death*
There was also no significant difference found in
Time to another study21 examining survival time between the
Variables Death, min 95% CI p Value
30 sedated patients and the 85 nonsedated patients
Hourly narcotic dose,† ⫺ 2.2 ⫺ 7.4–3.0 0.41 in a hospice inpatient unit. In a retrospective study of
mg/h 238 patients receiving palliative care during the last
Hourly benzodiazepine 10.4 ⫺ 8.7–29.5 0.28
dose,‡ mg/h
week of life, patients who received a marked increase
Age, yr 0.6 ⫺ 2.1–3.3 0.64 in opiate dosage did not have a shorter survival time
Sex ⫺ 5.2 ⫺ 95.2–84.7 0.91 compared to those who received no increases.22
Worst GCS score 25.5 ⫺ 4.3–55.4 0.093 Finally, among the 227 patients with terminal cancer
Intracranial hemorrhage ⫺ 11.6 ⫺ 98.4–75.2 0.79
who were admitted to a hospice unit in Taiwan,23
ICU length of stay, d ⫺ 2.5 ⫺ 4.7–⫺ 0.2 0.030
there was no statistically significant difference in
*CI ⫽ confidence interval. survival time between sedated and nonsedated pa-
†Estimate for hourly narcotic adjusted for benzodiazepine use, age,
sex, GCS, intracranial hemorrhage, and ICU length of stay.
tients. All but one of these studies was performed in
‡Estimate for hourly benzodiazepine adjusted for narcotic use, age, the hospice setting, and medication assessment was
sex, GCS, intracranial hemorrhage, and ICU length of stay. completed over a much longer spectrum of time

290 Ethics in Cardiopulmonary Medicine


Table 4 —Dose-Response Relationship Between sumption and coagulability, may promote protein
Average Hourly Narcotic and Sedative Medication Use catabolism and proinflammatory cytokine expres-
and Time From Ventilator Withdrawal to Death*
sion, and thus may trigger the systemic inflammatory
Time to response.24 –27 The anxiolytic property of the benzo-
Death, diazepines may have achieved a calming effect in
Variables min 95% CI p Value
these dying patients without the compromise of
Medication use 2 h before death hastening death. It is, however, important to empha-
Hourly narcotic dose,† mg/h ⫺ 2.3 ⫺ 5.0–0.5 0.11
size that the positive association between benzodiaz-
Hourly benzodiazepine 13.0 2.7–23.3 0.015
dose,‡ mg/h epine use and increasing time to death from me-
Age, yr 0.7 ⫺ 2.0–3.3 0.62 chanical ventilation withdrawal in this study can only
Sex 10.5 ⫺ 78.2–99.2 0.81 be considered as being hypothesis-generating until
Worst GCS score 25.8 ⫺ 4.0–55.5 0.089
these results can be confirmed with a larger study
Intracranial hemorrhage ⫺ 15.9 ⫺ 89.8–58.0 0.67
ICU length of stay, d ⫺ 2.6 ⫺ 4.8–⫺ 0.4 0.024 population.
Medication use 4 h before death The use of an average hourly amount of narcotics
Hourly narcotic dose,† mg/h ⫺ 1.4 ⫺ 6.1–3.3 0.56 and benzodiazepines from 1 h prior to the with-
Hourly benzodiazepine 11.7 ⫺ 2.4–25.8 0.10
drawal of mechanical ventilation until death as the
dose,‡ mg/h
Age, yr 0.8 ⫺ 1.9–3.4 0.57 marker of exposure to these medications is an arbi-
Sex 3.8 ⫺ 83.0–90.5 0.93 trary time period. We, however, believe that the 1-h
Worst GCS score 24.4 ⫺ 5.7–54.5 0.11 window prior to the withdrawal of mechanical ven-
Intracranial hemorrhage ⫺ 9.2 ⫺ 81.8–63.4 0.80
tilation allowed us to capture the possibility of
ICU length of stay, d ⫺ 2.4 ⫺ 4.5–⫺ 0.2 0.034
Medication use 8 h before death anticipatory dosing before withdrawal and that it is a
Hourly narcotic dose,† mg/h ⫺ 0.3 ⫺ 5.9–5.2 0.91 reasonable proxy for the “true” effect of these med-
Hourly benzodiazepine 13.7 ⫺ 0.7–28.1 0.062 ications preceding death. Furthermore, we postu-
dose,‡ mg/h
lated that medication use during the last 2 h of life is
Age, yr 1.0 ⫺ 1.6–3.7 0.45
Sex 3.9 ⫺ 81.2–89.1 0.93 the most clinically sensitive measure to detect an
Worst GCS score 24.2 ⫺ 5.6–54.1 0.11 association with hastening of death, as patients would
Intracranial hemorrhage ⫺ 0.5 ⫺ 71.9–70.9 0.99 be more susceptible to this effect of opiates and
ICU length of stay, d ⫺ 2.4 ⫺ 4.6–⫺ 0.3 0.029
benzodiazepines during the time immediately pre-
*See Table 3 for abbreviations not used in text. ceding death.
†Estimate for hourly narcotic adjusted for benzodiazepine use, age,
sex, GCS, intracranial hemorrhage, and ICU length of stay.
We documented an increase in medication use
‡Estimate for hourly benzodiazepine adjusted for narcotic use, age, during the last 4 to 8 h of life, which was consistent
sex, GCS, intracranial hemorrhage, and ICU length of stay. with that reported by others. Hall and Rocker11
showed that the increase in morphine administration
was most evident in the final 4 h before death, a time
frame that is consistent with the average time from
prior to death, but, nonetheless, our results are
the withdrawal of life support to death in their study.
consistent with these prior findings that opiate and
Although the medication dosages that we reported
sedative use is not associated with the hastening of
are similar to the findings from earlier studies,17,28
death.
Our results demonstrate no statistically significant there is tremendous variability in the range of these
dose-response relationship between either benzodi- medications. This variability is likely due to the fact
azepine or narcotic use during the time interval from that symptom burden is highly unpredictable, the
1 h prior to ventilator withdrawal until death and the assessment of symptoms can be difficult in the dying
outcome of time to death after ventilator withdrawal. critically ill population, and tolerance to narcotics
However, we found a statistically significant associ- and benzodiazepines is common, leading to large
ation between increased benzodiazepine dose during variations in medication administration.
the last 2 h of life and increased time from ventilator Our study has several important limitations. First,
withdrawal to death. Perhaps the most likely expla- the study was limited by a small sample size and may
nation for this finding is that those patients who not have sufficient power to detect small differences.
survived longer developed tolerance to benzodiaz- As this is an anonymous database obtained for quality
epines and therefore required a higher dose to improvement purposes, we are unable to add to the
maintain comfort. Alternatively, symptom distress sample size. The confirmation of our results with a
may hasten death in the setting of withdrawal of larger population would be useful. In addition, we
life-sustaining treatment. Physiologic stress from un- were unable to collect additional data such as acute
relieved pain and anxiety may increase oxygen con- physiology and chronic health evaluation (APACHE)

www.chestjournal.org CHEST / 126 / 1 / JULY, 2004 291


scores because of the anonymous nature of the data. References
However, it is not clear that severity of illness, 1 Prendergast TJ, Luce JM. Increasing incidence of withhold-
independent of neurologic status, would be associ- ing and withdrawal of life support from the critically ill. Am J
ated with opiate or benzodiazepine use and therefore Respir Crit Care Med 1997; 155:15–20
would contribute as a confounder. Second, the re- 2 Prendergast TJ, Claessens MT, Luce JM. A national survey of
end-of-life care for critically ill patients. Am J Respir Crit
striction to medication use during the last 2 h prior to Care Med 1998; 158:1163–1167
death may be a more clinically sensitive measure for 3 The SUPPORT Principal Investigators. A controlled trial to
detecting an association with hastening of death, but improve care for seriously ill hospitalized patients: the Study
it is problematic for the subset of patients (25% of to Understand Prognoses and Preferences for Outcomes and
the study population) who took longer than 2 h to die Risks of Treatments (SUPPORT). JAMA 1996; 274:1591–
1598
after ventilator withdrawal. This is because the as- 4 Desbiens NA, Wu AW. Pain and suffering in seriously ill
sessment of exposure (drug use in the last 2 h of life) hospitalized patients. J Am Geriatr Soc 2000; 48:S183–S186
occurs after the initiation of the outcome measure- 5 Nelson JE, Meier D, Oei EJ, et al. Self-reported symptom
ment (ie, time from ventilator withdrawal to death) experience of critically ill cancer patients receiving intensive
care. Crit Care Med 2001; 29:277–282
in these patients. Since an important criterion for a 6 Whipple JK, Lewis KS, Quebbeman EJ, et al. Analysis of pain
causal relationship is that the exposure must precede management in critically ill patients. Pharmacotherapy 1995;
the outcome, inferences of causality cannot be de- 15:592–599
finitively made. Third, an observational study cannot 7 Rubenfeld GD, Curtis JR, End-of-Life Care in the ICU
Working Group. End of life care in the intensive care: a
dismiss the possibility of residual confounding de- research agenda. Crit Care Med 2001; 29:2001–2006
spite analytic efforts through the adjustment of 8 Danis M, Federman D, Fins JJ, et al. Incorporating palliative
potential confounders. However, an observational care into critical care education: principles, challenges, and
study is the only ethical approach to this study opportunities. Crit Care Med 1999; 27:2005–2013
9 Truog RD, Cist AFM, Brackett SE, et al. Recommendations
question. Fourth, patient comfort or sedation level for end-of-life care in the intensive care unit: the Ethics
was not routinely recorded, and therefore we were Committee of the Society of Critical Care Medicine. Crit
not able to assess whether the levels of sedation and Care Med 2001; 29:2332–2347
analgesia were appropriate. Finally, our findings may 10 Faber-Langendoen K, Lanken PN. Dying patients in the
intensive care unit: forgoing treatment, maintaining care. Ann
have limited generalizability to other ICUs as the Intern Med 2000; 133:886 – 893
study population consisted of a substantial number of 11 Hall RI, Rocker GM. End-of-life care in the ICU: treatments
intracranial hemorrhage and trauma patients. Strat- provided when life support was or was not withdrawn. Chest
ification by diagnosis of intracranial hemorrhage was 2000; 118:1424 –1430
12 Cook DJ, Guyatt GH, Jaeschke R, et al. Determinants in
considered, but our sample size was too small to Canadian health care workers of the decision to withdraw life
explore effect modification by neurologic status. support from the critically ill. JAMA 1995; 273:703–708
Concerns about hastening death by oversedating 13 Asch DA, DeKay ML. Euthanasia among US critical care
patients are understandable, and the judicious use of nurses: practices, attitudes, and social and professional corre-
lates. Med Care 1997; 35:890 –900
narcotics and benzodiazepines is necessary. Never-
14 Asch DA, Shea JA, Jedrziewski MK, et al. The limits of
theless, clinicians should be aware of the difficulties suffering: critical care nurses’ views of hospital care at the end
of assessing discomfort in critically ill patients and of life. Soc Sci Med 1997; 45:1661–1668
should understand that many patients develop toler- 15 Faber-Langendoen K. The clinical management of dying
patients receiving mechanical ventilation: a survey of physi-
ance to sedative and opiate medications. When death
cian practice. Chest 1994; 106:880 – 888
is imminent, these medications should be given in a 16 Asch DA, Christakis NA. Why do physicians prefer to with-
way that alleviates suffering and achieves optimal draw some forms of life support over others? Intrinsic
patient comfort. The principle of double effect, attributes of life-sustaining treatments are associated with
physicians’ preferences. Med Care 1996; 34:103–111
along with our data suggesting that increasing doses
17 Wilson WC, Smedira NG, Fink C, et al. Ordering and
of narcotics and benzodiazepines were not associated administration of sedatives and analgesics during the with-
with hastened death, should reassure critical care holding and withdrawal of life support from critically ill
clinicians that they need not limit pain and symptom patients. JAMA 1992; 267:949 –953
18 Sulmasy DP, Pellegrino ED. The rule of double effect:
management in the setting of discomfort during the
clearing up the double talk. Arch Intern Med 1999; 159:545–
withdrawal of life-sustaining treatments. However, 550
when narcotic and benzodiazepine medications are 19 Daly BJ, Thomas D, Dyer MA. Procedures used in the
used to manage symptoms during end-of-life care, it withdrawal of mechanical ventilation. Am J Crit Care 1996;
is important for clinicians to record the reasons for 5:331–338
20 Ventafridda V, Ripamonti C, De Conno F, et al. Symptom
the escalating doses in order to document that these prevalence and control during cancer patients’ last days of
drugs are being used for the purpose of controlling life. J Palliat Care 1990; 6:7–11
symptoms.9,29 21 Stone P, Phillips C, Spruyt O, et al. A comparison of the use

292 Ethics in Cardiopulmonary Medicine


of sedatives in a hospital support team and in a hospice. Palliat artery disease: an update. Crit Care Med 1999; 27:2109 –
Med 1997; 11:140 –144 2112
22 Thorns A, Sykes N. Opioid use in last week of life and 27 Swinamer DL, Phang PT, Jones RL, et al. Effect of routine
implications for end-of-life decision-making. Lancet 2000; administration of analgesia on energy expenditure in critically
356:398 –399 ill patients. Chest 93:4 –10
23 Chiu TY, Hu WY, Lue BH, et al. Sedation for refractory 28 Keenan SP, Busche KD, Chen LM, et al. A retrospective
symptoms of terminal cancer patients in Taiwan. J Pain review of a large cohort of patients undergoing the process of
Symptom Manage 2001; 21:467– 472 withholding or withdrawal of life support. Crit Care Med
24 Epstein J, Breslow MJ. The stress response of critical illness. 1997; 22:1020 –1025
Crit Care Clin 1999; 15:17–33 29 Rubenfeld GD, Crawford S. Principles and practice of with-
25 O’Gara PT. The hemodynamic consequences of pain and its drawing life-sustaining treatments in the ICU. In: Curtis JR,
management. J Intensive Care Med 1988; 3:3–5 Rubenfeld GD, eds. Managing death in the intensive care
26 Srivastava S, Chatila W, Amoateng-Adjepong Y. Myocar- unit: the transition from cure to comfort. New York, NY:
dial ischemia and weaning failure in patients with coronary Oxford University Press, 2001; 127–148

www.chestjournal.org CHEST / 126 / 1 / JULY, 2004 293