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Patients: Consecutive critically ill patients who had mechanical ventilation withdrawn and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
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
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