Nonsedation or Light Sedation in Critically Ill

The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
Nonsedation or Light Sedation in Critically Ill,

Mechanically Ventilated Patients
Hanne T. Olsen, M.D., Helene K. Nedergaard, M.D., Ph.D.,
Thomas Strøm, M.D., Ph.D., Jakob Oxlund, M.D., Karl‑Andre Wian, M.D.,
Lars M. Ytrebø, M.D., Ph.D., Bjørn A. Kroken, M.D., Michelle Chew, M.D., Ph.D.,
Serkan Korkmaz, Jørgen T. Lauridsen, M.Sc., and Palle Toft, M.D., D.M.Sc.
A BS T R AC T
BACKGROUND
In critically ill, mechanically ventilated patients, daily interruption of sedation has been From the Departments of Anesthesiology
shown to reduce the time on ventilation and the length of stay in the intensive care unit and Intensive Care, Odense University
Hospital–Svendborg Hospital, Svendborg
(ICU). Data on whether a plan of no sedation, as compared with a plan of light sedation, (H.T.O.), the Departments of Clinical Re-
has an effect on mortality are lacking. search (H.T.O., H.K.N., T.S., J.O., P.T.)
and Business and Economics (S.K., J.T.L.),
METHODS University of Southern Denmark, and the
Department of Anesthesiology and In-
In a multicenter, randomized, controlled trial, we assigned, in a 1:1 ratio, mechanically tensive Care, Odense University Hospital
ventilated ICU patients to a plan of no sedation (nonsedation group) or to a plan of light (T.S., P.T.), Odense, the Department of
sedation (i.e., to a level at which the patient was arousable, defined as a score of −2 to −3 on Anesthesiology and Intensive Care, Hos-
pital Lillebaelt, Kolding (H.K.N.), and the
the Richmond Agitation and Sedation Scale [RASS], on which scores range from −5 [unre- Department of Anesthesiology and In-
sponsive] to +4 [combative]) (sedation group) with daily interruption. The primary outcome tensive Care, Esbjerg Hospital, Esbjerg
was mortality at 90 days. Secondary outcomes were the number of major thromboembolic (J.O.) — all in Denmark; the Department
of Anesthesiology and Intensive Care,
events, the number of days free from coma or delirium, acute kidney injury according to Vestfold Hospital, Tønsberg (K.-A.W.),
severity, the number of ICU-free days, and the number of ventilator-free days. Between-group and the Department of Anesthesiology
differences were calculated as the value in the nonsedation group minus the value in the and Intensive Care, University Hospital
of North Norway, Tromsø (L.M.Y., B.A.K.)
sedation group. — both in Norway; and the Department
of Anesthesiology and Intensive Care,
RESULTS Linköping University Hospital, Linköping,
A total of 710 patients underwent randomization, and 700 were included in the modified Sweden (M.C.). Address reprint requests
intention-to-treat analysis. The characteristics of the patients at baseline were similar in the to Dr. Toft at the Department of Anesthe-
siology and Intensive Care, Odense Uni-
two trial groups, except for the score on the Acute Physiology and Chronic Health Evaluation versity Hospital, 5000 Odense C, Den-
(APACHE) II, which was 1 point higher in the nonsedation group than in the sedation group, mark, or at palle.toft@rsyd.dk.
indicating a greater chance of in-hospital death. The mean RASS score in the nonsedation This article was published on February 16,
group increased from −1.3 on day 1 to −0.8 on day 7 and, in the sedation group, from −2.3 2020, at NEJM.org.
on day 1 to −1.8 on day 7. Mortality at 90 days was 42.4% in the nonsedation group and N Engl J Med 2020;382:1103-11.
37.0% in the sedated group (difference, 5.4 percentage points; 95% confidence interval [CI], DOI: 10.1056/NEJMoa1906759
−2.2 to 12.2; P = 0.65). The number of ICU-free days and of ventilator-free days did not differ Copyright © 2020 Massachusetts Medical Society.
significantly between the trial groups. The patients in the nonsedation group had a median
of 27 days free from coma or delirium, and those in the sedation group had a median of
26 days free from coma or delirium. A major thromboembolic event occurred in 1 patient
(0.3%) in the nonsedation group and in 10 patients (2.8%) in the sedation group (difference,
−2.5 percentage points; 95% CI, −4.8 to −0.7 [unadjusted for multiple comparisons]).
CONCLUSIONS
Among mechanically ventilated ICU patients, mortality at 90 days did not differ signifi-
cantly between those assigned to a plan of no sedation and those assigned to a plan of
light sedation with daily interruption. (Funded by the Danish Medical Research Council
and others; NONSEDA ClinicalTrials.gov number, NCT01967680.)
n engl j med 382;12 nejm.org March 19, 2020 1103

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T
he practice of sedating patients participating countries. Written informed con-
receiving mechanical ventilation has been sent was obtained from either the patient or the
standard care.1 Although advances in tech- patient’s closest relatives in accordance with
nology have made modern ventilators more national regulatory requirements. If consent was
comfortable for patients, it has generally been withdrawn, we asked for permission to continue
believed that light sedation should accompany the registration of clinical data in order to in-
mechanical ventilation.2 However, trials pub- clude patients in the final analysis. The trial was
lished in the last two decades have reported that funded by the Danish Medical Research Council,
the use of sedatives may worsen outcomes in Danielsens Foundation, and the Scandinavian
mechanically ventilated patients. A trial compar- Society of Anesthesiology and Intensive Care
ing daily interruption of sedation with no inter- Medicine. There was no industry involvement in
ruption showed that patients had shorter dura- the trial.
tions of mechanical ventilation and shorter stays
in the intensive care unit (ICU) with daily inter- Patient Selection and Randomization
ruption.3 A similar trial reported in the Journal Patients were eligible for inclusion in the trial if
showed that mortality was lower and the length they were 18 years of age or older, had under-
of hospital stay shorter among the patients who gone endotracheal intubation within 24 hours
had daily interruption of sedation than among before screening, and were expected to receive
those who had no interruption.4 mechanical ventilation for more than 24 hours.
In a single-center trial, we reported that a Patients were excluded if they had severe head
plan of no sedation was associated with more trauma, therapeutic hypothermia, or status epi-
days without mechanical ventilation and a shorter lepticus, had participated in our previous trial,5
stay in the ICU or hospital than a plan of seda- had transferred from another ICU with a length
tion with daily interruption.5 The trial was not of stay more than 48 hours, were comatose on
statistically powered to show a difference in mor- admission (not medically induced), were brain-
tality between the trial groups (the nonsedation dead, or had a ratio of the partial pressure of
group and the sedation group). A post hoc arterial oxygen (measured in kilopascals) to the
analysis showed a lower incidence of acute renal fraction of inspired oxygen of 9 or lower. They
failure in the nonsedation group.6 We conducted were also excluded if sedation was anticipated to
the current trial to investigate whether a plan of be necessary for oxygenation or for the patient
no sedation in patients receiving mechanical to remain in a prone position.
ventilation would result in a better survival out- Within 24 hours after intubation, the patients
come than a plan of light sedation with daily were randomly assigned in a 1:1 ratio to a plan
interruption. of no sedation (nonsedation group) or to a plan of
light sedation with daily interruption (sedation
group). Randomization was performed at a cen-
Me thods
tral location with the use of a computer-generated
Trial Design and Oversight assignment sequence with a variable block size.
The trial was conducted at eight centers — five Patients were stratified according to participat-
in Denmark (Aarhus, Kolding, Esbjerg, Svend- ing center, age (≤65 years or >65 years), and the
borg, and Odense), two in Norway (Tønsberg presence or absence of shock on arrival (systolic
and Tromsø), and one in Sweden (Linköping). blood pressure, <70 mm Hg or ≥70 mm Hg).
The first three authors and the last author de- Investigators, patients or their relatives, and phy-
signed the trial and wrote the first draft of the sicians caring for the patients were aware of the
manuscript. The statistical analyses were per- trial-group assignments. The protocol and sta-
formed by the authors from the Department of tistical analysis plan have been published previ-
Business and Economics, University of Southern ously7 and are available with the full text of this
Denmark. All the authors had full access to data article at NEJM.org.
and vouch for the accuracy and completeness of
the data, the fidelity of the trial to the protocol, Trial Interventions
and the complete reporting of adverse events. The patients in the nonsedation group did not
Approval for the trial was obtained from the receive any sedatives but could receive bolus
national ethics committee in each of the three doses of morphine for analgesia, as deemed
1104 n engl j med 382;12 nejm.org March 19, 2020

Nonsedation or Light Sedation in Ventilated Patients
necessary by the treating team. These patients ICU (CAM-ICU).11 The result could be either
were awake and able to communicate, and it was positive (delirium), negative (no delirium), or —
a goal to have them sustain a natural sleep if in coma — unable to evaluate. If treatment
rhythm. If, despite both nonpharmacologic (re- was needed for delirium, the initial choice was
assurance or mobilization) and pharmacologic to use nonpharmacologic measures (reassurance
(analgesia) treatment, it became necessary to se- or mobilization). If this was not sufficient and
date a patient, the patient was given medications pharmacologic treatment was needed, the proto-
similar to those used in the sedation group. col allowed for the use of either haloperidol or
Crossover between trial groups was not allowed. olanzapine. After extubation, patients were dis-
The patients in the sedation group received a charged from the ICU in accordance with the
continuous infusion of sedatives, with a goal of participating center’s usual practice and at the
achieving light sedation — that is, to a level at discretion of the treating physician. Thrombo-
which the patient was arousable (defined as a prophylactic measures were used in both trial
score of −2 to −3 on the Richmond Agitation and groups in accordance with the participating
Sedation Scale [RASS], on which scores range center’s usual practice.
from −5 [unresponsive] to +4 [combative])8; this
intervention was consistent with international Outcome Measures
guidelines.9 Propofol was used for sedation in the The primary outcome was all-cause mortality at
first 48 hours and was replaced by midazolam 90 days after randomization. Secondary outcomes
thereafter.10 Every morning, sedation was inter- were the number of days until death up to 90
rupted with the aim of full wakefulness, defined days after randomization, the number of throm-
as the ability to perform at least three of the boembolic events (pulmonary embolus or deep-
following four tasks: open the eyes in response vein thrombosis) up to 90 days after randomiza-
to oral commands, follow the examiner’s instruc- tion; the number of days free from coma or
tions with the eyes, squeeze the examiner’s delirium (RASS score of at least −3 and a nega-
hands on request, and stick out the tongue on tive CAM-ICU assessment) within 28 days after
request.4 During the wake-up period, the pa- randomization; the highest score on the Risk,
tients were weaned off the ventilator. After a Injury, Failure, Loss of Kidney Function, and
patient successfully performed three of the four End-Stage Kidney Disease (RIFLE) assessment,
aforementioned tasks, the infusion of sedatives which classifies acute kidney injury according to
was resumed at half the dose that was used be- severity, within 28 days after randomization12;
fore the interruption. If positive end-expiratory the length of stay in the ICU up to death or 28
pressure could be reduced to 5 cm of water and days after randomization, whichever occurred
the fraction of inspired oxygen could be reduced first; and the number of days without mechani-
to a level below 40%, sedation was not resumed. cal ventilation within 28 days after randomiza-
These values did not necessarily imply that extu- tion. Days free from coma or delirium were re-
bation was indicated. If the patient was unable corded during the ICU stay, and days alive after
to remain comfortably awake at these low set- discharge from the ICU up to day 28 were
tings, sedation was resumed. If the patient be- counted as delirium-free days.13
came uncomfortable during the wake-up period, Exploratory outcomes were all-cause mortal-
sedation was resumed. Symptoms such as anxi- ity at 28 days after randomization; the length of
ety or mild agitation resulting from withdrawal stay in the ICU up to death or 90 days after
of sedation could be treated with bolus doses of randomization, whichever occurred first; the
clonidine. The use of dexmedetomidine was dis- number of days until the patient was no longer
couraged in both trial groups. Both trial groups in need of mechanical ventilation within 90 days
received a basic analgesic regimen that included after randomization; the length of hospital stay
paracetamol and opioids as bolus doses in order within 90 days after randomization; organ fail-
to keep the patients free from pain. Epidural ure when the patient was discharged from the
anesthesia was used to control pain when ap- ICU; the number of accidental extubations that
propriate. led to reintubation within 1 hour; and the num-
Patients were assessed for delirium at least ber of accidental removals of central venous
two times a day (8 a.m. and 8 p.m.) with the use catheters that led to reinsertion within 4 hours.
of the Confusion Assessment Method for the Data for outcome measures were obtained from

patient files and from regional and national sion analysis. In the analysis of the secondary
registers by the trial investigators and nurses outcomes, we used unadjusted univariate logistic
during the 90-day observation period. Addition- regression. In the analysis of the exploratory
al details of the outcome measures are provided outcomes, we used multivariate logistic-regres-
in the protocol.7 sion analysis with adjustment for the randomiza-
tion stratification factors and for Simplified Acute
Statistical Analysis Physiology Score (SAPS) II, Sequential Organ-
In a previous single-center randomized trial of Failure Assessment (SOFA) score, shock at admis-
sedation or nonsedation in mechanically venti- sion, chronic kidney disease, chronic obstructive
lated ICU patients, mortality during hospitaliza- pulmonary disease, and daily use of benzodiaz-
tion in the intention-to-treat analysis was 36% in epine before randomization. We analyzed survival
the nonsedation group and 47% in the sedation data using Cox proportional-hazards regression,
group, findings that correspond to a 25% lower with and without adjustment for the randomiza-
relative risk in the nonsedation group.5 In other tion stratification factors and for other baseline
studies, trials, and meta-analyses, the 90-day clinical variables (additional details are provided
mortality among patients receiving mechanical in the statistical analysis plan). A Kaplan–Meier
ventilation has been approximately 40%.14,15 On plot was used to estimate the probability of sur-
the basis of this in-hospital mortality, we esti- vival at 90 days after randomization. Dichoto-
mated that given a maximum risk of type I error mous and continuous outcomes were analyzed
of 5% and of type II error of 20%, a sample size with the use of logistic regression. All statistical
of 700 patients (350 in each group) would pro- analyses were performed with R software (R Core
vide the trial with 80% power to show that an Team [2013]).
intervention would result in a 25% lower relative
risk of in-hospital death or to reject the hypoth- R e sult s
esis.5 We used a two-sided P value for the
between-group difference with respect to the Patient Characteristics
primary outcome. Between-group differences From January 2014 through November 2017, a
were calculated as the value in the nonsedation total of 2300 patients were assessed for eligibil-
group minus the value in the sedation group. ity, and 710 were enrolled in the trial and ran-
We performed the data analysis according to domly assigned to a trial group — 354 to the
the modified intention-to-treat principle. Because nonsedation group and 356 to the sedation
the statistical analysis plan did not include a group. After randomization, 10 patients were
provision for correcting for multiple compari- excluded (reasons for exclusion are provided in
sons when conducting tests for secondary out- Fig. 1), leaving a total of 700 patients in the
comes, those results are reported as point esti- modified intention-to-treat analysis. No patients
mates and unadjusted 95% confidence intervals, were lost to follow-up, and we obtained 90-day
from which no conclusions can be drawn re- follow-up data with respect to the primary out-
garding differences between the trial groups. All come from all 700 patients. With respect to the
the patients were followed for 90 days, unless secondary outcomes, observations were missing
they withdrew consent for the investigators to in less than 5% of the patients. Apart from the
acquire further data or use existing trial data, in score on the Acute Physiology and Chronic Health
which case the data were censored at the time Evaluation (APACHE) II, which was 1 point high-
consent was withdrawn. When analyzing indi- er in the nonsedation group than in the sedation
vidual variables, patients with any missing val- group (26 vs. 25), the characteristics of the pa-
ues on the variable in question were excluded. tients were similar in the two groups (Table 1).
Missing data were managed with the use of In the sedation group, the mean RASS score
multiple imputation procedures if at least 5% of was −2.3 on day 1 and increased to −1.8 on day
the patients had missing data and Little’s test 7, indicating a more alert state. In the nonseda-
was statistically significant. In the analysis of tion group, the mean RASS score was −1.3 on
the primary outcome of all-cause mortality at day 1 and increased to −0.8 on day 7, indicating
90 days, we used a multivariate logistic-regres- a more alert state. The mean RASS score was

2300 Patients were assessed for eligibility
1590 Were excluded

1254 Did not meet inclusion criteria
260 Were expected to be on ventilator
<24 hr
3 Were ≤18 yr of age
4 Were never intubated
76 Had severe head trauma with
increased intracranial pressure
88 Needed therapeutic hypothermia
72 Had status epilepticus
80 Had PaO2:FIO2 ≤9
28 Had participated in our previous trial
460 Were comatose at admission
183 Were transferred from other ICU with
length of stay >48 hr
336 Declined to participate
710 Underwent randomization
354 Were assigned to the nonsedation group 356 Were assigned to the sedation group
5 Were excluded 5 Were excluded

3 Withdrew consent 4 Withdrew consent
1 Needed home ventilation 1 Never received intervention
1 Was never intubated
349 Were included in the modified 351 Were included in the modified
intention-to-treat analysis intention-to-treat analysis
Figure 1. Enrollment, Randomization, and Analysis.

ICU denotes intensive care unit, and Pao2:Fio2 the ratio of the partial pressure of arterial oxygen (measured in kilo-
pascals) to the fraction of inspired oxygen.
numerically higher in the nonsedation group 12.2; P = 0.65) (Table 2 and Fig. 3). The second-
than in the sedation group on each day between ary outcome of the number of days until death
days 1 and 7 (Fig. 2). On day 1 of the trial, 27.0% up to 90 days was 13 days (interquartile range,
of the patients in the nonsedation group re- 6 to 27) in the nonsedation group and 12 days
ceived medication for sedation, and 38.4% re- (interquartile range, 5 to 28) in the sedation
ceived medication for sedation at some time group (unadjusted difference, 1 day; 95% CI, −2
during their ICU stay. The main reason for seda- to 5). A major thromboembolic event (pulmo-
tion was delirium. nary embolus or deep-vein thrombosis) within
90 days after randomization occurred in 1 pa-
Outcomes tient (0.3%) in the nonsedation group and in 10
In the modified intention-to-treat analysis of all- patients (2.8%) in the sedation group (unad-
cause mortality at 90 days after randomization, justed difference, −2.5 percentage points; 95%
148 patients (42.4%) in the nonsedation group CI, −4.8 to −0.7) (Table 2). All other secondary
had died and 130 patients (37.0%) in the seda- outcomes did not differ significantly between
tion group had died (difference, 5.4 percentage the trial groups, but no definite inferences can
points; 95% confidence interval [CI], −2.2 to be drawn from these data because of the ab-

Table 1. Baseline Characteristics of the Patients at ICU Admission.*
Characteristic Nonsedation Group Sedation Group Difference (95% CI)†

Age — yr
Median 72.0 70.0 2.0 (0.1 to 3.6)
Interquartile range 63.0 to 80.0 62.8 to 78.0
Female sex — no. (%) 126 (36.1) 147 (41.9) −5.8 (−13.1 to 1.2)
Weight — kg
Median 77.8 77.7 0.1 (−2.3 to 5.1)
Interquartile range 65.0 to 90.0 65.0 to 92.0
Height — cm
Median 173 171 2 (0 to 5)
Interquartile range 165 to 180 165 to 178
APACHE II score‡
Median 26 25 1 (0 to 3)
SAPS II§
Median 49 49 0 (−2 to 3)
SOFA score at day 1¶
Median 7 8 −1 (−3 to 0)
Type of admission — no. (%)
Medical 244 (69.9) 235 (67.0) 2.9 (−3.8 to 9.8)
Acute surgical 94 (26.9) 95 (27.1) −0.2 (−6.5 to 6.5)
Elective surgical 11 (3.2) 21 (6.0) −2.8 (−6.3 to 0.1)
Diagnosis at ICU admission — no. (%)
Pneumonia or ARDS 147 (42.1) 151 (43.0) −0.9 (−8.2 to 6.2)
Sepsis 84 (24.1) 74 (21.1) 3.0 (−3.2 to 9.2)
Exacerbation of COPD 24 (6.9) 21 (6.0) 0.9 (−2.7 to 4.8)
Gastrointestinal bleeding 4 (1.1) 4 (1.1) 0.0 (−1.8 to 1.8)
Trauma 11 (3.2) 18 (5.1) −1.9 (−5.1 to 1.0)
Severe acute asthma 11 (3.2) 7 (2.0) 1.2 (−1.4 to 3.6)
Postoperative complications 7 (2.0) 7 (2.0) 0.0 (−2.3 to 2.3)
Other 66 (18.9) 74 (21.1) −2.2 (−7.9 to 3.9)
* Data on age, female sex, weight, height, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Simplified
Acute Physiology Score (SAPS) II, Sequential Organ-Failure Assessment (SOFA) score, and type of admission are presented
for the 700 patients in the modified intention-to-treat population (349 patients in the nonsedation group and 351 in
the sedation group). Data on the diagnosis at intensive care unit (ICU) admission are presented for all 710 patients
who underwent randomization (354 patients in the nonsedation group and 356 in the sedation group). ARDS denotes
acute respiratory distress syndrome, and COPD chronic obstructive pulmonary disease. Percentages may not total 100
because of rounding.
† For continuous variables, the difference in medians is shown. For categorical variables, the absolute difference in per-
centage points is shown.
‡ APACHE II scores range from 0 to 71, with higher scores indicating more severe disease.
§ SAPS II is calculated from 17 variables; scores range from 0 to 163, with higher scores indicating more severe disease.
¶ SOFA scores range from 0 to 4 for each organ system, with higher aggregate scores indicating more severe organ dys-
function.

sence of a prespecified plan for adjustment for

multiple comparisons. The number of days free 0
from coma or delirium was 27 in the nonseda-

tion group and 26 in the sedation group (Ta- Nonsedation
ble 2). During the ICU stay, the number of days
−1
free from coma or delirium was 3 (range, 1 to 6)
Mean RASS Score

in the nonsedation group and 1 (range, 0 to 3)
in the sedation group. The highest measured
RIFLE score within 28 days after randomization −2
was 2 in both groups (scores range from 1 to 4,
with 1 indicating normal kidney function, 2 risk, Sedation
3 injury, and 4 failure). The RIFLE scores are
provided in Figure S2 in the Supplementary Ap- −3
pendix, available at NEJM.org. Exploratory out-
1 2 3 4 5 6 7
comes are reported in Table S3.
Day
Medication Use Figure 2. RASS Score during the First 7 Days of the Trial.
The total doses of sedatives, including propofol RASS denotes Richmond Agitation and Sedation Scale, on which scores
and midazolam, were higher in the sedation range from −5 (unresponsive) to +4 (combative).
group than in the nonsedation group (Table S1).
The mean dose of morphine was 0.0073 mg per
kilogram of body weight per hour (range, 0.0036 plan of light sedation with daily interruption.
to 0.0140) in the nonsedation group, as com- Time on mechanical ventilation, length of ICU
pared with 0.0060 mg per kilogram per hour stay, and length of hospital stay did not differ
(range, 0.0027 to 0.0110) in the sedation group, significantly between the trial groups. The num-
over the first 3 days (unadjusted risk difference, ber of days free from coma or delirium was 1 day
0.0013; 95% CI, −0.0001 to 0.0028) (Table S1). more in the nonsedation group than in the seda-
For all 7 days, the mean dose of morphine was tion group, and there were fewer thromboem-
0.0051 mg per kilogram per hour (range, 0.0023 to bolic events in the nonsedation group than in
0.0110) in the nonsedation group and 0.0045 mg the sedation group. The highest measured RIFLE
per kilogram per hour (range, 0.0018 to 0.0088) score did not differ significantly between the
in the sedation group. two groups. However, the lack of a plan for cor-
rection for multiple comparisons of secondary
Adverse Events outcomes did not allow formal inferences to be
An accidental extubation that led to reintubation made from these observations. The low numbers
within 1 hour occurred in four patients (1.1%) in of thromboembolic events may be explained by
the nonsedation group and in one patient (0.3%) the use of prophylactic low-molecular-weight
in the sedation group (unadjusted risk differ- heparin in all the patients in both trial groups.
ence, 0.8 percentage points; 95% CI, −0.7 to 2.6; Several trials have shown that lighter seda-
P = 0.20). No events of accidental removal of a tion results in shorter time on mechanical venti-
central venous catheter that led to reinsertion lation and shorter length of stay in the ICU or
within 4 hours occurred in either trial group. hospital.3,4,16 In contrast, we did not find that
Adverse events are reported in Table S2. time on mechanical ventilation or length of stay
in the ICU or hospital differed significantly be-
tween the trial groups, perhaps because the
Discussion
depth of sedation did not differ between the
In this multicenter, randomized, controlled trial groups as much as intended, especially on day 1.
involving mechanically ventilated ICU patients, According to recent international guidelines on
mortality at 90 days did not differ significantly sedation for mechanical ventilation, a RASS score
between those who were assigned to a plan of of −2 to + 1 is defined as light sedation.2 In our
no sedation and those who were assigned to a trial, the sedation target in the sedation group

Table 2. Primary and Secondary Outcomes.
Nonsedation Group Sedation Group Difference

Outcome (N = 349) (N = 351) (95% CI)*
Primary outcome
All-cause mortality at 90 days after randomization — no. (%) 148 (42.4) 130 (37.0) 5.4 (−2.2 to 12.2)†
Secondary outcomes
No. of days until death up to 90 days after randomization
Median 13 12 1 (−2 to 5)
Patients with a major thromboembolic event at 90 days after 1 (0.3) 10 (2.8) −2.5 (−4.8 to −0.7)
randomization — no. (%)
No. of days free from coma or delirium within 28 days after
randomization
Median 27 26 1 (0 to 2)
Highest measured RIFLE score within 28 days after
randomization‡
Median 2 2 0 (−1 to 1)
No. of days in the ICU until death or 28 days after random-
ization, whichever occurred first
Median 13 14 −1 (−7 to 4)
No. of days without mechanical ventilation within 28 days
after randomization
Median 20 19 1 (−3 to 3)
* For continuous variables, the difference in medians is shown. For categorical variables, the absolute difference in per-
centage points is shown. The widths of the 95% confidence intervals have not been adjusted for multiple comparisons;
thus, the intervals should not be used to infer treatment effects.
† P = 0.65.
‡ Scores on the Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease (RIFLE) assessment range
from 1 to 4, with 1 indicating normal kidney function, 2 risk, 3 injury, and 4 failure.
was a RASS score of −2 to −3, which is light-to-

1.00 moderate sedation. In the Sedation Practice in
Intensive Care Evaluation (SPICE) III trial, which
was recently published in the Journal, the seda-
Probability of Survival
0.75
Sedation
+
tion goal was light sedation, but the investigators
Nonsedation
+
reported a median RASS score of −3 to −5 for
0.50
more than 40% of the patients both groups.17 On
day 1 in our trial, the mean RASS score in the
0.25 sedation group was −2.3, gradually increasing to
−1.8 on day 7. A higher percentage of the pa-
0.00 tients in the nonsedation group were sedated
0 15 30 45 60 75 90 during the first week after randomization than
Days since Randomization reported in the aforementioned trial, which part-
No. at Risk ly accounted for the lower-than-intended between-
Sedation 351 273 250 236 227 224 221 group difference in the degree of sedation (see
Nonsedation 348 267 235 220 211 206 200
the Supplementary Appendix).18 We observed that
Figure 3. Kaplan–Meier Estimates of Survival at 90 Days. the nonsedation group had 1 more day free from
coma or delirium than the nonsedation group,

but because of the lack of adjustment for multi- tween those assigned to a plan of no sedation
ple comparisons, no inferences can be made from and those assigned to a plan of light sedation
this result. This difference in the number of (i.e., to a level at which the patient was arous-
days free from coma or delirium is similar to the able) with daily interruption. The plan of no se-
findings from a trial that compared nonsedation dation resulted in no important differences in the
with sedation in postoperative care.19 Although number of ventilator-free days or in the length
more events of accidental extubations occurred of ICU or hospital stay.
in the nonsedation group in our trial, few led to A data sharing statement provided by the authors is available
reintubations within 1 hour. The low number of with the full text of this article at NEJM.org.
accidental extubations in our trial might be due Supported by the Danish Medical Research Council, the
Danielsens Foundation, and the Scandinavian Society of Anes-
to the nurse-to-patient ratio of 1:1 in most of the thesiology and Intensive Care Medicine.
participating ICUs. Disclosure forms provided by the authors are available with
In conclusion, among critically ill adults re- the full text of this article at NEJM.org.
We thank all the patients for their participation in the trial
ceiving mechanical ventilation in the ICU, mor- and their relatives and acknowledge the support of the physi-
tality at 90 days did not differ significantly be- cians and nurses across all trial sites.
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Non-sedation versus sedation with a daily Hopkins RO, Needham DM. Statistical Copyright © 2020 Massachusetts Medical Society.


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The n e w e ng l a n d j o u r na l of m e dic i n e

Nonsedation or Light Sedation in Critically Ill,

n engl j med 382;12 nejm.org March 19, 2020 1103

1104 n engl j med 382;12 nejm.org March 19, 2020

The New England Journal of Medicine

n engl j med 382;12 nejm.org March 19, 2020 1105

1106 n engl j med 382;12 nejm.org March 19, 2020

The New England Journal of Medicine

2300 Patients were assessed for eligibility

1590 Were excluded

710 Underwent randomization

5 Were excluded 5 Were excluded

Figure 1. Enrollment, Randomization, and Analysis.

n engl j med 382;12 nejm.org March 19, 2020 1107

Table 1. Baseline Characteristics of the Patients at ICU Admission.*

Characteristic Nonsedation Group Sedation Group Difference (95% CI)†

1108 n engl j med 382;12 nejm.org March 19, 2020

The New England Journal of Medicine

sence of a prespecified plan for adjustment for

from coma or delirium was 27 in the nonseda-

Mean RASS Score

n engl j med 382;12 nejm.org March 19, 2020 1109

Table 2. Primary and Secondary Outcomes.

Nonsedation Group Sedation Group Difference

was a RASS score of −2 to −3, which is light-to-

1110 n engl j med 382;12 nejm.org March 19, 2020

The New England Journal of Medicine

n engl j med 382;12 nejm.org March 19, 2020 1111

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