REVIEW ARTICLE
The Effects of Perioperative and Intensive Care Unit
Sedation on Brain Organ Dysfunction
Christopher G. Hughes, MD,* and Pratik P. Pandharipande, MD, MSCI*†
February 10,2011.
Increasing research and evidence, however, has
implicated commonly prescribed sedative medications as
risk factors for untoward events and worse patient
outcomes, including brain organ dysfunction manifested
as delirium and coma.
The effect of sedatives on outcomes is also influenced by the
depth of sedation, making it imperative to reduce total exposure
to this class of medications. Juxtaposing the widespread necessity
and use of sedation with the cost of acute and long-term cognitive
dysfunction to patients and society, physicians must now strive to
balance patients’ demands and requisite for comfort with their
own oath to do no harm.
Delirium is an acute disturbance of consciousness accompanied by
inattention, disorganized thinking,and perceptual disturbances
that fluctuates over a short period of time.
Though previously underdiagnosed and often considered to be an
inconsequential occurrence associated with a patient’s
perioperative course or critical illness
delirium is now regarded as a form of acute brain organ dysfunction
that is independently associated with worse clinical outcomes,
including longer and more costly hospitalizations, longer
times on mechanical ventilation, increased rates of hospital
readmissions, increased risk of prolonged cognitive
dysfunction, and 3-fold higher mortality.
Furthermore, each additional day with delirium increases the risk
of dying by 10%, and longer periods of delirium are also associated
with greater degrees of cognitive decline when patients are
evaluated 1 year after hospital discharge.
50%–80% of patients with critical illness developing delirium
depending on the severity of illness and the need for mechanical
ventilation .
Although delirium, along with coma, represents acute brain
dysfunction, many surgical patients (with concurrent anesthesia
exposure) and critically ill patients also have long-term cognitive
impairment (chronic brain dysfunction), which may persist for
months to years after their hospitalization, significantly impacting
their quality of life.
There are numerous hypotheses that include neurotransmitter
imbalance
(e.g.,
dopamine,
γ-aminobutyricacid,
and
acetylcholine), inflammatory perturbations (e.g., tumor necrosis
factorI, interleukin-1, and other cytokines/chemokines),
impaired oxidative metabolism, cholinergic deficiency, and
changes in various aminoacid precursors
Contributing sources can be summarizedas patient-related actors
(e.g., age, previous dementia,diabetes, and heart failure) or
iatrogenic risk factors (e.g.,psychoactive medications, hypoxemia,
shock, and hypothermia)
SEDATIVE AND ANALGESIC MEDICATIONS AND ACUTE
AND CHRONIC BRAIN
DYSFUNCTION
Numerous associations between psychoactive medications and
worsening cognitive
outcomes in postsurgical patients have been published.
Insufficient pain relief, however, has also been shown to be a
risk factor for delirium and can contribute to sleep
disturbances, disorientation, anxiety,and long-term effects such
as posttraumatic stress disorder (PTSD).26 Morrison et al.27
conducted a prospective cohort study that enrolled patients
with hip fractures, none of whom had preoperative delirium.
Patients who received <10 mg of parenteral morphine
equivalents per day were more likely to develop delirium than
were patients who received more analgesia.27
However, providing adequate analgesia needs to be balanced
with the potential risk for predisposing patients to delirium due
to excess opiate administration. Marcantonio et al.24 studied
postoperative patients who developed delirium and found an
association between benzodiazepine and meperidine use and
the occurrence of delirium, and Dubois et al.22 have shown that
opiates (morphine and meperidine) administered either IV or
via an epidural route may be associated with the development of
delirium in surgical patients. The role of perioperative
benzodiazepine plasma levels has been further evaluated in a
small study but found no relationship between diazepam
concentration and cognitive dysfunction 1 week postoperatively
in elderly patients undergoing abdominal surgery.28 Two large
prospective studies have examined the effects of perioperative
psychoactive medications on emergence delirium in the
postanesthesia care unit. Lepouse et al.29
conducted a prospective study of 1359 consecutive patients who
were evaluated for emergence delirium in the postanesthesia care
unit. The authors found an incidence of emergence delirium of
4.7% and demonstrated an almost 2-fold increase in the odds of
developing emergence delirium if benzodiazepines were
administered as a preoperative medication. In the second study
by Radtke et al. 301868 patients were evaluated in the recovery
room and assessed for emergence delirium and hypoactive
emergence.These authors found the incidence of emergence
delirium to be 5% and that of hypoactive emergence to be 8%.
Significant risk factors for emergence
delirium were benzodiazepine premedication and etomidate
induction,whereas longer anesthetic duration was a risk factor for
hypoactive emergence.30 The International Study of
Postoperative Cognitive Dysfunction evaluated patients for
cognitive impairment after major noncardiac surgery and found
that approximately 25% had cognitive impairment at 1 week
postoperatively,10% at 3 months, and about 1% at 1 year.19,31
Although anesthetic duration was found to be a risk factor for
early cognitive impairment, only age was a risk factor for
cognitive impairment at 3 months.19 A follow-up May 2011 •
Volume 112 • Number 5 study showed no difference in cognitive
impairment at 1 week and 3 months in patients receiving regional
anesthesia versus general anesthesia, though the group receiving
general anesthesia had a slightly higher mortality.32The temporal
association of psychoactive medications and delirium in critically
ill patients has recently been studied in 3 separate
cohorts.11,14,25 Pandharipande et al.25followed a cohort of
mechanically ventilated medical ICU patients and found
that lorazepam was an independent risk factor for daily
development of delirium after adjusting for important
covariates such as age, severity of illness, and presence of
sepsis. Fentanyl, morphine, and propofol were associated
with higher but not statistically significant odds ratios.25
Similar associations between midazolam and worse
delirium outcomes have been found in trauma, surgical,
and burn ICU patients.11,14 It is important to note that the
data on opioids and brain dysfunction are not as consistent
as are those with benzodiazepines. Although meperidine
has been associated with delirium in most of the published
studies, data with other opioids have been less convincing.
In fact, some studies have suggested that morphine and thadone
have beneficial effects with regards to delirium.11,14,24,27 Thus, it
is possible that opioids are protective in patients at high risk for
pain but may be detrimental if utilized to achieve sedation.
DEPTH OF SEDATION AND OUTCOMES
Although sedative and analgesic medications have a very important role in
patient care,comfort, and safety, health care professionals must strive to
achieve the right balanceof drug administration. Inadequately treated pain
leads totachycardia, increased oxygen consumption,
hypercoagulability,immunosuppression, hypermetabolism, and increased
endogenous catecholamine activity.33,34 Additionally,hyperactive delirium or
agitation can become life threatening if it leads to the removal of devices such
as endotracheal tubes and intravascular lines, and unrelieved anxiety can be a
significant source of physical and psychological stress for patients both during
an acute event and in the long term, when PTSD may result.26 Similarly,
intraoperative awareness has also been associated with persistent
PTSD, attesting to the importance of adequate amnesia during general
anesthesia.35,35a
So how does this correlate with depth or choice of anesthesia? In theory, deeper levels
of anesthesia (e.g.,decreased levels of responsiveness) and benzodiazepine use would
decrease intraoperative awareness and PTSD.Results from the B-Aware Trial suggest
that using the bispectral index (BIS) for titration of anesthesia in a population at high
risk for awareness reduces the risk of recall.36 A study by Kerssens et al.37 examined the
ability of patients to recall lists of words played during BIS-guided anesthesia and
found that titration to BIS 50 to 60 did not necessarily offer any benefits. Farag et al.38
found that deeper levels of anesthesia according to the BIS were associated with
improved cognitive function 4 to 6 weeks postoperatively,particularly with respect to
the ability to process information.
However, BIS levels <45 used as a surrogate for deep sedation have been associated with
increased mortality at 1 year, 2 years, and even longer postoperatively.35,39,40 Monk et
al.39 followed 1064 patients undergoing general anesthesia for major noncardiac
surgery and found that cumulative deep hypnotic time (BIS <45) was an independent
predictor of mortality at 1 year in addition to patients’ comorbid diseases and
intraoperative hypotension. A followup study40 in 174 patients confirmed these
findings and extended the association of low levels of BIS with mortality up to 2 years,
but it cautioned that in comparison with the comorbid conditions, the contribution of
depth of anesthesia was weak. Finally, the B-Aware trial35 found that absence of BIS
values <40 for >5 minutes was associated with improved survival and reduced
morbidity. Recently, Sieber et al.41 demonstrated that sedation during spinal anesthesia
for hip surgery targeted towards higher BIS levels (e.g., lighter sedation and increased
levels of responsiveness;BIS P80) decreased the incidence of postoperative
delirium in elderly patients in comparison with patients sedated with propofol
to a BIS of approximately 50. A Cochrane Database review suggested that
regional anesthesia(and subsequent higher levels of consciousness in
comparison with general anesthesia) may decrease postoperative confusion in
hip surgery patients,42 but a more recent structured, evidence-based, clinical
update suggested that there was no significant difference in the incidence of
delirium or postoperative cognitive dysfunction when general anesthesia and
regional anesthesia were compared.43 The ongoing dexamethasone, light
anesthesia, and tight glucose control (DeLiT) trial will hopefully shed further
light on the effects of intraoperative anesthesia and cognitive outcomes.44
Oversedation, however, occurs commonly in ICU patients and is associated
with worse clinical outcomes,including longer time on mechanical ventilation
and in the ICU, greater need for radiological evaluations of mental status, and
higher probability of developing delirium.11,14,25,45,46 Furthermore, the
presence of burst suppression on encephalograms, associated with deep
sedation, has been shown to be an independent predictor of mortality in
critically ill ICU patients.47 Instituting daily interruption of sedatives and
analgesics, protocolizing their delivery, and instituting target-based sedation
have all been shown to decrease sedative administration and improve
patient outcomes, though many of these studies have not specifically
evaluated delirium rates or duration.
The Awakening and Breathing Controlled Trial 50 which combined daily
spontaneous awakening and breathing trials, showed a 50% reduction in
sedative use that was accompanied by a reduction in coma and ventilator days
during the ICU stay and, more importantly, in mortality at 12 months. Notably,
this linked approach was not associated with an increase in long-term
neuropsychological outcomes, including PTSD, attesting to the fact that deep
sedation and amnesia are not necessary in the majority of critically ill
patients.52,53 In fact, sedatives (lorazepam in particular) have been associated
with increased PTSD symptoms,54 and symptoms of depression and PTSD
have been positively associated with more days of sedation in the ICU.55
Unpleasant memories of the ICU stay may contribute to PTSD symptoms in
survivors,56–58 although data have shown that PTSD is more often related to
having delusional memories of the ICU stay and that factual memories, even if
painful, are less likely to cause PTSD.59,60 Similarly, patients who had recall of
their ICU stay had less cognitive dysfunction than did patients with no recall of
their ICU experience, further emphasizing that excessive sedation and amnesia
may have prolonged neuropsychological and cognitive effects.61 Initiating
physical therapy early during the patient’s ICU stay has also been associated
with improved outcomes, including decreased length of stay both in the
ICU and hospital.62 Taking this approach a step further, Schweickert et
al.63 examined the effect of combining daily interruption of sedation with
physical and occupational therapy on the development of ICU-acquired
weakness and delirium in mechanically ventilated patients. They
demonstrated that patients who underwent early mobilization had an
approximate 50% decrease in the duration of delirium in the ICU and
hospital and had significant improvement in functional status at hospital
discharge.63 Therefore, a liberation and animation strategy (ABCDEs)
focusing on Awakening and Breathing trials (AB), Choice of sedation (C),
Delirium monitoring and management (D), and early Exercise (E) during
critical illness can improve patient outcomes and likely reduce the
incidence and duration of acute and long-term brain dysfunction in
critically ill patients.64
CHANGING ICU SEDATION PARADIGMS TO IMPROVE PATIENT
OUTCOMES
Beyond target-based and goal-directed sedation with daily interruption of
sedatives, the choice of sedative has implications on cognitive impairment.
Studies comparing propofol with benzodiazepines have shown better
outcomes in patients randomized to the propofol group May 2011 • Volume
112 • Number 5 in the majority of the investigations.65,66 Similarly, analgesiabased approaches towards sedation with the use of remifentanil have shown
shorter times on mechanical ventilation, though we must be attentive to
withdrawal and hyperalgesia if remifentanil is considered.67,68
The MENDS study (a randomized controlled trial of the I2 agonist
dexmedetomidine versus lorazepam) provided evidence that sedation with
dexmedetomidine can decrease the duration of brain organ dysfunction, with
less likelihood of delirium development on subsequent days.69,70 The
SEDCOM study compared dexmedetomidine with midazolam and
demonstrated a reduction in delirium prevalence with dexmedetomidine
along with a shorter time on mechanical ventilation.71 Another recent
randomized controlled trial, the DEXCOM study, compared
dexmedetomidine with morphine and showed that dexmedetomidine
reduced the duration but not the incidence of delirium after cardiac surgery
in comparison with morphine-based therapy.72 These studies attest to the
fact that reducing benzodiazepine exposure by using alternative sedation
paradigms improves patient outcomes, including brain dysfunction.
Extrapolation of these data to the operating room environment is
challenging; ongoing clinical trials will hopefully answer important
questions with regards to the benefits and risks of preoperative anxiolysis
therapy and the practice of sedative administration while undergoing
surgical procedures under regional anesthesia.
DELIRIUM AND COGNITIVE DYSFUNCTION PREVENTION
The most important factor in preventing and managing delirium is to recognize
and proactively treat reversible causes of delirium. These include, but are not
limited to, pain, anxiety, sleep disturbances, hypoxia, hypercarbia,
hypoglycemia, metabolic derangements, shock, and medication effects. Beyond
that, just as the potential causes of delirium are multifactorial, the approach to
prevention must be multifaceted. A landmark study of medical patients
reduced the development of delirium by 40% by focusing on several key goals,
including regular provision of stimulating activities, a nonpharmacological
sleep protocol, early mobilization activities, appropriate and early removal of
catheters and restraints, optimization of sensory input, and attention to
hydration.73 Similar studies have shown a decrease in the duration and severity
of delirium without impacting overall incidence;74,75 others have shown
benefit only in subgroups of patients76 or have not shown any benefit at
all.77Unfortunately, there are few data about the efficacy of these strategies in
perioperative and ICU patients. As was mentioned earlier, a strategy focusing
on reducing sedative drug exposure via coordination of ABCDEs may reduce
the incidence and duration of acute and long-term brain dysfunction in
critically ill patients.64
DELIRIUM MANAGEMENT
Pharmacologic therapy to manage delirium should be attempted
only after correcting any contributing factors or underlying
physiologic abnormalities. Numerous studies have examined the
effects of antipsychotic medications on delirium, though large
randomized controlled trials comparing the efficacy of typical and
atypical antipsychotics to placebo are still lacking.
Contributing sources can be summarizedas patient-related
factors (e.g., age, previous dementia,diabetes, and heart failure) or
iatrogenic risk factors
(e.g.,psychoactive medications, hypoxemia, shock, and
hypothermia)
In one of the first studies in critically ill patients, olanzapine
and haloperidol were shown to be equally effective in reducing
the severity of delirium symptoms.In a small study of patients
with delirium and with orders to receive as needed
haloperidol,quetiapine was shown to be more effective than
placebo in time to resolution of delirium.
Prakanrattana et al. conducted a randomized controlled trial and
showed that a single dose of risperidone sublingually after
cardiac surgery reduced the incidence of delirium in comparison
with placebo.
Rivastigmine has been recently studied as an adjunct to
haloperidol and was not found to decrease the duration of
delirium while potentially contributing to increased mortality.
Additionally,
there
are
now
data
showing
that
dexmedetomidine reduced the time to tracheal extubation,
decreased ICU length of stay, and decreased the incidence of
tracheostomy in comparison with haloperidol in critically ill
patients with agitated delirium.
Although drugs used to treat delirium are intended to improve
cognition, there is an important caveat in that they all have
psychoactive effects that may further cloud the sensorium and
promote a longer overall duration of cognitive impairment.
Delirium is a prevalent and costly problem that is associated with
significant morbidity and mortality in our patient population. On
the basis of the available literature reviewed in this article,
anesthesiologists can significantly decrease the burden of this acute
brain dysfunction given our active roles in operating room and ICU
patient care.
Management techniques with an integrated approach that
includes alteration of sedative medication regimens,
deployment of preventative strategies, initiation of delirium
monitoring, and judicious use of pharmacologic therapy can
reduce the incidence and impact of this disease and,
plausibly, chronic brain dysfunction as well.