Page 1119 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

758 PART 6: Neurologic Disorders

Finally, medications commonly given to ICU patients, such as seda- A
tives, analgesics, vasopressors, β-agonists, and corticosteroids, disrupt 100
slow-wave and REM sleep. Further study of sleep in the ICU is 90
45
necessary to understand the underlying mechanisms for sleep disrup-
tion and the relationship between sleep and delirium. Meanwhile, 80
clinicians should attend to modifiable risk factors by reducing noise Probability of transitioning to delirium (%)
and light at night, minimizing other disruptions in the ICU environ- 70
ment, treating symptoms, and judiciously using sleep-disrupting
medications. 60
The deliriogenic effects of medications given for sedation and/or
analgesia—drugs used to treat nearly all ICU patients at some time 50 No drug 0-1 1-2 2-3 3-4 4+ Log scale
https://kat.cr/user/tahir99/
during their ICU stay—have received specific attention in many 0-2.7 2.7-7.4 7.4-20 20-55 55+ Original scale
studies, as they represent a potent yet potentially modifiable risk fac- Lorazepam dose (mg)
tor for delirium. Though sedative and analgesic medications are pre-
scribed to relieve pain and anxiety and to improve patient tolerance
of treatments during critical illness, these medications have important Midazolam
side effects. Continuous infusion of sedatives, for example, is associ- B 100
ated with prolonged mechanical ventilation, whereas interruption Users
31
of sedative infusions expedites weaning from mechanical ventilation, 80 Non-users
speeds discharge from the ICU and hospital, and improves long-term p = 0.014 p = 0.031
survival. 12,46 60
Multiple studies have now clearly demonstrated a link between % Days delirious
benzodiazepines and development of delirium. Lorazepam dose was 40
found to be an independent risk factor for the delirium in medical ICU
patients, such that each day a patient was treated with the drug, the odds 20
of being delirious the next day increased by 20%. In fact, patients treated
with greater than 20 mg of lorazepam in a day were nearly all delirious or 0
comatose the following day. Numerous other studies have consistently Surgical Trauma
13
found similar links between benzodiazepine administration (whether Daily midazolam use (exc. coma days)
lorazepam or midazolam) and delirium in patients in surgical, trauma,
burn, and mixed ICUs (Fig. 82-1). 14,15,17,36,38,39,47 FIGURE 82-1. Relationship between benzodiazepines and delirium. Multiple studies
Narcotic pain medications present a more complex picture in terms have demonstrated the association between benzodiazepines and delirium. As the daily dose
of their relationship with delirium in the ICU, in that they have been of lorazepam increased in medical ICU patients, the odds of transitioning to delirium increase,
associated with development of delirium in some studies but not in such that patients treated with >20 mg of lorazepam per day universally developed delirium
others. This is likely due to the differing indications for (or dual effects (A). Reproduced with permission from Girard TD, Pandharipande PP, Ely EW. Delirium in the
of) analgesics in the ICU. Narcotic pain medications are associated with intensive care unit. Crit Care. 2008;(12 suppl 3):S3. Similarly, daily midazolam use is associated
the development of delirium in populations frequently sedated with with an increase in the proportion of days with delirium in surgical and trauma ICU patients
these drugs, such as medical and surgical ICU patients. 9,17,37 In these (B). Reproduced with permission from Pandharipande P, Cotton BA, Shintani A. Prevalence
settings, narcotics are often co-administered with benzodiazepines; in and risk factors for development of delirium in surgical and trauma intensive care unit
one study, elderly ICU patients treated with benzodiazepines and opi- patients. J Trauma. July 2008;65(1):34-41.
oids had a longer duration of delirium. When narcotic medications
39
are used to induce coma, the odds of developing delirium triple. Thus,
36
clinicians should seek to minimize the use of heavily sedating medica- and inactivation of neurotransmitters—especially acetylcholine and
tions, whether benzodiazepines or narcotics, by using evidenced based dopamine—that control arousal and the sleep-wake cycle are the underly-
protocols to interrupt continuous sedative infusions 12,46 and seek to use ing mechanism leading to delirium. 49,50 Studies measuring the amount
nonbenzo diazepine sedative medications where possible. 14,15,48 Patients of anticholinergic activity in hospitalized patients found higher levels of
more often treated with narcotics because of pain, such as trauma ICU serum anticholinergic activity (SAA) were associated with an increased
patients, are found to have a lower risk of the development of delirium risk of delirium, even in patients not exposed to medications with anti-
when treated with fentanyl or morphine compared to patients who cholinergic properties. 51,52 Central cholinergic deficiency can theoretically
were not exposed to these drugs. Intravenous opiates and exposure result from derangements occurring anywhere along the continuum from
17
to methadone was protective against development of delirium in burn acetylcholine production and release to its action on postsynaptic recep-
ICU patients. 47 tors. In addition to cholinergic deficiency, dopamine excess is thought to
be associated with delirium, likely via its action on central dopamine recep-
PATHOPHYSIOLOGY tors that regulate acetylcholine production. 50-54 Finally, imbalances in the
production, release, and degradation of numerous other neurotransmitters,
The pathophysiology of delirium remains incompletely understood. such as serotonin, norepinephrine, glutamate, melatonin, and gamma-
Leading hypotheses, often drawn from research outside the ICU, pro- aminobutyric acid (GABA), have also been suspected to play a role in the
pose that delirium results from neurotransmitter imbalances and/or development of delirium. 49-54
factors that affect neurotransmitter production, such as availability of Large neutral amino acids (LNAAs), including leucine, valine, tryp-
large neutral amino acids, or systemic and central nervous system (CNS) tophan, tyrosine, and phenylalanine, are the precursors of several
inflammation. Delirium during critical illness is most likely a conse- neurotransmitters that are involved in arousal, attention, and cognition
quence of a complementary and interlinked series of events (Fig. 82-2). and are therefore hypothesized to be involved in the pathogenesis of
Delirium due to Atropa belladonna (a plant known as Deadly Nightshade, delirium. The synthesis of serotonin and melatonin depend on the
52
which contains the anticholinergic atropine) and anticholinergic availability of tryptophan, whereas the production of norepinephrine and
drugs, such as scopolamine, has been recognized for centuries, an obser- dopamine require both tyrosine and phenylalanine. The LNAAs compete
vation that led to the hypothesis that imbalances in the synthesis, release, for transfer across the blood-brain barrier, such that an increase in

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