Delirium, a disturbance of consciousness and cognition, may occur in up to 80% of intensive care unit (ICU) patients and is frequently underdiagnosed. Delirium is associated with longer durations of mechanical ventilation and ICU length of stay as well as an increased risk of death, disability, and long-term cognitive dysfunction.
This chapter aims to broadly define delirium, discuss the associated subtypes and risk factors, and provide the basis for clinicians to develop strategies aimed at preventing and treating delirium in their practice settings.
Definition
The Diagnostic and Statistical Manual of Mental Disorders ( DSM-5 ) defines delirium as (1) disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. (2) A change in cognition (e.g., memory deficit, disorientation, language disturbance) or development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia. (3) The disturbance develops over a short period (usually hours to days) and tends to fluctuate during the course of the day. (4) There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by a direct physiologic consequence of a general medical condition, an intoxicating substance, medication use, or more than one cause.
Delirium has been further differentiated according to the level of alertness; the motoric subtypes consist of hyperactive, hypoactive, and mixed subtypes. Distribution of delirium in medical and surgical patients suggests that the hypoactive subtype, characterized by a flat affect, withdrawal, apathy, or lethargy, is the most prevalent. The hyperactive delirious patient is described as agitated, restless, violent, or emotionally labile. Although challenging to manage clinically, the weight of evidence suggests a better overall prognosis for the hyperactive patient compared with the hypoactive delirious patient. Nevertheless, two published studies contradict these findings, suggesting either that the hyperactive subtype carries a poorer prognosis or that there is no difference in outcomes by subtype. The rates of prevalence of the subtypes of delirium in the ICU are 1.6% for the hyperactive subtype, 43.5% for the hypoactive subtype, and 54.1% for the mixed subtype. The Delirium Motor Subtype Scale may aid in making this diagnosis.
Risk Factors
The causes of delirium are multifactorial. The risk factors can be divided into predisposing factors (i.e., host factors) and precipitating factors ( Table 73-1 ). Patients in the hospital at a higher risk for having delirium include patients with dementia, chronic illness, advanced age, existing infection, and depression. Modifiable risk factors such as hypertension, poor nutrition, substance withdrawal, and tobacco use have also been shown to be associated with development of delirium in the hospital. Iatrogenic or potentially modifiable factors include hypoxia, metabolic and electrolyte disturbances, infection, dehydration, hyperthermia, sepsis, psychoactive medications, and sleep deprivation. There has been much research on postoperative delirium, especially in those undergoing cardiopulmonary bypass, with a retrospective study showing a decreased incidence of delirium in patients pretreated with statins. ICU statin use has been associated with reduced delirium, especially early during sepsis, whereas the discontinuation of a previously used statin was associated with increased delirium. Benzodiazepine use has also been associated with an increased incidence of delirium. In addition, heart surgery without cardiopulmonary bypass appears to confer an advantage in decreasing delirium, suggesting that electrolyte or metabolic disturbances play a role in the development of delirium.
| Host Factors | Acute Illness | Iatrogenic and Environmental Factors |
|---|---|---|
| Age 65 years or older | Acidosis | Immobilization |
| Male sex | Anemia | Medications (e.g., opioids, benzodiazepines) |
| Alcoholism | Fever, infection, sepsis | Anticholinergic drugs |
| Apolipoprotein E4 polymorphism | Hypotension | Alcohol or drug withdrawal |
| Cognitive impairment | Metabolic disturbances (e.g., sodium, calcium, blood urea nitrogen, bilirubin) | Sleep disturbances |
| Dementia | Respiratory disease | — |
| History of delirium | — | — |
| Depression | — | — |
| Hypertension | — | — |
| Smoking | — | — |
| Vision or hearing impairment | — | — |
Pathogenesis
The pathogenesis of delirium is complex and still poorly understood. Maldonado has postulated that the different mechanisms that may play a role in delirium are all “complementary, rather than competing.” Imbalance or derangement of multiple neurotransmitter systems has been implicated in the pathophysiology of delirium.
Neuroinflammatory Response Hypothesis
Inflammatory mediators such as cytokines and chemokines are readily expressed in critical illness, trauma, sepsis, and after surgical interventions. Animal studies have demonstrated that the release of endogenous inflammatory mediators correlates with exacerbated cognitive and motor symptoms and increased vascular permeability in the brain. Studies have shown that sepsis, severe sepsis, and septic shock are characterized by significantly elevated C-reactive protein (CRP), S-100β, and cortisol in those patients with delirium compared with those without delirium. Cerebral autoregulation is disturbed and inflammation may impede endothelial function of the cerebral vasculature, thus making the blood–brain barrier more permeable to inflammatory insults. In support of this theory, a recent study in ICU patients has shown that endothelial dysfunction is associated with greater duration of delirium. In another study, higher levels of procalcitonin at ICU admission were associated with prolonged duration of brain dysfunction, and higher levels of CRP showed trends toward an association. In addition, inflammation upregulates γ-aminobutryic acid (GABA) A receptors in the brain, contributing to the inhibitory tone within the brain and reducing brain synaptic connectivity. Thus, the iatrogenic administration of GABA-ergic medications such as benzodiazapines probably further contributes to the inhibition of neural pathways and increases the risk of delirium.
Cholinergic Deficiency Hypothesis
Impaired oxidative metabolism in the brain results in a cholinergic deficiency. The finding that hypoxia impairs acetylcholine synthesis supports this hypothesis. The reduction in cholinergic function results in an increase in the levels of glutamate, dopamine, and norepinephrine in the brain. Serotonin and GABA are also reduced, possibly contributing to delirium.
Monoamine Axis Hypothesis
Dopamine, norepinephrine, and serotonin have been implicated in acute brain dysfunction in the ICU. Dopamine is thought to increase the excitability of neurons, and acetylcholine and GABA decrease neuronal excitability. Norepinephrine activity has been associated with hyperactive delirium, and the elevated norepinephrine levels seen after traumatic brain injury have been associated with poor neurologic status, decreased survival, and longer hospital length of stay.
Serotonin
Elevated serotonin levels have been associated with impaired learning and memory and may be indirectly involved in the pathogenesis of acute brain dysfunction.
Amino Acid Hypothesis
Amino acid entry into the brain is regulated by a sodium-independent large neutral amino acid transporter type-1. Increased cerebral uptake of tryptophan and phenylalanine, compared with that of other large neutral amino acids, can lead to elevated levels of dopamine and norepinephrine, two neurotransmitters that have been implicated in the pathogenesis of delirium. Although tryptophan has been postulated to play a role in delirium, a major pathway for its metabolism also exists via the kynurenine pathway. Activation of this pathway in the presence of inflammation may produce neurotoxic metabolites, which may predispose patients to delirium.
Impaired Oxidative Metabolism
Oxygen deprivation in the brain through either hypoxia or hypoperfusion has been implicated in delirium. Engel and Romano discussed delirium as a state of “cerebral insufficiency” as early as 1959, when they showed that delirium was accompanied by diffuse slowing on electroencephalogram, suggesting a reduction in brain metabolism. This may be further accentuated in the patient who already has compromised blood flow secondary to vascular dementia. Decreases in oxidative metabolism, as well as acetylcholine release, have been demonstrated in the aging brain, and preexisting cognitive dysfunction in the elderly patient, suggestive of chronic changes from vascular insufficiency, has been shown to be the most significant predictor of the development of delirium in the postoperative period.
Recognition of Delirium
Early recognition of delirium is important, if only to avoid lengthening its course through exacerbation by iatrogenic factors. Therefore clinicians must use assessment tools that allow for timely, accurate assessment by a broad range of practitioners in various settings. Recognition becomes additionally difficult in the ICU setting because patients may have a purposefully altered sensorium secondary to sedation administered for procedures, pain, or mechanical ventilation. Therefore, assessment of a patient for delirium becomes a two – step process because it is important for the clinician first to establish the current level of sedation before assessing the patient for delirium. Examples of scales that can be used to assess sedation include the Ramsay Sedation Scale, the Riker Sedation-Agitation Scale, and the Richmond Agitation-Sedation Scale (RASS).
Once the level of sedation has been established and the patient is responsive to verbal stimulus, it is then appropriate for the clinician to assess for the presence of delirium. Although there have been multiple instruments validated for use in non-ICU patients, only two are validated for diagnosing delirium in mechanically ventilated patients: the Intensive Care Delirium Screening Checklist (ICDSC) and the Confusion Assessment Method for the ICU (CAM-ICU). The CAM-ICU is a scale that is based on the Confusion Assessment Method but is amended to increase its applicability in the ICU setting. It takes a trained ICU nurse approximately 2 minutes to complete the CAM-ICU, and accuracy over a set of 471 paired observations in the ICU setting resulted in an accuracy rate of 98.4% with excellent inter-rater reliability. It has been validated in multiple ICU settings.
A combination of the RASS for assessment of sedation ( Fig. 73-1 ) followed by the CAM-ICU ( Fig. 73-2 ) or the ICDSC ( Table 73-2 ) can be used for the establishment of delirium in ICU patients. The diagnosis of delirium using the CAM-ICU (after establishing a RASS score of −3 or less) requires (1) acute change or fluctuation in mental status (feature 1), and (2) inattention (feature 2), and (3) one of the following: (a) disorganized thinking (feature 3) or (b) altered level of consciousness (feature 4). Only those patients with a RASS score of −3 and higher are alert enough to respond to the test and thus can be assessed for delirium. For diagnosis of delirium with the ICDSC, patients who score at least 4 points are considered to have delirium.
| Patient Evaluation | |
|---|---|
| Altered level of consciousness (A-E) | Deep sedation/coma over entire shift [SAS= 1, 2; RASS = -4,-5] = Not assessableAgitation [SAS = 5, 6, or 7; RASS= 1-4] at any point = 1 pointNormal wakefulness [SAS = 4; RASS = 0] over the entire shift = 0 points Light sedation [SAS = 3; RASS= -1, -2, -3]: = 1 point (if no recent sedatives) = 0 points (if recent sedatives) |
| Inattention | Difficulty in following a conversation or instructions. Easily distracted by external stimuli. Difficulty in shifting focuses. Any of these scores 1 point. |
| Disorientation | Any obvious mistake in time, place, or person scores 1 point. |
| Hallucinations-delusion-psychosis | The unequivocal clinical manifestation of hallucination or of behavior probably due to hallucination or delusion. Gross impairment in reality testing. Any of these scores 1 point. |
| Psychomotor agitation or retardation | Hyperactivity requiring the use of additional sedative drugs or restraints to control potential danger to oneself or others. Hypoactivity or clinically noticeable psychomotor slowing. |
| Inappropriate speech or mood | Inappropriate, disorganized, or incoherent speech. Inappropriate display of emotion related to events or situation. Any of these scores 1 point. |
| Sleep/wake cycle disturbance | Sleeping less than 4 hours or waking frequently at night (do not consider wakefulness initiated by medical staff or loud environment). Sleeping during most of the day. Any of these scores 1 point. |
| Symptom fluctuation | Fluctuation of the manifestation of any item or symptom over 24 hours scores 1 point. |
| Total score (0-8) |
Some recent studies have questioned whether delirium evaluations should be done while on sedation. It is important to note that a small subset of patients (∼10%) may have rapidly reversible sedation-related delirium ; that is, their delirium resolves when sedation is turned off. Unfortunately, in the study evaluating rapidly reversible delirium, most patients continued to have persistent delirium even after sedation was interrupted. Thus, when feasible, delirium evaluation should also be done after interruption of sedation; however, delirium evaluations should not be forgone just because a patient is on sedation because the omission would be far worse than overdiagnosing delirium in a handful of patients.
Primary Prevention
The prevention of delirium in the ICU requires constant reassessment of patients’ clinical courses and treatments. Several potential pathophysiologic contributors to delirium have been previously outlined. All have endpoints associated with cellular mechanisms, suggesting that avoiding metabolic derangements, including electrolyte abnormalities, hypoglycemia, hypoxia, dehydration, and hyperthermia, are paramount in the prevention of delirium.
Medications have long been implicated in the development of delirium, either because of their side effects or their direct effects on the central nervous system. The number of medications administered and their psychoactive effects are suggestive of precipitating delirium.
Another potential risk factor for delirium is alteration of the sleep cycle. Disruption of the sleep–wake cycle in the ICU may be necessary to continuously monitor and manage the critically ill patient. However, the toll on the patient may be high because multiple studies have shown that sleep disruption has detrimental effects on cognition and memory even in the healthy, non-ICU patient. Maintaining a sleep–wake cycle whenever possible through nonpharmacologic or pharmacologic means may help prevent delirium.
There has been some debate about whether the “protocolization” of patient care may reduce the incidence of delirium. In a study that included 852 general medical patients older than 70 years, standardized geriatrician-led protocols were developed for six risk factors of delirium: cognitive impairment, sleep deprivation, immobility, visual impairment, hearing impairment, and dehydration. Using these protocols resulted in a 40% reduction in the initial development of delirium in the intervention patients (95 vs. 16%). When these patients were assessed after 6 months for 10 outcomes, including items such as functional status, cognitive status, delirium, and rehospitalization, only incontinence was slightly less common in the intervention group.
Patients in the ICU frequently receive continuous intravenous analgesics and sedatives. Accumulation in individual patients can predispose to a withdrawal syndrome on discontinuation. Because substance-induced delirium is one of the etiologies recognized by the DSM-5 , it is no surprise that analgesic and sedative polypharmacy contribute significantly; hence, strategies to reduce exposure to psychoactive medications need to be implemented.
For the improvement of patient outcome and recovery, a liberation strategy focusing on the ABCDEs (Awakening and Breathing Trials, Choice of appropriate sedation, Delirium monitoring and management, and Early mobility and Exercise) has been proposed and shown to decrease the incidence of delirium and coma and improve other patient outcomes.
Awaken the Patient Daily
Benzodiazepines are known to increase the risk of delirium in a dose-dependent manner. Many studies have shown that protocolized target-based sedation and daily spontaneous awakening trials reduce the number of days on mechanical ventilation. This also exposes the patient to lower cumulative doses of sedatives.
Spontaneous Breathing Trials
Studies have shown that daily interruption of mechanical ventilation is superior to other varied approaches to ventilator weaning. Thus incorporation of spontaneous breathing trials into practice reduced the total time on mechanical ventilation.
Coordination of Daily Awakening and Daily Breathing
The Awakening and Breathing controlled trial combined the spontaneous awakening trial with the spontaneous breathing trial. This combination was associated with shorter duration of mechanical ventilation, a 4-day reduction in hospital length of stay, a remarkable 32% decrease in risk of dying at 1 year, and no long-term neuropsychological consequences of waking patients during critical illness. Although delirium duration was not decreased, coma duration was reduced. Thus more patients in the intervention group qualified for delirium evaluation as compared with the control group, where they were more likely to be in a state of coma so ineligible for delirium evaluation.
Choosing the Right Sedative Regimen in Critically Ill Patients
Numerous studies have confirmed that benzodiazepines are associated with poor clinical outcomes. Two studies comparing dexmedetomidine (alpha-2 agonist) to benzodiazepine infusions showed that the former reduced the burden of brain dysfunction.
Delirium Management
The Society of Critical Care Medicine (SCCM) has published guidelines recommending routine monitoring for delirium in all ICU patients. Pharmacologic therapy for delirium should only be attempted after correcting any contributing factors or underlying physiologic abnormalities.
Exercise and Early Mobility
Morris et al. showed that early initiation of physical therapy in ICU patients was associated with decreased length of ICU and hospital polypharmacy. Schweikert et al. looked at the efficacy of combining daily interruption of sedation with physical and occupational therapy on patient outcomes. Patients in the intervention arm had better functional outcomes at discharge, and early physical therapy was also associated with a 50% decrease in the duration of delirium in ICU and hospital stay. Needham et al. conducted a quality improvement project with the use of a multidisciplinary team that focused on reducing sedation use. The authors reported that benzodiazepine use decreased and the patients had improved sedation and delirium status. A decrease in ICU and hospital length of stay was also noted.
We have included an empirical protocol ( Fig. 73-3 ) that we use to treat delirium in ICU settings that is based on the current SCCM Clinical Practice Guidelines. It is merely an example of such a protocol, and the use of a similar protocol should be updated with current data and designed to be implemented specifically at an individual institution. The choice of particular antipsychotics is not described because there are limited data guiding such recommendations.
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