Continuing Education Activity

Delirium is defined by DSM-5 criteria as an impairment in attention and awareness that develops over a relatively short time interval that is associated with additional cognitive deficits. There is a prevalence of delirium within the ICU setting (ICU delirium). This activity reviews the evaluation and treatment of ICU delirium and highlights the role of the interprofessional team in evaluating and treating critically ill patients with this condition.

Objectives:

• Identify the etiology and epidemiology of ICU delirium.

• Describe the appropriate history, physical, and evaluation of ICU delirium.

• List the management options available for ICU delirium.

• Discuss interprofessional team strategies for improving care coordination and communication to advance ICU delirium and improve outcomes.

Introduction

Delirium, also termed as an 'acute confusional state,' 'toxic or metabolic encephalopathy,' or 'acute brain failure,' is essentially defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria as an acute change in attention and awareness that develops over a relatively short time interval and associated with additional cognitive deficits such as memory deficit, disorientation, or perceptual disturbances. It is a common phenomenon, occurring in 20 to 70% of hospitalized patients.[1] The term 'ICU psychosis' is an unfortunate and outdated misnomer for delirium. This term, indeed, was previously used to refer to hyperactive delirium within the intensive care unit (ICU) setting and came into use when the high prevalence of delirium was recognized in this population. Several investigations proved that the higher incidence of delirium manifests in ICU patients on mechanical ventilation (MV). In this setting, delirium occurs in up to 80% of patients. [2][3]

Because delirium represents the most common clinical manifestation of acute brain dysfunction in the ICU, affecting up to 83% of ICU patients on mechanical ventilation (MV), new-onset confusion in adult patients always warrants further evaluation.[4] However, the clinical evaluation must be accurate as it can often be difficult to distinguish this phenomenon from other clinical conditions. DSM-5 criteria explicitly state that these new changes in mentation must be in the absence of a neurocognitive disorder that could explain the confusion and does not occur in the setting of a reduced level of arousal (e.g., coma). Thus, although an identifiable cause of delirium is often not found, a thorough evaluation for reversible causes of delirium is warranted, and multiple causes may be present in combination. In this regard, there is a large array of possible causes of delirium that range from intoxication and withdrawal states to other serious neurological insults like meningitis and stroke. The prevention, identification, and management of delirium have important consequences for patient outcomes, both during admission and after discharge.

Regardless of the classification, there are three subtypes of delirium categorized according to the psychomotor behavior:[5]

• Hyperactive delirium
• Hypoactive delirium
• Mixed delirium

While hyperactive delirium is the more commonly identified form of delirium outside the ICU, the hypoactive (24.5% to 43.5%) and mixed (52.5%) types are more often observed in the ICU setting. Hyperactive ICU delirium accounts for approximately 23% of cases.[6] It is characterized by agitation, restlessness, emotional lability, and positive psychotic features such as hallucinations and illusions that often interfere with the delivery of care. It should be remembered that new-onset psychotic symptoms in older adult patients are unlikely to be a primary mental illness, and search for a pharmacological or physiological cause should be carried out. Hypoactive delirium is commonly characterized by confusion, sedation, apathy, decreased responsiveness, slowed motor function, withdrawn attitude, lethargy, and drowsiness. This type of delirium is often underrated and is associated with a worse prognosis, as patients who suffered from hypoactive delirium showed increased 6-month mortality compared to the patients previously affected by other subtypes of delirium.[6][7] Mixed delirium is the most frequent type, accounting for about half of the total cases.[6] It is a combination of the two forms previously described, and patients manifest a fluctuation of hypoactive and hyperactive features.

This chapter is aimed at presenting clinical features, evaluation, prophylactic strategies, and treatment of delirium in the setting of ICU. The role of the interprofessional team in evaluating and treating critically ill patients with this condition is also addressed.

Etiology

Causes

It is necessary to maintain a broad differential and a low threshold for suspicion of other inciting insults that may be the cause of delirium. The identifiable leading causes of delirium broadly include, but are not limited to:

• Infectious
• Alcohol/substance intoxication or withdrawal
• Wernicke's disease
• Metabolic
• Hypoglycemia
• Medications
• Trauma
• Neurocognitive
• Seizures
• Vascular
• Hypoxia
• Vitamin deficiencies
• Endocrinopathies
• Toxin or heavy metal ingestion

Risk Factors for Delirium

The literature has identified multiple risk factors. Among these, the most studied are mentioned:[8]

• Older age
• Cognitive impairment
• Visual impairment
• Alcohol abuse
• Respiratory disorder
• Illness severity
• Terminal illnesses
• Comorbidity
• Infection
• Major surgery (e.g., complex abdominal, hip fracture, and cardiac surgery)

Interestingly, a mnemonic bundle (DELIRIUM) was proposed (Saint Louis University Geriatrics Division and St. Louis Veterans Affairs) for assessing the main causes of delirium:

D=DrugsE=Eyes, ears, and other sensory deficitsL=Low O2 states such as heart attack, stroke, and pulmonary embolismI=InfectionR=Retention (of urine or stool)I=Ictal stateU=Underhydraton/undernutritionM=Metabolic causes (e.g., diabetes, sodium abnormalities)

Within the ICU setting, numerous risks have been identified:[9]

• Pre-existing dementia
• Mechanical ventilation[10]
• Sepsis
• History of hypertension
• High severity of illness on admission
• Pain
• Stroke
• Psychiatric disorders
• Depression
• Traumatic head injury
• Myocardial infarction
• COPD
• Steroids[11]
• Hypertension[12]
• Psychoactive medications including narcotics[13]
• Deep levels of sedation 
• Environmental factors such as the absence of visible sunlight[13]
• Immobility and physical restraints
• Poor sleep quality
• Social factors like alcohol abuse and smoking[13]
• Lack of visitors[13]
• Anticholinergic drug exposure (e.g., diphenhydramine, promethazine, and cyclobenzaprine)[14]

Epidemiology

The prevalence of delirium in the community ranges from 1 to 2% but increases to up to 10% to 30% in elderly patients presenting to the emergency department. In the general medical unit, the prevalence further increases to approximately 14 to 24% and continues to rise to upwards of 70 to 87% within the ICU.[4] Post-operative rates range from approximately 15 to 53% of older adults.

Pathophysiology

The delirium pathophysiology is not fully elucidated and may not be due to a single pathway, given the wide variety of causes. It is generally thought to be an interplay between unique patient characteristics such as advanced age, cognition, and physiological insults. Many theoretical mechanisms have been proposed that range from neurotransmitter dysregulation, neuroinflammation with microglial activation, oxidative stress, neuronal aging, and sleep-wake cycle dysfunction, among other theories.

Derangements of different neurotransmitter pathways have been seen in the pathophysiology of delirium, most importantly, dopamine and acetylcholine. Dopamine excess and acetylcholine depletion have been found linked to delirium.[15][16] Other neurotransmitters like glutamate, gamma-aminobutyric acid, serotonin, and endorphins also play a role.

Inflammatory markers produced during a critical illness, like cytokines, chemokines, and tumor necrosis factor-alpha, initiate a sequence of events leading to microvascular compromise, thrombin formation, and endothelial damage.[17] Inflammation can cause brain dysfunction by decreasing cerebral blood flow due to the formation of macroaggregates of fibrin, platelets, neutrophils, and red blood cells in the cerebral microvasculature.

Another hypothesis is the reduction of cerebral oxidative metabolism leads to the alteration of neurotransmission. Failure of cerebral oxidative metabolism is found to be important in the pathogenesis of multiple organ dysfunction in critical illness.[18]

Neurotransmitter levels and function are directly influenced by plasma concentration of many amino acids, and decreased availability of neutral amino acids can lead to delirium in patients admitted to ICU.[19]

There may be some cross-talk between proposed pathways that explain the different phenotypic presentations of delirium (hyperactive, hypoactive, and mixed), but not enough evidence exists at this time to definitively describe the pathophysiology behind this condition.[20]

History and Physical

History will reveal deficits in attention and awareness with at least one alteration in cognition (per DSM-5 criteria for delirium). These changes often develop within a short time frame and are frequently noted to fluctuate during the day. An existing or emerging neurocognitive disorder must not better explain these changes. Of note, indeed, inattention and change in cognition cannot be explained as a baseline neurocognitive disorder such as dementia or a seriously reduced level of arousal due to sedative administration or coma.

Classic assessment of orientation to person, place, situation, and time may not be enough for the evaluation of delirium, as patients can be alert and oriented to all of these but still meet the criteria. The course of delirium can last days to months. Additional symptoms include positive psychotic symptoms, confusion, lethargy, and drowsiness, among other symptoms.

A complete neurological and physical exam should be performed and may reveal clues suggesting the cause of delirium. The presence of a fever, for example, provides clues of an infectious etiology, whereas focal neurological deficits may indicate a neurological or vascular cause of delirium.

A thorough patient history may reveal other clues, including a history of substance or alcohol abuse that may suggest intoxication, withdrawal, or relevant vitamin deficiency.

Evaluation

Laboratory and radiographic testing should be done in the light of the patient's history and physical exam, with the following investigations providing a partial list of what should be considered:

• Routine lab monitoring
• Investigation of possible/likely infectious causes (urinary tract infection, meningitis, etc.)
• Investigation of possible/likely metabolic disturbances (hypoglycemia, electrolytes, ammonia, etc.)
• Investigation of possible/likely intoxication or withdrawal (urine drug screen)
• Investigation of possible/likely neurological or vascular insults (imaging)
• Investigation of vitamin deficiencies
• Investigation of endocrinopathies

Treatment / Management

Monitoring

ICU Delirium Assessments

The Confusion Assessment Method-ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) are both extensively validated and used for delirium diagnosis and evaluation of delirium over time.[21][22] They allow the assessment of attention, orientation, and memory. Of note, both tools allow nonpsychiatric ICU personnel to diagnose the complication rapidly and reliably and can be adopted even when the patient is unable to speak due to endotracheal intubation.

The CAM-ICU provides two steps. In the first one, the level of consciousness/arousal is evaluated through a standardized sedation scale such as the Richmond Agitation-Sedation Scale (RASS). This latter is a 10-point scale ranging from +4 to -5, where a RASS value of 0 indicates a calm and alert patient; RASS scores of -4 and -5 are indicative of coma and cannot be further assessed for delirium. All other individuals (moderately sedated, RASS score -3 or more alert) should also be evaluated through the second step assesses patients for four characteristics of delirium. The categories include acute onset of altered mental status, inattention, disorganized thinking, or altered level of consciousness. Three out of four features are required for a diagnosis of delirium. The tools, validated in 1990, have been updated by Marcantonio et al.[23] in 2014, in the 3-Minute Diagnostic Assessment for Delirium (3D-CAM). It is an algorithm easy to perform and can be used by personnel with minimal additional training. 

Through the ICDSC, the level of consciousness is first evaluated on a 5-point scale (A to E) that ranges from unresponsive (A) to exaggerated response (E). Patients who are scored in the categories 'A=No response' or 'B=Response to intense and repeated stimulation' are not further assessed. The other patients (C to E levels of consciousness) are checked for information collected during the previous 24 hours, investigating eight items (rated present or absent) with a total score of 0 to 8. A score of 4 or greater is considered diagnostic of delirium.

Other evaluations

In addition to the tools for ICU detection, a careful clinical assessment must be performed. For instance, it is mandatory to perform frequent vitals and/or neuro checks.

Pharmacological and Non-pharmacological Management Strategies:

It is generally accepted that there are no identified therapies (medications or interventions) proven to decrease the duration of delirium. As a consequence, treating the underlying physiological insult is of key importance. Also, other interventions should be considered for delirium management:

• Treatment of the underlying cause
• Correction of potential electrolyte disturbances
• Removal of offending pharmacological agents
• Maintain proper sleep/wake cycles
• Manage pain
• Address sensory impairments (hearing, vision)
• Encourage family visits and frequent reorientation.
• Early mobilization

Interventions for symptomatic ICU treatment can be divided into pharmacological and non-pharmacological strategies. 

Medications

There is much debate regarding the utility of antipsychotics and other medications such as physostigmine, rivastigmine, and donepezil in preventing and decreasing the duration of delirium. In the ICU setting, although there is no evidence that treatment with haloperidol will reduce the duration of delirium, it is the most commonly adopted treatment. Moreover, there is some evidence that atypical antipsychotics may be useful.

• Antipsychotics. This category includes haloperidol and atypical antipsychotics. Haloperidol is a dopamine (D2) receptor antagonist. It is given at the dosage of 2-10 mg (IV every six h); it is useful, especially in the hyperactive form. Atypical antipsychotics used for this purpose are olanzapine (IM 5-10 mg; max: 30 mg/d), risperidone (0.5-8 mg), quetiapine (orally 50 mg; max 400 mg/d), and ziprasidone. A special issue concerns antipsychotic-related toxicity. For instance, cardiotoxicity such as QT interval (QT) prolongation, torsade de pointes, and hypotension are reported at high doses of haloperidol, whereas a dosage of 2 mg can be safely administered.[24] Of note, caution should be taken when antipsychotics are used with other QT-prolonging medications. Other commonly used classes of drugs that are associated with QT prolongation include, but are not limited to, antiarrhythmics, antibiotics, antiemetics, and antidepressants, as well as methadone, lithium, octreotide, and tacrolimus, among others. A baseline EKG and further assessment may be warranted. Antipsychotics can also induce extrapyramidal symptoms (EPSs) expressed as parkinsonism featuring dystonic reactions or akathisia.[25] Rarely, haloperidol can cause neuroleptic malignant syndrome[26], whereas insomnia and agitation can often be observed. In the case of atypical antipsychotics, EPSs can manifest at high doses. Again, olanzapine and quetiapine may induce excessive sedation, whereas ziprasidone is more associated with QT prolongation.
• Dexmedetomidine. This alpha-2-adrenergic agonist with sedative, analgesic, and anxiolytic actions is useful in adults under MV when hyperactive delirium can obstacle the weaning. Due to the low-quality evidence of investigations assessed, a panel of experts did not recommend its use.[27] Side effects include bradycardia and hypotension or hypertension.
• Short-acting benzodiazepines (BDZs). These agents, such as midazolam and lorazepam, can have a neurogenic effect. They are exclusively useful in patients with alcohol or sedative withdrawal or for delirium resulting from seizures. 
• Other drugs. Although rivastigmine, donepezil, and physostigmine have been proposed for ICU delirium management, evidence of effectiveness is currently very scarce.

Non-pharmacological interventions

• Behavioral strategies. This category includes several strategies focused on patient reorientation useful in cooperative patients with delirium. Occupational therapy [28], patient [29], and family training have been successfully proposed for this aim.[30]
• Mobilization. Early ICU mobility therapy can accelerate MV weaning, ICU length of stay, and delirium duration.[31]
• Use of restraints. Careful use of soft restraints only if and after behavioral and pharmacological interventions fail if reasonably possible. The use of restraints should be used for the shortest possible time and should be focused on deterring a specific behavior that is impeding the delivery of care.

Prevention

In the general medical ward, there is some evidence that targeting modifiable risk factors and multicomponent patient-centered approaches may decrease the incidence and average duration of delirium. These include interventions improving cognitive impairment, good sleep hygiene, mobility, vision, and hearing. Besides, strategies for preventing infection, dehydration, constipation, and hypoxia are mandatory.[32] Currently, no pharmacological agents have enough evidence to recommend their use in preventing delirium. In the ICU setting, mechanically ventilated adult patients at risk of developing delirium may benefit from dexmedetomidine infusions (e.g., 0.1 μg/kg per hour) over BDZs infusions in regards to decreasing the prevalence of delirium.[33] Melatonin is probably useful for ICU delirium, but further studies are needed.[34] There is also evidence that early mobilization of the adult ICU patient population may reduce the duration and incidence of delirium.

A mnemonic ABCDEF bundle was proposed for assessing and preventing the complication.[35] 

• A=Assess, prevent and manage pain
• B=Both Spontaneous Breathing Trials and Spontaneous Awakening Trials
• C=Choice of sedation and analgesia
• D=Delirium: assess, prevent, and manage
• E=Early mobility and exercise
• F=Family engagement and empowerment

Wassenaar et al.[36] proposed the UNDERPIN-ICU (nUrsiNg DEliRium Preventive INterventions in the ICU), which consists of standardized protocols aimed at implementing several modifiable risk factors for delirium. The interventions are mainly focused on cognitive impairment, sleep deprivation, immobility, and visual and hearing impairment. Different tools for ICU delirium prevision, such as the prediction model for delirium (PRE-DELIRIC) and the early prediction model for delirium (E-PRE-DELIRIC), have been proposed. Both models showed a moderate-to-good performance.[37]

Differential Diagnosis

Delirium is a diagnosis of exclusion and requires accurate clinical testing and observation. Several conditions must be considered for the differential diagnoses.

• Neurocognitive disorders
• Psychotic disorders such as brief psychotic disorder, schizophrenia, schizophreniform disorder, among others
• Mood disorders with psychotic features, including bipolar and depressive episodes
• Acute stress disorder
• Malingering and factitious disorder

Prognosis

Patients with delirium have a more extended hospital stay, and six months' survival is lower than the patients without delirium. Delirium can lead to long-term cognitive impairment in patients who survive critical illness.

Complications

Delirium in hospitalized patients is associated with several complications such as increased hospital costs, health care complications, and increased mortality. Moreover, a recent meta-analysis showed that the complication is linked to long-term cognitive decline in both surgical and nonsurgical patients.[2] Critically ill patients that develop delirium may have numerous complications including:

• Increased of mortality
• Longer duration of MV
• Longer lengths of stay in the ICU
• Higher incidence of unintentional removal of catheters, endotracheal tubes, and urinary catheters[38]
• Higher incidence of ICU readmissions
• Increased risk of post-ICU cognitive impairment

In addition, there is a rise in the cost of care[5]

Pearls and Other Issues

• Symptoms of ICU delirium usually manifest with acute onset and transient fluctuation throughout the day and may persist for days or months after the likely causes have been addressed.
• Delirium has severe consequences for patients while they are in the hospital (increased mortality and longer length of hospitalization) and after discharge (prolonged cognitive impairment).
• Hypoactive delirium is a severe and commonly missed form of delirium.
• Prevention of ICU delirium is imperative.
• Delirium is a diagnosis of exclusion. It requires accurate clinical testing and observation.
• Soft restraints should be used judiciously and only after trying behavioral and pharmacological interventions for agitation in the setting of delirium. They should be utilized for the shortest amount of time possible and only for specific behaviors that are directly impeding the delivery of necessary care.
• When verbal and non-verbal behavioral techniques are ineffective or not appropriate, haloperidol can be considered, starting at the lowest clinically effective dose.
• QT prolongation is a serious side effect of many antipsychotic medications, and care should be taken when using them, including baseline EKG, for agitation in the setting of delirium.

Enhancing Healthcare Team Outcomes

ICU critically ill patients are exposed to multiple risk factors for delirium. Although some of them, such as age and disease severity, cannot be corrected, many of these factors can be corrected or ameliorated beforehand. For this purpose, an interprofessional approach must be implemented. These strategies require the involvement of nurses, who play a key role in assessment and evaluation over time, but also of other professional figures such as psychologists, occupational therapists, and physical therapists. The aim is to design multi-component strategies that are tailored to the patient. Finally, these paths must involve non-pharmacological interventions (eg., light cycles, presence of family members) with particular attention to often underestimated problems such as pain management and the use of sedatives in a rational way.