Prevention and Management of Delirium in the Intensive Care Unit

Abstract

Delirium is a debilitating form of brain dysfunction frequently encountered in the intensive care unit (ICU). It is associated with increased morbidity and mortality, longer lengths of stay, higher hospital costs, and cognitive impairment that persists long after hospital discharge. Predisposing factors include smoking, hypertension, cardiac disease, sepsis, and premorbid dementia. Precipitating factors include respiratory failure and shock, metabolic disturbances, prolonged mechanical ventilation, pain, immobility, and sedatives and adverse environmental conditions impairing vision, hearing, and sleep. Historically, antipsychotic medications were the mainstay of delirium treatment in the critically ill. Based on more recent literature, the current Society of Critical Care Medicine (SCCM) guidelines suggest against routine use of antipsychotics for delirium in critically ill adults. Other pharmacologic interventions (e.g., dexmedetomidine) are under investigation and their impact is not yet clear. Nonpharmacologic interventions thus remain the cornerstone of delirium management. This approach is summarized in the ABCDEF bundle (Assess, prevent, and manage pain; Both SAT and SBT; Choice of analgesia and sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; Family engagement and empowerment). The implementation of this bundle reduces the odds of developing delirium and the chances of needing mechanical ventilation, yet there are challenges to its implementation. There is an urgent need for ongoing studies to more effectively mitigate risk factors and to better understand the pathobiology underlying ICU delirium so as to identify additional potential treatments. Further refinements of therapeutic options, from drugs to rehabilitation, are current areas ripe for study to improve the short- and long-term outcomes of critically ill patients with delirium.

Delirium is a common organ dysfunction encountered in critically ill adults and a significant cause of morbidity and mortality. Delirium has been identified with critical illness as far back as the ancient Roman empire, where the nobleman and encyclopedist Aulus Cornelius Celsus described the manifestations of delirium in patients with wound infections and head trauma in his seminal work, De Medicina.¹ More than half of all patients in modern intensive care units (ICUs) will go on to develop delirium at some point during their admission.^2–5 This is of particular importance, as delirium is independently associated with an increased risk of death.^6–8 Additionally, duration of delirium is the major risk factor for cognitive impairment after critical illness, a form of ICU-acquired dementia that is particularly debilitating.^4,9–11 Lastly, the development of delirium is associated with increased hospital length of stay and health care costs.^12–15

The mechanism of delirium is unclear and most likely a result of multiple pathways that are affected during critical illness that alters normal cognition. Numerous pathological mechanisms have been proposed, ranging from genetic defects to worsening brain inflammation and poor cerebral blood flow, and to neurotransmitter imbalance.^16–19 Multiple concurrent insults are likely responsible and vary depending on individual patients’ physiologic reserve and their severity of illness. Given the complex nature of the disease, a multifaceted approach to delirium is warranted.

The management of ICU delirium has historically been challenging, as there have been very few pharmacological options that have demonstrated efficacy in treating delirium once it develops. For example, antipsychotics have consistently shown little benefit in treating the disease.^20,21 The prevailing approach to management is focused on prevention and early recognition. Prevention includes strategies to limit risk factors, such as catheter removal and promoting a healthy sleep environment. It also includes targeted approach to analgosedation, such as avoidance of benzodiazepine-based sedation and focusing on providing light sedation in addition to encouraging patient mobilization. Early recognition of delirium involves the use of well-validated instruments to screen for the disease, and when it is identified, a focused search for potential etiologies such as occult infection should be pursued. A bundle of care, incorporating these evidence-based care processes for delirium management such as goal-directed light sedation and early mobilization, has demonstrated significant improvements in multiple important ICU outcomes, including delirium, days of mechanical ventilation, and mortality.^22,23 This synergistic bundle, called the ABCDEF bundle (Assess, prevent, and manage pain; Both SAT and SBT; Choice of analgesia and sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; Family engagement and empowerment), represents the best management strategy for critically ill patients with delirium. The future of delirium management will be focused on optimizing these processes of care as well as identifying the basic, mechanistic underpinnings of the disease to help develop novel treatment strategies to improve the care of the critically ill.

Manifestations and Outcomes of ICU Delirium

Manifestations

Delirium is a form of acute brain dysfunction that manifests as fluctuating attention and impaired cognitive function. It can present with a variety of symptoms, including significant psychomotor agitation, depressed level of consciousness, or both. According to the American Psychiatric Association’s Diagnostic and Statistical Manual—5th edition (DSM-5) guidelines, delirium is an acute confusional state defined by acute disturbances in attention, awareness, or cognition developing over hours to days due to disease or sedation that is not better explained by an alternative diagnosis or a comatose state.²⁴ Notably, delirium can and often does coexist with underlying neurological disease such as dementia, traumatic brain injury, and stroke and so is not precluded from developing in these patients.^25,26

The incidence of delirium varies among individual studies but is a frequent diagnosis in all inpatient care settings. Vasilevskis and colleagues estimated that approximately one-third of patients who were hospitalized ultimately developed delirium.²⁷ Delirium is especially common in the ICU, with three-quarters of mechanically ventilated patients suffering with disease and up to half of those not receiving mechanical ventilation developing delirium.^2,3,28,29

The symptomatology of delirium varies as well, particularly with respect to its psychomotor manifestations. Delirium is classified into hyperactive, hypoactive, and mixed subtypes. Hypoactive and mixed delirium are the most common presentations seen in the ICU, accounting for over 90% of cases.³⁰ Patients with hypoactive delirium are predominantly lethargic with reduced motor activity, in contrast to patients with hyperactive delirium who are often agitated and restless. Patients with mixed delirium have symptoms of both hypoactive and hyperactive delirium that can change over the course of the disease.

Outcomes

Advances in critical care medicine have substantially improved survival rates, yet delirium remains a frequent and significant cause of morbidity and mortality with significant downstream impairments in cognitive and physical functioning (Fig. 1). Patients with delirium have increased mortality, both in the hospital and in the year following hospitalization, as compared with nondelirious patients.^31,32 The presence of delirium within 24 hours of a critical care admission is strongly associated with increased in-hospital mortality.³³ Mechanically ventilated patients who develop delirium had greater 6-month mortality and a significantly longer length of stay in the hospital as compared with their counterparts without delirium.^7,12 Higher mortality has also been linked to delirium out to 1 year from admission among older critically ill adults.^6,34,35 Notably, hypoactive delirium is associated with higher mortality as compared with hyperactive delirium or mixed delirium.^36,37

Fig. 1.

Risk factors for and outcomes after ICU delirium. Pre-existing conditions, such as frailty or comorbid diseases, contribute to critical illness, and in combination with modifiable risks, such as immobility and drug use, lead to the development of delirium and its long-term complications. ICU, intensive care unit.

In addition to higher mortality, delirious patients suffer from other physical complications. Delirium has been consistently associated with both longer ICU and hospital length of stay.^7,34 Patients with delirium also spend a longer time on mechanical ventilation and have more respiratory complications with increased difficulty weaning.^34,38,39 Delirium has also been associated with an increased likelihood of being discharged to a long-term care facility, and patients with blood stream infections were also less likely to return to their baseline functional status.^34,40 Brummel and colleagues demonstrated that critically ill patients on mechanical ventilation who develop delirium had substantial impairments in their basic activities of daily living as well as worse sensory-motor function at 3 and 12 month follow-up.⁴¹ Prolonged mechanical ventilation and disability secondary to delirium prevents patients from returning to their baseline and reduces their overall quality of life.

The neurocognitive impact of delirium extends beyond the acute illness. Older delirious adults both with and without dementia demonstrated symptoms of delirium for months following their initial episode, including symptoms of inattention and disorientation.⁴² Among the critically ill, delirious patients have greater cognitive impairment at hospital discharge than those who were not delirious, with more severe delirium associated with greater cognitive impairment.⁴³ Girard and colleagues demonstrated that delirium was independently associated with cognitive impairment in ICU survivors at 3 and 12 months after hospitalization with over 70% of ICU survivors experiencing cognitive impairment at 12 months.⁹ This finding was confirmed by Pandharipande and colleagues in the BRAIN-ICU study.⁴ Cognitive impairment was seen across all age ranges in this cohort with similar incidence to the Girard study. Of these, over one-third of patients had evidence of moderate to severe cognitive impairment at 12 months. In a related study, delirium was associated with significant cognitive impairment at 18-months post-ICU.⁴⁴ Additionally, patients who experience delirium also experience an increased risk of dementia and greater cognitive decline. In older adults over the age 85 followed for 10 years, delirium was a strong independent predictor of incident dementia.⁴⁵ And in patients with pre-existing Alzheimer’s dementia, delirium was associated with a significantly worse cognitive trajectory as compared to those without delirium, adjusting for baseline disease severity and comorbidity.⁴⁶ In addition to the clinical manifestations, neuroimaging of delirium suggests important structural brain changes, such as atrophy and volume loss as well as white matter lesions.^47,48 Just as delirium worsens cognitive function in those with baseline dementia, pre-existing neurologic disease also increases the risk of developing delirium.^49,50 The persistent cognitive dysfunction related to delirium has significant socioeconomic impact in that it is also associated with reduced employment in ICU survivors.⁵¹ The link between delirium and cognitive impairment represents an unfortunate reciprocal relationship that impacts the most vulnerable critically ill patients.

Along with cognitive impairment and increased incidence of dementia, there is increasing recognition of the psychological sequelae of delirium. Approximately three-quarters of critically ill patients who were interviewed 2 weeks after surviving their initial illness reported delusions, and those with limited factual recall of their hospitalizations had significantly increased anxiety and symptoms of posttraumatic stress disorder (PTSD).⁵² Jackson and colleagues found that 37 and 33% of ICU survivors reported depressive symptoms at 3 and 12 months after critical illness, respectively, with 7% of all survivors having symptoms consistent with PTSD.⁵³ Patel et al found that one in 10 patients following critical illness had symptoms consistent with PTSD attributable to their ICU admission, and that pre-existing psychiatric diagnoses such as anxiety, depression, or military-service-related PTSD were associated with greater likelihood of ICU-related PTSD.⁵⁴

The important downstream sequelae of delirium remain a significant challenge for the world of critical care medicine. These complications of delirium range from higher in-hospital mortality and increased time of mechanical ventilation to long-term cognitive impairment, disability, and psychiatric disease. Such problems mandate urgency in further elucidating both the underlying pathophysiology and improving the clinical management of the disease. What is clear is that focusing on the prevention of delirium in combination with aggressive management of risk factors, as well as with other evidence-based practices to prevent iatrogenesis, will be the mainstay of treatment and research going forward.

Risk Factors and Proposed Mechanisms

Delirium is triggered by an acute medical event.^55,56 Despite its frequency and detrimental outcomes, the condition is often underdiagnosed,^55,57 and its pathophysiology is still poorly understood.⁵⁵ Identification of precipitating risk factors for delirium is important to implement, where possible, preventative strategies in patients who are most at risk. Multiple factors appear to contribute to the acute syndrome, and over 100 of them have been studied for a potential link with an increased risk for developing delirium in the ICU.²⁷ These risks can be grouped into two categories: risks that can predispose the patient to delirium (modifiable and nonmodifiable) and risks related to the treatment received while in the ICU or the environment (Fig. 2).⁵⁸

Fig. 2.

Predisposing and precipitating factors for developing ICU delirium. Delirium is a result of both baseline, or predisposing, risk factors (top) and acquired, or precipitating, risk factors (bottom). These may be modifiable (left) or nonmodifiable (right). ICU, intensive care unit.

Predisposing Factors

Patient Characteristics

Characteristics of the patient that have been consistently found to increase the delirium risk include advanced age,⁵⁹ pre-existing cognitive impairment,^5,60 and history of hypertension.⁶¹ Some studies have found that cigarette smoking^2,62 and alcohol use^60,61 increase the risk of delirium incidence, although the current evidence is insufficient to determine if they are independently associated with ICU delirium.⁵⁹ Of these predisposing factors, only uncontrolled hypertension, alcohol use, and cigarette smoking are potentially modifiable.

A high number of comorbidities,⁶³ cardiac disease,⁶⁴ and frailty^65,66 also appear to increase the risk, although the evidence is still inconclusive.⁵⁹ Patients with multiple comorbidities and frailty have a lower physical and cognitive physiological reserve,⁶⁷ which impairs the capacity to sustain normal brain functioning in response to the stress of critical illness and may ultimately lead to delirium.⁶⁸

Pharmacological Treatment

There are other risks that are associated with the treatment provided in the ICU. Studies have shown that the use of benzodiazepines (especially lorazepam and midazolam) is independently associated with increased risk of delirium.^29,69–71 In addition, these studies have demonstrated a dose-dependent relationship, whereby the risk is higher with higher benzodiazepine doses. This is particularly the case when benzodiazepines are used as sedatives for mechanical ventilation.^72–74

Opiates, especially morphine, have also been linked with delirium risk,^2,29,69,75 and there seems to be a correlation between administration of opiates with benzodiazepines and increased delirium duration.⁶⁹ The link between these medications and delirium may be related to the duration of action of these agents, which increases the risk of drug accumulation in the setting of altered organ function. Furthermore, administration of epidural analgesia² and sedation with propofol⁷⁶ also show some association, although the evidence is still inconclusive.

Anticholinergic agents can also precipitate delirium,⁷⁷ and systemic corticosteroids have been shown to be significantly associated with transitioning to delirium from a nondelirious or noncomatose state.⁷⁸ The connection between delirium and psychopharmacological agents is likely due to their effect on neurotransmitters that appear to be critical to the emergence of delirium, in particular gamma-amino butyric acid (GABA), acetylcholine, dopamine, and serotonin.⁷⁹ An imbalance in the synthesis, release, and inactivation of these neurotransmitters seems to be one of the mechanisms of delirium.⁸⁰

ICU Course

Critical illness constitutes a severe systemic insult, and patients admitted to intensive care with a high severity of illness or high Acute Physiology and Chronic Health Evaluation II (APACHE II) score,^61,69 polytrauma,^75,81,82 organ failure,⁸¹ and patients admitted to the ICU after emergency surgery^64,82,83 have a higher risk of delirium than patients with a less severe systemic insult.²⁷ Coma has also been shown to be a risk factor for delirium, in particular iatrogenic coma induced pharmacologically.^60,61

Moreover, studies have shown that prolonged mechanical ventilation,^60,84 emergence from delirium,^59,85,86 requirement of blood transfusions,^81,83,87 immobility,^{60,71,88–90} metabolic acidosis,^5,75 and pain^29,61 are all independent risk factors for higher delirium risk. It has been suggested that acute systemic inflammation, aging, and ischemic injury lead to the release of proinflammatory cytokines, which can threaten the integrity of the brain–blood barrier (BBB).^91,92 The disruption of the BBB in turns activates a series of events that can lead to delirium. There is increasing evidence suggesting that hypoxia can lead to increased brain dysfunction in critically ill patients, potentially contributing to long-term cognitive impairment.^93–95 Chronic intermittent hypoxia can induce neurodegenerative changes to brain tissue that may predispose patients to delirium.^96,97

Finally, research has shown that the presence of plasma tryptophan,^86,98 a precursor of the neurotransmitter serotonin, and inflammatory biomarkers (procalcitonin and C-reactive protein)^99–101 may be linked with the development of delirium. The mechanism behind C-reactive protein and delirium appears to be associated with a disruption in the BBB due to generation of reactive oxygen species.¹⁰² Research into biomarkers is a promising development in the field of delirium, as their identification could constitute a useful diagnostic tool which would enable early diagnosis and risk stratification.

Environment

Despite its importance for recovery, the quality of sleep in the ICU is known to be generally poor.¹⁰³ Factors that play a significant role include noise, frequent disruptions, administration of medications that alter sleep architecture,¹⁰⁴ and disturbance of the light–dark cycle due to decreased exposure to natural light.⁸⁰ Poor quality of sleep has been suggested as a potential modifiable risk factor for delirium^105,106; although this association has not yet been definitively established,¹⁰⁷ sleep promotion is considered important and is part of the strategy to prevent delirium proposed by the Society of Critical Care Medicine (SCCM).

Overall, there seems to be a complex relationship between predisposing and precipitating factors leading to delirium, involving structural characteristics, several neurotransmitters, immunologic, physiologic and genetic factors, as well as iatrogenic and environmental exposures. Thus, a highly fragile patient may develop delirium despite a lesser physiological insult, and equally a patient with less comorbidities and good functional state may require a more severe insult to develop delirium. A good understanding of these interrelated factors is important to stratify patients in different risk categories, so that preventive strategies can be developed leading to a reduction in the incidence of delirium.

Historical Perspective on Management

The last few decades have seen a dramatic shift in the prevailing perspective on effective management of delirium. For context, we provide a brief description of the historical observations and practices that led to the current state of the field.

Early Perspectives and the Use of Antipsychotics

The early literature on delirium management focused primarily on alcohol-related disturbances, in particular delirium tremens. For delirium in hospitalized psychiatric patients, a combination of chloral hydrate and potassium bromide was recommended.¹⁰⁸ During the mid-20th century, various treatments were proposed for “acute delirium” in association with hospitalization, systemic illness, or postoperative states. Such treatments included paraldehyde and sodium chloride,¹⁰⁹ physostigmine (particularly for delirium related to surgery and anticholinergic administration),¹¹⁰ phenothiazine drugs,¹¹¹ and even electroconvulsive therapy.¹¹² In 1978 the use of intravenous haloperidol was reported in a series of 15 delirious patients during recovery from cardiac surgery¹¹³ and this became the mainstay of treatment for delirium in the critically ill. The next several decades saw an increasing reliance on antipsychotic medications for this purpose. In 2002 the SCCM guidelines for use of sedatives and analgesics in ICU recommended haloperidol as the preferred agent for treatment of delirium.¹¹⁴

Changing Perspectives on Antipsychotics

The appropriateness of first-generation antipsychotics as treatment for delirium was challenged in the mid-2000s by reports that these medications increased mortality in the elderly.¹¹⁵ Pursuant to this, second-generation (“atypical”) antipsychotics such as quetiapine and risperidone began to gain popularity. The rationale was that these carry less risk of adverse effects such as cardiac arrhythmias and neuroleptic malignant syndrome. A systematic review of atypical antipsychotics versus haloperidol revealed that atypical antipsychotics were at least as efficacious as haloperidol for the treatment of delirium.¹¹⁶ In the past 10 years, however, it has become evident that antipsychotics do not diminish risk of ICU delirium nor do they improve the negative outcomes associated with this state of acute brain failure. The Hope-ICU study randomized 142 mechanically ventilated patients to receive intravenous haloperidol or normal saline until delirium-free or ICU discharge, but found no difference in number of coma-free and delirium-free days, delirium duration, or survival between the two groups.²¹ The HARPOON study randomized 245 acutely hospitalized elderly patients to prophylactic haloperidol versus placebo and found no clear differences in delirium incidence, duration, severity, or 3-month mortality.¹¹⁷ The MIND-USA study compared haloperidol, ziprasidone, and placebo in a randomized, double-blind trial and found no effect of either antipsychotic medication on the number of coma-free and delirium-free days (Fig. 3). Thirty day and 90-day survivals were also similar among the three groups.²⁰ Another randomized, double-blind study of haloperidol, risperidone, and placebo for delirium in inpatient hospice and palliative care patients found an increase in delirium symptom severity among patients receiving haloperidol or risperidone compared with placebo.¹¹⁸ A recent systematic review of antipsychotics for treating delirium in hospitalized adults found no difference among haloperidol, atypical antipsychotics, and placebo in terms of delirium duration, hospital length of stay, or mortality.¹¹⁹ A second review of antipsychotics for prevention of delirium found no evidence that haloperidol lowers incidence or duration of delirium, hospital length of stay, or mortality compared with placebo. The same review did, however, suggest a possibility that atypical antipsychotics may decrease the incidence of delirium specifically in postoperative patients.¹²⁰ The current SCCM guidelines suggest against routine use of haloperidol or atypical antipsychotics for prevention or treatment of delirium in critically ill adults.¹²¹

Fig. 3.

Effects of haloperidol, ziprasidone, and placebo on ICU delirium or coma. In a randomized clinical trial of 566 ICU patients receiving haloperidol, ziprasidone, or placebo for treatment of hypoactive or hyperactive delirium, there were no significant differences among groups in days with delirium, days with coma, or days alive without delirium or coma. These analyses were adjusted for age, pre-existing cognitive impairment, Clinical Frailty Score and Charlson Comorbidity Index score at baseline, and modified Sequential Organ Failure Assessment score and Richmond Agitation–Sedation Scale score at randomization. ICU, intensive care unit. Reproduced with permission from Girard et al.²⁰

Current Knowledge of Management and Prevention

The surprising results of systematic studies of haloperidol and other antipsychotics, once thought to be the mainstay of delirium management, have led clinicians and researchers alike to consider alternative therapies to prevent and treat delirium. However, the field is far from identifying a “silver bullet.” This section describes the most promising pharmacologic and nonpharmacologic therapies, the current state of investigation, and barriers or challenges impeding widespread implementation.

Pharmacological Management and Prevention

Dexmedetomidine

Dexmedetomidine is a selective α−2 adrenoreceptor agonist that may promote sleep–wake cycle regulation in addition to providing anxiolysis and sedation.¹²² Use of dexmedetomidine for the prevention of delirium is controversial. In two double-blind, randomized controlled trials, mechanically ventilated patients sedated with dexmedetomidine had a 23% lower risk of delirium compared with those sedated with midazolam,⁷³ and more than twice as many coma-free and delirium-free days compared with those sedated with lorazepam.⁷² An open-label, randomized controlled trial comparing dexmedetomidine to usual care for first choice of sedation in mechanically ventilated patients also found a slight increase in the number of coma-free and delirium-free days in the dexmedetomidine group. There was, however, no difference in 90-day mortality between the groups.¹²³ This study was limited by the fact that a large percentage of the dexmedetomidine group ultimately received other drugs such as propofol and fentanyl. There is a randomized controlled trial in progress that compares dexmedetomidine versus propofol in mechanically ventilated patients with sepsis.¹²⁴ Another randomized controlled trial will compare the incidence of delirium in elderly cardiac surgery patients with or without a single postoperative sleep-inducing dose of dexmedetomidine.¹²⁵ The results of these studies are eagerly awaited and will inform future potential uses of dexmedetomidine in the prevention of delirium.

Regarding pharmacologic treatmentonce delirium develops, a recent Cochrane analysis found evidence that dexmedetomidine may shorten duration of delirium, mechanical ventilation, and ICU stay. That study found no evidence of difference in coma-free or delirium-free days, long-term cognitive impairment, or mortality.¹²⁶

Statins

As described previously, one of the postulated mechanisms of delirium pathogenesis involves inflammation within the central nervous system causing breakdown of the BBB. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have been observed to exert an anti-inflammatory effect in humans and animals, and thus a protective effect of statins in ICU delirium has been postulated.¹²⁷ In support of this hypothesis, preoperative statins are associated with decreased risk of postoperative delirium in elderly patients undergoing cardiac surgery.¹²⁸ Observational studies suggest a protective effect of statins with respect to delirium development during critical illness¹²⁹ and that this effect may be mediated in part by the effect of statins on systemic inflammation as measured by the C-reactive protein levels.¹³⁰ However, an ancillary study of a prospective randomized controlled trial comparing rosuvastatin and placebo in acute respiratory distress syndrome found no effect on the incidence of delirium or on long-term cognitive impairment overall. Patients in the rosuvastatin group had slightly worse delayed memory scores at 6-month follow-up (mean difference in scores: −1.2; 95% confidence interval [CI]: −2.2 to −0.2, p = 0.017).¹³¹

Ketamine

Ketamine is an intravenous N-methyl-D-aspartate (NMDA) receptor antagonist with anesthetic, analgesic, antidepressant, and anti-inflammatory properties. Intraoperative administration of ketamine significantly decreases postoperative inter-leukin-6 concentrations¹³² as well as postoperative opiate requirements.¹³³ Hudetz et al found that ketamine administration during induction was also associated with an improvement in post-cardiac surgery cognitive dysfunction. The C-reactive protein concentration was also significantly lower in the ketamine group (median: 7.9 vs. 11.6 mg/dL, p < 0.01).¹³⁴ These findings suggest that ketamine may hold promise as a prophylactic or therapeutic drug for postoperative or critical illness delirium. Nevertheless, a randomized controlled trial comparing a single intraoperative subanesthetic dose of ketamine to placebo did not find a difference in incidence of postoperative delirium. The ketamine groups did, on the other hand, suffer an increased rate of hallucinations and nightmares.¹³⁵ Although this study used similar doses of ketamine to the Hudetz study, the studies differed with respect to timing and premedication protocols.

Thus far no pharmacologic agent has demonstrated efficacy in treating or preventing delirium. The current SCCM guidelines suggest against routine use of dexmedetomidine, statins, or ketamine for prevention of delirium in critically ill adults.¹²¹ One or more of these agents may turn out to be useful for delirium management, but given the heterogeneous nature of the disorder, optimal treatment will likely depend on the prevailing risk factors, the neurologic and systemic comorbidities, and the metabolic and physiologic profile of each patient.

Nonpharmacologic Interventions

For decades, nonpharmacologic interventions have been the cornerstone of delirium management and treatment.¹⁰⁹ Interventions such as promoting regular sleep–wake cycles, avoiding unnecessary invasive sensory stimulation, and regular reorientation have been refined over the decades and have become standard of care in ICUs worldwide. These interventions have largely been conceptualized in the continually evolving ABCDEF bundle.^136,137 Improvements in compliance with the ABCDEF bundle are associated with a reduction in mortality as well as a reduction in number of coma-free and delirium-free ICU days (Fig. 4).^22,23 The principal components of this approach can be summarized in the ABCDEF bundle, described in the sections below.

Fig. 4.

Association between proportional performance of the ABCDEF bundle and patient outcomes. Adjusted hazard ratio and 95% confidence interval for ICU discharge, hospital discharge, and death, comparing patients with a given proportion of eligible ABCDEF bundle elements performed on a given day with patients with none of the bundle elements performed that day. Hazard ratios are adjusted for baseline, ICU admission characteristics, and daily covariates, measured the same day as bundle performance. ICU, intensive care unit. Reproduced with permission from Pun et al.²²

Assess, Prevent, and Manage Pain

Critically ill patients experience pain at rest and with routine procedures. Inadequately treated pain can result in delirium as well as several other complications. Pain should be monitored routinely in all adult ICU patients. This can be done by self-report in awake, communicative patients, or using validated behavioral pain scales such as the Behavioral Pain Scale or the Critical Care Pain Observation Tool¹³⁸ in those who are unable to communicate pain.

Both SAT and SBT

Spontaneous awakening trials (SATs) are pauses of intravenous narcotics and sedatives. When appropriate, these medications are restarted at half the prior dose. Spontaneous breathing trials (SBTs) are periods of minimal ventilator support. A randomized, controlled trial comparing daily SBTs to standard of care in mechanically ventilated patients revealed that those receiving SBTs had shorter time on the ventilator (4.5 vs. 6 days, p = 0.003). The intervention arm also had less ventilator-related complications and lower costs of ICU care.¹³⁹ A randomized controlled trial comparing a daily SAT and SBT protocol with daily SBT plus routine sedation found that patients on the SAT plus SBT protocol spent more days breathing without assistance and less time in the ICU. Patients in the SAT arm were also less likely to die during the 12-month follow-up period. Reintubation rates were similar in the two groups.²⁸ The daily coordination of SATs and SBTs is a key part of the timely cessation of mechanical ventilation and leads to improved ICU outcomes.

Choice of Analgesia and Sedation

Effective management of pain, anxiety, and delirium is a primary objective in the ICU. This management needs to be based on agreed-upon, patient-oriented goals and standardized assessment measures. There are several validated scales published for assessment of sedation level in the ICU, for example the Richmond Agitation–Sedation Scale (RASS) or the Riker Sedation–Agitation Scale.

The most effective medication and titration protocol for sedation and analgesia is not yet clear, and likely depends on the clinical context and patient characteristics. The MENDS randomized controlled trial compared lorazepam and dexmedetomidine for sustained sedation in mechanically ventilated patients and found that the dexmedetomidine groups experienced more days alive without delirium or coma (median: 7.0 vs. 3.0 days, p = 0.01). Costs of care were similar between the two groups.⁷² The MENDS2 study will compare dexmedetomidine and propofol in septic patients on mechanical ventilation. Results from that study are pending as of the writing of this review.

Delirium: Assess, Prevent, and Manage

A key component of delirium management is monitoring for early identification and risk factor modification. The most widely used tool for delirium assessment in the ICU is the Confusion Assessment Method for the ICU (CAM-ICU).³ The CAM-ICU comprises four features: acute onset of mental status change or fluctuating curse; inattention; disorganized thinking; and altered level of consciousness. Its pooled values as a diagnostic test are 80% sensitivity and 95.9% specificity.¹⁴⁰ Other tools include the Intensive Care Delirium Screening Checklist (ICDSC).¹⁴¹ The ICDSC comprises eight items, including assessment of altered level of consciousness, inattention, hallucination/delusions/psychosis, psychomotor agitation or retardation, inappropriate speech or mood, sleep wake/cycle disturbance, and symptom fluctuation. Its pooled sensitivity and specificity are 74 and 81.9%, respectively.¹⁴⁰ It is important to assess patients regularly to reduce the risk of overlooking hypoactive delirium, and the optimal time for this assessment is during SATs.¹⁴²

Once delirium is identified, management entails revisiting primary prevention measures, including reorientation, an appropriate sleep environment, and adequate pain management. Many of these nonpharmacological interventions are outlined in Table 1. Since the duration of delirium predicts worse long-term outcomes,⁴ implementation of these nonpharmacologic measures can be expected to improve patient care.

Table 1.

Primary delirium prevention principles

Primary delirium prevention principles
Repeated reorientation Provisions of cognitively stimulating activities multiple times a day A sleep protocol Early mobilization Timely removal of catheters and physical restraints Use of eye glasses, magnifying lenses, hearing aids, and earwax disimpaction Correction of dehydration Use of a scheduled pain management protocol Minimization of unnecessary noise and tactile stimuli

Early Mobility and Exercise

Early mobility consists of a range of activities from passive range of motion to ambulation with assistance. It is safe and feasible in critically ill patients, and decreases days of delirium, duration of mechanical ventilation, ICU length of stay, and overall hospital length of stay. Any member of the care team can perform early mobility; the appropriate level of activity is determined based on the patient’s level of sedation. Early mobilization during SATs was associated with improved odds of return to independent functional status by discharge (odds ratio: 2.7; 95% CI: 1.2–6.1) in a series of critically ill adults on mechanical ventilation.¹⁴³ Early combined cognitive and physical therapy has been shown to be feasible in a similar population, and outcomes are currently under study.¹⁴⁴

Family Engagement and Empowerment

Empowering family members to be equal participants in patient care can improve ICU team performance and communication, reveal key insights into the patient condition, and keep providers focused on the most salient goals of care for each patient. This intervention may also lead to early identification of and reduction in the burden of ICU-related psychological and emotional stress among family members. Key elements of strategic communication with families include using simplified speech, being concrete, and avoiding rapid communication. A recent systematic review and meta-analysis of protocolized family support interventions found that such interventions reduce ICU length of stay without impacting mortality.¹³⁷ Additionally, specific programs have been developed to reproduce familiar environments for high-risk patients or to augment the presence of family members in person or online to decrease the cognitive deficit of critically ill patients at ICU discharge.¹⁴⁵ The importance of family involvement in cognitive rehabilitation has been recognized in other types of brain injury¹⁴⁶ and may provide a promising avenue for reducing the burden of brain injury due to delirium in ICU patients.^144,147 Other methods for creating comforting environments include music-based therapies, which can improve physiologic measures associated with delirium¹⁴⁸ and have been recognized as potentially beneficial during critical illness and at the end of life.¹⁴⁹ Such interventions are the subject of ongoing study.¹⁵⁰

Implementation Challenges and Difficulties

Delirium is often underrecognized^57,151; therefore the use of validated tools for its identification is essential to improve patients’ outcomes.^151,152 As previously mentioned, the Pain, Agitation/Sedation, Delirium Immobility, and Sleep Disruption (PADIS) guidelines by the SCCM recommend the use of either the CAM-ICU or the ICDSC to assess delirium in critically ill adult patients.¹²¹ Despite the excellent reliability of these tools, systematic screening for delirium is lacking in many ICUs^{151,153–155} due to several barriers.

Nurses often reported that delirium was difficult to evaluate in intubated patients,^{154,156–158} whereas others felt that sedated patients could not be assessed.^154,157 However, the CAM-ICU was specifically designed to assess nonverbal ICU patients receiving mechanical ventilation, and the current CAM-ICU training manual¹⁵⁹ indicates that the only condition to be tested with the CAM-ICU is responsiveness to verbal stimulation irrespective of sedative use (RASS ≤ 3).

Other studies^156,160 have noted that some clinicians believe that delirium can be identified without an assessment tool. This is contrary to the evidence found by Spronk et al,⁵⁷ which suggests that delirium was very often missed without a validated screening tool such as the CAM-ICU: nurses only recognized 35% of delirious days, while attending intensivists performed even worse (only 28% of days with delirium were recognized). In another study by van Eijk et al,¹⁶¹ almost three out of four patients of all ICU delirium were missed by doctors not using a validated assessment tool. Missed diagnosis may lead to lack of treatment, whereas false positives due to lack of objectivity may expose patients to unnecessary pharmacological therapy despite its unproven efficacy⁵⁶ and safety risks.^162,163

In some units delirium screening is perceived as too complex¹⁵⁴ or too time consuming^156,164 although assessment with the CAM-ICU or the ICDSC takes 2 to 5 minutes to complete.^158,165 Some clinicians feel that CAM-ICU is unreliable,^164,166 or unnecessary, often choosing to use clinical observation instead of validated tools to monitor agitation or to assess the ability to follow commands.¹⁵⁴ This is especially the case in the neurocritical care setting, where there is a perception that the CAM-ICU and ICDSC are unsuitable. This in contrast to the findings by Mitasova et al,¹⁶⁷ who have shown that the CAM-ICU has a sensitivity of 76% and a specificity of 98% in patients who have suffered a stroke. Moreover, Frenette et al¹⁶⁸ found that both the CAM-ICU and the ICDSC had good sensitivity and specificity in evaluating delirium in patients who had suffered a traumatic brain injury.^167,168 Despite these findings, the assessment of neurocritically ill patients is challenging especially in those with extreme depression, severe catatonia, and receptive aphasia. Therefore, more research is needed to find suitable tools to diagnose and prevent delirium in this population.

Other elements that have been reported as barriers for delirium assessment include lack of knowledge about delirium or training to use the assessment,^156,160,164 perception that it cannot be prevented or that assessment is futile as there is no treatment for it^{157,158,164,166}; lack of confidence performing the CAM-ICU¹⁵⁸; belief that the test is embarrassing for the patient¹⁶⁶; and low familiarity with the guidelines, lack of motivation to follow them, and perception that following guidelines regarding delirium screening would not impact positively on patient’s care.¹⁶⁴

More broadly, the implementation of the ABCDEF bundle as a whole has been shown to substantially improve outcomes, including reducing the odds of developing delirium and reducing the chances of needing mechanical ventilation.^23,136 Barriers for implementing the ABCDEF as a bundle are similar to the ones encountered when using a delirium assessment tool. Some are related to the patient, including safety concerns in terms of hemodynamical instability or lack of cooperation.¹⁶⁹ The majority are related to the clinician implementing the bundle, in particular lack of knowledge about its benefits, reluctance to follow guidelines, preference for autonomy, perceived increased workload,¹⁷⁰ and lack of confidence in the bundle’s efficacy.^169–171 Finally, there are barriers related to the structure of the ICU, including culture and organization, teamwork, physical environment, lack of resources, and inadequate management/leadership.^169,171,172

Practical Considerations for the Treatment of Delirium

At the individual level, for the clinician at the bedside, the management of delirium can be difficult. The physician must understand delirium as a form of acute organ failure, in this instance, a form of acute brain failure. One must be familiar with and look for the various manifestations of delirium, from hypoactive to hyperactive disease. Additionally, similar to other organ failures, a search for the cause is warranted. Whether in the ICU or on the medical/surgical wards, acute deliriogenic insults due to disease or treatment should be evaluated when evaluating a patient. There are several mnemonics that have been developed to remind the clinician of potential etiologies. One commonly used mnemonic is “Dr. DRE,” where “DRE” refers to categories of causes of delirium including diseases, drugs that need to be removed, and environmental risk factors (Table 2). This particular tool is useful for any patient that is hospitalized, not just the critically ill patient in the ICU. One should look for diseases, such as sepsis or heart failure, as potential etiologies, as well as sequelae of acute and chronic diseases, such as metabolic abnormalities. The clinician should also look for potentially harmful drugs, such as benzodiazepines or antihistamines, that could be contributing. In addition to evaluating for new or worsening disease processes and removing offending drugs, evaluation of the patient’s environment is paramount to addressing delirium. For example, is the patient restrained or immobile in bed with limited day time stimulus that orients the patient to place and time? Simple interventions, such as providing the patient’s eyeglasses and hearing aids and encouraging mobility during the day, are effective at reducing delirium and represent good clinical care. The clinician could also assess and make changes to night time vital checks or other bedside interventions in an effort to promote restful and restorative sleep.

Table 2.

“Dr. DRE” mnemonic for clinicians to address delirium at the bedside

Mnemonic	Clinical causes and interventions
Diseases	Evaluate the patient for new or worsening disease, such as congestive heart failure or sepsis, as well as other disease findings such as metabolic abnormalities
Drug Removal	Look for and stop deliriogenic medications including benzodiazepines, antihistamines, and inappropriate opioids
Environment	Encourage daytime mobilization and remove restraints, provide frequent reorientation as well as cues such as clocks and windows to the outside, reduce night-time interventions to promote restful sleep

Implementing the above assessments and interventions is the front-line of bedside management of delirium. While the majority of the scientific literature does not demonstrate any benefit to the use of medications such as antipsychotics to treat or reduce the duration of delirium, there may be uncommon indications for their use. For example, for the patient with significant hyperactive delirium who is a danger to themselves due to removing medical devices or for falls at the bedside, discrete, limited use of antipsychotics may be indicated to prevent harm. The clinician should understand that such use is not to treat or improve delirium but is instead to reduce agitation that may result in harm. If such an intervention is needed, one should also continue to look for reversible etiologies and nonpharmacological interventions to manage and reduce delirium. Using this judicious approach, in addition to systemic implementation of evidence-based bundles such as the ABCDEF bundle, will provide the best care for patients.

Conclusion and Future Directions

Delirium is a devastating condition in critically ill patients with wide-ranging impacts, from cognitive impairment to psychological distress to short-term, and perhaps long-term, mortality. It is common, with studies indicating that the majority of patients receiving routine critical care interventions such as mechanical ventilation develop the disease at some point in their hospitalization. The downstream consequences of delirium go beyond the ICU to impact patients for months to years after critical illness.

These facts have increased the urgency to better understand the disease and its pathobiology as well as identify potential treatments and mitigate risk factors. There has been substantial interest in pharmacological treatments for delirium, with widespread use of antipsychotics. It has been estimated that 1 in 10 critically ill patients are given antipsychotics in the setting of delirium,¹⁷³ with up to 30% of all adult, nonpsychiatric admissions to the hospital receiving antipsychotics.¹⁷⁴ Yet multiple, prospective studies of antipsychotics have shown that they are ineffective, and they are no longer recommended in care guidelines.^20,21,121 The most effective treatment, and the standard of care for critically ill patients, is the ABCDEF bundle. It has demonstrated a significant reduction in delirium in a dose-responsive manner, in addition to improving other important outcomes such as days of mechanical ventilation and readmission rates.^22,23 The future picture of the critically ill patient is no longer one of a deeply sedated, immobile patient on mechanical ventilation, but instead one of a patient up and out of bed, walking, interacting with family and the care team, even with invasive interventions such as mechanical ventilation or continuous renal replacement therapy. Going forward, all ICU patients should be managed utilizing the guidelines and framework as outlined in the ABCDEF bundle to reduce delirium, limit iatrogenesis, and optimize patient-centered outcomes.

There remain numerous areas of investigation to tackle the scourge of delirium in the most critically ill patients. Ongoing mechanistic studies are needed to further understand the complex and inter-related pathways that are at work in the development of delirium. Such studies will provide other potential targets for therapeutic interventions and also help elucidate other risk factors that could be mitigated in the critical care environment. For example, future medications that can selectively modify the neuroinflammation and neurotransmitter disturbances may be developed from ongoing basic science studies of delirium, and care practices that impact delirium such as optimizing the sleep environment and limiting noxious stimuli will be increasingly understood at the molecular level. There also remain questions regarding our optimal practices in the ICU to prevent or reduce delirium—what is the best sedation choice for patients requiring mechanical ventilation? How, and to what extent, should we mobilize and exercise our critically ill patients? The data surrounding the ABCDEF bundle are convincing and represent a significant advance in delirium care and for ICU care as a whole. Further investigation into the best practices to implement the bundle widely, in both large and small ICUs, will be needed to optimize care universally. Following critical illness, questions regarding care abound—for example, how can primary care physicians and post-ICU recovery clinics work together to reduce the untoward sequelae of critical illness? Each of these ongoing areas of investigation is important and necessary to address in the future to improve patient care and outcomes.

As the care of the critically ill patient improves, so does our understanding of delirium and its consequences. As knowledge advances, the importance of unraveling both the pathways of disease and improving its prevention and treatment increases exponentially. While no single agent has been identified yet that prevents and/or treats delirium, significant advances have been made. Increasingly, the standard of care in the ICU for managing delirium centers upon integrated, symbiotic care processes such as those outlined in the ABCDEF bundle, which both prevents delirium and limits its duration. Further refinements of therapeutic options, from drugs to rehabilitation, are needed and are current areas ripe for study to improve the lives of critically ill, delirious patients.