Delirium, also termed as 'acute confusional state', 'toxic or metabolic encephalopathy', '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. The term 'ICU psychosis' is an unfortunate and outdated misnomer for delirium.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. 
Because delirium represents the most common clinical manifestation of acute brain dysfunction in ICU, affecting up to 83% of ICU patients on mechanical ventilation (MV), new-onset confusion in the adult patient always warrants further evaluation. 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 do not occur in the setting of a reduced level of arousal (e.g., coma). Thus, although an identifiable cause of the 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 has 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:
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. It is characterized by agitation, restlessness, emotional lability, and positive psychotic features such as hallucinations, 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. Mixed delirium is the most frequent type, accounting for about half of the total cases. 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.
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:
Risk Factors for Delirium
The literature has identified multiple risk factors. Among these, the most studied are mentioned:
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:
The prevalence of delirium in the community ranges from 1 to 2% but increases to up to 10-30% in elderly patients presenting to the emergency department. On 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. Post-operative rates range from approximately 15 to 53% of older adults.
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, and 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. Other neurotransmitters like glutamate, gamma-aminobutyric acid, serotonin, and endorphins also play a role.
Inflammatory markers produced during a critical illness like cytokines, chemokines, tumor necrosis factor-alpha initiate a sequence of events leading to microvascular compromise, thrombin formation, and endothelial damage. Inflammation can cause brain dysfunction by decreasing cerebral blood flow due to the formation of microaggregates of fibrin, platelets, neutrophils, red blood cells in the cerebral microvasculature.
Another hypothesis is the reduction of cerebral oxidative metabolism leading to alteration of neurotransmission. Failure of cerebral oxidative metabolism is found to be important in the pathogenesis of multiple organ dysfunction in critical illness.
Neurotransmitters level 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.
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.
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 evaluation of delirium, as patients can be alert and oriented to all of these but still meet 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 the delirium.
Thorough patient history may reveal other clues, including a history of substance or alcohol abuse that may suggest intoxication, withdrawal, or relevant vitamin deficiency.
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:
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. They allow the assessment of attention, orientation, 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, has been updated by Marcantonio et al. 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 firstly 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 no 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.
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:
Interventions for symptomatic ICU treatment can be divided into pharmacological and non-pharmacological strategies.
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.
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. 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. Melatonin is probably useful for ICU delirium, but further studies are needed. 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.
Wassenaar et al. 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 have moderate-to-good performance.
Delirium is a diagnosis of exclusion and requires accurate clinical testing and observation. Several conditions must be considered for the differential diagnoses.
Patients with delirium have a more extended hospital stay, and six months' survival is lower than do the patients without delirium. Delirium can lead to long term cognitive impairment in patients who survive critical illness.
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. Critically ill patients that develop delirium may have numerous complications including:
In addition, there is a rise in the cost of care
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, multidisciplinary approaches 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, physical therapists. The aim is to design multi-component strategies that are tailored to the patient. Finally, these paths must involve non-pharmacological interventions (e.g., 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.
|||McIsaac DI,MacDonald DB,Aucoin SD, Frailty for Perioperative Clinicians: A Narrative Review. Anesthesia and analgesia. 2020 Jun; [PubMed PMID: 32384334]|
|||Goldberg TE,Chen C,Wang Y,Jung E,Swanson A,Ing C,Garcia PS,Whittington RA,Moitra V, Association of Delirium With Long-term Cognitive Decline: A Meta-analysis. JAMA neurology. 2020 Jul 13; [PubMed PMID: 32658246]|
|||Kotfis K,Marra A,Ely EW, ICU delirium - a diagnostic and therapeutic challenge in the intensive care unit. Anaesthesiology intensive therapy. 2018 [PubMed PMID: 29882581]|
|||Ely EW,Inouye SK,Bernard GR,Gordon S,Francis J,May L,Truman B,Speroff T,Gautam S,Margolin R,Hart RP,Dittus R, Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001 Dec 5; [PubMed PMID: 11730446]|
|||Cascella M,Fiore M,Leone S,Carbone D,Di Napoli R, Current controversies and future perspectives on treatment of intensive care unit delirium in adults. World journal of critical care medicine. 2019 Jun 12; [PubMed PMID: 31240172]|
|||Collet MO,Caballero J,Sonneville R,Bozza FA,Nydahl P,Schandl A,Wøien H,Citerio G,van den Boogaard M,Hästbacka J,Haenggi M,Colpaert K,Rose L,Barbateskovic M,Lange T,Jensen A,Krog MB,Egerod I,Nibro HL,Wetterslev J,Perner A, Prevalence and risk factors related to haloperidol use for delirium in adult intensive care patients: the multinational AID-ICU inception cohort study. Intensive care medicine. 2018 Jul; [PubMed PMID: 29767323]|
|||Robinson TN,Raeburn CD,Tran ZV,Brenner LA,Moss M, Motor subtypes of postoperative delirium in older adults. Archives of surgery (Chicago, Ill. : 1960). 2011 Mar [PubMed PMID: 21422360]|
|||Webber C,Watt CL,Bush SH,Lawlor PG,Talarico R,Tanuseputro P, The occurrence and timing of delirium in acute care hospitalizations in the last year of life: A population-based retrospective cohort study. Palliative medicine. 2020 Sep; [PubMed PMID: 32515283]|
|||Li X,Zhang L,Gong F,Ai Y, Incidence and Risk Factors for Delirium in Older Patients Following Intensive Care Unit Admission: A Prospective Observational Study. The journal of nursing research : JNR. 2020 Aug; [PubMed PMID: 32692119]|
|||Von Rueden KT,Wallizer B,Thurman P,McQuillan K,Andrews T,Merenda J,Son H, Delirium in Trauma Patients: Prevalence and Predictors. Critical care nurse. 2017 Feb [PubMed PMID: 28148613]|
|||Schreiber MP,Colantuoni E,Bienvenu OJ,Neufeld KJ,Chen KF,Shanholtz C,Mendez-Tellez PA,Needham DM, Corticosteroids and transition to delirium in patients with acute lung injury. Critical care medicine. 2014 Jun [PubMed PMID: 24589640]|
|||Jones SF,Pisani MA, ICU delirium: an update. Current opinion in critical care. 2012 Apr; [PubMed PMID: 22322260]|
|||Van Rompaey B,Elseviers MM,Schuurmans MJ,Shortridge-Baggett LM,Truijen S,Bossaert L, Risk factors for delirium in intensive care patients: a prospective cohort study. Critical care (London, England). 2009 [PubMed PMID: 19457226]|
|||Vondeling AM,Knol W,Egberts TCG,Slooter AJC, Anticholinergic drug exposure at intensive care unit admission affects the occurrence of delirium. A prospective cohort study. European journal of internal medicine. 2020 May 30; [PubMed PMID: 32487370]|
|||Trzepacz PT, Delirium. Advances in diagnosis, pathophysiology, and treatment. The Psychiatric clinics of North America. 1996 Sep [PubMed PMID: 8856810]|
|||Flacker JM,Cummings V,Mach JR Jr,Bettin K,Kiely DK,Wei J, The association of serum anticholinergic activity with delirium in elderly medical patients. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 1998 Winter [PubMed PMID: 9469212]|
|||Wheeler AP,Bernard GR, Treating patients with severe sepsis. The New England journal of medicine. 1999 Jan 21 [PubMed PMID: 9895401]|
|||Fink MP,Evans TW, Mechanisms of organ dysfunction in critical illness: report from a Round Table Conference held in Brussels. Intensive care medicine. 2002 Mar [PubMed PMID: 11904670]|
|||van der Mast RC, Pathophysiology of delirium. Journal of geriatric psychiatry and neurology. 1998 Fall [PubMed PMID: 9894732]|
|||Cascella M,Muzio MR,Bimonte S,Cuomo A,Jakobsson JG, Postoperative delirium and postoperative cognitive dysfunction: updates in pathophysiology, potential translational approaches to clinical practice and further research perspectives. Minerva anestesiologica. 2018 Feb; [PubMed PMID: 28984099]|
|||Davidson JE,Winkelman C,Gélinas C,Dermenchyan A, Pain, agitation, and delirium guidelines: nurses' involvement in development and implementation. Critical care nurse. 2015 Jun; [PubMed PMID: 26033098]|
|||Pal S,Sharma N,Singh SM,Bhutungru S,Pannu AK, A prospective cohort study on predictors of mortality of delirium in an emergency observational unit. QJM : monthly journal of the Association of Physicians. 2020 Jun 1; [PubMed PMID: 32483589]|
|||Marcantonio ER,Ngo LH,O'Connor M,Jones RN,Crane PK,Metzger ED,Inouye SK, 3D-CAM: derivation and validation of a 3-minute diagnostic interview for CAM-defined delirium: a cross-sectional diagnostic test study. Annals of internal medicine. 2014 Oct 21; [PubMed PMID: 25329203]|
|||Meyer-Massetti C,Cheng CM,Sharpe BA,Meier CR,Guglielmo BJ, The FDA extended warning for intravenous haloperidol and torsades de pointes: how should institutions respond? Journal of hospital medicine. 2010 Apr; [PubMed PMID: 20394022]|
|||Lee J,Muzio MR, Neuroanatomy, Extrapyramidal System 2020 Jan; [PubMed PMID: 32119429]|
|||Pezza M,Busiello L,Palmese S,Cascella M,Di Domenico MG,De Robertis E, [Rhabdomyolysis associated with respiratory infection in chronic psychiatric patients during neuroleptic treatment]. Minerva anestesiologica. 2003 Jun; [PubMed PMID: 14564256]|
|||Devlin JW,Skrobik Y,Gélinas C,Needham DM,Slooter AJC,Pandharipande PP,Watson PL,Weinhouse GL,Nunnally ME,Rochwerg B,Balas MC,van den Boogaard M,Bosma KJ,Brummel NE,Chanques G,Denehy L,Drouot X,Fraser GL,Harris JE,Joffe AM,Kho ME,Kress JP,Lanphere JA,McKinley S,Neufeld KJ,Pisani MA,Payen JF,Pun BT,Puntillo KA,Riker RR,Robinson BRH,Shehabi Y,Szumita PM,Winkelman C,Centofanti JE,Price C,Nikayin S,Misak CJ,Flood PD,Kiedrowski K,Alhazzani W, Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Critical care medicine. 2018 Sep; [PubMed PMID: 30113379]|
|||Pozzi C,Tatzer VC,Álvarez EA,Lanzoni A,Graff MJL, The applicability and feasibility of occupational therapy in delirium care. European geriatric medicine. 2020 Apr; [PubMed PMID: 32297202]|
|||Wassenaar A,Rood P,Boelen D,Schoonhoven L,Pickkers P,van den Boogaard M, Feasibility of Cognitive Training in Critically Ill Patients: A Pilot Study. American journal of critical care : an official publication, American Association of Critical-Care Nurses. 2018 Mar; [PubMed PMID: 29496769]|
|||McKenzie J,Joy A, Family intervention improves outcomes for patients with delirium: Systematic review and meta-analysis. Australasian journal on ageing. 2020 Mar; [PubMed PMID: 31250961]|
|||Morris PE,Goad A,Thompson C,Taylor K,Harry B,Passmore L,Ross A,Anderson L,Baker S,Sanchez M,Penley L,Howard A,Dixon L,Leach S,Small R,Hite RD,Haponik E, Early intensive care unit mobility therapy in the treatment of acute respiratory failure. Critical care medicine. 2008 Aug; [PubMed PMID: 18596631]|
|||Gavin P, Preventing Hospital-Induced Delirium in the ICU. The American journal of nursing. 2019 Sep; [PubMed PMID: 31449103]|
|||Herling SF,Greve IE,Vasilevskis EE,Egerod I,Bekker Mortensen C,Møller AM,Svenningsen H,Thomsen T, Interventions for preventing intensive care unit delirium in adults. The Cochrane database of systematic reviews. 2018 Nov 23; [PubMed PMID: 30484283]|
|||Joseph SG, Melatonin supplementation for the prevention of hospital-associated delirium. The mental health clinician. 2017 Jul; [PubMed PMID: 29955513]|
|||DeMellow JM,Kim TY,Romano PS,Drake C,Balas MC, Factors associated with ABCDE bundle adherence in critically ill adults requiring mechanical ventilation: An observational design. Intensive [PubMed PMID: 32414557]|
|||Wassenaar A,Rood P,Schoonhoven L,Teerenstra S,Zegers M,Pickkers P,van den Boogaard M, The impact of nUrsiNg DEliRium Preventive INnterventions in the Intensive Care Unit (UNDERPIN-ICU): A study protocol for a multi-centre, stepped wedge randomized controlled trial. International journal of nursing studies. 2017 Mar; [PubMed PMID: 28013104]|
|||Wassenaar A,Schoonhoven L,Devlin JW,van Haren FMP,Slooter AJC,Jorens PG,van der Jagt M,Simons KS,Egerod I,Burry LD,Beishuizen A,Matos J,Donders ART,Pickkers P,van den Boogaard M, Delirium prediction in the intensive care unit: comparison of two delirium prediction models. Critical care (London, England). 2018 May 5; [PubMed PMID: 29728150]|
|||Tilouche N,Hassen MF,Ali HBS,Jaoued O,Gharbi R,El Atrous SS, Delirium in the Intensive Care Unit: Incidence, Risk Factors, and Impact on Outcome. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine. 2018 Mar; [PubMed PMID: 29657370]|