Delirium is an acute, fluctuating, multifactorial syndrome characterised by inattention, disorganised thinking, and an altered level of consciousness. It may be accompanied by short-term memory dysfunction, attention deficit disorder, and disorientation.1,2 According to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (DSM-IV),3 the criteria for diagnosing delirium are as follows:

• A

  Disturbance of consciousness (i.e., reduced clarity of awareness of the surroundings) with reduced ability to focus, sustain, or shift attention.

• B

  A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a pre-existing, established, or evolving dementia.

• C

  The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate over the course of the day.

• D

  There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition.

The fifth edition of the DSM (DSM-V) published in 20137 includes the criterion of disturbance in attention, and states that delirium is not a results of a pre-existing, established or evolving neurocognitive disorder and does not occur in the context of a severely reduced level of arousal such as coma. Delirium can be considered an acute brain failure and, like heart failure, is the common end result of multiple mechanisms.4 The cause is multifactorial, and includes serious pathologies, intoxication or withdrawal. The syndrome includes sepsis-induced encephalopathy, alcohol withdrawal syndrome, and hepatic encephalopathy.5

The cause of delirium is multifactorial. The prevailing hypotheses on the pathogenesis of delirium focus on the role of neurotransmitters, inflammation, and chronic stress, which converge in a cholinergic deficit coupled with elevated dopamine.6,7 The development of delirium is also influenced by predisposing and precipitating risk factors (Fig. 1). Predisposing factors include advanced age, previous cognitive impairment, and alcoholism. These factors are entirely patient-related and are rarely modifiable. Precipitating factors are potentially modifiable, and include treatment with benzodiazepines, prolonged stay and intubation in the ICU, immobilization, invasive monitoring catheters, noise and light levels that disrupt sleep patterns, etc. Early identification of modifiable factors can mitigate their impact on patient outcomes and prevent and reduce the incidence of delirium.8

Figure 1.

Risk factors for delirium.

The prevalence of delirium at hospital admission ranges from 14% to 24%, and can occur during hospitalization in as many as 56% of patients.9,10 The incidence of delirium in patients over 65 years of age who are admitted for surgery is between 15% and 25%. Postoperative delirium (POD) usually occurs within the first 3 postoperative days,11 and incidence varies depending on the type of surgery performed. Recent meta-analyses have shown that the incidence of delirium among patients undergoing gastrointestinal surgery ranges from 15% to 35%,12 and from 5.8% to 45.8% in patients undergoing heart surgery13,14 The incidence of delirium in patients admitted to a critical care unit generally ranges from 11% to 87%.15

Delirium can be classified as hyperactive (agitation and motor activity predominate), hypoactive, or mixed, depending on the patient’s level of consciousness and psychomotor activity.16–19 Hypoactive delirium is characterized by attention deficit, altered thinking, and decreased level of consciousness without agitation. This type of delirium can be overlooked, and therefore has a worse prognosis.20,21 In ICUs, hyperactive delirium accounts for less than 2% of cases, hypoactive for 35%, and the most frequent type is mixed delirium, which occurs in 64% of patients.22

POD is associated with worse outcomes, a higher incidence of complications, prolonged mechanical ventilation, increased length of stay in the ICU and on the ward, increased readmission rates, and therefore higher healthcare costs. In the long term, it is also associated with impaired cognitive function, decreased physical capacity and quality of life, and increased mortality after discharge.11,14,23

Delirium is an important syndrome, because many special critical care units (SCCU) have not yet introduced routine delirium screening and strategies to treat and prevent this syndrome. Staff that are able to recognise and diagnose delirium can prevent it, treat it and reduce its incidence, which in turn reduces morbidity, mortality and costs. The Zero Delirium Project (ZDP) was created with this aim in mind.

Population ageing is leading to a disproportionate number of frail, multimorbid patients requiring care in a public health system that is geared towards treating specific diseases. Two-thirds of hospital beds are occupied by patients aged over 65, and up to half of these patients have cognitive impairments such as dementia or delirium - circumstances that are particularly important in patients scheduled for surgical interventions, since they will often require care in Special Critical Care Units (SCCU) such as an intensive care unit (ICU) or a postoperative intensive care unit (PICU).

The neurocognitive impairment typical of delirium is associated with symptoms and communication difficulties that cause considerable stress to both the patient and their family. Delirium in SCCU patients is associated with increased morbidity and mortality1 and is sometimes under-diagnosed.2,3

The detection of delirium in SCCUs is based on the administration of specific diagnostic scales. Failure to routinely administer these scales in clinical practice has led directly to the under-diagnosis of this syndrome,24 and training SCCU staff to administer validated scales will improve diagnosis of delirium and can reduce the number of cases by up to 60%.25

The gold standard diagnostic scale is the Confusion Assessment Method for the ICU (CAM-ICU), followed by the Intensive Care Delirium Screening Checklist (ICDSC). Up to 95% of delirium cases are diagnosed with one of these scales26:

• -

  The CAM-ICU can be administered by nurses or doctors in 3−5 min to obtain a rapid diagnosis of delirium, and has also been validated for the diagnosis of delirium in critically ill and even mechanically ventilated patients who are momentarily unable to speak.27,28 It has a sensitivity of 97%, a specificity of 98%, and high inter-rater reliability (κ = 0.96, 95% CI = 0.92−0.99).29 The CAM-ICU assesses 4 features of delirium: acute onset or fluctuating course, inattention, disorganized thinking, and altered level of consciousness (Table 2, and Fig. 2). The test is positive if features 1 and 2 and either feature 3 or 4 is present. Before administering this scale in critically ill patients their level of state of sedation must be assessed using Riker’s Sedation Agitation Scale (SAS)30 (Table 3) or the Richmond Agitation-Sedation Scale (RASS)31 (Table 4). The aim of sedation scales is to differentiate hyperactive delirium (RASS score of +1 to +4) from hypoactive (RASS score of −3 to 0) or mixed (a positive, neutral or negative RASS result) delirium.32 The CAM-ICU scale cannot be administered in coma patients or in those under deep sedation (RASS score of −4 or −5).33

  Table 2.

  CAM-ICU (this scale has been adapted and validated in Spanish).

  Features	Positive	Negative
  Feature 1. Acute onset Positive if you answer ‘yes’ to either 1A or 1B 1A Is there evidence of an acute change in mental status from the baseline? 1B Or, did the (abnormal) behaviour fluctuate during the past 24 h, that is, tend to come and go or increase and decrease in severity as evidenced by fluctuations on the Richmond Agitation Sedation Scale (RASS) or the Glasgow Coma Scale?
  Feature 2. Inattention Positive if either score for 2A or 2B is less than 8 (out of a maximum of 10) 2A Attempt the ASE (Attention Screening Examination) letters first. If the patient is able to perform this test and the score is clear, record this score and move to Feature 3. 2B If pt is unable to perform this test or the score is unclear, then perform the ASE Pictures. If you perform both tests, use the ASE Pictures’ results to score the Feature.
  Feature 3. Disorganized thinking Positive if the combined score (3A and 3B) is less than 4 (out of a maximum of 5) 3A Yes/no questions (use either Set A or Set B, alternate on consecutive days if necessary): Group A Group B Will a stone float on water?Will a leaf float on water? Are there fish in the sea? Are there giraffes in the sea? Does 1 kilo weigh more than 2 kilos? Do 2 kilos weigh more than 1 kilo? Can you use a hammer to pound a nail?Can you use a hammer to cut wood? Score: Patient earns 1 point for each correct answer out of 4 3B Command Say to the patient: “Hold up this many fingers” Examiner holds 2 fingers in front of the patient Then say: “Now do the same thing with the other hand”. If the patient is unable to move both arms, for the second part of the command say: “add one more finger.” Score: Patient earns 1 point if able to successfully complete the entire command.
  Feature 4. Altered Level of Consciousness Positive if the SAS is anything other than 4, or the RASS is anything other than “0” (zero)
  The presence of features 1 and 2 and either 3 or 4 confirm the presence of delirium.

  Reference Tobar et al.151.
  
  

  Figure 2.

  Attention Screening Exam in the CAM-ICU.

  Source: Tobar et al.151
  Table 3.

  Sedation-agitation scale.

  Sedation-Agitation Scale (SAS)
  Unarousable	Minimal or no response to noxious stimuli, does not communicate or follow commands.
  Very sedated	Arouses to physical stimuli but does not communicate or follow commands, may move spontaneously.
  Sedated	Difficult to arouse but awakens to verbal stimuli or gentle shaking, follows simple commands but drifts off again.
  Calm and cooperative	Calm, easily arousable, follows commands.
  Agitated	Anxious or physically agitated, calms to verbal instructions.
  Very agitated	Requiring restraint and frequent verbal reminding of limits, biting ETT.
  Dangerous agitation	Pulling at ET tube, trying to remove catheters, climbing over bedrail, striking at staff, thrashing side-to-side.

  Reference Riker et al.30
  Table 4.

  Richmond Agitation-Sedation Scale (RASS).

  RASS SCALE
  Score	Classification	Description
  +4	Combative	Combative, violent, danger to staff
  +3	Very agitated	Pulls or removes tube(s) or catheters; aggressive
  +2	Agitated	Frequent non-purposeful movement, fights ventilator
  +1	Restless	Anxious, apprehensive, but not aggressive
  0	Alert and calm
  −1	Drowsy	Not fully alert, but has sustained wakening (more than 10 seconds)
  −2	Light sedation	Briefly awakens to voice (eye opening/contact) <10 seconds
  −3	Moderate sedation	Moderate sedation; movement or eye opening. No eye contact
  −4	Deep sedation	No response to voice, but movement or eye opening to physical stimulation
  −5	Unarousable	No response to voice or physical stimulation

  Reference Ely et al.31.

A number of variants of the original CAM-ICU have been developed, such as the 3-Minute Diagnostic Interview for CAM-Defined Delirium (3D-CAM) (Fig. 3), which is a short (3-minute) version of the CAM that has a sensitivity and specificity of >94%,34 and the CAM-ICU-7 (Table 5), a 7-item (0–7) scale derived from the CAM-ICU and the RASS scale.35

Figure 3.

3-Minute Diagnostic Interview for CAM-defined Delirium (3D-CAM).

Reference: Palihnich et al.152

The CAM-ICU flowsheet is a simple algorithm that speeds up the diagnosis of delirium (Fig. 4). Studies have found excellent correlation (kappa 0.96) between the CAM-ICU flowsheet and the CAM-ICU for the diagnosis of delirium.36

Figure 4.

CAM-ICU Flowsheet.

Reference: Miranda et al.153

The ICDSC37 checklist contains 8 items: altered level of consciousness, inattention, disorientation, hallucination-delusion-psychosis, psychomotor agitation or retardation, inappropriate speech or mood, sleep-wake cycle disturbance, and symptom fluctuation (Table 6). The presence of 4 or more of the above items indicates delirium/ The ICDSC is less popular than the CAM-ICU, except is some countries such as Japan, where it is more widely used than the CAM-ICU.26

Two scales have been developed to assess the severity of delirium symptoms: the Delirium Rating Scale-Revised-98 (DRS-R-98) and the Cognitive Test for Delirium (CTD). The DRS-R-98 (Table 7) is a 16-item scale (sleep-wake cycle disturbance, perceptual disturbances and hallucinations, delusions. lability of affect, language, thought process abnormalities, motor agitation, motor retardation, orientation, attention, short-term memory, long-term memory, visuospatial ability, temporal onset of symptoms, fluctuation of symptom severity, physical disorder). Thirteen of these items are indicative of severity and 3 are diagnostic. Each is scored from 0 to 3 to obtain a maximum of 46 points; the higher the score, the greater the severity of delirium. The scale has high sensitivity and specificity, and excellent inter-rater reliability (intraclass correlation 0.97).38,39

The CTD scale assesses neurocognition without requiring a verbal response, and consists of 9 items grouped into 5 categories. The items contain descriptors, and each category is scored from 0 to 6 using a conversion table. Scores range from 0 to 30; the lower the score, the greater the severity of delirium. The diagnostic cut-off point for delirium is ≤18. The Delirium Motor Checklist (DMC) is used to assess the number of hyper- and hypoactive symptoms.33

A history of dementia is an important risk factor for developing delirium in the ICU. Identifying patients with previous cognitive impairment or at risk of developing such impairment could indicate which are more likely to develop delirium. The CDR scale (Table 8) is the gold standard for detecting the different stages of dementia: 0 - no dementia; 0.5 - questionable dementia, 1 - mild dementia, 2 - moderate dementia and 3 - severe dementia.39

The AD8 test (Table 9) is derived from the CDR. Although it only consists of 8 yes/no questions, it has high sensitivity (97%) and a high negative predictive value (86%) for detecting mild, moderate or severe dementia (CDR greater than or equal to 1).39

Patients can be screened for delirium by trained nurses prior to undergoing a medical diagnosis. Nurse-administered scales include:

• -

  The Delirium-O-meter (Table 10) - an observational delirium scale that requires minimal training. It consists of 12 observational behavioural items: sustained attention, shifting attention, orientation, consciousness, apathy, hypokinesia/psychomotor retardation, incoherence, fluctuations in functioning, restlessness, delusions, hallucinations, anxiety/fear. The total score ranges from 0 to 36, with 36 indicating the most severe delirium.40

  Table 10.

  Delirium-O-meter.

  	0	1	2	3
  Sustained attention	Is able to concentrate for longer periods of time during activities/conversations.	Absent-minded, questions need to be repeated sometimes	Easily distracted, questions need to be repeated most of the time.	Not able to maintain attention at all, reacts to all kinds of stimuli.
  Shifting attention	Switches between conversation topics or activities without any problem.	Occasionally continues talking about a previously discussed topic.	Much difficulty shifting attention towards new activities/topics.	Not at all able to raise attention or shift it towards new topics/activities.
  Orientation	Says correct date, knows where he/she is and his/her way around, recognizes people	No problems other than saying the correct date and day of the week.	Disoriented to time and place, cannot find his/her own room, doesn't know where he/she is.	Disoriented to time, place and person, recognises family members insufficiently
  Consciousness	Appears wide awake and alert during the day.	Distracted look, as if he/she has just woken up and is not fully awake.	Clearly appears sleepy, eyes frequently closed, but does respond	Hard to awaken, hardly responds when spoken to
  Apathy	Starts conversation, shows interest, appears to be motivated to do something	Shows interest only when others invite him/her, but does not appear “empty"	Almost no initiative and shows little interest in others (appears “empty”)	Does not do anything, appears to be emotionally "empty"
  Hypokinesia/psychomotor retardation	Normal spontaneous pattern of movements.	Often sits inactively but just a little encouragement leads to activity	Little spontaneous movement, arms motionless or crossed	No movement of arms or legs unless stimulated strongly
  Incoherence	What the patient says is easy to understand even for someone who doesn't know him/her very well.	What the patient says is not always easy to understand, sometimes jumps from one topic to another.	Clearly difficult to follow, associative, sentences seem unrelated, sometimes stops in the middle	Not able to express a coherent thought, unfinished sentences, loose words, yells, moans.
  Fluctuations in functioning	No diurnal variation in functioning, normal sleep-wake cycle.	Minimal fluctuations (during the day or during the sleep-wake cycle)	Moderate fluctuations (during the day or during the sleep-wake cycle)	Very marked diurnal variations or severely altered sleep-wake cycle.
  Restlessness	Is able to sit down and relax, work on something or talk to someone without getting restless.	A little bit jumpy, fidgety, restless, rocks chair.	Agitated, paces up and down the room, slightly irritated, restless arm movements.	Extremely restless, irritable, plucking, oppositional behaviour, pulls out catheter, restrictive measures used.
  Delusions	Thoughts are "in sync" with reality, there are no unfounded or unrealistic beliefs, patient is not suspicious or distrustful.	Somewhat suspicious, distrustful, sometimes feels like he left behind, often asks “why is this…”	Clearly suspicious, has unrealistic, unfounded or strange ideas, for example, says he lives in the hospital	Extremely suspicious or convinced of strange ideas, making it very difficult to redirect his or her thoughts
  Hallucinations	Perception; what patient sees/hears/smells/touches/feels matches reality	Occasional distorted perception of objects, e.g. curtains/wallpaper motifs seen as little animals	Perceives people, objects, smells, tastes, sounds or animals that are not really there, but can be redirected.	Constantly perceives things that are not there, cannot be redirected, interaction is difficult.
  Anxiety/fear	Feels at ease, not anxious	Somewhat apprehensive about what is going on or what will happen.	Clearly anxious, fearful, needs some reassurance	Extremely anxious, frightened, needs a lot of reassurance

  Reference: de Jonghe et al.158
• -

  The Nursing Delirium Screening Scale (Nu-DESC) (Table 11) - a delirium screening tool for nurses that assesses 5 features: disorientation, inappropriate behaviour, inappropriate communication, illusions/hallucinations, and psychomotor delay. Each item is scored from 0 to 2, with 0 indicating no symptoms and 2 severe symptoms. A score greater than or equal to 2 indicates a positive screening for delirium29,41

  Table 11.

  The Nursing Delirium Screening Scale (Nu-DESC).

  Symptom	00: 00am/8: 00am	8: 00am/4: 00 pm	4: 00 pm/00: 00am
  1. Disorientation Verbal or behavioural manifestation of not being oriented to time or place or misperceiving persons in the environment
  2. Inappropriate behaviour Behaviour inappropriate to place and/or for the person
  3. Inappropriate communication Communication inappropriate to place and/or for the person
  4. Illusions/hallucinations Seeing or hearing things that are not there; distortions of visual objects
  5. Psychomotor retardation Delayed responsiveness, few or no spontaneous actions/words

  Reference: Gaudreau et al.159

  Each feature is rated from 0 to 2 for severity, where 0 = absent, 1 = mild, and 2 = severe. Positive Nu-DESC is a score ≥2, the maximum total score is 10.
• -

  The 4A test (4AT) can be administered in less than 2 min by healthcare professionals without special training in screening for delirium. It consists of 4 items: the first measures the patient's level of alertness as observed by the operator (score 0 or 4); items 2 and 3 measure orientation and attention using the Abbreviated Mental Test (AMT) and Backward Months Test. Each item is scored from 0 to 2; and item 4 assesses acute change or fluctuating course (score 0–4). A score of 0 indicates unlikely delirium; a score of 1−3 indicates possible cognitive impairment, and a score ≥4 suggests delirium.40 (Table 12)

  Table 12.

  4AT Test.

  ALERTNESS This includes patients who may be markedly drowsy (e.g., difficult to rouse and/or obviously sleepy during assessment) or agitated/hyperactive. Observe the patient. If asleep, attempt to wake with speech or gentle touch on shoulder. Ask the patient to state his or her name and address to proceed with scoring.	Normal (patient is fully alert (but not agitated) throughout assessment): 0 points Briefly sleepy for <10 seconds after waking, then normal: 0 points Clearly abnormally drowsy: 4 points
  AMT4 Age, date of birth, place (name of the hospital or building), current year.	No mistakes: 0 points 1 mistake: 1 point 2 or more mistakes/untestable: 2 points
  Attention Ask the patient: "Please tell me the months of the year backwards, starting at December”. To assist initial understanding one prompt of "what is the month before December?" is permitted.	Recites 7 months or more correctly: 0 points Starts but scores <7 months, or refuses to start: 1 point Untestable (cannot start because unwell, drowsy, inattentive): 2 points
  ACUTE CHANGE OR FLUCTUATING COURSE Evidence of significant change or fluctuation in: alertness, cognition, other mental function (e.g., paranoia, hallucinations) arising over the last 2 weeks and still evident in last 24 h.	No: 0 points Yes: 4 points

  4 or more points: possible delirium +/− cognitive impairment.

  1−3 points: possible cognitive impairment.

  0 points: Delirium or severe cognitive impairment unlikely but possible if information is incomplete.

  Reference: Saller et al.160

According to the neuroinflammatory hypothesis of delirium, proinflammatory factors such as procalcitonin, IL-8, IL-6, and S100 beta play an important role in the development of the syndrome. These factors could cause neuronal apoptosis and synaptic dysfunction, promoting the development of delirium. New lines of research are attempting to determine how these proinflammatory molecules can be used as a diagnostic tool. The platelet-lymphocyte ratio (PLR) is calculated on admission to the ICU by dividing the platelet count by the lymphocyte count. It is a simple, inexpensive procedure that could be used to predict delirium in critically ill patients. A high PLR (>100) on admission to the ICU has been associated with a higher incidence of delirium. PRL, however, is not a validated diagnostic method.15

Specific EEG patterns associated with postoperative delirium have been described.42 Comatose ICU patients who spend more time in burst suppression are more likely to develop delirium after recovery from coma.43

Further studies are needed to validate these approaches to diagnosing delirium.

Clinicians need to consider both widely applicable non-pharmacological and pharmacological strategies when treating delirium.

The acute, potentially life-threatening causes of delirium must be taken into account when treating this disorder. These include hypoxaemia, hypotension, hypoglycaemia, electrolyte disturbances, and drug intoxication or withdrawal, in addition to pain, medication, etc. Prevailing circumstances, such as the patient’s surroundings (reducing noise) and sleep hygiene, must also be optimized. Up to 50% of delirium episodes in patients admitted to palliative care units can be reversed, particularly when delirium has been triggered by medications, infections or electrolyte disturbances.104,105 Drugs are one of the most common causes of delirium.106

The standard therapeutic approach to delirium includes cognitive training programs, reorientation measures, administration of neuroleptics, and adequate pain treatment.107,108 The first step in treating delirium should be to investigate the underlying medical triggers and optimise non-pharmacological interventions.109–111 In patients that are severely distressed by their symptoms, pose a safety risk to themselves or others, or impede essential care procedures, it is acceptable to treat the symptoms of delirium with drugs.112

Each unit must develop its own roadmap for the introduction of ZDP recommendations in clinical practice. They will need to adapt the recommendations to their setting and create a schedule for implementing the proposed changes.

In hospitalized patients, nursing staff can be crucial in implementing non-pharmacological measures aimed at promoting night-time rest, early mobilization, adequate pain management, and family engagement.145

Given the evidence on the effectiveness of interprofessional strategies in the management of delirium, it is important to clarify the definition of interprofessional collaboration and education in order to determine the impact that interventions to improve collaboration and quality of care can have on delirium outcomes.

Some studies have shown that after receiving training in the diagnosis and treatment of delirium, nurses on critical care units and on general, surgical and geriatric wards were able to apply early delirium prevention and diagnostic strategies and implement adequate treatment.146 However, some authors have observed major gaps in team performance and uncertainties regarding the role of each professional in the management of delirium patients, and have drawn attention to the need for interprofessional educational programs.147

These programs are effective in improving knowledge of delirium among the professionals involved,148 and also in improving early detection of delirium, adherence to protocols, and team performance and intercommunication. These improvements impact patient outcomes by facilitating the management of delirium and reducing its prevalence.149,150