K.H. Polderman and A.J.C. Slooter
Introduction
Until a few years ago, the occurrence of delirium or ‘intensive care unit (ICU) psy- chosis’ was regarded as a routine feature of life in the ICU. Delirium occurred with such a high frequency that it was often considered to be a routine consequence of prolonged stay – a combined effect of the patient’s underlying illness and perhaps the administration of large amounts of sedatives.
Attending physicians tended not to worry about delirium too much; it was assumed that the problem would resolve once the patient’s somatic condition improved, and delirium was regarded more as a nuisance and a patient management problem than as a life-threatening event. Delirium was usually not treated; treatment was mostly given only if the patient was completely unmanageable due to his/her restlessness, or became violent towards the medical and nursing staff. In many of these cases delirious patients were treated with sedatives rather than with antipsy- chotics.
In general, until the early 1990s, ICU policies regarding use of sedatives, mor- phine-like analgesics and neuromuscular blocking agents in mechanically ventilated patients were much more liberal, and very large doses were routinely used in most ICU patients. The reason for this was the widely held assumption that patients could otherwise not tolerate mechanical ventilation and other invasive ICU treatments, and that sedation and paralysis would also allow the patient to ‘rest’ and recover.
More mundane factors also played a role; often the practices and treatments used for general anesthesia during major surgery were simply continued for longer-term management of patients in the ICU.
This attitude began to change in the mid-1990s, when it was realized that long- term use of very high doses of sedatives, opiates, and neuromuscular blocking agents was linked to adverse outcome and increased length of stay in the ICU. Kress and co-workers showed that length of stay in the ICU and hospital could be reduced by early tapering and daily interruption of sedative-drug infusions in mechanically ventilated patients [1]. These observations have led to a significant decrease in the use of sedatives, opiates and neuromuscular blocking agents in recent years, and thus to a rise in the number of more or less conscious patients in the ICU, especially in the recovery phase after acute illness. This in turn led to the realization that even more patients than presumed develop alterations in their mental status in the acute phase of critical illness and in later phases.
The true incidence of delirium remains a matter of debate. Various studies, using different assessment methods, have reported that between 16 % and 83 % of ICU patients become delirious during their stay in the ICU [2 – 13]. Part of this wide
range is probably explained by use of different assessment methods (see below) and differences in case mix. In addition, there are three distinct subtypes of delirium (hyperactive, hypoactive, and mixed), which may complicate the diagnosis as they, especially the hypoactive form, may be difficult to recognize particularly in ICU patients. Therefore, we will briefly discuss the difficulties and diagnostic aspects of delirium in critically ill patients.
Terminology and Definition
The terminology and definitions of ICU delirium can sometimes be somewhat con- fusing. Delirium is described in the Diagnostic and Statistical Manual of Mental Dis- orders (DSM IV) as “a disturbance of consciousness with inattention, accompanied by a change in cognition or perceptual disturbance, that develops over a short period of time (hours to days) and fluctuates over time” [14]. However, many differ- ent terms have been used to describe the syndrome of cognitive impairment in criti- cally ill patients. Sometimes these terms are linked to specific disease states or con- ditions, such as the term septic encephalopathy. Sometimes they refer to a general state of confusion, e.g., terms such as ICU psychosis, acute confusional state, acute brain failure, ICU syndrome, etc. Sometimes the term encephalopathy is used to describe hypoactive delirium, whereas the other terms listed above refer to hyperac- tive delirium. As explained above the true incidence of delirium (especially in the ICU) remains a matter for debate, but it is clear that hypoactive delirium is far more common than the more easily recognizable pure hyperactive delirium. For example, Peterson et al. reported a frequency of delirium of 61 % in a population of 614 criti- cally ill patients, of whom only 2 % had pure hyperactive delirium, while 43 % had hypoactive delirium, and 55 % had mixed-type delirium [10]. The pure hyperactive form was observed more frequently in younger patients, whereas the purely hypoac- tive form was more common in older patients [10].
Various assessment methods have been developed specifically to establish a diag- nosis of delirium in critically ill patients. In the early 1990s, Inouye et al. developed the Confusion Assessment Method (CAM) for use as a quick delirium screening tool for patients in the general ward [15]. This method was subsequently adapted for use in the intensive care setting by Ely and co-workers, as the Confusion Assessment Method for the ICU (CAM-ICU); the first paper describing this screening method was published in 2001 [2]. Another screening system specifically designed for use in the ICU setting, the Intensive Care Delirium Screening Checklist (ICDSC) developed by Bergeron et al., was published in the same year [3].
Studies using the CAM-ICU scale to screen for delirium have mostly reported higher incidences of delirium than those using the ICDSC; this may be partly due to the assessment of patients with decreased consciousness, who are excluded in the ICDSC scale but who may be diagnosed as delirious with the CAM-ICU system.
Incidence and assessment systems
The reported incidence of delirium in ICU patients has varied significantly. The fol- lowing numbers have been reported in the medical literature in recent years: 11 % [4], 16 % [3, 5], 19 % [6], 22 % [7], 32 % [13], 48 % [8], 70 % [9], 71.8 % [10], 81.3 % [11], 81.7 % [12], and 83.3 % [2]. These differences may be due to variations in case
mix and severity of illness in the populations studied, as well as differences in age and other factors. In addition, the screening method used (CAM-ICU, ICDSC, or other systems not specific for ICU patients) may play a role, with studies using the CAM-ICU systems mostly reporting a higher incidence of delirium (48 %-83 %) than those using the ICDSC system (11 %-32 %).
Detecting delirium in the ICU can be difficult because many patients are mechan- ically ventilated and are, therefore, not able to communicate verbally. In addition, the patient’s level of consciousness and awareness may be affected by treatments with sedatives, opiate analgesics and other drugs. Peterson et al. identified several independent risk factors for under-recognition of delirium by nurses in the ICU set- ting. These included hypoactive delirium (odds ratio [OR] 7.4, 95 % confidence interval [CI] 4.2 – 12.9), age & 80 years (OR 2.8, 95% CI 1.7–4.7), vision impairment (OR 2.2, 95 % CI 1.2 – 4.0), and pre-existing cognitive impairment (OR 2.1, 95 % CI 1.2 – 3.7). The risk for under-recognition increased with the number of risk factors present, from 2 % when no risk factors were present to 44 % when 3 or more risk factors were present [10].
Impact on Clinical Outcome
In spite of the relatively wide range in the reported incidence of delirium in the ICU, most of the studies listed above have reported an association between delirium and adverse outcome, increased length of stay in the ICU, and hospital and higher mor- tality [5, 8, 11 – 13]. One study reported a threefold increase in risk of death associ- ated with the development of delirium [12]. The association between delirium and unfavorable outcome persists when adjustments are made for age, co-morbidity, and severity of illness, which suggests that delirium may be causally related to these adverse events. This has been demonstrated most clearly in severely ill patients with prolonged length of stay in the ICU; however, similar observations have been made in less severely ill patients. For example, Thomason and associates found that delir- ium was a predictor of longer stay in the ICU (average: 1 day) and hospital (average:
2 days) in non-mechanically ventilated patients with an average APACHE score at admission of 15 [8].
An association between delirium and adverse outcome, including mortality, has also been reported outside the ICU setting in general hospital wards and other set- tings [20 – 21]. Not all studies have found a higher mortality associated with devel- opment of delirium, but almost all have linked delirium to increased length of stay in the ICU and hospital, regardless of the initial severity of illness [1 – 13].
Most of the studies listed above [5 – 8, 11 – 13,] as well as various others have also reported that developing delirium leads to significant additional costs. One study in ICU patients reported an average increase in costs of 40 %, after adjustment for vari- ables such as severity of disease and co-morbidities [22]. Ely has estimated that the annual additional health care expenditure linked to ICU delirium in the USA alone lies between $1.5 billion and $20 billion (c1.2–16 billion) [23]. Even if the true fig- ure lies at the low end of this estimate or even lower, the potential for reducing expenditure by prevention or early treatment of delirium seems huge.
However, it should be realized that although many studies have documented a relationship between delirium and adverse outcome, no prospective studies have so far been performed showing that early and/or aggressive treatment of delirium can actually improve patient outcome [25]. However, this does seem highly likely (par-
ticularly in hyperactive delirium, which increases the risk of complications such as auto-extubation and accidental removal of central lines), and the viewpoint that rec- ognition and early treatment of delirium is an important issue in critically ill patients has become more or less generally accepted.
Risk Factors and Therapeutic Options
Numerous risk factors for developing ICU delirium have been identified in various clinical trials. These are listed in Table 1. As explained above, no prospective studies assessing the impact of preventive and therapeutic measures against delirium on ICU mortality have so far been performed. However, it is generally accepted that prevention of delirium is likely to improve outcome, if only through prevention of complications such as self-extubation and other ICU complications [23 – 26].
It has been shown that simple preventive measures can be highly effective in pre- venting and/or mitigating delirium. These are also listed in Table 1. Inouye et al.
were able to reduce the incidence of delirium by 40 % in elderly patients who had been admitted to a general ward through a combined strategy of avoiding sleep dep- rivation, dehydration, electrolyte disorders and hypoxemia, and by applying cogni- tive therapies, correcting visual and auditory impairments, repeated re-orientation, and early mobilization [27]. Preventive measures should also include regular screen- ing of ICU patients for delirium, and increasing awareness in the medical and nurs- ing staff.
Another potential method to reduce the incidence of delirium is the administra- tion of prophylactic drugs. Kalisvaart and co-workers [28] recently published the results of a randomized placebo-controlled trial in which low-dose prophylactic treatment with haloperidol was used to prevent delirium in the post-operative set- ting. Although the overall incidence of delirium was not reduced significantly in this study, the authors did report a positive effect on the severity and duration of delir- ium. In addition, patients receiving haloperidol prophylaxis had a decreased length of stay in the hospital. Trials are ongoing to assess whether haloperidol prophylaxis could have a similar beneficial effect in ICU patients.
Development of delirium may signify the presence of an acute somatic illness, such as a nosocomial infection or a severe metabolic disorder. This should be kept in mind, and the presence of an underlying somatic disorder should be ruled out if a patient develops delirium. Care should also be taken to determine that a patient’s acute confusional state is not caused by pain.
The next step is to make sure whether the ‘simple’ preventive measures listed above and in Table1 have been implemented, and if not to rectify this situation. Nor- malization of sleep-wake cycles may be particularly important, and this is something often overlooked in the daily routine in the ICU. Aizawa et al. performed a random- ized study to assess the effect of diazepam and pethidine administration during the first three nights following a surgical intervention, and reported a reduction in the occurrence of delirium from 35 % to 5 % [29]. This would suggest that the prophy- lactic use of sedatives to simulate a normal sleep-wake rhythm could be an effective strategy to prevent delirium. However, others have reported that the use of benzodi- azepine prophylaxis can actually increase the risk for delirium [30]. Thus further studies will be needed to clarify this issue.
Pharmacologic options include discontinuation of drugs that can cause or aggra- vate delirium (including benzodiazepines and narcotics, which are often inappropri-
Table 1. Risk factors and therapeutic options in delirium.
Risk Factors for Delirium Prior medical history High age
Dementia
Other neurological diseases with cognitive impairment Vascular disease
Hypertension Diabetes Smoking Alcohol abuse Visual impairment Hypothyroidism Status at ICU admission
Greater severity of illness (as indicated by high APACHE, SAPS or SOFA scores) Course of illness during ICU stay
Development of sepsis/nosocomial infections Development of organ dysfunction Hypoxemia
Electrolyte disorders ICU treatments
(Excessive) use of sedatives (Excessive) use of opiate analgesics Sleep deprivation
Dehydration
Restraints, immobilization
Number of different drugs used to treat the patient Therapeutic Options
Preventive strategies
Awareness in medical and nursing staff
Early and regular screening for delirium (especially hypoactive form) Avoiding sleep deprivation
Cognitive stimulation Early mobilization
Avoiding or promptly treating hypoxia, dehydration, uremia and electrolyte disorders Early use of visual aids (glasses) and hearing aids
ICU noise-reduction strategies Music listening, television, etc.
If possible: early removal of central lines, catheters etc.
Consider family involvement
Avoid excessive use of sedatives and opiates Pharmacological options
Conventional antipsychotic agents ) Haloperidol
) Droperidol ) Chlorpromazine
‘Second generation’ antipsychotic agents ) Olanzepine
) Quetiapine ) Risperidone ) Ziprasidone
ately used in the ICU to treat ‘confusion’). This is especially important if the patient is in pain; this of course requires appropriate analgesia, and sedating patients who are in pain will significantly increase the risk of developing delirium (pain + seda- tion/decreased consciousness = delirium). Some preliminary evidence suggests that perhaps the use of short-acting sedatives such as dexmedetomidine could help decrease the risk of developing delirium, particularly for short but painful and/or unpleasant procedures [23, 31]. However, the evidence for this is still limited.
Ouimet and co-workers recently reported that even extremely brief periods of sedation, for example to facilitate the performance of procedures such as a bronchos- copy, were associated with increased risk of delirium [13]. For this and other reasons the unnecessary and/or excessive use of sedatives (and opioids) should be avoided in critically ill patients. In addition, doses of sedation (and opiate analgesia) should be tapered whenever possible (while, of course, avoiding under-treatment and providing sufficient levels of comfort to the patient with the lowest possible doses).
If and when delirium develops in ICU patients, treatment with antipsychotics such as haloperidol should be considered. Unfortunately, no prospective studies assessing the use and effectiveness of haloperidol in the ICU setting have so far been performed. However, based on anecdotal reports and non-randomized studies, halo- peridol appears to be effective, and its use to treat delirium in the ICU is recom- mended in the guidelines of the Society of Critical Care Medicine (SCCM) [32]. Hal- operidol is a dopamine D2receptor antagonist which may work in part by enhancing the release of acetylcholine [33]. Other drugs with similar mechanisms include dro- peridol (which has just been re-introduced to the market) and chloropromazine.
Other antipsychotics and neuroleptic agents with broader receptor affinities (such as risperidol, olanzapine, ziprasidone) may be (more) effective, especially in non- agitated hypoactive delirium. Apart from the dopamine D2 receptors these drugs also target other neurotransmitters such as serotonin, acetylcholine, and norepi- nephrine [34]. However, these drugs have not been well studied in the ICU setting.
Therefore, in most situations haloperidol remains the drug of choice to treat delir- ium in the ICU.
All patients receiving first or second generation antipsychotics should be care- fully monitored for side effects such as QT prolongation and polymorphous ventric- ular tachycardia (’torsade de pointes’) [26]. This is especially important because many other drugs commonly used in the ICU (macrolides, fluoroquinolones, azole antifungals, amiodarone, some calcium channel blockers) can also influence QT time, putting the ICU patients receiving several of these drugs simultaneously at a cumulative risk of developing QT prolongation. Other side effects include extrapyra- midal effects, malignant hyperthermia, hypotension, and anticholinergic effects as well as glucose and lipid dysregulation. Although antipsychotics are generally well tolerated and the likelihood for developing these side effects is relatively low, patients should nevertheless be carefully monitored. In recent years a number of authors have described successful treatment of persistent delirium with cholinester- ase inhibitors [35 – 37]. This deserves further study in ICU patients.
Conclusion
ICU patients appear to be at high risk of developing delirium. Various studies have shown that developing delirium significantly increases the risk of death, as well as the length of stay in ICU and hospital, and health care costs. Therefore, a concerted
effort to prevent and aggressively treat delirium seems warranted, although no pro- spective studies have so far been performed demonstrating benefits in survival resulting from these strategies.
A number of preventive measures can help decrease the likelihood of developing delirium, and these should be applied (adapted to local circumstances) to improve outcome and prevent delirium in the ICU. A potential problem is that inattention and disorganized thinking, which are considered to be the key features of delirium, can be difficult to assess in patients who are mildly or moderately sedated. Hypoac- tive (‘silent’) delirium may, in particular, be easily overlooked.
Two assessment systems, CAM-ICU and ICDSC, are available, which have been designed specifically to screen for delirium in patients who are unable to communi- cate verbally. A number of other assessment systems have been tested only outside the ICU. At this moment insufficient evidence exists to recommend one over the other. Based on the available evidence all forms of delirium should be treated promptly, and a pro-active approach with early and regular screening for delirium seems warranted. If preventive measures are insufficient, treatment with haloperidol or another antipsychotic should be initiated, and patients should be carefully moni- tored for side effects, especially QT prolongation.
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