Description of the condition
Delirium is a complex acute organic syndrome characterised by a reduced ability to focus, sustain, or shift attention, and either a change in cognition (memory deficits, disorientation, or language disturbance) or the development of a perceptual disturbance (hallucinations or delusions) [
1]. The pathophysiology of delirium is superficially understood, and the mechanisms involved are likely to be multiple [
2,
3]. Delirium has been classified into motoric subtypes: (1) hypoactive delirium (pure lethargy, withdrawal, flat affect, apathy and decreased responsiveness), (2) hyperactive delirium (agitation, restlessness, attempting to remove catheters and emotional lability), and (3) a mixed form delirium (fluctuation between hypoactive and hyperactive delirium) [
4].
The prevalence of delirium is highest in hospitalised older individuals and varies depending on the patient characteristics, setting of care, and sensitivity of the detection method. In the community, the overall prevalence of delirium is low (1 to 2%) but increases with age, rising to 14% in individuals older than 85 years [
5]. In nursing homes and residential homes, the prevalence of delirium is 8 to 9% [
6]. At the time of hospital admission, the prevalence of delirium is an estimated 14 to 24% and the incidence 6 to 56% [
7]. Delirium occurs in 9 to 87% of individuals postoperatively [
8], in 40 to 60% of the spontaneously breathing patients in intensive care, in 60 to 89% of the mechanically ventilated patients in intensive care [
9], and up to 83% of all individuals at the end of life [
10].
Delirium is increasingly being recognised as a significant contributor to the morbidity and mortality of the intensive care unit (ICU) patients. Studies have shown an increase in total ventilator days, ICU length of stay, and long-term cognitive impairment [
11,
12]. Pandharipande et al. [
11] followed 821 surgical and medical ICU patients and found that longer duration of delirium was an independent risk factor for worse global cognition scores at both 3 and 12 months after discharge. Ely et al. [
12] evaluated a smaller cohort of 224 ICU patients, and their results showed that delirium was independently associated with 3.2 (95% Cl 1.4–7.7;
P = .008) increased risk of 6-month mortality. Contrary to this, in a larger cohort of 1112 ICU patients, Klouwenberg et al. [
13] did not find an association between delirium and mortality after adjusting for changes in disease severity before the onset of delirium. Delirium complicates hospital stay for at least 20% of the 12.5 million patients 65 years of age or older who are hospitalised each year and increases hospital costs by $2500 per patient. An estimated $6.9 billion of medical hospital expenditures are attributable to delirium [
5]. Substantial additional costs accumulate after hospital discharge because of the need for institutionalisation and rehabilitation services. In the ICU, within the mechanically ventilated patients, delirium has been associated with 39% higher intensive care costs and 31% higher hospital costs [
14].
Different tools exist for the assessment of delirium in the ICU. The Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) are often used [
15]. Studies have indicated that delirium might be undetected in more than 65% of the ICU patients when comparing clinical identification of the presence of delirium to identification by the CAM-ICU or ICDSC scores [
16,
17]. Hypoactive and mixed form delirium are the most common within the ICU patients [
18,
19], and hypoactive delirium has been suggested to be more deleterious than the mixed form with worse outcomes and more long-term harmful effects [
4].
Description of the interventions
Abnormalities in cerebral oxidative metabolism, direct neurotoxic effects of inflammatory cytokine alterations in neurotransmitters (e.g. cholinergic, dopaminergic, serotonergic), and gamma-aminobutyric pathways are all believed to be involved in the pathophysiology of delirium [
20]. Pharmacological interventions for delirium have focused on alterations in neurotransmitter pathways, in particular, dopaminergic and cholinergic pathways.
Several pharmacological strategies for delirium in the ICU patients have been investigated:
1.
Antipsychotics (both typical antipsychotics e.g. haloperidol and atypical antipsychotics e.g. olanzapine, quetiapine, risperidone, aripiprazol, and ziprasidone)
2.
Sedatives (e.g. benzodiazepines (midazolam, lorazepam, diazepam), propofol, and dexmedetomidine (alpha-2-antagonist))
3.
Cholinesterase inhibitors (rivastigmine)
5.
Melatonine and melatonine antagonists (e.g. ramelteon)
How the interventions might work
Given the multiple mechanisms possibly resulting in the development of delirium, a range of pharmacological drugs have been studied. These different drugs target the suspected neurotransmitter or receptor imbalances, which may cause the distressing cognitive symptoms, hallucinations, risky physical behaviour, etc.
In the following, we describe the theoretical therapeutic rationale for each type of drug.
Antipsychotics (dopaminergic pathway)
The therapeutic effects of antipsychotics in delirium may be mediated via a number of different mechanisms that include sedative or anxiolytic effects, antipsychotic actions, or direct effects upon the proposed core neurochemical disturbances of delirium [
28].
Sedatives
The benzodiazepines midazolam and lorazepam (and to a lesser extent, diazepam), propofol and dexmedetomidine are the commonly used sedatives within the ICU [
29]. The opioid remifentanil is also used because of its sedative effects. Benzodiazepines may act through g-aminobutyric acid type A (GABAA) receptors, as in part does propofol, whereas dexmedetomidine is an a2-adrenoceptor agonist, and remifentanil is a μ-opioid receptor agonist [
3].
Cholinesterase inhibitors
Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. In patients with delirium, serum anticholinergic activity has been found to be increased [
30] and, particularly in elderly patients, drugs with anticholinergic effects can cause delirium [
31].
Opioids
Unrelieved pain induces stress responses characterised by tachycardia, increased myocardial oxygen consumption, hyper-coagulability, immunosuppression, and persistent catabolism. Ensuring adequate pain control might be essential. At low doses, opioids provide analgesia and in high doses, they provide anxiolysis and sedation [
32]. The mechanism of action of pain management with ketamine, a N-methyl-D-aspartate receptor blocker, is not well understood.
Melatonine
Melatonine is a hormone normally produced in the pineal gland. It is assumed to help regulate sleep-wake cycles or the circadian rhythm. Production of melatonine is stimulated by darkness and inhibited by light. Patients admitted to the ICU develop impaired sleep patterns. Factors which contribute to the sleep impairment include the use of opioids and benzodiazepines, which disrupt rapid eye movement (REM), the impact of specific patient therapies such as asynchrony to mechanical ventilation, arousal related to patient care-related activities, environmental noise, and non-phasic light exposure [
33]. Lower levels of melatonine and disrupted circadian release of melatonine have been associated with ICU delirium [
34].
Why it is important to do this overview
In the critically ill patients, 40 to 89% are reported to be affected by delirium and poor clinical outcomes are associated with the syndrome [
9,
35‐
38]. Delirium patients may experience functional decline and long-term cognitive impairment [
39‐
41]. Furthermore, delirium is associated with increased morbidity, lengthened duration of mechanical ventilation, ICU and hospital lengths of stay, and mortality [
12,
14,
36,
39‐
43].
The economic burden of delirium is significant [
44]. In hospitals, ICU beds are expensive, and some countries spend 0.7% of the national gross product on intensive care [
44]. Due to an aging population and the increasingly advanced medical and surgical care, the number of patients in need of intensive care is expected to increase in the coming years [
45].
The evidence on the effects of pharmaceutical interventions
A number of trials investigating pharmacological prevention or management options have been published. However, uncertainty regarding the benefits and harms of pharmacological interventions, remains considerable, and trials have shown either positive [
46,
47], equipoise [
48,
49], or negative results [
50].
Trials investigating the effects of antipsychotics (quetiapine, ziprazidone, risperiodene, haloperidol) have been conducted [
46,
48,
51,
52]. The use of antipsychotics is associated with neurological side effects, including the development of extrapyramidal side effects, tardive dyskinesia, and neuroleptic malignant syndrome [
1]. Management of delirium with haloperidol has been found to lengthen the QT interval, which can lead to torsades de pointes tachycardia that can degenerate to ventricular fibrillation and sudden death [
53].
No sedative agent has been reported to improve survival in randomised clinical trials, despite at least 90 trials comparing sedative regimens in a systematic review [
54]. In another meta-analysis comparing propofol to any sedative agent, propofol did not show to reduce mortality but may result in a reduction in the length of stay in the ICU when compared to benzodiazepines, but not when compared to midazolam [
55]. Dexmedetomidine may have advantages compared with benzodiazepines, since it produces analgesia, causes less respiratory distress, and provides a different type of sedation in which patients are more interactive and so their needs are potentially easier communicated [
56]. Dexmedetomidine compared to lorazepam and midazolam in randomised clinical trials has been shown to result in less delirium and a shorter duration of mechanical ventilation [
56‐
58].
Morphine has been compared with haloperidol in the management of hyperactive delirium and was found to have a quick beneficial effect and no adverse effects [
59]. Ketamine has been compared to placebo in the prevention of delirium and was found to lower the incidence of delirium [
60].
Rivastigmine has in one trial been compared to placebo for the management of delirium, as an adjunct to usual care based on haloperidol. The trial was stopped early due to increased mortality in the rivastigmine group; thus, rivastigmine is not recommended to manage delirium in the ICU [
50].