Postoperative delirium (POD) is a common and severe but potentially preventable condition in older individuals. Often known as geriatric syndrome, POD can also occur in younger patients. Even today, the medical and economic consequences of delirium are often underestimated. Especially in older patients, POD is associated with cognitive impairments relevant to everyday life [1▪]. The mortality of a POD is similar to that of a myocardial infarction [2▪]. In addition, the rate of rehospitalization is increased, and POD leads to economic disadvantage to the hospital [3▪▪]. Due to this medical and also economic impact, concepts for prevention and treatment of POD are urgently needed and are currently under discussion.
The most predisposing risk factors for delirium are higher age (≥65 years), cognitive impairment, comorbidities and the associated polypharmacy [4▪]. The cause of POD is not an underlying psychiatric disease, but always has a somatic genesis. It requires an acute noxious event or complication in intensive care stay such as infection, prolonged general anesthesia, prolonged intensive care, exsiccosis or electrolyte disorder to promote delirium [5▪].
POD is multicausal. Several risk factors are known to increase the incidence. Here, it takes an acute noxious agent or complication during pre, peri or postoperative management such as infection, exsiccosis, prolonged analgosedation, intensive care stay or electrolyte imbalance to induce a delirium [5▪].
In contrast to dementia, delirium is based on an acute neurotransmitter imbalance that is not yet fully clarified. Different physiological trigger factors lead to the same symptoms. The common end of all the published hypotheses is an increased dopamine activity accompanied by an additional cholinergic deficit . Inflammation processes such as oxidative stress during surgery, infection or pain all activate neuronal microglia cells [7,8]. The activation of microglia cells is also triggered by reduced cholinergic inhibition. Thus, patients with reduced cholinergic synthesis caused by Alzheimer's disease or use of anticholinergic medication carry a high risk to develop a delirium .
A reasonable number of pharmacological agents were introduced and intensively investigated to prevent POD. This incorporates various pharmacological approaches such as, among others, antipsychotics and acetylcholinesterase inhibitors. As neuroinflammation and neuronal injury increase the incidence of delirium, steroids and statins have also been examined. In summary, all these approaches failed to hold their promise. There is no evidence to advocate the use of these substances in the pharmacological prevention of delirium . Maybe one exception is Dexmedetomidine that might be recommended as the only preventive agent, in particular in older patients. However, a very recent large-scale multicentre trial in elderly cardiac surgery patients showed no significant benefits in preventing POD [10▪▪]. Conclusively, the authors do not recommend the use of Dexmedetomidine as a prevention of delirium in elderly patients.
It is deemed that one of the most important aspects in pharmacological prevention is pharmaceutical counselling, in particular the evaluation of the home-medication. Before surgery, a clinical pharmacist has to evaluate the home-medication and has to stop or exchange drugs with, for example high anticholinergic burden, such as promethazine, tricyclic antidepressants or urological spasmolytics, as well as benzodiazepines as a sleep-inducing medication or long-term neuroleptic therapy without underlying psychiatric disease [11▪▪]. Pharmaceutical counselling comprises the verification of indications, aims to find adequate alternatives when appropriate and triggers a patient tailored, adequate dosing of medication (Table 1).
Table 1 -
Inappropriate medication and recommended alternatives
|Potentially inadequate medication
||Appropriated alternative medication
|Benzodiazepines for insomnia
||Mirtazapine 7.5--15 mg
|Nonbenzodiazepines (Zopiclone, zolpidem)
||Mirtazapine 7.5--15 mgMelperone 25 mg
||Mirtazapine 7.5--15 mgPregabaline
|Antipsychotics for sedation (e.g. Promethazine)
||Mirtazapine 20–40 mgMelperone 25 mgPipamperone 20 mg
|Typical/ atypical antipychotics without any indication or off-label use for dementia
||Stop medication, no alternatives
|Morphine (except palliative care)
|Fentanyl (except palliative care)
|Buprenorphin (except palliative care)
||Cephalosporines, Fosfomycin or Pivmecillinam for uncomplicated cystitis in females
SSRI, selective serotonin reuptake inhibitors.
NONPHARMACOLOGICAL PREVENTION STRATEGIES
Unfortunately, the evidence for nonpharmacological strategies to reduce POD is also low [12▪]. It is necessary to identify patients at high risk for delirium to implement preventive interventions. As there are several and multifactorial risk factors for a POD, multicomponent interventions are required [12▪,13▪]. Table 2 summarizes the nonpharmaceutical interventions with the strongest evidence. A combination of these interventions decrease the incidence rate of POD by 44% [12▪,14]. In addition, there is less evidence that single-component interventions such as staff education and reorientation may help to prevent POD. Other interventions such as bright light therapy, using earplugs and music therapy, have not been proven to be significant [12▪]. The Hospital Elder Life Program (HELP) is a worldwide implemented, multidisciplinary and multifactorial evidence-based model for elderly persons in hospitals, which includes the prevention and therapeutic management of a delirium. The program effectively reduces the incidence of delirium by 53% [15▪▪], especially by using many of the mentioned nonpharmaceutical interventions.
Table 2 -
Nonpharmaceutical intervention and treatment
of postoperative delirium
|Staff education [12▪]
||Assessment toolsTheoretical foundationsSensitization
|Early mobilization [12▪,13▪]
||Minimization of immobilizing equipmentCollaboration with physical therapists, occupational therapists
|Pain control [12▪]
||Constant use of adequate pain assessments
||Use of hearing and visual aidsOrientation guides (clock, calendar)Orientating communicationApproach of family members, friendsAvoiding room changes
|Sleep-wake cycle preservation [12▪,14]
||Environmental cues for normal sleep-wake cyclesMinimize sound and light in the nightUse of ear-plugs
|Optimization of hydration and nutrition [12▪]
||Fluid repletionCollaboration with dietician
One must however realize that many of the studies on preventive interventions are of poor quality and rather heterogenous in design. Moreover, healthcare systems and structures in different countries are difficult to compare. It is reasonable to recommend that nonpharmaceutical interventions should be tailored to the existing hospital structure and healthcare system.
Various interventions have been investigated in different populations and various types of surgery are subjects of ongoing trials . Due to the multifactorial genesis of delirium, the results are largely conflicting and clear recommendations are thus impossible; however, as in prophylaxis, reasonable measures as part of prevention bundles might be valuable bricks in the basement of solid defense walls against delirium [17▪].
One brick is avoiding known triggers of delirium. Maintaining normothermia and homeostasis as well as avoiding long periods of sedation and blood-pressure fluctuations prevent delirious symptoms. Especially, preoperative medication with anticholinergic effects (including Diphenhydramine) and (long acting) benzodiazepines should be avoided. Well tolerated and effective pharmacological approaches for premedication do not exist, especially in older patients. Only Melatonine appears to be well tolerated, with a small, but certain benefit with regards to preoperative sleep stress [18▪]. The best choice for drugs during anaesthesia is unclear as well. To whether or not perform total intravenous anaesthesia or to use volatile anesthetics, including Xenon, appears to be irrelevant with regard to safety and postoperative delirious symptoms [19▪].
The highly selective α2-adrenergic receptor agonist Dexmedetomidine administered as prophylaxis during and post anaesthesia lately emerged as an upcoming star to lighten the dark field of delirium. Safety and a reduction of delirium were suggested in many trials in various settings at the prize of side effects such as relevant bradycardia. Summarizing the results, these effects still appear to hold true, although the trials are largely heterogeneous and mostly of low quality . Confusingly, a very recent high-quality large prospective multicenter trial (DECADE) showed no positive effect with respect to delirium in older cardiac surgery patients, but a significantly increased number of critical events and was therefore stopped after the last interim analysis [10▪▪].
Another brick in the defense wall against delirium is adequate pain therapy. But how to achieve ‘adequate’ remains unclear. Neither regional anesthesia techniques nor sophisticated regimes based on systemic drugs proved superiority in large meta-analysis; however, regional techniques are well tolerated and frequently provide favourable pain relief [21▪]. A third brick might be to avoid inadequate depth of sedation during anaesthesia. Indeed, there is moderate-quality evidence that anaesthesia guided by processed EEG monitoring to indicate brain state could reduce the risk of POD, especially in patients aged older than 60 years . However, a very recent large prospective trial (ENGAGES) in elderly patients could not undermine this notion . The maintenance of adequate cerebral oxygen supply is another brick in the wall, although difficult to quantify during anesthesia. Several sophisticated methods have been suggested, their benefit surmounting a meticulous control of arterial blood-pressure to individual normal values remains to be elucidated [24▪].
Conclusively, a solid basement for well tolerated anaesthesia in patients at risk for delirium is an individually patient and hospital-tailored bundle comprising procedures and technical support with special respect to avoiding the mentioned delirium triggers, assuring an adequate depth of sedation and sufficient pain therapy.
NONPHARMACOLOGICAL TREATMENT OF POSTOPERATIVE DELIRIUM
The first step to deal with POD is the identification of delirium. Standardized and routine screening of patients with an elevated risk of delirium after surgery is essential. A valid and the most established screening tool for delirium identification is the CAM-ICU (Confusion Assessment Method for the Intensive Care Unit) with a sensitivity of 0.79 and a specificity of 0.97 . Other assessment tools to detect a delirium (e.g. Memorial Delirium Assessment Scale, Delirium Rating Scale-Revised-98) could be useful, but are described as less valid and more time consuming in clinical routine [13▪]. To manage POD in the daily routine, the staff needs to be qualified and sensitized. Specific staff education is the mainstay for effective delirium management [13▪]. It is also useful to have elder-life specialists in different professions, as considered, for example, by the HELP model [25▪].
In summary, the focus of nonpharmaceutical POD management is to avoid or to minimize trigger factors of delirium [13▪]. Programs are always complex and require a multidisciplinary team approache [15▪▪]. Thus, nonpharmacological interventions for POD are akin to preventive interventions shown in Table 2.
PHARMACOLOGICAL TREATMENT OF POSTOPERATIVE DELIRIUM
The pharmacological treatment of delirium symptoms in older patients is important and necessary. It should be always a temporary medication regimen consisting of an antipsychotic and a sedative medication, if necessary. Thus, regularly monitoring of symptoms is important, and we recommended the CAM [26▪].
- (1) Atypical antipsychotics are used to treat the positive symptoms such as optical hallucinations and delusions. Atypical antipsychotics have a limited effect on sedation (only in high doses), and should not used as sedative medication. Risperidone is recommended for a temporary treatment of hallucinations and aggression in older patients, especially with existing cognitive deficits [27▪,28▪▪]. Haloperidol is not or barely effective in older patients [29▪▪]. It is possible to use Haloperidol up to 2 mg per day (maximum daily dose) in patients less than 70 years of age with psychotic symptoms and without any neurodegenerative and cardiac diseases. Haloperidol is an unselective dopamine agonist and regularly leads to arrhythmia and extrapyramidal symptoms. An intravenous injection is not effective for treating delirium because a constant drug level cannot be reached, which is important for the antipsychotic effect [29▪▪].
- (2) Treatment of psychomotor agitation, which originates from hallucinations and delusions and often lead to endangerment oneself and others, should be treated with sedative antipsychotics. Melperone and Pipamperone have no anticholinergic side effects and are mostly used and recommended. Benzodiazepines should not be use in the elderly due to paradoxical effects (up to 30%), increased risk of falls and fractures, risk of dependency, deterioration of cognitive deficits.
The combination of two antipsychotics increases the risk of QTc-prolongation. Before starting treatment, an ECG should be conducted [30▪]. Pharmacological treatment period should not exceed 7 days. The treatment of delirium differs from patients with alcohol withdrawal and from patients with Parkinson's syndrome. Alcohol withdrawal delirium should be treated according to the current guidelines, prefering Thiamin substitution and long-term benzodiazepines, because of their effective GABAergic potency [31,32]. The only antipsychotics that are recommended in delirious patients with Parkinson's syndrome are Clozapine and Quetiapine, because they have only a minor effect on dopamine D2 receptors (see Table 3 for an overview).
Table 3 -
Overview of recommended medication for delirium treatment
|Typical und atypical antipsychotics
||0.5 - 0 - 0.5 - 0 mg pomax. 1 - 0 - 1 - 0 mg po
||Reduction by GFR <15 ml/min
||1 - 0 - 1 - 0 mg po
||Patients >70 years no intravenous application
||25 - 0 - 25 - 50 mg pomax. 150 mg/day
||Low antipsychotic effect. Recommended use for Parkinson's-syndrome
||0 - 0 - 25 - 0 mg po
||Agranulocytosis as a main side effect
||0 - 0 - 25 - 50 mg or25 - 0 - 50 - 0 mg
||Dosage depends on psychomotor agitationHalf-life of 7.5 h
||0 - 0 - 40 - 0 mg or20 - 0 - 40 - 0 mg
||Dosage depends on psychomotor agitationHalf-life of 20 h
|Short acting types of benzodiazepines for an acute situation
||2 mg i.v.
||Single dosing, until patient amenable to oral medication
Dosing refers to interval of four times a day.GFR, glomerular filtration rate; i.v., intravenous; po, per os.
The prevention and treatment of POD is an interdisciplinary task. There is no evidence for an effective pharmacological prevention, so avoiding trigger factors seems essential. Nonpharmaceutical prevention programmes already exist, but they need to be adapted to the healthcare system. A pharmaceutical consultation is important, because prodelirogenic polypharmacy is an important trigger factor.
There is no evidence that one anesthetic technique is ‘safer’, with respect to limiting POD, than any other technique. It is an individual patient and hospital-tailored bundle with special attention focused on avoiding delirium triggers, assuring an adequate depth of sedation and sufficient pain therapy.
The nonpharmaceutical treatment is similar to prevention. It is essential to establish a delirium screening. The evidence for pharmacotherapy is poor, but benzodiazepines and permanent neuroleptic therapy should be avoided.
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Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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